Vitiligo and Other

Hypomelanoses of
H air and Skin

TOPICS IN DERMA TOLOGY

Series Editors: John A. Parrish and Thomas B. Fitzpatrick
Harvard Medical School, Boston, Massachusetts

VITILIGO AND OTHER HYPOMELANOSES OF HAIR AND SKIN

Jean-Paul Ortonne, David B. Mosher, and Thomas B. Fitzpatrick

Vitiligo and Other

Hypomelanoses of
Hair and Skin
Jean-Paul Ortonne, M.D.
H6pital Pasteur
Centre Hospitalier Universitaire
Nice, France

David B. Mosher, M.D.

and

Thomas B. Fitzpatrick, M.D.

Massachusetts General Hospital

Harvard Medical School
Boston, Massachusetts

PLENUM MEDICAL BOOK COMPANY

New York and London

Library of Congress Cataloging in Publication Data

Ortonne, Jean-Paul, 1943Vitiligo and other hypo melanoses of hair and skin.
(Topics in dermatology)
Includes bilbiographical references and index.
1. Vitiligo. 2. Pigmentation disorders. I. Mosher, David B. II. Fitzpatrick,
Thomas B. III. Title. IV. Series. [DNLM: 1. Pigmentation disorders. 2. Skin
manifestations. WR 265 078v]
RL790.077 1982
616.5 1 5
82-16490
e-ISBN-13: 978-1-4615-9272-3
ISBN-13: 978-1-4615-9274-7
DOl: 10.1 007/978-1-4615-9272-3

1983 Plenum Publishing Corporation

Softcover reprint of the hardcover 1st edition

1983

233 Spring Street, New York, N.Y. 10013

Plenum Medical Book Company is an imprint of Plenum Publishing Corporation
All rights reserved
No part of this book may be reproduced, stored in a retrieval system, or transmitted
in any form or by any means, electronic, mechanical, photocopying, microfilming,
recording, or otherwise, without written permission from the Publisher

Acknowledgments
The authors wish to acknowledge the assistance of the many colleagues who
have inspired and assisted them in this endeavor. Particularly appreciated is
the editorial review of Dr. John A. Parrish and the assistance of Dr. Madhu A.
Pathak particularly in the areas of chemical leukoderma and vitiligo. Diane
Patry assisted with typing and copy preparation. We are particularly indebted
to Pat K. Novak for her tireless diligence as copy editor.

Preface
Leukoderma is a generic term for any pigmentary dilution, be it congenital or
acquired, circumscribed or generalized, devoid of or partially lacking in pigmentation. In the approach to the diagnosis of leukoderma, we have generally
first considered the age of onset, whether leukoderma was congenital or acquired, the extent and pattern of involvement, and the degree of pigmentary
dilution. The organization of this monograph reflects this approach. For example, we have separated the section devoted to various disease entities into
diffuse and circumscribed leukoderma and the latter into various etiologies
such as genetic, metabolic, infectious, and endocrinologic.
One of several justifications for this monograph is to present an approach
to the diagnosis of leukoderma, as detailed in Part II. In formulating a guide
for the physician, we have found some limitations to our previous approach;
we therefore offer the following new classification based upon a clinical-pathologic correlation. This could provide the means to describe both the
clinical and pathologic findings in one term.
I. Melanocytopenic leukoderma (reduction or absence of melanocytes)
A. Vitiligo
B. Piebaldism
C. Chemical leukoderma
D. Waardenburg's syndrome
II. Melanopenic leukoderma (reduction or absence of melanin)
A. Albinism
B. White macule of tuberous sclerosis
C. Nevus depigmentosis
In the melanocytopenic leukodermas, melanocytes are absent and the macules are usually pure white. However, in the melanopenic leukodermas, melanocytes are present, but there is a reduction of melanin, due to a defect in
melanosome formation, melanization of melanosomes, melanosome transfer,
or other process, so that mild to very marked pigmentary dilution is apparent.
Differential diagnosis of a melanocytopenic leukoderma that is congenital
and circumscribed would, for example, have to include piebaldism, whereas
if it were acquired and circumscribed, vitiligo and chemical leukoderma would

vii

viii
PREFACE

have to be considered. Per contra, a melanopenic leukoderma that is acquired

and circumscribed would include tinea versicolor, postinfiammatory hypomelanosis, leprosy, sarcoidosis, and idiopathic guttatehypomelanosis. Melanopenic leukoderma that is congenital and circumscribed would include the white
macules in tuberous sclerosis and nevus depigmentosis.
Most of the diffuse hypomelanoses are congenital melanopenic disordersthese include albinism and phenylketonuria. Diffuse hypomelanoses that are
exceptions include vitiligo universalis, which is an acquired melanocytopenia.
While this monograph itself does not embrace the newer terms "melanopenic" and "melanocytopenic," the tables, descriptive paragraphs, clinical photographs, and photomicrographs provide corresponding bases for the new terms
which designate clinical-pathologic findings.
Jean-Paul Ortonne
David B. Mosher
Thomas B. Fitzpatrick

Contents
PART I. SKIN COLOR AND THE MELANIN PIGMENTARY SYSTEM
Melanins ............................................ .
Epidermal Dendritic Cells ............................ .
Origin of Melanocytes ................................ .
Biologic Basis of Melanin Pigmentation ................ .
Race, Light, Age, and Melanocytes ..................... .
Factors Controlling Pigmentation ...................... .
References ........................................... .

1
3
7
9
11
20
22
28

PART II. APPROACH TO THE PROBLEM OF LEUKODERMA . ...... . 37

History .............................................. .
Physical Examination ................................ .
Histology and Electron Microscopy .................... .
Pathogenesis ......................................... .
Reference ............................................ .

40
41
51
54
56

PART III. HYPOMELANOTIC DISORDERS ....................... .

57

Chapter 1. Genetic and Congenital Disorders . ............. .

59

Section 1. Disorders with Features of Oculocutaneous

Albinism ...................................... .

59

Introduction ......................................... .
Tyrosinase-Negative Oculocutaneous Albinism ......... .
Tyrosinase-Positive Oculocutaneous Albinism .......... .
Yellow-Mutant Oculocutaneous Albinism .............. .
Hermansky-Pudlak Syndrome ........................ .
Chediak-Higashi Syndrome ........................... .
Albinism and Immunodeficiency ...................... .
Cross-McKusick-Breen Syndrome .................... .
Oculocutaneous Albinoidism ......................... .
Ocular Albinism ..................................... .

59
65
69
74
75
79
87
88
89
89

ix

x
CONTENTS

Abnormalities of the Optic Pathway in Albinism ........

Other Defects in Albinos. . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Differential Diagnosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Treatment of Albinism ................................
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

92
93
93
93
95

Section 2. Disorders with Relative Generalized Decreased

Pigmentation ................................... 102
Copper Deficiency. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Histidinemia ..........................................
Phenylketonuria ......................................
Disorders of Methionine Metabolism ....................
Tietz Syndrome. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
References ............................................

102
107
109
119

123
123

Section 3. Disorders with Circumscribed Hypomelanosis .... 129

Vitiligo ...............................................
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Piebaldism ...........................................
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Waardenburg Syndrome ...............................
References ..........................................
Piebaldism with Deafness (Woolf Syndrome) ............
References ..........................................
Ziprkowski-Margolis Syndrome ........................
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Tuberous Sclerosis ....................................
References ..........................................
Nevus Depigmentosus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
References ..........................................
Incontinentia Pigmenti Achromians ....................
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Incontinentia Pigmenti ................................
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Ataxia-Telangiectasia ..................................
References ..........................................
Xeroderma Pigmentosum ..............................
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Neurofibromatosis .....................................
References ..........................................
Dyschromatosis Symmetrica; Dyschromatosis Universalis
Hereditaria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Hypopigmented Markings in Dark-Skinned People:
Pigmentary Demarcation Lines . . . . . . . . . . . . . . . . . . . ..
References ..........................................

129
286
310
334
337
364
369
372
373
374
375
396
398
410
411

426
427
432
433
435
435
438
438
440
440
444
444
451

Other Miscellaneous Syndromes ...................... .

Darier-White Disease ............................... .
Autosomal Recessive Deafness Associated with Vitiligo
(Rozycki Syndrome) .............................. .
Focal Dermal Hypoplasia Syndrome ................... .
Hypopigmentation with Punctate Kp.ratosis of the Palms
and Soles ........................................ .
Hypomelanoses in Possible Ectodermal Dysplasia
Syndromes ...................................... .
References ........................................... .

452
452
452
456
456
460
46

Section 4. Disorders Affecting Hair Pigmentation without

Affecting Skin Pigmentation .................... . 461
Premolar Aplasia, Hyperhidrosis, and Canities Prematura
Fanconi Syndrome ................................... .
Rothmund-Thomson Syndrome ....................... .
Dystrophia Myotonica ................................ .
Premature Aging Syndromes .......................... .
Werner Syndrome (Pangeria) ........................ .
Hutchinson-Gilford Syndrome (Progeria) ............ .
Fisch Syndrome ..................................... .
Kappa Chain Deficiency .............................. .
Hereditary Premature Canities ......................... .
Bird-Headed Dwarfism (Seckel Syndrome) ............. .
Treacher Collins Syndrome, Pierre Robin Syndrome,
Hallerman-Streiff Syndrome, Down Syndrome,
Chromosome Five p-Syndrome .................... .
Prolidase Deficiency ................................. .
References ........................................... .

461
461
462
462
462
462
463
464
464
464
465
465
466
466

Chapter 2. Hypomelanoses Associated with Nutritional and

Metabolic Disorders . .......................... . 467

Kwashiorkor ..........................................
Generalized Dyschromia in a Malnourished Infant . . . . . ..
Pigmentary Changes in the Hair of Patients with
Nephrosis, Ulcerative Colitis, or Extensive Resection
of the Gut . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Severe Iron Deficiency ............................... "
Copper Deficiency .....................................
Vitamin B12 Deficiency (Pernicious Anemia) .............
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

467
469
470
470
470
471
471

Chapter 3. Hypomelanosis Associated with Endocrine

Disorders . ..................................... 473

Hyperthyroidism ...................................... 473

Hypopituitarism ...................................... 473

xi

CONTENTS

xii
CONTENTS

Addison Disease ......................................

Cushing Syndrome ....................................
Hypogonadism ........................................
Hypoparathyroidism, Addison Disease, and Chronic
Mucocutaneous Candidiasis ........................
Goiter and Paratertiary Butylphenol Depigmentation .....
References ............................................

473
473
474
474
474
474

Chapter 4. Hypomelanosis Secondary to Irradiation and

Physical Trauma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 475
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 477
Chapter 5. Chemical Hypomelanosis . . . . . . . . . . . . . . . . . . . . . .. 479
Phenolic Compounds. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Sulfhydryl Compounds. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Cinnamic Aldehyde. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Metals ...............................................
Hydrogen Peroxide. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Guanonitrofuracin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Mephenesin Carbamate. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Triparanol (MER-29) ..................................
Dinitrochlorobenzene (DNCB) . . . . . . . . . . . . . . . . . . . . . . . . ..
Arsenic ..............................................
Nitrogen Mustard and Thiotepa . . . . . . . . . . . . . . . . . . . . . . ..
Corticosteroids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Butyrophenone .......................................
Chloroquine Diphosphate. . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Eserine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Epinephrine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Phototoxic Drugs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

482
496
497
497
497
497
498
498
498
499
499
499
500
501
502
502
503
503

Chapter 6. Hypomelanosis Associated with Inflammation ... 509

Eczematous Dermatitis and Atopic Dermatitis ..... . . . . ..
Lupus Erythematosus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Achromic Guttate Parapsoriasis ........................
Psoriasis .............................................
Pityriasis Alba ........................................
References ............................................

509
509
512
513
516
521

Chapter 7. Infectious and Parasitic Hypomelanosis ......... 523

Leprosy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
yaws .................................................
Pinta .................................................
Endemic Syphilis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Leukoderma in Secondary Syphilis . . . . . . . . . . . . . . . . . . . ..

523
534
536
542
543

Herpes Zoster. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Tinea Versicolor. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Onchocerciasis ........................................
Post-Kala-Azar Dermatosis. . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Tuberculosis ..........................................
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

544
545
555
559
562
563

Chapter 8. Leukoderma Acquisitum Centrifugum: Halo

Nevus and Other Hypomelanoses Associated with
Neoplasms .................................... 567
Halo Nevus .......................................... ,
Halo Phenomena around Lesions Other Than Nevus Cell
Nevus ............................................
Pathogenesis ..........................................
Diagnosis ........................................... "
Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

567
595
599
606
607
607

Chapter 9. Miscellaneous Hypomelanoses . . . . . . . . . . . . . . . . .. 613

Sarcoidosis ...........................................
Idiopathic Guttate Hypomelanosis ......................
Macular Tropical Hypochromia ........................
Vogt-Koyanagi-Harada Syndrome ......................
Alezzandrini Syndrome ...............................
Senile Graying of Hair. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Sudden Whitening of Hair . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Alopecia Areata. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Vagabond's Leukomelanoderma ........................
Heterochromia Irides and Horner Syndrome. . . . . . . . . . . ..
Hypomelanosis in Scleroderma. . . . . . . . . . . . . . . . . . . . . . . ..
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

613
619
627
627
641
641
651
656
657
662
663
664

PART IV. LEUKODERMAS WITHOUT HYPOMELANOSIS ........... 673

Nevus Anemicus ......................................
Edema of the Skin ....................................
Anemia ..............................................
References ............................................
INDEX

673
677

677
677

................................. , .................. 679

xiii

CONTENTS

Vitiligo and Other

Hypomelanoses of
Hair and Skin

FIGURE 1. Components of skin color. Any variation in skin color arises from
different ratios of blue, red, brown. and yellow. (From: Quevedo WC Jr: The control
of color in mammals. Am Zool 9:531-540. 1969. Copyright. 1969. American Society
of Zoologists. Used with permission.)

I
Skin Color and the Melanin
Pigmentary System
The skin is a complex organ system endowed with the capacity to undergo a
wide array of color changes. Normal skin color arises from a mixture of red,
blue, yellow, and brown colored pigments (Fig. 1). In normal skin, melanin is
the major pigment or color determinant and imparts a color ranging from a
very light tan to a deep brown or black, depending on the quantity of melanin
in the epidermis. A yellow hue may be imparted by carotenoids, red by oxygenated hemoglobin in the capillaries, and blue by reduced hemoglobin in the
dermal venules and by pigment in the dermis.
Melanin is synthesized by a specialized cell, the melanocyte, which is a
dendritic cell found in the basal layer of the epidermis, though some melanocytes higher in the epidermis and a few in the dermis may be found. The
melanin pigmentary system consists of millions of such melanocytes, each of
which is functionally associated with 36 keratinocytes (Fig. 2); this cluster of
keratinocytes and the associated melanocyte is referred to as the "epidermal
melanin unit" [1-3] which appears to be a structural and functional entity.
Within each functioning melanocyte, melanin is synthesized and packaged in
specialized pigment organelles called "melanosomes." The dendritic processes
of the melanocytes project in between keratinocytes so that a single melanocyte
supplies melanosomes to its group of 36 keratinocytes. These melanosomes
migrate centrifugally along the dendritic processes of the melanocytes and are
then transferred to or captured by keratinocytes. Although the number of active
epidermal melanin units per unit area varies markedly over various regions of
the human skin [4-6], the keratinocyte/melanocyte ratio remains constant [7].
It has been suggested that the epidermal melanin unit is the functional integrator
of the multicellular system of melanin pigmentation in humans and animals
[1].

Although skin color may be conceptually envisioned as an admixture of

the above colors of red, blue, yellow, and brown, normal skin color and racial
differences in skin color are a function of the number, size, and distribution
of the melanin-laden organelles. It is the melanosomes distributed to the keratinocytes that impart skin color. In the absence of disease, the other color

PART I

FIGURE 2. The epidermal melanin unit. Relationship of basal melanocyte high-level Langerhans
cells and keratinocytes in mammalian epidermis. (From: Quevedo WC Jr: The control of color in
mammals. Am Zo019:531-540. 1969. Copyright. 1969. American Society of Zoologists. Used with
permission.)

contributors have minor or insignificant roles. Hence, in the absence of melanin,

the skin remains essentially white, as in tyrosinase-negative albinism or macules of vitiligo.
Recent evidence that the movement of keratinocytes within the epidermis
is more complex than was originally thought [8] is not inconsistent with the
epidermal melanin unit concept. Keratinocytes do not just divide randomly in
the germinal layer of certain types of human and of mouse epidermis [9-11].
Mitoses may also occur in suprabasilar keratinocytes [12,13]. According to the
epidermal proliferation unit concept, the young basal cells divide and move
peripherally in the epidermis before final division and formation of orderly
columns of cornified cells [13-16]. Each or several epidermal proliferative units
then may be associated with a donor melanocyte.
Study of the melanin-producing mechanism must be approached at five
scientific levels [17]: macromolecular (visual )-the skin viewed as an organ
system; multicellular (histologic)-the epidermal melanin unit; cellular-me-

lanocytes as unicellular secretory glands; subcellular (electron microscopic)the melanosome as a metabolic unit of melanogenesis; and macromolecular
(biochemical)-tyrosinase, the enzyme, and melanoprotein, the end product of
melanogenesis. This chapter touches each of these levels but concentrates on
the cellular, subcellular, and macromolecular aspects.

MELANINS
There are three different melanins-eumelanin, phaeomelanin, and neuromelanin. Eumelanin is the brown-black pigment of skin and hair and most
responsible for skin color. Phaeomelanin is a red-yellow pigment found in
hair in humans. Neuromelanin is present in neurons of the central nervous
system, in adrenal medulla, and in other areas of the chromaffin system.

Eumelanin
Eumelanin is a high-molecular-weight polymer of which the precise molecular structure has yet to be determined, in part because eumelanin is insoluble in most solvents and resists most chemical alterations and degradations.
Observations based on the work of Raper [18] with plant tyrosinases and modified by Mason [19] led to the conclusion that melanin is a polymer of indole5,6-quinone units. Use of labeled precursors, however, showed this to be an
oversimplification [20,21]. Work of Nicolaus and Piatelli [22] with squid melanin showed melanin to be a complex heteropolymer composed of 5,6-dihydroxyindole and 5,6-hydroxyindole-2-carboxylic acid moieties at various oxidative levels. The proportion of various subunits, molecular chain length, and
molecular weight of eumelanin are still unknown. Blois et a1. [23] consider
melanin to be a highly irregular three-dimensional polymer joined by covalent
bonds. Melanin possesses a free radical character [24] related to a semiquinonoid form of 5,6-dihydroxyindole stabilized by resonance throughout the
highly conjugated polymer [23]. Melanin may be able to function as a mild free
radical quencher and may also have some weak acid cation exchange capabilities. Melanin has specific absorption peaks only in the infrared region at 3
and 6 J.L [23], but shows a rather nonspecific wide absorption band from 200
to 2400 nm.
Tyrosine-Melanin Pathway

Melanin is formed by the enzymatic conversion of a colorless, naturally

occurring amino acid tyrosine to a brown polymer (Fig. 3). Many early observations showed tyrosine to be the substrate for melanin synthesis. Early work
was done by Raper [18], who studied the aerobic oxidation of tyrosine and
dopa in the presence of mealworm tyrosinase. Hogeboom and Adams [25]
demonstrated tyrosinase activity in mouse melanoma extracts. Fitzpatrick et
a1. [26] found tyrosinase activity in normal human skin irradiated with ultra-

SKIN COLOR AND

THE MELANIN
PIGMENTARY
SYSTEM

4
PART!

OM
7
~
at - ....2
COOM

OM

oil/NOt

I'lOOtJC ,

OM

-s - ~~- at - COOM

s - Cllz - f" - ~

NM:z

~~
~ - II~

NM:z

COOM

S - S - CYSTD_

- S - cysn:l~

S.I . DIKYDIIOXYlllOOU

FIGURE 3. Metabolic pathway of eumelanin and phaeomelanin biosynthesis. Both begin with
the enzymatic (tyrosinase) conversion of tyrosine to dopa to dopaquinone. (From: Jimbow K et al:
Some aspects of melanin biology: 1950-1975. J Invest Dermoto! 67:72-89, 1976. Copyright, 1976,
The Williams & Wilkins Company. Used with permission.)

violet radiation in vivo. Subsequent studies in which radioactive tyrosinase

was incorporated in vertebrate melanocytes have established that tyrosine is
involved in melanogenesis.
In the classical tyrosine-melanin conversion scheme of Raper and Mason
[18,19), tyrosine in the presence of tyrosinase and molecular oxygen is oxidized
to dopa which in turn is irreversibly oxidized to dopaquinone. In vitro 14C_
labeled dopa [27,28] and tyrosine [29] are incorporated into melanosomes.
Dopaquinone then undergoes spontaneous rapid and irreversible intramolecular change to form 5,6-dihydroxyindole-2-carboxylic acid (leukodopachrome) which is readily and reversibly oxidized to dopachrome. Dopachrome
then is decarboxylated and rearranged to form 5,6-dihydroxyindole, which is
readily oxidized to indole-5,6-quinone. According to the Raper-Mason scheme,
melanin is a homopolymer of covalently bonded indole-5,6-quinone units.
However, experimental results of labeled precursor studies of Swan [20,21]'
Nicolaus and Piatelli [22], and Hempel [30,31] have shown melanin is not such
a simple polymer compound but rather is a complex heteropolymer composed
of intermediates, namely 5,6-dihydroxyindole and 5,6-dihydroxyindole-2-car-

boxylic acid moieties at various oxidative levels; many different indoles combine to form this complex polymer, which becomes protein-bound to form
melanoprotein.
Tyrosinase

Tyrosinase is a specific copper-requiring enzyme responsible for oxidation

of tyrosine to dopa. Although there are champions of a two-enzyme system,
most investigators consider the tyrosine-to-melanin pathway a single enzyme
system. Tyrosinase is present throughout the phylogenetic scale, but different
tyrosinases have different characteristics. Studies using polyacrylamide gel
electrophoresis have separated multiple forms of tyrosinase from a variety of
pigmented mammalian tissues [32-36). Three active tyrosinases have been
found. The two soluble tyrosinases, Tl and Tz, were found to have similar
molecular weights (MW) (66,600 and 56,700) but to have different amino acid
compositions. It is possible that both T 1 and T z are dimers, as a few polypeptides
with tyrosinase activity and a MW of 30,000 were found [34). The third tyrosinase is an insoluble protein. These multiple tyrosinase forms, derived from
mouse melanoma and from hair bulbs, can utilize both tyrosine and dopa in
the initial steps of melanin synthesis [37). Yet Holstein et al. [38) have shown
in electrophoretic studies that mouse melanoma and hair bulb tyrosinase utilize
both tyrosine and dopa. They also showed that all forms of tyrosinase may
convert tyrosine and dopa to melanin in the presence of adequate catalase to
block peroxidase. Hearing [39) and Hearing and Eckel [40) also demonstrated
both substrates were utilized by tyrosinase in mouse melanoma. Jimbow et al.
[41) demonstrated that the (purified, solubilized) melanosomal enzyme(s) released by nonionic detergent BRIJ 35, which is greatly inactivated by trypsin
[39,41]' uses both tyrosine and dopa as substrates to form melanin.
Some controversy remains, however. Edelstein et al. [37) were also unable
to demonstrate tyrosine utilization by the enzyme released by trypsin from
melanosomes of B-16 mouse melanomas. Okun et al. [37,42,43) concluded from
electron microscopic and electrophoretic studies in which they were unable
to demonstrate the tyrosine-melanin reaction with melanosomes and melanocytes, that one enzyme is not responsible for both the conversion of tyrosine
to dopa and of dopa to dopaquinone. Rather, they suggest that a peroxidase
present in melanosomes causes hydroxylation of tyrosine to dopa and that dopa
oxidase converts dopa to dopaquinone. This is the two-step, two-enzyme theory
of conversion of tyrosine to melanin: The question of a "protyrosinase" activated by a specific protease has also been raised [38,44,45). The two-step theory
is not widely accepted because others have not been able to isolate a second
enzyme system. Lerner et al. [46) were unable to separate tyrosinase activity
from dopa oxidase activity reported [25) responsible for activation of the second
step in melanin synthesis. It was found that the so-called dopa activity was,
in fact, tyrosinase activity with such a long induction period that it appeared
to have no relationship to the oxidation of tyrosine. The presence of dopa
shortens the induction period by a logarithmic function of the amount of dopa
added.
For the moment, the balance of evidence favors the single-enzyme hy-

SKIN COLOR AND

THE MELANIN
PIGMENTARY
SYSTEM

PART!

pothesis-that tyrosinase is the only enzyme responsible for catabolism of

tyrosine to melanin.

Phaeomelanin
Phaeomelanins are yellow and red sulfur-containing pigments found in
the hair of mammals. Unlike eumelanin, phaeomelanin is soluble in dilute
alkali. Phaeomelanins, like eumelanin, are derived from tyrosine via dopaquinone. But it is the interaction of cysteine with dopaquinone at this level which
results in phaeomelanin synthesis. With a 1,6 addition of cysteine to dopaquinone, 13-(5-S-cysteinyl-3,4-dehydroxyphenyl)alanine or 2-S-cysteinyldopa
is formed [47,48]. This is further oxidized to form phaeomelanin [49]. A minor
product of the 1,6 addition may be 2-S-cysteinyldopa [50,51]. Sulfhydryl compounds have a role in in vivo synthesis [52]; in fact, under some experimental
conditions, sulfhydryl compounds may induce pigment cells to produce yellow
pigment [53].
The curious genetic control affecting the common pathway of eumelanin
and phaeomelanin synthesis is reflected in the agouti mouse, which has only
a few subapical phaeomelanosomes, the rest being eumelanogenic. The follicular melanocytes initially produce brown-black eumelanin, temporarily switch
to yellow phaeomelanin production, and soon revert to the original eumelanin
synthesis. Guinea pig studies have shown melanosomes in red or yellow follicles to be spherical whereas those of black follicles are ellipsoidal [54].
Various differences in biochemical behavior have been observed between
eumelanin and phaeomelanin. It has been demonstrated that more sulfhydryl
compounds containing glutathione and cysteine are incorporated into phaeomelanogenic melanocytes and phaeomelanin than into eumelanic melanocytes
and eumelanin. In the presence of adequate reduced glutathione in vitro, melanocytes that in vivo synthesize only eumelanin elaborate phaeomelanin. It
has been suggested that the agouti band in the agouti mouse is derived from
cyclically changing patterns of competition by keratinocytes and melanocytes
for substrate common to hair growth and to melanogenesis. So it was suggested
that cyclic changes in the type of melanin synthesized may involve histochemical changes, not genetic intervention [52]. The failure of Knisely et al. [55] to
confirm these findings with yellow (AY/a) specimens in similar conditions and
in cultures of (A/A) agouti skin may relate to such histochemical factors not
extant in these systems. Although cysteine is an established substrate for phaeomelanogenesis, cysteinyldopa, and phaeomelanin may be produced by eumelanogenic melanocytes [56]. Furthermore, it has become clear that there is
a third melanocyte pigment, namely, trichochrome [57], which like eumelanin
and phaeomelanin has dopaquinone as a critical intermediate. The factors that
select one final pathway over another remain unclear.

Neuromelanin
The trigeminal and dorsal root ganglia, substantia nigra, locus caeruleus,
and the pigmented nuclei of the basal ganglia contain cytoplasmic organelles
containing a brown pigment called "neuromelanin." There appear to be important differences between eumelanin and neuromelanin. Since patients with

oculocutaneous albinism have normal amounts of neuromelanin, it seems unlikely that neuromelanin is formed by the action of tyrosinase. There are other
significant differences between melanin and neuromelanin. The pigment particles of the substantia nigra appear to have a higher electron density than
melanosomes, a size range from 0.5 to 2.5 f.L, a single limiting membrane, and
no longitudinal or cross-striations typical of eumelanin melanosomes [58]. The
presence of labeled tyrosine in the area of pigmented granules in neurons has
persuaded investigators that tyrosine must be present. The enzyme catalyzing
the hydroxylation of tyrosine to dopa is probably tyrosine hydroxylase [29],
and not the copper-requiring oxidase tyrosinase. Since tyrosine hydroxylase
catabolizes only CNS tyrosine, CNS abnormalities should not be expected with
disorders of eumelanin synthesis, and disorders of neuromelanin (such as Parkinson disease) would not be expected to have obligate aberrations of cutaneous
eumelanogenesis.

EPIDERMAL DENDRITIC CELLS

The epidermis is populated with three types of identifiable dendritic cells.
These are melanocytes, Langerhans cells, and a-dendritic or indeterminate
cells. The melanocyte and Langerhans cell can be distinguished by their nuclear
characteristics, the presence of specific organelles, and characteristic cytoplasm. The indeterminate cell lacks organelles characteristic of the other two
types of dendritic cells; it is a "ghost cell," one of uncertain lineage.
Nucleus
Cytoplasm
Organelle

Melanocyte
Oval
Granular
Melanosome
(round to oval)

Langerhans cell
Indeterminate cell
Lobulated
Lobulated
Clear
Clear
Langerhans or Birbeck
None
(rod-disc)

Langerhans cells are dendritic cells found in the epidermis and once thought
to be related to melanocytes but demonstrated by Breathnach [59] not to be of
neural crest origin. These cells are characterized by a clear cytoplasm, a lobulated nucleus, absence of desmosomes, and presence of specific organelles
called "Birbeck" or "Langerhans" granules. These granules have a disclike form
and may appear under the electron microscope as rod-like bodies with rounded
ends and a central striated line. Some of these granules have a blown-out
boundary membrane at one end along with an enclosed clear zone; these assume
the general shape of a hand mirror or tennis racket. Langerhans cells arise in
the bone marrow from some precursor of the mononuclear phagocyte system
[59a]; but it does appear to be an immunologically significant cell and not just
a macrophage that has migrated from the dermis to the epidermis. Although
Langerhans cells can phagocytize melanin granules, these cells are not typical
macrophages. To dramatize its possible role in the epidermis, like that of the
osteoblast in bone, Prunieras [60] has suggested calling the Langerhans cell an
"epidermoclast. "
Further more recent evidence has illuminated the role of the Langerhans
cell. Langerhans cells have been shown to have a role in allergic contact reactions in which they lie in close apposition to lymphocytes [61]. The cellular

SKIN COLOR AND

THE MELANIN
PIGMENTARY
SYSTEM

8
PART!

membrane has been shown to have Fc receptor sites for IgG, C3, and IgA antigens
[62,63]. It would appear that Langerhans cells are part of the monocyte-macrophage-histiocyte [64] line and have an important role in the afferent
limb of the immune system [65].
The "a-dendritic" or "indeterminate" cell is even more of a mystery. It
resembles a Langerhans cell without Langerhans granules. The origin and role
of this third type of dendritic cell are unknown. It may be a premelanocyte
with induction potential, an effete melanocyte, a displaced dermal phagocyte,
an undifferentiated cell capable of becoming a Langerhans cell or melanocyte,
or some totally unrelated cell. The work of Mishima and Kawasaki [66] and
Mottaz and Zelickson [67], in which for a time, in vitiligo, melanocytes and
indeterminate cell populations seemed inversely related quantitatively, certainly suggests some direct relationship between the a-dendritic cell and the
melanocyte.
Melanocytes are dendritic cells with a granular cytoplasm, an oval nucleus
with a nucleolus, cell-specific organelles called melanosomes, and no desmosomes (Fig. 4).

FIGURE 4.
epidermis.

Electron microscopic view of a melanocyte and surrounding keratinocyte in human

ORIGIN OF MELANOCYTES

In mammals and other vertebrates, melanocytes originate from the neural

crest (Fig. 5), and migrate to the skin, eyes, leptomeninges, and inner ear in
early embryonic life (Fig. 6). The neural crest origin of melanocytes was established by Rawles [68,69], who grafted mouse somite tissue together with
overlying ectoderm to chick embryo coelom. When the neural crest or cells
derived therefrom were excluded, no pigment formed in the grafts. However,
with neural crest tissue present, growth of pigmented hairs and differentiation
of melanocytes was observed in host tissue adjacent to the grafts. Neural crest
tissue was clearly essential for pigment cell formation and pigment elaboration.
By cleverly timing the stages at which grafts were obtained, Rawles was able
to plot the migration of melanoblasts from the neural crest. Melanoblasts appeared cranially and moved in a caudal direction along the anteroposterior
axis.
Mintz [70] demonstrated that the skin of mice is colonized by clones of
melanoblasts. Cleaving fertilized mouse ova, placed adjacently in vitro, will
combine to form a single blastocyst which can be returned to the mouse uterus
to develop into a normal mouse. Combination of black and albino cleaving ova
produced a mouse that was variegated in color and often striped. The stripes
tended to be 17 alternating black and white bands on each side, the right side
appearing to be independent of the left. It is as if each region were colonized
by one of 34 melanoblasts divided equally between two longitudinal middorsal
chains (neural crest). Each primary melanoblast must proliferate laterally and
to a much lesser extent longitudinally to give rise to a clone of melanoblasts
which colonize a specific region of the skin.
Undifferentiated melanocyte precursors which initially invade the dermis
and then the epidermis and hair follicles can be found in the human skin by
the eighth week of fetal development. "Premelanin granules" have been found
by light microscopy in the 10th week in a black fetus [71]. The first few epidermal melanocytes are usually present by the 11th fetal week and become
much more numerous during the 12th to 14th weeks.

N!;~L

CR!;ST

M(;LANOBLAS TS

"M!;LANOGONIA"

M~LANO(VH.S

FIGURE 5. Development and migration of melanoblasts. Melanoblasts migrated from the neural
crest in early fetal development and appeared as undifferentiated melanocyte precursors in the
eighth week. Epidermal melanocytes usually first appear in the 11th week.

SKIN COLOR AND

THE MELANIN
PIGMENTARY
SYSTEM

10
PART!

MISCEllANEOUS
SITES
Mucous mtm brone
Internal ear
Orb ital cavil,
Metenle"

FIGURE 6. The embryonic origin. dispersion. and development of melanocytes in humans. Retinal melanocytes (A); choroidal melanocytes (B). (From: Fitzpatrick TB. Quevedo WC Jr: Albinism.
in The Metabolic Basis of Inherited Disease. 2nd ed. Edited by JB Wyngaarden. DS Fredrickson.
Copyright. 1966. McGraw-Hill Book Company. Used with permission.)

Dermal melanocytes then precede the epidermal ones by about two weeks.
In early fetal development, the density of the skin melanocyte population is
reduced in a cephalocaudal direction corresponding to the anteroposterior wave
of migration observed by Rawles. This gradually disappears with time. The
number of dermal melanocytes decreases with development until only a few
remain after birth (Mongolian spots).
The differentiation of melanoblasts into melanocytes is a function of the
genetic constitution of the melanoblasts and the nature of the environment into
which they migrate. Weiss and Andres [72] injected melanoblasts of young

chick embryo of one breed into the circulation of another breed; they found
differentiation of the melanoblasts to melanocytes in the regions of the host
corresponding to those anticipated in the donor.
In humans, melanocytes are present not only in the skin but also in the
leptomeninges, inner ear, uveal tract, and retinal epithelium. The retinal cells
arise from the optic cup, not from the leptomeninges.
Melanocytes are present in the basal layer of the epidermis and around
hair follicles. These may be identified selectively with the split dopa technique *
in which the melanocytes appear as dark dendritic cells (Fig. 7).

BIOLOGIC BASIS OF MELANIN PIGMENTATION (FIG. 8)

Melanin pigmentation is a result of four basic processes:
Formation of melanosomes in melanocytes.
Melanization of melanosomes in melanocytes.
Transfer of melanosomes from melanocytes to keratinocytes.
Transport of melanosomes by keratinocytes with or without degradation
into lysosome-like organelles.
1.
2.
3.
4.

Melanosome Formation in Melanocytes

Melanin formation and deposition occur in certain cytoplasmic organelles-melanosomes-which contain the essential enzyme tyrosinase. The melanosome concept grew from the observation of Fitzpatrick et al. [26] that
tyrosine melanin appeared as definite brown granules, and out of the work by
Seiji et al. [73], who applied ultracentrifugal density gradient techniques to
isolate melanocyte fractions which were then monitored with the electron
microscope. Further evidence for this grew out of electron microscopic studies
that showed electron-dense material, identified as melanin, gradually being
accumulated on developing melanosomes.
Melanosome formation results from assembly of structural proteins, tyrosinase "membranes", and possibly other enzymes. That tyrosinase activity
has been found in ribosomes on smooth-surface and rough-surface membranes
[28] suggests ribosomes are responsible for tyrosinase synthesis. Further support comes from in vivo studies in which incorporation of leucine 14C into
soluble tyrosinase of various cell particles suggested tyrosinase first accumulates in small particles, presumably ribosomes, and later into large particles,
likely to be melanosomes.
It is now clear that tyrosinase is synthesized in ribosomes and transferred
via the endoplasmic reticulum (rough-surface membrane) to the area of the
Golgi apparatus [74]. Tyrosinase is contained in units, each surrounded by a
smooth-surface membrane to form a vesicle. This membrane-filled vesicle seems
to arise from Golgi vesicles, Golgi-associated endoplasmic reticulum, or the
Tissue is incubated in NaBr to split the dermis from the epidermis, and then in dopa which
labels brown-black tyrosinase-containing cells, specifically, melanocytes.

11

SKIN COLOR AND

THE MELANIN
PIGMENTARY
SYSTEM

12
PART I

13
SKIN COLOR AND
THE MELANIN
PIGMENTARY
SYSTEM

rleVCUZ.D INT"R/'Q)IAT~S]-[ \;lJI'Ii:LANIN

( Y5T{; IN[;

5 -S- CYSWNYlDOPA

[INT~RM~ DIAT~S] _lpI-IA~(}"fLANIN I

FIGURE 8. Diagram summarizing major events in the early development of melanocytes, their
subsequent differentiation, and interaction throughout life. G, Golgi apparatus; E, endoplasmic
reticulum; N, nucleus; M, mitochrondia; PMS, early melanosomes; MS, fully melanized melanosomes; I, II, III, and IV, stages in melanosomal development shown in upper left corner in dendritic
process. (From: Jimbow K et al: Some aspects of melanin biology: 1950-1975. J Invest Dermatol
67:72-89,1976. Copyright, 1976, The William & Wilkins Company. Used with permission.)

general endoplasmic reticulum. Such early melanosomes are, then, vesicles

composed of tyrosinase and "membranes" and, in addition, structural proteins
and possibly certain auxiliary enzymes.
The exact mechanism of organization of tyrosinase and structural protein
into these early melanosomes is unclear. Jimbow et al. [8] suggested four hypotheses to explain the mechanism of this melanosome organization:
1. Tyrosinase formed in membrane-bound ribosomes passes through the
rough and smooth endoplasmic reticulum to the Golgi apparatus; here enlargement or fusion of protein-laden vesicles forms Stage I melanosomes [28,75].
2. Stage I melanosomes are formed from enlargement and pinching off of
portions of the expanded tip of the Golgi apparatus or of the smooth endoplasmic reticulum connected with the Golgi apparatus where tyrosinase has
aggregated [76-78].
(

FIGURE 7. a: Melanocytes in human epidermis. The epidermis was separated ("split") from the
dermis with trypsin and treated with dopa. The melanocytes are recognizable as dark cells with
dendrites meandering between the very slightly stained keratinocytes of the basal layer (x 500).
b: High-power view of split sheets of human epidermis. The dendritic nature of melanocytes is
well shown (x 1150). (a and b from Fitzpatrick TB et al: The biology of the melanin pigmentary
system, in Dermatology in General Medicine. Edited by TB Fitzpatrick et al. Copyright, 1971,
McGraw-Hill Book Company. Used with permission.)

14
PART I

3. Random aggregation of structural proteins and tyrosinase formed from

membrane-bound ribosomes forms a unit distinct from the endoplasmic reticulum or the Golgi apparatus [79-81].
4. Tyrosinase accumulates in one particular area of the Golgi apparatus
and "condenses" in coated vesicles which are transferred to diluted tubules of
the smooth endoplasmic reticulum where the structural proteins forming the
inner lamellae are aggregated [82-84].
Experimental evidence based on the embryonic chicken suggests tyrosinase
is added to the melanosome after the matrix is formed from structural protein
[85]. The traditional concept is that tyrosinase forms part of the entire melanosomal matrix [7,75], but it has been suggested that tyrosinase is limited to
the outer membrane of the melanosome [86].
Within the early melanosome, the sequestered protein associates to form
a matrix which consists of several concentrically arranged sheets [79,87,88].
This is unlike the matrix of the mouse melanosome, which has been observed
to be a filamentous sheetlike structure [89] or a series of independent melanofilaments [90].

Melanization of Melanosomes
Melanization is the gradual accumulation on developing melanosomes of
an electron-dense material, melanoprotein. The spherical vesicle gradually becomes elongated, loses its characteristic internal filamentous periodicity, and
becomes electron-opaque. Four stages of melanosome formation have been
characterized [86] (Fig. 9):
Stage I is a spherical membrane-limited vesicle which has a periodicity of

100

A and can be shown with the help of histochemical techniques to contain

tyrosinase.

Stage II is an oval organelle characterized by typical periodicity and by

numerous membranous filaments both with and without cross-linking.
Stage III refers to an oval organelle-like Stage II in which the internal
structure has become partially obscured by electron-dense melanin.
Stage N refers to the oval organelle which has become so electron-dense
that the internal structure cannot be discerned by standard techniques.

Although the matrix of Stage IV or fully melanized melanosomes is usually

considered to be amorphous and totally electron-opaque, several electron microscopic studies [87,91-93] have revealed the presence of spherical electrontranslucent structures about 400 A in diameter. They are attached to the surface
of the lamellae of the inner matrices [94], present in an early stage of melanosome development, are increased in number in developing stages, covered
with fine grains of melanin, not known to melanize during melanosomal development, remain constant in size, and are not degraded once incorporated
into inner matrices. In fowl feather melanosomes these "vesicoglobular bodies,"
as they have been called, are dopa-positive. It may be that these are tyrosinase
carrier vesicles. Possibly the early tyrosinase carried herein is inactive in the
early stages of melanosome development; later when the melanocyte becomes

15

SKIN COLOR AND

THE MELANIN
PIGMENTARY
SYSTEM

II

III

IV

FIGURE 9. Stages in the development of melanosomes. Stage I: a spherical, membrane-delineated

vesicle may be called a melanosome if it (1) is shown to contain tyrosinase by electron microscopy
combined with histochemistry, or (2) contains filaments that have a distinct periodicity. Stage II:
the organelle is oval or shows numerous membranous filaments, with or without cross-linking,
having a distinct periodicity. Stage III: the internal structure characteristic of Stage II has become
partially obscured by electron-dense melanin. Stage IV: the oval organelle is electron-opaque
without discernible internal structure in routine preparations. (From: Fitzpatrick TB et al: The
biology of the melanin pigmentary system, in Dermatology in General Medicine. Edited by TB
Fitzpatrick et al. Copyright, 1971, McGraw-Hill Book Company. Used with permission.)

active, tyrosinase is released and the vesicles break down to form "empty"
carriers within the melanosome. Although these "vesicoglobular bodies" may
be enzyme carriers in humans, their true role remains unknown. Phaeomelanosomes differ from eumelanosomes. They are spherical and contain coarse
granular material inside [94a].

Movement of Melanosomes within Melanocytes

The mechanism of movement of melanosomes from the perinuclear and
endoplasmic reticulum regions toward the tips of the dendritic processes before
transfer to surrounding keratinocytes is not fully understood. Effects of MSH
on intracellular migration have been studied in melanophores and melanocytes
of frog and fish skin [95], but equivalent information on mammalian systems
is lacking. Such migration of pigment granules may result from local differences
in membrane potential between the central and the peripheral parts of the cell
[96], resulting in intracellular current flow, ionic release or exchange of membrane-bound ions [97], or sol and gel transformation which causes changes in
hydrostatic pressure of the cytoplasm [98]. These must be consistent with
studies which show melanosomes move within channels surrounded by mi-

16
PART!

crotubules on melanocytes [99,100]. In the melanophores of the fish Fundulus

heteroclitus, the pigment granules move along relatively fixed channels arranged in rows parallel to the long axes of the dendrites. Surrounding these
channels are microtubules that are about 225 A in diameter and are aligned
parallel to the direction of the pigment granules [101]. These microtubules
seem to be a "cytoskeletal" element which maintains the extended form of the
dendrites and which defines the migratory channels for the pigment granules.
Cytochalasin-sensitive microfilaments (65-75 A) have also been found in
melanocytes of frog epidermis. These seem to be intermediate between adenyl
cyclase activation and melanosome dispersion. In a-MSH-treated frog melanocytes these microfilaments can be disrupted by cytochalasin B, which thus
prevents pigment granule dispersion' [102]. This finding, as well as electron
microscopic studies, suggests that intramelanocytic movement of melanosomes
is dependent on microtubules and micro filaments [99,100], which Moellmann
et al. [103] later redesignated "100-A filaments." Since both microtubules and
micro filaments crystallized in the presence of vinblastine, it was suggested
these structures are interconvertible and achieve an equilibrium during MSHinduced skin darkening. Colchicine and vinblastine have been found to inhibit
melanosome translocation [104]. However, in shrimp chromatophores [105],
cytochalasin B, colchicine, or vinblastine do not inhibit the movement of pigment granules (even though the latter causes crystalline complexes of microtubular proteins in place of normal microtubule bundles). In human melanocytes, 100-A filaments are unaffected by cytochalasin B or vinblastine [106].
Studies of ultraviolet radiation-induced tanning of human skin or of
light-dark adaptation of chick eyes show melanocytes to contain 100-A (intermediate) filaments which are involved in elongation of dendrites and in the
movement of melanosomes [107]. Microtubules were believed not to be involved in melanosome movement. These conclusions are based on the observations that (a) ultraviolet irradiation and subsequent dark recovery reversibly
changed the orientation of melanocytic filaments; (b) melanosomes were shifted
from the endoplasmic reticulum and perinuclear area to the dendritic tips and
transferred to keratinocytes; (c) melanosomes shifted to dendrites were in bundles or clusters of melanocytic filaments; (d) microtubules and melanosomes
were not morphologically associated, and (e) microtubules were rarely seen in
the dendrites [82,83,108].
Since neither cytochalasin nor vinblastine inhibits the movement of melanosomes, the melanocytic filaments must be unaffected by these agents. The
primary site of effect of cytochalasin is the surface of the plasma membrane,
not the thin microfilaments. It is still not known whether or not these microfilaments are directly involved in the transfer of melanosomes from melanocytes
to keratinocytes. Neither is it known what first stimulates translocation of
melanosomes.

Transfer of Melanosomes
Melanosomes synthesized by melanocytes are transferred to keratinocytes,
where they are packaged as singles (nonaggregated) or as groups (aggregated)
with membrane-limited vesicles. Melanosomes in the keratinocytes are present

as discrete isolated particles (nonaggregated), or as groups of three or more

particles (aggregated) within membrane-limited organelles. These melanosomecontaining organelles (melanosome complexes) resemble phagolysosomes, which
are membrane-limited melanosome-containing organelles identified within
macrophages. In African and American blacks, melanosomes are large and are
packaged as "singles," whereas in the keratinocytes of unexposed skin of Caucasians, the elliptical melanosomes are smaller and are predominantly aggregated [109-113) (Figs. 10-12). In the darker Caucasoids, there is an increasing
proportion of "singles" as opposed to "complexes." The melanosomes in keratinocytes of pigmented hair of all racial groups are large and packaged as
singles [114).
Some nondendritic melanocytes and certain dendritic melanocytes, for
example of the leptomeninges and uveal tract, are not melanosome secretors

FIGURE 10. Melanosome complexes from a Caucasoid, Mongoloid, and Negroid. a: Melanosome
complexes
from
a
malpighian cell of a Caucasoid.
The complexes are surrounded
by a membrane and contain small
particles in addition to Stage IV
melanosomes. b: Melanosome
complexes from a malpighian cell
of a Mongoloid (Chinese). There
is less ground substance between
the melanosomes in this specimen than in (a). c: Melanosomes
in the malpighian cell of a Negroid. Almost all melanosomes
are individually dispersed and are
much larger than those of a Caucasoid or Mongoloid (x 45,750).
(From: Szabo G et al: Racial differences in the fate of melanosomes in human epidermis.
Nature 222:1081-1082, 1969.
Copyright, 1969, MacMillan
Journals Ltd. Used with permission.)

17
SKIN COLOR AND
THE MELANIN
PIGMENTARY
SYSTEM

18

PART I

FIGURE 11. Diagram of racial differences

in the mode of melanosome transfer from
the melanocyte (MC) to the keratinocyte
(KC). Left: Caucasoid and Mongoloid melanosomes from "melanosome complexes"
within keratinocytes and melanosome degradation is seen within lysosome-like complexes. Right: Negroid and Australoid melanosomes are larger than those of Caucasoids
and Mongoloids and are arranged singly
within keratinocytes. (From: Jimbow K et
al: Some aspects of melanin biology:
1950-1975. J Invest Dermoto1 67:72-89,
1976. Copyright, 1976, The Williams &
Wilkins Company. Used with permission.)

[17], but all normal cutaneous melanocytes have the capacity to transfer melanosomes.
The mechanism of this melanosome transfer, termed "cytocrine activity"
by Masson [108], is not clearly defined. Bubbling of the melanocyte cell membrane in the region of a melanosome does suggest the beginning of melanosome
transfer [1151. Based on electron microscopy studies [671 and cell culture experiments [60,116-118]' three mechanisms have been suggested. These mechanisms are not mutually exclusive.
The first possibility is that melanosomes are secreted by the dendrites of
the melanocytes into the extracellular space and subsequently the extracytoplasmic melanosome particles are picked up by the keratinocytes.
An alternative hypothesis is termed "cytophagocytosis," by which the den-

FIGURE 12. a: Epidermal melanin unit in Caucasians or Mongoloids. Melanosomes are aggregated
within the keratinocytes. b: Epidermal melanin unit in Negroes and Australian aborigines. Melano somes are packaged into "singles."

drite of the melanocyte approaches and contacts the cell membrane of a keratinocyte. The receptor keratinocyte pinches off the tip of the melanocytic
dendrite which contains the melanosome and encloses this within a phagocytic
vacuole. The observation of phagocytic vacuoles containing melanosomes surrounded by a double membrane provides support for this hypothesis [119], yet
most keratinocyte vacuoles have a single not a double membrane. It has been
suggested that the double membrane may be an artifact.
The third hypothesis also involves phagocytic action of the keratinocyte
in pinching off the tip of the melanocytic dendrite. However, this pinched-off
dendrite then disperses the melanosome within the keratinocyte. Packaging
may be a function of melanosome size. Studies of animal experiments using
melanosomes of varied sizes have demonstrated cytophagocytosis in which
large melanosomes are packaged as singles and smaller ones clustered [120].
None of these hypotheses explains the problem of packaging as singles or
aggregates within keratinocytes. By the first postulate, in which melanosomes
are extracytoplasmic particles, the melanosomes are seen as foreign bodies by
the keratinocytes and are phagocytized and packaged according to size. Since
"singles" are usually large melanosomes, whereas aggregates are composed of
small particles, it would seem that packaging of melanosomes within keratinocytes is a size-dependent phenomenon [109,121]. Intracutaneous injection of
various sizes of melanosomes into albino guinea pigs and subsequent phagocytosis by keratinocytes have shown that smaller melanosomes do indeed aggregate, whereas the larger ones remain "single" [120]. However, there is no
agreement as to the critical size above which melanosomes become single
within the keratinocytes, but estimates range from 0.4 to 1 fLm [122]. This does
not explain why then extracellular melanosomes are rarely observed or what
happens to the double membrane.

Degradation of Melanosomes
Melanosomes within keratinocytes are subject to degradation by lysosomes.
The membrane-limited vacuoles which contain aggregated melanosomes have
acid phosphatase activity [123] as well as fine grains of what seem to be degraded melanin and other melanosome components. At the level of the horny
layer, the limiting membrane is lost and the melanosomes disperse individually. The larger ellipsoidal melanosomes appear to resist degradation and,
particularly in deeply pigmented peoples, intact melanosomes appear to be
present in the stratum corneum. Clearly, then, some melanosomes are not
degraded within the epidermis [17].
Autophagocytosis or degradation of melanosomes within the melanocyte
may also occur. This is found in skin hyperpigmented from exposure to ultraviolet radiation and in hyperpigmented macules derived from malignant melanocytes [124-126]. Lysosomal hydrolases (e.g., acid phosphatase and aryl
sulfatase) are also found in melanocytes [127]. Autophagocytosis can also result
in hypomelanosis in animals. The tyrosinase-positive feathers of White Leghorn
chickens are hypomelanotic because the melanocytes are fewer and shorterlived than in normally pigmented chickens. Recent ultrastructural studies [128]

19

SKIN COLOR AND

THE MELANIN
PIGMENTARY
SYSTEM

20

PART I

have shown that the White Leghorn hypomelanosis is related to abnormal

melanosome degradation in melanocytes and that this intramelanocytic destruction of the melanosomes is eventually followed by destruction of the
melanocyte itself.

Regulation and Variables in Melanogenesis

The amount of melanin pigmentation in human skin must be considered
on two planes [129). The first is the constitutive skin color, which applies to
the amount of cutaneous melanin pigmentation genetically present in the absence of direct influence of solar irradiation. Constitutive skin color is that
level of pigmentation in those parts of the body habitually shielded from sunlight and may be considered the "baseline" skin color. The second is the facultative or inducible skin color, which is that degree of skin color that may be
elicited or induced by ultraviolet radiation exposure or by other factors, such
as levels of chalones or cyclic AMP or various endocrine changes. This reflects
the capacity to increase pigmentation. Facultative skin color, then, arises from
a complex interplay of light, hormones, and the genetic potential of the epidermal melanin unit. Facultative skin color, in its most common form, is the
color of habitually sun-exposed areas of the human skin.
The intensity of skin color reflecting the degree of melanin pigmentation
is sensitive to many different biologic and pathologic influences. The neural
control of pigmentation apparent in various fish and amphibians does not seem
to be present in humans. Nutritional as well as metabolic factors have been
reported to influence melanin pigmentation. Because many of these factors
have been implicated in the pathogenesis of certain melanin disorders, a summary of each one of these factors is necessary to understand normal as well as
abnormal pigmentation.

RACE, LIGHT, AGE, AND MELANOCYTES

Although there is considerable anatomical regional variation in the number
of epidermal melanocytes in anyone individual (Fig. 13), such regional density
is remarkably constant from person to person. Darkly pigmented people have
the same number and density of melanocytes as fair-skinned individuals. Rather,
it is the size, number, and clustering of melanosomes in keratinocytes that
distinguish the light-skinned from the dark-skinned races. Blacks have many
melanosomes which are large and well melanized, whereas light-skinned persons have fewer melanosomes which are smaller, less fully melanized, and
gathered in clusters in the keratinocytes.
The number and activity of functioning melanocytes can be increased by
UVA (320-400 nm), UVB (290-320 nm), and, probably to a lesser extent, visible
light exposure. Increased pigmentation may result from replication of functional melanocytes, increased melanogenesis by active melanocytes, activation

21

~
1220!10

SKIN COLOR AND

THE MELANIN
PIGMENTARY
SYSTEM

FOREHEAO

-roiO'!2IO
140cr.1O

1 400!220!!!..~

~-'~1
Human melanocyte
density in average number of mel anocytes per square millimeter. S.
(From: Fitzpatrick TB, Szabo G: The
melanocyte: cytology and cytochemistry. J Invest Dermatol
32:197-209, 1959. Copyright, 1959,
The Williams & Wilkins Company.
Used with permission.)
FIGURE 13.

~ _ /I \
rsao:MOLV
ZtOO! tOO

12 101 120)
1110:40 UPP(A

~
~IIOOt.1O

.....-1120 ..-0

+--1000:1

~_

~ 11 30!1O ~

.....--

I~UO ! 110

of dormant or partially active melanocytes [130,131], activation or replication

of "melanogonia" (melanocyte stem cells), or transformation of other epidermal
cell types [126,132]. Mitotic melanocytes have been observed in human skin
but the mitotic index is much less than that of keratinocytes. The frequency
of labeling reported seems appropriate for melanocytes keeping pace with keratinocyte turnover adequate to maintain effective barrier function [133]. That
mitoses occur [134] in unirradiated skin simply demonstrates that melanocytes
have an inherent turnover capacity, independent of ultraviolet radiation exposure.
The natural course of the melanocyte population is to decrease in number
over time. Quevedo et al. [135] observed an age-dependent decrease in the
melanocytes of dorsal trunk epidermis in the pigmented mouse; the number
of dopa-positive melanocytes was maximal two days after birth, but was nearly
zero by the 30th day. In humans, after birth the absolute number of melanocytes
peaks and then the number of dopa-positive melanocytes gradually decreases
throughout life [136,137]. Similarly, the number of dopa-positive melanocytes
stimulated by tanning decreases with time [138].

22
PART!

The investigation of the physiology of normal pigment darkening is hampered by an inability to identify melanoblasts or by inactive melanocytes lacking characteristic organelles.

FACTORS CONTROLLING PIGMENTATION

Genetic Control of Pigmentation
Studies on the laboratory mouse have clarified the nature of genetic control
of mammalian pigmentation. Although mouse melanocytes are not identical to
human melanocytes, there are such similarities in structure that the mouse
model has applicability to humans. Approximately 70 genes at 40 loci are now
known to influence pigmentation in mice [139].
There are four important factors in melanocyte form and function-melanoblast genotype, environmental cell genotype, environmental history of the
melanocyte, and the characteristics of differentiated environmental cells. Events
under genetic control include early events in melanoblast development, melanocyte morphology, melanosomal matrix structure formation, tyrosinase activity, type of melanin synthesized, and patterns of melanosomal transport
within receptor cells. It is the interaction of genetic factors at loci at each of
these levels that affects the morphogenesis and expression of pigment patterns.
There are some interesting observations among these mouse model systems.
In the agouti mouse it appears that two types of melanosomes may be produced
by the same melanocyte; ovoid black eumelanin granules are deposited in
keratinocytes distal and proximal to the agouti band, which is formed of round
yellow phaeomelanin granules. The a or agouti locus influences the phaeomelanin to eumelanin ratio within the hair coat; extrafollicular melanocytes
must be under separate genetic control as only eumelanin is synthesized by
these melanocytes [140]. Alleles at the b locus regulate the type of melanocyte
eumelanin produced-ovoid black granules in black (BIB) melanocytes and
round brown granules in brown (bib) melanocytes. The b locus may control
the structural protein matrix to which tyrosinase is attached [49]. The e locus
controls the structure of tyrosinase. The dominant e allele permits full deep
coloration whereas the homozygote in the lowest allelic state (e/e) produces
albinism with fair hair, skin, and eyes; intermedial alleles give gradation of
coat pigmentation. Tyrosinase activity increases as allele substitutions are made
from e/e to CIC. The e locus also exerts some control over the number, size,
and melanization of melanosomes [141]. Findings of other investigators that
show presence of tyrosinase activity on albino mouse skin and eyes suggest
the e locus may be more of a regulatory genome than a structural one [142,143].
Morphologic changes in melanocytes result from changes in the d and In
loci, which have been associated with less than well-developed melanocytic
dendrites [144]. The same appearance may result from less-pigmented dendrites
that are not well visualized; unlike uniformly distributed melanin, in did and
emlem hairs melanin is deposited in irregular clumps.
A recessive gene at the p locus results in pigmentary dilution of hair and
eyes. Melanosomal matrix is normal in pigmented mice. Limited tyrosine may

be available for melanin synthesis in such patients. Six chromosomes are also
involved, although in mice only one of two is metabolically active [145,146];
the one that is "switched off" occurs as a matter of chance. The mottled (mo),
dappled (Modp), and brindled (Mobr) are found on the X chromosome and are
lethal in the homozygous female or the male hemizygote. The role of the mottled
gene in melanogenesis is unknown but may influence the availability of copper
in the pigmentary pathway [147]. The molecular level of the genetic influence
needs scrutiny. No doubt DNA nucleotide sequences dictate primary provocative attributes of melanosomes, but these may be determined by regulation at
the level of gene transfer or translation or both [129,148]. The number of melanosomes synthesized and the shape, size, melanization, and internal structure
of individual melanosomes may be dictated by interplay of the latter two mechanisms. Congenital or inherited defects could result from abnormalities of the
primary structures of elementary melanosomic protein or from any aberration
in the presentation of melanosomes for assembly. The observation of macromelanosomes in various pigmentary disorders provides support for this theory
[8,149].
Melanosome size clearly is genetically determined, but other factors are
important; ultraviolet radiation, for example, has an effect on the size of melanosomes in the epidermal melanocytes [114,150]. The genetic milieu is the
stage on which these and environmental influences interact to result in macroscopic pigmentary changes.

Racial Differences in Human Melanocytes

The variables underlying racial color differences in humans are not fully
understood. All races, regardless of pigmentation, have a similar distribution
of melanocytes. On the basis of somewhat imperfect genetic studies, it appears
that the interaction of three or four additional gene repairs accounts for the
range of skin color in blacks and whites in the United States [132]. The racial
differences in melanocytes reflect the variation of the area occupied by the
rough endoplasmic reticulum, development of the Golgi apparatus, and relative
proportions of each of the melanosomes' four stages of development. In Caucasoids who tan moderately, Stage I, II, and III melanosomes predominate in
the perikaryon. Few Stage IV melanosomes are found within the dendrites, but
are present in the surrounding keratinocytes, often in groups or aggregates. In
Mongoloids, there are numerous Stage II, III, and IV melanosomes in the melanocyte perikaryon, whereas in blacks, Stage IV [111] melanosomes predominate but there are some Stage II and III melanosomes. Ultraviolet radiation
increases the number of melanosomes in keratinocytes in all races, but racial
differences still exist. Ultraviolet radiation exposure results in numerous Stage
IV melanosomes in the melanocytes of whites, even in those who are fairskinned with red hair. Caucasoid melanocytes without Stage IV melanosomes
before irradiation have them in increased numbers thereafter. Mongoloids and
Negroids have increased numbers of melanosomes of all stages. Stage II melanosomes seldom found in unirradiated Negroid skin are more frequent after
ultraviolet irradiation (Figs. 10-12).

23

SKIN COLOR AND

THE MELANIN
PIGMENTARY
SYSTEM

24
PART!

The pathogenesis of melanosomes also varies among races. In Caucasoids

and Mongoloids, small melanosomes are usually clustered in groups or aggregates surrounded by a single membrane. In blacks or Australian aborigines,
melanosomes are large, nonaggregated, and single particles surrounded by a
membrane. In a study of 14 American blacks with light and dark skin, it appeared that the degree of nonaggregation correlated with the relative darkening
of the skin [151].

Tissue Factors
Feedback Control of Melanocyte Function
It has become increasingly evident that there are cues arising from the
dermis throughout the complex functional levels of the epidermal melanin unit
and that these cues have an important influence on the biosynthesis of melanosomes. The arrival of melanosomes from melanocytes may alter the metabolic
activity of the keratinocytes and, by a feedback influence, affects the melanocyte
of that epidermal melanin unit. Also, it is possible that melanosome degradation
products may pass downward through or by the keratinocytes to exert some
sort of regulatory influence on melanocyte function [152,153].

Chalones and Cyclic AMP

Tissue-specific chalones, glycoproteins, and glycopolypeptides, byexerting a negative feedback control, are thought to regulate the mitotic activity of
melanocytes and keratinocytes [154-159]. If such chalones are, in fact, a sort
of regulatory factor, then the maintenance of a fixed ratio of keratinocytes to
melanocytes would require constant and precise balance in the production and
utilization of a number of very specific cell chalones. Adrenaline and glucocorticoids such as hydrocortisone are required for full chalone activity [102].
The rate at which melanosomes are transferred from melanocytes to proliferative keratinocytes may also be an important regulatory factor in melanosome
synthesis [129]. Voorhees et al. [160-162] modified the chalone theory and
suggested interaction of chalones and cyclic AMP. The chalone may be only
one part of a complex mechanism that regulates cyclic AMP levels. The adenyl
cyclase-cyclic AMP mechanism as elucidated by Sutherland [163] may have
a central role in the regulation of epidermal keratinocyte kinetics. Since the
epidermis contains prostaglandin E2 which may influence epidermal adenyl
cyclase activity, the latter may be influenced by cell surface chalone, prostaglandin E2 , and certain hormones including epinephrine and local neurotransmitters. This perceives chalones as among the factors regulating adenyl cyclase
activity and also cell division. However, there is evidence for the activation of
the adenyl cyclase-cyclic AMP system by direct binding of epinephrine to the
beta-adrenergic receptive sites on the cell membrane of keratinocytes. It has
been demonstrated that cyclic AMP stimulates tyrosinase synthesis within
melanocytes [164,165]. Possibly, cyclic AMP acts on intracellular melanin syn-

thesis and melanosome formation as well as on melanocyte mitotic activity. A

nonspecific dermal factor which promotes mitoses and which regulates mitotic
activity in mammalian epidermis has also been suggested to be operative in
addition to the tissue-specific inhibitory effects of chalones [156].

Hormonal Factors
Various hormones are known to influence melanin pigmentation in human
skin and in other mammals [166]. MSH induces dramatic changes in the melanosome distribution of the melanophores of fish, amphibians, and reptiles.
In mammalian melanoma cells, MSH increases cyclic AMP levels and stimulates melanogenesis within normal melanocytes [167,168]. Considerable evidence suggests that cyclic AMP is the "second messenger" in MSH regulation
of melanosome movement in the melanophores of fish, amphibians, and reptiles. Cyclic AMP may stimulate tyrosinase synthesis as a primary step in
increased melanogenesis. In humans, administration of a-MSH results in a
marked diffuse hyperpigmentation of the skin; the melanocytes appear highly
dendritic and contain an increased number of melanosomes as do the keratinocytes. This suggests that MSH causes translocation of melanosomes within
melanocytes, and thereby enhances melanocyte "dendricity," transfer to keratinocytes, and melanogenic activity in mammals [165,168]. Increased tyrosinase activity has been associated with the darkening effect of MSH on the skin
or hair of humans, guinea pigs, hamsters, and mice [165]; Lerner [165] suggested
this results not simply from activation of tyrosine already present in the melanocytes, but rather from increased tyrosinase synthesis. More recent evidence
suggests that MSH-activated tyrosinase activity results from conversion of inactive tyrosinase to active tyrosinase through inactivation of an enzyme inhibitor [164]. Ultraviolet radiation-induced photoconversion of 7-dehydrocholesterol to cholecalciferol increases melanoma cell tyrosinase activity with resultant
increased melanogenesis [169].
Pituitary release of MSH is regulated by the hypothalamus, but the mechanism of MSH regulation and of the hypothalamic-pituitary apparatus is unclear. Both MSH-releasing factors and an inhibitor of MSH release [170,171]
have been described in mammalian hypothalamus.
ACTH, a-MSH, and [3-MSH are powerful stimulants of human melanogenesis and also cause dispersion of melanosomes in frog melanocytes in vitro
[129,172,173]. The hyperpigmentation seen in Addison disease may be due to
elevated MSH levels or elevated ACTH levels [166]. That male eunuchs have
pale skin and tan poorly suggests a yet undefined action of androgens on
melanin pigmentation. In vivo studies have shown that testosterone increases
cutaneous melanogenesis [174] but seems to have no consistent effect in humans [137] or animals [175].
In females, gonadal hormones, especially estrogen, are strong stimulants
of melanogenesis. Area-specific melanocytes are very sensitive to estrogens.
Abnormal hyperpigmentation in the pregnant human female occurs around the
nipples, and to a lesser extent on the face and on the midline anterior abdominal
wall and the genitalia [137]. Abdominal wall skin biopsies have shown the

25

SKIN COLOR AND

THE MELANIN
PIGMENTARY
SYSTEM

26

PART!

darkening to reflect an increased number of active melanocytes [137]. Melasma

associated with oral contraceptive use or with pregnancy is probably related
to estrogen and progesterone. Regional-specific pigment darkening following
administration of exogenous androgens and estrogens to castrated guinea pigs
reinforces the concept of regional sensitivity of melanocytes to these hormones
[166].

Clinical and experimental observations in humans and animals suggested

a thyroid hormone effect on melanin pigmentation [166]. For example, in the
absence of thyroid hormone, tadpoles fail to develop pigmentation. Intradermal
thyroxin injection causes an increase in pigmentation in rabbits [176] and a
decreased pigmentation in chickens and rabbits [177].
Melatonin, a hormone considered to act on the hypothalamus to inhibit
release of appropriate releasing hormones that affect pituitary gonadotropins
and possibly MSH, has a reversible lightening effect on frog melanocytes but
no direct effect on mammalian melanocytes [178,179]. However, in denervated
black guinea pig skin that has been grafted into a white area, melatonin has
been shown to decrease the pigment spread in the surrounding skin compared
to controls [180]. In animal systems, melatonin activity is determined by the
quantity of light to which the animal is exposed [181]. Melatonin also promotes
the discharge of MSH-releasing inhibitory hormones from the hypothalamus
[182]. Although melatonin has been isolated from the human pineal gland, its
role in human pigmentation is unknown.

Neural Control of Pigmentation

While direct neural control of pigmentation has been described in fish and
an anatomic relationship has been observed between nerve cells and melanocytes in a few reports, the functional interaction has yet to be elucidated. In
fish, amphibians, and reptiles, melanophores have alpha- and/or beta-adrenergic receptors. Specific and respective stimuli induce aggregation of melanosomes for the former and dispersion of melanosomes for the latter [183-185].
In mammals, the only evidence that links catecholamine and depigmentation
has been suggested by the observation that rabbit ocular tyrosinase appears
dependent on adrenergic innervation [186].

Nutritional and Metabolic Factors

Nutritional deficiencies, both in animals and in humans, are known to alter
melanin pigmentation [187]. Copper and zinc deficiencies have been reported
to induce hypopigmentation in various animals [188-192]. Hypopigmentation
of the skin and hair results from copper deficiency in humans [193]; the depigmentation associated with chronic excessive molybdenum intake [194] is
probably related to a decreased storage of copper in the liver. Copper would
seem of prime importance because tyrosinase is a known copper-requiring
enzyme. The vitamins pantothenic acid, para-aminobenzoic acid, and biotin
have been variably implicated in the induction of animal hypopigmentation

[195]. However, it is not clear whether the hypopigmentation associated with

severe nutritional deficiency in humans is related to vitamin, protein, or mineral

deficiency.

Naturally Occurring Tyrosinase Inhibitors

The natural occurrence of tyrosinase inhibitors has been described [196,197].
There is a dialyzable water-soluble sulfhydryl-containing compound in human
epidermis that inhibits plant tyrosinase [198]. Irradiation of the skin decreases
the epidermal SH content. The suggestion is that both tyrosine and tyrosinase
are present in melanocytes, but unable to interact because of the presence of
SH compounds. Various stimuli such as ultraviolet radiation might act by
oxidizing or otherwise inhibiting these SH compounds. Halprin and Ohkawara
[199] suggested that this compound is a tripeptide-reduced glutathione (GSH
or gamma glutamyl-cysteinyl-glycine). In vivo-reduced glutathione was shown
to be present in adequate concentrations to inhibit in vivo melanogenesis. These
authors also demonstrated that black skin contains less reduced glutathione
and glutathione reductase than does Caucasian skin, and that ultraviolet radiation induces a change in the glutathione system prior to the appearance of
tanning. However, as these inhibitory factors are found in keratinocytes, not
melanocytes, these relationships to melanocyte mitosis must be considered
speculative.
The inhibition of melanin formation by sulfhydryl compounds such as
cysteine and glutathione is believed to occur by the combination of copper
present in tyrosinase or by the formation of complexes intermediate in the
tyrosine-to-melanin reaction [200-202]. The reader is directed to the works of
Flawn and Wilde [203,204] for detailed discussions of the naturally occurring
inhibitors of the melanin-producing system.
Tyrosinase inhibitors have been found in hamster melanoma and mouse
melanoma [197,205]; the latter was defective against only soluble tyrosinase,
not that found in melanosomes.

Ultraviolet Radiation
"Tanning" is the pigment darkening resulting from increased melanin pigmentation of, or rearrangement of, melanin granules in human skin that follows
exposure to natural sunlight or to artificial ultraviolet radiation sources. The
two phases of this tanning phenomenon are immediate pigment darkening (IPD)
and delayed tanning (DT).
IPD, which may be induced both by UV A and to a lesser degree by visible
light and UVB, is an immediate process occurring during the exposure of the
skin to light. IPD is dose related, may occur within minutes of exposure, peaks
in one to two hours, may last longer than two hours, and is observed then to
decrease between two and three hours after the exposure. It may not occur in
normally unexposed Type I skin. IPD is probably an oxidation reaction involving generation of unstable semiquinone-like free radicals in melanin [206].

27
SKIN COLOR AND
THE MELANIN
PIGMENTARY
SYSTEM

28
PART I

While no recognizable changes in the ultrastructure of the melanogenic organelles have yet been reported, IPD is known to be characterized by changes in
the distribution pattern of melanosome filaments and microtubules [207].
DT is optimally stimulated by exposure to intermediate-wavelength ultraviolet radiation (UVB) and, to a lesser extent, to long-wave ultraviolet radiation
(UVA) and to visible light [208]. DT involves increased numbers of dopapositive melanocytes, synthesis of new melanosomes, an augmented functional
state of melanocytes (increased perikaryon size, increased dendrite arborization), and increased melanin content in the keratinocytes. Thus, at the ultrastructural level, there is an increase in the formation, melanization, and transfer
of melanosomes and a marked change in the contour of the nucleus and in the
size and the chromatin pattern of the nucleus and of the nucleolus [207].

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1949

29

SKIN COLOR AND

THE MELANIN
PIGMENTARY
SYSTEM

30

PART I

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35
SKIN COLOR AND
THE MELANIN
PIGMENTARY
SYSTEM

II
Approach to the Problem of
Leukoderma
"The skin calls for faculty of close observation and attention to detail."
Louis A. Duhring, Valedictory Address
University of Pennsylvania School of Medicine, 1894

The study of diminished skin color requires a special vocabulary. Various terms
have been used to refer to decreased melanin content in the skin. These terms
are intended to be purely descriptive and not to imply anyone particular
diagnosis or disease entity.
Leukoderma is a generic term which connotes a mild to marked decrease
in normal skin color. This decrease may be secondary to a disturbance of normal
melanogenesis, or, as in the case of nevus anemicus, to some other factor. Most
leukodermas are, in fact, defects of melanogenesis.
Hypomelanosis refers to a leukoderma characterized by reduced or absent
melanin content. The terms "pigmentary dilution" and "hypopigmentation"
are synonymous with hypomelanosis. Amelanosis refers to hypomelanosis in
which melanin pigmentation is totally absent.
Depigmentation implies a loss of preexisting melanin pigmentation. It is
incorrect to apply the term "depigmentation" to cases of congenital hypomelanosis. Leukomelanoderma refers to melanin disturbances characterized by
both hyper- and hypomelanosis in the same general area of skin.
Poliosis is a term applied to a localized hypomelanosis of hair, whereas
canities implies a more generalized pigmentary dilution of hair. Graying of
hair is a localized or generalized hypomelanosis in which there is an admixture
of normally pigmented and depigmented hair. Generalized graying of hair is a
form of canities. Whitening of hair is the endpoint of canities.
Vitiligo implies a specific leukoderma, and the term is correctly applied
only to that disorder.
Diagnosis of a leukoderma requires both a complete history and physical
examination of the skin. A hand lens, Wood's light, and biopsy equipment are
the tools which should be at hand.
A classification of hypomelanosis in humans is presented in Table 1. Hereditary leukodermas are distinguished from those of metabolic, endocrine,

37

38

PART II

TABLE 1. Classification of Hypomelanosis in Humansa

Hereditary
Phenylketonuria (d,h,e)
Homocystinuria (d,h), oasthouse disease (h)
Histidinemia (d,h,e)
Fanconi syndrome (h)
Tyrosinase-negative oculocutaneous
albinism (d,h,e)
Tyrosinase-positive oculocutaneous
albinism (d,h,e)
Dominant oculocutaneous albinism (d,h,e)
Albinism with immunodeficiency (d,h)
Hermansky-Pudlak syndrome (d,h,e)
Yellow mutant albinism (d,h,e)
Chediak-Higashi syndrome (d,h,e)
Cross-McKusick-Breen syndrome (d,h,e)
Tietz syndrome (d,h,e)b
Menkes syndrome (d,h)
Vitiligo (c or d,h)
Piebaldism (c,h)
Woolf syndrome (c,h)
Ziprkowski-Margolis syndrome (c,h,e)
Waardenburg syndrome (c,h)
Rozcki syndrome (C)b
Tuberous sclerosis (c,h)
Nevus depigmentosus (c,h)
Neurofibromatosis (c,h)b
Incontinentia pigmenti achromians (c)
Incontinentia pigmenti (c)
Ataxia-telangiectasia (c)
Kappa-chain deficiency (d,h)b
Xeroderma pigmentosum (C)b
Dyschromatosis hereditaria (c)
Hypomelanosis with punctate keratosis of
the palms and soles (c)b
Pigmentary demarcation lines (c)
Darier-White disease (C)b
Focal dermal hypoplasia (c)
Hereditary premature canities (h)
"Bird-headed" dwarfism (c,h)b
Premature aging syndromes (h)
Progeria
Werner syndrome
Rothmund-Thomson syndrome (h)
Book syndrome (h)b
Fisch syndrome (h)b
Myotonia dystrophica (h)b
Down syndrome (h)b
Pierre Robin syndrome (h)b
Hallerman-Streiff syndrome (h)b
Treacher Collins syndrome (h)b
Prolidase deficiency (h)b

Metabolic
Copper deficiency (d,h)
Iron deficiency (h)b
Endocrine
Hypopituitarism (d)
Hyperthyroidism (h)
Cushing syndrome (c)b
Nutritional
Chronic protein deficiency or loss
Kwashiorkor (c,h)
Nephrosis (h)
Ulcerative colitis (h)
Malabsorption syndrome (h)
Vitamin B'2 deficiency (h)
Chemical and pharmacologic agents
Hydroquinone (c)
Monobenzylether of hydroquinone and
other hydroquinone derivatives (c)
Paratertiary butyl phenol and paratertiary
amylphenol (c)
Paratertiary butyicatechol (c)
Alkyl phenols (c)
Arsenical intoxication (c)
Topical steroids (c)
DNCB (c)
5-Fluorouracil-methenamine mandelate (c)
Guanonitrofurazone (c,h)
Hydrogen peroxide (h)
Mephenesin carbamate (h)
Triparanol (h)
Fluorobutyrophenone (h)
Chloroquinone and hydroxychloroquine (h)
Physical agents
Burns: thermal, ultraviolet (c,h)
Ionizing radiation (c,h)
Trauma (c,h)
Infection
Treponematoses
Pinta (c)
Endemic nonvenereal syphilis (c)
Yaws (c)
Secondary syphilis (c)
Leprosy (c)
Tinea versicolor (c)
Onchocerciasis (c)
Post-kala-azar dermatoses (c)
Herpes zoster (h)
(Continued)

TABLE 1. (continued)
Inflammatory
Pityriasis alba (c)
Psoriasis (c)
Postinflammatory hypomelanosis, atopic
dermatitis, discoid lupus
erythematosus, chronic guttate
parapsoriasis (c)

Neoplastic
Leukoderma acquisitum centrifugum (c,h)
Halo nevus
Other benign pigmented tumors
Malignant melanoma (primary or
metastases)

Various types of leukoderma associated

with malignant melanoma (c,h)
Miscellaneous
Alezzandrini syndrome (c,h,e)
Vogt-Koyanagi-Harada syndrome (c,h,e)
Sarcoidosis (c)
Vagabond's leukoderma (c)
Idiopathic guttate hypomelanosis (c)
Macular tropical hypochromia (c)
Senile canities and sudden whitening of hair (h)
Alopecia areata (h)
Heterochromia irides, Horner syndrome,
vitiligo irides (e)
Amyloidosis (c)

Abbreviations: c, circumscribed hypomelanosis of the skin; d, diffuse hypomelanosis of the skin; e, eye involvement; h, hair involvement.
b Questionable (occasional reports).

TABLE 2. Hypomelanosis of Scalp Hair in HumansO

Genetic
Albinism with immunodeficiency (d)
Tyrosinase-negative oculocutaneous
albinism (d)
Phenylketonuria (d)
Homocystinuria (d), oasthouse disease (d)
Histidinemia (d)
Fanconi syndrome (d)
Dominant oculocutaneous albinism (d)
Hermansky-Pudlak syndrome (d)
Chediak-Higashi syndrome (d)
Cross-McKusick-Breen syndrome (d)
Menkes syndrome (d)
Vitiligo (c or d)
Piebaldism (c)
Woolf syndrome (d)
Ziprkowski-Margolis syndrome (d)
Waardenburg syndrome (c or d)
Tuberous sclerosis (c)
Neurofibromatosis (C)b
Hereditary premature canities (d)
"Bird-headed" dwarfism (d)b
Premature aging syndrome (d)
Progeria (d)
Werner syndrome (d)
Rothmund-Thomson syndrome (d)
Book syndrome (d)b
Fisch syndrome (d)b
Myotonia dystrophica (d)b
Down syndrome (d)b
a
b

Hallerman-Streiff syndrome (d)b

Treacher Collins syndrome (d)b
Prolidase deficiency (a or d)b
Metabolic
Copper deficiency (d)
Endocrine
Hyperthyroidism (d)
Nutritional
Chronic protein loss or deficiency (d)
Kwashiorkor (d)
Nephrosis (d)
Ulcerative colitis (d)
Malabsorption syndrome (d)
Physical
Burns: thermal, ultraviolet (c)
Ionizing radiation (c)
Trauma (c)
Neoplastic
Leukoderma acquisitum centrifugum (c)
Miscellaneous
Alezzandrini syndrome (c)
Vogt-Koyanagi-Harada syndrome (c)
Senile canities or sudden whitening of hair
(c or d)
Alopecia areata (c)

Abbreviations: c, pigment decrease or loss is circumscribed (poliosis), d; pigment decrease or loss is diffuse.
Occasional reports.

39

APPROACH TO
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TABLE 3. Premature Graying of

Scalp Hair in Humans

40
PART II

Genetic
Hereditary premature canities
"Bird-headed" dwarfism
Premature aging syndrome
Progeria
Werner syndrome
Rothmund-Thomson syndrome
Waardenburg syndrome
Book syndrome
Homocystinuria
Ataxia-telangiectasia
Myotonia dystrophica
Fisch syndrome
Prolidase deficiency
Endocrine
Hyperthyroidism
Nutritional
Vitamin B12 deficiency
Miscellaneous
Rapid or sudden whitening of hair
Cardiovascular disease (questionable)

nutritional, physical, chemical, infectious, inflammatory, and neoplastic origin.

Other disorders of uncertain association are classified under a miscellaneous
heading. Hypomelanoses of the scalp and hair in humans are presented in
Table 2, premature graying of scalp hair in Table 3.
HISTORY

The history of the time of onset and course of a hypo melanotic disorder
is important. A circumscribed hypomelanosis present at birth suggests nevus
depigmentosus, tuberous sclerosis, piebaldism, Waardenburg syndrome, Ziprkowski-Margolis syndrome, or some other rare hereditary hypomelanosis.
Vitiligo, the most common hypomelanosis in nonendemic leprosy areas, is
usually acquired but may in fact, very rarely, be present at birth. History can
be misleading because a congenital hypomelanosis may not be observed for
months or longer either because it simply is overlooked or because, in the
absence of sun-induced melanogenesis of normal skin, the lesion is inapparent.
Thus, the history of a lesion appearing at six months, for example, may mislead
one to conclude a congenital hypomelanosis is acquired. In temperate latitudes,
most hypomelanoses become more apparent in the late spring or summer, after
the patient has had a chance to tan his normal skin. Only tinea versicolor seems
to have a seasonal onset.
Not all congenital hypopigmentation represents hypomelanosis; nevus
anemicus is a vascular lesion and not a pigmentary lesion.

The history of progression or repigmentation of hypomelanosis is useful

diagnostically. Nearly all congenital lesions are morphologically stable, that is,
do not exacerbate or remit over the life of the patient. Congenital vitiligo,
incontinentia pigmenti, and incontinentia pigmenti achromians may change
with time. Most acquired lesions, however, are potentially unstable. A history
of other cutaneous disturbances should be investigated. Simple trauma to the
skin, including sunburn, may immediately precede the onset of vitiligo. A
hypomelanosis may have followed another cutaneous eruption. Occupational
history, such as exposure to rubber products, may reveal possible exposure to
a phenol derivative known to induce hypomelanosis. The history of travel to
areas of the world endemic for cutaneous diseases associated with hypomelanosis suggests that an infectious or parasitic process should be included in
the differential diagnosis. For the hereditary disorders, investigation of the
family history can distinguish among hypomelanoses which are autosomal
dominant, autosomal recessive, and sex-linked (Table 4).
Past medical history must be obtained to exclude other dermatoses, endocrine disorders (as hypothyroidism), infectious disease (as syphilis), or use
of medications associated with induction of hypomelanosis.

PHYSICAL EXAMINATION
Physical examination of the patient is the most useful tool for the clinician
in the diagnosis of leukoderma. The patient should be completely undressed
and fully examined. Every examination should include use of the Wood's light
(Table 5).

Extent
The extent of the leukoderma must first be noted. In universal leukoderma,
the entire cutaneous surface is affected. A circumscribed leukoderma with
identifiable borders between hypopigmented and normal skin can be either
generalized or localized.
Universally decreased pigmentation of the skin and hair suggests one of
only a few diseases in which the degree of hypomelanosis is moderate or marked
(Table 6). In some of these disorders (see Table 7), the degree of pigment dilution
is so subtle as to be apparent only when the skin or hair of the affected patient
is compared to that of an unaffected member of the same family or another
individual of the same ethnic group.
A circumscribed localized hypomelanosis suggests one of the conditions
listed in Table 8. The list of circumscribed generalized hypomelanoses is so
long that one needs to look for other clinical clues to the diagnosis. Symmetrical
distribution suggests vitiligo, piebaldism, Waardenburg syndrome, often chemically induced leukoderma, and occasionally leprosy. Incontinentia pigmenti
achromians is often symmetrical, whereas nevus depigmentosus is usually not.

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APPROACH TO
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TABLE 4. Modes of Inheritance of Hereditary

Hypomelanosis

42

PART II

Autosomal dominant
Vitiligo
Dominant oculocutaneous albinism
Piebaldism
Waardenburg syndrome
Tuberous sclerosis
Incontinentia pigmenti achromians
Dyschromatosis
Pigmentary demarcation lines
Darier-White disease
Neurofibromatosis
Hypopigmentation with punctate keratosis of palms and soles
Tietz syndrome
Fisch syndrome
Book syndrome
Dystrophia myotonia
Hereditary premature canities
Seckel syndrome
Autosomal recessive
Tyrosinase-negative oculocutaneous albinism
Tyrosinase-positive oculocutaneous albinism
Yellow mutant
Hermansky-Pudlak syndrome
Cross-McKusick-Breen syndrome
CMdiak-Higashi syndrome
Werner syndrome
Progeria
Phenylketonuria
Homocystinuria
Histidinemia
Rozycki syndrome
Woolf syndrome
Xeroderma pigmentosum
Rothmund-Thomson syndrome
Sex-linked
Menkes syndrome
Incontinentia pigmenti
Ziprkowski-Margolis syndrome
Ocular albinism

Distribution
The distribution of hypomelanotic macules is important because several
disorders have characteristic cutaneous areas of involvement. A central white
forelock with associated hypomelanotic macules and the presence of a leukoderma of the ventral midline and the distal extremities suggest piebaldism
or the Waardenburg syndrome. The lesions of tuberous sclerosis are most common on the lower back, in contrast to tinea versicolor which most commonly
involves the upper anterior and posterior chest. Periorificial involvement and

TABLE 5. Clinically Useful Features in the Diagnosis

of Leukoderma
Visible light examination
Extent
Circumscribed or universal
If circumscribed (identifiable borders)
Distribution
Localized or generalized
Symmetrical or asymmetrical
Configuration
Patterned or non patterned
If patterned
Linear
Whorled (Blaschko's lines)
Dermatomal or segmental
Symmetrical
Shape
Artificial (artifactual)
Leaf-shaped
Polygonal
Oval, round, polycyclic
Guttate
Bizarre
Size and number of lesions
Koebner phenomenon
Morphology of borders
Well- or ill-defined
Raised or hyperpigmented
Repigmentation
Inflammatory and sensory changes
Mucous membrane involvement
Wood's light examination
Contrast increases
Implies epidermal pigment is decreased in light area or
increased in dark area
Contrast disappears
Implies hypopigmentation results from nonmelanogenic
factors or dermal factors but not epidermal
melanocyte changes, e.g., nevus anemicus

TABLE 6. Conditions with Marked

Universal Decrease of Normal Skin Color
(3 + Hypomelanoses)
Tyrosinase-negative oculocutaneous albinism
Tyrosinase-positive oculocutaneous albinism
Dominant oculocutaneous albinism
Yellow-mutant albinism
Hermansky-Pudlak syndrome
Chediak-Higashi syndrome
Cross-McKusick-Breen syndrome
Vitiligo universalis
Hypopituitarism

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APPROACH TO
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44

TABLE 7. Conditions with

Relative Universal Decrease
of Skin Color (1 +
Hypomelanoses)

PART II

Phenylketonuria
Homocystinuria
Histidinemia
Menkes syndrome
Nutritional copper deficiency

involvement of extensor body prominences and sites of trauma suggest vitiligo.

Involvement of anterior lower legs should suggest idiopathic guttate hypomelanosis or vitiligo. Palm and sole depigmentation is most likely to be vitiligo.

Shape of the Lesion

The shape of hypomelanotic macules is in some instances a function of
the disease (Fig. 14). Most circumscribed hypo melanotic lesions have convex
borders. The presence of stellate lesions or lesions with only concave borders
suggests a diffuse hypomelanosis with only scattered islands of sparing. The
following shapes of hypomelanotic macules are fairly characteristic of a specific
disease or diseases:
"Artificial," angular borders

Trauma or Koebner phenomenon in vitiligo, pigmentary demarcation lines (Fig.

Lance-ovate or "ash-leaf"
Polygonal or "thumbprint"

Tuberous sclerosis, vitiligo

Tuberous sclerosis, vitiligo, tinea versicolor
Idiopathic guttate hypomelanosis; uncommonly vitiligo, tuberous sclerosis,
chemical depigmentation
Incontinentia pigmenti, incontinentia
pigmenti achromians, nevus depigmentosus

15)

Guttate
Bizarre or disorganized

TABLE 8. Conditions in
Which Circumscribed Areas of
Leukoderma are Usually
Localized to One Area of the
Skin
Nevus depigmentosus
Segmental or focal vitiligo
Tuberous sclerosis (segmental)
Pigmentary demarcation lines
Nevus anemicus

45

APPROACH TO
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Some typical patterns of

hypomelanotic macules. a: Leaf-shaped
hypomelanotic macule (tuberous sclerosis); b: Whorled pattern (incontinentia pigmenti achromians); c: Circumscribed hypomelanosis (nevus
depigmentosus); d: Segmental or dermatomal hypomelanosis (depigmentosus).
FIGURE 14.

Certain patterns are also characteristic. For example, linear hypomelanosis

suggests nevus depigmentosus, posttraumatic leukoderma, or the Koebner phenomenon in vitiligo. Pigmentary demarcation lines or Fletcher's lines may give
a linear array.
Nevus depigmentosus, vitiligo, or tuberous sclerosis may occur along a
dermatomal distribution, with almost a nevoid pattern. A whorled pattern of
hypomelanosis is characteristic of incontinentia pigmenti or incontinentia pigmenti achromians.

Size of the Lesions

The lesions may vary in size from a few millimeters to many centimeters,
but lesions of less than one centimeter should suggest tuberous sclerosis, halo
Linear hypomelanosis. a: Koebner phenomenon
in vitiligo. (From: Dupre A et al:
Une variante du vitiligo trichrome de Fitzpatrick: vitiligo en
concorde et vitiligo lineaire sur
cicatrice. Bull Soc Fr Dermato1
Syphiligr 81:530-532, 1974.
Copyright, 1974, Masson et Cie.
Used with permission.) b: Pigmentary demarcation lines. (From
Selmanowitz VI. Krivo JM: Pigmentary demarcation lines. Br J
Derma/o1 93:371-377, 1975. Copyright, 1975, Blackwell Scientific Publications. Used with
permission.)
FIGURE 15.

46

PART II

FIGURE 16. Small hypo melanotic

macules. a: Idiopathic guttate hypomelanosis; b: Vagabond's disease;
c: Pityriasis lichenoides chronica; d:
Tuberous sclerosis (confetti spots).

nevus (resolved), idiopathic guttate hypomelanosis, tinea versicolor, chemically induced depigmentation, and occasionally vitiligo. Small lesions may
also be seen in pityriasis lichenoides chronica, vagabond's disease, and chronic
actinic skin damage without true poikiloderma (Fig. 16).

Number of Lesions
The number of lesions may vary from one to 100 or more. The presence
of only a few lesions suggests tuberous sclerosis, nevus depigmentosus, nevus
anemicus, and vitiligo. Idiopathic guttate hypomelanosis, vitiligo, and tinea
versicolor may have a few or many lesions.

Morphology of the Borders of the Lesions

Examination of the borders of the lesions is helpful in establishing several
diagnoses. Hyperpigmented borders surrounding a hypomelanotic macule may
be seen in vitiligo, piebaldism, and tinea versicolor. The presence of a zone of
intermediate color between the hypopigmented and the normal skin usually
represents trichrome vitiligo.
Sharp and discrete margins characterize the hypomelanotic macules of
vitiligo, piebaldism, Waardenburg syndrome, idiopathic guttate hypomelanosis, and nevus depigmentosus, whereas in pityriasis alba, leprosy, and postinflammatory hypopigmentation the margins appear feathered. The margins of
tinea versicolor may be fairly discrete or feathered.
Raised borders are discrete in tinea versicolor and rounded if present in
vitiligo.

Degree of Hypomelanosis
Observation of the degree of hypomelanosis is a very useful clinical parameter (Fig. 17). Hypomelanosis may be graded on the following four-step
scale:
Type
Type
Type
Type

0 hypomelanosis:
1 hypomelanosis:

normal pigmentation
barely perceptible hypomelanosis
2 hypomelanosis: definite but not complete amelanosis
3 hypomelanosis: totally absent pigmentation or amelanosis

Pure white macules (Type 3) are characteristic of piebaldism, Waardenburg

syndrome, Woolf syndrome, Ziprkowski-Margolis syndrome, vitiligo, and
chemical depigmentation, "Off-white" macules (Type 1 or 2) are found in tuberous sclerosis, idiopathic guttate hypomelanosis, pityriasis alba, leprosy,
postinflammatory depigmentation, trichrome vitiligo, and pigmentary demarcation lines.
Hyperpigmented macules and/or small islands of sparing, that is, focal
areas of normal skin within the area of hypomelanosis, may be seen in piebaldism, Waardenburg syndrome, Ziprkowski-Margolis syndrome, Woolf syndrome, vitiligo, and chemical depigmentation. Of these, in only vitiligo and
chemically induced depigmentation does the size and number of pigmented
islands change with time. The spontaneous or induced repigmentation of hypomelanosis, observed as pigmented macules within the white macule, may
be seen in halo nevus, tinea versicolor, postinflammatory and chemical depigmentation, and vitiligo. In incontinentia pigmenti and incontinentia pigmenti
achromians, the hypomelanosis gradually becomes less apparent with age.

Other Epidermal Changes of Involved Skin

Most hypomelanotic macules have no other epidermal abnormalities. However, scaling (Fig. 18) is present in tinea versicolor and pityriasis alba. Scaling
may also be seen with postinflammatory hypomelanoses. Erythema may occur
in pityriasis alba and in most hypomelanotic macules after sun exposure. In
rare instances, vitiligo macules may have inflammatory borders.
Lesions that are atrophic and hypomelanotic have generally not been included here (morphea, lichen sclerosus et atrophicus). Careful physical examination with an adequate hand lens can exclude these entities.

Involvement of Hair Pigmentation

The body hair in hypopigmented patches may be affected. White hairs in
the hypomelanotic macules may be seen in piebaldism, Waardenburg syndrome, Woolf syndrome, Ziprkowski-Margolis syndrome, tuberous sclerosis,
nevus depigmentosus, idiopathic guttate hypomelanosis, vitiligo, and chemical
depigmentation. Diffuse whitening of the hair is seen in universalleukoderms.
Poliosis may be associated with underlying or remote hypomelanosis of

47

APPROACH TO
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48

PART II

FIGURE 17. The color of the

hypomelanotic lesion provides a
clue to the diagnosis. a: Vitiligo
(pure white); b: Pinta (pure white);
c: Trichrome vitiligo (brown, tan,
white); d: Trichrome vitiligo; e:
Piebaldism (brown, white, with
hyperpigmented macules) ; f: Repigmentation in vitiligo (hyperpigmented macules, particularly
at margins of white macules); g:
Discrete repigmentation in halo
nevus (brown macules coalescent); h: Tinea versicolor (yellow, tan, white).

the skin, or poliosis may be the only cutaneous abnormality, as in the Waardenburg syndrome. The same can be said of canities.
Alopecia in the white macules is common in leprosy.

Other Features of the Hypomelanotic Macules

Most hypomelanotic macules are asymptomatic, but pruritus may occur
after sun exposure. Occasional patients with tinea versicolor, pityriasis alba,

49

APPROACH TO
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LEUKODERMA

FIGURE 18. Nonpigmentary surface epidermal features of the hypopigmented macules. a: Pityriasis alba with powdery scale; b: Pityriasis alba with scaling; c: Postinflammatory hypopigmentosis;
d: Tinea versicolor with fine scaling, occasionally slightly raised surfaces.

and vitiligo with raised borders report pruritus or a burning sensation. Anesthesia or hypesthesia of the hypopigmented lesions is diagnostic of leprosy.
Nevus anemicus, which is not a pigmentary anomaly, can be distinguished
from hypomelanosis because, in contrast to normal skin, vigorous stroking and
application of heat or cold fail to produce erythema.
Certain postinflammatory hypomelanoses may have a blue-gray cast because of melanin incontinence (dermal melanosis).

Wood's Light Examination

Wood's light examination should be a part of every evaluation of hypomelanosis. This is a simple procedure which may add very useful information
that can be gathered in no other way. The Wood's light (320-400 nm with peak
emission at 365 nm) or any other ultraviolet radiation source filtered to emit
primarily UVA, can help to distinguish epidermal from dermal pigmentation;
increased or decreased epidermal pigmentation becomes more marked, whereas

50
PART II

dermal pigmentation becomes less obvious or totally inapparent. The greater

the loss of epidermal pigmentation in comparison to normal skin, the more
marked the contrast on Wood's light examination. A macule that appears pure
white (Type 3) suggests melanoses found in vitiligo, Waardenburg syndrome,
piebaldism, Ziprkowski-Margolis syndrome, and chemical depigmentation.
Lesions that are tan-white or gray-white (Type I or II) are relatively hypomelanotic, such as in tuberous sclerosis, tinea versicolor, pityriasis alba, leprosy,
and postinflammatory hypopigmentation. Clearly, Wood's light examination is
most useful in very fair-skinned individuals in whom the normal skin is so
light that the hypopigmented macules are hard to discern by visual examination. In all areas of Skin Types I and II and in habitually unexposed areas in
others, the Wood's light examination is necessary to identify the presence and
location of hypomelanotic macules. Many cases of tuberous sclerosis have not
been diagnosed until midchildhood because Wood's light examination was not
performed at the time of the first seizure.
The Wood's light can help to distinguish a vascular lesion, such as nevus
anemicus, from a hypomelanotic lesion, such as nevus depigmentosus. With
Wood's light examination nevus anemicus becomes inapparent, whereas a hypomelanotic lesion is accentuated.
Ultraviolet radiation photography provides a permanent record of the information gathered with the Wood's light. Because visible light photography
records poorly the contrast in fair-skinned individuals, it may be that ultraviolet
radiation photography is the best medium for following and documenting the
progression or repigmentation of hypomelanosis in such patients. For particularly darkly pigmented individuals, standard black and white photographs
may be equally useful.

Associated Dermatologic Findings

Other pigmentary abnormalities may be associated with certain leukodermas. A pigmented lesion centered in a round white macule is characteristic of
leukoderma acquisitum centrifugum. Hyperpigmented macules separate from
the patches of leukoderma may be found in piebaldism, tuberous sclerosis,
neurofibromatosis, Waardenburg syndrome, and dyschromatosis symmetrica.
In leukodermas such as vagabond's disease and secondary syphilis, hypopigmentation is intermingled with hyperpigmentation (leukomelanoderma). In
incontinentia pigmenti, typical hyperpigmentation may be associated with hypopigmentation.
The coexistence of another dermatosis, such as psoriasis, atopic dermatitis,
eczematous dermatitis, discoid lupus erythematosus, pityriasis lichenoides
chronica, or pemphigus, suggests a postinflammatory hypomelanosis. In tinea
versicolor, typical scaling macules may be associated with hypopigmentation.
In any of these it is not uncommon to find that the primary eruption has
disappeared and only the hypopigmentation remains.
Hypomelanosis of the mucous membrane may be a feature of vitiligo and
uncommonly of piebaldism. The presence of hypopigmented oral mucosa in
fair-skinned individuals is so subtle that it is doubtlessly frequently missed.

Other Clinical Findings

Other features of the general physical examination may provide clues to
the diagnosis of a hypomelanosis, particularly one of hereditary origin.
An eye examination is probably the most important ancillary examination
in patients with congenital leukoderma. Characteristic ocular changes occur in
all disorders with clinical features of oculocutaneous albinism. Dystopia canthorum and heterochromia irides are characteristic of Waardenburg syndrome;
heterochromia irides alone suggests Ziprkowski-Margolis syndrome. Uveitis
with cutaneous depigmentation occurs in Vogt-Koyanagi-Harada syndrome.
Retinal pigmentary changes are also found in onchocercosis and in Alezzandrini syndrome. A few patients with vitiligo may have depigmentation of the
retina or tigroid changes. Most patients with phenylketonuria and histidinemia
have blue irides, which is interpreted as pigment dilution, compared to unaffected siblings.
The association of auditory changes with cutaneous disturbances is characteristic of the Waardenburg syndrome, Woolf syndrome, Ziprkowski-Margolis syndrome, Rozycki syndrome, and Vogt-Koyanagi-Harada syndrome (Table 9).
Neurologic impairment (particularly seizures and mental retardation) accompanies leukoderma in phenylketonuria, homocystinuria, Menkes syndrome, nutritional copper deficiency, tuberous sclerosis, nevus depigmentosus,
incontinentia pigmenti, incontinentia pigmenti achromians, and ataxia-telangiectasia (Table 9).
Endocrinologic abnormalities in association with leukoderma occur in hypopituitarism and in vitiligo, which may be associated with hypothyroidism
or hyperthyroidism and Addison disease (Table 10).
Hematologic examination may show characteristic changes. Leukocyte
granules are seen in Chediak-Higashi syndrome. Anemia occurs in nutritional
copper deficiency, and blood coagulation abnormalities in Hermansky-Pudlak
syndrome. Pernicious anemia may be associated with vitiligo and premature
graying of the hair.
Immunologic disturbances in association with leukoderma are observed in
Chediak-Higashi syndrome, ataxia-telangiectasia, kappa-chain deficiency, and
in albinism with immunodeficiency.
Malignancy in association with leukoderma has thus far been reported
only in certain patients with malignant melanoma.

HISTOLOGY AND ELECTRON MICROSCOPY

Definitive histologic classification of hypomelanosis must be based on both
light and electron microscopy. In most cases of hypomelanosis, the only finding
on light microscopy is the presence or absence of melanin. Uncommonly, other
findings help to establish the diagnosis. For example, a potassium hydroxide
preparation of skin scrapings is diagnostic for tinea versicolor. The presence
of acid-fast bacilli is seen in certain types of leprosy. The histology of various
dermatoses associated with leukoderma (eczematous dermatitis, psoriasis, dis-

51
APPROACH TO
THE PROBLEM OF
LEUKODERMA

TABLE 9. Neurocutaneous Disorders with Hypomelanosis

5Z

PART II

Pigmentary abnormality

Disorder
Alezzandrini syndrome
Ataxia-telangiectasia
Chediak-Higashi syndrome
Cross-McKusick-Breen
syndrome
Histidinemia
Homocystinuria
Incontinentia pigmenti
achromians and
incontinentia pigmenti
Leprosy
Menkes syndrome
Phenylketonuria
Rozycki syndrome
Tietz syndrome
Tuberous sclerosis
Vogt-Koyanagi-Harada
syndrome
Waardenburg syndrome
Woolf syndrome
Ziprkowski-Margolis
syndrome

Hypomelanotic macules,
poliosis
White patches
Dilution of skin, hair, and iris
pigmentation
Dilution of skin, hair, and iris
pigmentation
Dilution of skin, hair, and iris
pigmentation
Dilution of hair and iris and
possibly skin pigmentation
Whorled hypomelanotic
macules
Hypopigmented macules
Dilution of skin and hair
Dilution of skin, hair, and iris
pigmentation
Hypopigmented macules
Dilution of skin and hair
pigmentation
Hypomelanotic macules,
poliosis
Hypomelanotic macules,
poliosis
White forelock, premature
graying of hair,
hypomelanotic macules
Hypopigmented macules and
hair depigmentation
Hyper- and hypomelanotic
macules

Neurologic manifestation
Deafness
Choreoathetosis, ataxia,
mental retardation
Signs of cerebral disease
Mental retardation, athetosis,
seizures, deafness
Mental retardation
Mental retardation, seizures
Mental retardation, seizures
Sensory disturbances
Mental retardation, seizures,
pyramidal signs
Mental retardation, seizures
Deafness
Deafness
Mental retardation, seizures
Signs of lymphocytic
meningitis
Deafness
Deafness
Deafness

TABLE 10. Hypomelanosis and Endocrine Disorders

Diabetes mellitus
Hyperthyroidism
Goiter
Addison disease
Hypopituitarism
Hypoandrogenism
Hypoparathyroidism, Addison disease,
chronic mucocutaneous candidiasis
Multiple endocrinopathy syndrome

Vitiligo
Vitiligo
Premature graying of hair
Paratertiary butylcatechol-induced
depigmentation
Vitiligo
Generalized hypopigmentation most
evident in the genital area
Hypopigmentation of genital skin
(controversial)
Vitiligo
Vitiligo

coid lupus erythematosus, pityriasis lichenoides chronica, sarcoidosis) is that

of the primary process.
The presence of melanocytes may be established with dopa reaction, split
dopa, or thick sections for electron microscopy. Hypomelanotic lesions may
have a normal, decreased, or nearly absent number of melanocytes, whereas
amelanotic lesions are likely but not necessarily devoid of identifiable melanocytes.
Hypomelanoses may feature alteration in number, size, melanization, and
shape of melanosomes in melanocytes or in the number of melanosomes in
keratinocytes. A classification of hypomelanoses based on electron microscopic
abnormalities is given in Table 11.

TABLE 11. Cellular and Subcellular Basis for Hypomelanosis in Humans

Alteration of melanocyte number
Absence
Piebaldism
Waardenburg syndrome
Xeroderma pigmentosum (hypopigmented
macules)
Vitiligo
Leukoderma acquisitum centrifugum
Whitening of hair with aging
Chemical depigmentation
Depigmentation by physical agents
Decrease
Cross-McKusick-Breen syndrome
Incontinentia pigmenti achromians
Leprosy
Graying of hair with aging
Vagabond's leukoderma
Alteration in production or structure of
melanosomes
Quantitative
Decrease in number
Tuberous sclerosis
Nevus depigmentosus
Incontinentia pigmenti achromians
Leprosy
Increase in number
Tinea versicolor
Qualitative
Decreased size
Tuberous sclerosis
Tinea versicolor
Incontinentia pigmenti achromians
Increased size
Chediak-Higashi syndrome (unclear)
Abnormal shape
Tinea versicolor

Alteration in production or structure of

melanosomes (continued)
Abnormal inner structure
Tinea versicolor
Oculocutaneous labinism
Alterations in melanosome melanization
Oculocutaneous albinism
Yellow mutant
Hermansky-Pudlak syndrome
Chemical depigmentation
Tinea versicolor
Idiopathic guttate hypomelanosis
Graying of hair with aging

Alterations in melanosome transfer (normal

melanocyte number but decreased
number of melanosomes in
keratinocytes)
Tyrosinase-positive oculocutaneous
albinism
Nevus depigmentosus
Vagabond's leukoderma
Psoriasis
Eczema and eczematous dermatitis
Postinflammatory hypopigmentation
Topical corticosteroid depigmentation
Increased degradation of melanosomes
Within melanocytes (autophagy)
Nevus depigmentosus
Vagabond's leukoderma (questionable)
Within keratinocytes
Chediak-Higashi syndrome
Tinea versicolor (questionable)

53
APPROACH TO
THE PROBLEM OF
LEUKODERMA

54
PART II

PATHOGENESIS
Leukoderma is a generic term for abnormally white skin. It implies no
specific etiology or mechanism, just as the term "anemia" does not explain low
hemoglobin. While leukoderma implies decreased or absent pigmentation, the
appearance of pale skin may also result from profound anemia, nevus anemicus,
or from vasoconstriction as in the Raynaud phenomenon.
The problem of leukoderma resulting from decreased melanin in the skin
must be viewed as a defect at some level of melanogenesis.
There are 11 possible mechanisms to explain hypomelanosis or leukoderma
in humans (see Fig. 19, Table 12).
Mechanism I: No melanocytes are present because of failure of melanoblasts to migrate from the neural crest to the skin or because of failure of
melanoblast or melanocyte survival.
Mechanism II: Melanoblasts fail to differentiate into melanocytes. The leukoderma observed in Waardenburg syndrome, piebaldism, Woolf syndrome,
and Ziprkowski-Margolis syndrome is characterized by an absence of melanocytes. Either Mechanism I or II may explain this observation.

Melanin Removal
w ith Loss of
Stratum Corneum

T
1I

10

Migration of
Melanoblasts

Melanosome
Degradation

t
1

Mitotic Division
of Melanocytes

1
MELAHOCYTE

Melanosome
Transfer

IMelanosome I
: Melanization ,
7
Melanoaome
Formation

6
Tyrosinase
Transport

5
Melanosome
Matrix
Synthesis

4
TyroslnMe
SynthNIs

FIGURE 19. Morphologic and metabolic pathway of epidermal melanin pigmentation.

TABLE 12. Theoretical Mechanisms of Hypomelanosis

(see Fig. 19)
Mechanism I

Melanocytes are absent because of a failure of

melanoblasts to invade the skin or to survive
within specific areas of the skin.

Mechanism II

Melanocytes are absent because of a failure of

melanoblasts to differentiate into melanocytes.

Mechanism III

Melanocytes are absent or decreased because

of failure of melanocyte mitosis or because
of melanocyte destruction.

Mechanism IV

Melanocytes are present, but tyrosinase synthesis is

defective, decreased, or absent.

Mechanism V

Melanocytes are present, dopa stain is positive, but

melanosome matrix is abnormal.

Mechanism VI

Melanocytes are present, dopa stain is positive, but

tyrosinase is not found in melanosomes.

Mechanism VII

Melanocytes are present but fail to synthesize normal

melanosomes.

Mechanism VIII

Melanocytes are present but fail to deposit melanin

within melanosomes.

Mechanism IX

Melanocytes are present, but there is a failure or a

disturbance in the transfer of melanosomes from
melanocytes to keratinocytes.

Mechanism X

Melanocytes are present, but there is an increased

destruction of newly synthesized melanosomes.

Mechanism XI

Melanocytes are present, but melanin removal is

accelerated by increased loss of stratum corneum.

Mechanism III: Melanocytes disappear from the skin or fail to divide.

Melanocytes may be destroyed or inactivated so that their presence cannot be
identified by present techniques. Vitiligo, chemical depigmentation, graying
and whitening of hair, and the halo phenomenon are examples of this mechanism.
Mechanism N: Decreased or absent tyrosinase synthesis may cause hypopigmentation, as in albinism.
Mechanism V: Melanosome matrix synthesis is abnormal. Melanosomes
are present, but the internal lamina ultrastructural changes may preclude normal melanization. This may also occur in albinism.
Mechanism VI: Tyrosinase transport may be defective. Melanocytes are
present, vesicles are present, and dopa stain is positive, but no melanosomes
beyond Stage I are formed.

55

APPROACH TO
THE PROBLEM OF
LEUKODERMA

56
PART II

Mechanism VII: Melanocytes are present but there is an apparent failure

in the production of normal melanosomes. There are a number of hypomelanoses, either acquired or hereditary, in which this appears to be an important
defect. For example, tuberous sclerosis is characterized by a decreased number
and size of melanosomes. Chediak-Higashi syndrome features melanosomes
of increased size, a finding that may reflect a membrane defect of cellular
organelles.
Mechanism VIII: Melanocytes are present but they fail to deposit melanin
within melanosomes. Failure of melanization may result from a substrate deficiency or defect (possibly chronic protein loss or deficiency, alteration in
tyrosinase molecules, copper deficiency, and Menkes kinky hair disease); from
the absence of functioning tyrosinase (tyrosinase-negative albinism); from competitive inhibition of tyrosinase (phenylketonuria); and from chemical inhibition of tyrosinase (chemical depigmentation). It may be that Mycobacterium
leprae interferes with the synthesis of normal melanosomes. It has been suggested that M. Leprae induces a metabolic block by utilizing dopa as a respiratory carrier.
Mechanism IX: Melanocytes are present but there is a failure or a disturbance in the transfer of melanosomes from melanocytes to keratinocytes. Decreased or absent melanin transfer may result from an underdevelopment of
melanocytic dendrites, from pathologic changes in the malpighian cells (discoid
lupus erythematosus, eczematous dermatitis), or from increased keratinocyte
turnover (psoriasis).
Mechanism X: Melanocytes are present and contain normal melanosomes,
but there is an increased destruction of newly synthesized melanosomes. Increased degradation of melanosomes in keratinocytes or autophagocytosis of
melanosomes in melanocytes is observed in nevus depigmentosus, Chediak-Higashi syndrome, and possibly vagabond's disease and tinea versicolor.
However, it should not be concluded that this mechanism alone is responsible
for depigmentation in these disorders.
Mechanism XI: Melanin removal is accelerated by increased removal of
stratum corneum.
In many hypomelanoses, various combinations of the above mechanisms
may be operative. Among the 11 mechanisms postulated to cause hypopigmentation, most have presumptive models in humans except for the increased
melanosome destruction, which has been found to cause depigmentation in
chickens [1] but not in humans.

REFERENCE
1. Jimbow K et al: Ultrastructural investigation of autophagocytosis of melanosomes and pro-

grammed death of melanocytes in white Leghorn feathers: a study of morphogenetic events

leading to hypomelanosis. Dev BioI 36:8-23, 1974

III
Hypomelanotic Disorders

1
Genetic and Congenital Disorders

One purpose of any classification is to categorize, organize, and increase understanding of the disorders classified. For hereditary leukodermas, the presence or absence of certain common features permits a useful subclassification
(see Table 13, page 60). Those disorders with features of oculocutaneous albinism (3 + hypomelanosis) must be distinguished from those having a relative
(1 or 2 + hypomelanosis) generalized pigmentary dilution. In the latter, the
hypomelanosis may be apparent only in comparison to family members or
individuals of the same ethnic background, and these are readily distinguished
from entities usually featuring circumscribed hypomelanosis. The fourth category involves hereditary disorders in which pigmentation of the hair but not
of the skin is affected.

SECTION 1. DISORDERS WITH FEATURES OF

OCULOCUTANEOUS ALBINISM
INTRODUCTION
There is one complexion so singular ... that I never saw nor heard of any like them
in any part of the world .... They are white ... 'tis rather a milk-white, lighter than
the colour of any Europeans, and much like that of a white hourse .... From their
seeing so clear as they do in a moon-shiny night, we us'd to call them moon-ey'd.
For they see not very well in the sun, poring in the clearest Day; their eyes being but
weak, and running with water if the sun shine toward them so that in the day-time
they dare not to go abroad .... When moon-shiny night's come, they are all life and
activity, running abroad, and into the woods, skipping about like wild bucks; and
running as fast by moon-light, even in the gloom and shade of the woods, as the other
indians by Day, being as nimble as they, tho' not so strong and lusty .... Neither is
the child of a man and woman of these white indians white like the parents, but
copper-colour'd as their parents were .... They were but short-liv'd.
[Lionel Wafer, 1691)

Albinism is an inherited disorder of the melanin pigmentary system, found

among humans, other mammals, fish, amphibians, reptiles, and birds [2-5],
characterized by a decrease or an absence of melanin in the skin, hair, and

59

60

CHAPTER 1

TABLE 13. Classification of Hereditary Hypomelanoses

Disorders with features of oculocutaneous albinism
Tyrosinase-negative oculocutaneous albinism
Tyrosinase-positive oculocutaneous albinism
Yellow- mutant oculocutaneous albinism
Hermansky-Pudlak syndrome
Albinism with immunodeficiency
Chediak-Higashi syndrome
Cross-McKusick-Breen syndrome
Oculocutaneous albinoidism
Ocular albinism
Disorders with relative generalized decreased pigmentation
Copper deficiency
Histidinemia
Phenylketonuria
Deficiencies in methionine metabolism
Disorders with circumscribed hypomelanosis
Vitiligo
Piebaldism
Waardenburg syndrome
Tuberous sclerosis
Nevus depigmentosus
Incontinentia pigmenti achromians
Incontinentia pigmenti
Dyschromatosis
Hypopigmented markings in dark-skinned people: pigmentary demarcation lines
Ataxia-telangiectasia
Xeroderma pigmentosum
Darier-White disease
Neurofibromatosis
Tietz syndrome
Ziprkowski-Margolis syndrome
Autosomal recessive deafness associated with vitiligo
Piebaldism with deafness (Woolf syndrome)
Focal dermal hypoplasia syndrome
Hypopigmentation with punctate keratosis of the palms and soles
Disorders affecting hair pigmentation alone
Premolar aplasia, hyperhidrosis, and canities prematura (PHC syndrome)
Fanconi syndrome
Rothmund-Thomson syndrome
Dystrophia myotonica
Fisch syndrome
Kappa-chain deficiency
Hereditary premature canities
Bird-headed dwarfism (Seckel syndrome)
Treacher Collins syndrome, Pierre Robin syndrome, Hallerman-Streiff syndrome, and Down
syndrome
Prolidase deficiency

eyes. The outstanding characteristics are the "milk-white" skin and hair color,
photophobia, and nystagmus.

Historical Background
The term "albino" is believed to have derived from the Latin adjective
albus, meaning "white," and was first applied by Balthazar Tellez to certain
"white" Negroes observed on the west coast of Africa [6]. The striking contrast
of albino skin with the darkly pigmented normal skin of Indians and Negroes
sets them apart, and many myths have featured these strange "moon-ey'd"
people. Several albino heroes are prominent in the mythology of the Cuna
Indians living on the San BIas Islands located off the coast of Panama.
Sir Archibald Garrod [7] considered albinism to be an inborn error of
metabolism. In 1908 he suggested three possible mechanisms: (a) the cells that
usually contain pigment fail to take up melanins formed elsewhere; (b) the
albino has an unusual power of destroying these pigments; or (c) the albino
fails to form melanin pigment. Garrod concluded:
Evidence available indicates that the pigment is formed in situ. probably by the action
of intracellular enzymes .... Only certain specialized cells appear to have the power
of forming melanin .... Taking all the known facts into consideration, the theory that
what the albino lacks is the power of forming melanin which is normally possessed
by certain specialized cells is that which has most in its favour and is probably the
true one. If so, an intracellular enzyme is probably wanting in the subject of this
anomaly.

Through the ages albinos have been social curiosities, and even today
albinos may be exploited for their "carnival" value.

Definition
The metabolic defect which presents as albinism may involve the melanocytes at a specific site (ocular albinism) or the entire melanocyte system (oculocutaneous albinism). The term albinism should be restricted to congenital
heritable hypomelanoses limited to the eye (ocular albinism) or to the eye and
integument (oculocutaneous albinism). The basic defect is expressed as a partial
or total reduction of melanin deposition in the melanosomes.

Classification
The six types of oculocutaneous albinism (OCA) include tyrosinase-negative OCA, tyrosinase-positive OCA, yellow-mutant OCA, Hermansky-Pudlak
syndrome (HPS), Cross-McKusick-Breen syndrome (CMBS), and CMdiak-Higashi syndrome (CHS). This group of autosomal recessive disorders is
characterized by congenital absence or reduction in melanin pigment of the
skin, hair, and eyes, nystagmus, photophobia, and decreased visual acuity [8,9].

61

GENETIC AND
CONGENITAL
DISORDERS

62
CHAPTER 1

The features of the currently recognized types of ocular and oculocutaneous

albinism in humans [10] are listed in Tables 14 and 15. Among the types of
oculocutaneous albinism, there is variation in the severity of each of these
features [11]. Each can be distinguished from the others by clinical features,
biochemical criteria [12-15], distribution among various populations [9,16-18],
and genetic characteristics determined by matings of albinos of different genotypes [19-21] (Fig. 20).
Oculocutaneous albinoidism, an autosomal dominant hypomelanosis of
the skin and hair, features a fine punctate or diffuse pattern of depigmentation
of the irides and fundi [22-24], in contrast to the diffuse hypopigmentation of
the eyes as seen in oculocutaneous albinism. Nystagmus, photophobia, and
markedly decreased visual acuity are not features of oculocutaneous albinoidism.

TABLE 14. Comparison of the Characteristics of the Various Forms of Ocular

Albinisma
Characteristic
Hair color
Skin color
Pigmented nevi and
freckles
Susceptibility to skin
neoplasia
Eye color
Transillumination of
iris
Red reflex
Fundal pigment
Nystagmus
Photophobia
Visual acuity
Serum tyrosine levels
I3-MSH levels
Melanosomes in hair
bulbs
Incubation of hair
bulbs in tyrosine
Other

X-linked
ocular albinism

X-linked
Forsius-Eriksson

A-R ocular
albinism

Normal to slight
lightening
Normal
Present

Normal

Normal

Normal
Present

Normal
Present

No

No

No

Normal range
Males, cartwheel;
females,
diaphanous
Present, males
Males, 0; females,
mosaic fundus
++to++++
+ + to + + +
Moderate to severe
decrease; 20/50
to 20/400
Unknown
Unknown
Normal Stage IV

Normal range
Females, normal;
males,
diaphanous
Present, males
Males, 0

Normal range
Cartwheel to normal

Pigmentation
X-linked. Severe
affecting males;
in carrier
females, mosaic
retina

++to++++
+ + to + + + +
Moderate
Unknown
Unknown
Unknown; probably
normal
Unknown; probably
normal
X-linked. Males
protanopia;
females, no
mosaic retina

Present, males
Males and females,
o to +
+ + + to + + + +
++to+++
Moderate to severe
decrease; 20/60 to
20/400+
Unknown
Unknown
Normal Stage IV
Pigmentation
Autosomal
recessive. Males
and females
equally involved

Source: Quevedo WC Jr et al: Albinism, in The Metabolic Basis of Inherited Disease, 4th ed. Edited by JB
Stanbury et al. New York, McGraw-Hill, 1976. Used with permission.

63

GENETIC AND
CONGENITAL
DISORDERS

FIGURE 20. These two black albino parents have a normally pigmented daughter. Biologic examination showed that the father had ty-neg oculocutaneous albinism while the mother had typos oculocutaneous albinism. This indicates that genes at separate loci are involved in the production of the two forms of oculocutaneous albinism. These genes appear to be completely complementary in the double heterozygote. (From Witkop CJ Jr: Albinism, in Advances in Human
Genetics. Edited by H Harris, K Hirschhorn. Copyright, 1971, Plenum Press. Used with permission.)

Patients with ocular albinism have nystagmus, photophobia, decreased

visual acuity, and hypopigmented irides and fundi. Two types of X-linked
ocular albinism have been observed. The more common form was described
by Vogt [25] and included heterozygous females usually with mosaic patterns
of retinal pigment compatible with Lyonization effect of genes on the X-chromosomes [26-28]. In the other, the Aland type, retinal mosaicism has not been
observed [29,30]. Much rarer is an autosomal recessive form of ocular albinism
which has been observed in four kindreds in which males and females were
both affected with equal severity [31]. Although cutaneous pigmentation is
generally normal among families with the X-linked (Vogt) form of ocular albinism [32,33]' in some, slight hypopigmentation of the skin and hair is found
to occur.

General Incidence
The general incidence of all types of albinism is estimated to be 1:20,000
[6]. A frequency of 1:10,000 has been reported among the Irish [34,35]. The
incidence, of course, is much higher among the partially sighted. Albinism

accounts for 4% of the severely visually handicapped in Australia [36] and

10% in the United States [9,15,21]; of the latter, 10% have ocular albinism and
90% have the other forms of albinism.
The frequency of the types of albinism varies between blacks and whites.
While in blacks tyrosine-positive (ty-pos) is more common than tyrosine-negative (ty-neg), in Caucasians from the United States, ty-pos and ty-neg seem to
occur with equal frequency [9] (Table 16). Both ty-pos and ty-neg albinism are
more common among blacks than among whites. The incidence is much higher
among the Amish and Mennonites.

64
CHAPTER 1

TABLE 15. Comparison of the Characteristics of Hypomelanotic

Ty-neg

Characteristic
Hair color

White throughout life

Skin color

Pink to red

Pigmented nevi and

freckles
Susceptibility to skin
neoplasia
Eye color

Absent
++++
Gray to blue
No visible pigment

Red reflex

Present

Fundal pigment
Nystagmus
Photophobia
Visual acuity

0
++++
++++
Most legally blind;
constant or worse
with age. 20/200 to
20/400+
Normal
Normal
Stage I and II only

Source: Quevedo

No pigmentation

we Jr et al: Albinism,

White-yellow-red;
darkens with age
Pink-white to cream
May be present and
numerous
+++

Transillumination of
iris

Serum tyrosine levels

f3-MSH levels
Melanosomes in hair
bulbs
Incubation of hair bulbs
in tyrosine
Other

Ty-pos

Ym
White at birth; yellowred by 6 months
White at birth; cream.
slight tan on exposed
skin
Present
Unknown

Blue. yellow. brown;

age and race
dependent
Pigment cartwheel
effect at pupil and
limbus
May be absent in darkrace adults

Cartwheel effect in
adults

o to

o to

+ in adults
++to+++
+ + to + + +
Children. severe defect;
adults. same or
beUer. 20/90 to 20/
400
Low to normal
Normal
To early Stage III,
polyphagosomes
Pigmentation
3HOH test suggests
heterogeneity in typos albinos

Blue in infancy;
darkens with age

Marked retinal
hypopigmentation
+ + in adults
+ to +++
+ to ++
Same as ty-neg; may
improve with age.
20/90 to 20/400
Normal
Unknown
To Stage III
polyphagosomes
None to questionable
increase
Hair bulb test
increased red or
yellow with tyrosinecysteine incubation

in The Metabolic Basis of Inherited Disease, 4th ed. Edited by JB Stanbury et al.

TYROSINASE-NEGATIVE OCULOCUTANEOUS ALBINISM

Tyrosinase-negative (ty-neg) oculocutaneous albinism [16,37], which has
also been called complete perfect albinism [6,38,39], albinoidism [40,41]' and
albinism I [42,43], may be considered the classic [40] type of albinism. In the
United States, ty-neg albinism is the most common type of albinism; the frequency is estimated to be 1:39,000 among Caucasians and 1:28,000 among
blacks. Clinically detectable pigment is absent in skin, hair, and eyes, and there
is no evidence of tyrosinase activity in tissues incubated in L-tyrosine or L-

Diseases with Features of Oculocutaneous Albinisma

HPS

CHS

CMBS

Dominant albinoidism

White-red-dark redbrown
Cream-gray to light
normal

Blond to dark brown;

steel gray tint
Pink to pink-white

White to light blond

White to light blond

Pink to pink-white

Pink to pink-white

Present

Present

Present

Unknown

+++

++

Unknown

Unknown

Blue-gray to brown;
age and race
dependent
None to cartwheel
effect

Blue to dark brown

Gray-blue

Blue

Cartwheel to normal

Unknown; cataracts

Punctate pigmentation

Present in light
Caucasians; not in
dark races
o to + + + in adults
+to+++
+to++++
Moderate decrease to
normal

Present. less after 5

years

Unknown; cataracts

Present

+to+++
++
++
Normal to moderate
decrease

Unknown; cataracts
+++to++++
Unknown
Blind

Punctate pigmentation
No
No
Normal to mild. 20/30 to

Normal
Unknown
To Stage III
polyphagosomes
Pigmentation

Normal
Unknown
Giant to normal Stage
IV
Pigmentation

Normal
Unknown
Scanty; Stage III;
some Stage IV
Pigmentation

Platelet defect; ceroid

storage;
cytoplasmic bodies
in leukocytes

Susceptibility to
infection; giant
lysosomal-like
granules;
lymphoreticular-like
malignancy

Oligophrenia;
microphthalmia;
gingival
fibromatosis;
athetosis

o to
o to

New York. McGraw-Hill. 1976. Used with permission.

20/40

Unknown
Unknown
Probably
Pigmentation

65

GENETIC AND
CONGENITAL
DISORDERS

TABLE 16. Estimates of Frequency of Ty-Pos and

Ty-Neg Albinism in the General Population of the
United States by Race b

66
CHAPTER 1

Albinism frequency
Population

Ty-neg

Ty-pos

Combined

Caucasian
Negro
Total U.S.

1:39,999
1:28,000
1:37,000

1:40,000
1:15,000
1:33,000

1:20,000
1:10,000
1:18,000

Corrected for 88% Caucasian and 12% black, disregarding other racial
components.
b Source: Quevedo WC Jr et al: Albinism, in The Metabolic Basis of
Inherited Disease, 4th ed. Edited by JB Stanbury et al. New York,
McGraw-Hill, 1976. Used with permission.
a

dopa [9,13,21]. Incubation of hair bulbs in L-tyrosine or L-dopa (Kugelman and

Van Scott method) [37] reveals no pigment that can be identified visually or
electron microscopically, Light and electron microscopy reveal no discernible
pigment in the hair bulbs of patients with this type of albinism, While melanocytes are present in skin, hair, and eyes, only Stage I and Stage II melanosomes
are present but there is no evidence of accumulation of pigment on the melanosome matrix,

Clinical Characteristics
Regardless of racial background, ty-neg albinos have similar phenotypic
characteristics which include snow-white hair, pink-white skin, and various
eye findings. Instead of the usual brown pigmented nevi on the skin, accumulations of nevus cells appear as small reddish or purplish-red cutaneous
spots (Fig. 21). That the tips of hairs may turn yellow after prolonged sunlight
exposure has been attributed to a change in the keratin configuration. The
ophthalmologic features include gray to blue-gray irides with tangential illumination, a prominent red reflex as a result of a completely unmelanized fundus
which has a "pink eye" appearance, very diaphanous irides with no cartwheel
effect on transillumination, severe nystagmus, photophobia (Fig. 22), and markedly decreased visual acuity [15,44]. Of the ty-neg albinos examined to date,
about 90% have had moderate to moderately severe strabismus, 80% an esotropia, and 20% an exotropia. Both the nystagmus and the strabismus are more
apparent when the patient is exposed to bright sunlight. In most ty-neg albinos,
the visual acuity is 20/200 or worse and remains stable or deteriorates with age
[15].

Histology and Electron Microscopy (Fig. 23)

Electron photomicrography of ty-neg albino hair bulbs reveals melanosomes to be present and packed into the melanocytic dendrites, and passed to
keratinocytes. There are numerous melanocytes filled with Stage I intermediate

67
GENETIC AND
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DISORDERS

FIGURE 21. In albinos, accumulations of nevus cells appear as small reddish or purplish-red
spots on the skin.

FIGURE 22. Dilution of skin color and photophobia in

a 9-year-old boy. (Courtesy of O. C. Stegmaier, M.D.)

68

CHAPTER 1

decreased melanosome
melanization

FIGURE 23. Hypomelanosis in ty-neg oculocutaneous albinism.

vesicles and Stage II early melanosomes in which the unmelanized matrix is

plainly visible [21,45,46]. The cross-linked fibers of the matrix of albino hair
melanosomes resemble those found in Stage II melanosomes of normal hair.
Incubation in L-tyrosine or L-dopa does not increase pigmentation in the Stage
II melanosomes or precipitate changes in the Golgi apparatus or endoplasmic
reticulum [9,21,46]. No Stage III or Stage IV melanosomes are present.

Biochemical Abnormalities
In ty-neg albinos, serum levels of L-tyrosine, copper, and J3-melanocytestimulating hormone (J3-MSH) are within normal limits. There is no evidence
of a circulating inhibitor of pigment formation [9,14,47] . If hair bulbs from
normal red-haired individuals and from ty-pos albinos are incubated in ty-neg
albino serum, pigment forms readily.
The ty-neg mutation appears to involve the tyrosinase locus so that no
active tyrosinase is synthesized; the defect may involve the operator portion
of the genetic control mechanism [9,21].

Pathophysiology
Witkop and his associates concluded that ty-neg oculocutaneous albinism
results from a tyrosinase defect [9,13,21]. Depilated hair bulb melanocytes
incubated in a buffered solution of tyrosine do not deposit melanin. That there
is no melanin deposition in Stage I or Stage II melanosomes supports an absence
of tyrosinase activity, although the precise nature of the defect is unknown.

In animals, e locus albinism is most likely the homolog of ty-neg albinism

in humans. Since tyrosinase is regulated by the alleles at this locus, the e locus
consequently dictates the overall intensity of pigmentation. While the dominant
allele of the e locus in mice allows development of the appropriate full color,
the lowest allelic member, when present in the homozygous state (c/e), produces
all the features of albinism, namely complete absence of melanin pigment from
the hair, skin, and eyes. Any intermediate alleles result in gradations of coat
color somewhere between albinism and full color.
Under the electron microscope, the skin of albino mice is observed to have
melanosomes that lack melanin deposition. These "pseudo-Stage II" melanosomes, which are transferred to the keratinocytes of the hair follicles [48], seem
to possess normal structural proteins but lack tyrosinase activity. The alleles
at the e locus seem to influence the structure of tyrosinase and ultimately to
regulate the number and size of melanosomes and the amount of melanin
deposited on each [49]. Within the melanosome, tyrosinase activity increases
when progressive allelic substitutions from c/e to CIC [50] are made.
Pomerantz and Li [51] and Hearing [52] found evidence of tyrosinase activity in the skin and eyes of albino mice. Accordingly, Hearing has postulated
that the e locus may be a regulatory rather than a structural locus for tyrosinase.
While it is possible that tyrosinase activity may be present but undetected by
the methods presently available [51], present evidence suggests the gene regulating ty-neg albinism in humans may be a regulatory rather than a structural
one.
Abnormal iris translucency is found in some ty-neg Caucasian [32,33,53]
heterozygotes, but it is rarely encountered in Negro heterozygotes. Even among
Caucasians, however, this sign is not sufficiently specific to make it a reliable
indicator of the carrier state [15]. King, utilizing a micromethod adapted from
that of Pomerantz [54], reported a technique of chemical detection of the heterozygote state of ty-neg albinism [55]; this method is based upon the detection
of 3(H)OH production from a tritiated tyrosine substrate and utilizes anagen
hair bulbs as the tissue source of enzyme activity. When incubated in 3(H)_
tyrosine, ty-neg albino hair bulbs produce no increase in 3(H)OH. The obligate
heterozygotes of ty-neg albinism produce approximately half the amount of
tritiated water from the substrate compared to most normally pigmented controls.
Linkage studies in mice and rats show albinism (e locus) and the hemoglobin locus to be linked [56,57]. What may have been ty-neg albinism and
sickle-cell hemoglobin have been observed to involve the same patients in one
kindred [58], suggesting that a similar association may occur in other humans.
In the Brandywine isolate, ty-pos albinism and sickle-cell hemoglobin occur
in high frequency. Analysis of appropriate kindreds shows no evidence for
linkage [9].
TYROSINASE-POSITIVE OCULOCUTANEOUS ALBINISM

Tyrosinase-positive (ty-pos) oculocutaneous albinism [9,13,21,37,59,60] is

synonymous with the older terms "complete perfect albinism" [38,39], "albinoidism" [41], and "albinism II" [42,43].

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70

CHAPTER 1

Ty-pos is the second most common type of albinism in the United States
and is much more common among blacks than among Caucasians (1 :15,000 vs.
1:40,000) [9]. Isolated populations have a particularly high incidence of ty-pos
albinism; all involved American Indians and Chinese tested by Witkop [10]
have been ty-pos.

Clinical Characteristics
The major clinical difference between ty-pos and ty-neg albinism is that
in the former some melanin pigment is formed and is clinically detectable in
skin, hair, and eyes. Since the onset of visible pigment formation is delayed,
ty-pos infants, regardless of their racial background, may phenotypically resemble and be identical with ty-neg albino infants. As the ty-pos albino ages,
however, he accumulates small amounts of pigment, the intensity of which is
a function of the pigmentary (racial) background of the patient (Figs. 24, 25).
Irrespective of the age of the patient, however, incubation of tissues such
as hair in L-tyrosine or L-dopa [9,13,37,59] usually shows evidence of tyrosinase
activity. Hair bulbs from these patients frequently have a few pigment granules
observable under the light microscope, and lightly pigmented Stage III melanosomes can be identified in thin-section electron photomicrographs. Unlike
ty-neg hair, incubation of ty-pos hair bulbs by the method of Kugelman and
Van Scott [37] forms increased amounts of pigment discernible by light microscopy, and increased melanosomal melanization identifiable by electron
microscopy.
Phenotypically, the clinical characteristics of the ty-pos albino overlap
those of the ty-neg albino on one hand, and normal lightly pigmented individuals on the other hand. In fact, some ty-pos adult black albinos have been
observed to have darker skin color than that of some normal blond Caucasians .

Oculocutaneous albinism in two black patients. The color of the skin is milk-white
and some tanning of sun-exposed areas is apparent (a, b).

'l GURE 24.

71
GENETIC AND
CONGENITAL
DISORDERS

FIGURE 25.

Oculocutaneous albinism in a Caucasoid; both freckling and tanning are observed.

Most ty-pos albino infants of all racial backgrounds have white hair, but with
age they frequently gradually accumulate pigment so that the hair color turns
to cream, yellow, light brown, or even red.
There is often also a history of change in eye color from light gray to blue,
yellow, hazel, or even brown. A red reflex is usually easily elicited in most
infants and adult Caucasians with ty-pos albinism. However, it may be absent
or diminished in American Indian and American black ty-pos albino children
and adults. Adult Caucasian albinos usually have a light retina compared to
adult black and Indian albinos, but some darkening may be noted with age.
The macular reflex is usually markedly diminished or absent. Of 52 ty-pos
albinos from the Brandywine isolate, only 10% had a normal macular reflex;
25% had mesodermal remnants on the anterior surface of the iris and on the
posterior surface of the cornea on slit-lamp examination, and 20% had strabismus, usually esotropia. On transillumination, the irides are diaphanous, less
so in ty-pos albinism than in the ty-neg type [15,61]; there is a prominent
"cartwheel effect" with pigment accumulation particularly at the pupillary
border of the iris and the limbus [9]. All albinos examined had horizontal or
rotatory nystagmus and photophobia which appear to be less severe in the typos than in the ty-neg type of albinism. In some subjects, it has been observed
that photophobia and nystagmus decrease with age [6].
In general, visual acuity is more variable but, like nystagmus, less severe
among ty-pos than ty-neg albinos. Ty-pos adults may have better visual acuity

72
CHAPTER 1

and less severe nystagmus than they had as children [15] in contradistinction
to ty-neg albinos who tend to have the same or more severe defects as adults
than they had as children.
Pigmentation of the locus caeruleus and substantia nigra of ty-pos albinos
is normal; clearly neuromelanin is present in these structures [62,63].

Histology and Electron Microscopy

Electron microscopy of freshly epilated ty-pos hair bulbs and skin melanocytes show numerous Stage I intermediate vesicles, Stage II melanosomes,
partially pigmented Stage III melanosomes, and, only rarely, fully pigmented
Stage IV melanosomes.
Ty-pos albino melanocytes frequently contain one or more polyphagosome
complexes in which there are aggregates of melanosomes at various stages of
development. Strands of endoplasmic reticulum are observed to undergo destruction in the cytoplasm of the melanocyte. Partially pigmented early Stage
III melanosomes are observed in dendrites of the ty-pos melanocyte. Melanosomes in various stages of development are transferred to keratinocytes.
If ty-pos albino hair bulbs are pre-fixed in glutaraldehyde and then stained
with osmic acid and glutaraldehyde, it is apparent that nearly all melanosomes
are of the Stage IV type. The terminal layers of the Golgi dictyosomes may also
be stained to demonstrate the presence of uncomplexed tyrosinase in this structure. Pigmented Stage II-IV melanosomes pass to keratinocytes, where they are
observed singly or in melanosome complexes.

Biochemical Abnormalities
Serum copper levels and ~-melanocyte-stimulating hormone (~-MSH) levels are normal in ty-pos albinos.
Tyrosine levels have been variably reported to be low normal or normal.
Ty-pos albinos have approximately half of the normal concentration of salivary
tyrosine. This suggests a tyrosine transport defect [64]. If hair bulb incubation
studies are performed with a dilution gradient of substrate concentration, there
is no evidence for a defect in substrate transport in ty-pos albinism [9].
King [55] assayed tyrosinase activity of hair bulbs from a number of albinos
whose hair bulbs formed increased pigment when tested by the method of
Kugelman and Van Scott [37]. His studies suggest that there are two types of
ty-pos albinos. He found Type I ty-pos albinos to have a two- to fourfold increase
in tyrosinase activity compared to hair bulb assays of normal blond, brown,
and black hair, whereas Type II tyrosinase activity was no different from that
of normally pigmented subjects. The ty-pos albinos thus must be biochemically
and genetically somewhat heterogenous.
If the skin of ty-pos albinos is stripped with cellulose tape to the point of
punctate bleeding, is packed for one week with wet gauze packs containing a
solution of L-tyrosine and L-dopa, and is then irradiated by ultraviolet radiation
[11], pigmentation will result. However, oral L-dopa alone does not overwhelm

the metabolic block. One ty-pos albino subject ingested L-dopa, 5.5 g daily for
100 days, with no resultant increase in pigmentation of skin, hair, or eyes;
addition of 500 mg of pyridoxine to the above regimen for two weeks had no
effect on pigmentation [17].

Pathophysiology
The basic defect in ty-pos albinism remains unknown. Serum tyrosine and
phenylalanine levels are generally normal [17]. Since hair bulbs from ty-pos
albinos as well as from normal blonds will pigment in vitro in their own serum
without the addition of substrate, no serum inhibitory factor can be present
[9]. The minimum substrate concentration needed to induce visible or microscopic hair pigment formation over a given time is no different for ty-pos albinos
than for normals [9,14]. The tyrosinase activity of hair bulbs in vitro ranges
from normal to four times normal [55]. Pigmentation is not increased in vivo
by prolonged oral administration of L-dopa or by ultraviolet radiation.
In mice, a recessive allele at the p locus reduces the melanin content of
eyes and hair while the absolute amount of pigment is a function of another
gene locus. The overall features of the pink-eyed dilution mutant strongly
resemble ty-pos oculocutaneous albinism in humans. Limitations in the amount
of tyrosine available for melanin synthesis and not an impaired tyrosinase
(enzyme) system are primarily responsible for the restricted melanin deposition
within pip melanosomes. The pip melanosomes in retinal melanocytes exhibit
a defective alignment and cross-linkage of many compound fibers [65,66]. Melanosomes of the pip follicular melanocytes, unlike the pip retinal melanocytes
[65], appear to have essentially normal matrices [67]. A normal structure of the
melanosomal matrix in pigmented tissues of the eyes of pip mice also has been
reported [68].
The plucked hair bulbs of ty-pos oculocutaneous albinos have tyrosinase
activity and will darken if incubated in buffered tyrosine solution. This darkening of hair bulbs forms the basis for two classes of ty-pos oculocutaneous
albinism. Type I has a two- to fourfold increase in tyrosinase activity compared
to normal blond-, brown-, and black-haired people, whereas Type II activity is
within the normal range. It was once thought it was limited availability of
tyrosine within melanosomes which resulted in failure of melanogenesis. This
was thought to result from reduced or absent "permease," a substance required
for tyrosine to penetrate into melanosomes. More recent evidence, however,
does not support this view.
Other possible mechanisms to explain the pigmentary changes in ty-pos
oculocutaneous albinism are a defect in cAMP, phosphokinase activation of
tyrosinase, presence of an intracellular inhibitor, or a defect in the feedback
control mechanism. The presence of inhibitors andlor reduced amounts of
tyrosinase cannot be excluded. Abnormal matrices in some melanosomes in
oculocutaneous albinism have been described [69] but it is not known to which
type of oculocutaneous albinism this applies.
No reliable clinical or biochemical tests are available to identify ty-pos
albino heterozygotes. Iris translucency in ty-pos obligate heterozygotes is ob-

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GENETIC AND
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74
CHAPTER 1

served not to differ significantly from the range of values of normally pigmented
subjects [15,61]. Neither is there any difference in tyrosinase activity as measured by the conversion of 3H-tyrosine to L-dopa and 3(H)OH in ty-pos obligate
heterozygotes.

YELLOW-MUTANT OCULOCUTANEOUS ALBINISM

Yellow-mutant (Ym) oculocutaneous albinism has also been termed Amish
albinism [70] or xanthous albinism [6,71]. It is particularly common in the
Amish and has been seen in Polish-Americans, German-Americans, U.S. blacks,
Ceylonese blacks, and African blacks.
The clinical features of the Ym albino include yellow to yellow-red or
yellow-brown hair and fair skin which tans slightly when exposed to sunlight.
The hair bulb test of Kugelman and Van Scott [37] is either negative or equivocal. While melanocytes are present in skin, hair, and eyes, melanosomes develop only to Stage III and there is even pigmentation of the melanosomal
matrix.
The phenotypic expression of the Ym gene varies according to the ethnic
origin of the patient. At birth, Caucasian Ym albinos have no visible pigment
and resemble ty-neg albino infants. They are born with dead-white hair which
gradually turns a bright yellow at from six weeks to six months of age. At
approximately the same time, the skin becomes a very light cream color and
shows a very minimal but distinct capacity to tan after sun exposure. However,
in black Ym mutants, the skin has a definite dark cream color and, frequently,
numerous pigmented nevi; the hair varies from dark yellow to red-brown. By
midinfancy, the irides have usually become pigmented and by three years of
age transillumination reveals a distinct, readily detectable cartwheel effect.
Photophobia and nystagmus, which are universally present, are in general less
severe than in the ty-pos type. Funduscopic examination of black Ym albinos
may reveal a very slight amount of retinal pigment which may be absent in
Caucasian Ym albinos. The macular reflex is diminished or absent.
The hair bulb incubation test which is positive in ty-pos albinos is equivocal or negative in the Ym albinos. In contrast to the ty-pos albino hair bulbs,
microscopically distinguishable pigment granules are nearly always present in
the Ym hair bulb and often in the Ym hair shaft. The pigment of the freshly
epilated hair bulbs of Caucasian Ym albinos has a definite golden tint and the
color of the hair shaft varies from light to very bright yellow. However, the hair
bulb in black Ym albinos may appear from bright yellow to yellow-brown, and
frequently has a reddish tint. Ym albino hair bulbs incubated in L-tyrosine or
L-dopa do not form black eumelanin. Particularly in the Ym albinos from more
deeply pigmented families, very slight hair bulb darkening may occasionally
be seen. The definite dark pigmentation seen in the ty-pos type albino, however,
is lacking.
The ultrastructure of Ym melanocytes and keratinocytes very closely resembles that of the Hermansky-Pudlak syndrome albino. The melanocytes
appear to be packed with abnormal numbers of melanosomes which are in
various stages of development. The melanosomes, which resemble red hair

phaeomelanosomes, are numerous and either round and unevenly pigmented

or elongated and partially pigmented. The increased density of melanosomes
observed in the ty-pos melanocytes [9] incubated in tyrosine is not seen in Ym
melanosomes. Fibrillar material resembling that found in leaf frogs is noted in
the keratinocytes.
The melanogenic defect in Ym oculocutaneous albinism may involve
phaeomelanogenesis rather than eumelanogenesis. Incubation of Ym hair bulb
melanocytes in tyrosine and cysteine gives phaeomelanin deposition, but incubation in a tyrosine solution fails to cause eumelanin synthesis.

HERMANSKY-PUDLAK SYNDROME
The Hermansky-Pudlak syndrome (HPS) [72] or albinism with hemorrhagic diathesis [73] is an autosomal recessive disorder consisting of a triad of
ty-pos oculocutaneous albinism, hemorrhagic diathesis due to storage-pooldeficient platelets, and an accumulation of a ceroid-like material in the reticuloendothelial system, oral mucosa, and urine [72-79] (Fig. 26).
The essential features of this syndrome were first described by Hermansky
and Pudlack in two 33-year-old albino patients who had repeated episodes of
epistaxis, bruising, or prolonged bleeding following tooth extraction. Approximately 50 patients with HPS have been reported.
HPS is particularly common among Puerto Ricans. It is also said to be
particularly common among the natives of South Holland and those of the
Madras State of India.
A genetically determined enzyme defect is presumed to account for the
diverse alterations in pigment formation, a defect in the platelet storage-pool,
and a storage defect of an abnormal lipid-like material. That all three defects
are segregated as a unit trait within kindreds indicates that the three defects
can be attributed to a pleiotropic effect of a single autosomal recessive gene

FIGURE 26.

Jr .. M.D.)

Three patients with Hermansky-Pudlak syndrome (a-c). (Courtesy of C.

J. Witkop

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GENETIC AND
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CHAPTER 1

mutation or to the effect of two or more closely linked mutations [80]. Since
current genetic theory dictates that recessive traits primarily involve enzymatic
protein defects whereas dominant traits primarily represent mutations of structural proteins [81], the basic defect in HPS probably involves an enzyme alteration.

Clinical Characteristics
The phenotypic expression of the pigment disorder in HPS is a function
of the age and the racial ancestry of the patient. While pigmentation of patients
of Northern European ancestry may closely resemble that of the ty-neg phenotype, patients from India and Puerto Rico resemble normal Northern Europeans. The essential pigmentary dilution of the HPS patient may be apparent
only when patients with nystagmus and photophobia are compared to their
deeply pigmented unaffected family members.
The patients of Hermansky and Pudlak [72] had some obvious yellowgreen iris pigment and were of intermediate phenotypic expression. Several
extremely blond Irish and Dutch patients [82,83] have been noted to resemble
closely ty-neg albinos. These patients had no visually detectable pigment in
their hair or skin, had marked nystagmus, a prominent red reflex, completely
depigmented irides, and light gray-blue eyes with little evidence of a cartwheel
effect of transillumination. However, other Dutch patients [84] of relatively
darkly pigmented parents were observed to have reddish-brown hair. In the
absence of nystagmus, photophobia, and bleeding defect in these families, the
isolated finding of altered pigmentation was insufficient evidence to arouse
clinical suspicion that these patients were obviously unusual.
HPS among Puerto Ricans frequently appears to present with considerable
pigmentation in skin, eyes, and hair, the latter often being red or red-brown.
One such patient [85] had reddish-brown hair, mottled brown irides, pigmented
nevi, freckles, and deposits of pigment in the normally sun-exposed skin. The
patient, who had been a sugarcane cutter exposed to intense sunlight, showed
granular deposits of melanin in the dermis not unlike those observed in patients
with xeroderma pigmentosum. Deposits of brown pigment were prominent,
especially at the lumbus and at the pupillary borders of the irides. Although
a red reflex could be elicited, it was not a prominent feature of his disorder
[17]. Pigmentary features of patients of East Indian (Madras) extraction [17]
resemble those of normal U.S. Caucasians; that is, they have cream-colored
skin which can show some tanning effect, light brown hair, green to hazel eyes,
frank or latent nystagmus, photophobia, depigmented fundi, and the biochemical features of HPS.
Hemorrhagic episodes are a cardinal feature of the syndrome. Most patients
give a history of mild bleeding events including easy bruisability, epistaxis,
gingival bleeding, prolonged bleeding following tooth extraction, and hemoptysis. In a few cases massive fatal bleeding has occurred. Women with HPS
have had massive bleeding following childbirth and have required blood transfusions with each delivery [17,82,84]. In one kindred, an affected sister of the
propositus married an unaffected cousin and died of massive hemorrhage at
the time of the birth of an affected daughter. At age 26 this daughter developed

gastric symptoms for which she ingested an aspirin-containing antacid. Her

death, heralded by a massive gastric hemorrhage, was attributed to carcinoma
of the stomach; however no autopsy was performed. Considering the rarity of
stomach cancer among females of this age group, it seems more likely she had
a gastric ulcer; aspirin then intensified her bleeding diathesis by blocking the
release of already markedly deficient platelet storage-pool constituents. Among
the first 18 patients reported with HPS, 15 had prolonged bleeding following
tooth extraction [81]. It may be that aspirin and aspirin-containing drugs frequently given to patients after tooth extraction are responsible for intensifying
the bleeding diathesis to the point of fatal bleeding.
Chest x-rays of some patients with HPS show changes which may result
from deposition of ceroid-like material in lung tissue. Although the original
patients described by Hermansky and Pudlak [72] had chest x-ray changes
diagnosed as interstitial pulmonary fibrosis, at autopsy they had extensive
pulmonary deposits of ceroid-like material [74,86].

Pathophysiology
The underlying pathologic defect in HPS remains unknown. It is attractive
to think that an enzymatic alteration may be responsible for the platelet storagepool defect, the lipid storage disorder, and the pigment defect. A defect in
glutathione peroxidase as proposed by Witkop et al. [79] seems unlikely, as no
abnormality of this enzyme has been found in platelets. A prostaglandin defect
that has been found in storage-pool disease without albinism may explain HPS.
More recent studies have shown the selective immunologic defect in CHS
to be a markedly decreased natural killer activity of peripheral lymphocytes
[86a,86b].

The Pigment Defect

Hair bulbs incubated in L-tyrosine or L-dopa show increased pigmentation.
Under the electron microscope the HPS hair bulbs have numerous atypical
irregularly pigmented phaeomelanosomes which resemble those of normal redhaired subjects. Stage I, II, and III melanosomes are abundant, but fully formed
Stage IV melanosomes are rarely observed [15,17,79]. Fusion of adjacent melanosomes results in the formation of atypical large melanosomes with matrix
fibers running at various angles. The melanosomes in keratinocytes appear as
individual organelles and as membrane-bound aggregates within which the
melanosomes seem to be in varying stages of formation. Giant melanosomes
have been found on the hypopigmented skin of two patients with HPS [86c].
Incubation of hair bulbs in L-tyrosine results in conversion of all early
melanosomes to fully pigmented melanosomes, so clearly the cells have the
ability to form mature melanosomes. The tyrosinase step is intact. Incubation
in L-tyrosine results in pigmentation of the terminal dictyosome layer of the
Golgi apparatus [73], thus indicating the presence in this structure [87] of
tyrosinase uncomplexed with melanosomal matrix.

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HPS melanocytes may contain occasional vacuoles which seem to resemble

the lipid inclusion vacuoles seen in macrophages and epithelial cells in HPS.

The Platelet Defect

HPS platelets are storage-pool-deficient platelets with morphologic, chemical, and functional defects [17,32,75-78,88-92]. There is a decreased number
of electron-dense granules or storage organelles corresponding to deficiencies
of 5-hydroxytryptophan, adenosine diphosphate, and calcium [75-77,83,92,93].
Uptake, metabolism, and release of serotonin [90,94] and epinephrine are altered. HPS platelets also have abnormal responses to such potent aggregating
agents as adenosine diphosphate, epinephrine, thrombin, collagen, and bacteria
but, if storage-pool constituents are present, HPS platelets will aggregate. The
aspirin-induced platelet defect and the HPS platelet defect are mutually correctable; mixture of 30% aspirin platelets with 70% HPS platelet-rich plasma
will result in an essentially normal aggregation curve [78].

The Lipid Defect

Two types of lipids accumulate in the reticuloendothelial system, oral
mucosa, and other cells, and can also be found in the urinary sediment
[72,74-77,79,82,85,95-97]. One type is composed of neutral fats, fatty acids,
cholesterol, and cholesterol esters [79]; the other has features of ceroid and
lipofuscin but probably is a storage lipid unique to HPS. Such ceroid-like
accumulations can be identified in pigmented macrophages in liver, spleen,
lungs, bone marrow, circulating leukocytes, urinary sediment, and oral epithelial cells. That the bone marrow pigment-laden macrophages contain a pigment that stains sea-blue with azure dye has led to classification of HPS as a
syndrome of the sea-blue histiocyte [17,72,74,82,86,96,98,99]. HPS macrophage
inclusions, however, are not identical to other reported examples of sea-blue

histiocytes [17,100,101].
No abnormal lipids nor abnormal levels of normal lipids have been reported
in the plasma (serum) of HPS patients [17,79].

The Leukocyte Defect

Two types of inclusions have been noted in the cytoplasm of circulating
leukocytes. One of these resembles the ceroid-like lipid complex described in
bone marrow macrophages and the other is a membrane-bound particle with
an electron-dense core and a peripheral fibrillar material.
Small vesicles and vacuoles have been described [96] in the circulating
lymphocytes of one HPS patient. One of the membrane-bound inclusions in
circulating monocytes [97,99] resembles structures identified in melanocytes
of a single species of leaf frogs. The inclusions may represent a new type of
melanosome which produces a red pigment that is not phaeomelanin or eumelanin [102]. These have not been observed in the hair cells of HPS patients
[17,103].

CHEDIAK-HIGASHI SYNDROME
Chediak-Higashi syndrome (CHS) is a rare autosomal recessive disease
characterized by oculocutaneous albinism, hematologic and neurologic abnormalities, and usually death before the age of 10.

Historical Background
In 1943, Beguez-Cesar [104] reported the first three cases of CHS among
three children of consanguinous marriage. Death resulted at an early age. In
1948 Steinbrinck [105] and in 1954 Higashi [106] each reported a case; the
latter had been diagnosed as xeroderma pigmentosum. In 1952 in a review of
this syndrome, a Cuban hematologist, Chediak [107], emphasized the hematologic findings. Sato [108] in 1955 applied the Chediak-Higashi eponym, and
outlined the clinical features of albinism, photophobia, characteristic blood
morphology, and early death from lymphoma. He concluded that early death
is related to a leukocyte abnormality transmitted by each or either of healthy
consanguinous parents. Kritzler et al. [109] reported defects in various tissues.

Clinical Characteristics
CHS is a truly rare disease; by 1972 only 59 cases had been reported [110].
Cases have been reported from North and South America, Europe, and Asia,
but no cases are reported among blacks [111]. Moran and Estevez [112] reported
an incidence of three per 15,500 hospital admissions.
Of 56 reported patients [110], 26 were males and 30 were females. Fortyeight percent were born of consanguinous marriages. The mean age reported
was 5.8 years, with only 13 over 10 years and two ages 21 and 25. Of the 56
patients, 37 had died at an average age of 3.1 years; the 19 living had an average
age of 9.2 years. Several patients surviving to over 30 years of age have been
reported.

Pigmentation Abnormalities
CHS patients have a pigmentary dilution that involves skin, hair, and eyes.
Of 55 patients with CHS, 53 were found to have pigmentary dilution in at least
one of skin, hair, or eyes. All three were involved in 38 patients and two of
the three in seven patients [110]. The cutaneous pigmentary defect is partial
to complete albinism and may be overlooked in patients of fair-skinned ancestry. The color of the skin varies from light cream to slate-gray. Even moderate
sunlight exposure may cause a sunburn. Some darkening of exposed skin and
darkening of the skin with age have been reported [113]. Hypopigmentation of
nipples, areolae, genitalia, and axillae has been described [114,115]. Lentigines,
cafe-au-Iait spots, and nevi may occur in some CHS patients [116]. Hair color

79

GENETIC AND
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DISORDERS

80

CHAPTER 1

FIGURE 27. Loss of iris pigmentation in a patient with Chediak-Higashi syndrome (a,b).

varies from light blond to brunette, but may assume an unusual frosted metallicgray sheen, which is characteristic.
The eyes are usually pigmented, with a pale blue-violet to a brown color,
usually as a function of parentage (Fig. 27). Many patients have been found to
have a loss of iris pigmentation, increased red reflex, and photophobia. Cases
of iris hyperpigmentation have also been described [109,117]. There may be
moderately to markedly decreased retinal pigmentation [118-120].

Leukocyte Abnormalities
Neutrophils from CHS patients contain a few giant (up to 4 J.1) azurophilicstaining granules [121-124] (Fig. 28). In vivo neutrophils show reduced migration into inflammatory sites and in vitro chemotaxis is defective [125-127].
Following bacterial ingestion, there is delayed degranulation of leukocytes
accompanied by an absence of peroxidase activity and by reduced bactericidal
activity [125-129]. Lysosomal enzymes, alkaline phosphatase, (3-g1ucuronidase,
and myeloperoxidase are reduced [127], and the cell is believed to be unable

C.HS

CHS

FIGURE 28. Giant granules in leukocytes in the Chediak-Higashi syndrome. (Courtesy of O. C.

Stegmaier, M.D.)

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GENETIC AND
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82

CHAPTER 1

to deliver lysosomal enzymes to normal phagocytic vacuoles. Giant lysosomal

granules may occasionally be found in leukocytes of obligate heterozygotes.

Other Manifestations
In early childhood, routine inoculations are well tolerated. There are recurrent staphylococcal and streptococcal infections. At about five years of age,
convulsions and neuropathy frequently develop. Neuropathic changes include
cranial and peripheral neuropathy, a wide-based stamping gait [109,130]' muscle weakness, foot drop, and decreased deep tendon reflexes [131].
Later, anemia (88% of patients), thrombocytopenia (50%), and absolute
neutropenia (44%) develop. In the later stages, mediastinal and hilar lymphadenopathy, jaundice [132]' marked splenomegaly, moderate hepatomegaly, a
leukemic type of gingivitis, and pseudomembranous sloughing of buccal mucosa may occur [130]. The latter may be regarded as harbingers of a lymphoreticular malignancy and are poor prognostic signs.

Histology and Electron Microscopy (Fig. 29)

The number and distribution of melanocytes is normal in CHS. Tyrosinase
activity is present and fully pigmented Stage IV melanosomes may be observed
[14,120,124,133]. Although some normal-sized melanosomes (0.5-1.0 j.L) may
be formed and are passed to the keratinocytes [134,135], most of the melanosomes are abnormally large structures (1.0-2.0 j.L) that transfer only with difficulty to the keratinocytes [120,124,131] (Fig. 30).

l
increased
melanosome
degradation

FIGURE 29. Hypopigmentation in the Chediak-Higashi

syndrome.

83

GENETIC AND
CONGENITAL
DISORDERS

FIGURE 30. The massive Chediak-Higashi granules have a bizarre pattern and reach tremendous
proportions(x 27,394). (From: Zelickson AS et al: The Chediak-Higashi syndrome: formation of
giant melanosomes and the basis of hypopigmentation. J Invest Dermato149:575-581, 1967. Copyright, 1967, The Williams & Wilkins Company. Used with permission.)

Pierini and Abulafia [136] found melanin granules to be increased in number and size. Stegmaier and Schneider [113] were unable to find fully formed
melanin granules, but they found a few tyrosinase-positive cells in the epidermis. They reported electron microscopy studies to show degeneration and
vacuolization of epithelial cells and melanocytes. In six homozygous patients,
Bedoya [117] found some to have complete absence of pigment, but others to
have large clumps of enlarged melanin granules in both the epidermis and the
dermis. In the dermis, melanin was found in histiocytes, endothelial cells,
perithelial cells, fibroblasts, and Schwann cells, but in the interstitial areas
none was found. Changes in the heterozygotes included segmental basal deposition of normal melanin, clumping of irregyJar somewhat enlarged melanin
granules, mild atrophy of the malpighian layer with scattered cell vacuolization,
and abundant melanin in the melanophages in the papillary dermis associated
with a mononuclear infiltrate. Windhorst [137] found the early melanosomes
in CHS to be extremely large. The pattern of the membrane of maturing CHS
melanosomes suggested fusion of smaller forms. Based on this, plus demonstration of adequate tyrosinase activity, Windhorst suggested that the pigmentary dilution in CHS was secondary to a primary defect in melanosome structure

84
CHAPTER 1

FIGURE 31. The pigment granules that are passed to the epidermal cells are located in lysosomelike structures, often surrounding the nucleus (x 29,410). (From: Zelickson AS et al: The Chediak-Higashi syndrome: formation of giant melanosomes and the basis of hypopigmentation. J
Invest Dermato149:575-581, 1967. Copyright, 1967, The Williams & Wilkins Company. Used with
permission.)

[120] (Figs. 31, 32). Zelickson et al. [138] showed the destruction of melanosomes within the keratinocytes may be accelerated. Lutzner and Lowrie [139]
suggested in the mutant beige (bg) mouse (an animal model of CHS) that "giant
beige melanin granules are formed through the continual deposition of melanofilaments by granule fusion and/or failure of size-control mechanisms." Whether
the giant pigment granules result from abnormal synthesis or fusion of smaller
granules is not completely established, though evidence favors the latter.
Hair incubated in tyrosinase undergoes darkening of the matrix. Examination of unstained hair mounts shows abnormally large but sparsely clustered
melanin granules. Similar granules are seen in the hair follicles [112]. Large
melanin granules have also been found in the retina and in the choroid of
mammalian models and humans, as well as in the pia-arachnoid of humans
[117,120,139a].

85

GENETIC AND
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DISORDERS

FIGURE 32. The hypopigmentation in Chediak-Higashi syndrome is most likely due to abnormal
packaging of normal melanosomes in giant epidermal celllysosomes( x 39.825). (From: Zelickson
AS et al: The Chediak-Higashi syndrome: formation of giant melanosomes and the basis of hypopigmentation. J Invest Dermatol 49:575-581, 1967. Copyright, 1967, The Williams & Wilkins
Company. Used with permission.)

Pathogenesis
Animal models of CHS are known and have facilitated understanding of
the genesis of this disease [140) (Table 17).
The giant granules found in this disease were first studied in leukocytes,
where it was shown that histochemically they stained positively for acid phosphate and peroxidase [104,121-124), both of which localize in lysosomes. These
abnormal membrane-bound lysosomal-like organelles have also been found in
cells of buccal, gastric, and duodenal mucosa, the adrenal and pituitary glands,
the pancreas, liver, spleen, and kidney, and in bone marrow, hair, skin, and
iris [123,131,141). Many of these abnormal granulations show fragility of their
limiting membranes and undergo fragmentation and degeneration within leukocytes, Schwann cells, melanocytes, and keratinocytes [131,134,141).

TABLE 17. Comparative Aspects of the Chediak-Higashi Syndrome of Humans,

Mink, Cattle, and Miceo

86

CHAPTER 1

Characteristic
Autosomal recessive mode of
inheritance
Clinical studies
1. Increased susceptibility
to infection
2. Similar distribution of
enlarged granules
3. Similar morphology of
enlarged granules
4. Similar histochemistry of
enlarged granules
5. Bleeding tendency
6. Similar inflammatory
response
7. Immunologic deficiency
8. Pigmentary dilution
9. Accelerated phase
10. Elevated muramidase
levels
Experimental studies
1. Delayed chemotaxis in
vitro
2. Decreased serotonin
levels
3. Virus-like particles
observed
4. Sequestration vacuoles
observed
5. Abnormal serum lipid
pattern
6. Autophagy
7. Abnormally fragile
enlarged granules
8. Abnormal bactericidal
capabilities of
neutrophils
9. Abnormal membrane
permeability
10. Decreased renal tubular
catabolic function
a

Humans

Cattle

Mink

Mice

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes
Yes

Yes
Yes

Yes
Yes

Yes
?

No
Yes
Yes
Yes

No
Yes
No
No

No
Yes
No
No

?
Yes
No
No

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Occasional

No

Occasional

No

Occasional

No

No

No

Yes

No

No

No

Occasional
Yes

No
No

No
No

No
No

No

Occasional

No

No

Yes

Yes

Source: Windhorst DB, Padgett G: The CMdiak-Higashi syndrome and the homologous trait in animals. J.

Invest Dennatol 60:529-537, 1973. Copyright, 1973, The Williams & Wilkins Co. Used with permission.

The mechanism of formation of giant granules characteristic of CHS is

unclear. However, granulocyte studies [142] revealed that certain granulocyte
granules are unable to fuse with phagocyte vacuoles because of a defect in
membrane fusion. Furthermore, that CHS giant leukocyte granules take an acid
phosphatase stain much more rapidly than adjacent normal-appearing granules

further supports a membrane defect [124]. A defect in protein degradation has

also been suggested from the study of degradation of exogenous horseradish
peroxidase by the tubular cells of the kidney of the beige mouse [143]. In fact,
the mechanism of formation of the giant granules has not been established.

Diagnosis
The presence of oculocutaneous albinism, recurrent infections, neurologic
abnormalities, and peculiar leukocyte inclusion in a young child suggests the
diagnosis of CHS.

Prognosis
The prognosis for longevity is poor. Although childhood infections and
inoculations are handled well and although delayed hypersensitivity and antibodies are normal, most patients succumb by age 10 because of infection or
hemorrhage.
Clinical management problems include diagnosis and treatment of infection, maintenance of hemostasis, and correction of anemia and pancytopenia.
Infiltrative lesions may regress with antimetabolite therapy. Peripheral neuropathy may improve as the infiltrative lesions regress.
Khan et al. [144] reported one patient with abnormal delayed hypersensitivity (poor lymphocyte blastogenesis, failure to respond to DNCB sensitization, and negative delayed hypersensitivity skin test) who improved clinically and in terms of delayed hypersensitivity parameters in response to transfer
factor.

ALBINISM AND IMMUNODEFICIENCY

An entity different from the Chediak-Rigashi syndrome has been described
in children from two different families [144a]. This disorder, which is probably
autosomal recessive, is characterized by pigmentary dilution and recurrent
pyogenic infections. Unlike CRS, there are no giant granulocytic inclusions.
The patients were hypogammaglobulinemic, had deficient antibody production, and defective delayed hypersensitivity.
The skin of these patients displayed very large clumps of oval, irregularly
distributed pigment interspersed with normal, regularly distributed melanin
granules. An unusually large number of mature Type IV melanosomes was
observed. Stage I melanosomes were close to the Golgi apparatus, but there
were few Stage II or III melanosomes. Those melanosomes present were slightly
decreased in size and nonaggregated. Only those keratinocytes in direct contact
with melanocytes had melanin granules. No Langerhans cells were observed

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CHAPTER 1

in one patient but a few were found in the other. Skin from two parents and
two siblings of one patient was normal by light and electron microscopy. These
findings together with the presence of a very limited number of dendrites
suggest a transfer defect such as the dilute (d/d) mouse.
Granulocytes were morphologically normal and bactericidal activity was
only moderately reduced. T and B cells were quantitatively normal but studies
suggested defective serum immunoglobulins and diminished antibody production secondary to defective helper function by T cells. Defective distribution
of Con A receptors of polymorphonuclear membrane was observed and could
be corrected in vitro by cyclic GMP or its activators. Unlike CHS, leukocytespecific protease activity was normal.

CROSS-McKUSICK-BREEN SYNDROME
Cross-McKusick-Breen syndrome (CMBS), also referred to as "oculocerebral-hypopigmentation syndrome" [145], "hypopigmentation and microphthalmia" [9], "gingival fibromatosis, hypopigmentation, microphthalmia,
oligophrenia, and athetosis" [146-148], is an extremely rare syndrome originally described in a girl and two boys who were products of multiple consanguinous marriages in an Amish family in Ohio [145]. CMBS is characterized
by extremely blond hair with a slight yellow-gray metallic sheen and by absolutely white skin which is present at birth and is exquisitely sensitive to
sunburn reaction. Lightly pigmented nevi may be present.
Ocular findings include microphthalmia, cloudy corneas, and coarse, jerky
nystagmus. All children by late infancy have opacified and vascular corneas.
All are below the third percentile in height and weight and suffer from severe
mental retardation. By three months of age, the typical patient has developed
writhing motions of the arms and legs, a constant sucking movement, and a
weak high-pitched cry. In general, physical development is so severely retarded
that sitting unassisted is impossible. The eruption ofthe primary teeth [146,147]
is accompanied by development of gingival fibromatosis.
No chemical abnormalities have been detected in urine, serum, or cerebrospinal fluid. Serum tyrosine and phenylalanine levels are in the high normal
range. Routinely prepared formalin-fixed tissue specimens from one child who
died at 12 years of age from inanition and respiratory failure failed to show
abnormal inclusions in the brain, liver, spleen, or bone marrow [149].
Light microscopy reveals no pigment in fresh hair bulbs [9], but L-tyrosine
or L-dopa incubation reveals a weakly positive reaction, demonstrating the
presence of a few melanocytes in the hair bulb. Electron photomicrographs
show a scanty number of melanocytes and these contain small clusters of
melanosomes of all four stages. Incubation in L-tyrosine converts most mel anosomes to fully pigmented Stage IV melanosomes [9,17].
The basic defect in CMBS is unknown. Two features of CMBS-pigmentation and microphthalmia-are seen in mice homozygous for mi/mi (microphthalmia gene). These mice have been described as mock albinos because
of a deficiency of melanocytes [5].

OCULOCUTANEOUS ALBINOIDISM
A few families with a rare form of inh.erited ocular and cutaneous hypopigmentation have been reported [22-24) (Figs. 33, 34). Unlike all forms of
oculocutaneous albinism, oculocutaneous albinoidism is inherited as an autosomal dominant trait, and only rarely do patients have associated nystagmus,
photophobia, and markedly decreased visual acuity. The color of the hair is
white to slightly yellow or reddish tinged, and the skin which is pink-white
is very sensitive to sunburn reaction. Very slight tanning has been reported
[22,24]. L-tyrosine incubation of hair bulbs results in increased pigment [22].
Tangential lighting reveals blue irides and transillumination of the irides shows
a diffuse pattern of pigment distribution which is also present on the retina
[22].

None of the above families exhibited deafness. Other reports of oculocutaneous albinos born to albino parents probably represent pseudodominance
of a recessive oculocutaneous albinism arising from inbreeding [6,9,116,150].

OCULAR ALBINISM
Ocular albinism is most commonly inherited as an X-linked trait in which
only ocular pigmentation is abnormal [25,32,151,152]. In addition to the two
known types of X-linked ocular albinism, the Vogt type [25] and the Forsius-Eriksson type [29], there is a much rarer form of ocular albinism that has
been observed in four families and which appears to be inherited as an autosomal recessive trait [31).

FIGURE 33. Transmission of dominant oculocutaneous hypomelanosisin a family. (From: Quevedo WC Jr et al: Light and skin color, in Sunlight and Man: Normal and Abnormal Photobiologic
Responses. Edited by MA Pathak et al. Copyright, 1974, University of Tokyo Press. Used with
permission. )

89

GENETIC AND
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DISORDERS

90
CHAPTER

FIGURE 34. Oculocutaneous hypomelanosis in a family illustrating a clear dominant trait. The
light-skinned, light-haired, blue-eyed mother and two sons contrast strikingly with the dark-skinned,
dark-haired daughter (not shown) who has dark brown eyes and a marked ability to tan. (From:
Quevedo WC Jr et al: Light and skin color, in Sunlight and Man: Normal and Abnormal Photobiologic Responses. Edited by MA Pathak et al. Copyright. 1974. University of Tokyo Press. Used
with permission.)

Ocular Albinism, X-Linked or Vogt Type [25]

X-linked ocular albinism or hereditary sex-linked nystagmus [153,154) is
characterized by normal or very slightly reduced ocular pigmentation and classically no other pigmentary anomalies [43). However, Hambrick et al. [155)
described a black kindred with X-linked ocular albinism; seven of nine affected
males had congenitally hypopigmented macules.
Among the affected males with reduced iris pigmentation, color may vary
from blue to light green although an occasional patient may show a pattern in
which the pigment is most prominent at the pupillary border. The irides are
diaphanous. Nystagmus, usually horizontal with or without a rotatory component, nearly always presents in the primary position and is more prominent
in the dark-adapted eye exposed to light. Over the years, nystagmus tends to
decrease and the iris color to darken [151). Severe photophobia is usually
present. In about half of the affected males [151], head nodding and head tilting
are prominent features.

Visual acuity is seldom better than 20/100 and usually 20/200 or worse.
However, close vision is barely adequate; most patients are able to read N5 or
N6 type at four to five inches. About 60% also have strabismus. Exotropia is
about four times more common than esotropia [151] in contradistinction to typos albinism in which exactly the opposite prevails [9].
The background of the fundus is pale yellow to pale yellow-orange, not
dead-white as in choroidermia [43,151]. The choroidal vessels are easily visualized. The electroretinogram is usually normal [156].
While heterozygous females generally show minor pigmentary changes in
irides and retina, hemizygous males are severely affected. Females heterozygous
for X-chromosomal ocular albinism usually show only translucent irides and
a mosaic pattern of pigment distribution in the fundus [25-28,124,135,151,
157,158]. The mosaic appearance of the fundus, which has been described as
tigroid, pigment dusting, or "splashes of mud" [26-28]' has been attributed to
a Lyonizing effect [159]. Occasionally, apparent X-linked inheritance has been
observed in a female who then may be affected as severely as a male; nystagmus,
photophobia, and severe iris and fundal hypopigmentation [33,160] are observed. This probably represents the chance selection by nearly all progenitor
optic pigment cells of the X-chromosome bearing the mutant gene as the active
X-chromosome.
Macromelanosomes have been observed in the eyes and the normal skin
of patients with X-linked albinism [160a,160b].
Measurable linkage between ocular albinism and Xg blood group from
combined kindreds estimates the recombination fraction to be 0.15 [161-163].

Ocular Albinism, Forsius-Eriksson Type, or Aland Eye Disease

Ocular albinism or Aland eye disease was described by Forsius and Eriksson [29] who studied an extensive kindred from the Aland Islands in the
Gulf of Bothnia; among the affected families were patients with an X-linked
ocular albinism with clinical features different from those of the more common
X-linked ocular albinism described by Vogt [25]. Compared to the Vogt type
of albinism, the Aland type has less severe hypopigmentation, a higher frequency of protanopic color blindness, and an absence of the mosaic retinal
pigment patterns among female carriers [30,164,165]. However, females may
show latent nystagmus and slight defects in color discrimination. Variable
dyschromatopsia was found within kindreds and was possibly related to the
association of nystagmus to X-linked color blindness [166]. Linkage studies
with Xg blood locus shows a recombination fraction of about 0.12 [167]; thus,
this type may be allelic or pseudoallelic (adjacent locus) to the common form
[165].

Autosomal Recessive Ocular Albinism

Four families with a form of ocular albinism that affects both sexes with
equal severity have been observed [31]. In addition, a number of isolated affected females suspected of having the same disorder have been observed by

91

GENETIC AND
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DISORDERS

92
CHAPTER 1

the same authors. All of the former have normal pigmentation of skin and hair
and a normal hair bulb test. All the expected features of ocular albinismdecreased visual acuity, prominent red reflex, photophobia, nystagmus, strabismus, diaphanous irides, and light yellow fundi-are observed. Except for
diaphanous irides, the fathers have no sign of the disorder. No mosaic pigment
patterns of the fundi are present. The mothers have no history of affected male
relatives. In some cases, parents have been shown to have diaphanous irides
but this has not been detectable in other deeply pigmented families. Two of
the families were Amish and the parents were multiply consanguinous. This
syndrome did not resemble the Ym albinism [70], Cross-McKusick-Breen syndrome [145-147], or ty-neg oculocutaneous albinism which have been described among Amish families. There was no evidence of Turner syndrome in
the affected women; buccal Barr bodies were of normal female pattern and
chromosomal analysis of lymphocytes from one patient revealed a normal female karyotype. A similarly affected female without familial or chromosomal
evidence of X-linkage was described by Scialfa [168]. An autosomal recessive
form of ocular albinism has been described in rabbits [169].
Ocular albinism features a characteristic pigmentary dilution of the iris
and of the fundus. The amount of pigment is reduced but the biochemical
abnormality and the ultrastructural appearance of melanosomes is unknown.
It is possible but not established that a mechanism comparable to that in typos oculocutaneous albinism is operative. The presence of a mosaic pattern of
pigmentation in the fundus of heterozygous females presumably results from
X-inactivation during early embryonic development. Thus, some retinal pigment cells have an active X-chromosome with the recessive ocular albinism
allele, whereas the others have an active X-chromosome containing the normal
allele.

ABNORMALITIES OF THE OPTIC PATHWAY IN ALBINISM

The behavioral [50] and electrophysiologic [170-172] defects in albino
animals have a simple pathophysiology. Whereas usually most of the optic
nerve fibers from the temporal retina remain ipsilateral throughout the optic
tract, in the albino these fibers decussate [173-183]. There is also an abnormal
distribution and arrangement of the optic neurons in the lateral geniculate body
and there are variable defects in the projections from the lateral geniculate body
to the visual cortex [184]. In one ty-pos albino, the lateral geniculate nuclei
were found to be defective in size, orientation, and layered segments [185].
Microscopically, the geniculate ganglia was inapparent and lacked characteristic swelling. Also noted were rotation of the nucleus and abnormal fusions.
These defects occur in any affected albino animal and have been demonstrated
in various mutations of the c locus (tyrosinase locus) in the albino (c/c) guinea
pig [171,175], rat [170,172,178,181,186,187], rabbit [174,182,188], mink [183],
ferret [177], Siamese (cs/CS ) cat [173,176,189-192]' and chinchilla (cch/cch) white
tiger [180]. Such anatomic disorientation of the optic fibers results in lack of
binocular vision. Human studies have shown the defect not to be restricted to
animals with c locus mutations [193].

A similar defect has been described in cats in the geniculate ganglion in

which optic fibers from similar visual fields lie adjacent in two layers and are
projected into the visual cortex in an ordered sequence so as to reflect the order
of the image. Among Siamese cats, fibers from the same visual fields are not
represented in two adjacent layers. Cell groups that receive an abnormal or
crossed input tend to fuse with adjacent layers (which also receive crossed
input), while groups that receive a normal or uncrossed input always remain
distinct [176,177,183).

OTHER DEFECTS IN ALBINOS

Many albinos have strabismus, but there is usually no visual field defect.
Pigmentation is normal in the central nervous system of albinos; neuromelanin is present in both the locus caeruleus and the substantia nigra [63,185).
Mental development is usually normal [194,195). Reports of oligophrenia
probably represent chance associations in consanguinous families.
Albinos who do not assiduously avoid sun exposure from early life develop
chronic actinic skin changes and cutaneous malignancies, often by the end of
the second to third decades.

DIFFERENTIAL DIAGNOSIS
The presence of at least some pigment in skin, hair, and eyes, pigmented
nevi, freckles, and a positive tyrosine incubation test of hair bulbs will distinguish ty-pos from ty-neg albinism. Ym albinos may be more difficult to distinguish, but characteristically they have pigment in hair, skin, and eyes, exhibit
slight sun-induced melanogenesis, and have a negative or faintly positive hair
bulb test. A bleeding diathesis and multisystem abnormal inclusions suggest
HPS. CHS patients have repeated infections, giant peroxidase-positive granules,
a steel-gray sheen to their hair, and, in some cases, abnormal neurologic findings. The CMBS features severe oligophrenia, athetosis, gingival fibromatosis,
and microphthalmia.

TREATMENT OF ALBINISM
There is no treatment for the pigmentary abnormalities in any type of
albino. Psoralen therapy to induce melanogenesis is unlikely to offer significant
solar protection in ty-pos and Ym albinos.
The major problems that confront most albinos are ease of sunburn (Fig.
35), susceptibility to skin cancer, marked photophobia, and decreased visual
acuity. All albinos should be encouraged to avoid sun exposure, particularly
between 10:00 a.m. and 3:00 p.m. in the northern summers. Any sun exposure
should be preceded by application of an effective sunscreen. Albinos should
be checked yearly for skin cancers.
The use of sun glasses (NoIR) will reduce photophobia. In albinos, unlike

93

GENETIC AND
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DISORDERS

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CHAPTER 1

FIGURE 35. Oculocutaneous hypomelanosis in the propositus who complained of marked intolerance to sunlight with increased sunburning. There is dilution of hair, eye, and skin color.
(From Quevedo WC Jr et al: Light and skin color, in Sunlight and Man: Normal and Abnormal
Photobiologic Responses. Edited by MA Pathak et al. Copyright, 1974, University of Tokyo Press.
Used with permission.)

normal persons, early correction of strabismus does not restore binocular vision.
Although distant visual acuity is limited, close vision is good enough that
children, if properly seated in the classroom, generally do better in public
schools than in special schools for the visually handicapped [10].
Genetic counseling should be undertaken in all cases. Patients should be
aware that their children will carry the albinism gene and that marriage to an
albino of the same type will produce albino offspring. Children of an oculocutaneous albinoid have a one in two chance of being affected, even if one
parent is normal.
Caution should be exercised in the administration of aspirin or aspirincontaining medications to HPS patients. Routine platelet aggregation studies
should probably be done in those HPS patients who must use salicylates.
CHS patients will require appropriate antibiotic treatment of infections.
The lymphoma-like stage should be treated with systemic antimetabolites and
corticosteroids.

REFERENCES
Albinism
1. Wafer L: New Voyage and Description of the Isthmus of America, Giving an Account of the
Author's Abode There. London, 1699, p 134 (Cited by Pearson K et al: A Monograph on
Albinism in Man. Drapers' Company Research Memoirs, Biometric Series VI, Part I. London,
Dulau, 1911-1913, pp 17-18
2. Little CC: Coat color genes in rodents and carnivores. Q Rev BioI 33:103-317, 1958
3. Noble GK: The Biology of the Amphibia. New York, Dover, 1954, p 577
4. Searle AG: Comparative Genetics of Coat Colour in Mammals. London, Logos (New York,
Academic),1968
5. Shufeldt RW: Albinism in American animals. Proc Zool Soc Lond, p 540, 1916
6. Pearson K et al: A Monograph on Albinism in Man. Drapers' Company Research Memoirs,
Biometric Series VI, VIII, IX, Parts I, II, IV. London, Dulau, 1911-1913
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184. Kupfer C et al: Quantitative histology of optic nerve, optic tract, and lateral geniculate nucleus
of man. J Anat 101:393-401, 1967
185. Guillery RW et al: Abnormal visual pathways in the brain of a human albino. Brain Res
96:373-377,1975
186. Creel DJ, Sheridan CL: Monocular acquisition and interocular transfer in albino rats with
unilateral striate ablations. Psychonomic Science 6:89-90, 1966
187. Cunningham TJ, Lund RD: Laminar patterns in the dorsal division of the lateral geniculate
nucleus of the rat. Brain Res 34:394-397, 1971
188. Giolli RA, Guthrie MD: Organization of subcortical projections of visual areas I and II in the
rabbit. An experimental degeneration study. J Comp NeuroI142:351-376, 1971
189. Creel DJ: Differences of ipsilateral and contralateral visually evoked responses in the cat:
strains compared. J Comp Physiol Psychol 77:161-165, 1971
190. Guillery RW, Kaas JH: A study of normal and congenitally abnormal retinogeniculate projections in cats. J Comp NeuroI143:73-99, 1971

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191. Kaas JH, Guillery RW: The transfer of abnormal visual field representations from the dorsallateral geniculate nucleus to the visual cortex in Siamese cats. Brain Res 59:61-95, 1973
192. Kalil RE et al: Anomalous retinal pathways in the Siamese cat: an inadequate substrate for
normal binocular vision. Science 174:302-305, 1971
193. Creel 0 et al: Asymmetric visually evoked potentials in human albinos: evidence for visual

system anomalies. Invest OphthalmolI3:430-440, 1974

194. Beckham AS: Albinism in Negro children. J Genet Psychol 69:199-215, 1946
195. Stewart HF Jr, Keeler CE: A comparison of the intelligence and personality of moon-child

albino and control Cuna Indians. J Genet Psycholl06:319-324, 1965

SECTION 2. DISORDERS WITH RELATIVE GENERALIZED

DECREASED PIGMENTATION
COPPER DEFICIENCY
Although copper deficiency alone is not hereditary, discussion of this
entity is necessary to the understanding of Menkes kinky hair syndrome, which
results from hereditary copper deficiency.
Cunningham [1], in 1931, first described the active role of copper in the
tyrosinase system. That copper is essential for mammalian tyrosinase activity
was shown by Lerner et al. [2], and it is now clear that tyrosinase is a coppercontaining enzyme. Defective copper metabolism, albeit rare in animals and
humans, could be expected to result in pigmentary disturbances and to provide
a useful model for the study of the role of copper in the synthesis of melanin.
Copper deficiency may be either acquired (nutritional deficiency) or hereditary.

Copper Deficiency in Infants and Nutritional Deficiency

Copper deficiencies in humans is usually a concomitant of multiple nutritional deficiencies. Most reports contain no mention of hair and skin depigmentation [3-5]. The first report in 1971 [6] of an isolated copper-deficiency
syndrome in a premature infant likewise contains no mention of hair or skin
depigmentation. In 1973, Ashkenazi et al. [7] reported a six-month-old premature "pale," fair-haired, almost albino infant with central nervous system
abnormalities (hypotonia, psychomotor retardation, difficulties with sight), long
bone changes (osteoporosis with blurring and cupping of the metaphyses), and
sideroblastic anemia resistant to therapy other than copper (with vacuolation
of erythroid and myeloid bone marrow cells and iron depletion in the vacuoles
and in some mitochondria). No skin biopsy was performed. Copper deficiency
was confirmed by low blood copper levels and markedly decreased blood ceruloplasmin level. Copper therapy resulted in dramatic clinical and hematologic
improvement. There is no mention that the therapy resulted in any changes of
hair or skin pigmentation.
Although there are insufficient reports to characterize accurately this syndrome, Ashkenazi et al. [7], on the basis of human clinical and experimental
observations, proposed the features listed in Table 18. Hypopigmentation of
skin and hair seems to accompany copper deficiency in humans.
Depigmentation of the hair has been reported in many copper-deficient

TABLE 18. Copper Deficiency in Infanls a

Occurrence
Small premature infants
Newborn on prolonged intravenous alimentation
Secondary to malnutrition and kwashiorkor
Symptoms
Failure to thrive
Apathy
Signs
Hypotonia
Hypothermia
Psychomotor retardation
Impairment of vision
Enlarged veins and tortuous arteries
Hypopigmented skin and hair
Osteoporosis with metaphyseal flaring, cupping, and spurs
Seborrheic dermatitis
Laboratory
Anemia: hypochromic, unresponsive to iron therapy
Leukopenia (segmentopenia)
Bone marrow: sideroblasts, vacuolization of erythroid and
myeloid cells
Low serum copper and ceruloplasmin
Impaired ferrokinetics (utilization of iron)
a

Source: Ashkenazi A et al: The syndrome of neonatal copper deficiency.

Pediatrics 52:525-533, 1973. Copyright, 1973, American Academy of Pediatrics. Used with permission.

animals [8]: rats [9-11], guinea pigs [12], rabbits [9,13]' cats [9], cattle [14],
goats [14], and sheep [15], Although the exact mechanism of depigmentation
is unknown, there is evidence that pantothenic acid may be directly involved
in copper metabolism. Pantothenic acid-deficient rats that have depigmented
skin have a cutaneous copper concentration five times normal [16], Furthermore, addition of either copper or pantothenic acid restores normal pigmentation in depigmented rats subsisting on copper-deficient diets [17], The evidence suggests that the presence of pantothenic acid is essential to the catalytic
role of copper in the skin melanogenesis. Pantothenic acid may be important
in the binding of copper to the protein moiety of tyrosinase [17].

Hereditary Copper Deficiency (Menkes Kinky Hair Syndrome [18],

Trichopoliodystrophy [19,20])
In 1962, Menkes et al. [18] described five boys with a sex-linked disorder
characterized by growth retardation, hair abnormalities, and focal and cerebellar degeneration. Since that time, 25 additional cases have been described
in the literature [18,19,21-29]. Increased blood levels of glutamic acid have
been reported in this disease [18,29]' but not by all investigators. Danks et al.
[25,30] reported decreased levels of serum copper and ceruloplasmin as well

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104
CHAPTER 1

as decreased hepatic copper levels in children with kinky hair disease. Experimental studies implicated a defect in copper absorption [25] from the small
intestine secondary either to inadequate intracellular transport or to a defect
in migration across intestinal mucosa [31]. Furthermore, Danks et al. [32] found
that fibroblastic skin cultures of both hemizygote and heterozygote patients
develop metachromasia which clears on serial cultures. They considered this,
which may be related to the high copper content of the calf serum used in the
culture medium, to be characteristic of cells with the kinky hair gene [31].
O'Brien et al. [33] found lipid abnormalities in the gray matter of the brain but
were unable to relate this to the pathogenesis of Menkes kinky hair syndrome.
Similar copper concentrations in affected and unaffected brains have been
demonstrated [34]. Administration of oral or parenteral copper do not appear
to reverse the syndrome [24,35].
Pigmentary Dilution in Menkes Kinky Hair Syndrome

Although pigmentary abnormalities are not universal features of Menkes

kinky hair syndrome, hypopigmentation occurs frequently. Menkes et al. [18]
found sparse, coarse, and stubby scalp hair "devoid of pigment" in a six-weekold patient. At four months of age, the scalp hair remained poorly formed,
sparse, wiry, and depigmented. In other reports, the hair is reported to be
"almost colorless" [25], "ivory in color" [23], "devoid of proper pigment" [26],
("white" [22,36] or "whitish blonde" [19]). Aguilar et al. [21] noted that the
coarse, black, kinky hair present in the first few months had faded to brown
by about four months. Witkop [37] noted in 1971 that all reported children,
whether born with black, brown, or white hair, had ivory-white hair by the age
of six weeks.
Decreased cutaneous depigmentation has also been noted [26]. Volpintesta
[27] reported a black infant whose light-colored skin was much fairer than that
of his dark-skinned parents. This patient's sister, heterozygous for Menkes
syndrome, had blotchy depigmentation of the skin but normal serum copper
levels.
Biopsy of a section of occipital scalp [18] showed the papillae, hair follicles,
and hair to be devoid of pigment; only a few cells in the hair follicles gave a
positive dopa reaction. Witkop [37] reported a hair test to be tyrosinase-positive.
Amino acid analysis of hair hydrolysates have generally been normal [19,31],
but Danks et al. [31] found a ninefold increase in the free sulfhydryl content
of the hair of two patients. Singh and Bresnan [26] reported low copper levels
in hair, but this was not a constant finding because the copper was normal at
nine months and abnormal at 11 months of age.
Pathogenesis

Hypopigmentation probably results from enzymatic (tyrosinase) dysfunction secondary to copper deficiency. This functional disturbance may be related
to covalent bonding of copper by the increased sulfhydryl groups found in
Menkes kinky hair syndrome.
There is an animal model for Menkes kinky hair syndrome. Hunt [38]
described a primary defect of copper transport in mottled mouse mutants (Mobr)

105

GENETIC AND
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DISORDERS

FIGURE 36. Severe pigmentary dilution in an Mobr male mouse. (From: Hunt DM: Primary defect
in copper transport underlies mottled mutants in the mouse. Nature 249:852-854, 1974. Copyright,
1974, MacMillan Journals, Ltd. Used with permission.)

(Fig. 36). Danks [39] concluded there is defective transport of copper from the
serum to the intracellular site of tyrosinase activity. A number of different
mutant alleles at the "mottled locus" are known. If the male hemizygote survives
beyond birth, there is a severe pigmentary dilution. All individual hairs are
pigmented at the ends. The hair structure is altered and the whiskers are curly.
Phenotype variation from random X inactivation in a female to an X-linked
coat color mutant depends on the cell autonomy of the mutant defect. This
varied appearance of the mottled heterozygote therefore suggests the presence
of a copper-transport defect in the follicle and pigment cells of the skin [38].
Copper-deficient cells would be expected to be at a selective disadvantage in
competition with their normal counterparts, resulting in progressive dilution
of mutant cells during development. The depigmented patches are clones of
cells in which chromosomes carrying the normal alleles are inactivated so that
only the mutant gene is active. The progressive darkening of Mobr heterozygotes
with age is consistent with the hypothesis.
Histology and Electron Microscopy
Epidermal and follicular melanocytes show decreased dopa oxidase activity. Ultrastructurally there is a decrease in the number of Stage III and IV
melanosomes, suggesting an impairment of their melanization [39a].
Other Features in Menkes Kinky Hair Syndrome
Menkes kinky hair syndrome has been associated with the abnormalities
summarized in Table 19.
Diagnosis and Treatment
The diagnosis of Menkes kinky hair syndrome must be based on clinical
findings; the pigmentary dilution is a nonspecific finding.

106

CHAPTER 1

TABLE 19. Systemic Features in Menkes Kinky Hair Syndrome

Central nervous system abnormalities
Seizures (minor or major motor, focal) [18,19,21-28)
Pyramidal signs (spasticity, hyperreflexia, quadriparesis) [18,19,21,23-25,28,29)
Hypotonicity [18,19,22,26,28,36)
Nystagmus [18,27,36)
Mental retardation or regression [18,19,21-29,36)
Failure to thrive [18,22,28,36)
EEG abnormalities [18,19,21-23,27-29,36)
Subdural hematomas [18,21,25); subdural "hydromas" [29]
Pneumoencephalogram abnormalities [18,21,22,29,36)
Cerebral and cerebellar atrophy [18,21,25,28)
Ocular abnormalities
Microcysts in the pigment epithelium of the iris [40)
Decreased number of ganglion cells in the retina [40)
Optic disc dysplasia [24)
Retinal and iridal changes [19)
Electroretinogram abnormalities [19,22,27)
Skeletal changes
Micrognathia [12,18); occipital and parietal prominences [22); frontal prominences [24); left
parietal prominence [19); pectus excavatum [17-22); pectus carinatum [36); bilateral
equinovarus deformities [18); club feet [18); premature closing of lambdoidal suture [18)
High arched palate [18,19,22,26,36)
Metaphyseal spurring of long bones [21,22,25-28,36)
Wormian bones [19,25,26,28)
Flaring of ribs [21,22,25,26,28,36)
Diaphyseal periostal reaction [21,26,28,36)
Vascular abnormalities
Increased tortuosity of cerebral arteries [21,26,28) or systemic arteries [25,26,28)
Growth retardation [18,21,22,26,29)
Hair abnormalities
Pili torti [18,19,21,22,25-28,36]
Trichorrhexis nodosa [18,19,25,26,36)
Monilethrix [18,21-23,26,28]
Unspecified [24,29]
Hypothermia [19,24,25,27,36]
Anorexia and difficulty with feeding [25,28)
Vomiting [18,19,25,28); diarrhea [19,22,25,26,36); constipation [19,21,28)
Hepatomegaly [23]; splenomegaly [22,23)
Increased susceptibility to infectious processes
Pulmonary [19,21,25,28,36); urinary [25); septicemia [25,28)
Oral moniliasis [19)
Cutaneous signs
Hypopigmented hair [19,21-23,25,28)
Hypopigmented skin [27)
Seborrheic dermatitis [25) or other dermatitis [25,27); dry skin [36)
(Continued)

TABLE 19. (continued)

Miscellaneous
Noneruptive teeth [18,22]
Segmental atelectasis of the right upper lobe [22]
Right inguinal hernia [24]
Hiatus hernia [18]
Laboratory findings
Hypochromic anemia [28)
Low blood copper [25-27,36)
Low urinary copper [26]
Low blood ceruloplasmin [18,25-27]
Premature death
(between 3! and 21 months) [18,19,21,23,25)

In the light of the findings of Danks et al. [25,31,32,35,39) and of observations in animals, Menkes kinky hair syndrome appears associated with copper deficiency. However, copper supplement does not appear helpful. No effective treatment is available.

HISTIDINEMIA
Histidinemia is a rare autosomal recessive inborn error of histidine metabolism. It was first described in 1961 by Ghadimi, Partington, and Hunter
[41) in two sisters with elevated blood and urinary histidine levels. Neville et
al. [42), in 1972, found 42 reported cases in a survey of the literature. In 1962,
Auerbach et al. [43) identified a patient with imidazolepyruvic, imidazoleacetic,
and imidazolelactic acids in the urine and attributed the positive ferric chloride
test to the presence of imidazolepyruvic acid accumulated because of the absence of histidase. Histidase deficiency has been demonstrated in the skin by
Ladu et al. [44), and in the liver by Auerbach et al. [45).

Pigmentary Disturbances in Histidinemia

Patients with histidinemia are described as having blond hair, fair skin,
and blue eyes [46). Of the 42 reported patients collected by Neville et al. [42),
10 had blue eyes, and seven brown or light brown eyes. Five had fair skin. Ten
had fair hair, and two had hair described as "reddish." However, in many
papers the color of eyes or depth of pigmentation of skin has not been mentioned
[47).

One three-year-old boy described by Woody et al. [46) had a few areas of
cutaneous depigmentation over the left flank and scalp suggestive of tuberous
sclerosis.

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GENETIC AND
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DISORDERS

TABLE 20. Other Features in Histidinemia (in 42 Cases)Q

108
CHAPTER 1

CNS abnormalities
Mental retardation (23/42 cases)
Speech difficulties (18/42)
Convulsions (6/42)
Ataxia (3/42)
Infantile psychosis (2/42)
Tremor of the hands (1/42)
Emotional disturbance (1/42)
Signs of degenerative brain disease (1/42)
Abnormal behavior and short attention span (1/42)
Other features
Small stature (1/42 cases)
Recurrent infections (1/42)
Anemia (3/42) or congenital hypoplastic anemia (1/42)
Proteinuria (1/42)
Blond or fair hair (10/42), fair skin (5/42), and blue eyes (10142)
a

From: Neville BGR et al: Histidinemia. Study of relation between clinical and
biological findings in seven subjects. Arch Dis Child 47:190-200, 1972.

Other Clinical Features in Histidinemia

See Table 20.

Biochemical Features
The biochemical features of histidinemia include elevated blood and urinary histidine levels, a positive urinary ferric chloride test, and defective histidase activity in the skin and liver.

Diagnosis
Some authors consider the triad of fair hair, blue eyes, and mental retardation as highly suggestive of the diagnosis of histidinemia. The diagnosis must
be confirmed by biochemical assays.

Treatment
By analogy with other inborn errors of metabolism, treatment with a low
histidine diet has been undertaken as a trial to attempt to prevent permanent
eNS damage and other changes, but at the present time the success of this
treatment is unknown.

PHENYLKETONURIA
Phenylketonuria (PKU) is an autosomal recessive disorder of phenylalanine
metabolism characterized by mental retardation and pigmentary dilution of
skin, hair, and eyes (Fig. 37). Hypomelanosis in PKU is one of the rare pigmentary diseases for which a specific biochemical defect is known-there is a
deficiency of phenylalanine hydroxylase. Since phenylalanine normally is metabolized to tyrosine, a melanin precursor, this disease is central to interest in
pigmentation.
Today in many areas, mass biochemical neonatal screening is used to
diagnose the disease so as to institute effective treatment before irreversible
mental retardation develops.

History
In 1934 F~lling [48] first described PKU in 10 patients, including several
siblings, discovered in a survey of 430 mentally retarded patients in Norway.
F~lling discovered phenylpyruvic acid in the urine of these patients and coined
the term "imbecillitas phenylpyruvica" for this disease. Various other terms
used to refer to this disease include "phenylpyruvic amentia" and "phenylpyruvic oligophrenia." In 1937, Penrose and Quastel [49] introduced the now
universally accepted name "phenylketonuria. " In 1939, Jervis [50] recognized
PKU to be an autosomal recessive trait.

FIGURE 37. The hair of this Japanese child with

phenylketonuria is lighter in color than that of his
mother (background), (Courtesy of M. Seiji, M.D.)

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GENETIC AND
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110

CHAPTER 1

Clinical Features
Incidence

There have been various estimates of the frequency of PKU. Jervis [51]
estimated the general incidence in the United States to be 4/100,000. Nearly
the same frequency (1/24,000) was reported by Knox [52]. An incidence of
2/100,000 has beenreportedin England [53], whereas 3.5/100,000 is the reported
incidence in Sweden [54]. Other estimates vary from 5.3/100,000 in Israel to
22.2/100,000 in Ireland [55]. Considered together, the average frequency calculated from 12,412,716 individuals is 8.5/100,000.
Among institutionalized mentally retarded individuals, the incidence of
PKU is estimated to be 0.64% [51].
Race

Although PKU seems most common in Northern Europeans or Scandinavians [51], the disease is not restricted to anyone ethnic group. PKU has been
reported in Mongoloids [56-58] as well as in blacks [59,60]. However, the
incidence of PKU in American blacks and Indians is much lower than one
would expect [55]. In Israel, PKU is rare among Ashkenazi Jews, but it occurs
in Oriental (Yemenite) Jews [61].
Sex

Males and females are equally affected. Among 465 cases of PKU, 51%
were females and 49% were males [50].
Heredity

Familial cases were present (three sibling pairs) in the initial description
of the disease by F~lling [48]. Jervis [51] later recognized the disease to be
autosomal recessive. Parental consanguinity is frequently observed.

Pigmentary Dilution in PKU

F~lling [48,62] first observed a dilution of skin, hair, and eye color in
phenylketonuric patients and interpreted this as evidence of pleiotropism of
the gene. He speculated that it might be linked to the ordinary recessive gene
for blue eyes. Although his hypothesis has not been proved correct, his basic
observation, namely blond hair, blue eyes, and fair skin, is now considered
characteristic of PKU. Jervis [51] reported in one of the largest series of patients
that 90% were "fair-haired and fair-skinned with light blue eyes" (Fig. 38).
Knox [52] reported that 62% of patients with PKU have blond hair and blue
eyes. However, the pigmentary dilution is such that it may become apparent
only when affected individuals are compared with unaffected relatives or controls.

111

GENETIC AND
CONGENITAL
DISORDERS

FIGURE 38. Lighter color of hair

in a patient with PKU.

Although the hair color in PKU spans the spectrum from light blond to
dark brown [49], blond hair predominates in most series (Figs. 39, 40). All the
23 cases of Fleisher and Zeligman [63] had blond hair. Jervis [60] found blond
hair in 86% of his patients. Paine [64] observed 60% of patients with PKU to
have blond hair and the remainder light brown or brown hair. Cowie [65]
observed that 14 of his patients had either red or fair hair, the darkest hair
being medium brown in color. Only eight of the 17 cases reported by Hassel
and Brunsting [66] had blond hair. Hair darkening with age does occur.
There are several striking examples of this hair pigmentary dilution. Jervis
[60] described "an idiot baby with blond hair and blue eyes who belonged to
a family of Sicilian extraction, all members of which, for at least three generations, were dark-haired." Turpin et al. [67] reported a strikingly blond patient
in a family of darkly pigmented Spaniards. In the Japanese, PKU is associated
with dark brown hair color which is distinguished from the normal black color
of Japanese hair [68] (Fig. 40). Stadler et al. [69] also observed a PKU mulatto
with sandy blond hair.
Objective evidence of hair pigmentary dilution has been obtained. Penrose
et al. [70] and Cowie and Penrose [71], by reflectance spectrophotometry, consistently demonstrated a pigment dilution of hair in PKU patients compared
with unaffected relatives.
Light skin or fair skin is associated with pigmentary dilution of hair. Jervis
[60] noted that most of his patients had fair skin. Gibson [72] reported a pallid
complexion in six of his seven cases. Fourteen of the 15 patients of Cowie's
series [65] were fair-skinned, as were the 23 cases reported by Fleisher and
Zeligman [63].
Photosensitivity was observed in a 22-year-old New Zealand female with
PKU [73]. Epstein [74] classified PKU as a disease with photosensitivity because

112
CHAPTER 1

FIGURE 39. Difference in color between the hair of an affected child (a) and that of a normal
control (b). (Courtesy of M. Seiji, M,D.)

113

GENETIC AND
CONGENITAL
DISORDERS

FIGURE 40. Lighter hair color in children with PKU compared to that of normal mother.

of deficient photoprotection. Fitzpatrick and Mihm [75], quoting 1. I. Woolf,

related an interesting story about F~lling and the question of photosensitivity
in PKU. Apparently, when F~lling visited an institution for mental defectives,
in order to locate those with PKU, he would first ask to see all the children
who sunburned easily. That some tanning reaction can, however, occur was
demonstrated by Hassel and Brunsting [66] who exposed six patients with PKU
to hot quartz ultraviolet light and observed delayed pigment darkening to follow.
Pigmentary dilution also affects the eye in PKU. Berg and Stern [76] demonstrated a significantly lighter iris color in PKU patients than in controls or
unaffected siblings. Sixty-six percent of the 50 cases reported by Jervis [60]
and 77% of the 17 observed by Hassel and Brunsting [66] had blue eyes. Paine
[64] reported 64% to have blue eyes and 17% to have brown eyes. Blue irides
were also found in 13 of 14 patients by Cowie [65], and in 19 of 23 patients
by Fleisher and Zeligman [63]. Another case of blue eyes has been reported in
a mulatto [69].
Not all patients have pigmentary dilution. However, it has been postulated
that in PKU "the lighter the complexion, the lower the I.Q." One of the patients
reported by Cowie [65] and subsequently described by Cowie and Brandon [77]
seemed to support this assessment. Although the patient undoubtedly had PKU,

114
CHAPTER 1

he had dark brown hair, olive skin, almost black irides, average intelligence,
and none of the other features characteristic of PKU. The metabolic disturbance
was mild and the plasma level of phenylalanine was 15 mg per 100 ml. Coates
et al. [78] also reported a case with medium brown hair and high I.Q. In this
patient, the excretion of phenylpyruvic acid was about 25% less than in other
patients with PKU. These two cases suggest that the correlation of normal hair
color with normal intelligence is not happenstance; there is either a lower
concentration of some inhibiting substance or a greater resistance to inhibition
of the chemical reactions needed for melanin formation and for the transmission
of neural impulses. However, Paine [64] and Schanenberg et al. [79] could not
correlate hair and eye color and intelligence levels [64,79]' although in neither
of two studies reported was the color dilution established by a comparison of
the hair and eye color to that of siblings. Neither were Berg and Stern [76] able
to relate the I.Q. of phenylketonuric patients to the iris pigmentary dilution.
In general, it has not been possible to correlate pigmentary dilution and mentation.
Lack of pigmentation in the normally pigmented areas of the brain, such
as the substantia nigra and locus ceruleus, has also been reported in phenylketonuric patients [80,81].

Histology and Electron Microscopy

Standard hematoxylin and eosin preparations show normal skin or mildly
eczematous changes. Split dopa studies show a normal or decreased number
of melanocytes, which appear stubby.
Electron microscopy studies of the skin in PKU [82] showed a decreased
number of melanocytes and a few mature melanosomes in the melanocytes.

Other Clinical Features in PKU

Neurologic Changes

A variety of neurologic and behavioral manifestations appear later in life

in a majority of untreated patients. These include the following clinical features
[52]:

Mental retardation
Agitation
Seizures and EEG abnormalities
Muscular hypertonicity
Microcephaly
Hyperactive reflexes
Inability to talk
Hyperkinesis
Inability to walk
Incontinence
Tremors

The brain is critically affected in PKU. Brain weight is reduced and there
is defective myelinization. The biochemical basis for this is not clearly understood, but it is possible that a combination of biochemical events rather than
a single one is responsible for the brain damage. A low phenylalanine diet, if
instituted within the first few years of life, can prevent intellectual impairment
or may reverse recently established impairment [83-87]. This suggests that the
phenylketonuric infant is normal at birth. The retardation begins in the first
months of life and become progressively more severe. Later, the retardation
becomes irreversible.
Growth retardation, decreased birth weight, and reduced life expectancy
are characteristic of untreated PKU.
Skin Lesions

Dermatographism [62,72,88] and acrocyanosis or poor peripheral circulation [60] have been frequently mentioned. Scleroderma-like changes have
been observed in patients with PKU [89].
Multiple nerve tumors [90], pigmented nevi, melanotic macules [66], and
cafe-au-lait spots are also seen though not necessarily with significant frequency
[63].
F~lling [48] and Jervis [60] stressed the description of skin disorders "consisting of more or less diffuse eczema." Jervis observed diffuse patches of eczema
in over half of his cases reported in 1937. Examination of patients with PKU
by F~lling [62] failed to establish any connection between the "skin affections"
and the metabolic disorder. Fleisher and Zeligman [63] found atopic dermatitis
in three of 23 patients with PKU and in none of 21 controls. However, these
authors could not draw any definite conclusions from their small population.

Miscellaneous Clinical Findings

A large number of other abnormalities have been described, each in a small

number of patients and most of them probably casual associations. They include
the following: kyphosis, pes planus, spina bifida, syndactylia of toes, intraventricular conduction defect, hypogonadism, hypersegmentation of neutrophils, decreased galactose tolerance, increased basal metabolism and widely
spaced incisors and epicanthal folds [52].
An indisputable smell, described as a "musty," "mousey," "wolflike," or
"mulberry" odor of the urine and the sweat has been described in many patients.

Diagnosis
Knox and Hsia [91] said, "few human diseases are so uniformly and precisely identifiable as PKU." The clinical picture of untreated PKU is characteristic. However, awaiting the typical clinical picture often means irreversible
mental retardation.
Several methods have been used for early diagnosis and mass screening
for PKU. Addition of ferric chloride to urine containing phenylpyruvic acid

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DISORDERS

116

CHAPTER 1

imparts a bluish-green discoloration [48]. However, when urine testing for

phenylpyruvic acid and its derivatives is used as the only basis for screening
[92], the diagnosis will be missed in one-quarter to one-half of infants with
PKU.
Several methods (bacterial inhibition assay, fluorometric methods, partition chromatographic methods) are used for blood screening to detect hyperphenylalanemic states [55] .
Identification of heterozygotes is of value for genetic counseling. Two types
of investigations are used with variable accuracy and efficiency [55]:
1. A phenylalanine loading test may be used to challenge the reduced
capacity of phenylalanine hydroxylation in the heterozygote (oral or intravenous loading test).
2. Measurements of steady-state levels of phenylalanine and tyrosine in
plasma under carefully controlled conditions may reveal an increased phenylalanine/tyrosine ratio.

Enzymatic Defect and Biochemical Features in PKU

In PKU there is a single metabolic block in the conversion of phenylalanine
to tyrosine (Fig. 41). F~lling [48], who first isolated and identified phenylpyruvic acid in the urine of PKU patients, later found elevated phenylalanine
DIETARY

PROTE IN

NORMAL

DIETARY

PROTEIN

PHENYLKETONURI A

Pheny l aceric ac i d
p- OH ' Phe nylacltic acid

FIGURE 41. Scheme of pathogenesis of hypomelanosis of hair in phenylketonuria. (From:

Fitzpatrick TB, Mihm Me Jr: Abnormalities in the melanin pigmentary system, in Dermatology in
General Medicine. Edited by TB Fitzpatrick et al. New York, McGraw-Hill, 1971, pp 1591-1637.
Copyright, 1971, McGraw-Hill Book Company. Used with permission.)

levels in the serum and the urine. Jervis [93] demonstrated that there is a lack
of transient rise of the serum tyrosine levels in phenylketonuric patients after
phenylalanine loading; he concluded that phenylalanine is the primary metabolite that accumulates. With in vitro liver studies he further demonstrated
that there is a lack of phenylalanine hydroxylation. Phenylalanine to tyrosine
conversion was often found to be less than 10% of that expected. Mitoma et
al. [94], Wallace et al. [95], and Kaufman [96] showed that the deficiency
involved the labile hepatic enzyme, phenylalanine hydroxylase, and not the
cofactor system. This was confirmed by Justice et al. [97] and Friedman et al.
[98]. There is now no question that the inactivity of phenylalanine hydroxylase,
which normally catalyzes the oxidation of L-phenylalanine to L-tyrosine, is the
primary phenotypic defect in PKU.
The chemical consequences of such a metabolic block are extensive. Phenylalanine accumulates in body fluids so long as constant dietary intake continues. In PKU, the plasma phenylalanine concentration typically exceeds 16.5
mg per 100 ml and may reach as high as 90 mg per 100 ml [75]. There is a
relative deficiency of tyrosine, which becomes an essential dietary amino acid.
Also, numerous aromatic compounds accumulate and are found in abnormally
high amounts in the blood and the urine [75]. These include various derivatives
of phenylalanine, namely, phenylpyruvic acid, phenyllactic acid, phenylacetic
acid, and acetylglutamine. Aromatic compounds accumulate in much smaller
amounts than do phenylalanine, and their degradation products include derivatives of tyrosine: p-hydroxyphenylpyruvic acid, p-hydroxyphenyllactic acid,
p-hydroxyphenylacetic acid, a-tyrosine, a-hydroxyphenylpyruvic acid, 0hydroxyphenylacetic acid, and tryptophan breakdown products, indoleacetic
acid and indolelactic acid.

Pathogenesis of Melanin Hypopigmentation in PKU

Dalgliesh [99], in 1955, advanced three possible hypotheses to explain the
decreased melanin formation in PKU: either there is (1) an absence or decrease
in the melanin precursor, tyrosine; (2) an absence or decreased amount of
tyrosinase in the melanocytes; or (3) inhibition of the tyrosine to melanin
reaction by phenylalanine or other metabolites that accumulate.
Since there are some melanosomes in the melanocytes of PKU skin and
PKU patients may tan [66], the tyrosine deficiency concept alone is not favored.
Much evidence, in fact, favors the third mechanism. Darkening of hair color
is associated with the return of blood phenylalanine and presumably tissue
phenylalanine levels to normal in PKU patients receiving a low phenylalanine
diet [86,100-104]. In one series, a definite darkening of hair color was observed
in 42% of PKU patients maintained on diets low in phenylalanine [86] over a
period of eight to 12 months. Bickel et al. [101,102] reported darkening of hair
color in a few weeks from "a fair to a dark brown color" in one of their patients.
While lowering the serum phenylalanine levels causes the PKU hair to
darken, raising the serum tyrosine level induces the same phenomenon. Snydermann et al. [105] found that the oral administration of 1 g of tyrosine per
kg of body weight per day caused the blond hair to become dark brown in PKU

117

GENETIC AND
CONGENITAL
DISORDERS

118

CHAPTER 1

patients. This suggested a relative tyrosine deficiency at the melanocyte level

or a competitive inhibition of tyrosinase by phenylalanine or phenylalanine
degradation products circulating in the blood of patients with PKU.
In 1955 Dancis and Balis [106] showed mushroom tyrosinase in vitro inhibition by a concentration of phenylalanine 10 times that of tyrosine. This
suggested that phenylalanine and tyrosine, which are structurally similar, compete for tyrosinase. With large amounts of phenylalanine and relatively small
amounts of tyrosine, most of the tyrosinase is inactivated by phenylalanine,
and only a small amount is available for tyrosine. Even with normal amounts
of tyrosinase, melanogenesis is inhibited in such a system. This hypothesis
explains the restoration of melanin synthesis either by lowering the concentration of serum phenylalanine or by increasing the concentration of serum
tyrosine.
Miyamoto and Fitzpatrick [107] also demonstrated the inhibition of melanin formation by phenylalanine and other aromatic metabolites with the use
of mammalian tyrosinase and L-phenylalanine at the same concentration as
that in the blood of patients with PKU. However, both the enzyme (tyrosinase)
and the substrate (tyrosine) are present in the melanocyte in much smaller
concentrations than used in the in vitro studies. Hence, a greater inhibition by
L-phenylalanine might be expected in vivo. Boylen and Quastel [108] provided
evidence that the phenylalanine concentration in PKU is adequate to inhibit
melanin formation. The other abnormal aromatic metabolites in the blood in
this disease occur in such low concentrations that it is unlikely that they are
significant to the decreased melanogenesis. For example, the level of phenylpyruvic acid in the blood of patients is reported to be 0.31 to 1.78 mg per 100
ml (1.89 x 10-5 to 1.09 X 10-4 M) and at this range virtually no inhibition is
observed. Hassel and Brunsting [66], by incubation of ultraviolet-irradiated skin
of PKU patients in tyrosine solutions, showed that restoration of a favorable
tyrosine to tyrosinase ratio leads to normal melanin synthesis.
Phenylalanine reversibly inhibits melanin formation in isolates of embryonal dorsal skin from chicks [109]. Media containing 25 x 10-5 to 100 X
10-5 M phenylalanine inhibited melanin formation, and this effect was reversed
in the presence of a tyrosine excess. Apparently, the chick embryo is able to
metabolize large amounts of phenylalanine in vivo, inasmuch as Seiji and
Fitzpatrick (unpublished data) were unable to inhibit melanogenesis in feathers
of Black Minorca chick embryos after injection of fairly large concentrations
(10-2 M) of L-phenylalanine into the yolk sac on the fifth day of development.
All these experiments support the conclusion that the increased L-phenylalanine in the extracellular fluid is the single most important factor responsible
for the decreased melanin pigmentation in PKU and that the other metabolites
have only a slight, if any, influence on melanin formation in vivo.
The mechanism of decreased melanin formation in the hair bulb in PKU
is schematically shown in Figure 41. It has also been suggested that phenylalanine may be a regulatory factor in normal melanin formation. If the activity
of tyrosinase is a function of the quantity of enzyme, then its rate of synthesis
will be a major factor in pigmentation. It is possible that phenylalanine by its
tyrosinase inhibitory role may control the rate of synthesis of tyrosinase. Riley
[110] suggested that perhaps the hypopigmentation of PKU is a combination

of a repressor and a competitive inhibitor effect. However, this has not yet been
possible to establish in vivo.

Treatment
The only practical mode of therapy of PKU is restriction of dietary phenylalanine. Pigment darkening occurs with treatment in most of the patients and
is best observed at the zone of new growth at the hair roots. With the exception
of structural defects and severe brain damage, most of the signs of PKU are
ameliorated by treatment. Mental retardation, once apparent, is largely irreversible, but is perfectly preventable by physician awareness, mass PKU screening programs, and early dietary restriction.

DISORDERS OF METHIONINE METABOLISM

Homocystinuria
Homocystinuria, first described in 1962 by Field et al. [111], is an autosomal
recessive inborn error of metabolism of methionine which is an essential sulfurcontaining amino acid. The frequency of homo cystinuria ranges between
1 : 100,000 and 1 : 200,000 births [112]. Homocystinuria may be inapparent at
birth but may in time involve hair and skin changes, ocular changes, central
nervous system abnormalities, Marfan-like features, thromboembolic events,
and skeletal abnormalities.
Anyone of three metabolic defects may cause homocystinuria. Of these,
cystathionine synthetase deficiency is the most common, but deficiencies of 5methyltetrahydrofolate methyltransferase [113,114] and of 5,10-methylene tetrahydrofolate reductase [115] also occur.
Cystathionine synthetase deficiency was first recognized and described by
a Belfast-London group [116] and presents a rather distinct clinical picture
[117]. This deficiency alone among the biochemical forms of homo cystinuria
is associated with hair and skin pigmentary abnormalities.
Pigmentary Dilution in Cystathionine Synthetase Deficiency (Table 21)
In general, patients with cystathionine synthetase deficiency have fine
blond hair, blue eyes, and fair skin [116-130]. Blond hair was found in 34%
of 91 cases [118]. In another series [117], 10 patients had blond hair, whereas
in another [127], only two cases with blond hair were found among 38 patients.
Patients with black or dark brown hair have been documented [122,131]. The
blond hair is otherwise normal on routine microscopic examination but acridine orange stain gives an orange-red fluorescence, not the green fluorescence
expected of normal hair.
Compared to the hair color of unaffected siblings, the light hair color in
homocystinuria is most impressive, particularly in those of Mediterranean extraction [132]. That the metabolic defect is important to hair color is emphasized

119

GENETIC AND
CONGENITAL
DISORDERS

120
CHAPTER 1

TABLE 21. The Pigmentary Dilution in Cystathionine

Synthetase Deficiency
Onset

Birth, childhood

Areas affected
Hair
Eyes
Skin

Fine, fair, blond

Blue
Fair

Mechanism

Unknown; possibly reversed in the

hair by pyridoxine supplement

Associated dermatologic
or systemic findings

Usually present (see Table 22)

by the darkening of hair that occurs both with restricted methionine intake
[132] and with pyridoxine supplement [133,134].
Barber and Spaeth [133] observed striking repigmentation of the hair in
one of their patients treated with pyridoxine. A picture of the hair showed a
central band of blond hair which represents a 30-day period during which
treatment was interrupted (Fig. 42). Analysis of the dark hair revealed considerably more cysteine than in the light hair that formed prior to treatment. The
authors noted this difference in one of four controls. They suggest that increased
pigmentation after pyridoxine treatment may result from derepression of melanin formation. Tyrosinase may be inhibited by homocysteine in tissues.
Pyridoxine-deficient hair depigmentation was found in a 16-year-old white
girl with homo cystinuria and yellow-blond hair [134]. The initial trial of pyr-

FIGURE 42. Effect of pyridoxine treatment on hair pigmentation in a patient with homocystinuria. There is dark hair near
the scalp and a dark band further
out. The intermediate light zone
represents a 30-day period during which treatment was interrupted. (From: Barber JW, Spaeth
JH: The successful treatment of
homo cystinuria with pyridoxine. J Pediatr 75:463-478, 1969.
Copyright, 1969, The C. V. Mosby
Company. Used with permission.)

idoxine hydrochloride therapy resulted in marked darkening of the scalp hair.

Cessation of therapy was associated with prompt lightening of the hair to a
yellow-blond color. Resumption of the pyridoxine after six weeks again led to
darkening of hair. Examination of the hair showed three bands. The distal band
was a 25-mm-wide band of dark black hair that had emerged during therapy
with 500 mg pyridoxine hydrochloride daily. The middle band (15 mm in
length) was light blond and corresponded to the six-week period during which
pyridoxine hydrochloride was omitted. The final, proximal, band was dark,
corresponding to reinstitution of pyridoxine hydrochloride therapy. Microscopically, the light blond hair had relatively few melanin granules in the cortex
in contrast to the black and brown hairs which were richly melanized. Fluorescent microscopy showed a faint blue-yellow fluorescence in the unstained
section mounts of only the blond band of hair. Shelley et a1. [134] called this
darkening of hair "melanotrichia" since it was associated with a marked increase in the number of pigment granules in the hair cortex.
The authors suggest that altered biochemical pathways in these patients
may result in constant elaboration of phaeomelanins by the hair melanocytes.
Pyridoxine may then convert the system to eumelanin synthesis. Because such
darkening of the hair has not been observed with pyridoxine therapy in other
patients with homocystinuria, Shelley et a1. [134] suggested that perhaps their
patient and that of Barber and Spaeth [133] had an additional hereditary defect
that was pyridoxine-dependent and critical to melanin synthesis.
The darkening of the hair induced with pyridoxine in one control [133]
suggests that the hair darkening with pyridoxine may not be unique to homocystinuria. Further studies are required to determine whether "melanotrichia"
occurs in other groups of blond patients, that is, those without homocystinuria.
Pigmentary changes other than fair skin are sometimes mentioned. Premature graying of the hair is a feature of cystathionine synthetase deficiency.
Although many cases of homo cystinuria with blue eyes have been reported
[117-119,122,124,128,129,133,135]' incidence figures as low as 0 to 13.2% have
been recorded [118]. Fair skin has been reported [131,133,135] but no histologic
data are available.

Other Clinical and Biochemical Features in Cystathionine Synthetase

Deficiency

The more common systemic features of cystathionine synthetase deficiency

are summarized in Table 22.

Diagnosis

The clinical presentation should suggest the diagnosis. Although these

subjects appeared Marfan-like, they are distinguished from Marfan syndrome
by mental retardation, difficulty in walking, thromboembolic events, malar
flush, and fine, fair hair, blue eyes, and fair skin. The presence of homocystinuria clearly establishes the diagnosis.

121

GENETIC AND
CONGENITAL
DISORDERS

TABLE 22. Systemic Features in Cystathionine Synthetase Deficiency

122
CHAPTER 1

Ocular abnormalities (90.1%)

Ectopia lentis
Iridodonesis
Retinal degeneration or detachment
Uveitis
Glaucoma

Skeletal abnormalities

Osteoporosis
Dolichostenomelia
Genu valgum (35.1%1"
Pes cavus or planus (19.8%)
Pectus carinetum or excavatum
Kyphoscoliosis
Long extremities and digits
Marfan-like appearance (30.7%t
Mental retardation (74.7%t
Seizures (major or minor motor type) or EEG
abnormalities (25.2%)

Arterial and venous thromboses.

Abnormal platelet stickiness

(32.9%)

Cardiac abnormalities

Cardiac murmurs (17.5%)

Cardiomegaly
Hypertension secondary to narrowing of renal arteries

Hepatomegaly (fatty liver)

Fibrous intimal blood vessel changes; low content of

glycoprotein and protein polysaccharide matrix

Anemia
Cutaneous abnormalities

Malar flush
Livedo reticularis (extensor surface of the limbs)
Decreased subcutaneous fat
Blue eyes (13.2%) and blond, fine, fair hair (34%)

Biochemical abnormalities

Increased methionine and homocysteine blood levels

Abnormal amounts of urinary homocysteine and reduced
capacity to form inorganic sulfate from methionine
Deficient cystathionine synthetase activity in hair [136]
Absence of cystathionine [120] and of cystathionine
synthetase activity [137] in the brain
Absence of cystathionine synthetase activity in cultured
skin fibroblasts [138] and amniotic fluid cells [139],
PHA-stimulated lymphocytes [140], cultured long-term
lymphoid cell lines [141]

Percentages as reported by Gaudier et al. [1181.

Treatment

Dietary restriction of methionine and supplementation with cysteine [142]

have been used. Since pyridoxine phosphate is a cofactor for cystathionine
synthetase, vitamin Ba therapy seems logical [133]. But, it is now clear that
there are some cases of cystathionine synthetase deficiency that do not respond

to massive dosages of vitamin B6 [143]. The mechanism of action of vitamin

B6 in cystathionine synthetase deficiency is unknown.

Methionine Malabsorption Syndrome ("Oasthouse Urine Disease")

Two cases of methionine malabsorption syndrome [144,145] have been
reported. This syndrome includes convulsions, mental retardation, hyperpnea,
and urine with an odor of an oasthouse or dried celery. The two patients,
several months and two years old, had white hair.
Methionine was reported to be the most prominent amino acid in the urine
in the first patient. Large quantities of branched-chain amino acids, phenylalanine, and tyrosine were also found. Plasma amino acids were not assayed.
Both cases were reported to have large amounts of urinary a-hydroxybutyric
acid. Large amounts of methionine and of a-hydroxybutyric acid were reported
in the feces of the second patient in whom an oral-methionine-loading-testprovoked diarrhea and increased urinary and fecal a-hydroxybutyric acid. Hooft
et al. [144] concluded that these patients were unable to absorb dietary methionine.

Tietz Syndrome
In 1963, Tietz [146] reported a six-generation pedigree with a syndrome
of deaf-mutism, hypoplasia of the eyebrows, blue eyes, and a cutaneous depigmentation, which was referred to by the author as albinism. This syndrome,
which was observed in 14 (eight females, six males) of the 68 individuals in
this family, showed autosomal dominant inheritance and complete penetrance.
The cutaneous depigmentation in this disease is described as generalized.
The hair is light blond. The eyes are blue, but there is no photophobia, no
nystagmus, and the fundi are normal. There is no dystopia canthorum. The
deafness is of the perceptive type. Skin biopsies in one of the patients revealed
complete lack of melanin.
However, no other reports mention this syndrome and Witkop [147] regards
it as a questionable entity. Reed et al. [148] were able to reexamine two siblings
of this family and pointed out that the patients had freckling, that one had a
black patch in the nuchal area, and that one female of this kindred was light
blond but not deaf. The mother and her four sisters noted darkening of their
hair, and tanning was observed in the mother and her sons. It was suggested
that perhaps these individuals were very blond normal individuals with autosomal dominant deafness. Furthermore, since one of the female siblings was
blond and her brothers were not deaf, there are serious doubts as to the existence
of this disorder.

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Arch Dis Child 32:313-317, 1957
79. Schanenberg H et al: Der phenylbrenztraubensaure Schwachsinn. Z Kinderheilk 77:363-383,
1955
80. Weinhouse S, Millington RH: Ketone body formation from tyrosine (letter). J BioI Chern
175:995-996, 1948
81. Weinhouse S, Millington RH: Ketone body formation from tyrosine. J BioI Chern 181:645-653,
1949
82. Bechelli LM et al: Dyschromie et etude quantitative ultrastructurale de la couche basale de
l'epiderme dans 3 cas de phenylcetonurie. Presented at the XVth Congres de l'Association
des Dermatologistes et Syphiligraphes de Langue Francaise, Ajaccio, 1976
83. Armstrong MD et al: Studies on phenylketonuria, IX. Further observations on the effect of
phenylalanine restricted diet on patients with phenylketonuria. Am J Clin Nutr 5:543-551,
1957
84. Blainey ]D, Gulliford R: Phenylalanine restricted diets in the treatment of phenylketonuria.
Arch Dis Child 31:452-466, 1956
85. Horner FA et al: Effect of phenylalanine-restricted diet in phenylketonuria. J Dis Child
93:615-618, 1957
86. Hsia DYY et al: A one year controlled study of the effect of low-phenylalanine diet on
phenylketonuria. Pediatrics 21:178-202, 1958
87. Woolf LI et al: Dietary treatment of phenylketonuria. Arch Dis Child 33:31-45, 1958
88. Bates RM: Three cases of phenylpyruvic oligophrenia. J Ment Sci 85:273-275, 1938
89. ]ablonska S et al: Skin and muscle induration in phenylketonuria. Arch Dermatol 95:443-450,
1967
90. Penrose LS: Phenylketonuria, a problem in eugenics. Lancet 1:949-953, 1946
91. Knox WE, Hsia DYY: Pathogenetic problems in phenylketonuria. Am JMed 22:687-707,1957
92. Medical Research Council: Working party on phenylketonuria. Present status of different
mass screening procedures for phenylketonuria. Br Med J 4:7-13, 1968

93. Jervis GA: Phenylpyruvic oligophrenia: deficiency of phenylalanine oxidizing system. Proc
Soc Exp Biol Med 82:514-515, 1953
94. Mitoma C et al: On the nature of enzymic defect in phenylpyruvic oligophrenia. Proc Soc
Exp Biol Med 94:634-635, 1957
95. Wallace HW et al: Studies on conversion of phenylalanine to tyrosine in phenylpyruvic
oligophrenia. Proc Soc Exp Biol Med 94:632-633, 1957
96. Kaufman S: Enzymatic conversion of phenylalanine to tyrosine. J Biol Chern 226:511-524,
1957
97. Justice P et al: Clinical and biochemical observations of patients with atypical phenylketonuria. Pediatrics 45:83-92, 1970
98. Friedman PA et al: Detection of hepatic phenylalanine 4-hydroxylase in classical phenylketonuria. Proc Natl Acad Sci USA 70:552-556, 1973
99. Dalgiesh CE: Metabolism of the aromatic amino acids. Adv Protein Chern 10:31-150, 1955
100. Armstrong MD, Tyler FH: Studies on phenylketonuria, I. Restricted phenylalanine intake in
phenylketonuria. J Clin Invest 34:565-580, 1955
101. Bickel H: Effects of phenylalanine-free and phenylalanine-poor diet in phenylpyruvic oligophrenia. Exp Med Surg 12:114-118,1954
102. Bickel H et al: The influence of phenylalanine intake on the chemistry and behaviour of a
phenylketonuric child. Acta Paediatr Scand 43:64-77, 1954
103. Braude H: Phenylketonuria: a case report in an European child treated with a diet low in
phenylalanine. S Afr Med J 30:83-85, 1955
104. Woolf LI et al: Treatment of phenylketonuria with a diet low in phenylalanine. Br J Med
1:57-64, 1955
105. Snydermann SE et al: Effect of tyrosine administration in phenylketonuria. Fed Proc 14:450-451,
1955
106. Dancis J, Balis ME: A possible mechanism for disturbance in tyrosine metabolism in phenylpyruvic oligophrenia. Pediatrics 15:63-66, 1955
107. Miyamoto M, Fitzpatrick TB: Competitive inhibition of mammalian tyrosinase by phenylalanine and its relationship to hair pigmentation in phenylketonuria. Nature 179:199-200,
1957
108. Boylen JB, Quastel JH: Effects of L-phenylalanine and sodium phenyl pyruvate on the formation of melanin from L tyrosine in melanoma. Nature 193:376-377, 1962
109. Saunders JW et al: The effects of tyrosine and phenylalanine on the synthesis of pigment in
melanocytes of embryonic chick skin cultured in vitro. J Natl Cancer Inst 16:475-487,1955
110. Riley PA: The biochemistry of pigment formation, in The Physiology and Pathophysiology
of the Skin. Edited by A Jarrett. London, Academic, 1974, vol 3, pp 1149-1165

Disorders of Methionine Metabolism

111. Field CMB et al: In, Xth International Congress of Paediatrics, Lisbon, 1962. Book of Abstracts,
p 274 (Quoted in Reference 135)
112. Levy HL: Neonatal screening for inborn errors of amino acid metabolism. Clin Endocrinol
Metabol 3:153-166, 1974
113. Goodman SI et al: Homocystinuria with methylmalonic aciduria: two cases in a sibship.
Biochem Med 4:500-515, 1970
114. Mudd SH et al: A derangement in B12 metabolism leading to homocystinemia, cystathioninemia and methyl malonic aciduria. Biochem Biophys Res Commun 35:121-126, 1969
115. Mudd SH et al: Homocystinuria associated with decreased methylenetetrahydroplate reductase deficiency. Biochem Biophys Res Commun 46:905-912, 1972
116. Carson AJ et al: Homocystinuria: a new inborn error of metabolism associated with mental
deficiency. Arch Dis Child 38:425-436, 1963
117. Carson NAJ et al: Homocystinuria: clinical and pathological review of ten cases. Pediatrics
66:565-583, 1965
118. Gaudier Bet al: L'homocystinurie (a propos de trois observations). Arch Fr Pediatr 25:541-560,
1968
119. Arndt EJ, Greaves DP: Ocular involvement in homocystinuria. Br J Ophthalmol 48:688-689,
1964

127
GENETIC AND
CONGENITAL
DISORDERS

128

CHAPTER 1

120. Brenton DP et al: Homocystinuria. Biochemical studies of tissues including a comparison

with cystathionuria. Pediatrics 35:50-56, 1965
121. Dunn HG et al: Homocystinuria: a recently discovered cause of mental defect and cerebrovascular thrombosis. Neurology 16:407--420, 1966
122. Gaudier B et al: L'homocystinurie: a propos d'une observation. Pediatrie 21:889-898, 1966
123. Henkind P, Ashton N: Ocular pathology in homocystinuria. Trans Ophthalmol Soc UK 85:21-38,
1965
124. Hooft C, Carton D: L'homocystinurie, presented to Soc BeIge de Pediatric. Verh Kon Vlaam
Acad Geneesk Belg 29:119-151, 1967
125. Kennedy C et al: Homocystinuria: a report in two siblings. Pediatrics 36:736-741, 1965
126. Komrover GM, Wilson VK: Homocystinuria. Proc R Soc Med 56:996-997, 1963
127. Schimke RN et al: Homocystinuria: studies of twenty families with 38 affected members.
JAMA 193:711-719,1965
128. Spaeth GL, Barger GW: Homocystinuria in a mentally retarded child and her normal cousin.
Trans Am Acad Ophthalmol Otolaryngol 69:912-930, 1965
129. Werder EA et al: Homocystinurie. Helv Paediatr Acta 21:1-18, 1966
130. White HH et al: Homocystinuria. Arch Neural 13:455--470, 1965
131. Yoshida T et al: Homocystinuria of vitamin B6-dependent type. Tohoku J Exp Med 96:235-242,
1968
132. McKusick VA et al; The clinical and genetic characteristics of homocystinuria, in Inherited
Disorders of Sulfur Metabolism. Edited by NAJ Carson, DN Raine. London, Churchill Livingtstone, 1971, pp 179-203
133. Barber GW, Spaeth GL: The successful treatment of homocystinuria with pyridoxine. J Pediatr
75:463--478, 1969
134. Shelley WB: Pyridoxine-dependent hair pigmentation in association with homocystinuria.
The induction of melanotrichia. Arch Dermatol 106:228-230, 1972
135. Brenton DP et al: Homocystinuria: clinical and dietary studies. Q J Med 35:325-346, 1966
136. Mudd SH et al: Homocystinuria: an enzymatic defect. Science 143:1443-1445, 1964
137. Pinnell SR, McKusick VA: Heritable disorders of connective tissue with skin changes, in
Dermatology in General Medicine, 2nd ed. Edited by TB Fitzpatrick et a1. New York, McGraw-Hill, 1979, pp 1147-1148
138. Fleisher LD, Gaul GE: Methionine metabolism in man: development and deficiencies. Clin
Endocrinol Metabol 1:37-54, 1974
139. Uhlendorf BW, Mudd SH: Cystathionine synthetase in tissue culture derived from human
skin: enzyme defect in homocystinuria. Science 160:1007-1009, 1968
140. Goldstein JL et al: Cystathionine synthetase activity in human lymphocyte induction by
phytohemagglutinin. J Clin Invest 51:1034-1037, 1972
141. Fleisher LD: Detection of cystathionine synthase in long-term lymphoid cell lines (letter).
Lancet 2:482, 1972
142. Komrover GM et al: Dietary treatment of homocystinuria. Arch Dis Child 41:666-671,1966
143. Finkelstein JD: Methionine metabolism in mammals. The biochemical basis for homocystinuria. Metabolism 23:381-398, 1973
144. Hooft C et al: Methionine malabsorption syndrome. Ann Paediatr (Basel) 205:73-84, 1965
145. Smith AJ, Strang LB: An inborn error of metabolism with the urinary excretion of a-hydroxybutyric acid and phenylpyruvic acid. Arch Dis Child 33:109-113, 1958

Tietz Syndrome
146. Tietz W: A syndrome of deaf-mutism associated with albinism showing dominant autosomal
inheritance. Am J Hum Genet 15:259-264, 1963
147. Witkop CJ Jr: Albinism, in Advances in Human Genetics. Edited by H lJarris, K Hirschhorn.
New York, Plenum, 1971, vol 2, pp 61-142
148. Reed WB et al: Pigmentary disorders in association with congenital deafness. Arch Dermatol
95:176-186, 1967

SECTION 3. DISORDERS WITH CIRCUMSCRIBED

HYPOMELANOSIS
VITILIGO
... and the priest shall look on the plague in the skin of the flesh; and when the hair
in the plague is turned white, and the plague in sight be deeper than the skin of his
flesh, it is a plague of leprosy; and the priest shall look on him, and pronounce him
unclean. If the bright spot be white in the skin of his flesh, and in sight be not deeper
than the skin, and the hair thereof be not turned white; then the priest shall shut up
him that hath the plague seven days ... and the priest shall look on him again the
seventh day; and behold if the plague be somewhat dark, and the plague spread not
in the skin, the priest shall pronounce him clean; it is but a scab; and he shall wash
his clothes, and be clean.
Leviticus XIII:3,4,6

Definition
Vitiligo is the prototype of hypomelanotic disorders. It is an idiopathic,
acquired, circumscribed leukoderma which often is associated with a positive
family history and is characterized by discrete, pale white macules, few or
many in number, that tend to enlarge centrifugally over time. Vitiligo is one
of the most common leukodermas known, and whether it is associated with
other disorders or is a cosmetic problem that does not affect the general health
of the patient, the physical disfigurement perceived by those afflicted and those
they confront often leads to social embarrassment and psychologic turmoil.

Historical Background
Early Confusion of Leprosy and Vitiligo

The stigma associated with vitiligo must date from ancient times when
vitiligo was confused with contagious or severely disfiguring disease entities.
The earliest reference to vitiligo would seem to be the Ebers Papyrus which
attempted to distinguish two types of pigmentary dilution. One type had tumors
and mutations "thou shalt not do anything about it" and in the other "thou
findast only change of colour." The former probably represented leprosy and
the latter vitiligo, which, according to the Ebers Papyrus, was treatable.
In a sacred Indian book, Atharva Veda, dating to 1400 B.C., the condition
"shwetakustha" likely referred to vitiligo.
White spots were also described in the Greek literature; Herodotus (484-425
B.C.) wrote in Clio 1:138 in 449 B.C.:
If a Persian has leprosy or white sickness he is not allowed to enter into a city or to
have dealings with other Persians, he must, they say, have sinned against the sun.
Foreigners attacked by this disorder are forced to leave the country, even white pigeons
are often driven away as guilty of the same offense. [1]

129

GENETIC AND
CONGENITAL
DISORDERS

130
CHAPTER 1

Biblical references to leukoderma as leprosy date from the translation by

scholars of the Septuagint in 250 B.C. of the Hebrew word "zora'at" in Leviticus,
Chapter XIII, as "lepra." The ancient Hebrews considered this affliction a punishment; "it is not a natural phenomenon but a Divine visitation" [1]. Leviticus
XIII was used by priests to determine the contagiousness and prognosis of the
disorder. Yet Goldman et al. [1] reviewed the clinical description in Leviticus
XIII, and concluded, as stated by Archbishop Iakovas of the Greek Orthodox
Church, " ... it appears that the Greek word as discussed in Leviticus, Chapter
XIII refers to a variety of contagious skin diseases prevalent in Biblical times
rather than to leprosy as it is now known." That The Bible does not describe
sensory changes supports the assertion of modern dermatologists and theologians that biblical leprosy probably represented not a specific illness but psoriasis or leukoderma and other disorders perceived to be associated with a
spiritual uncleanliness that demanded sacrifice.
Aristotle directed himself to skin whiteness which in his day was a disturbing sign, particularly among those of dark skin color:
Why do boys and women suffer less from white leprosy than men, and old women
more than young ones? Is it because leprosy is an escape of breath, and bodies of
boys are not well ventilated but are thick and those of women are less well ventilated
than those of men? For the breath is absorbed in the menses; the smoothness shows
the thickness of the flesh. But the flesh of older men and of old women is well aired;
for they alone like old buildings have gaps in the construction of their parts. [11

Aristotle also observed that gray hair was a feature of leprosy and reasoned
that those who do not get gray hair cannot have leprosy.
Although skin disorders with anesthesia and paresthesia were described
in 7th Century China, as were various skin disorders in India as far back as
7000 years, and alopecia with sensory changes and skin disturbance in the
Berlin Papyrus and the Ebers Papyrus, no evidence for leprosy has been found
among ancient Egyptian mummies or in the pre-Columbian Americas (although
ceramics of pre-Columbian Middle Andean civilizations display evidence of
many other disease entities). Leprosy then must not have been so common and
many leukodermas must have been other than leprosy.
Against a clear description of leukoderma among the ancients, the first
clear account of leprosy, according to Kaposi [2], was given by Danielssen and
Boeck [3] in 1842. Since throughout early literature it is not possible to find
definite evidence for leprosy, qua leprosy, until the nineteenth century, much
historical "leprosy" may be vitiligo. The old Hebrew "zora'at" may not even
apply to leukodermas or epidermal proliferative disorders.
Yet from the historical associations with leprosy-pandemics in the Middle
Ages and uncleanliness of biblical times-the stigma of leprosy, bolstered by
old edicts and cruel laws, remains. Following the urging of Pope Pius XII in
1943 and with the official American Catholic translation in 1952 with reference
to Leviticus XIII, the Church added the following footnote:
Various kinds of skin blemishes are treated here which were not contagious but simply
disqualified their subjects from associations with others, especially in public worship,
until they were declared ritually clean. The Hebrew term used does not refer to
Hansen's disease, currently called leprosy.

Still, in the 1963 New English translation of the New Testament, "lepra"
is still translated "leprosy." Hence, literal confusion is perpetuated.
Vitiligo in Ancient Times
The term "vitiligo" was first used in the 2nd Century A.D. by Celsus, who
observed the appearance of the patches of vitiligo resembled the white patches
of a spotted calf. "Vitiligo" has often been said to have been derived from the
Latin vitellus, meaning "calf." Professor Herbert Block* has suggested "vitiligo"
is derived from "vituim" (defect or blemish) plus the suffix "igo" (condition
or disease of) with the "I" introduced for euphony.
Many earlier terms have been applied to what we now call "vitiligo."
Ancient Indian culture [4] is replete with references to vitiligo. The sacred
Indian book Atharva Veda (1500-1000 B.C.) mentions the words "kilas" meaning white spot or patch on the skin and "palita" which applies to the yellow
tinge of these spots. That "palita" is derived from "pal," meaning "old" or
"aged," suggests this term applies to the canities or leukotrichia associated with
aging.
"Shvetkushtha" is derived from "shvet" (white) and "kushtha" (referring
to skin diseases in general) and according to the Sanskrit dictionary means
"that which makes the body ugly or spoils the blood." Villagers applied the
term "charak," meaning "that which is secret" or "that which spreads"; both
interpretations seem appropriate for a progressive condition with marked social
stigma.
From the Far East in Makatominoharai, a collection of Shinto prayers
dating from 1200 B.C., "shira-bito" or white man is mentioned. This also could
have been vitiligo [5].
In the Buddhist sacred book Vinay Pitah (624-544 B.C.), "kilas" is mentioned; those afflicted with leukoderma could not be ordained.
Manusmriti (200 B.C.) shows the lack of respect accorded one with "svitra,"
a term applied to vitiligo. One who had stolen clothing in his former life might
be reincarnated with "svitra."
In Amarkosha (600 A.D.) the term "svitra" was used synonymously with
"padasphota" (flower of legs), "twakpuspi" (flower of skin), and "sidhmali"
(spreading whiteness).
"Bohak," "bahah," and "baras" are the Arabic names for vitiligo [6]. In the
Koran (3:48, 5:109), "In accord with God's will Jesus was able to cure patients
with Baras."
Later Descriptions of Vitiligo
Casual use of the terms "vitiligo" and "leukoderma" has introduced considerable confusion into the scientific literature over the last century and to
this day. Beigel [7], in his memoir of 1864, reserved the term vitiligo for those
cases with observable change of structure as well as loss of pigment in the skin.
* Professor of Classics, Harvard University.

131
GENETIC AND
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DISORDERS

132
CHAPTER 1

This clearly does not apply to vitiligo as we diagnose it today. Pearson et al.
[8], just after the end of the 19th century, used the term "leukoderma" to
designate a disease which seems to be vitiligo.
The geographically scattered early reports of vitiligo emphasized the global
incidence of the condition and often dramatized the social seriousness of it.
Fifteen cases of vitiligo in blacks were recorded between 1698 and 1910. The
first case, that of Byrd [9], was of a black boy who had been "dappleI'd" with
white spots in several places. "The spots are wonderfully white at least equal
to the skin of the fairest lady and have advantage in this, that they are not able
to be tanned." Early cases were also reported in Europeans, North American
Indians, Egyptians, and Bengalese [8].
It is clear, from the clinical description of the disease by Pearson et al. [8]
in 1911 that early clinicians appreciated many of the features of this condition.
While in the twentieth century there has been general agreement about the
broad nature of vitiligo, significant controversy remains. Many leukodermas of
various origin-chemical depigmentation, tuberous sclerosis, melanoma, halo
nevus, etc.-have been and still are described under the title "vitiligo."
Modern Nomenclature and Definition

Vitiligo is a circumscribed, acquired, idiopathic, progressive hypomelanosis of skin and hair which is often familial and which is characterized microscopically by a total absence of melanocytes. Melanocytes of the skin and
of the hair are the commonly recognized end organs of this disorder in which
melanocytes of the leptomeninges, retinal pigment epithelium, uveal tract, and
inner ear may also possibly be involved. The cutaneous patches are chalkwhite, separate and discrete, often progressively confluent, and on occasion
universal. The presence of disease associations and autoantibodies in too many
patients to be coincidental suggests that vitiligo must be a systemic and not
just a purely cutaneous disease. The definition, by stressing an "absence of
etiology," carefully excludes chemically induced depigmentation, depigmentation associated with melanoma, depigmentation secondary to various other
dermatoses, and other entities for which the precipitating factor seems clear.
Since no specific biochemical features of vitiligo have been identified and
since the most characteristic histologic feature is a total absence of melanocytes,
rigid laboratory criteria for a diagnosis of vitiligo are lacking. It is uncertain
whether vitiligo is one disease entity with a specific pathogenesis or a final
common pathway of several different processes.

Clinical Features
Incidence

The world incidence of vitiligo is generally accepted to be 1% [10] but the

reported incidence figures vary from 0.1% to 8.8% (Table 23).
One cannot quite conclude from the literature that vitiligo is evenly spread

among all peoples of the world. Review of the various studies on vitiligo in
different countries reveals a generally higher incidence in India and Mexico
than in Japan and a relatively lower incidence in all of Europe. The incidence
figures reported for the United States vary from 0.14% to 8%, but the overall
incidence is thought to be 1% of the entire population [29].

TABLE 23. Incidence of Vitiligo in Various Countries

Incidence
Author
EI Mofty (1968) [6]

Country
AFRICA
Egypt

Seghal (1974) [17]

Arakawa"
Ito (1952) [19]
Kooh Don Teik (1962) [20]

ASIA
India
Calcutta
Vellore
Calcutta
Aramavati
Delhi
Rural South Gujanat
Urban South Gujanat
Goa
Japan
Sendai
Malaysia (Singapore)

Howitz et al. (1979) [21]

Grunnet et al. (1970) [22]
Dawbar (1968) [23]
Radcliffe-Crocker"
Desmons (1974) [24]
Perrot et al. (1973) [25]
Fornara"
Polotebroff"
Robert (1941) [18]

EUROPE
Denmark
Denmark
England
England
France
France
Italy
Russia
Switzerland

Panja (1.947) [11]

Levai (1958) [12]
Dutta and Mandai (1969) [13]
Punshi and Thakre (1969) [14]
Behl and Bhathia (1972) [15]
Mehta et al. (1973) [16]

Canizares (1960) [26]

Ruiz-Maldonado et al. (1977) [27]
Allison and Curtis (1955) [28]
Lerner (1959) [29]
Gaul (1959) [30]
Fitzpatrick et al. (1974) [31]

NORTH AMERICA
Mexico
Mexico
United States
Michigan University
Pendleton (Oregon)
Nevada (Missouri)
Indiana University
Massachusetts General
Hospital

Sample
population'

(%)

D.O.

6
4
4.3
8
8.8

2.9
1.64
1.3
0.7

D.O.
D.O.
D.O.
G.O.P.
D.O.
P.L.
P.L.
D.O.
G.O.P.
D.O.
D.O.

0.38
1.44
0.15
0.42
3
0.6
0.3
0.14
0.39

P.L.
G.I.P.
0.1.
D.O.
Children
D.O.
Children
D.O.
D.O.

4
2.6

D.O.
D.O.

0.66
0.14
0.19
3.2
8

G.I.P.
P.L.
P.L.
P.L.
D.O.

~::~ }1.79

Quoted by Robert [18].

Weighted average.
C Abbreviations' D.O .. dermatologic outpatients; D.l., dermatologic inpatients; G.O.P., general outpatients; G.l.P., general
inpatients; P.L., population at large.

133
GENETIC AND
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DISORDERS

134
CHAPTER 1

These differences among various global populations are likely more apparent than real because the reported incidence is often directly related to the
depth of constitutive pigmentation. Vitiligo seems most common in populations
in which the contrast in skin color is readily apparent. In India, it is the
association with social stigma that compels a greater percentage of afflicted
individuals in this population to seek medical care as opposed to populations
in which vitiligo is socially insignificant; surveys from India may show a falsely
increased incidence for this reason. It is, however, possible that such highly
active melanogenic pathways are somehow predisposed to vitiligo.
Basic differences among the sample populations are also partially responsible for the wide scattering of reported incidence figures. Dermatologic outpatients or general inpatients are not necessarily representative of the population at large. For example, the 8% incidence reported from the Dermatology
Department at Massachusetts General Hospital, Boston, Massachusetts [32] reflects the long-standing interest of this department in pigmentary abnormalities.
The low incidence reported from the University of Michigan [28] is based on
a retrospective study of hospitalized patients; since patients are not hospitalized
for the treatment of vitiligo and since vitiligo is probably overlooked in the
inpatient record of medical diagnoses, an artificially low incidence figure is
not unexpected. The studies from Pendleton, Nevada [29] were based entirely
on the observations of patients; those with only a few macules or very fair skin
would not all be expected to be aware of their disease. The only studies of
populations at large are from the United States [29,30], India [16], and Denmark
[21], and these incidence figures vary from 0.14% to 3.2%. Probably the worldwide incidence is at least 1% or more and all geographic areas of the globe are
equally affected.
Race
Vitiligo affects all races [8]. Most reported series are of Caucasians but there
are several among Orientals [19,20] and a few among blacks [33]. A statistical
tabulation [34] of 3860 consecutive black dermatologic outpatients revealed a
1.6% incidence of vitiligo, no different from the 0.7% to 1.6% reported from
Orientals.
Sex Prevalence
In 13 of 18 series (Table 24), there are more women than men. Among all
series, 41 % to 73% are women, and 27% to 59% are men. The generally reported
prevalence in women is considered not to represent a real difference. Rather
it is likely that women are more sensitive to cosmetic disfigurement and more
likely than men to present themselves for treatment. Probably neither sex is
predisposed to vitiligo.
Heredity
Even the early writings on vitiligo included many cases of familial vitiligo.
In 1911, Pearson et al [8], noting a patient with a rather heterogeneous genetic
background, suggested a hereditary factor and stated, "There is some evidence

TABLE 24. Male-Female Ratio of Vitiligo

Author

Males
(%)

Sidi et a1. (1957) [35]

Levai (1958) [12]
Lerner (1959) [29]
Shukla and Mukerji (1960) [36]
Khoo Oon Theik (1962) [20]
EI Mofty (1968) [6]
Dutta and MandaI (1969) [13]
Grupper et a1. (1970) [37]
Fitzpatrick and Mihm (1971) [32]
Behl and Bhathia (1972) [15]
Mehta et a1. (1973) [16]
Perrot et a1. (1973) [25]
Howitz and Rehfeld (1974) [38]
Ortonne (1974) [39]
Seghal (1974) [17]
Howitz et a1. (1977) [21]
Metzker et a1. (1977) [40]

34.7
59
32.5
57
28
45.9
53.25
34.7
27
48
48.9
42
26.7
41
48
48
51

Females
(%)

135

Total no.
of patients

65.3
41
67.5
43
72
54.1
46.75
65.3
73
52
51.1
58
73.3
59
52
52
49

70
405
200
340
60
545
650
70
380
400
129
200
116
100
202
179
430

for supporting that leukoderma ... may occur as a result of pigmentation upset
following hybridisation."
The prevalence of a positive family history of vitiligo varies from 6.25%
to 38% (Table 25). Lerner [29] stated that the prevalence figure of 38% is
probably minimal. Artificially low incidence figures may result from lack of
communication among relatives and from unawareness or nonchalance because
of late onset of the condition. The highest prevalence, 78.27%, has been reported
from India [16] but the small size (46 patients) of this series diminishes the

TABLE 25. Familial Vitiligo: Percentage of Patients

with One or More Other Family Member with Vitiligo
Author
Panja (1947) [11]
Sidi et a1. (1957) [35]
Levai (1958) [12]
Lerner (1959) [29]
Fitzpatrick (1964) [41]
EI Mofty (1968) [6]
Dutta and MandaI (1969) [13]
Behl and Bathia (1972) [15]
Bleehen (1972) [42]
Mehta et a1. (1973) [16]
Ortonne (1974) [39]
Seghal (1974) [17]

Incidence

(%)

Total no.
of patients

6.5
22
11
38
35
35.25
17.75
6.25
33
78.25
18.75
6.9

700
219
244
200
430
545
650
400
340
46
96
202

GENETIC AND
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DISORDERS

136
CHAPTER 1

representativeness of the observation. The prevalence is probably between 20%

and 40%.
It is not uncommon for more than two members of a family to have vitiligo.
Fitzpatrick [41] states that about 10% of his series of 430 patients had more
than one other family member involved. Lerner [29] found that of his 75 patients
with positive family histories, 36 had one relative, 23 had two, 13 had three,
and three had four or more relatives with vitiligo. Similar results were obtained
by Ortonne [39] and Mehta et al. [16]. There are many recorded instances of
families with multiple individuals affected [43-46]. Up to eight cases of vitiligo
in one family have been reported [47].
Familial vitiligo may occur in several members of a single generation or
of several generations (Fig. 43). Vitiligo has been reported in three children of
normal parents [48] and in the two daughters, but not the two sons, of a woman
with vitiligo [49]. Involvement of a grandmother, mother, and daughter has
been reported [50]. In a study of 39 patients, vitiligo was present in each of
three generations [51].
Vitiligo has also been described in twins [52-56]. In 1951, a pair of identical
twins with onset of vitiligo at about the same age and with somewhat similar
distribution of lesions [53] was reported. The mother of the twins also had
vitiligo. Sidi et al. [35] observed twins with vitiligo beginning at nearly the
same time and having similar clinical courses; the distribution and the extent
of vitiligo in these two patients was strikingly but not exactly similar. In another
set of male twins, one developed vitiligo at age 13 and the other at 22; in these
brothers there was good concordance of the sites of the depigmented lesions
[52]. Vitiligo in only one of two mono zygomatic twins has also been observed
[54]; we have made a similar observation in two 67-year-old twin women.
That vitiligo has an identifiable inheritance pattern was appreciated as
early as 1933 when Cockayne [57] suggested an irregular dominant pattern of

FIGURE 43. Familial vitiligo. a: Vitiligo in identical twins: distribution of leukoderma is similar.
b: Vitiligo affecting father and son (forearms and hands of father and trunk of son are shown).

inheritance. A bimodal defect was postulated by EI Mofty [6] who suggested

that defective melanogenesis results from a genetically determined structural
abnormality and an unidentified metabolic defect. Vitiligo seems to be autosomal dominant [58], but there must be modulating factors that affect penetration and expression [59].
Often the dermatologist is confronted with the fears of a patient that his
or her children may also develop vitiligo. This, in the absence of a strong family
history of vitiligo, should be answered cautiously; while the children certainly
are at increased risk, they are less than likely to develop vitiligo.
Skin Type

In vitiligo patients, the uninvolved skin tans normally. At times, vitiligo

appears more prevalent among those who have intense constitutive skin color
and a history of deep facultative skin color. Lerner [29] found 89% of his patients
considered themselves good tanners, whereas 11 % sunburned readily. Ortonne
[39] reported 84% of his patients obtained a tan without burning, 12% sunburned easily, and 4% never tanned their normal skin.
Fitzpatrick [60] has proposed a clinical classification of skin that is based
on the reaction pattern of untanned skin to an initial 30 minutes of midday
June sun exposure:
I: Always burn, no tan
Type
Type II: Usually burn, then light tan
Type III: Sometimes burn, good tan
Type IV: No burn, good tan
Type V: American Indians, Mexicans, Indians, Orientals
Type VI: Blacks
Although the classification is somewhat subjective for Types I to IV, and
although it may be difficult to distinguish a Type II from a Type III, this classification does facilitate discussion based on cutaneous sensitivity to sunlight.
In a review of 100 vitiligo patients seen at the Massachusetts General
Hospital, Type III was most common. (Type I, 1%; Type II, 9%; Type III, 59%;
Type IV, 23%; Type V, 3%; Type VI, 5%) (Fig. 44). This compares to a control
population based on a random sampling of Dermatology Clinic outpatients at
the Massachusetts General Hospital of 23% Type I, 18% Type II, 38% Type III,
21 % Type IV. Although these figures suggest vitiligo is more common in darkerpigmented skin types than among normal controls, it may simply be more
apparent; a Type I individual would not notice any contrast and many Type
II individuals avoid sunlight for fear of sunburn of their normal skin, hence
their vitiligo also remains relatively inapparent.
Hair Color

Dark brown is the most common scalp hair color in vitiligo populations.
In a population of 100 French patients [39], 76% were found to have dark
brown hair, 13% light brown, 7% black, and 4% blond hair. Of 100 Massachu-

137

GENETIC AND
CONGENITAL
DISORDERS

138

Type I

CHAPTER 1

Type II

Type III

Type IV

Type V

Type VI

70
l!l

60

50

....
o
...

40

<:

8!.
<:

'"
~
'"

c..

30
20

10
0----~V~C~--~~~---LV~7CL---~V~~CL---~~~--~~~

FIGURE 44. Skin Types in 100 vitiligo and 100 control patients. V = vitiligo patients; C = control
patients.

setts General Hospital vitiligo patients, 36% were found to have dark brown
hair, 11% medium brown hair, and 30% light brown hair. Black, blond, and
red hair occurred in 11%, 10%, and 2% of patients, respectively.
Eye Color
Most vitiligo patients have brown eyes. Ortonne [39] found 77% of his
vitiligo patients to have brown eyes, 13% blue, 5% blue-green, and 5% dark
brown to black. Of 100 Massachusetts General Hospital general dermatology
patients without vitiligo, 48% had brown eyes, 25% blue eyes, 14% green eyes,
and 13% hazel eyes. Lerner [39], who found four patients with vitiligo in one
family, observed that only those with brown eyes were affected and suggested
a genetic linkage between brown eyes and vitiligo. No definite linkage, however,
has been established. We have one patient who has observed a change of her
iris color from brown to blue and another case has been reported [61].
Age of Onset
Vitiligo may first appear from birth to senescence (Table 26), though onset
between 10 and 30 years of age is most common.
Although vitiligo is generally considered an acquired condition, several
cases of "congenital vitiligo" have been described. Depigmentation in a threeday-old child was surely congenital vitiligo [62]. Panja [11] found seven of his
260 cases to be congenital. In one of the two "congenital" cases reported by El
Mofty [6], the depigmentation appeared as a linear streak down the inner left
leg. In the other there were depigmented macules on one side of the abdomen.
Although further information is not available on each case, these most likely
represent nevus depigmentosus and not vitiligo. In another case of what probably is congenital vitiligo [63], there was evidence of spontaneous repigmentation and marked improvement with oral psoralens and ultraviolet irradiation.
Another, who was born with a large patch of amelanosis on the right hand,
was 14 years of age before any other new macules appeared. Several months
of 8-methoxypsoralen treatment resulted in islands of repigmentation in the

TABLE 26. Age of Onset of Vitiligo

Age of onset

Author
Levai (1958) [12]
Lerner (1959) [29]
Dutta and Mandai (1969) [13]
Fitzpatrick and Mihm (1971) [32]
Behl and Bathia (1972) [15]
Ortonne (1974) [39]
Howitz et al. (1977) [21J

139

6 months
8 months
6 months
1 year
8 months
4 years
Birth

to
to
to
to
to
to
to

70
70
72
69
75
81
85

years
years
years
years
years
years
years

new lesion, but not in the congenital one; unfortunately electron microscopy
was not available to confirm the diagnosis of the congenital lesion which could
have been nevus depigmentosus.
Nearly all vitiligo is acquired relatively early in life. The average age of
onset is around 20. The peak onset has been reported to be between five and
10 [11], six and 15 [16], seven and 12 [40], 10 and 19 [17], 11 and 30 [15], 22
and 30 [6], 25 and 45 [35], and 50 and 59 [21]. Lerner [29] observed 50% of
his patients had incurred the disease by the age of 20, 45% between 20 and
40, and only 5% developed it after the age of 40. Of 129 patients, Mehta et al.
[16] found one to be less than five years of age and 15 older than 55. Seghal
[17] noted 8.6% of males and 9.6% of females in the age group of birth to four
years, and 0% and 1.1%, respectively, greater than 70 years of age. There is
one epidemiologic survey, that of Howitz et al. [21], which is atypical in that
over half of the patients reported onset after the age of 40. Onset as late as 75
and even 81 years has been reported [15,39]. Vitiligo most commonly begins
between 10 and 30 years of age and rarely in infancy or senescence (Fig. 45).
All surveys but that of Howitz et al., however, are flawed by being extracted
from average vitiligo populations which tend to be young; those who develop
vitiligo in older age may not see their physician about it.
Many reports suggest that the mean age of onset is younger in females than
in males. Levai [12] from India found the average age of onset to be 18 for
females and 26 for males, while Howitz et al. [21] found virtually no difference-3 6.7 and 38.7 years , respectively-among the Danes. Seghal [17] reported
that 62.7% of females and 55.5% of males surveyed had developed their diseases
by the age of 19. He found the majority of patients between 10 and 19 and
again in old age to be females, whereas male onset predominated among those
in the third and fourth decades. This is similar to the observation of Ortonne
[39] who found a slightly earlier onset among females with clustering among
the second and third decades. It seems unlikely that the age of onset should
vary between the sexes. That women may have a heightened concern about the
appearance of their skin may contribute to an early awareness of the condition.
Duration and Age of Presentation for Evaluation
In general, females present for treatment for their vitiligo earlier than do
males. Seghal [17] found that 50.5% of females and 38.2% of males eventually
seen with vitiligo had presented for evaluation by the age of 19. Levai [12]

GENETIC AND
CONGENITAL
DISORDERS

30

140
CHAPTER 1

25

...c:'"

20
r-

Ql

.;:;

'"a.

15

r-

'0

r-

10

5
0

~ill

9 19 29 39 49 59 69 79
Age (years)

~Total
Males
Females

FIGURE 45. Age of onset of vitiligo. ( From: Ortonne J-P: Le Vitiligo: Maladie ou Syndrome. These
Medicine, Lyon, 1974.1

found the average age of presentation to be 21 for females and 29 for males.
Mehta et al. [16] noted in the evaluation of 66 cases that the duration of the
condition was less than one year in 12, from one to five years in 33, from five
to 10 years in 70, and more than 10 years in 14. Seghal [17] found 18.1% of
females and 22.7% of males had had the condition less than three months and
23.8% of females and 20.6% of males longer than five years. Levai [12] found
the duration of the condition to be two weeks to 30 years, with an average of
three years. It may be that patients delay being seen because of the notion
among general practitioners and the population at large that no treatment is
available.
Precipitating Factors
There is no single factor known to cause vitiligo. However, some patients
and physicians have observed that one or more events seem to precipitate or
at least to antedate the initial awareness of vitiligo. From 10% to 76% [13,15]
of vitiligo patients are able to implicate a precipitating cause such as physical
injury, sunburn, emotional trauma, illness, etc. Many can cite an emotionally
traumatic event such as a quarrel, death of a parent or spouse, bad accident,
or other event after which they first became aware of their vitiligo [64-69].
Huriez et al. [70] found significant psychologic factors in 58.3% of his 72 cases.
Lerner [29] found among his patients that 30% claimed an antecedent emotional
upset, that 39% could cite an antecedent accident, illness, operation, or parturition, and that only 31 % were unable to associate their condition with any
type of stress event. In another series [13], 40.75% implicated local trauma,
17.5% gastrointestinal complaints, 8.25% emotional upset and insomnia, 2.5%

pregnancy and delivery, 1.5% operations and accidents, and 5.5% miscellaneous illnesses; 25% could identify no single precipitating event.
Certainly many patients link the onset or progression of their disease to
specific physically or emotionally traumatic events. However, such events may
heighten individual awareness of oneself and permit discovery of a previously
established but unnoticed pigment defect.
Psychologic Factors
Reporting on a patient whose leukoderma began after the Jamaican earthquake of 1907, Pearson et al. [8] comment skeptically, "We do not wholly
dismiss shock as a possible initial source but only wish to indicate that neither
shock nor sudden illness seems essential."
The literature is replete with cases of "acute vitiligo" attributed to various
emotionally traumatic events. In a young girl with vitiligo, the depigmentation
became generalized after an explosion [71]. Another young girl thought she
had developed vitiligo overnight; the morning after she had been nearly hit by
gunfire, she awakened to note the presence of macules of vitiligo [72]. After a
woman was found to have a malignancy, her father and daughter developed
vitiligo [39]. Abrupt onset was observed by the wife and the son of a man
revealed to be homosexual. The authors [73] suggested that vitiligo represents
an equivalent or consequence of traumatic anxiety or the equivalent of object
loss.
Gajwani and Seghal [74] have reported a woman in whom hypnotherapy
led to repigmentation of perioral vitiligo.
A significant increase in the incidence of psychologic trauma has been
reported among vitiligo patients as opposed to controls [75]. This raises the
question of the premorbid psychologic constitution of the afflicted individual
or a "vitiligo personality." The psychiatric profile of 16 other patients with
vitiligo was found to include de~nite premorbid abnormalities including neurotic behavior, psychomotor agitation, insomnia, and emotional immaturity
[76]. Only four of the cases displayed significant psychologic reaction to the
disease. However, 12 had been able to associate their vitiligo with a specific
emotional event, and in several there was particular symbolic meaning to the
localization of the macules (genital involvement in a man whose wife was
unfaithful, vitiligo of the feet in a prisoner, and vitiligo of the abdomen in a
pregnant female).
It has been suggested that emotional factors are of greatest significance in
acrofacial vitiligo and of least significance in the zosteriform type.
While it is possible that these observations may be explained by a neuropsychiatric factor responsible for vitiligo-a mediator acting at the terminal
end plate or at a more central level such as the hypothalamus to inhibit the
melanogenic pathway-all of these anecdotes-must be interpreted with caution.
In most people, emotionally significant events occur, yet vitiligo is uncommonly the result. Furthermore, there is always, in the phase of development
of the condition, a tendency to feel compelled to affix "blame," and here emotional trauma may be found causally guilty but be, in fact, only casually present.
Cause and effect is not established. Since the presence of the leukoderma must

141

GENETIC AND
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CHAPTER 1

evoke some emotional reaction, particularly among dark-skinned people, one

must expect a period of adjustment in the image of self. How well and how
rapidly it is accomplished must be a function of the premorbid personality.
Becker and Obermayer [77] also noted the majority of their patients to be
neurotic. They found that regardless of presence of absence of specific precipitating factors, the condition did have major secondary psychological effects,
particularly in the dark-skinned peoples. Obermayer [78] also found a greater
incidence of vitiligo among psychotics than among general dermatology clinic
outpatients.
Certainly many vitiligo patients harbor special feelings about their disease.
While some accept their vitiligo as a curiosity, others are deeply distressed.
The following is an actual verbatim precis a vitiligo patient wrote to one of us
about herself and her condition:
Many people seem to believe that it shouldn't bother me, because it isn't painful.
Sure it isn't painful but it certainly is doing a job on me mentally.
I began getting this ugly skin problem at 18 years of age. At first I got just a few small
patches and I assumed I would take after my uncle who hasn't very much of it. I
could have lived with that. My sister also has vitiligo. She started getting it after her
two children were born and hasn't too much of it.
It wasn't long before I came to realize that I was taking after a different uncle who
has it much worse. When I got married at 20 I still had it only slightly. One year later
I had a daughter and it started spreading. Now at 30 I have two children and I am
quite covered with vitiligo. I had it on my face at one time. Now I have it on my
hands, arms, feet, legs, back and neck. I was lucky in one respect, and that is that I
didn't have it as a child. Children can be so cruel to another who is different. Most
adults are mature enough to realize it isn't something we wanted or a fault of ours.
Yet there are still quite a few cruel and stupid people who will snub or point you
out in a crowd. I once wore shorts and a halter top to the mall and I sat on a bench
to rest. A grown man saw me and pointed me out to the woman he was with and he
was so upset over the sight of me I figured I'd best leave before he gets sick. I have
been told it looks like funny road maps all over me, or that I look like someone threw
a bottle of bleach at me, or that I must have been in a terrible fire. These all have a
definite way of making me feel very ugly.

Well, I have had vitiligo almost half my life and to be honest I feel as though life
stopped somewhere around age 23 or so for me. This is when it started getting bad.
Since then I have been in a sort of limbo waiting for a miracle cure to take place. I
am not enjoying life the way it was meant to be. I am simply existing, waiting for my
cure so I can catch up with and join the rest of the beautiful people. I may sound
bitter about this and maybe I am. I don't recall doing anything bad enough to deserve
this, and why has it been decided for me to have it instead of you, anyway? Why did
I get it now instead of when I got real old and wouldn't care? People expect me to
just accept it and continue on. I wonder if, in my shoes, they could, and if they had
two beautiful children who have a good chance of getting it, would they just sit and
say "This is fine, we don't mind if we're covered with crud, if we're stared at, snubbed,
laughed at." Would they really just take it as easily as they expect me to? They can't
possibly answer as they really haven't any way of knowing how it actually is till they
have been there.
Before I joined the ugly group, I used to work next to a woman covered with vitiligo.
I, like all the rest of the human race, couldn't talk to her. All I could do was look the
other way and think "My god, is she ever messed up!" Well if I were she I would
rather be dead than go through life like that. I wish I could have spoken to her as if
she were normal. So I do realize how people feel about us ugly ones. People can't
accept anything that is less than perfect and that is why I can't accept it.

Friends try to tell me not to let it bother me, to get into a bathing suit and go to the
beach. The fun I may have isn't worth the snubs, pointed fingers, and gossip. I get
these disgusted looks, as if "Here she comes, the walking talking horror show." I feel
I should join the circus as one of their freak acts. They have the snake man, albino
lady, fat lady, now what they need is the bleach lady. I feel like "Casper the friendly
ghost." All I want is to be friends, but the sight of me makes people feel ill at ease,
very uncomfortable with me.
When the doctor asked me what vitiligo means to me, my first answer was that I feel
like a mistake. If it isn't a mistake then all you one-colored-persons are the mistake.
I don't see all you one-colored-persons trying to get bleached out till you're two colors.
So this shows that it is just that: I am a mistake!
I believe if there were no hope for me I would crack up, but if I were lucky I would
end it all first. They say where there is life there is hope. The doctors say they will
treat me only as long as I am repigmenting. At least fully dressed, with long pants
and long sleeved shirts, I look almost like one of you humans. To be rid of vitiligo
would be like being reborn for me, to be normal and happy,

Perhaps this patient is a bit more overtly angry and hostile about her
affliction than most, but some of her expressed feelings exist to a lesser or
greater degree in many vitiligo patients we see. However, whether or not there
is a preexistent vitiligo personality is uncertain.
One study has attempted to catalogue the psychologic ramifications of
vitiligo. These were found to include inferiority complexes, variable aggressiveness, shame, seclusion, and resentfulness [79]. The following factors were
found to be important to the adjustment of the patient to the condition: the
premorbid psychologic makeup, the anatomic area of the body involved and
the social, economic, and physiognomic importance thereof (most difficult for
adolescents and very young adults), the insidious or acute nature of the condition (patients adjust better to slow evolution than to abrupt changes), and
the duration of the condition and course (rate of progression). A certain emotional adaptation seems to occur over time; patients "learn to live" with their
condition and after a time no longer actively seek treatment.
Many of the patients who present for treatment of their vitiligo are aggressive and often angry individuals. It may be that this behavior pattern results
from the condition, but more aggressive patients are those more likely to seek
treatment. Since dermatologists generally see only those patients who seek
treatment, it may not be correct to assume that the personality profile of vitiligo
patients who seek help is representative of the vitiligo population at large.
Physical Trauma
Some patients have attributed their vitiligo to actual physical injury [29].
Vitiligo has been observed to begin at the site of a recent injury. Onset of vitiligo
of the neck was observed after contusion of the occiput [80] in one patient and
a direct blow with a bowling ball to the right temple area seemed to result in
segmental vitiligo of the right side of the face in another. In one case, whitening
of the scalp and pubic hair was first observed six months after a contusion.
There are many other cases of vitiligo appearing after head injury [32]. An
occasional patient may report hislher vitiligo initially began on a site of trauma
or at a surgical site and later spread centrifugally or new macules developed

143

GENETIC AND
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elsewhere. Curiously, there are several reports of vitiligo appearing at sites of,
and corresponding to, the array of injuries incurred four to five years earlier
[81].

This development of vitiligo induced by physical trauma is referred to as

the Koebner or isomorphic phenomenon. Injury may precipitate the initial
macule, or cause pigmentation in patients with well-established vitiligo. In a
patient with vitiligo, a laceration may heal with a depigmented scar; if the
wound is sutured, not only the laceration but also the entry and exit wounds
of the suture needle may become depigmented.
Influence of Pregnancy and Oral Contraceptives
Several observations have led to the suggestion that estrogens or progesterones may somehow precipitate vitiligo. Other pigmentary changes, namely
areola hyperpigmentation and melasma, both occur commonly during pregnancy. In women, vitiligo most often develops between menarche and menopause (not surprising, as this encompasses a span of 30 to 35 years). A few
patients have reported onset or exacerbation of vitiligo during pregnancy. In
fact, several authors have described a "gravidic vitiligo" [83-84]. Three reports
of development of vitiligo after the termination of pregnancy, by abortion in
one case, suggested a sudden decrease in circulating estrogen or progesterone
levels as the precipitating cause [12]. In one Indian series [13], pregnancy and
delivery were thought to precipitate vitiligo in 2.5% and to cause significant
worsening in 6.5%. In another series, of those patients who attributed their
vitiligo to a specific event, 20% related it to pregnancy or abortion [15].
But it appears that pregnancy has no consistent effect on vitiligo. Among
62 vitiligo patients who became pregnant, most observed no change in the
degree of depigmentation during or immediately after pregnancy. Vitiligo increased in severity in 7% and decreased in 3%. However, postpartum extension
was noted in 31 %. In one case, the extent of vitiligo decreased during pregnancy
but then increased after delivery [29]. In another study of 18 women, three
observed spread of vitiligo during pregnancy, whereas in four it improved and
in the remainder it was unchanged [6]. One vitiligo patient became pregnant
five times with never any apparent effect on her vitiligo.
The effect of oral anovulatory agents on vitiligo has also been considered.
Regolisti et al. [85] noted one woman whose vitiligo improved while she was
taking oral contraceptives. Among 10 patients using anovulatory agents, Ortonne [39] found no effect on the vitiligo. The use of oral contraceptives has
become very widespread and there is no evidence to implicate these agents in
the exacerbation or remission of vitiligo.
Sunlight and Artificial Ultraviolet Radiation
The appearance of vitiligo following sunburn, artificial ultraviolet radiation
burn [86,87], or suntan suggests that ultraviolet radiation is a precipitating
factor in vitiligo. Seven of the 100 cases of Ortonne [39] first noticed their
vitiligo after an acute sunburn reaction and delayed tanning. Lerner [29] also
noted that in 15% of his cases sunburn was associated with the spread of vitiligo.
The appearance of vitiligo following a good tan without preceding sunburn

reaction has also been reported [35]. A role of sunlight is further suggested by
the fact that in about 70% of cases, vitiligo seems to appear first on sun-exposed
areas of the skin-80% [29], 70.9% [6], 66% [39], 53% [32], according to various
series. However, vitiligo is a well-known Koebnerizing disease and onset or
spread following a burn is an example of this phenomenon. Among lightskinned people and on normally unexposed cutaneous areas of any Caucasian,
newly acquired vitiligo macules may not be noticed until the normal skin
becomes tanned enough to provide contrast. This may explain why most of the
vitiligo patients date the onset of vitiligo to spring [39].
Vitiliginous skin is more sensitive to sunburn than is normally pigmented
skin [88]. A decreased minimal erythema dose in macules of vitiligo [89] and)
increased tendency to sunburn in macules of vitiligo compared to normally
pigmented skin of the same patient [90] is well established. Patients who normally tan well and who rarely if ever burn their normal skin may develop a
severe acute sunburn reaction in their vitiligo macules but not on their normally
pigmented skin. Some patients do observe hardening, that is, their vitiligo
macules are less likely to burn after several sun exposures than with the initial
exposure of the season. This has been attributed to ultraviolet radiation-induced
thickening of the stratum corneum of vitiligo macules; this thickening, in turn,
is somewhat photo protective to the vitiligo macules [91]. This phenomenon is
probably of minor clinical significance however.

Clinical Findings
Typical Lesions
The typical lesion of vitiligo is a discrete, well-circumscribed, chalk-white
macule, a few centimeters in size, with sharp, convex margins (Fig. 46). Although the margins of the lesion are sharp, they are not so sharp or punchedout as are lesions of idiopathic guttate hypomelanosis. Often the vitiligo macules appear to be invading the normally pigmented skin (Fig. 47). There are
usually no other epidermal changes and the skin appears otherwise normal.
Color of Macules
The most common form of vitiligo is a totally amelanotic macule surrounded by normal skin. The color of the macule is usually uniformly pure
white or chalk-white. In very fair-skinned people, the lesions are not very
apparent but are easily distinguishable with Wood's light examination or after
delayed tanning of uninvolved skin. In dark-skinned people, the contrast between vitiliginous skin and normally pigmented skin is striking, even in habitually unexposed areas of Skin Types V and VI.
While vitiligo macules are characteristically uniformly chalk-white in color,
two other pigmentary changes are observed in many cases. In addition to totally
depigmented white macules, there may be pigmentation that takes on an intermediate tan (trichrome) color, and hyperpigmented dark brown islands either
within or at the periphery of these vitiliginous patches. All these color reaction
patterns may occur in a single patient, or either trichrome or hyperpigmented

145

GENETIC AND
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CHAPTER 1

FIGURE 46. Typical macule of

vitiligo. Margins are discrete. The
lesion is amelanotic (3 + leukoderma). The pigmented macules
within the lesion occurred during psoralen therapy. This is an
example of segmental vitiligo.

Few remaining pigmented macules in a patient with vitiligo; hypomelanosis seems

to invade pigmented areas.

FIGURE 47.

macules may accompany the depigmented macules. The presence of all these
color patterns together-normal, achromic, trichrome, and hyperpigmentedwe refer to as "quadrichrome."
The third color, or trichrome (tan), on rare occasions, is the only feature
of vitiligo; usually there is a tan zone of varying width between the normal
and the totally depigmented skin and this exhibits the intermediate hue. The
term "trichrome vitiligo" was suggested in 1964 by Fitzpatrick [41] who observed this gradual change of color from milk-white in the center through light
tan to normal brown at the periphery of the lesions in both Caucasian and darkskinned individuals (Fig. 48). Siemens [92] called this "vitiligo gradata." The
German term "Stufen-Vitiligo" (vitiligo by steps) also denotes this phenomenon.
Lerner [29] also noted around depigmented macules a "lightly colored broad
band, one to three centimeters in width," but observed the intermediate hue
to be surrounded peripherally by a hyperpigmented border, an observation not
commonly made by others (and named quadrichrome by us). This intermediate
hue is particularly accentuated in those who tan deeply. Trichrome is not a
gradation of color from white to normal, but rather a fairly uniform intermediate
hue; the color is generally uniform from macule to macule in a given patient.
Sometimes the entire vitiligo macule is only hypopigmented and not totally
depigmented. These lesions have an intermediate, uniform tan color identical
to the light brown color of trichrome. All of these types of hypomelanosis may
coexist in a single patient.
Several reports show trichrome to be part of a dynamic process. Dupre et
al. [93,94] reported "cockade vitiligo" in a fair-skinned French boy and in a
North African who had usually two but sometimes more trichrome concentric
rings or lines surrounding an achromic line corresponding to former scratches.
This was the first description of trichrome as an isomorphic phenomenon. Small
achromic macules in the intermediate hypochromic area and numerous brown
speckles were also observed. A gradually spreading "symmetrical primary leukomelanoderma" described by Basset [95] and Sarrat and Nouhouayi [96] in
black patients is also probably trichrome vitiligo.
The significance of trichrome is unknown, but clearly it is a metastable or
transitional pigmentary state, though it may persist for months to years with
little change. Fitzpatrick [41] and Pincus [97] interpreted trichrome as suggestive of a gradual centrifugal spread of hypomelanosis or stepwise depigmentation. But Dupre et al. [93,94] pointed out that the sharp demarcation between
the three areas in their cases, as well as the lack of gradual changes of color
and the stability of the lesions, is inconsistent with the interpretation of trichrome vitiligo as an active centrifugally spreading lesion. Evidence for the
lack of stability, however, includes the observation that when a trichrome area
repigments, the trichrome is lost as the perifollicular dots appear (unpublished
observation).
Other color changes are also described. Sidi et al. [35] mention "vitiligo
ponctue," small depigmented macules occurring on a hyperpigmented macule.
These confetti or tiny discrete hypomelanotic macules may also occur on otherwise normally pigmented skin (Fig. 49). "Speckled vitiligo" or "vitiligo
mouchete," as described by Sezary and Dupuy [98], denotes pigmentary islands
scattered throughout the vitiliginous macules. These macular islands are perifollicular and represent repigmentation arising from the hair follicles. Occa-

147
GENETIC AND
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CHAPTER 1

FIGURE 48. Trichrome vitiligo. a:

Sheets of trichrome; area of trichrome
seems much larger than that of amelanosis . Note the uniformity of the trichrome fields. Confetti spots are also
present. b: Trichrome of the upper back.
c: Extensive trichrome vitiligo; dark macules represent only remaining areas of
normal pigmentation.

sionally in dark-skinned people (Negro, Indian, or Asiatic), the depigmented

macules may have a faint gray-blue hue because of the presence of melanin in
the dermal macrophages.
A hyperpigmented margin around a macule of leukoderma has been said
to be specific for vitiligo. This is not, however, a common feature of vitiligo;
Seghal [17] observed hyperpigmented borders in only 11 of his 202 patients.
Hyperpigmented borders may also be seen in tinea versicolor.
Erythema representing acute sunburn reaction in the vitiliginous macules
may follow prolonged sun exposure. Erythema of a margin of a vitiligo macule
is sometimes present; this represents the uncommon "inflammatory" vitiligo.

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GENETIC AND
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Confetti hypomelanosis in two

vitiligo patients. a: Close-up view of confetti
macules; considerable trichrome is present. b:
Confetti macules with trichrome and many
larger macules of typical amelanotic vitiligo.
FIGURE 49.

150

Shape, Size, and Margins of Macules

CHAPTER 1

Generally, vitiligo macules have fairly discrete margins and are rounded,
oval, or linear in shape (Fig. 50). The borders of these lesions are usually convex,
as if the depigmenting process were "invading" the normally pigmented skin
[32]. The concave borders of the normally pigmented skin in a vitiligo patient
may help to distinguish a remaining pigmented macule in a patient with generalized vitiligo from an isolated area of hyperpigmentation in a very fairskinned individual (Fig. 51). In the former, remaining pigmented skin has
concave borders and in the latter "abnormally" pigmented skin shows convex
borders. Vitiligo macules enlarge centrifugally over time but the rate of change
may be slow to rapid.
In trichrome vitiligo, the presence of a tan band of varied width between
the normally pigmented skin and the depigmented macule of vitiligo may give

FIGURE 50. a and b: Contour of

typical vitiligo macules which
appear to be invading normally
pigmented skin.

151

FIGURE 51. a and b: Irregular margins of macules of normal pigmentation surrounded by vitiligo.
The concave borders portray the invasive nature of vitiligo.

a feathered appearance to the margin of the vitiligo macule, but close inspection
reveals a distinct margin between normal skin color and the intermediate hue
and also between the latter and the white central area.
Generally, the macules of an area of involved skin have no uniformity of
size. Vitiligo macules may be millimeters to centimeters in size (Fig. 52) and
increase centrifugally in size over time. Several sizes often prevail in a single
patient. The macules become confluent and develop serpiginous margins as
they enlarge and coalesce.
Lichenification, inflammation, and raised borders have, on a few occasions,

FIGURE 52. Macules may be variable in size. a: Small macules on knees; confetti spots are also
present. b: Large macules with a few small macules on knees; trichrome is also apparent.

GENETIC AND
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CHAPTER 1

been observed at the margins of the depigmented macules. Several authors

[99-101] reported lichenification of the borders of the macules, but this is likely
a variant of the "raised border" type of vitiligo (Fig. 53). Garb and Wise [102]'
who reported one such case in 1948, mentioned that they had found only two
other cases in the literature; however, other cases have been reported [103-109].
Of seven patients, three were females and four males, five to 47 years of age
[110] . In two cases, inflammation preceded depigmentation; in two others,
raised erythematous borders were first observed two months after the vitiligo
was first noted in one patient and seven years later in the other. One patient
also had mild pruritus. Michaelson [105] suggested an "increased sensitivity"

FIGURE 53. a and b: Inflammatory vitiligo with raised borders which usually are somewhat erythematous. The raised
border represents an advancing
front of depigmentation.

of the margin. Certainly the raised margins are a rare macroscopic presentation
of what must be characteristic of active vitiligo macules-some degree of inflammation at the margins of the macules of progressive lesions. Vitiligo macules with raised margins otherwise resemble those with flat margins.
Number of Depigmented Macules
The number of lesions varies considerably from one patient to another.
Levai [12) noted that 118 of her 410 patients had single lesions. whereas the
remaining 292 averaged lesions in three different locations. While some individuals have only one macule which remains little changed for a long period
of time. others have up to several hundred macules and seem to develop new
lesions periodically. The vitiligo may be so extensive that depigmentation of
the entire skin occurs. The number of macules present in a patient usually
increases with age but may remain the same or rarely decrease spontaneously.
Distribution of Depigmented Macules (Fig. 54)
Vitiligo has distinguishable patterns. Vitiligo lesions may be localized or
generalized. the latter being more common. Localized vitiligo involves vitiligo

FIGURE 54. Typical distribution pattern of vitiligo.

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GENETIC AND
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154
CHAPTER 1

macules restricted to one general area including a segmental or quasidermatomal distribution. Segmental vitiligo is vitiligo roughly corresponding to areas
of innervation of one or more of the cutaneous nerves, is strictly unilateral,
and does not extend beyond the midline. Generalized vitiligo implies more
than one general area of involvement; the macules are usually found on both
sides of the trunk either symmetrically or asymmetrically arrayed (Fig. 55).
Segmental involvement may coexist with generalized vitiligo (mixed type).
Dutta and MandaI [13] found bilateral lesions in 74.5% of their 650 cases. Seghal
[17] observed unilateral lesions in 11 of his 65 patients with upper limb in-

FIGURE 55. a-c: Examples of symmetrical generalized vitiligo; similar areas are involved on each side,
although one side is not the mirror image of the other.

volvement and in 16 of 107 patients with leg involvement. Dutta and MandaI
[13] found unilateral focal or segmental lesions in 25.5% of patients.
Although vitiligo may occur anywhere on the skin, there are characteristic
patterns of involvement. One of the most fascinating features of the localization
of vitiligo is its frequent localization to the sites that are normally hyperpigmented, such as the face and dorsal hands (facultative tanning reaction), axillae,
umbilicus, nipples, sacrum, and inguinal and pudendal regions (constitutive
color) (Fig. 56).
Typically, vitiligo occurs around the eyes and mouth (periorificial), the
anterior neck, extensor elbows and digits, perineum, palmar wrists and dorsal
ankles, anterior tibial regions, and low back (Figs. 57, 58). Dutta and MandaI
[13] found the most commonly involved sites to be the lower extremities,
particularly the pretibial areas (27.5%), the upper extremities with maximum
involvement of the hands (22%), the face (20.5%), the hair (8.7%), the chest
(5.8%), the neck (4%), the back (3.7%), and the abdomen (3.6%). In 365 Indian
patients, 72% had involvement of the legs, 57% the feet, 55% the arms, 51%
the back, 50% the face, 47% the chest, 47% the hands, and 31% the neck
(personal observations). Seghal [17) noted that women are more likely to have
involvement of the face, arms, and legs, while the chest and back are more

FIGURE 56. Vitiligo is commonly observed

to involve areas that are usually hyperpigmented such as areolae (a) and genitalia (b).

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GENETIC AND
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156
CHAPTER 1

FIGURE 57. Typical case of generalized vitiligo involving dorsal hands, including periungual areas (a), extensor forearms (b), axillae and
low back (c).

commonly involved in males. Other studies have shown involvement of the

upper limbs to be more common than involvement of the lower limbs [391
Many of the most common sites of occurrence of the vitiligo macules are
areas subjected to repeated trauma. Such common sites include the bony prominences (extensor surfaces of joints-elbows, knees, digits, etc.), the extensor
forearms, the ventral wrists, the dorsal hands and distal phalanges, the malleoli,
the prepatellar regions, the skin overlying the greater trochanters, the anteromedial lower legs, the dorsal feet, and the sacrum (Fig. 59). Periungual involvement of one or more digits may be associated with lip depigmentation.
Other typical sites are those in repeated contact with clothing (under a
truss, a belt or garters, shoulder strap, collar area), and the body folds (axillae,
genitalia, perineal areas) where there is repeated friction during movement and
cleansing. The lips, the corners of the mouth, and the eyelids~all frequently
rubbed-often show depigmentation.

157
GENETIC AND
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FIGURE 58. More extensive involvement with vitiligo; large macules of trichrome are present
and trichrome borders many of the amelanotic macules.

Involvement of palms and soles has heretofore not been well appreciated
(Fig. 60). Costa [50] observed palm and sole vitiligo in two Brazilian patients
in 1928; Ferraz-Alvim and Guerner [111] reported one case of palm and sole
involvement in a vitiligo patient with goiter and mental confusion. Ochi and
De Groot [112] reported palm and sole involvement in three of their six patients
who also had Graves disease; they suggested that this distribution of vitiligo
marked the presence of thyroid disease. Seghal [17] makes no mention of palm
and sole involvement but Dutta and MandaI [13] noted that palms, and particularly the soles, are quite often affected. Of our 365 Indian patients, 117 have
palm and/or sole involvement (unpublished observation). Probably palm and
sole involvement in whites is underreported because the normal light skin
color of Caucasoid palms makes vitiligo difficult to visualize without Wood's
light examination.
Mucous membrane involvement (Figs. 61, 62) in vitiligo seems historically
to be uncommon, if not rare. However, the early cases reported by Bate [113]
in 1760, by Jefferson [114] in 1787, and by Brown [115] in 1824 probably had
involvement of the mouth and lips. In 1917, Pusey [116] reported a dark-skinned
patient with vitiligo of the lips. Other isolated cases of mucosal involvement
have been observed on the vaginal mucosae [82] and on the lower lip [117].
Brunnauer [118] stated that vitiligo of the lips occurs only in blacks, but Montgomery [119] described involvement of the upper lip in a Japanese farmer. In
1944, Arguelles-Casals [120] also reported two cases with mucosal involvement,
one in a black and the other in a Cuban. Costa [50] in Brazil observed several

158

CHAPTER 1

FIGURE 59. Typical examples of vitiligo. a: Patchy periorificial involvement; macules of repigmentation on the neck are a result of psoralen therapy. b: Vitiligo of periorbital skin. lips. and

dorsal hands. c: Vitiligo of extensor surfaces, particularly over metacarpal-phalangeal joints and
proximal interphalangeal joints. d: Periungual depigmentation is not uncommon.

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GENETIC AND
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DISORDERS

FIGURE 59 (Continued). e: Vitiligo of upper and mid-lower central back, medial arms , and extensor surfaces of elbows. f: More extensive vitiligo of the anterior lower legs and extensor surface
of the knees . g: Flexor wrists are commonly involved; as in this case, the leukoderma may extend
onto the palms.

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CHAPTER 1

FIGURE 60. Vitiligo of the palms. In this patient some sparing of folds has occurred. Wood's
lamp examination may be required to appreciate palm and sole involvement in a light-skinned
Caucasian.

FIGURE 61.

of the lips.

a-c: Three examples of vitiligo

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GENETIC AND
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DISORDERS

FIGURE 62. Vitiligo macules on the glans

penis.

cases with involvement of the lip. Dummet [121] described an American black
with complete clinical depigmentation of the oral mucosa.
In our study of 365 East Indians we have found lip involvement in 189
(unpublished observation). Of 202 vitiligo patients, Seghal [17] found isolated
mucous membrane involvement in 10.3% of males and 3.8% of females; 28.9%
of males and 26.7% of females had some mucosal involvement (total of 27.8%).
The age of onset of "vitiligo mucosae" was 24.4 16.1 years (20.9 in all types)
and the mean age of reporting was 28 15.1 years , no different from other
types of vitiligo. Lip involvement was equally distributed among men and
women. Genital involvement alone occurred in seven cases, five of whom were
men. Of 100 cases of leukoderma of the lips observed by Coondoo et al. [122],
52% had evidence of vitiligo in other areas; of those with lip leukoderma alone,
many had antecedent lip rashes , suggesting postinflammatory hypomelanosis
or a Koebner reaction.
In many series, mucosal involvement is not mentioned or is said to be rare.
One presumes that the apparent low incidence in Caucasians is a reflection of
the normally light color of the mucosa.
Involvement of Body Hair and Scalp Hair

There may be depigmentation of the body hair in vitiliginous macules.

Involvement is variable; a few or many hairs of a single macule may be amelanotic and not all macules are uniformly involved (Fig. 63).
Dutta and MandaI [13] observed achromotrichia in about 45% of their 650
cases, but Seghal [17] noted leukotrichia to be present in only 18 of his 202
patients. Of 365 of our vitiligo patients, 203 had white hairs in the vitiligo
macules (unpublished observation) . The true incidence reflects how carefully
the patients are examined.
Vitiligo of the scalp usually presents as a localized patch of white or gray

162
CHAPTER 1

FIGURE 63. This patient had extensive vitiligo of his chest yet few hairs were depigmented.

hair, but total depigmentation of all scalp hair may occur. This may occur with
or without vitiligo of associated scalp macules. Vitiligo may involve only the
skin of the scalp though less commonly than the face or neck (Fig. 64). Dutta
and MandaI [13] noted scalp involvement in only 2.5% of their cases. Khoo
Oon Teik [20] observed that forehead involvement often extends to include the
scalp skin and hair. Nearly one-third of our cases had white scalp hair (unpublished observation). Scalp involvement without leukotrichia is probably
much more common than with leukotrichia.
Presence of leukotrichia has been accorded special significance. According
to Lerner and Nordlund [123], people with much gray hair before 30, that is,
those who "are mostly gray by age 25 or 30," but still do not have white spots
on the skin, have vitiligo; this is a broader use of the term vitiligo than we
accept. Dutta and MandaI [13] noted that variable repigmentation, either spontaneous or posttherapeutic, occurs in 59% of cases without achromotrichia,
while it occurs in only 24% of those with white hair. They concluded that
absence of hair depigmentation is a favorable prognostic sign. Our studies do
not support this conclusion (unpublished observations).

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GENETIC AND
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DISORDERS

b
FIGURE 64. Macules of vitiligo extending onto the scalp line. a: Scattered hairs are amelanotic.
Some macules of psoralen-induced repigmentation are apparent. b: Extensive depigmentation of
hair in woman with vitiligo of the face, scalp, and neck.

Such dissociated behavior of follicular and nonfollicular melanocytes is

not unusual in vitiligo. Often there are isolated or few macules of normal
pigmentation within vitiligo macules. These, except on palms, soles, and mucosal surfaces, occur around hair follicles. The follicular melanocytes seem to
retain their pigment while those of the dermal-epidermal junction do not.
Spontaneous or light-induced repigmentation appears to arise in most cases
from these follicular reservoirs [124]. The basis of this dissociated sensitivity
of follicular and nonfollicular melanocytes is still not understood [125].
Sites of Trauma and Isomorphic (or Koebner) Phenomenon

A unique feature of the normally pigmented skin of patients with vitiligo

is that hypomelanosis may result from injury inflicted by physical trauma, such
as that induced by a sharp instrument [32]. This Koebner or isomorphic phenomenon is a constant and unique feature of vitiligo and is helpful in differentiating lesions of localized vitiligo from the white macules of piebaldism
(Fig. 65) in which the isomorphic phenomenon does not occur.
The Koebner phenomenon explains much of vitiligo that commonly localizes to skin areas exposed to single or repeated bouts of trauma. Levai [126]
studied the relationship of pruritus and various localized skin conditions to

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CHAPTER 1

FIGURE 65. The Koebner or isomorphic phenomenon is leukoderma developing in sites of trauma.
The macules are usually remarkably linear or correspond to the shape of the offending agent. a:
Scratch macules. several with trichrome. b: Vitiligo from pressure of a Canadian crutch. c: Site of
a laceration; note leukoderma along laceration and with suture lines. d: Trichrome vitiligo or an
isomorphic phenomenon. (From: Dupre A et al: Une variante du vitiligo trichrome de Fitzpatrick:
vitiligo en concorde et vitiligo lineaire sur cicatrice. Bull Soc Fr Dermotol Syphiligr 81:530-532,
1974. Copyright, 1974, Masson et Cie. Used with permission.)

the development of vitiligo. Whenever another cutaneous condition, pruritic

or not, involved a patient with vitiligo, there was an increased chance that the
primary eruption would clear with resultant depigmentation. There were cases
of depigmentation of the waist where the Indian sari string bound very tightly,
of the lips in heavy smokers, and of the forehead in a person who habitually
wore a hat. Fifteen percent of her patients had depigmented lesions in such
areas of constant pressure or irritation. This suggested that in the presence of
a vitiligo diathesis, irritation or pruritus may determine a site of depigmentation. Bleehen and Hall-Smith [127] reported a case of marked depigmentation
of the skin in areas in direct contact with an elasticized brassiere containing
Spandex yarn. The authors suggested that this probably represented an isomorphic phenomenon. The isomorphic phenomenon seems to be the best explanation for onset or spread of vitiligo after ultraviolet radiation exposure.
Significant injury appears to be required to cause Koebnerization. Gopinathan [128] showed that epidermal scarification adjacent to vitiliginous macules left depigmented scars in nine (69%) of 13 vitiligo patients; scarification
of totally uninvolved skin resulted in depigmentation in five out of 13. Only
one of the 13 controls subjected to the same trauma developed depigmentation.
On the other hand, epidermal trauma by stripping with cellulose tape failed
to produce depigmentation in any of the vitiligo patients. Thus, while there is
a propensity for depigmentation in traumatized clinically normal skin in vitiligo subjects, there appears to be a minimal threshold of injury required for a
Koebner phenomenon to occur.
Clinically these isomorphic depigmented lesions are easily recognizable
by their artifactual or elongated "streak-line" shape. Over 30% of our patients
show such a finding (unpublished observation). The isomorphic phenomenon
can also take on the appearance of trichrome [93,94].
While most lesions probably develop two to four weeks after the injury,
scratches or scars that occur as much as five years prior to the appearance of
vitiligo may become achromic once the vitiligo develops. One teenager scratched
out the girl's name "Mandy" on his forearm; months later when the incident
had been long forgotten, vitiligo appeared elsewhere and the letters of Mandy
reappeared as vitiligo [81].
Lerner and Nordlund have applied the term "veloce vitiligo" to rapidly
evolving vitiligo after physical or emotional trauma [123].
Clinical Classification of Vitiligo

There have been many attempts to classify types of vitiligo, often with
confusing results. The classification of vitiligo is usually based on the distribution or localization of hypopigmented macules. A common classification
provides four general types of vitiligo as follows:
Focal: One or several macules in one area (Fig. 66).
Segmental: One or more macules more or less along one or more dermatomes, always unilateral (Fig. 67).
Generalized: Macules distributed over several or more areas of the skin,
mayor may not be unilateral (Fig. 68).
Universal: Extensive vitiligo with only a few or no areas of normal pigmented skin remaining (Fig. 69).

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FIGURE 66. One discrete macule of vitiligo on the

shoulder. The three pigmented macules are the result
of psoralen therapy.

Of 365 vitiligo patients in our series from India, 17 were classified as focal,
nine as segmental, 339 as generalized, and none as universal (unpublished
observations) .
The classification system is important because of special significance assigned by some to each type of vitiligo. For example, vitiligo vulgaris is reportedly more common in women and vitiligo zosteriformis and mucosal vitiligo in men. Vitiligo acrofacialis has been reported to be slightly more common
among females than males, although this seems unlikely. Zosteriform vitiligo
may have the earliest age of onset and acrofacial and mucosal later onset. In
response to psoralen therapy, vitiligo areata (focal) does better than vitiligo
acrofacialis; mucosal types do poorly. Zosteriform or segmental types are not
necessarily poor responders (unpublished observations).
Many classification systems have been proposed. Robert [18] distinguished
localized, bilaterally symmetrical, asymmetrical generalized; and lateral, asymmetrical, and symmetrical exanthematous forms.
Another classification system [20] distinguished three groups: peripheral,

FIGURE 67. Segmental vitiligo

affecting the inferior chin and
upper neck. There is a small hypomelanotic macule inferior to
the right angle of the jaw.

167
GENETIC AND
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FIGURE 68. Generalized vitiligo in two patients. a: All areas are not uniformly involved. The
arms still have large areas of normal pigmentation but on the abdomen most of the skin is vitiliginous. b: Koebner phenomenon across abdomen at the site of a surgical scar.

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CHAPTER 1

FIGURE 69. Vitiligo universalis. a: Vitiligo universalis

in a black patient with alopecia areata totalis; only a few
macules of pigment remained. Neither of his children have
vitiligo. b: Total body vitiligo with white hair. c: Face of
woman with vitiligo universalis.

central, and mixed vitiligo, the latter combining the first two types. Each of
these groups is further divided into the blotchy (massive) and punctate (discrete) types.
Lerner [29] suggested three groups: (1) segmental, localized, partial or iocal
vitiligo, corresponding to a dermatome or adjacent dermatomes; (2) generalized
vitiligo or vitiligo vulgaris involving hands, face, axillae, and occasionally also
macules in a segmental array; and (3) complete, total or universal vitiligo of
all or nearly all the skin. Among 25 vitiligo patients, Lerner noted 21 with
generalized, three with segmental, and one with total vitiligo.
Dutta and MandaI [13] found 74% of their 650 cases to have one of two
types of multifocal vitiligo. Both types-vulgaris and acrofacialis-are nearly
bilaterally symmetrical. Vulgaris, occurring in 51 %, was often symmetrical but
scattered over different parts of the body, whereas acrofacial, affecting 23%,
primarily involved the distal arms and legs, principally fingers and toes, palms
and soles. Perioral and forehead skin, and occasionally other areas, were sooner
or later involved.
Dutta and MandaI found zosteriformis or pseudosegmental vitiligo in 21%.
The areata (focal) form, characterized by one or two isolated lesions remaining
stationary for months to years, was found in only 4%; this was considered to
be a transitional or early phase of vitiligo vulgaris.
A periorificial distribution which often accompanies generalized vitiligo
is well recognized and involves the perioral, periorbital, and perianal skin.
Macules may also occur elsewhere (Fig. 70).
Koga [129] suggested Type A (nondermatomal) and Type B (dermatomal).
Based on sweat stimulation studies, Type A was considered an autoimmune
disease, had normal sympathetic function, and responded to steroids. Type B,

FIGURE 70.

Periorificial vitiligo; the lips are extensively depigmented.

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GENETIC AND
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CHAPTER 1

with sympathetic dysfunction, was treatable with oral nalimide. This distinction remains to be confirmed.
Goudie et al. [130] suggest the variants of generalized vitiligo are a function
of underlying associated disease. They noted eight cases of vitiligo on the
eyelids and skin overlying the thyroid gland; two of these were thyrotoxic.
Other variants included the following: an ankylosing spondylitis variant, affecting skin over the sacrum, vertebral column, shoulder girdle, tibial tuberosities, and anterior chest wall; an ulcerative colitis variant affecting the groin
and abdominal wall; and a rheumatoid arthritis variant with depigmentation
overlying affected joints. A reciprocal pattern sparing normally involved areas
was also suggested.
Seghal [17] observed vitiligo mucosae in which only mucous membranes
are involved.
The following classification recognizes the most common patterns described:
A. Localized
Focal: One or more macules in one area, but not clearly in a segmental
or zosteriform distribution (Fig. 71).

FIGURE 71. Focal vitiligo.

Segmental: One or more macules in a quasidermatomal pattern (Fig.

72).

Mucosal: Mucous membrane alone.

B. Generalized
Acrofacial: Distal extremities and face (Fig. 73).
Vulgaris: Scattered macules (Fig. 74).
Mixed: Acrofacial and vulgaris, or segmental and acrofacial and/or vulgaris.
C. Universal: Complete or nearly complete depigmentation (Fig. 75).
Whether or not this classification system is an improvement over other
systems depends on whether or not it provides a useful segregation of vitiligo
types. In our experience, over 90% of vitiligo patients are of the generalized
type. Localized vitiligo is more common than universal vitiligo, which occurs
in less than 10% of cases. Localized (focal and segmental) types are unlikely
to spread. Acrofacial types may not do quite as well with psoralen therapy.

FIGURE 72. Segmental vitiligo.

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GENETIC AND
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CHAPTER 1

FIGURE 73. Acrofacial vitiligo.

Universal types may be more likely to have associated diseases. Mixed types,
particularly acrofacial or vulgaris with a segmental pattern, are an enigma. The
more generalized areas in these patients may be progressive, whereas the segmental pattern may be relatively stationary.
Course of the Disease
Mode of Onset
The onset of vitiligo is insidious. Most patients become aware of depigmented patches on their skin, often in the anogenital area and particularly on
sun-exposed areas during spring or summer when repeated sun exposures
increase the contrast between involved and uninvolved skin.
Curiously, the exact evolutionary appearance of early lesions is unknown,
but probably the early macules gradually uniformly lose pigment until a discrete

173
GENETIC AND
CONGENITAL
DISORDERS
KOEBNER PHENOMENON
IN SITE OF TRAUMA

FIGURE 74. Vitiligo vulgaris.

white macule is apparent, perhaps up to several centimeters in size; the macule

then enlarges centrifugally. The onset of the disease is usually asymptomatic.
Clinical erythema rarely precedes vitiligo. In the earlier French literature,
some authors described the occurrence of a previtiliginous erythema [132 ,133);
this was thought to favor the syphilitic origin of vitiligo. It is likely that most
of these observations, in fact, represent syphilis or other inflammatory dermatoses associated with the development of postinflammatory leukoderma.
Erythema may, however, be associated with vitiligo in two instances: clinically
inflammatory vitiligo, a rare event; and acute sunburn reaction or delayed
erythema, a common occurrence.
Vitiligo appears initially as single or, less often, multiple macules (Table
27). Nearly 75% of the cases state that their vitiligo began with only one macule,
usually located on normally or habitually sun-exposed areas of the skin (Table
28) (53% to 78% of the cases) . Lerner [29) observed initial involvement to be
in sun-exposed areas alone in 78%, in unexposed areas in 14%, and in both in
8%. Among those who reported unicentric onset, Lerner [29) found vitiligo
most common on hands, arms, neck, and face. In 53% of patients, Fitzpatrick
and Mihm [32) found the initial involvement on the head, neck, and/or hands.

174
CHAPTER 1

\ j

FIGURE 75. Vitiligo universalis.

In mapping primary lesions, Mehta et al. [16] found 53% to be on the lower
extremities, 11% on the head, face, neck, and scalp, 7% on the upper extremities, and 5% on the thorax.
Progression and Repigmentation
The course of vitiligo on a case by case basis is unpredictable. Vitiligo
becomes more extensive either by appearance of new depigmented macules,
TABLE 27.

Mode of Onset of Vitiligo (Unicentric or

Multicentric)
Unicentric

Multicentric

Author

(%)

(%)

Dutta and Mandai (1969) [13)

Lerner (1959) [29)
Ortonne (1974) [39)

74
75
73

26
25
27

TABLE 28. Site of Onset of Vitiligo (Exposed or

Unexposed Areas)
Exposed
skin

Unexposed
skin

Author

(%)

(%)

Lerner (1959) (29)

El Mofty (1968) (6)
Fitzpatrick and Mihm (1971) (32)
Ortonne (1974) (39)

80
70.9
53
66

20
29.1
47
34

by centrifugal enlargement of the preexisting lesions, or both. The condition

may appear localized or stable for a long period of time before the appearance
of other depigmented macules. The natural course of the disease is usually one
of slow progression, but it may stabilize or exacerbate rapidly. Of our patients,
12% reported their vitiligo was exacerbating rapidly, 53% slowly, and 35%
were stable (unpublished observations). Cases of total body involvement developing within a few weeks or even in a few days are well known. For example,
Mishima et al. [133] reported a case of "vitiligo fulminans" appearing overnight.
El Mofty [6] observed the shortest period of time for considerable spread to be
two months. Sometimes the patients attributed this acute spread of the disease
to mental stress or physical trauma, including severe sunburn reaction.
Some degree of sun-induced or spontaneous repigmentation is not uncommon in vitiligo, but complete and stable repigmentation is rare. Kaposi [2]
remarked "that both patients and physicians have noted that a white patch may
become again normally pigmented" but he thought these were observational
errors. "The process is incurable," he added. Usually repigmentation occurs as
small perifollicular pigmented macules, often located at the margins of the
vitiligo macules and most often found on sun-exposed areas of the skin. Such
small macules may enlarge in size and increase in number to repigment a
vitiligo macule. In 1927, Christoph [134] reported several cases of "reticular
vitiligo" which appeared to be spontaneously repigmenting. It was first thought
that this perifollicular pigmentation, or "speckled vitiligo" resembling panther
skin, represented perifollicular sparing, that is, pigment that has not yet been
lost. However, Robert [124] correctly observed that repigmentation, spontaneous or induced, is frequently first noted about hair follicles. Most of these
observations of pigmented dots are probably pigment returning rather than
pigment being lost (Table 29).
The prevalence of some degree of repigmentation unrelated to therapy is
between 10% and 50%. Lerner [29] noted "spontaneous" repigmentation, even
though slight, in 44% of all his patients and in 49% of those who had had
vitiligo for two or more years. Dutta and MandaI [13] found 1% of those with
leukotrichia and 5% of those without leukotrichia to have some degree of
spontaneous repigmentation. The incidence of spontaneous repigmentation
was found to be 32% in the patients observed by Fitzpatrick and Mihm [32].
Only 11% of our patients reported spontaneous repigmentation (unpublished
observations). An occasional patient does repigment to a significant degree with
sunlight alone. Few patients give a history of totally repigmenting a macule

175
GENETIC AND
CONGENITAL
DISORDERS

TABLE 29. Incidence of Spontaneous Repigmentation of Vitiligo

176

Spontaneous
repigmentationa

CHAPTER 1

Author
Lerner (1959) [29)
Dutta and MandaI (1969) [13)

Fitzpatrick (1964) [41)

Fitzpatrick et al. (1974) [31)
Ortonne (1974) [39)
Parrish et al. (1976) [135)
a

(%)
44
6
(1 leukotrichia)
(5 without leukotrichia)
30
10
22
(20 sun-exposed skin)
(2 unexposed skin)
0

Total no.
of patients
179
650

430
84
100
26

Not generalized, but in small perifollicular macules.

without treatment. It is rare for a significant degree of repigmentation to occur

and extraordinary for total repigmentation to be seen. Patients need always be
aware that there is little hope for spontaneous repigmentation. While repigmentation occurs in one area, progression may occur elsewhere.
The mechanism of spontaneous repigmentation is unknown, but it does
appear that "spontaneous" is largely ultraviolet-induced or "sun-induced" repigmentation, as most of the macules that repigment do so over the summer
and in sun-exposed areas of skin.
In summary, the natural course is one of slow progression marked with
periods of stability followed by times of progression, occasionally rapid. In
most cases the course is predictable based on past history, but rapid depigmentation in a patient who has had stable vitiligo may occasionally occur.
Pruritus
Usually, vitiliginous macules are asymptomatic, but occasionally the vitiligo skin may be pruritic. Of 75 cases [136] reported as "vitiligo" associated
with pruritus generally confined to the white macules, 59 patients in fact had
prurigo, chronic eczema, or neurodermatitis, and likely a postinflammatory
hypomelanosis, not vitiligo. But the occurrence of pruritus in the other 16
patients, who probably had vitiligo, is striking. In other series, 39% of vitiligo
patients have been reported to have pruritus [137] and 15% to have localized
burning and/or pruritus [17]. It is highly probable that in vitiligo most instances
of pruritus are not related to the pathogenesis of the disease, but rather to the
increased photosensitivity of depigmented skin. It is not established whether
pruritus without sun exposure is more common in inflammatory or raisedborder vitiligo, but this seems a reasonable supposition.

Ocular Changes
The uveal tract (iris, ciliary body, and choroid) and retinal pigment epithelium have been traditionally considered unaffected in vitiligo. However,
ocular abnormalities in vitiligo patients have been observed. Chronic uveitis,

chorioretinal depigmentation, iris and conjunctival depigmentation (partial),

and retinitis pigmentosa have been described in patients with typical vitiligo
[138-144]. Some of these cases may represent Vogt-Koyanagi-Harada syndrome [32], or vitiligo associated with other incidental ophthalmologic conditions.
There are several interesting case reports of fundus pigmentary abnormalities in vitiligo patients. Crocker [138], in 1903, observed a case in which
leukoderma was associated with retinitis pigmentosa. Although the patient
stated the leukoderma began at the same time as the visual defect, Crocker
cautioned against accepting any causal relationship between the two conditions. In 1953, Gordon [140] reported a case of retinitis pigmentosa "sine pigmento" associated with vitiligo of the skin. This 25-year-old woman had had
night blindness since childhood and vitiligo since age 23. The fundi were
semialbinotic. There was no history of uveitis or of auditory abnormalities. As
five other nonvitiliginous family members also had retinitis pigmentosa, this
case probably represents the fortuitous association of vitiligo and retinitis pigmentosa. Typical retinitis pigmentosa in a 47-year-old man with a 27-year
history of vitiligo has also been reported [141]. A 45-year-old black woman
with a 15-year history of vitiligo was found to have chronic uveitis, chorioretinal
depigmentation, and partial depigmentation of the iris and conjunctiva [144].
Since until recently these cases represented only isolated and exceptional
findings among the many thousands of patients with vitiligo who have been
observed, Fitzpatrick and Mihm [32] concluded that there are no consistent
ocular changes associated with vitiligo. Robert [18] also reported normal
ophthalmologic examinations in 14 patients with vitiligo. However, Nordlund
et a1. [145,145a] have recently reported pigmentary abnormalities of the retina;
in one study 12 of 30 vitiligo patients had retinal pigmentary changes and two
had iris abnormalities discovered only on slit-lamp examination. Moynahan
observed one patient with extensive vitiligo to have undergone iris color lightening from brown to blue [61]; one of our patients also gives a history of iris
color change. In addition, two of 70 of our vitiligo patients have been observed
to have retinal depigmentation, seven notable retinal pigmentary patterns, and
two a history of iris color change (unpublished observations).
Recently, Gass [145b] reported 11 patients with "vitiliginous chorioretinitis," some of whom also had white macules on the skin. Nordlund et a1. found
that vitiligo is more common than expected in patients with uveitis [145c].

Auditory Changes

Auditory abnormalities are not characteristic of patients with vitiligo. However, we have seen two patients with a family history of vitiligo and otosclerosis.
Interestingly, there is a report of autosomal recessive congenital deafness and
vitiligo occurring in an inbred family in a remote small village where multiple,
repeatedly consanguinous marriages are common [145d]. In this kindred, seven
had profound, severe, bilateral, nonprogressive, sensorineural hearing loss and
five had vitiligo. Of these, three had both vitiligo and hearing loss; their parents
were unaffected but two brothers were deaf. The vitiligo in all those affected
appeared initially at the waist beginning at six to eight years of age and pro-

177

GENETIC AND
CONGENITAL
DISORDERS

178
CHAPTER 1

gressed slowly. Audiometric studies of apparently unaffected individuals suggested heterozygotes may be predisposed to noise-induced hearing loss.
Nail Involvement

There is no specific nail abnormality in vitiligo. Costa [50] did report two
cases of vitiligo and discoloration of the nails, a condition he called "ungual
vitiligo." Aleixo [146] reported that melanonychia and hyperchromia of the
nail matrix may result from vitiligo. He also suggested that leukonychia may
occur and ascribed to this the same significance as the discoloration of hair in
achromic vitiligo macules. We have observed one vitiligo patient with nail
plate hypochromia. Leukonychia is a rare feature of vitiligo. Linear hypochromic bands may also occur, particularly in patients with periungual vitiligo.
A 34-year-old woman with vitiligo and periodic seasonal detachment of
all fingernails has been reported [147].
Lerner [148] described three cases with a syndrome of total alopecia, total
vitiligo, and nail changes (fine pitting, friability, and horizontal splitting). Two
similar cases were reported by Demis and Weiner [149]. In these patients,
however, the nail changes were characteristic of alopecia areata, which has
been associated with vitiligo.
Vitiligo and Blood Groups

ABO Groups (Table 30)

The familial occurrence of vitiligo and the association of gastric hypochlorhydria-known to be associated with blood group A-with vitiligo, suggested a possible association of vitiligo and ABO blood grouping. However,
among seven different studies of ABO classification in vitiligo patients, no
consistent blood type can be identified. Series demonstrating an increased
incidence of blood types B [150], AB [151,153]' and AB and a [152] have been
reported. In another series, A and B were increased and a was decreased [154].
Dutta et al. [155] found no significant difference among the groups. A study
from India in 1977 may settle this controversy: ABO blood groupings of 1000
vitiligo patients were compared to 2000 blood donors and 2500 people among
the local population at large. No differences were discovered [156]. It appears
that there is no characteristic ABO group marker for vitiligo.
Rh Factor
Ortonne [39] found 88% of his vitiligo patients to be Rh + and 12% to be
Rh -. This is not significantly different from the 85% Rh factor positivity in
the general population.
Secretory State (Table 31)
The interest in ABO-specific blood grouping in vitiligo precipitated investigations of blood group-specific substances present in saliva. Seghal and
Dube [157,158] found more secretors among vitiligo patients than among con-

44.6

25.53

16.4

37.54

39.7

48.55 0

19.3

26.020
8.80

6.58

9.9

8.20

23 0

33.26

27

24.74

29
8.67

8.88

17.64 0

36.24

27.46

23.94

15.68

7.83

9.43

10.98

100

35.08

35

36.69

39.940

AB group
(%)

24.34

23.27

19.17

B group
(%)

ABO Blood Groups in Vitiligo

25

Abnormal incidence figures are underlined.

Srivastava and Shukla

(1965) [150]
El Hefnawi et al.
(1966) [151]
Gupta and Gupta
(1966) [152]
Singh and Shankar
(1966) [153]
Seghal and Dube
(1968) [154]
Dutta et al. (1969)
[155]

Author

A group
(%)

TABLE 30.

33.20

16.76

30

39.210

30

29.89

(%)

30.35

31.1

33.80

30.94

32.75

30.58

o group

250

173

100

102

80

535

No. of
patients

tIl"">
:::o>Z
cnrt:l

Oel...,
:::0 tIl ......
t:l~C")

c;::ZtIl

C")el

t:lO~

=
"I

...

TABLE 31.

180

Secretory State and Vitiligo

CHAPTER 1

Seghal and Dube (1967) [157]

Dutta et al. (1969) [155]
Seghal and Dube (1969) [158]
Heid et al. (1974) [159]

Secretors

Nonsecretors

(%)

(%)

Vitiligo

Controls

Vitiligo

Controls

86.7
68.8
18.1
75.6

70
73.3
70
70

13.3
31.2
18.9
24.4

30
26.7
30
30

troIs, and concluded, that the presence of this dominant factor is associated
with increased susceptibility to vitiligo. Other authors have been able to substantiate a statistically significant increase in the number of secretors among
vitiligo patients as opposed to controls.
Seghal and Dube [157,158] claimed a statistically better therapeutic response among the nonsecretors than among the secretors. In a study from India,
nonsecretors were found to be more responsive to psoralen therapy than secretors [158a]. However, Heid et al. [159] found the presence or absence of
secretory factor of no prognostic value. Further study is required to determine
any meaningful relationship between vitiligo and secretory state.
HLA Typing
Although there has been considerable interest in identifying an HLA marker
for vitiligo, convincing evidence is lacking. In a study of 48 unrelated blacks,
the incidences of HLA-Al, -A2, and -Aw31 were higher and HLA-Al0 lower
than in 107 normally pigmented black controls; the presence or absence of
associated diseases in these patients was not reported [160]. Another study
showed four of five children with vitiligo and juvenile diabetes mellitus to
have HLA-B8 or HLA-Bio 15, both found in insulin-dependent diabetes. Three
of eight with vitiligo but not diabetes also had HLA-B8 [161]. Another study
[162] showed no HLA pattern among 35 vitiliginous blacks. HLA typing of 90
other vitiligo patients revealed no HLA pattern characteristic of vitiligo [163,164]
or any subpattern characteristic of any clinical feature (sex, age of onset, extent,
precipitating factor, follicular involvement). Furthermore, HLA typing did not
distinguish familial from nonfamilial vitiligo, nor did it distinguish those affected from those unaffected in a family in which vitiligo was present (Fig. 76).
There was, however, an increased incidence of HLA-13 in those vitiligo patients
who had antithyroid antibodies. This result is curious because HLA-13 is not
normally related to the presence of antithyroid antibodies in normally pigmented patients with or without thyroid diseases. No particular HLA pattern
was found to characterize patients having both vitiligo and thyroid disease.
Furthermore, in this study the incidence of antithyroid antibodies in the control
group is unknown. Despite the two reports of specific (but different) HLA
antigens in vitiligo patients, it appears that a specific HLA marker for vitiligo,
if there is one, has yet to be identified.

181
GENETIC AND
CONGENITAL
DISORDERS

II

III

W30-HL-A13
HL-A3-HL-A12

0+

Do

W30-HL-A13
HL-A3-HL-A12

0+

W28-W16
HL-A9-W18
O~

vitiligo

o~
FIGURE 76. HLA typing in a family with vitiligo. Only two HLA antigens are found in patient
1-1. Patients 11-2 and 11-5 have the same HLA phenotype. Patient III-2 has a different phenotype,
but has haplotype 3-12 like patients 11-2 and 11-5. His brother, with the same HLA phenotype, is
normal. (From: Retornaz G: Les groupes HLA en dermatologie. Revue bibliographique. Etude personelle de 90 vitiligos et 14 sclerodermies. These Medecine, Lyon, 1975.)

T Cells and B Cells

Ortonne and Alario [165] compared T and B lymphocytes in 38 vitiligo
patients compared to 44 controls. Studies of sheep RBC formation, C3 rosettes,
and 19 G rosettes showed no alteration of the T-cell population. Immunofluorescence and immunofluorescence-elution techniques showed no difference
in B cells. Another study of 24 vitiligo patients showed 55.2% T cells compared
to 74.9% among controls; 22 of the 24 patients had reduced T-cell levels. Two
of these also hadDow-n's syndrome and Hashimoto thyroiditis [166]. If there is
a quantitative difference in the T- and B-cell population, it is likely minor.
Dermatoglyphic Studies
Dermatoglyphic features have been studied in 50 children with vitiligo

[167]. Compared to normals, males with vitiligo had a decreased frequency of

whorls and an increased incidence of radial loops. Radial loops and arches
were found in increased frequency on the second and third digits, respectively.
On the fifth digit, the ulnar loops were increased and the whorls decreased.

182
CHAPTER 1

In females with vitiligo, arches were present in increased frequency, whereas ulnar loops were present in decreased frequency on the third digit, and
thenarlII patterns were significantly reduced. On the right hand, ulnar loops
were significantly reduced.
Sahasrabudhe et a1. concluded that vitiligo is characterized by certain
significant dermatoglyphic features and that this supports the importance of
heredity in vitiligo.

Associated Disorders
While most vitiligo patients are generally healthy, several disorders have
been found in many patients. Though the frequency is still disputed, clearly
the established associations must be excluded in all patients.
Established Associations
Vitiligo appears to be a marker for certain diseases. Thyroid disease, diabetes mellitus, pernicious anemia, and Addison disease are reported frequently
enough to be considered definite associations. Other established associations
include three cutaneous markers, namely, halo nevi, prematurely gray hair,
and alopecia areata.
Vitiligo and Thyroid Disease
Trousseau [168], in 1877, was probably the first to report an association
between vitiligo and thyroid disease. Thibierge [169], in his 1895 textbook,
mentioned the existence of vitiligo in patients with exophthalmic goiter. In
1899, Caracoussi [170] noted the appearance of vitiligo during an exacerbation
of Basedow disease (thyrotoxicosis with exophthalmic goiter). Darier [80], in
1904, stated that vitiligo was relatively common in patients with exophthalmic
goiter. It was later suggested that vitiligo occurs in 10% of patients with Graves
disease [104,171].
At the turn of the century, the association of thyroid disease and vitiligo
was reported several times and, in 1929, in a review of the European literature,
Parhon and Derevici [172] collected 25 reports of vitiligo associated with Graves
disease. In 1923, Ayers [173] reported in the North American literature a case
of vitiligo associated with severe hyperthyroidism and alopecia areata. Other
cases of vitiligo and hyperthyroidism were described in 1927 by Pierini and
Herrera [174] in Argentina, and in 1928 by Ferraz-Alvim and Guerner in Brazil
[111].

In 1926, Peynet [175] noted the course of vitiligo to parallel that of exophthalmic goiter, and in one of the cases mentioned by Sainton et a1. [176]
in 1928, vitiligo disappeared after treatment of Graves disease.
While most of the reported cases relate vitiligo to exophthalmic goiter and
hyperthyroidism, myxedema has also been mentioned [177,178]. Faber [179],
in 1934, noted vitiligo in a patient with myxedema and facial hemiatrophy.

TABLE 32. Incidence of Vitiligo in Thyroid Diseases

Patients with vitiligo
and thyroid disease
Number Percent of total

Author
Miklaszewska et al. (1972) [180]
Perrot et al. (1973) [25]
Allison and Curtis (1955) [28]

7
41
28

183
GENETIC AND
CONGENITAL
DISORDERS

Total no.
of patients
56
4627
475

12.5
0.9
0.6

Incidence of Vitiligo in Patients with Thyroid Disease

The only large studies purporting to show the frequency of vitiligo among
all thyropathies are two retrospective chart reviews of endocrine clinic patients
(Table 32). Allison and Curtis [28] reported a vitiligo incidence of 0.62% in
457 patients and Perrot et al. [25] 0.9% in 4627 patients. This is no more than
expected in the population at large. It seems likely that these incidence figures
are low because vitiligo either was not observed or was observed but not recorded among the list of diagnoses. Miklaszewska et al. [180] did observe
vitiligo in 12.5% of thyroid patients, and although their sample size of 56 is
too small to be conclusive, it suggests a real association.
The distinction becomes clear when thyroid diseases are separated by
disease entity. Vitiligo is associated with hyperthyroidism. The incidence of
vitiligo in hyperthyroid patients (Table 33) has been reported to be from 0%
to 27.7%. These series suggest the true incidence is 6% or less; the only series
TABLE 33. Incidence of Vitiligo in Hyperthyroidism and Graves Disease
Patients with vitiligo
and thyroid disease
Author
Allison and Curtis
(1955) [28]
Morgans (1964)
[181]
Ochi and De Groot
(1969) [112]
Caravati et al. (1969)
[182]
Miklaszewska et al.
(1972) [180]
Perrot et al.
(1973) [25]

Davis and Davis

(1974) [183]

Number

Percent of total

Total no.
of patients

Hyperthyroidism

0.5

1289

Hyperthyroidism

5.7

140

Graves disease

6.6

90

Hyperthyroidism

154

5
4
27
21
0
6

27.7
36
1.4
1.7
0
1.7

18
11
1994
2297
450
347

2.3

85

Diagnosis

Hyperthyroidism
Graves disease
Hyperthyroidism
Graves disease
Toxic adenoma
Diffuse goiter with
secondary
Basedow disease
Hyperthyroidism

TABLE 34. Incidence of Vitiligo in Thyroiditis

184
CHAPTER 1

Patients with vitiligo

and thyroid disease
Author
Miklaszewska et al. (1972) [180]
Perrot et al. (1973) [25]

Number

Percent of total

25

Total no.
of patients

Hashimoto thyroiditis.
b Type of thyroiditis not specified.

recording a higher incidence was based on only 18 patients with hyperthyroidism. Two cases of vitiligo were found among 85 hyperthyroid patients over
the age of 65 [183] but this represents the incidence expected in the population
at large.
According to the literature, the incidence of vitiligo in Graves disease
would seem to be between 1.7% and 6.6%. A series reporting an incidence of
36% is based on a sample size of 11 [180]. One endocrinologist has found
leukoderma to be common in Graves disease patients over the age of 50 (L.
Wood, personal communication); the definitive study has yet to be done.
Vitiligo may also be associated with toxic adenomas, but in the series of
Perrot et al. [25] 1.7% of 347 patients with toxic goiter had vitiligo. No case of
vitiligo was found among 450 cases of toxic adenomas [25]. In another series,
one case of vitiligo was found among seven patients with toxic adenomas [180].
Reported cases of vitiligo with thyroiditis are too few to be conclusive.
None of 130 patients with thyroiditis (Table 34) were found to have vitiligo
[25], but Miklaszewska et al. [180] found two cases of vitiligo among eight
patients with thyroiditis.
Vitiligo does not appear to be more frequent among those with myxedema
or thyroid carcinoma than expected in control populations. The incidence of
vitiligo among myxedema patients (Table 35) has been reported to be 0.88%
to 1.43% and that of vitiligo in nontoxic goiter to be from 0% of 18 patients to
0.6% of 2122 (Table 36). Perrot et al. [25] found vitiligo in 0.3% of 268 patients
with carcinoma of the thyroid (Table 37).
It is notable that the series of Miklaszewska et al. [180] consistently reports
high incidence figures for vitiligo in hyperthyroidism, Graves disease, and toxic
goiter. Perhaps vitiligo is underreported in most other thyroid series.
TABLE 35. Incidence of Vitiligo in Myxedema
Patients with vitiligo
and myxedema
Author
Allison and Curtis (1955) [28]
Sandrasekar et al. (1973) [184]
Perrot et al. (1973) [25]

Number

Percent of total

5
1
1

1.1

Total no.
of patients

1.4

470
70

0.9

113

TABLE 36. Incidence of Vitiligo in Goiter

Patients with vitiligo
and goiter
Percent of total

Number

Author

Total no.
of patients

Miklaszewska et al. (1972) [180]

Perrot et al. (1973) [25]

185

12

18
2122

0.06

Incidence of Thyroid Disease in Vitiligo

Thyroid diseases in general, particularly hyperthyroidism, thyroiditis, and
myxedema, are more common in vitiligo patients than in controls. The incidence of all thyroid diseases in vitiligo appears from the literature to be between
1.28% and 30% (Table 38). The overall incidence of thyroid disorders in the
population at large is probably less than 4% [190]. Past surveys, because they
relied to a great extent on patient awareness of disease and on limited laboratory
tests, may well have led to underreporting; in a survey of 18 vitiligo patients
over the age of 50, one was clinically hyperthyroid and another myxedematous
[191]; TSH testing revealed another five to be hypothyroid.
Hyperthyroidism, Graves disease, and toxic goiter are much more common
in vitiligo patients than in the population at large. Hyperthyroidism has been
reported among 0.9% to 12.2% of vitiligo patients; Graves disease in from 1%
to 12.5%; and toxic adenoma in from 2.4% to 3.5% of vitiligo patients (Table
39). The general incidence of Graves disease is 0.03% [192].
The incidence of thyroiditis in vitiligo has been reported to be 1.9% to
12.5% (Table 40), of nontoxic goiter 3% to 8.9% (Table 41), and of myxedema
0.36% to 3.3% (Table 42). The respective incidence figures in the general population are 0.03% to 0.06%, 4%, and 0.01% to 0.08%, respectively [193].
Association of Vitiligo and Thyroid Disease
In assessing the frequency of vitiligo in thyroid disorders, the 1% incidence
of vitiligo in the general population must be considered. Clearly vitiligo occurs
with increased frequency-probably four to six times normal-in patients with
hyperthyroidism, Graves disease, and toxic adenomas. Vitiligo has not appeared
to be more common in those with myxedema or thyroid carcinoma. Despite
the small series of Miklaszewska et al. [180], vitiligo has not yet been shown
to occur with increased frequency among those with thyroiditis. We suspect,
TABLE 37. Incidence of Vitiligo in Thyroid Carcinoma
Patients with vitiligo
and thyroid carcinoma
Author
Perrot et al. (1973) [25]

Number

Percent of total

Total no.
of patients

0.37

268

GENETIC AND
CONGENITAL
DISORDERS

186
CHAPTER 1

TABLE 38. Incidence of Thyroid Diseases in Vitiligo

Associated vitiligo
Author
Allison and Curtis (1955) [28]
Lerner (1959) [29]
Cunliffe et al. (1968) [185]
EI Mofty (1968) [6]
Bor et al. (1969) [186]
Grupper et al. (1970) [37]
Howitz and Schwartz (1971) [187]
Peracchi et al. (1971) [188]
Bleehen (1972) [42]
Miklaszewska et al. (1972) [180]
Perrot et al. (1973) [25]
Ortonne (1974) [39]
Howitz and Rehfeld (1974) [38]
Heid et al. (1974) [159]
Schnitzler et al. (1974) [189]

Number

% of Total

Total no.
of patients

12
7
17
7
1
4
6
2
4
7
41
7
3
7
4

2.2
3.8
30.4
1.3
1.6
5.7
5.9
6.6
12.5
17.1
20.5
7.0
2.6
14.5
13.3

531
183
56
545
62
70
102
30
32
41
200
100
116
48
30

TABLE 39. Incidence of Hyperthyroidism in Vitiligo

Associated
hyperthyroidism
Author
Allison and Curtis
(1955) [28]
Lerner (1959) [29]
Cunliffe et al.
(1968) [185]
EI Mofty (1968) [6]
Peracchi et al. (1971)
[188]
Howitz and Schwartz
(1971) [187]
Bleehen (1972) [42]
Miklaszewska et al.
(1972) [180]
Ortonne (1974) [39]
Howitz and Rehfeld
(1974) [38]
Schnitzler et al. (1974)
[189]

Diagnosis

Number

% of Total

Total no.
of patients

Hyperthyroidism

1.3

531

Hyperthyroidism
Hyperthyroidism
Graves disease
Toxic adenoma
Hyperthyroidism
Hyperthyroidism

5
5
3
2
5
2

3.3
8.9
5.3
3.5
0.9
6.6

183
56
56
56
545
30

Graves disease

2.9

102

Graves disease
Hyperthyroidism
Graves disease
Toxic adenoma
Hyperthyroidism
Graves disease

4
5
4
1
3
2

12.5
12.2
9.8
2.4
3.0
1.7

32
41
41
41
100
116

Graves disease

10.0

30

TABLE 40. Incidence of Hashimoto Thyroiditis in Vitiligo

Associated thyroiditis
Author
Cunliffe et al. (1968) [185]
Howitz and Schwartz (1971) [187]
Miklaszewska et al. (1972) [180]

Number

Percent of total

7
2
2

12.5

187

Total no.
of patients
56
102

1.9
4.9

41

however, that if older patients are examined, vitiligo will be found in many
patients with thyroiditis or myxedema.
However, among vitiligo patients, the incidence of Graves disease, hyperthyroidism, toxic adenoma, thyroiditis, and myxedema clearly is increased.
Nontoxic goiter has not been shown to be associated.
The issue of association of thyroid disease with vitiligo is an important
one. Underreporting has resulted from the relatively young average age of patients in most series-often around 20 years. For example, among 212 of our
patients surveyed, with an average age of 25, the incidence of known thyroid
disease was 10%. Another group of 40 patients, surveyed at an average age of
40, was found to have a 24% incidence of thyroid disease by history alone.
Furthermore, among 20 vitiligo patients over 50 years of age contacted for
thyroid studies, 18 of whom were studied, only two had clinical symptoms of,
or were aware they had, thyroid disease. Two other patients were under treatment for thyroid disease and refused to be studied. The total incidence of known
thyroid disease in this small group, then, was 20%; five others also had borderline or abnormal TSH, the significance of which was confirmed with abnormal TRH stimulation tests. The latter five patients (25%) were thus found
to be hypothyroid. The prevalence of clinical and subclinical thyroid disease
in this group was 45%. Two conclusions are appropriate from all these observations. First, thyroid disease is more likely to be observed as vitiligo patients
become older and, second, vitiligo must be considered an important marker
for present or impending thyroid disease, particularly thyroid failure in older
age groups [1911.
Clinical Features of Vitiligo Associated with Thyroid Disease
There appear to be no distinguishing features of vitiligo associated with
thyroid disease. Although Ochi and De Groot [112] suggested that vitiligo associated with thyroid disease has a characteristic pattern-involvement of the
TABLE 41. Incidence of Nontoxic Goiter in Vitiligo
Associated goiter
Author
Cunliffe et al. (1968) [185]
Grupper et al. (1970) [37]
Ortonne and Alario (1978) [165]

Number

Percent of total

Total no.
of patients

8.9
5.7
3.0

56
70
100

GENETIC AND
CONGENITAL
DISORDERS

TABLE 42. Incidence of Myxedema in Vitiligo

188

Associated myxedema

CHAPTER 1
Author

Number

Percent of total

Total no.
of patients

5
1
2
2
3
1
1
1

0.9
0.5
0.4
1.6
2.9
1.0
0.9
3.3

531
183
545
62
102
100
116
30

Allison and Curtis (1955) [28]

Lerner (1959) [29]
El Mofty (1968) [6]
Bor et al. (1969) [186]
Howitz and Schwartz (1971) [187]
Ortonne (1974) [39]
Howitz and Rehfeld (1974) [38]
Schnitzler et al. (1974) [189]

palms and soles and minor involvement elsewhere-there seems to be no clinical picture of vitiligo predictive of the presence or absence of associated or
impending thyroid disease.
Ochi and De Groot stated that in their cases the onset of thyroid disease
always preceded the appearance of vitiligo; but in an examination of 17 patients,
Perrot et al. [25] found only seven whose thyroid disease preceded the vitiligo,
as opposed to five in whom the vitiligo preceded the thyroid disease, and
another five in whom the two conditions were observed to occur simultaneously. In a survey of 10 of 40 vitiligo patients with thyroid disease, we have
also found vitiligo to precede or follow vitiligo with equal frequency (unpublished observations). Perrot et al. [25] also observed that treatment of thyroid
disease did not appear to alter the course of vitiligo. Of our five patients with
elevated TSH values, one observed her vitiligo to improve for six months on
thyroid replacement. This, however, gradually reversed despite continued thyroid therapy. The other patients observed no pigmentary changes as a result
of thyroid replacement.
Thyroid Studies in Vitiligo Patients
Thyroid function has generally been considered normal in vitiligo patients,
but this may be misleading. Increased basal metabolic rate (BMR) has been
reported in 10 out of 20 vitiligo patients [18] and functional thyroid abnormalities (generally increased) in 57 out of 100 patients [194]. However, proteinbound iodine in vitiligo patients has been reported to be normal [29,180].
Normal radioactive iodine uptake was found in 22 patients, and increased
uptake in two [29]. In 30 vitiligo patients, Jacyk et al [195] noted abnormal
radioactive iodine uptake in seven, three of whom had both thyroid disease
and diabetes mellitus. Recent studies of Wood et al [191] have demonstrated
abnormal TSH values in 39% of 18 patients over the age of 50, all but one of
whom had normal T4 determinations and had been considered euthyroid. The
overall incidence of thyroid diseases in the vitiligo clinic at the Massachusetts
General Hospital has been 8% to 10%, representing a population with an average
age of 25; results of the preliminary study of Wood et al suggest this may be a
minimal incidence figure and that the incidence of clinical and subclinical
thyroid disease among vitiligo patients may increase dramatically with age.

TABLE 43. Incidence of Antithyroid Antibodies

(Antithyroglobulin + Antimicrosomal) in Vitiligo

189
GENETIC AND
CONGENITAL
DISORDERS

Antithyroid antibodies
Vitiligo

Controls

Author

(%)

(%)

Total no.
of patients

Cunliffe et al. (1968) [185]

Brostoff et al. (1969) [196]
Grupper et al. (1970) [37]
Peracchi et al. (1971) [188]
Perrot et al. (1973) [25]
Heid et al. (1974) [159]
Ortonne (1974) [39]

32.6
30
20
53.3
28
14.9
51.7

3.8
6
5
20
9
0
9.2

52
80
70
30
93
107
59

Pal et al. [195aJ found T3 and T4 significantly lower in vitiligo patients as

compared to controls; levels returned to normal after the administration of
TSH. There was a delayed and exaggerated response of TSH to TRH; the
hypothyroidism associated with vitiligo is secondary to some defect at the
suprahypophyseallevel [195bJ.
Antithyroid antibodies have been reported in from 14.9% to 53.3% of
vitiligo patients, compared to 0% to 20% among controls (Table 43). Increases
in both antithyroglobulin and antimicrosomal antibodies have been observed
(Tables 44, 45). The incidence of antithyroid antibodies is much greater in
those vitiligo patients with thyroid diseases than in those without thyroid
diseases (Table 46).
Relationship of Vitiligo to Thyroid Disease
The clear association of thyroid disease and vitiligo suggests a pathogenic
link between these disease states. The relationship between vitiligo and thyroid
disease could result from an effect of MSH-releasing hormone, melatonin, MSH,
tyrosinase, or intermediates or metabolites in the melanin pathway on TSH,
TABLE 44. Incidence of Antithyroids (Antithyroglobulin)
Antibodies in Vitiligo
Antithyroglobulin
antibodies
Vitiligo
Author

(%)

Cunliffe et al. (1968) [185]

Brostoff et al. (1969) [196]
Peracchi et al. (1971) [188]
Dobmeier and Sams (1971) [197]
Perrot et al. (1973) [25]
Schnitzler et al. (1974) [189]
Ortonne (1974) [39]
Woolfson et al. (1975) [198]

24.5
8.7
43.3
50.0
5.3
44.4
12.1
7.1

Controls
(%)

4.0

16.6

Total no.
of patients
52
80
30
10
93
27
58
42

190
CHAPTER 1

TABLE 45. Incidence of Antithyroid (Antimicrosomal) Antibodies

in Vitiligo
Antimicrosomal
antibodies
Vitiligo

Controls

Author

(%)

(%)

Cunliffe et al. (1968) [185)

Brostoff et al. (1969) [196)
Peracchi et al. (1971) [188)
Perrot et al. (1973) [25)
Schnitzler et al. (1974) [189)
Ortonne (1974) [39)
Woolfson et al. (1975) [198)

11.6
27.5
23.3
25.8
37.0
43.1
11.9

0
7.5
3.3

Total no.
of patients
52
80
30
93
27
58
42

4.7

thyroxine, or the thyroid cell; an effect of TSH or thyroid hormone on the

melanocytes; or an effect of an unknown agent on both systems. Since both
melanin and thyroxine synthesis pathways originate with tyrosine, it is possible
that an alteration in the tyrosine-melanin pathway could permit formation of
circulating antibodies or stimulate cell-mediated immunity directed against
crossover sites in the melanin and thyroxine synthesis pathways. There are
other observations that show functional relationships between the two systems.
Injection of thyroid extracts and thyroxine into chickens was demonstrated in
1928 by Sainton et al. [176] to cause depigmentation of feathers. Similar depigmentation was also observed in rabbits. Robert [124] suggested such depigmentation occurs because hyperthyroidism results in decreased oxidation. Lerner and Fitzpatrick [199] hypothesized that there is in hyperthyroidism
competitive inhibition of melanin production; they suggested that conversion
of tyrosine to thyroxine occurred preferentially over the production of dopa
and dopaquinone with resulting depigmentation. But the mechanism must be
more complex because vitiligo patients with thyrotoxicosis have been shown
to have increased plasma tyrosine levels whereas those with vitiligo alone have
TABLE 46. Correlation between Vitiligo, Thyroid Diseases, and Thyroid
Antibodiesa
Vitiligo associated with
thyroid diseases (28)b

Type of antibodies
Thyroid microsome
+ thyroglobulin
Thyroid microsome
Thyroglobulin

Percent of
patients
affected

No. of
patients
affected

Vitiligo without
thyroid diseases (65)b
Percent of
patients
affected

No. of
patients
affected

46

13

20

13

46
14.2

13
4

18.4
1.6

12
1

'From: Perrot H et al: Vitiligo, thyreopathies et autoimmunisation. Lyon Med 230:325-331, 1973.
b Total number of patients.

normal tyrosine levels. Regardless, such a hypothesis could explain only the
association of hyperthyroidism and not hypothyroidism with vitiligo.
Additional occurrences observed in some factory workers adds considerable credence to the common pathogenesis theory [200,201]. Three men working in a factory producing paratertiary butylphenol developed, over one to two
years, vitiligo-like skin changes, hepatosplenomegaly, and diffuse goiter with
increased TSH secretion.
Morgans [181] suggested that vitiligo could be one manifestation of a genetic link which, under certain circumstances, could present as thyroid disease.
The observation that there is an increased incidence of thyroid disease among
the relatives of patients with vitiligo supports a genetic basis for the link between these two conditions.
Vitiligo and Addison Disease
Thomas Addison [202] in 1855 in his book, On the Constitutional and
Local Effects of the Disease of the Suprarenal Capsules, noted in one instance
that "there were in the midst of this dark mottling certain insular portions of
integument presenting a blanched or morbidly white appearance ... from an
actual defect of coloring matter in this part." It appears that one of the first
patients with Addison disease was suffering from vitiligo. In 1891, Mathieu
[203] reported a case of vitiligo which he suggested was a sign of Addison
disease.
Many cases and diverse theories surround the association between vitiligo
and Addison disease. Levi [204] found 12 cases of Addison disease with albinotic decoloration. In his 1920 textbook of internal pathology, Dieulafoy [205]
related the two diseases. In 1922, Pieri [206] based his thesis on 16 cases of
Addison disease and vitiligo. Artom [207], in 1926, reported an Addisonian
woman who developed vitiligo during pregnancy; he attempted to relate the
hormonal alterations of pregnancy to the pigmentary disorder. In 1939 there
were two case reports of vitiligo, melancholy, and adrenal cortical insufficiency,
with a parallel evolution of these three conditions [208]. The same year also
saw a report of a case of vitiligo and Addison disease in a 12-year-old girl with
increased creatinuria [209]. Many cases of Addison disease associated with
vitiligo have been reported [210-224].

The Association of Vitiligo and Addison Disease

The incidence of vitiligo in patients with Addison disease is reported to
be from 3.1% to 20% (Table 47). Vitiligo appears to be three to four and onehalf times more frequently associated with idiopathic Addison disease than
with tuberculous Addison disease (Table 48). The incidence of Addison disease
in vitiligo, however, is reported to be 0% to 2% (Table 49).
Considering that the incidence of Addison disease in the general population is 25 per million [233], it appears that Addison disease is more common
among vitiligo patients than in the population at large. Vitiligo is clearly more
common in patients with Addison disease than in the general population.

191

GENETIC AND
CONGENITAL
DISORDERS

TABLE 47. Incidence of Vitiligo in Addison Disease

192

Associated vitiligo

CHAPTER 1
Author

Number

Percent of total

6
20
6
15
4
3.1
7.5
5.7

Sorkin (1949) [225]

Thorn (1951) [226]
Soffer et a1. (1961) [227]
Forsham (1968) [228]
Pousset et a1. (1970) [229]
Knowlton (1971) [230]
Irvine and Barnes (1972) [231]
Irvine and Barnes (1975) [232]
a

4
2
17
19

Total no.
of patients
50

100
63
224
329

Not specified.

TABLE 48. Incidence of Vitiligo in Various Types of Addison Disease

Idiopathic
Addison disease
No. of
patients

Author
Pousset et a1. (1970) [229]
Irvine and Barnes (1972) [231]
Irvine and Barnes (1975) [232]
a

Tuberculous
Addison disease

Associated
vitiligo

174
261

(%)

No. of
patients

3
9.1
7.8

46
1

Associated
vitiligo

Others

(%)

No. of
patients

1
2.1
1.6

4
4

TABLE 49. Incidence of Addison Disease in Vitiligo

Author

(%)

Cunliffe et a1. (1968) [185]

Grupper et a1. (1970) [37]
Howitz and Schwartz (1971) [187]
Perrot et a1. (1973) [25]
Ortonne (1974) [39]
Howitz and Rehfeld (1974) [38]

0
0
0
1.0
1.0
0

Total no.
of patients
56
70
102
200
100
116

TABLE 50. Incidence of Adrenal Cortex Antibodies in Vitiligo

Adrenal cortex antibodies
Author
Brostoff et a1. (1969) [196]
Grupper et a1. (1970) [37]
Ortonne (1974) [39]
Schnitzler et a1. (1974) [189]
Woolfson et a1. (1975) [198]

Vitiligo

Controls

(%)

(%)

4.0
4.1
0
7.1
0

0
5

(%)
0
0

Not specified.

Associated Addison
disease

Associated
vitiligo

Total no.
of patients
80
24
53
14
42

Adrenal Cortex Function Studies in Vitiligo

193

Adrenal cortical function studies in vitiligo patients are usually normal,

but there have been a few reported exceptions. In one study [29] four of five
males and four of 15 females had decreased urinary 17-ketosteroid levels, and
one female patient had an increased 17-ketosteroid level. Increased [234], decreased [235], and normal [236] 17-ketosteroid levels have been reported.
Adrenal insufficiency, based on abnormal Thorn tests, has been reported
in 10 of 20 patients with vitiligo [237]. Pal et al [237a] reported that cortisol is
higher and ACTH significantly lower in vitiligo patients as compared to controls. Furthermore, they observed an exaggerated response to ACTH in vitiligo
patients. Borisenko [238], in 1970, noted frequent reduction in adrenal cortical
activity in patients with vitiligo. Such adrenal insufficiency should be associated with increased MSH levels. Of 22 vitiligo patients, Lerner [29] found
normal MSH levels in 20 vitiligo patients and increased levels in two, both of
whom had normal 17-ketosteroids. Desaux et al. [239] also reported normal
MSH levels in two patients.
The reports of the presence of adrenal cortex antibodies in vitiligo are of
doubtful significance (Table 50). An incidence of 0% to 4.1 % has been reported
in vitiligo and 0% to 5% in controls [37,196,198]. Irvine and Barnes [232]
investigated the incidence of steroid cell antibodies in patients with Addison
disease and found no difference among those who had vitiligo and those who
did not (Table 51). Adrenal cortex and steroid cell antibodies do not appear to
occur in significant titers in vitiligo patients.
Possible Mechanisms for Explaining Relationship between Vitiligo and
Addison Disease
Unfortunately, there are no recorded in vitro experiments that help explain
the concurrence of vitiligo and Addison disease. Lerner [29] has suggested that
the increased melanogenesis of Addison disease results in overstimulation of
the melanocytes, increased melanocyte destruction (self-destruct theory), and
resultant depigmentation. For this to apply to vitiligo alone, more patients
would be expected to have increased MSH levels. Any relationship between
Addison disease and vitiligo could be based upon a primary effect of the
TABLE 51. Correlation between Idiopathic Adrenal Insufficiency, Steroid Cell Antibodies,
and Vitiligo [232]
Addison disease without
steroid cell antibodies
in 221 patients

Addison disease with

steroid cell antibodies
in 40 patients
Associated
with vitiligo

Not associated
with vitiligo

Associated
with vitiligo

Not associated
with vitiligo

Number Percent of total Number Percent of total Number Percent of total Number Percent of total
38

95

5.0

205

92.7

16

7.3

GENETIC AND
CONGENITAL
DISORDERS

194
CHAPTER 1

ACTH-adrenal gland axis on the melanocytes, of an intermediate in the melanin

synthesis pathway on the adrenals, or of some other factors.
Vitiligo and Pernicious Anemia
Until the mid 1950s, there were but a few early scattered reports of pernicious anemia occurring in patients with vitiligo [240-242]. Today, there is
considerable accumulated evidence to support an association of these two
diseases [243,244].
Incidence of Vitiligo in Pernicious Anemia (Table 52)
There appears to be a significant association between vitiligo and pernicious anemia [245,246]. The reported incidence figures range from 1.6% to
10.6% in three series. In Denmark, the incidence of vitiligo in pernicious anemia
is reported to be 10.6% as opposed to 1.44% in the general population [22].
Allison and Curtis [28] found a 1.6% incidence of vitiligo in pernicious anemia,
but such a relatively low figure may result from the nature of the study and
from the fact that often the diagnosis of vitiligo is not mentioned in the medical
records. These authors did, however, conclude that vitiligo is more than casually associated with pernicious anemia.
Incidence of Pernicious Anemia in Vitiligo (Table

53)

An increased prevalence of pernicious anemia is found among vitiligo

patients. The reported frequency ranges from 0% to 9.2%. Although EI Mofty's
[6] and Lerner's [29] series include no cases of pernicious anemia, it is possible
that in the former series not all the patients were investigated for this disease
by laboratory tests. Lerner [29], who studied more than 200 vitiligo patients,
later found four patients to have pernicious anemia. In nine other series, the
incidence of pernicious anemia in vitiligo varied from 1% to 9.2%. Grunnet et
al. [22) concluded that the association is statistically significant and that pernicious anemia is about 30 times as frequent among patients with vitiligo as
in the general population. Cunliffe et al. [185] and Bor et al. [186] also observed
that there is an increased occurrence of pernicious anemia in relatives of patients with vitiligo.
Clinical Features of Vitiligo Associated with Pernicious Anemia
There are no clinical features of the vitiligo associated with pernicious
anemia that distinguish it from vitiligo without pernicious anemia. Various
TABLE 52. Incidence of Vitiligo in Pernicious Anemia
Associated vitiligo
Author
Allison and Curtis (1955) [28]
Grunnet et al. (1970) [22]
Dawber (1970) [245]

Number

Percent of total

22

1.6

10.6
8.8

11

Total no.
of patients
with
pernicious anemia
1398
84
125

TABLE 53.

Incidence of Pernicious Anemia in Vitiligo

195

Associated pernicious
anemia
Author
Allison and Curtis (1955) [28]
Cunliffe et al. (1968) [185]
El Mofty (1968) [6]
Bor et al. (1969) [186]
Bleifeld and Gehrmann (1969) [247]
Grunnet et al. (1970) [22]
Howitz and Schwartz (1971) [187]
Pottgen et al. (1971) [248]
Perrot et al. (1973) [25]

No. of
patients

Percent of total

Total no.
of patients

22
3
0
2
5
5
8
3
2

4.1
5.3
0
3.2
9.2
3.7
7.8
8.1
1

531
56
545
62
54
135
102
37
200

attempts have been made to attach particular significance to various features,

but all are isolated observations. Grunnet et al. [22] noted that the cases of
vitiligo associated with pernicious anemia seemed to have the most widespread
depigmentation. Dawber [245] observed that eight of his 11 patients with both
vitiligo and pernicious anemia developed vitiligo after 40 years of age; he
concluded that late-onset vitiligo appears to have a closer association with
pernicious anemia than does vitiligo occurring at a younger age. Others, however, have suspected that the mean age of the onset of vitiligo does not correlate
with pernicious anemia, gastric achlorhydria or hypochlorhydria, or normal
acid secretion [38]. According to the same authors, the greatly increased incidence of fasting achlorhydria and pernicious anemia among patients with
vitiligo is found only in women and there is no male vitiligo subset that is
predisposed to gastric achlorhydria or pernicious anemia.
Gastric Function Studies in Patients with Vitiligo
Reports of gastric function abnormalities date from 1931 when Francis
[249] reported four patients with vitiligo and achlorhydria. Allison [250] found

that only three out of 28 patients with vitiligo had normal gastric acid secretion.
Huriez et al. [70] also found an increased frequency of gastric hypochlorhydria
in vitiligo patients, and Ishida [251] reported achlorhydria in patients with
vitiligo.
Abnormal histamine stimulation tests have also been reported. Lerner [29]
found achlorhydria after subcutaneous histamine injection in one out of five
males and in two of 15 females and concluded that the average female patient
with vitiligo secretes abnormally small amounts of free hydrochloric acid in
response to histamine stimulation. Howitz and Schwartz [187] performed augmented histamine tests in 102 vitiligo patients. Twenty of the patients (nearly
20%) were found to have achlorhydria; eight of these had frank pernicious
anemia and one had latent pernicious anemia. Of another 26 vitiligo patients
subjected to augmented histamine or histamine infusion testing, five were
achlorhydric by the former technique, a finding confirmed by the latter technique in two; three were hypochlorhydric. The five had significantly elevated

GENETIC AND
CONGENITAL
DISORDERS

196
CHAPTER 1

average gastrin levels and one had frank pernicious anemia [252]. Among 540
vitiligo patients, Shukla and Mukerji [36] found 40 had gastric achlorhydria
after alcohol stimulation but a normal response to histamine stimulation.
Shukla [253], in 1961, found reduced gastric pepsin levels in 30 vitiligo
patients; he proposed [254] treatment with a mixture of psoralen, isopsoralen,
and proteolytic enzymes.
Decreased vitamin B1z absorption has been observed in vitiligo patients.
Bleifeld and Gehrmann [247,255], in 1967, performed Schilling tests on 54
patients and found defective vitamin B12 absorption in roughly one-third, five
of whom were said to have pernicious anemia. Watzig [256] also reported
decreased B12 absorption in a patient with vitiligo and alopecia areata. Howitz
and Schwartz [187] observed significantly lower serum B12 levels in vitiligo
patients with pernicious anemia, but found the serum B12 level not to vary
significantly between the groups of vitiligo patients with hypo- or achlorhydria
and those with normal acid secretion. Repigmentation in two patients was
reported after oral administration of dilute hydrochloric acid and vitamin B
complex [257]. Of the next 14 vitiligo patients so treated, seven repigmented,
but two of them only partially.
Decreased intrinsic factor production was found in 15 vitiligo patients with
gastric achlorhydria or hypochlorhydria [187].
Howitz and Rehfeld [38] found raised serum gastrin concentrations in 25
of 29 patients with hypo- or achlorhydria; 87 patients with normal acid secretion had normal gastrin concentrations. Okosdinossian et al. [252] found elevated gastrin levels in five of 26 vitiligo patients; two were achlorhydric and
three hypochlorhydric on histamine infusion tests. One was found to have
frank pernicious anemia.
A difference between the turnover of transcobalamin I in a control group
and in patients with vitiligo or pernicious anemia has been reported [258].
However, another study, using purified trans cobalamin I labeled with radioactive iodine and cobalamin for turnover studies showed no differences between healthy controls, patients with vitiligo, and those with vitiligo and hypoor achlorhydria or pernicious anemia [259].
Pottgen et al. [248], in 1971, found normal gastric mucosal histology in
only five of 26 vitiligo patients biopsled. Chronic superficial gastritis and chromatrophic gastritis were observed in 11 and 10 patients, respectively. Of the
one-third of the 26 patients over 50 years of age, none had histologically normal
gastric mucosa. The gastric mucosal changes resulting in chronic atrophic gastritis were considered to occur earlier, more frequently, and to a greater extent
in patients with vitiligo. Hypertrophic gastritis has also been described [260].
Pathogenic Relationship between Vitiligo and Pernicious Anemia
Observations of an association between vitiligo and pernicious anemia have
led to several theories and therapeutic trials. Hathaway [257] found two patients
treated with B complex for pellagrous dermatitis who reported complete clearing of long-standing vitiligo. Shukla and Mukerji [36] presumed that pyridoxine
deficiency is the common etiologic factor in vitiligo and gastric hypochlorhydria. Shukla [254] suggested that gastric hypochlorhydria and reduced pepsin

levels result in decreased protein hydrolysis at the more centrally located peptide linkage of the alpha-carboxyl group of decarboxylic amino acid and the
alpha-amino radical of aromatic amino acid; as this type of peptide linkage is
present in L-tyrosine and L-phenylalanine residues, less of the latter is available
for melanin synthesis. Paradda [261] suggested that deficient conversion of
pepsinogen to pepsin in the presence of achlorhydria interferes with the release
of L-tyrosine from proteins. But these hypotheses are untenable because serum
tyrosine levels are usually normal in vitiligo patients.
The possibility of a common etiologic mechanism for both gastric mucosa
changes or pernicious anemia and vitiligo was raised when Bor et al. [186], in
1969, found a significantly increased incidence of gastric parietal cell antibodies
(PCA) in 62 vitiligo patients compared with an age- and sex-matched control
group of hospitalized patients; 22.5% of the patients had PCA compared to 8%
of the controls. None of the vitiligo patients had been reported to have pernicious anemia. Nine other series (Table 54) mention an increased incidence
of PCA in vitiligo, but not all of these series include controls. Only Woolfson
et al. [198] have observed a higher incidence of PCA in controls (19%) than in
vitiligo patients (14.2%). In vitiligo patients with gastric achlorhydria, the incidence of PCA has been reported to be 80%, as opposed to 7% among normal
acid secretors [38,187]; both elevated serum gastrin concentrations and PCA
were found in 72% of vitiligo patients with hypochlorhydria or achlorhydria.
Anti-intrinsic factor antibodies have been reported in those patients with both
vitiligo and pernicious anemia [38,187,248] but not in those with vitiligo alone.
According to Howitz and Schwartz [187] vitiligo patients with gastric
achlorhydria have an increased incidence of insulin-dependent diabetes and
thyrotoxicosis or Hashimoto struma. They suggested that females with vitiligo
and achlorhydria are subject to immunologic disorders marked by increased
autoantibody formation and an increased incidence of organ-specific
autoimmune disease. They suggested two types of vitiligo seem to exist. First,
there is "hereditary vitiligo" which is closely associated with achlorhydria and
organ-specific autoimmune disease, and, second, a vitiligo in which the patients
TABLE 54. Incidence of Gastric Parietal Cell Antibodies in Vitiligo
Gastric parietal cell
antibodies
Vitiligo

Controls

Author

(%)

(%)

Bor et al. (1969) [186]

Brostoff et al. (1969) [196]
Grupper et al. (1970) [37]
Howitz and Schwartz (1971) [187]
Pottgen et al. (1971) [248]
Dobmeier and Sams (1971) [197]
Howitz and Rehfeld (1974) [38]
Ortonne (1974) [39]
Heid et al. (1974) [159]
Schnitzler et al. (1974) [189]
Woolfson et al. (1975) [198]

22.5
21.2
45.4
20.0
32.4
20.0
25.0
11.8
14.0
40.0
14.2

8
1.2
35
6.0

6
1.8
19

No. of
vitiligo
patients
62
80
70
102
37
10
116
59
107
25
42

197
GENETIC AND
CONGENITAL
DISORDERS

198
CHAPTER 1

are otherwise normal and have no abnormalities of gastric secretion or

evidence of immunologic disturbances.
In conclusion, there seems to be a significant association between pernicious anemia and vitiligo. Considering that an autoimmune pathogenesis is
suggested for pernicious anemia and that there is an increased incidence of
PCA in vitiligo, it is attractive to suggest a common autoimmune mechanism
for both diseases. It is also possible that a totally different mechanism explains
the common occurrence of these two disorders. For example, Gilliam and Cox
[262] suggested that vitamin B12 deficiency produces a decreased intracellular
reduction potential with concomitant decrease in the GSH-reduced glutathione/
GSSG-oxidized glutathione ratio. This results in decreased tyrosinase inhibition
by GSH and increased melanogenesis. This explains hyperpigmentation in B12
deficiency, but depigmentation is more difficult to explain unless the selfdestruct hypothesis is invoked; increased melanogenesis, induced by vitamin
B12 deficiency may lead to the premature melanocyte destruction [263].
Vitiligo and Diabetes Mellitus
Sezary and Dupuy were the first to mention the association of diabetes and
vitiligo and attributed the discoloration of the skin to some pancreatic influence.
Since that time, many cases of diabetes mellitus associated with vitiligo have
been reported [264-266]. Diabetes mellitus, like vitiligo, is a common disease;
and like vitiligo the incidence is in some measure a function of how carefully
the diagnosis is pursued. The frequency of diabetes mellitus in the population
at large is thought to be 1% to 3%.
Incidence of Diabetes Mellitus in Vitiligo
Among 14 series, the incidence of diabetes mellitus in vitiligo ranges from
1% to 7.1% (Table 55). Howitz and Schwartz [187] found insulin-dependent
diabetes mellitus in four of 102 vitiligo patients (all were females with achlor-

hydria and two had pernicious anemia). Non-insulin-dependent diabetes mellitus was found in one male with normal gastric acid production. Blood glucose
levels are usually normal in patients with vitiligo [37,70], although Chojnacki
et al. found hyperglycemia in glucose tolerance tests of six of 17 nondiabetic
vitiligo patients with a positive family history of vitiligo and in seven of 26
nondiabetic vitiligo patients with a negative family history of vitiligo; two in
the former and one in the latter group were frankly diabetic [267]. Grupper et
al. [37] were unable to find anti pancreas antibodies in 20 vitiligo patients.
Diabetes is often present in close relatives of patients with vitiligo [37,185,186,268].
Incidence of Vitiligo in Diabetes Mellitus [Table 56)
The incidence of vitiligo among 520 diabetic patients has been reported
to be 4.8% as opposed to 0.7% among 433 nondiabetic controls [23]. The female
and male prevalence figures were 6.1% and 2.9%, respectively, against 0.7%
and 0.6% in controls. Dawber observed that in his 25 cases, only six had

TABLE 55. Incidence of Diabetes Mellitus in Vitiligo

Vitiligo patients
with
diabetes mellitus
Author

(%)

No. of
vitiligo patients

Lerner (1959) [29]

El Mofty (1968) [6]
Cunliffe et al. (1968) [185]
Bor et al. (1969) [186]
Grupper et al. (1970) [37]
Howitz and Schwartz (1971) [187]
Perrachi et al. (1971) [188)
Bleehen (1972) [42)
Perrot et al. (1973) [25]
Howitz and Rehfeld (1974) [38]
Seghal (1974) [17]
Ortonne (1974) [39]
Heid et al. (1974) [159)
Schnitzler et al. (1974) [189]
Chojnacki et al. (1976) [267)

1
1.6
7.1
1.6
2.8
5
3.3
3.1
7.0
1.7
2.9
5.0
6.2
6.6
5.5

182
545
56
62
70
102
30
32
200
116
202
100
48
30
54

acquired their vitiligo before the age of 40 [23]. He suggested, therefore, that
diabetes mellitus should be excluded in cases of late-onset vitiligo.
Macaron et al. found vitiligo among 1.66% of 300 juvenile insulin-dependent diabetics [161]; it is likely that a follow-up survey in a decade would
show an increased incidence.
Vitiligo seems to be associated with both adult-onset and juvenile-onset
diabetes. Some of the adult patients are insulin-dependent and others are not.
The incidence figures of 1% to 7.1% strongly support the existence of a link
between vitiligo and diabetes mellitus. Diabetes has been suggested to be of
autoimmune or viral origin in a susceptible individual. Two-thirds of patients
with insulin-dependent diabetes have HLA-B8 and/or HLA-Bw15 antigens. Although an autoimmune mechanism for diabetes mellitus has not been proved,
anti-islet cell antibodies have been found in juvenile-onset diabetes [269]. Other
observations that support the concept of autoimmunity include the presence
of a lymphocytic infiltrate in the pancreas of a newly diagnosed case of insulindependent diabetes, islet-cell antibodies, cell-mediated immunity to human
pancreas, and the increased frequency of gastric, adrenal, and thyroid antibodies [161]. Whittingham et al. [270] noted an increased level of various
TABLE 56. Incidence of Vitiligo in Diabetes
Diabetic patients
with
vitiligo
Author

(%)

No. of
diabetic patients

Dawber (1968) [23)

Macaron et al. (1977) [161]

4.8
1.7

520
3000

Juvenile diabetes.

199
GENETIC AND
CONGENITAL
DISORDERS

45

58

52

60

Christy et al. (1962)

[273]

Decourt et al. (1963)

[274]

De Mowbray (1965)
[275]

Meecham and Jones

(1967) [276]

Bleifeld and Gehrmann

(1967) [255]

40

33

Burgess and Warner

(1926) [272]

28

Age

Catanzaro Mannino
(1919) [271]

Reference

Case

Sex

Disease

Vitiligo
Pernicious anemia
Hypothyroidism

Addison disease
Vitiligo
Pernicious anemia

Vitiligo
Addison disease
Pernicious anemia
Hypothyroidism
Insulin-dependent
diabetes mellitus

Vitiligo
Adrenal insufficiency
Myxedema
Hypogonadism

Ovarian insufficiency
Hyperthyroidism
Addison disease
Insulin-dependent
diabetes mellitus
Vitiligo

Addison disease
Vitiligo
Graves disease

30

52

32

14
45
45
45

29
31
31
38

27

Age of
onset

Anti-intrinsic factor

Antithyroid
Antigastric parietal
cell
Anti-intrinsic factor

Antithyroid
Antiadrenal

Autoantibodies

Vitiligo and Multiglandular Insufficiencies

Vitiligo
Pernicious anemia
Hypothyroidism

TABLE 57.

Family history of
pernicious anemia
and of antithyroid and
antigastric antibodies

Family history of
vitiligo (maternal. son.
uncle) and Graves
disease (son)

Additional
history

63

81

50

Strickland (1969) [278]

MacGregor et al. (1972)

[279]

MacGregor et al. (1972)

[279]

MacGregor et al. (1972)

[279]

MacGregor et al. (1972)

[279]

MacGregor et al. (1972)

[279]

10

11

12

13

14

58

51

73

57

MacKay (1967) [277]

15
43
56

16
46
50

Vitiligo
Pernicious anemia
Hypothyroidism
Vitiligo
Diabetes mellitus
Pernicious anemia

47
50
57

17
48
49

40
75
76

33
41
63

30
61
68

Hypothyroidism
Vitiligo
Pernicious anemia

Vitiligo
Pernicious anemia
Hypothyroidism

Vitiligo
Pernicious anemia
Diabetes mellitus

Vitiligo
Hypothyroidism
Addison disease
Pernicious anemia

Vitiligo
Pernicious anemia
Thyroiditis

Antithyroglobulin

Antithyroglobulin
Antigastric parietal
cell
ANA

Antithyroglobulin
Antigastric parietal
cell
ANA

Antithyroglobulin
Antigastric parietal
cell
ANA

Antigastric parietal
cell
ANA

Antigastric parietal
cell
Anti-intrinsic factor
Antiadrenal

Antithyroglobulin
Antigastric parietal
cell
Anti-intrinsic factor

(Continued)

Family history of
pernicious anemia
and hypothyroidism

Alopecia areata

Family history of
vitiligo (both parents),
hypothyroidism
and diabetes mellitus
(mother), pernicious
anemia (father,
paternal
grandmother, uncle)

Chronic ulcerative
colitis and alopecia
areata
Antithyroid

28
28
14
25
25
34
29
55

Vitiligo
Thyroiditis
Addison disease
Pernicious anemia

36

65

Forcier (1972) [282]

Heymans and Lustman

(1971) [283]

19

20

Vitiligo
Insulin-dependent
diabetes mellitus
Thyroiditis

Family history of
vitiligo and possibly
thyroiditis
Antithyroid
Antigastric parietal
cell
Antiadrenal

18
22
23

Vitiligo
Graves disease
Insulin-dependent
diabetes mellitus
Addison disease
Pernicious anemia

28

Linquette et al. (1972)

[281]

18

57
58

28
35

Addison disease
Thyrotoxicosis
Vitiligo

29

Burns-Cox and Pearson

(1972) [280]

17

Alopecia areata; family

history of
thyrotoxicosis
(mother)
Alopecia areata

Antithyroid
Antigastric parietal
cell
Anti-intrinsic factor
Antiadrenal
Antithyroid
Antiadrenal
Antigastric parietal
cell

Family history of
vitiligo, diabetes
mellitus, pernicious
anemia (brother)

44
50
54

Vitiligo
Hypothyroidism
Pernicious anemia

54

MacGregor et al. (1972)

[279]

16

Antithyroglobulin
ANA

19
74
78

Vitiligo
Diabetes mellitus
Hypothyroidism

79

MacGregor et al. (1972)

[279]

Additional
history

15

Autoantibodies

Sex

Case

Age

Age of
onset

(continued)

Reference

Disease

TABLE 57.

TTnc;:.np.r+fip.cL

Antimel anocyte
3
3
3
6
9
16

Candidi asis
Alopeci a totalis
Vitiligo
Hypopa rathyroi dism
Addison disease
Primary ovarian failure

18

Hertz et al. (1977) [287)

26

Antimel anocyte

6
6
9
13
15
28
34

Alopeci a areata
Candidi asis
Hypopa rathyroi dism
Pernicio us anemia
Primary ovarian failure
Vitiligo
Addison disease

34

Hertz et al. (1977) [287)

25

Pancrea titis. complet e

heart block

Antithy roglobu lin

Antimic rosome
Antigas tric parietal
cell
Antipan creatitic
cell
Anti-int rinsic factor

Adolesc ence
45
75

Vitiligo
Pernicio us anemia
Hypothy roidism

75

Fairfax and Leatham

(1975) [286)

24

Family history of
diabetes mellitus and
Graves disease

Antithy roid
Antiadr enal

20
46
55

Vitiligo
Graves disease
Addison disease
Insulin- depende nt
diabetes mellitus

64

DeGenn es et al. (1973)

[285)

23

Family history of
diabetes mellitus and
Graves disease

Pretibia l myxede ma

Antithy roid
Antiadr enal

23
27
31

Vitiligo
Addison disease
Graves disease

66

DeGenn es et al. (1973)

[285)

22

Antithy roglobu lin

LATS
ANA

36
41

Vitiligo
Graves disease
Diabetes mellitus

51

Lynch et al. (1973) [284)

21

204

CHAPTER 1

autoantibodies in 400 diabetics, particularly in those patients with insulindependent diabetes. The mechanistic relationship between diabetes mellitus
and vitiligo is unclear. Expanded studies are required to isolate vitiligo patients
who are most predisposed to diabetes mellitus at any age.
Vitiligo and Multiglandular Insufficiency Syndromes (Table 57)
Vitiligo has been reported among many patients with multiglandular insufficiencies [247,271-278,280-283,285,286,288]. Of 26 such vitiligo patients,
20 had thyroid disease (11 hypothyroidism, six hyperthyroidism or Graves
disease, and three thyroiditis), 16 pernicious anemia, 12 Addison disease, nine
diabetes mellitus, and four gonadal dysfunction. These observations generally
support the autoimmune hypothesis for the pathogenesis of vitiligo. A hereditary factor among this cluster of patients has also been suggested [285].
Vitiligo and Hypoparathyroidism, Addison Disease, and Chronic
Mucocutaneous Candidiasis Syndrome (Fig. 77)
In 1937, Martinez-Jaureguy and Mendez-Schiaffino [289] published two
cases in which vitiligo improved after surgical removal of the parathyroids.
One patient had scleroderma, hypercalcemia, and possible hyperthyroidism.
The second patient also had hypercalcemia as well as chronic arthritis. Fisher
and Fitzpatrick [290] described a 20-year-old female with a syndrome of vitiligo,
Addison disease, hypoparathyroidism, and chronic mucocutaneous candidiasis. Other similar cases include a patient with this syndrome and vitiligo
universalis [32] and a 15-year-old Caucasoid with hypoparathyroidism, mucocutaneous candidiasis, diffuse nonscarring alopecia, and vitiligo [291]. Among
series of patients with hypoparathyroidism alone there is no mention of vitiligo
[292]. In two such patients with the syndrome of hypoparathyroidism, Addison

FIGURE 77. a: Vitiligo universalis in a patient with hypoparathyroidism, chronic mucocutaneous

candidiasis, and Addison disease. b: Vitiligo associated with cutaneous candidiasis affecting skin
and nails.

disease, alopecia areata, vitiligo, and chronic mucocutaneous candidiasis, Hertz

et al. [287] identified circulating antimelanocyte antibodies. Antipigment cell
factors may be found in patients with mucocutaneous candidiasis in the absence
of vitiligo. This suggests that these factors are not cytotoxic to pigment cell and
thus not the cause of vitiligo [292a].
Vitiligo and Alopecia Areata
Pincus in 1872 [293], Senator in 1889 [294], Casenave and Bonnet in 1898
[295], and others [296-301] have reported alopecia areata to be associated with
vitiligo (Fig. 69a).
Incidence of Vitiligo in Alopecia Areata (Table 58)
In seven different series, the incidence of vitiligo among patients with
alopecia areata was between 1.6% and 16%. Although Main et al. [307] noted
seven patients with vitiligo among 78 with alopecia areata as opposed to one
in 78 age- and sex-matched controls, this difference was not considered statistically significant. The lowest-1.6%-incidence of vitiligo in alopecia areata
patients was observed by MacAlpine [305], but the 4% to 16% incidence observed in the six other series is significantly greater than the 1% expected in
the general population.
Incidence of Alopecia Areata in Vitiligo (Table 59)
In 12 series, alopecia areata was found in from 0.39% to 16% of vitiligo
patients. In one controlled series, alopecia areata occurred in 16% of the vitiligo
patients but in only 2% of the patients with psoriasis. Alopecia areata seemed
to be more common in females with vitiligo.
Clinical Features of Vitiligo Associated with Alopecia Areata
Muller and Winkelmann [306] found 33 patients with coexisting vitiligo
and alopecia areata. In all but five instances, the appearance of vitiligo preceded
the onset of alopecia areata although hardly by significant time intervals. In
these cases, the vitiligo was progressive and extensive but never universal.
TABLE 58. Incidence of Vitiligo in Alopecia Areata

Author
Roxburgh (1929) [302]
Waisman and Kepler (1941) [303]
Anderson (1950) [304]
MacAlpine (1958) [305]
Demis and Weiner (1963) [149]
Muller and Winkelmann (1963) [306]
Main et al. (1975) [307]

Perccent of alopecia
areata
patients with vitiligo

No. of patients
with
alopecia areata

4
4.3
4.4
1.6
15.6
3.9
8.9

42
138
114
125
45
736
78

205

GENETIC AND
CONGENITAL
DISORDERS

TABLE 59. Incidence of Alopecia Areata in Vitiligo

206

Percent of vitiligo patients

with alopecia areata

No. of patients
with
vitiligo

0.4
1.6
16
1.5
4.8
2.5
4.3
9.3
1.5
2.0
3.4
3.3

253
62
56
545
62
650
70
32
200
100
202
30

CHAPTER 1
Author
Levai (1958) [12]
Chorazak and Rzempoluch (1968) [308]
Cunliffe et al. (1968) [185]
EI Mofty (1968) [6]
Bor et al. (1969) [186]
Dutta and Mandall (1969) [13]
Grupper et al. (1970) [37]
Bleehen (1972) [42]
Perrot et al. (1973) [25]
Ortonne (1974) [39]
Seghal (1974) [17]
Schnitzler et al. (1974) [189]

El Mofty [6], in eight patients, noted that hair loss preceded, accompanied, or
followed the onset of depigmentation. One of his cases had alopecia totalis and
the others alopecia areata, either localized to a single patch or in multiple
round patches of the scalp or beard area. None of these eight patients had the
nail involvement observed by Lerner [148] and Demis and Weiner [149] in
patients with total vitiligo and alopecia totalis.
The presence of alopecia areata may carry no prognostic significance with
regard to vitiligo. However, in three cases of alopecia universalis and very
extensive vitiligo vulgaris seen at Massachusetts General Hospital, both disease
entities were refractory to psoralen photo chemotherapy.
Pathogenetic Relationship between Vitiligo and Alopecia Areata
Enough parallels between vitiligo and alopecia areata exist to suggest a
common pathogenesis. Sidi et al. [35] pointed out that there are similarities in
the clinical course of both diseases. Onset of either condition may follow physical or mental trauma [302,309]. Both conditions have been said to respond to
psoralen therapy. The hair regrowth in a patch of alopecia areata is usually
white. Both vitiligo and alopecia areata have been associated with thyroid
diseases [173,310]; 8% of 736 patients with alopecia areata have been reported
to have thyroid abnormalities [306]. Alopecia areata and vitiligo are both seen
in those with multiple glandular insufficiencies [279-281,283].
A significant correlation between alopecia areata and the presence of autoantibodies to thyroglobulin, parietal cells, adrenal cells, thyroid cells, and smooth
muscle has been reported [311]. The histologic presence of lymphocytes in
alopecia areata is consistent with an autoimmune mechanism [307]. The number of T cells was found decreased in patients with alopecia areata, Down
syndrome, and vitiligo [166]. Future definition of any etiologic relationship
between alopecia areata and vitiligo, however, remains elusive.

Vitiligo and Premature Graying of Hair

In 1959, Lerner [29] suggested that graying of hair is a clinical form of
vitiligo. He found that in vitiliginous individuals, graying of hair occurs at
younger ages than in unaffected persons, and that premature graying of hair is
seen frequently in relatives of vitiliginous individuals. El Mofty [6] found 37
of 100 vitiligo patients with premature graying of hair, either themselves or
among their relatives; no control population was surveyed, however. Furthermore, premature graying of hair and vitiligo both are associated with pernicious
anemia. Dawber [245] found 14 cases with gray hair before the age of 20 years,
and 69 cases with gray hair before 50 years of age among 125 patients with
pernicious anemia, whereas these features were found in three and 38 of 132
controls, respectively. Both these differences are statistically significant.
At the ultrastructural level, the dendritic cell population of the hair matrix
of senile white hair and white vitiliginous hair is similar [311a].
If one accepts Lerner's hypothesis, then vitiligo becomes a normal concomitant of aging and everyone is destined to develop vitiligo. The melanocyte
density normally decreases after age 10 so that graying of hair is a normal
physiologic process on a nearly universal basis. Graying of hair normally begins
in the thirties, but over half of those with vitiligo will demonstrate it by their
early twenties; the age-prevalence curves are hardly congruent. Since vitiligo
may spare follicular melanocytes and pigmentation preferentially returns from
follicular melanocytes, vitiligo must differ from a process that selectively destroys follicular melanocytes. Furthermore, whereas some degree of repigmentation of vitiliginous epidermis is not uncommon, repigmentation of senile gray
hair is rare. Although graying of hair occurs with increasing frequency among
vitiligo patients compared to controls, it must be considered an "arm" of vitiligo,
like alopecia areata, halo nevi, etc.
Possible Associations

Many conditions have been reported with enough frequency among vitiligo
patients to deserve special notice even though there is not yet adequate evidence
to consider them definitely correlated with vitiligo.
Vitiligo and Psoriasis
Neumann in 1890 [312] was probably the first to associate vitiligo and
psoriasis. de Moragas and Winkelmann, in a survey of the literature, found
more than 20 cases reported between 1898 and 1965. Vitiligo has also been
observed [313,314] with psoriatic arthritis.
Incidence

of Vitiligo in Psoriasis

Cunliffe et a1. [185] found no vitiligo among 56 psoriatic patients, and

vitiligo was observed in only one of the relatives of one psoriatic patient.

207

GENETIC AND
CONGENITAL
DISORDERS

TABLE 60. Incidence of Psoriasis in Vitiligo

208

Percent of vitiligo patients

with psoriasis

No. of patients
with
vitiligo

0.4
0.7
4.8
0.5
4.0
4.1

253
545
62
200
100
48

CHAPTER 1

Author
Levai (1958) [126]
El Mofty (1968) [6]
Bor et a1. (1969) [186]
Perrot et a1. (1973) [25]
Ortonne (1974) [39]
Heid et a1. (1974) [159]

Incidence of Psoriasis in Vitiligo [Table 60)

In six different series of patients with vitiligo, the incidence of psoriasis
was reported to be between 0.4% and 4.5%. As the incidence of psoriasis in
the general population is probably greater than 1%, psoriasis would not appear
to be more common in vitiligo than in control patients. However, it has been
suggested that there is an interrelationship between melanin pigmentation and
psoriasis [315]. Patients with psoriatic plaques confined to macules of vitiligo,
but no psoriatic involvement of the normally pigmented skin, have been reported [315,316]. However, Chapman [317] reported a patient in whom areas
of involvement of psoriasis and vitiligo did not correspond. We have personally
seen both types of involvement and are not impressed that clearing of the
psoriasis is associated with repigmentation; so the leukoderma confined to
psoriatic plaques does not appear to be simply a postinflammatory hypomelanosis. The psoriasis may appear before, as the same time as, or after vitiligo.
The occurrence together of vitiligo and psoriasis has suggested that there
is some epidermal regulation of melanocyte function such that vitiligo and
psoriasis may coexist. Lorincz and Rothman [288] suggested that vitiligo as
well as psoriasis together reflect a low-grade autoimmune mechanistic disorder.
Vitiligo-Like Leukoderma and Melanoma
The occurrence of a vitiligo-like depigmentation in both males and females
with melanoma has been reported. Although the clinical appearance of this
leukoderma resembles vitiligo, we prefer the term "vitiligo-like leukoderma"
or "melanoma-associated leukoderma" to describe this entity. The presence of
an identifiable precipitating factor with melanoma and the absence of one with
vitiligo seems adequate justification to separate these entities.
The prevalence of depigmentation among patients with melanoma is unknown. In a survey of the literature, we found 34 well-documented cases (Table
61), but others have been mentioned [25,330-334] and we have personally
observed three cases. Lerner and Cage [333] stated that 20% of the patients with
melanomas show a vitiligo-like depigmentation, but Milton et al. [326] found
depigmentation in only 11 of 800 melanoma patients. This 1.3% incidence is
not significantly different from that of vitiligo in the general population, but
these authors stated that the true incidence of vitiligo-like depigmentation in

TABLE 61. Malignant Melanomas and

Vitiligo--like Depigmentation (Detailed
Reports)
Author
Ito and Yoshida (1952) [318]
Matsuzawa et al. (1953) [319]
Miura and Nakajima (1959) [320]
Karcher (1960) [321]
Burdick and Hawk (1964) [322]
Balabanov et al. (1969) [323]
Roth (1968) [324]
Frenk (1969) [325]
Milton et al. (1971) [326]
Donaldson et al. (1974) [327]
Fodor and Bodrogi (1975) [328]
Happle et al. (1975) [329]
Ortonne et al. (1978) [333a]

No. of
cases
1
1
1
2
1
2
1
2
9
2
6
1
8

melanoma patients is likely to be higher than is apparent from their data,

especially if only cases with known metastasis are considered. At the Massachusetts General Hospital Melanoma Clinic where all patients are screened by
Wood's light examination, leukoderma is uncommonly observed (A. Sober,
personal communication). Nevertheless, the true incidence of this phenomenon
is probably higher than some of the literature suggests.
In all the 42 reported patients, there was a fairly close temporal relationship
between the onset of the depigmentation and the appearance or the discovery
of the melanoma. In many, the vitiligo-like depigmentation appeared between
several months and five years after the appearance of the tumor. In most of
these cases, the depigmentation began after 40 years of age. Lerner and Cage
[333] mention, however, two patients whose vitiligo preceded the melanoma
by several years. None of the 42 reported patients had a positive family history
of vitiligo. Onset after the melanoma, the late age of onset, and the absence of
a positive family history of vitiligo are distinctive enough to suggest this as a
disease process distinctive from classical vitiligo. The leukoderma sometimes
seen in the graft site of a widely excised melanoma is not vitiligo or vitiligolike depigmentation [326,328].
All types of melanomas, including uveal melanomas [334,334a), may be
associated with the vitiligo-like depigmentation. The cutaneous depigmentation associated with melanoma clinically resembles ordinary vitiligo. The distribution may be symmetrical or asymmetrical [325]. Most reported cases also
had visceral or lymph node metastases. Halo nevi may also appear at the same
time as vitiligo-like depigmentation [327]. Repigmentation of melanoma-associated leukoderma may occur.
Uveitis associated with the cutaneous depigmentation has been reported
in two patients treated with BCG immunotherapy [327] and in one untreated
patient [335].

209
GENETIC AND
CONGENITAL
DISORDERS

210
CHAPTER 1

The presence of leukoderma carries an uncertain prognosis for the melanoma patient. There are reported cases of vitiligo progressing and metastatic
melanoma regressing and others of 10-year or more survival after metastatic
melanoma and vitiligo [336]. Lerner and Nordlund have cited three cases of
coexisting early vitiligo and melanoma with two to 19 years' survival [337].
Others have also suggested that the depigmentation associated with melanoma
carries a favorable prognosis but further observations revealed no correlation
between the clinical course of vitiligo and melanoma [326]. Furthermore, in
two patients repigmentation preceded death by only several months. Treatment
of the melanoma does not seem to affect the vitiligo-like depigmentation. It is
difficult to ascribe prognostic significance to any of the types of depigmentation
associated with melanoma. The suggestion of Lerner and Nordlund that lateonset vitiligo developing in patients with melanoma may be a poor prognostic
sign, suggests the immunologic system may have been overwhelmed [337].
This requires documentation.
The histology of the depigmented macules mayor may not mimic that of
vitiligo. In some cases histopathology of the depigmented skin of these patients
reveals a nearly complete loss of melanin, negative dopa reaction, and an
absence of melanocytes. Balabanov et al. [323] used zinc osmium iodide staining to show a lack of high-level epidermal dendritic cells, a finding that was
not confirmed by Frenk [325] who found the same dendritic cell population
in vitiliginous skin and in the depigmented skin from melanoma patients.
Recent studies of depigmented macules in three melanoma patients have shown
a reduced number of dopa-positive melanocytes; these giant melanocytes are
three times normal size [338].
Several hypotheses are extant to explain the phenomenon of cutaneous
depigmentation. Melanoma therapy has been implicated. It has been suggested
that x-ray therapy [321,324] initiates a series of neuroendocrine changes which
may be responsible for the cutaneous depigmentation or the destruction of
melanoma cells with resultant release of antigenic substances, so that specific
antimelanocyte antibodies are formed. However, in many patients the vitiligolike depigmentation precedes treatment.
The suggestion [326] that depigmentation could result from the "stressful
situation" in these patients seems unlikely because of the considerable lag time
between the diagnosis of the melanoma, hence the stress, and the appearance
of the depigmentation. Furthermore, the stress is universal in melanoma patients and the depigmentation is uncommon.
With much evidence accumulating to show humoral and cell-mediated
immunologic reactions in patients with melanoma, an immune pathogenesis
for these phenomena seems most likely. The association of melanoma and
leukoderma is observed to occur spontaneously in swine [339] and various
strains of horses [333].
Vitiligo and Halo Nevus
See "Halo Nevus" in Chapter VIII.

Isolated Cases of Association

211

Dermatoses
There are many scattered reports of this or that disease occurring in vitiligo
patients. Those reported multiple times merit special attention; the others are
tabulated at the end of this discussion. As time passes, these lists will undoubtedly lengthen.
Vitiligo and Lichen Planus
The early reports of Wielander [340] in 1894 of lichen planus and vitiligo
were thought by Sezary and Dupuy [98] to represent fortuitous association. As
both lichen planus and vitiligo are common diseases, it is not surprising that
they have been reported to occur in the same patients [341]. The incidence of
lichen planus in three series of vitiligo patients varies from 0.5% to 4.8% as
opposed to the incidence of 1% in the general population (Table 62). There is
no statistical evidence to substantiate a correlation between vitiligo and lichen
planus.
In the case of coexisting vitiligo and lichen planus, the lesions may be
observed on the same or different sites [342,343]. Both lichen planus and vitiligo
have been associated with scleroderma and chronic active hepatitis [344], scleroderma [345], lichen sclerosus et atrophicus and morphea [346], and ulcerative
colitis and alopecia areata in a patient with myasthenia gravis [347].
Vitiligo and Atopic Dermatitis
Although Kierland [348] asserted that vitiligo is seen more frequently in
patients with atopic dermatitis, this is unsubstantiated. One patient with eczematous lesions surrounding but not involving the vitiliginous skin has been
reported [349]. However, the "delayed blanch" phenomenon, considered as
a specific stigma in atopic dermatitis, was observed both in dermatitic and
vitiliginous skin. In most vitiligo series, atopic dermatitis is not mentioned.
Vitiligo and Scleroderma [Fig. 78)
Pautrier and Lepinay [350], in 1932, observed morphea and vitiligo in a
37-year-old man. Three other cases of morphea and vitiligo have been reported
TABLE 62. Incidence of Lichen Planus in Vitiligo

Author
Bor et al. (1969) [186]
Perrot et al. (1973) [25]
Ortonne (1974) [39]

Percent of vitiligo patients

with lichen planus
4.8
0.5
1.0

No. of patients
with
vitiligo
62
200
100

GENETIC AND
CONGENITAL
DISORDERS

212
CHAPTER 1

FIGURE 78. a-c: Vitiligo associated with morphea.

by Lerner and Nordlund [123]. In 1935, Grenet and Isaac-Georges [351] observed
linear scleroderma in an eight-and-one-half-year-old girl with vitiligo. Progressive systemic sclerosis together with vitiligo was reported in 1939 by Deglos
and st. Girons [352] . Many other cases have been reported [344-346,353-359].
In a review of four cases of coexistent morphea and vitiligo, Saihan and Peachey

[360] cite 31 other cases reported in the literature. In most cases the disorders
did not involve the same anatomic areas of skin. In 47% of 22 cases of circumscribed scleroderma and vitiligo, foci of scleroderma developed before the
occurrence of vitiligo, in 26.5% they appeared simultaneously, and in 26.5%
vitiligo preceded scleroderma [361,362]. Since we also have observed four cases
of morphea in 300 cases of vitiligo, the relationship is probably more than
fortuitous (personal observation).
Vitiligo and Lichen Sclerosus et Atrophicus
There are only a few reports of lichen sclerosus et atrophicus and vitiligo.
One of the 52 vitiligo patients of Chorazak and Rzempoluch [308] had lichen
sclerosus et atrophicus. Wallace [363] found several cases of vitiligo in a series
of patients with lichen sclerosus et atrophicus. The number of reports is inadequate to conclude these reports reflect other than chance associations.
Vitiligo and Porphyria
One case of vitiligo has been reported among four patients with congenital
porphyria. Four of 52 cases of porphyria cutanea tarda [364] also had vitiligo.
Guseinov thought this association to be significant and hypothesized that in
these patients free porphyrins might be inhibiting melanin synthesis. Many
patients with porphyria cutanea tarda and erythropoietic protoporphyria show
hyperpigmented macules on the exposed skin but no evidence of vitiligo. The
association of vitiligo with porphyria, not reported in most series, is more likely
to represent a chance occurrence.
Vitiligo and Lupus Erythematosus (Table 63)
In 1921, Barber [365] reported a patient with alopecia areata who, some
years later, developed vitiligo and lupus erythematosus. Both systemic and
discoid lupus erythrematosus have been reported in patients with vitiligo
[70,366-369]. In a few cases, lesions of discoid lupus erythematosus were
located almost exclusively on the hypopigmented skin [369a]. However, the
occurrence of only two cases of lupus in 253 vitiligo patients in one series and
only one case of systemic lupus erythematosus in another series of 200 vitiligo
patients is weak evidence for any association [25,126]. Most series do not
mention discoid or systemic lupus erythematosus.
TABLE 63. Incidence of Lupus Erythematosus (DLE - SLE) in
Vitiligo

Author
Cunliffe et al. (1968) [185)
Perrot et al. (1973) [25)

Associated
lupus erythematosus
(%)
0
0
0.5

(SLE)
(OLE)
(SLE)

Total no.
of patients
56
200

213

GENETIC AND
CONGENITAL
DISORDERS

TABLE 64. Incidence of Antinuclear Antibodies in Vitiligo

214
CHAPTER 1

Antinuclear antibodies
Controls

(%)

(%)

No. of vitiligo
patients

3.7
15.4
7.1

2.5

80
26
28
58
107
42

Vitiligo
Author
Brostoff et al. (1969) [196]
Grupper et al. (1970) [37]
Pottgen et al. (1971) [248]
Ortonne (1974) [39]
Heid et al. (1974) [159]
Woolfson et al. (1975) [198]

1.7

3.7
14.2

2.1
16.6

In a few cases, lesions of discoid lupud erythematosus were located almost

exclusively on the hypopigmented skin [369a]. Among six different reports
(Table 64) there was no increased incidence of positive ANAs.
Endocrinopathies
Vitiligo and Hypopituitarism
In the 1920s, dysfunction of the hypothalamic-pituitary axis was a popular
explanation for vitiligo [370,371]. Patients with vitiligo and acromegaly, adiposogenital syndrome [372,373], Simmond disease [372], and diabetes insipidus [372] have been reported. It was suggested that vitiligo frequently complicated hypopituitarism, hypogonadism, and dwarfism [370]. The report of
vitiligo and short stature in a 20-year-old man as well as his maternal grandfather, aunt, uncle, and one sister suggested pituitary dysfunction [372].
Even among the cases of pluriglandular deficiency associated with vitiligo
[29] there is no evidence of pituitary dysfunction. There is no evidence that
there is any association between vitiligo and pituitary disease.
Hormonotherapy has been attempted. Although circulating MSH levels are
usually normal in vitiligo [29], eight of 11 vitiligo patients treated by intradermal injection of melanotropic hormone were said to repigment even at sites
remote from that of injection [374,375]. However, these results have not been
confirmed. ACTH administration has also been used with some benefit [376].

Vitiligo and Hypogonadism

Several reports have related vitiligo to ovarian insufficiency [377,378]. In
1921, Jayle and Aubry [82] wrote that a woman with abdominal and genital
vitiligo had ovarian insufficiency. In other cases, onset of vitiligo followed
oophorectomy [8,379]. But these cases are just of historical interest, for gonadal
or ovarian dysfunction has not been found in vitiligo patients nor is there
evidence of abnormal estrogen, progesterone, or testosterone levels.

TABLE 65. Incidence of Rheumatoid Arthritis in Vitiligo

No. of patients
with
vitiligo

Percent of vitiligo patients

with rheumatoid arthritis

Author
Cunliffe et al. (1968) [185]
Bor et al. (1969) [186]
Ortonne (1974) [39]

215

56
62
100

3.5
6.4

3.0

Vitiligo and Rheumatoid Arthritis (Table 65)

It should be no surprise that these two common conditions have been
reported together. Two cases of rheumatoid arthritis were found among 56
patients with vitiligo, whereas no case was observed among 56 patients with
psoriasis [185]. Two relatives of the vitiligo patients also had rheumatoid arthritis. No conclusions can be drawn from such a small sample, particularly
as one would anticipate up to a 10% incidence of psoriatic arthritis among the
56 psoriatic controls. In two other series, four rheumatoids were noted among
62 vitiligo patients [186] and two among 100 vitiligo patients [39]; neither series
reported the incidence in the control population. Durance [380] reported a 48year-old woman with rheumatoid arthritis, vitiligo, myasthenia gravis, and
autoimmune hemolytic anemia. A patient with vitiligo, juvenile rheumatoid
arthritis, and primary ovarian failure was found to have circulating antiovarian
antibodies [381]. Rheumatoid arthritis is a very common disease and there is
no convincing evidence that vitiligo and rheumatoid arthritis coexist other than
by chance. The incidence of positive rheumatoid factor in vitiligo appears to
be normal (Table 66).

Vitiligo and Parkinson Disease

Parkes et al [382] hypothesized that cutaneous pigmentary changes could
occur in Parkinson disease, a condition in which there is an impairment in the
synthesis of neuromelanin; but he found only one case of vitiligo in 102 patients
with idiopathic Parkinson disease. Since different pathways are involved in
the synthesis of neuromelanin and of eumelanin [383], a common defect in
vitiligo and Parkinsonism would not be expected.
TABLE 66. Incidence of Rheumatoid Factor in Vitiligo
Percent of patients having
rheumatoid factor
Author
Grupper et al. (1970) [37]
Ortonne (1974) [39]
Woolfson et al. (1975) [198]

Method
Waaler-Rose
Latex
Waaler-Rose
Rheumaton

Vitiligo
2.7
0
28.2
19.0

Controls

No. of
vitiligo
patients

7.1

36
36
46
42

GENETIC AND
CONGENITAL
DISORDERS

216

Vitiligo and Hepatobiliary Disease

CHAPTER 1

In 1908 Gandy and Paillard [384] reported two patients in whom vitiligo
occurred in the course of jaundice or cirrhosis of the liver and suggested a
biliary origin of some cases of vitiligo. Banerjee and Pal [385], who in 1956
found amebiasis in 85% of 125 cases of vitiligo, suggested that liver damage
may be an important etiologic factor. However, Levai [12] found only 1.5% of
her vitiligo patients to have Entamoeba histolytica, 10% a history of jaundice,
and only 1% liver or gallbladder disease. The incidence of these in the normal
Indian population is not reported. But only isolated cases of vitiligo associated
with chronic active hepatitis [344], hemochromatosis [386], primary biliary
cirrhosis [387], hepatoma [388], and cirrhosis [389] have been reported. Clinically, there seems to be no connection between vitiligo and liver disease.
Most series report normal liver functions in vitiligo patients [12,29,308].
There have been some scattered exceptions. In one series from India [390],
increased transaminase was noted in 43%, increased alkaline phosphatase in
42%, and decreased paraphenylene diamine oxidase in 8%. A Polish study
[391], however, reported decreased alkaline phosphatase. Leucine amino peptidase is normal in vitiligo [392].
Antimitochondrial antibodies, which are associated with chronic active
hepatitis and primary biliary cirrhosis, are not present in vitiligo (Table 67).
Danzig [389] reported a case of vitiligo and cirrhosis of the liver with
jaundice; there were no signs of icterus in the depigmented vitiliginous macules
although the surrounding skin was jaundiced. Bilirubin was absent from the
depigmented skin. Lerner [29] suggested that the involved skin does not become
icteric because the blood vessels are constricted in macules of vitiligo. Another
patient was reported to show jaundice in both normal and in vitiliginous skin
[393]. A patient with vitiligo treated by mepacrine did not appear yellow in
the vitiliginous skin; however, the fluorescent dye was found in the vitiliginous
skin and the depigmented skin appeared yellow when seen against a white
background (M. A. Pathak, F. Dall'Acqua, G. Rodighiero, unpublished observations).
Vitiligo and Dysglobulinemia

While occasionally there are reported abnormalities of serum proteins in

vitiligo, particularly a-globulin and l3-globulin [308,394] or haptoglobulin [395],
the 'Y-globulin and albumin fractions are usually normal.
IgM, IgG, and IgA levels are normal [39]. However, decreased IgA has been
reported in five patients with vitiligo [396]. An eight-year-old female with
vitiligo and a dysglobulinemia was found to have absent IgA, very low IgG,
and normal IgM [397]; the T-cell immune system was intact but other family
members had low or absent IgA levels. This case probably represents a chance
occurrence of vitiligo with a hereditary immunodeficiency syndrome. In a larger
study of 45 children with vitiligo, there was no evidence of IgA deficiency
[398].

The circulating antibody identified by Hertz et al. [287] was characterized

as IgG.

TABLE 67. Incidence of Antimitochondrial Antibodies in Vitiligo

Antimitochondrial
antibodies
Author
Ortonne (1974) [39]
Heid et al. (1974) [159]
Woolfson et al. (1975) [198]
o

Vitiligo

Controls

(%)

(%)

No. of vitiligo
patients

0
0
0

1.4
4.7

107
42

72

Not done.

Hematologic Disorders (Other Than Pernicious Anemia)

There are scattered case reports of other hematologic abnormalities. There

is a single case report of vitiligo, hyperthyroidism, and anti thyroglobulin antibodies in a 19-year-old girl with idiopathic thrombocytopenic purpura. MSH
levels were normal and no anti-MSH antibodies were detected [399]. A case
with a Coombs-positive anemia, chronic thrombocytopenia, and vitiligo has
been reported [400]. Autoimmune hemolytic anemia, myasthenia gravis, and
rheumatoid arthritis have been reported in a 48-year-old man with vitiligo [380].
Another patient, a 52-year-old woman with a two-year history of vitiligo, developed a hemolytic anemia and was found to have T-cell dysfunction, namely,
decreased E-rosette-forming lymphocytes and a negative graft vs. host reaction
test [401]. Roder [402] described a defect in erythrocyte maturation in several
patients with vitiligo.
Malignancies
Vitiligo and Internal Malignancies
The association of vitiligo with various carcinomas is discussed several
times in the literature [403-407]. In 1956, D'Agostino [404] distinguished a
particular form of vitiligo that he called "vitiligo preneoplastic." Various clinical features such as onset often after the age of 40, limited involvement, and
ill-defined borders of the depigmented macules distinguished this vitiligo from
that unassociated with malignancy. Of nine patients with vitiligo and internal
malignant disease, five had gastrointestinal tumors, two intracranial tumors,
one a breast tumor, and one a uterine tumor [405]. In three of these cases, there
was a close temporal relationship between the appearance of vitiligo and the
diagnosis of malignancy. In three others, vitiligo occurred first and malignancy
was diagnosed two to three years after the appearance of the depigmentation.
In the remaining three cases, vitiligo preceded the internal malignancy by six
years in two and 61 years in the other. In only two of these nine patients did
vitiligo begin before age 40. The authors state that patients with late-onset
vitiligo are five times more likely than all patients with vitiligo to have a
malignancy and that therefore a thorough search for occult malignancy is warranted in patients in whom vitiligo begins after the age of 40. However, this

217
GENETIC AND
CONGENITAL
DISORDERS

218

CHAPTER 1

conclusion is based on a limited sample; furthermore, the denominator for

comparison should be an age-matched older nonvitiliginous population, in
whom the expected incidence of malignancy is higher.
Gastric mucosal changes in the absence of frank pernicious anemia are
frequently encountered in vitiligo. An argument could be made for the association of gastric carcinoma and vitiligo because both may complicate pernicious anemia [407]. But, in fact, vitiligo patients do not seem to be at increased
risk for gastric carcinoma.
The increased frequency of thyroid disease in vitiligo might suggest a
possible relationship between the vitiligo and thyroid carcinoma. Vitiligo associated with thyroid carcinoma [25] has in fact been reported, but there is no
statistical evidence that vitiligo is associated with an increased proclivity to
thyroid carcinoma.
Vitiligo has also been reported with multiple myeloma [123], Sezary syndrome [123], lymphoma [123], abdominal carcinomatosis [82], hepatoma [388],
bronchogenic carcinoma [121], and Cowden disease [408]. Out of 77 patients
with brain tumors, two had vitiligo. In both cases, the two disorders appeared
simultaneously [409].
There is inadequate evidence in these cases for clinically parallel courses
of the two diseases. Treatment of the malignancy does not seem to influence
the course of vitiligo. Vitiligo at any age clearly is not a marker for malignant
diseases.
Vitiligo and Cutaneous Malignancies
As suggested by Lisi [410], because of the amelanosis of involved skin,
actinic damage to vitiligo skin like albino skin should be common and apparent.
But Fitzpatrick and Mihm [32] pointed out that, curiously enough, solar keratoses have only rarely been noted in vitiliginous skin of patients living in the
lower latitudes, and only a few cases of skin cancers in vitiligo patients have
been reported [410a].
In 1972, Lassus et al. [405] reported skin cancer in two vitiligo patients, a
51-year-old with a squamous cell carcinoma and a 68-year-old with a basal cell
carcinoma. The authors do not mention whether the tumors were located on
the vitiliginous macules. As vitiligo preceded the onset of the tumors by only
two and six years, respectively, it seems unlikely that absence of pigment was
a significant predisposing factor. However, Lisi [410] reported two cases of
cutaneous tumors in vitiligo macules repeatedly exposed to sunlight. Seborrheic keratoses, keratoacanthoma, and squamous and intermediary cell carcinoma were noted in a 78-year-old man and seborrheic keratoses and a basal
cell carcinoma in an 85-year-old man. One recent case with actinic keratoses
confined to the vitiliginous macules of the face has been observed (Fig. 79).
An isolated case of sarcomatosis cutis with vitiligo has been reported [411].
One vitiligo patient with Kaposi disease has also been described [25].
The apparently low incidence of skin cancers in vitiligo is unexplained.
Either vitiligo patients uniformly avoid sun exposure or use a topical sunscreen
regularly, or some factor other than melanin affords some cutaneous photopro-

219

GENETIC AND
CONGENITAL
DISORDERS

FIGURE 79. Patient with multiple actinic keratoses

confined to macules of vitiligo skin. This appears to
be an uncommon occurrence perhaps in part because
vitiligo patients learn to protect their skin or avoid
sunlight to prevent sunburn.

tection. Certainly one would expect to observe some late actinic changes in
those who developed facial vitiligo before their teens.
Gastroenteropathies
Vitiligo and Protein-Losing Gastropathy
Two cases have been reported. One was noted to have multiple gastric
polyps and a protein clearance rate of 15 times normal from the gastrointestinal
tract. Gastric histology showed hypertrophic mucosal glands and cystic dilation
deep to the mucosal layer [260]. The authors point out that occasionally such
changes were observed in atrophic gastritis, known to be associated with vitiligo.
Vitiligo and Celiac Disease
One case of vitiligo has been reported among 57 patients with biopsyproved celiac disease [412]. This patient, a 62-year-old female, had developed
both progressive vitiligo and celiac disease at the age of 40. Smooth muscle
antibodies were present but antireticulin antibodies were not. Among patients
with celiac disease, 19% had an associated autoimmune disease and 30% had
antireticulin antibodies. The authors could not use this case to support an
autoimmune pathogenesis of vitiligo, as they concluded that there may exist
an association between celiac and autoimmune disease but not between celiac
disease and vitiligo.

220

Vitiligo and Crohn Disease

CHAPTER 1

McCallum and Kinmont [413] found three cases of vitiligo among 138
patients with Crahn disease. An additional case of almost simultaneous occurrence of vitiligo and regional enteritis has been described [414]. In another
series of 101 cases, none had vitiligo. All reported incidence figures are within
expected limits.
Vitiligo and Ulcerative Colitis
Among 56 patients with vitiligo, one case of ulcerative colitis was noted
and another was found among their relatives [185]. One patient with ulcerative
colitis, vitiligo, atypical lichen planus, alopecia areata, and myasthenia gravis
[347], and another with alopecia areata, vitiligo, and scleroderma [415] are
described in the literature. Although three patients with vitiligo are among 40
cases of ulcerative colitis in one series [416], other large series of patients with
the gastrointestinal diseases contain no mention of vitiligo. There is no statistically significant correlation between vitiligo and ulcerative colitis.
Vitiligo and Intestinal Parasitism
Especially in India, intestinal infection (parasitic or helminthic) has very
often been incriminated in the pathogenesis of vitiligo. One study associated
enteric helminths, especially ascariasis, with vitiligo; treatment was said to
result in repigmentation [417]. But, in 650 patients, Dutta and MandaI [13]
found no more intestinal parasitism than in controls. Levai [12] found the same
incidence of intestinal parasitism in 206 vitiligo patients and in 488 controls.
Vitiligo and Myasthenia Gravis
Four cases of myasthenia gravis and vitiligo have been reported in the
literature. In two of these patients, vitiligo became apparent two months after
thymectomy [418]. In the two other patients, vitiligo preceded [380] or followed
[347] the onset of myasthenia gravis. However, Cunliffe et al. [185] did not
observe myasthenia gravis in any of their 56 vitiligo patients and it is not
described in most series. We have seen myasthenia gravis also in the father of
a girl with vitiligo.
The incidence of striated muscle antibodies seen in myasthenia gravis has
been reported to be higher in vitiligo patients than in controls [37] (Table 68).
The incidence of smooth muscle antibodies is not increased in vitiligo (Table
69).

Vitiligo and Idiopathic Heart Block

Five of 100 patients with chronic heart block also had vitiligo [286]. According to the authors, this incidence was significant when compared with
controls. In their population, 16% had one or more of vitiligo, Graves disease,

TABLE 68. Incidence of Striated Muscle Antibodies in Vitiligo

Incidence of striated
muscle antibodies
Controls

Author

(%)

(%)

No. of vitiligo
patients

Grupper et al. (1970) [37]

Schnitzler et al. (1974) [189]

38.4
25.0

18

Vitiligo

a Not done.

hypothyroidism. pernicious anemia. and diabetes mellitus. Although antiorgan

antibodies were not present in most of the patients. the authors suggested that.
among patients with idiopathic heart block. there is a subgroup with multiple
autoimmune disorders. Unfortunately no age-matched control group was reported; it seems doubtful that the figures reported are beyond normal limits.
No studies of the incidence of vitiligo in an older population have been done;
5% may well be involved in a population over 50 years of age.
Other Associations
It is no surprise that such a common disorder as vitiligo has been reported
in association with many other conditions. The following have been reported
with vitiligo and likely represent chance occurrences: Capgras syndrome [419],
Down syndrome [166]. trisomy 21 [420], Lobstein disease [421], Hurler polydystrophy [422]. Leber syndrome [423], osteopoecilia [424], ichthyosis vulgaris
[56], Peutz-Jeghers syndrome [425], Hailey-Hailey disease [235], von Recklinghausen disease [426]. anetoderma and macular atrophy [427.428], facial
hemiatrophy [177.429]. partial hemiatrophy [430,431], Rubenstein-Taybi syndrome [432], Maffucci-Kast syndrome [433], dermatitis herpetiformis [434,435]
(antibasement membrane or anti-intercellular substance antibodies are absent
in vitiligo; Table 70). benign mucosal pemphigoid [436], acne conglobata [437].
Mach syndrome [125], and Gougerot-Sjogren syndrome [189.356] (salivary duct
antibodies are usually not present in patients with vitiligo; Table 71).

TABLE 69. Incidence of Smooth Muscle Antibodies in Vitiligo

Incidence of smooth
muscle antibodies
Vitiligo

Controls

Author

(%)

(%)

Brostoff et al. (1969) [196]

Ortonne (1974) [39]
Heid et al. (1974) [159]
Woolfson et al. (1975) [198]

0
4.1
0
9.5

aNot done.

No. of vitiligo
patients
80
72

0.7
9.5

107
42

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GENETIC AND
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222

TABLE 70. Incidence of Basement Membrane (BM) and Intercellular Substance

(IeS) in Vitiligo

CHAPTER 1

Incidence of skin antibodies

Vitiligo

(%)

Author
Grupper et al. (1970) [37]
Ortonne (1974) [39]
a
b

BM
ICS
BM
ICS

Controls

(%)

24.4

No. of
vitiligo
patients

40

o
o
o

o
72

72

Not specified.
Not done.

Pathologic Findings
The characteristic histologic picture of vitiligo is the total absence of melanin and identifiable melanocytes. In general, the epidermis and dermis are
otherwise normal.

Disturbances in the Pigmentary System of the Skin

The Silver Stain
The silver stain generally reveals no argentaffin granules in the totally
depigmented macules of vitiligo. Hu et al. [63] did note in two of their patients
small islands of cells marked with intracytoplasmic argentaffin granules and
observed that these two patients repigmented more readily and more extensively with methoxsalen and ultraviolet radiation than did the other 13 patients.
It seems likely that, in these two cases, there were subclinical islands of sparing
or possibly islands of spontaneous or sun-induced repigmentation.
At the hyperchromic ring, an abrupt increase occurs in the number of
argentaffin granules at the outer border of the ring, and a gradual decrease in
number at the zone of transition from the hyperchromic ring to the achromic
macule.
TABLE 71. Incidence of Salivary Duct Antibodies in Vitiligo
Incidence of salivary duct
antibodies
Vitiligo

Controls

Author

(%)

(%)

No. of
vitiligo
patients

Brostoff et al. (1969) [196]

Woolfson et al. (1975) [198]

0
2.3

0
2.3

80
42

The Dopa Reaction

Hu et al [63] reported, and it is generally agreed, that there are no histochemically recognizable melanocytes in vitiliginous skin, whereas melanocytes
are present in normal numbers in the uninvolved skin of the same individuals.
In vitiligo macules, the dopa reaction is negative, but it is normal in unaffected
surrounding skin. Bloch [438] considered the negative dopa reaction of vitiliginous macules as a failure of the "ferment to function." Although vitiligo
macules are generally considered to be dopa-negative, Jarrett and Szabo [439],
in a study of 33 biopsies of vitiligo, distinguished three histologic types of
melanocytes: the classical type or "Absolute Type" in which there are no dopapositive melanocytes, a group called "Relative Type I," and a group called
"Relative Type II." In the Relative Type I (clinically hypopigmented but not
depigmented), melanocytes were present in normal numbers but were only
slightly dopa-positive. In Relative Type II, melanocytes were reduced in number
but had elongated dendritic processes. Relative Type II changes were observed
at the borders of vitiligo macules. The Relative Types were considered possible
forerunners of the Absolute Type. Not all lesions, however, progressed to absolute vitiligo.
Yokota [440] also found that the dopa reactions of areas of incomplete
depigmentation (trichrome) were generally of the Relative Type, and that areas
of complete depigmentation were of the Absolute Type. He was not, however,
able to correlate this reaction with the clinical course of vitiligo. Studies of
Bleehen et al. [441] showed an abrupt transition from normal to vitiliginous
skin; the few remaining melanocytes were weakly dopa-positive with abnormally shaped dendrites. Others [442] have found large dendritic melanocytes
at the borders of vitiligo macules. The different findings are not necessarily
incompatible. It seems reasonable that the Relative Types of Jarrett and Szabo
must exist for a period of time-though perhaps quite a brief one in rapidly
progressive vitiligo-in all patients. Probably a vitiligo macule passes from
normal to Relative I, then Relative II, and finally the Absolute or depigmented
stage.
Resolution of the issue requires correlation with clinical course; studies
of a patient with rapidly progressive vitiligo should demonstrate this entire
kaleidoscope of progressive degenerative changes in the melanocytes. However,
in the hyperpigmented borders, the number of dopa-positive melanocytes may
be increased, and these cells have well-formed dendrites.
Tschernosemski et al. [443] used 3H-labeled thymidine autoradiography,
then dopa reaction to study repigmentation; sun-induced repigmentation begins
about hair follicles and at the margins of vitiligo macules.
Other Stains and the Dendritic Cell Population
Many investigators have used various other staining techniques. Mojamdar
et al. [444] suggested the use of peroxidase-dependent oxidation of tyrosine to
melanin to identify melanocytes in vitiligo skin. With the observation that
vitiliginous skin has a higher peroxidase activity than does normal skin, they

223
GENETIC AND
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DISORDERS

224

CHAPTER 1

postulated that there are inactive melanocytes present in vitiliginous skin. In

order to exclude tyrosinase-induced melanin formation from tyrosine [444],
sections of skin were preincubated in diethyldithiocarbamate, a copper-chelating agent (the investigators suggested that in vitiligo the melanocytes have
the capacity to convert tyrosine to dopa but not to dopaquinone or more distant
steps in the production of melanin). However, it is not clear that all peroxidase
activity is of melanocytic origin, and if peroxidase activity is present in vitiliginous skin, then it must reside somewhere other than in the normal melanogenic organelles. This is based on acceptance of the controversial [445] twostep/two-enzyme process hypothesis of normal melanogenesis. If, as most agree,
melanogenesis is a one-enzyme (tyrosinase) process, the observations of Mojamdar et al. are of uncertain significance.
Other staining techniques have been used to identify the epidermal dendritic cell population in vitiligo skin. Using supramethylene blue stain, Hu et
al. [63] found in depigmented macules, isolated oval or stellate cells which
appeared to take a little more blue stain than the adjacent polyhedral epithelial
cells. Although Hu et al. could not satisfactorily characterize these cells, they
considered them to be inactive melanocytes.
With Suzuki's silver stain, Mori [446] found no quantitative or qualitative
changes in epidermal dendritic cells of vitiligo compared to normal skin.
Mishima and Miller-Millinska [447] used the osmium iodide zinc reaction
and the Ferreira-Marques reaction to demonstrate an increased number of Langerhans cells. Since some of the osmium iodide zinc-labeled dendritic cells were
also dopa-positive, osmium iodide zinc had reacted with both melanocytes and
nonmelanin-producing dendritic cells and cannot be said to be of value in
distinguishing dendritic cell types from one another.
Brown et al. [448], in 1967, used ATPase to identify Langerhans cells in
normal and in vitiliginous skin and found similar dendritic cell populations
in these two areas. The authors concluded that since the Langerhans cells were
quantitatively and morphologically similar in involved and in uninvolved vitiligo skin, Langerhans cells are unrelated to the melanocytes and thereby of no
etiologic significance in vitiligo. Riley [449], on the other hand, found more
ATPase positivity in depigmented than in normally pigmented skin, but concluded the difference was not significant. Yokota [440] reported decreased
ATPase activity, particularly at the basal layer. Zelickson and Mottaz [450] later
found that ATPase is not specific for Langerhans cells. The ATPase technique
is, however, considered by many pathologists to be useful to quantitate Langerhans cells.
Zelickson and Mottaz [450] preferred the specificity and accuracy of the
gold chloride technique at the ultrastructural level. Birbeck et al. [451] found
gold-positive dendritic cells at the suprabasal level of vitiligo epidermis but
few positively stained cells in the pigmented epidermis. On the other hand,
these gold-labeled cells were consistently demonstrated in normal epidermis
from normal controls, albeit less intensively distributed than in the depigmented vitiliginous skin.
None of these histologic studies clearly defines the complex relationship
between the dendritic cell types of the epidermis, and none of the stains seems
to offer the specificity of the dopa reaction for melanocytes.

Other Epidermal Disturbances

Apart from the absence of melanin and of identifiable melanocytes, vitiliginous epidermis appears to be normal. However, sporadic reports of abnormalities do appear in the literature. Recently, vacuolated keratinocytes have
been observed in normally pigmented and perilesional skin in vitiligo patients
[451a].
Various parameters of epidermal function have been studied. Gopinathan
[128] found no difference in epidermal thickness between vitiliginous and
adjacent or contralateral normally pigmented epidermis. Tsvetkova et al. [452]
found reduced protein and keratin synthesis in the epidermis of achromic
macules. Mori [446] described karyolysis of the epidermal cell nuclei in all his
cases of vitiligo over three years' duration, but not in younger lesions. These
changes are those observed in the epidermis of denervated skin on the seventh
day post sympathectomy. Decreased acid phosphatase levels have been reported in vitiliginous epidermis [440].
Abdullakhodzhaeva and Abidov [453] found low RNA and tyrosine levels
and high sulfhydryl levels in the depigmented epidermis. Chaudhuri et al.
[454] also found RNA and tyrosine in vitiliginous epidermis and noted larger
than normal nuclei of basal cells and prickle cells. Nucleoli were more fragmented and there was a weak DNA reaction. However, hyaluronic acid, mucopolysaccharides, and alkaline phosphatase activities were stronger in nuclei.
Garner and Everett [455] found staining in vitiliginous epidermis negative for
tyrosine but positive for epinephrine. Califano [456] reported nuclear abnormalities of the basal germinal elements. Using acridine orange fluorescent staining, he described in the vitiliginous epidermis zones of germinal cells characterized by nuclear abnormalities and quantiative alterations of DNA content.
The basement membrane also stained poorly.
Other Histologic Disturbances

Inflammatory Changes
Although the dermis is usually normal in standard hematoxylin and eosin
preparations of vitiliginous skin, lymphocytes may occasionally be seen, particularly in inflammatory vitiligo. Inflammatory cells, mainly lymphocytes,
have been observed in the upper dermis and a focal collection of mononuclear
cells occasionally at the dermal-epidermal junction of the epidermis of the
border of early vitiligo [128]. A perivascular infiltrate may sometimes be observed [35]. Breathnach et al. [457] found in the de pigmented and marginal
areas an increased number of mast cells around nerves and small vessels and
in the upper dermis. Lymphocytes and fibroblasts were numerically increased.
Vesicular structures with internal reticular material were also commonly seen.
In one study of "leukomelanodermie," which is probably trichrome, a dense
inflammatory infiltrate was found in the dermis. The uncommon cases characterized by raised borders generally have a mononuclear dermal infiltrate.
Perrot et al. [458] described many abnormalities. Numerous histiocytes
were found in achromic skin. Macrophages with melanophagosomes were more
numerous at the periphery of the lesions. In one case, at the periphery of a

225
GENETIC AND
CONGENITAL
DISORDERS

ZZ6
CHAPTER 1

macule there was a cell in the dermis in close proximity to the dermal-epidermal junction, facing a melanocyte and in direct contact with a weakly
active melanocyte. The identity of this cell could, however, not be established.
Beneath the basement membrane were cellular fragments rich in ribosomes or
glycogen. The authors noted frequent hyaline bodies, not all of which had
crossed the basement membrane and which may represent necrotic keratinocytes or dendritic cells.
Pigmentary Incontinence
Numerous oval, stellate, and branched pigment cells around blood vessels,
hair follicles, and sebaceous glands in macules of vitiligo have been observed
[298]. These could represent melanophages. Pigmentary incontinence may be
seen at the border of a macule of vitiligo.
Dermal Connective Tissue
Califano [456] described degenerative changes in the dermal connective
tissue architecture, particularly vacuolization of the superficial papillary dermis. Investigation with polarizing light revealed a sharp line of demarcation
between the papillary dermis of the vitiliginous area and the adjacent papillary
dermis, the former being doubly refractive and the latter practically not at all.
Sweat and Sebaceous Glands
Yokota [440] noted in some cases that the Nadi reagent activity (indophenol
oxidase) in the sweat and sebaceous glands was lower in vitiliginous skin than
in normal skin. The degree of difference seemed to be related to the duration
of the disease. To assess sweat gland function, Gokhale et al. [458a] studied
resistance to direct electric current. In some patients they observed increased
resistance which they correlated with inflammation and fatty alveolar degeneration of sweat glands.
Neural Structures
Although no consistent neural abnormalities are present in vitiligo, there
have been reports of alterations of peripheral nerves in vitiliginous skin. Shao
Chan Gen [459] noted peculiar dystrophic changes that were more apparent in
older lesions. In four-year-old lesions, a silver stain revealed thickening and
irregularity of contours of the neutrophils, influx of axoplasm, and varicose
dilatations along the thin axial cylinder. In 14-year-old lesions, there was a
dramatic decrease in the number of cutaneous nerve elements, a nearly total
absence of nerve endings, as well as other dystrophic changes. Iijima [460],
with the use of Gomori's modification of cholinesterase staining and Falck's
fluorescent technique for catecholamines, found the adrenergic nerve fibers of
the blood vessels and the arrector pili muscle to appear unchanged. However,
in depigmented skin, an occasional fibrillar structure was seen in the papillary
dermis, whereas no such structures were seen in the normal skin. Yokota [440]

pointed out that in normal skin nonspecific cholinesterases could hardly be

demonstrated but the intraepidermal nerves stained very clearly in vitiliginous
skin; subepidermal nerves, however, were similarly present in both. Autonomic
nerve fiber degeneration was also seen in vitiliginous skin. Mori [446] used
Suzuki's silver stain to show changes of both sensory and autonomic nerve
fibers in the vitiliginous skin. In all cases of vitiligo, he observed breaking,
disarrangement, and diminution of arginophile granules consistent with regressive changes of the autonomic nerves.
A relationship between taste cells and melanocytes suggested that organic
and functional changes of taste cells at the autonomic nerve terminals could
lead to disruption of melanogenesis. Seven days after sympathectomy, changes
similar to those observed in vitiliginous skin were seen throughout the entire
epidermis of a patch of denervated but otherwise normal skin [446J. This suggested that vitiligo results from some disturbances of autonomic nerve function.
However, Thies [461J and others have found no pathologic changes in the
neural apparatus of vitiliginous skin. Although there is no reason to doubt the
veracity of the repeated anatomic abnormalities, these changes must be interpreted with great caution. Absence of demonstrable anatomic changes, however, does not exclude physiologic dysfunction (see also discussion of neural
hypothesis, page 250).
Dendritic Cells and Electron Microscopy
In typical vitiligo macules (Table 72) there is a progressive decrease and
finally a total disappearance of identifiable melanocytes. In vitiligo of recent
onset or in hypopigmented lesions, the few melanocytes that may be observed
both in the basal layer and in the hair follicles of a vitiligo macule are characterized by indented nuclei and only a few melanosomes in dendritic processes.
In light and electron microscopic studies of trichrome vitiligo, Szabo and
TABLE 72. Subcellular
Characteristics in Vitiligo
Melanocytes
Number
Dopa reaction
Dendrites

a
a
a

Melanosomes in melanocytes
Number
Size
Shape
Melanization
Secretion

a
a
a
a
a

Melanosomes in keratinocytes
Number
Distribution
Degradation

a
a
a

227
GENETIC AND
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DISORDERS

228
CHAPTER 1

Fitzpatrick [462] have shown the clinical color of the macule reflects the number
of melanocytes. Where the color is intermediate between the normally dark
brown skin and the white vitiliginous skin, there is a marked reduction in the
number of melanocytes and the individual melanocytes are hardly recognizable
because of profound changes in morphology, namely, loss of dendrites and
disappearance of melanosomes. In the completely amelanotic zones, there are
very, very few, if any, melanocytes present. Bleehen et al. [441] found marginal
melanocytes to have small, incompletely melanized melanosomes, some damaged and degenerating.
Electron microscopy of vitiliginous skin (Figs. 80,81,82) reveals two dendritic cell populations, one being Langerhans cells (LCs) with typical organelles
and the other indeterminate cells (ICs) or alpha-dendritic cells which lack any
identifiable organelles. The IC is probably of the melanocyte-macrophage line
and the LC of the monocyte-macrophage line.
The first ultrastructural study of vitiligo was reported by Birbeck et al. in
1961 [451]. Cells identical to LCs were observed apparently to have replaced
basal melanocytes and to be present in increased numbers in the suprabasal
layers of the epidermis. Breathnach [463], attempting to explain this observation, suggested that at intervals individual melanocytes divide into two daughter cells that resemble LCs. One of these daughter cells, representing an immediate postdivision stage of a mature, previously active melanocyte, immediately
ascends to the suprabasallevel, is never active in melanogenesis, and is eventually sloughed off with the stratum corneum. The other daughter cell was
thought to remain in the basal layer to become an active melanocyte and later
to divide to repeat the cycle. Vitiligo then would result from a failure of the
second type of daughter cell to mature. This hypothesis explained the disappearance of melanocytes from the basal layer, their replacement by LCs, and
the increased number of LCs in the suprabasallayers. However, Breathnach et
al. [464], in 1968, disproved this hypothesis by demonstrating LCs in the skin
of neural crest-free mice, in which melanocytes were absent. The authors concluded that the Les do not arise from the neural crest and, therefore, they
cannot belong to the melanocyte cell line which is of neural crest origin.
More recent studies have shown Les to be dynamic rather than static cells.
Zelickson and Mottaz [465], in 1970, found increased numbers of Les in vitiliginous skin exposed either to sun or to ultraviolet radiation. Perrot et al.
[458,466] found older lesions to have only Langerhans-type dendritic cells with
a normal or decreased number of typical granules. LCs were frequently present
in the upper epidermis. In one case, LCs with melanophagosomes were observed. Migration of dendritic cells thought to be LCs was observed to occur
from the dermis. In occasional specimens, ICs were also observed, usually at
the basal layer, but occasionally at the upper levels. Perrot et al. suggested that
an increased number of LCs in the depigmented skin marked the onset of the
disease, and attributed their presence to migration of Les from the dermis and
not to a redistribution of cells within the epidermis. This suggested the LC
could be a macrophage or a lymphocyte that migrates from the dermis. But
although LCs may have phagocytic function and take up ferritin and thorotrast,
keratinocytes are much better phagocytes. It would seem that Les must be
present for other reasons. Les have been found in epidermis, dermis, lymph

229

GENETIC AND
CONGENITAL
DISORDERS

FIGURE 80. Vitiliginous skin. a: Indeterminate cell in suprabasal layer (x 18,000). b: Indeterminate cell in contact with disrupted basement membrane (x 2000). c: Macrophages in vitiliginous
epidermis (x 6500). d: Melanosomes and various inclusions within macrophages (x 40,600). Mb.
basement membrane; K. keratinocyte; Ma, macrophage. (From: Perrot H et al: Etude ultrastructurale
du vitiligo. Lyon Med 232:439-446, 1974. Copyright, 1974, Lyon-Medical. Used with permission.)

nodes [467], and thymus tissue; in addition, cells resembling LCs have been
observed in histiocytosis X, monocytic leukemia. and reticulum cell sarcoma.
This and other observations have shown the LC to be an immunologically active
cell. In guinea pig epidermis, the LC is the only cell that forms rosettes with
IgG to antibody-coated bovine red blood cells. Ia antigens are expressed and
there are Fc and C3 receptor sites on LCs of guinea pig epidermis. Like other

230

CHAPTER 1

FIGURE 81. Border of vitiliginous macules. a: Layering of basement membrane and adjacent
melanocyte (x 25,000). b: Melanocyte containing vacuoles and round melanosomes (x 32,000).
c: Melanocyte of basal layer (x 8,800). d: Necrotic melanocyte (x 16,200). Me, melanocyte; m,
melanosome; K, keratinocyte; Mh, basement membrane; v, vacuole. (From: Perrot H et al: Etude
ultrastructurale du vitiligo. Lyon Med 232:439-446, 1974. Copyright, 1974, Lyon-Medical. Used
with permission.)

231

GENETIC AND
CONGENITAL
DISORDERS

FIGURE 82. Border of vitiliginous macule. a: Indeterminate cell containing granular cell and
altered mitochondria (x 16,000). b: Hyaline material near basement membrane (x 16,000). c :
Contact between melanocyte and dermal histiocyte with disruption of basement membrane (x
8000). Me, melanocyte; K, keratinocyte; Mb, basement membrane; Ve, vesicle; H, histiocyte. (From:
Perrot H et al: Etude ultrastructurale du vitiligo. Lyon Med 232:439-446, 1974. Copyright, 1974,
Lyon-Medical. Used with permission.)

immune cells, LCs have high metabolic activity and certain hydrolytic enzymes
in common [468]. Also, mononuclear cell-LC apposition has been found in
delayed contact sensitivity. LCs may be visualized as an epidermal contact
antigen trap [469]. Damaged LCs have been observed at sites of specific challenge to a variety of contact allergens in actively sensitized patients and guinea
pigs and in passively sensitized guinea pigs in which LCs are found in dermal
blood vessels resembling lymphatics. The number of dermal LCs is increased
after a challenge with contact allergens [470]. Some LCs in vitiligo lesions have
shown marked vacuolar fonnation, suggesting degenerative changes [252]. While
the number of LCs appears to be increased in vitiliginous macules and although
mononuclear leukocytes have been observed in the epidermis, actual contact
between these cell types is not well documented [471]. The presence of such
cells, probably in increased numbers at least in the basal layer [472] of vitiligo

Z3Z
CHAPTER 1

epidermis, suggests that an immunologic mechanism must playa primary or

secondary role.
ICs or alpha-dendritic cells are observed in vitiligo macules. Niebauer [473]
noted the presence of a third type of dendritic cell quite similar to the other
two types, but lacking cell-specific organelles. He called these unknown cells
"indeterminate cells." These cells are found in both normal and vitiliginous
skin, in which they may occupy about 1% of the epidermis. Direct measurement
of the dendritic cells in normal and vitiliginous skin revealed them to be similar
in size. These are typical dendritic cells with clear cytoplasm and indented
nuclei but without identifiable melanosomes or Langerhans granules. Very little
is understood about these ICs. Some have suggested that ICs may be an artifact
of sectioning. Many, however, feel the IC is a ghost cell or an inactive melanocyte. Bleehen et al. [441] found melanocytes to be replaced by ICs and LCs.
Miyazaki et al. [474] concluded from an electron microscopic study of epidermal dendritic cells in hairless mice after ultraviolet irradiation and topical
DNCB that ICs are composed of two types of cell lines, one being an amelanogenic melanocyte and the other a precursor of the LC. However, there is not
enough accumulated evidence to distinguish among the possibilities that the
IC represents a premelanocyte, a "worn out" melanocyte, an undifferentiated
stem cell, or a completely unrelated cell line.
Many studies have attempted to interrelate the dendritic cell populations.
Changes in the absolute and relative numbers of LCs and ICs remain a matter
of dispute. In 1935, Miescher and Schaff [475] reported equal numbers of LCs
in pigmented and depigmented epidermis and concluded that the LC is not
directly related to the melanocyte. Becker et al. [476], in 1952, also reported
no difference in the number of LCs or of melanocytes between normal and
vitiliginous skin. They considered the LCs identical to melanocytes and regarded vitiligo as a physiologic dysfunction and not a depletion of melanocytes.
Other studies showed differences in the LC population. The initial study of
Birbeck et al. [451] suggested the number of LCs was increased in vitiliginous
skin. Zelickson and MoUaz [450], in 1969, also demonstrated a moderate increase in the LC population in the vitiliginous epidermis, but an overall decrease in total number of dendritic cells. Niebauer [473] noted that as the
number of melanocytes decreased, the number of LCs increased, while the total
number of epidermal dendritic cells decreased slightly. The LCs appeared morphologically similar in the normal and in the depigmented epidermis.
The work of Mishima et al. [133] supports a dynamic relationship between
melanocytes and ICs. Five specimens of vitiligo present from seven months to
18 years were studied. The average number of LCs was unchanged, with the
exception of a single case less than a year old in which the number of epidermal
LCs was increased. However, the number of LCs in the basal layer was increased
while the number in the suprabasal layer was decreased. Typical Langerhans
granules were sparse and the majority of basal LCs were cushioned by adjacent
keratinocytes as opposed to resting directly on the basal membrane as in normal
skin. The number of ICs, however, was markedly increased in the basal layer,
particularly in relatively young lesions. For example, examination of a case of
vitiligo fulminans (overnight appearance) revealed a decreased number of melanocytes and increased numbers of ICs and LCs. In general, the number of

melanocytes decreased as one progressed from normal to hypopigmented to

totally depigmented lesions. The number of ICs appeared to increase in proportion to the decrease in the number of melanocytes. They hypothesized that
active melanocytes are transformed to ICs with or without an intermediate stage
of inactive melanocytes. These cells are then degraded in the later stages of
the disease process, until Les remain as the only dendritic cells in the epidermis. Thus, the following two phases can be distinguished in the cytokinetics
of vitiligo: first, as the number of melanocytes decreases, the number of les
increases, so that the total dendritic cell population remains constant; secondly,
as the melanocyte population approaches or reaches zero, the population of
les begins to decrease until no melanocytes or les remain.
The Mishima et al. hypothesis [133] is attractive and supported by several
other observations. Zelickson and Mottaz [465] observed, 48 hours after a single
ultraviolet radiation exposure, an increased number of melanocytes and a decreased number of les. Ito [477] studied the dendritic cell population in repigmented areas of vitiligo and concluded that inactive melanocytes can change
into active melanocytes. Bleehen et al. [441] found melanocytes were replaced
by les and Les. Kukita et al. [478], in 1971, identified les in the melanocytic
portion of hair matrix in white hair from vitiligo subjects. No melanocytes
could be identified, and Les and Langerhans granules were similar to those of
normal epidermis. This picture was similar to that of senile white hair. All
these studies, which support an inverse relationship between the melanocyte
and Ie number, at least suggest the two dendritic cell types may be of the same
cell line. If true, one might, as suggested by Bleehen et al. [441], on careful
sectioning of actively depigmenting vitiligo macules, see dissolution and disruption of melanocytes. If the Ie is an effete melanocyte, nowhere in the transition should one see disruption of the nucleus or of the cell membrane.
Keratinocytes

Epidermal keratinocytes are morphologically normal in vitiliginous epidermis [451]. They, of course, contain few or no melanin granules. Keratinocytes contain more melanin per cell in the hyperpigmented ring than in the
surrounding normal skin [442]. Breathnach et al. [457] reported in one case the
presence of vesicles in the perinuclear region of the keratinocytes of the depigmented epidermis. Also vacuolated keratinocytes have been found on l-lJ.m
sections in normal and perilesional skin of vitiligo patients [451a]. Mast cells
have also been observed in the vitiliginous epidermis [457,458].
Basement Membrane Abnormalities and Immunofluorescence

The basement membrane is intact and unaltered in vitiliginous skin. Two

investigators have noted reduplication of the basement membrane in perilesional skin. Breathnach et al. [457] found multiple replication or layering of
the basement. membrane directly beneath the melanocytes on the pigmented
side of a vitiligo margin. In some instances, up to 10 layers were observed.
Perrot et al. [458] reported several layers separated by 200- or 300-mm spaces
containing filamentous material and collagen fibers and interpreted this as being

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secondary to swelling and necrosis of melanocytes. Direct immunofluorescence

on involved and uninvolved skin is said to be negative [441]; positive indirect
immunofluorescence has been reported in patients with mucocutaneous candidiasis, Addison disease, alopecia areata, and vitiligo [287].
Abnormalities of Skin Immediately Surrounding Vitiligo Skin
On the pigmented side of the margin of a macule of vitiligo, Breathnach
et a1. [457] observed that many melanocytes will produce only a few normalappearing melanosomes and predominantly rounded melanosomes with a finely
granular internal structure. Closer to the depigmented margin, fewer melanocytes were observed and those present had decreased melanogenic activity.
Filamentous structures became more evident within the cytoplasm of these
cells. The authors stressed the resemblance of these melanocytes to those of
pale epidermis of freckled subjects. Breathnach et a1. [457] also found increased
numbers of Langerhans cells, some of which contained phagocytized melanin
granules.
Perrot et a1. [458] found increased intercellular space between melanocytes
and keratinocytes and observed the number of melanocytic dendrites to be
decreased or absent. The melanocytic cell membrane was often ill defined and
in some cases absent. Organelles were occasionally found to be extracellular.
Other melanocytes were observed to have filamentous cytoplasmic structures
and mitochondrial abnormalities. The shape of melanosomes varied; some melanosomes were large with a clear halo. In the lower epidermis, there was an
increased number of Langerhans cells, many of which were in contact with
altered melanocytes.
Biochemical Studies
A great number of studies have been done in a futile attempt to find a
consistent and typical biochemical abnormality in the melanin pathway in
vitiligo.
Tyrosine
There is no evidence for any consistent local abnormality in tyrosine metabolism in vitiliginous skin or any systemic metabolic tyrosine defect in vitiligo
patients. Some historical works suggest that tyrosine, the initial substrate for
melanogenesis, is decreased in vitiliginous skin [453,454]. Ito [479] found the
serum tyrosine in 93 vitiligo patients to be nearly within normal limits, but
noted that the seasonal fluctuations in serum tyrosine are somewhat smaller
in vitiligo patients than in normal controls.
Tyrosinase
Tyrosinase appears to be absent in vitiliginous skin. Routine histochemical
examination of dopa-incubated vitiliginous skin is negative for tyrosinase. That
dopa oxidase activity is decreased or absent in vitiliginous skin is shown by

negative split-dopa preparations. Voulot and Ortonne [480] did an electrophoretic gel study of vitiliginous skin extract and then used the dopa histochemical
reaction to identify melanotic bands. Such bands, which are present in normal
skin, are different in their electrophoretic mobility from the other dopa melanin
bands observed in human melanoma and nevus and from those described by
Burnett and Seiler [481] as soluble tyrosinases. While the study of Voulot and
Ortonne suggests tyrosinase is present in vitiliginous skin extracts, the dopa
reaction is not specific for tyrosinase. A dopa melanin band is observed on the
gels with hemoglobin [482] or with ceruloplasmin [480]. Tyrosinase may be
inhibited in vivo but not in extract preparation and electrophoretic separation
processes. More recently, tyrosinase activity has been demonstrated in vitiligo
epidermal homogenates by a highly sensitive fluorometric method, as well as
by 14C(U)-L-tyrosine incorporation into melanin [482a].
Copper
Since tyrosinase is a copper-requiring enzyme, it has been suggested that
vitiligo results from a disturbance of copper metabolism. The occurrence of
hypomelanosis in Menkes kinky hair further suggests a defect in copper metabolism can affect pigmentation. Furthermore, copper therapy has been reported to result in repigmentation [483,484]. But the very diverse results of the
many works done on this subject make it impossible to identify any definite
copper-related defect.
Low serum copper levels have been reported [70,309,314,485,486] in up
to 60% of cases of vitiligo. It has been reported that decreased serum copper
levels are more marked in children or in those with vitiligo of less than one
year's duration [487]. The serum copper levels have been observed to rise during
treatment with oral meladinine (8-methoxypsoralen and 8-isoamylinoxypsoralen) [488]. This rise, which was not significant at the 5% level, was attributed
to the 8-methoxypsoralen fraction of the meladinine [489]. EI Mofty et al.
[490,491] postulated that psoralens work through mobilization of hepatic copper stores. El Hefnawi et al. [394] suggested that the psoralens influence the
incorporation of copper into the protein to form ceruloplasmin. This would
explain the authors' observation that most rapid psoralen repigmentation occurs
in vitiligo patients with normal serum globulins and normal serum copper.
Increased serum copper levels have also been reported. The finding of
Genov et al. [492] of 30% higher serum copper levels in vitiligo patients than
in normal healthy controls suggested a functional impairment of serum copper
in vitiligo. A few cases of vitiligo with elevated copper levels were said to have
other diseases that may explain the biochemical abnormality [70]. In others,
the levels were only slightly elevated [493] or were not elevated to a statistically
significant degree [494].
Among 28 vitiligo patients, Ito [495] observed that 10 had elevated serum
copper levels, three decreased levels, and 15 were normal. Most agree serum
copper levels are normal [496,497].
Although decreased copper levels have been reported [497,498] in vitiliginous skin, in a study of the skin of 12 vitiligo patients, no difference was
observed in the copper levels in vitiliginous compared to normal skin. Molokhia

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and Portnoy [499] found significantly lower levels of copper in vitiliginous

skin, but interpreted this with caution; they suggested it is unlikely that vitiligo
is a result of a focal copper deficiency, but that this low copper content results
from absent melanogenesis or from the absence of melanocytes in the vitiliginous area. Arya et a1. [497], who also found decreased epidermal and dermal
lesional copper levels, suggested that this results from sulfhydryl binding of
tyrosinase. Lonshakov et a1. [487] found in 10 patients with normal serum
copper levels that copper was increased in the hyperpigmented border skin
and decreased in hypopigmented vitiligo skin.
Ceruloplasmin abnormalities have been noted by a few investigators. Huriez et a1. [70] reported that 39% of their 72 patients had low serum ceruloplasmin levels. A decrease in blood ceruloplasmin following heliotherapy and
clinical repigmentation of vitiligo has been reported [492].
Two hypotheses have been advanced to implicate the copper in the pathogenesis of vitiligo. Genov et a1. [492] hypothesized that decreased incorporation of copper into tyrosinase resulted in increased serum copper levels and
low tyrosinase activity in the depigmented areas. The increased serum copper
level then activates hepatic synthesis of ceruloplasmin which binds firmly to
the excess copper. The pivotal defect would have to be a hereditary defect in
the structure of the tyrosinase molecule, with resultant decreased copper binding. According to the authors, intense irradiation may reverse this defect; high
energy quanta will increase the binding of copper to tyrosinase. The other
hypothesis suggested is that there is an inhibitor which binds tyrosinase-copper
complex in the skin. Ultraviolet radiation would disrupt this inhibitor-tyrosinase complex, restore the enzymatic activity, and stimulate melanogenesis.
Although these hypotheses are attractive, the evidence that supports them
is contradictory and unconvincing.
Other Elemental Metals
Scattered abnormalities of various other metals have been reported among
vitiligo patients. Hypoferremia has been reported [308,487] in up to 43.4% of
cases of vitiligo [37]. In one Indian study [12] of 196 vitiligo patients, the
hemoglobin was normal in 66%, decreased in 26%, and markedly decreased
in 8%. However, nutritional factors cannot be exluded. Decreased iron content
of vitiliginous skin has also been reported [500].
Zinc has been reported to be present in the melanosomes [501] and to be
concentrated in the retinal pigment epithelium in some mammals. In rats, zinc
deficiency leads to depigmentation of the hair [502]. Reduced serum zinc levels
in the involved vitiligo dermis have also been noted [499]. However, the exact
role of zinc in human melanogenesis is still unknown.
Manganese, nickel, and calcium studies have been reported. Manganese
has been found in normal amounts in the blood of vitiligo patients [487,503]
and elevated levels have been reported in vitiligo skin [503]. Serum nickel
levels are reported to be normal in vitiligo [487]. Kapina [504] reported elevated
serum calcium in 25 of his 33 patients, but hypercalcemia and hyperparathyroidism are not usually associated with vitiligo.

All of these reports must be interpreted with caution. Disturbances of iron

and calcium metabolism do not appear to be characteristic of vitiligo. Whether
zinc and manganese abnormalities can be implicated requires further investigation.
Thiamine
Takenouchi [505] noted thiamine experimentally increased the lag time
for induction of the tyrosine-tyrosinase reaction and suggested that thiamine
disrupts the equilibrium of the dopa-dopaquinone reaction. The resultant decrease in dopa then lengthens the induction period of the tyrosine-tyrosinase
reaction.
Jadassohn [506] reported increased thiamine levels in vitiliginous skin in
seven of 12 patients and slightly decreased levels in the other five patients. All
levels increased after administration of aneurin. Vitamin Bl injection caused
a greater increase in tissue thiamine levels in vitiliginous skin than in normal
skin. Circulating vitamin Bl levels are usually normal in patients with vitiligo.
The absence of other markers of thiamine deficiency and the general good
nutritional state of vitiligo patients is consistent with thiamine deficiency as
important to vitiligo.
Ascorbic Acid
Ascorbic acid is a potent reducing agent capable of retarding various oxidative reactions in the melanogenesis pathway; clinically it does reduce the
degree of pigmentation in Addison disease and oxidizes black to brown melanin. However, normal ascorbic acid levels in skin, plasma, and urine have
been reported [507]; in another report of four cases, decreased cutaneous levels
have been found in vitiligo skin [508,509].
Copper-Binding Agents and Other Inhibitors of Melanin Synthesis
Reactive sulfhydryl groups can bind copper to form weakly dissociable
complexes which inactivate tyrosinase. Lajmanovitch and Magnin [510] found
no significant differences in the number of SH groups in normal compared to
vitiliginous skin. But Van Scott et al. [511] found that vitiliginous skin had a
higher SH content than areas of normally pigmented Caucasian skin. In six
patients, Rao et al. [509] found the concentration of tissue sulfhydryl groups
in vitiliginous skin to be higher than that in contralateral normally pigmented
skin. Lorincz [512] suggested two interpretations: either the high sulfhydryl
content inhibits tyrosinase and thereby prevents melanogenesis, or sulfhydryl
groups accumulate secondarily because no melanin is formed.
The sulfhydryl content in the vitiliginous skin has been correlated with
the tissue ascorbic acid level [513]. Rao et al. [511] reported tissue ascorbic
acid to be significantly decreased in vitiliginous macules. Ratnam et al. [507]
also found somewhat decreased ascorbic acid levels in vitiligo skin; this was,
however, not considered significant. Plasma and urinary ascorbic acid levels
were normal compared to controls.

237
GENETIC AND
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238

Melanin Metabolites

CHAPTER 1

One theory of the pathogenesis of vitiligo suggests a precursor or metabolite

of a precursor in melanin synthesis destroys or inhibits melanocytes [514] and
many investigators have demonstrated inherent autotoxicity in cells synthesizing melanin [263,515]. Graham et al. have shown one intermediate, dopaquinone, to be such a toxic metabolite, but to date this has not been assayed
in vitiligo patients [516]. The possibility of a circulating or local inhibitor of
melanogenesis is an attractive notion. But Iijima [460] showed that the serum
from patients with vitiligo has no inhibitory effect on the melanogenesis in
vitro. No inhibitor has been identified or isolated from the vitiliginous skin.
Other limited studies have been done. Reabsorption of decomposition products
of sweat has been suggested to be an etiologic factor in vitiligo [517]. Seutter
and Sutorius [518] found melanin precursors in sweat of vitiligo patients. Specimens of black precipitate from sweat contained a black substance with an
infrared spectrum resembling melanin. These authors detected a melanogen in
normal but not in vitiliginous skin. The urine contained no melanogens.
Urinary indole metabolites have been studied in vitiligo [519,520]. No
significant difference was found between the pattern of urinary phenolic acids
in 25 vitiligo patients compared to 25 controls. However, some differences were
observed in a few chromatograms of vitiligo patients; feuroylglycine and four
unidentified spots seen in some chromatograms of patients with vitiligo were
not seen in chromatograms of normal controls [521].
Chakravorty and Chaudhuri [519] studied urinary indole metabolites in 30
vitiligo patients and 20 controls. They found similar levels of indoleacetic acid
but generally increased levels of 5-hydroxyindoleacetic acid and 5-hydroxyacetic acid in vitiligo patients. They concluded that there is an abnormality of
tryptophan metabolism in vitiligo. The significance of these findings is unknown.
Since no definite biochemical abnormalities can be considered characteristic of vitiligo skin, it seems most likely that these scattered abnormalities are
secondary to the primary process in vitiligo.
Functional Abnormalities of Vitiligo Skin

Sensory Function
There are no gross abnormalities of sensation in vitiligo macules. Studies
of cutaneous sensation in vitiligo macules have given somewhat contradictory
results. No changes were reported by Habermann [104] and Rothman et al.
[522], although two of the 10 patients with vitiligo volunteered that during
galvonic testing they felt less burning in the vitiliginous macules than in the
surrounding area. This latter observation seemed to support the statement of
Konigstein [523] of decreased perception of pain in vitiligo skin.
Ono [524] measured sensory thresholds in 30 cases of vitiligo and found
normal tactile sensation in skin that had depigmented within the previous year,
markedly decreased sensation in macules a year older, and moderately decreased sensation in those macules of more than two years'duration. Pain per-

ception in vitiligo skin was abnormal in macules within one year of onset, was
more marked in two or three years, and became relatively mild thereafter. These
disturbances of tactile and pain senses were not considered significant enough
to suggest a sensory neuropathy. The author presumed that such sensory disturbance in vitiligo macules could be a secondary phenomenon.
Maiti et al. [525] studied the tactile gnosis of the involved skin and of the
contralateral normally pigmented areas in 23 patients with segmental vitiligo.
That there was no significant difference between the sides excluded any disturbance of somesthesis in vitiliginous skin. There is no difference in the distribution of sensory receptors for pain, touch, heat, and cold in the vitiliginous
skin compared to normal skin of vitiligo patients or to normal skin or normal
controls.
Cutaneous Blood Flow
Various techniques and observations have been used in an attempt to
demonstrate aberrations of cutaneous blood flow in vitiliginous skin. Lerner
[29] has quoted reports that vitiligo skin does not yellow from ingestion of
quinacrine or become jaundiced and noted that blood constriction has been
reported in vitiligo macules. With the use of reflection photoelectric phlethysmography, Ono [524] simultaneously observed the cutaneous blood flow in
the depigmented skin and in the contralateral normally pigmented skin. In 10
of 56 cases, differences in vasomotor reflexes and blood flow pattern were
observed. Marked differences of the pulse wave amplitudes were seen in 13
cases, particularly in the relatively new cases of vitiligo. Grana and Marchiolo
[526] used radioisotopic studies to demonstrate abnormal blood flow in vitiligo
macules.
Altered vascular responses of cooled or warmed vitiligo skin have also
been reported. Maiti et al. [525] concluded that cold exposure gave relatively
more numbness in fingers affected with vitiligo than unaffected normal fingers
in control subjects. Dutta et al. [527] observed a slow rate of warming in vitiliginous skin exposed to cold. This was considered indirect evidence of hypertonic vasomotor reflex and supportive of the hypothesis of peripheral adrenergic hyperactivity in vitiliginous skin.
The average blister resorption time has been reported to be increased nearly
60% in vitiliginous skin compared with normally pigmented skin [528].
Skin Temperature
Skin temperature measurements were compared before and after sweating
in 22 vitiligo patients [529]. Nine of these registered higher temperatures in
vitiliginous skin, both before and after sweating, although the latter was less
markedly increased. Studies of vitiliginous skin with the bolometer and the
thermovisual camera revealed six cases in which there were minimal differences, the depigmented skin being warmer by O.lC to 0.3C by direct measurement. One patient with both malignant melanoma and vitiligo-like depigmentation showed depigmented skin to be 0.8C warmer than normally pigmented
skin. Lowered temperature in vitiligo skin, even during psoralen therapy, has

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been described [39]. As emphasized by Chanco-Turner and Lerner [529], if

dilatation or constriction of the cutaneous blood vessels is responsible for
variations in skin temperature, cutaneous temperature measurements then should
reflect cutaneous blood flow (see previous discussion of cutaneous blood flow).
Any such measurements may be influenced by thickening of the stratum corneum and enhanced sunburn reaction, both of which apply to vitiligo macules.
Sweat Secretion
There have been numerous studies of sweat response of vitiliginous skin.
Gopinathan [128] found that the vitiliginous skin at rest lost no more nor less
water through insensible perspiration than did the normal skin of the same
patients. On the other hand, Ono [524] found generally increased vapor pressure
on the depigmented skin of 12 cases of vitiligo in which he measured insensible
perspiration. Ono [524] also found sluggish sweating response curves from
depigmented skin abutting normal skin in patients with vitiligo. In 11 of 12
cases, the sweat reaction in the depigmented skin was markedly decreased,
almost proportional to the duration of the disease. With use of a neurodermometer, Lerner [29] found vitiliginous skin to be a better electrical conductor
than pigmented skin. Lerner interpreted this increased conductivity to reflect
increased cutaneous moisture content, and postulated there may be a greater
activity of the sweat glands in the areas of vitiligo than in normal skin.
Chanco-Turner and Lerner [529] studied heat-induced sweating in 20 patients. Sweating in vitiliginous skin was increased in 16, decreased in three,
and unchanged in one. Rothman et al. [522] found no difference in heat-induced
sweating between normal and vitiligo skin. Halter [530] found heat-induced
sweating to be absent in vitiliginous skin.
Pharmacologic stimulation studies to induce sweating have also produced
contradictory results. Halter [530] found the response to pilocarpine to be
normal. Zebracka et al. [531], however, noted increased sweating in vitiliginous
skin in response to intradermal injection of methacholine chloride in 19 of 20
patients. Rothman et al. [522] found no difference between the sweating response of depigmented and normal skin in response to intradermal acetylcholine stimulation. Gopinathan [128] noted no difference either in the onset or
in the extent of acetylcholine-induced sweating between vitiliginous and normal skin. Chanco-Turner and Lerner [529] observed normal sweating reactions
to acetylcholine, epinephrine, or histamine injections.
Dutta [532] studied the sudomotor reaction of both the direct and the axon
reflex type in 95 patients. Acetylcholine chloride and nicotine tartrate solutions
were injected intradermally into vitiligo and control sites. Results with acetylcholine were equivalent, whereas nicotine tartrate induced decreased sweating in 70% of cases. The sluggish axon reflex sweat response secondary to
nicotine tartrate was postulated to be due to excessive discharge of adrenaline
or adrenaline-like substances capable of inhibiting the reflex. The site of inhibition in these circumstances was said to be confined to the receptor apparatus.
Studies of physostigmine stimulation comparing normal and segmental
vitiliginous skin sweat response showed markedly diminished sweat response

in the segmental vitiligo macules. Vitiliginous macules in patients with nonsegmental vitiligo had normal sweat responses. The investigators [129] suggest
segmental vitiligo is different pathogenetically from vitiligo vulgaris, which
has a normal stimulation response. Segmental vitiligo was found to repigment
with nialamide, a monoamine oxidase inhibitor.
Bleeding Times
Abnormal bleeding times have been noted. Chanco-Turner and Lerner [529]
compared the bleeding time in vitiliginous and normal skin in 10 patients with
vitiligo and found it to be consistently increased in six patients, decreased in
one, and unchanged in two. (In one subject it was slightly decreased in one
area and increased in another.) The mean bleeding time in vitiliginous skin
was 30 seconds longer than in normal skin. The authors concluded that this
increased bleeding time in vitiliginous skin may reflect increased blood flow.
Dutta and Dermat [533] found a nearly 29% increase of bleeding times in the
vitiligo skin. Zebracka et al. [531] made similar observations. However, bleeding
time determinations tend to be somewhat imprecise and there is no evidence
to suggest that clinically significant prolonged bleeding times prevail in vitiligo.

Animal Models (Table 73)

Several animal models provide insight into the pathogenesis of vitiligo.
Depigmentation has been observed in animals with melanocytic tumors.
Millikan et al. [339] reported in Sinclair swine an unusually large number of
pigmentary tumors that ultrastructurally resemble human melanocytic nevi and
superficial spreading melanomas (Fig. 83). These tumors often regress dramatically. In these black animals, depigmentation of hairs about the lesions is
often the first sign of regression. This depigmentation often begins symmetrically like vitiligo, and may progress to nearly total depigmentation. At the
electron microscopic level, regressing lesions show a near absence of melanocytes. No immunologic data on these animals are available.
Both depigmentation and melanomas occur in Arabian, Lippizaner, Percheron, and Camargue horses [333]. These horses, which are dark at birth, begin
to gray at about two years of age and are completely white by the age of nine.
Almost all of these animals developed melanomas around the rectum after the
age of six. It appears that depigmentation precedes the melanomas. Although
TABLE 73. Animal Model Systems
Spontaneous depigmentation
Sinclair swine
Horses (Lippizaner, Camargue, Arabian, Percheron)
Chickens (White Leghorn, DAM)
Induced depigmentation
By hyperimmunization with human melanoma cells in
chimpanzees
By sensitization with human uveal pigments in rabbits

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FIGURE 83. Sinclair swine provide an animal model for depigmentation; these animals have
many pigmentary tumors resembling the human melanocytic nevus and superficial spreading
melanoma. Hair depigmentation of lesions often is an early sign of regression.

the melanomas do not resolve, the horses seem to tolerate them well. Their
longevity is not compromised unless the metastases implant themselves in a
vital area, such as the surface of the small intestine or the heart.
Several investigators have used immunologic techniques to induce depigmentation in animals. Hornung and Krementz [534] injected antihuman melanoma cells into adult normal chimpanzees. Depigmentation occurred remote
to the sites of injection.
Boissy et al. [535] have developed a mutant line of chickens which begins
to develop amelanosis at five weeks. They also develop degeneration of choroidal melanocytes. A very few chickens develop some small degree of repigmentation. Electron microscopy has shown absence of melanotic melanocytes
except in cases of repigmentation where smaller cell bodies without normal
dendritic processes were observed. The White Leghorn chicken studied by
Jimbow et al. [535a] undergoes in utero autophagocytosis of melanocytes. A
family of elephants which develops progressive whitening of their ears and
other areas has been observed in the zoo in Sri Lanka (Dr. Subash Chaula,
personal communication).
Antiskin and antierythrocyte antibodies have been observed in rabbits,
depigmented by paratertiary butyphenols [536].
Kahan et al. [537] sensitized rabbits with human uveal pigments and induced depigmentation.

Pathogenesis

243

Over the years, the concept of the pathogenesis of vitiligo has survived
notions of infections, paraneoplasia, evil vapors, and more. Today, there are
three prevailing theories of the pathogenesis of vitiligo: the immune hypothesis,
the neural hypothesis, and the self-destruct hypothesis. All have their champions and supporting evidence. None is without some conceptual problems.
When the answer is known, it is likely each theory will be shown to be relevant.
Although they are discussed separately, in the end they must be considered
together (the composite hypothesis).
Immune Hypothesis of Vitiligo

One of the most attractive theories to explain vitiligo is that there is induced
an antigen antibody reaction which results in melanocyte dysfunction, destruction, or both (Fig. 84).
Two immunologic mechanisms could explain the pathogenesis of vitiligo
(Fig. 85).
A primary disturbance in the immunologic system may result in autoimmunization with the formation of autoantibodies against an antigen of the
melanogenic system. This results in inhibition of melanin formation or in
melanocytotoxicity. An alternative mechanism is that there is some injury to
the melanocytes which results in release of an antigenic substance so that
antibody formation occurs and melanogenesis is inhibited. The first mechanism
implies only one defect, autoimmunization, whereas the second mechanism
implies a primary inducing factor and a secondary autoimmunization.
This concept of an immunologic basis for depigmentation is not new; in
fact. Rohdenburg [538] suggested. in 1927. that halo nevus results from an

FIGURE 84. Disappearance of epidermal melanocytes.

GENETIC AND
CONGENITAL
DISORDERS

First Hypothesis

244
CHAPTER 1

Primary disturbance
in the
immune system

Antibody against
component of the
melanogenesis sytem

Antiorgan antibodies

Destruction and
disappearance of
melanocytes

Second Hypothesis

FIGURE 85. Two hypotheses for immune pathogenesis of vitiligo.

immune mechanism. Lorincz [512], noting that Wheeler had been able to induce
antityrosinase antibodies, first speculated that vitiligo might result from specific
inactivation of the protein component of tyrosinase. Since that time, considerable clinical and histopathologic evidence has accumulated to support an
immunologic basis of depigmentation in vitiligo.

Clinical Evidence (Table 74)

There is considerable evidence that depigmentation may be an important
feature of several disorders with immune markers. Depigmentation seen with
halo nevus, malignant melanoma, Vogt-Koyanagi-Harada syndrome, and at
sites remote from certain chemical exposures suggests a possible immune basis
for the leukoderma in humans. Patients with a halo nevus, which is now
considered to be an immune process, may develop depigmentation remote to
the halo nevus. In fact, vitiligo has been reported in 1% to 47.8% of patients
with halo nevi, and halo nevus in 1% to 10% of patients with vitiligo. Clinical
depigmentation and poliosis occur in Vogt-Koyanagi-Harada syndrome in which
hypersensitivity to uveal pigment and disturbances of cell-mediated immunity
are found.
.
While the true incidence of depigmentation in patients with malignant
melanoma must be considered low, that the pathogenesis involves antimelanocyte antibodies must be accurate. Depigmentation may occur about the site
of a primary melanoma, at the site of a metastasis, or at the site where a
melanoma has undergone total spontaneous regression [332]. Depigmentation
may also occur within a melanoma that has partially regressed [332]. Halo nevi
have also been reported to develop during the evolution of an untreated malignant melanoma [332,539]. Four of six immunologically uncompromised patients with malignant melanoma underwent partial to complete resolution of
TABLE 74. Clinical Observations That Support an Immunologic Basis
for Depigmentation
1.

Halo nevi

2.

Vogt-Koyanagi-Harada syndrome

3.

Malignant melanoma
a. Halos around primary or metastatic cutaneous malignant melanoma
-at sites of partial regression and within the primary lesion of
malignant melanoma
-at site of total spontaneous regression of primary malignant melanoma
b. Distinct from the primary melanoma or its metastases
-vitiligo-like depigmentation
-nonspecific hypopigmentary phenomenon
c. Appearance of halo nevi in the course of an evolving malignant
melanoma prior to or after treatment but without hypopigmentation
around the primary
d. Vogt-Koyanagi-Harada-like syndrome in melanoma patients
-spontaneous
-after immunotherapy

4. Chemically or thermally induced depigmentation

a. Remote depigmentation after monobenzylether of hydroquinone
exposure
b. Halo nevi after monobenzylether of hydroquinone or guanonitrofurazone
exposure
c. Remote depigmentation after local burns

245

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CHAPTER 1

metastatic tumor following delayed hypersensitivity challenge [540]. In two of

these patients, lesions exposed to immune-challenge reactions apparently converted to "benign halo nevi" as they spontaneously regressed. At sites distant
from the primary lesion both vitiligo-like and nonspecific depigmentation have
been described [332]. A Vogt-Koyanagi-Harada-like syndrome has also been
observed to occur both spontaneously and after BCG immunotherapy in melanoma patients [327,335].
Some features of chemically induced depigmentation support an immune
pathogenesis of vitiligo-like leukoderma. For example, patients treated with
monobenzylether of hydroquinone (MBEH) may develop depigmentation remote from the site of chemical application. One of our patients developed
depigmentation of the hands from contact with rubber gloves; later, distant
macules resembling vitiligo appeared. Guanofuracin [541] and MBEH [542]
have been reported to induce halo nevi. Becker and Spencer [543] suggested
that topical application of MBEH may precipitate production of a foreign material which then becomes attached to the melanin granule to form a hapten
which enters the dermis, is recognized as antigenic by the immune system,
and thus induces the production of an antibody that is capable of inhibiting
melanogenesis.
Histologic and Electron Microscopic Findings
There is considerable histologic evidence that is consistent with an immunologic basis of depigmentation. Lymphocytes have been demonstrated in
a few cases of vitiligo but are probably present in all, at least when the vitiligo
macule begins. Histologic examination of the raised borders of a macule of
inflammatory vitiligo shows a lymphohistiocytic infiltrate. Under the electron
microscope, vitiligo appears similar to conditions associated with antibody
formation, halo nevus, vitiligo associated with halo nevus, some vitiligo-like
depigmentation associated with melanoma, and cutaneous depigmentation in
Vogt-Koyanagi-Harada syndrome. Perrot et al. [458,466] have also observed
dermal cells in contact with melanocytes in perilesional skin.
In addition, in halo nevi, there is a mononuclear cell infiltrate within and
around the nevus. Destruction and absence of melanocytes, tumor cells, and
pigment is apparent in the areas actively regressing. Similar histologic findings
may be observed in some halos around melanomas. Jacobs et al. [544] demonstrated that antigenically active lymphocytes infiltrate and replace nevus
cells in a halo nevus. Roenigk et al. [545] suggest that this cell-mediated immunity may be responsible for destruction, not only of nevus cells, but also of
surrounding melanocytes.
The presence of increased numbers of Langerhans cells (LCs) in some
studies is intriguing. Recent studies have shown that these cells, which have
been shown to have Fc, IgM, and C3 receptor sites, have a possible role in the
afferent loops of immunologic reaction. LCs may bind contact allergens, migrate
to lymph nodes where LCs have also been found, and sensitize the host, then
return to the skin to serve as effector cells. Les have also been found adjacent
to lymphocytes and, although they do have some phagocytic function, the fact

that keratinocytes are much more effective in this role also suggests LCs must
have a function other than plragocytosis.
Immunologic Studies
A considerable number of laboratory observations also support an immunologic basis for depigmentation (Table 75). Three of five patients with
active vitiligo and one of six with inactive vitiligo were found to have (like
patients with active halo nevi) urinary protein that can inhibit cytoplasmic
staining of melanoma cells by specific rabbit antihuman melanoma antiserum
[546]. It is not clear whether it is humoral or cell-mediated immunity that is
implicated, or both.
Humoral Immunity

Specific circulating antibodies have been reported in various disorders

associated with depigmentation.
Cleariy there are components of melanocytes that are antigenic. Circulating
malignant melanoma cell cytoplasmic antibodies and cell membrane antibodies
have been found in patients with uveal and cutaneous malignant melanoma
[547-552]. Malignant melanoma nucleolar antibodies have also been reported
[553]. Copeman et al. [554,555], in 1973, reported anti cytoplasmic melanoma
cell antibodies in patients with resolving halo nevi; these antibodies could no
longer be found after the nevus had been excised or had spontaneously resolved.
TABLE 75. Immunologic Basis for Depigmentation
Humoral immunity
a. "Specific" circulating antibodies in various disorders associated with depigmentation
-uveal or cutaneous malignant melanoma
-halo nevi associated with malignant melanoma
-halo nevi
-Vogt-Koyanagi-Harada syndrome
b. Cytotoxicity of these "specific" circulating antibodies
-against melanoma cells in culture
-against normal melanocytes in culture
Cell-Mediated Immunity
a. Specific delayed hypersensitivity
-to melanoma antigens
-malignant melanoma (skin testing)
- halo nevi associated with malignant melanoma (lymphocyte stimulation. MIF
production. and rosette-forming lymphocytes)
-to "melanin" (uveal bovine pigment)
-Vogt-Koyanagi-Harada syndrome (skin testing - lymphocyte stimulation)
b. Cytotoxicity of peripheral blood lymphocytes in various disorders associated with
depigmentation against cultured melanoma cells from the same or other patients
-malignant melanoma
-malignant melanoma with halo nevus. vitiligo-like depigmentation. and nonspecific
depigmentary phenomena
-halo nevi

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Kahan et al. [537] reported circulating uveal pigment hemaglutinin antibodies

in Vogt-Koyanagi-Harada syndrome and sympathetic ophthalmia.
In 1965 Langhof et al. reported antimelanin antibodies in vitiligo patients
[556]. Repeated attempts to find antibodies in subsequent studies proved unrewarding until Hertz et al. found complement-binding circulating antibodies to
melanoma cells, nevus cells, and melanocytes [287] in two patients with vitiligo, alopecia areata, chronic mucocutaneous candidiasis, and multiple endocrinopathies. Betterle et al. [557] have reported two vitiligo subjects with
multiple endocrine deficiencies and a positive indirect immunofluorescence
complement fixation test (ICFT) in one, but negative direct immunofluorescence
in both. The positive ICFT showed a bright fluorescence pattern of cells scattered regularly along the basal layer. There is also evidence that antimelanin
antibodies can be produced in other mammals. Mason et al. [558] demonstrated
antimelanin antibodies in rabbits injected with melanin from Harding-Passey
mouse melanoma. Vial and Callahan [559], using extracts of human melanomas,
demonstrated antimelanin antibodies in rabbits; however, subsequent injection
of these antibodies into the tumor or the systemic circulation of the donors
caused no tumor regression.
In vitro cytotoxicity of the antimelanoma antibodies in cutaneous melanomas has been demonstrated [547,550]. Epstein et al. [539] found cytotoxic
antibodies to melanoma antigens in two patients with halo nevi and malignant
melanomas. More significantly, a factor cytotoxic to normal melanocytes in
culture has been described in the serum of several patients with multiple halo
nevi [560]. This complement-dependent cytotoxic factor has not been further
characterized.
Cell-Mediated Immunity

T- and B-cells seem normal [165] but one study has shown decreased Tcell levels [166]. Extracts of autologous tumor cells [561-563] have been used
to demonstrate melanoma antigen-specific delayed hypersensitivity in malignant melanoma patients. In a study of five patients with halo nevi and malignant
melanoma, Epstein et al. [539] found strong cellular immunity against melanoma antigens (lymphocyte stimulation, migratory inhibitory factor production, and rosette-forming lymphocytes).
Friedenwald [564] and MacPherson and Woods [565] respectively demonstrated delayed-type hypersensitivity to ultracutaneous uveal pigment in
sympathetic ophthalmia and Vogt-Koyanagi-Harada syndrome. Kahan et al.
[537] correlated the results of skin tests (sterile bovine uveal pigment) with
disease activity. Specific lymphocyte transformation with bovine uveal pigment
in patients with Vogt-Koyanagi-Harada syndrome and sympathetic ophthalmia has been reported. This suggests that these diseases are of pigment autoaggressive and delayed hypersensitivity nature [566].
Cytotoxic peripheral lymphocytes have been reported against cultured homologous and autologous melanoma cells in patients with malignant melanoma
[319,567-569] and against homologous cultured melanoma cells in patients
with halo nevi and malignant melanoma-associated halo nevi, vitiligo, and
nonspecific depigmentary phenomena [332,539,545,570]. Lymphocytes of pa-

tients with halo nevi without melanoma are cytotoxic to melanoma cell lines
(W. H. Clark Jr., K. L. Leung, M. J. Mastrangelo, unpublished data), but those
of individuals with vitiligo alone are not [570a].
Mishima [472] showed abnormally high blastoid formation against premelanosome antigens in a number of cases of vitiligo vulgaris but not in the
segmental or localized type. Mishima suggests generalized vitiligo is an immunologic disorder and segmental is not.
Where the Immune Hypothesis Fails
The immune hypothesis of vitiligo, although increasingly attractive, is by
no means universally accepted.
Absence of eye involvement has been regarded against the immune hypothesis. Recent reports of pigmentary abnormalities in the retinae of some
vitiligo patients suggests this objection is no longer completely valid.
The usual absence of a mononuclear infiltrate in the macules of vitiligo
seems inconsistent with an immune mechanism. However, it is possible that,
as in resolved halo nevus, the white macules represent the end stage of an
auto immunologic process in which the immunologic marker has disappeared.
In chimpanzees hyperimmunized with human melanoma cells, the mononuclear infiltrate occurs only at the site of injection which does not depigment,
and not at the remote sites of pigment loss [534]. If activated lymphocytes
stimulate Langerhans cells to migrate into the epidermis to alter melanocytes,
the paucity of lymphocytes would be of little conceptual consequence.
No circulating melanocyte antibodies (antigens from normally pigmented
skin or malignant melanoma) [197], antitumor antibodies (antigens from malignant melanoma, lentigo simplex, and benign blue nevus) [198,460]' or malignant melanoma cytoplasmic antibodies [554] have been observed in patients
with vitiligo alone.
Furthermore, the work of Langhof et al. in identifying antimelanin antibodies in vitiligo sera [556] has never been confirmed. Sera from their patients,
containing antimelanin antibodies, were not cytotoxic against melanoma cells.
Since, as pointed out by Wasserman and Van der Waalt [571], the melanin
preparations used by Langhof et al. [556] contained many cellular elements, it
is possible that the antibody reported by Langhof et al. was directed towards
an antigen other than melanin. It has even been suggested that melanin may
not be antigenic. Blois [572], using synthetic melanin, and Wasserman and Van
der Waalt [571], using melanoprotein of baboon eyes, were unable to produce
specific antimelanin antibodies. But Mason et al. [558] and Vial and Callahan
[559] did produce antimelanin antibodies in rabbits. It is possible that Langhof
et al. [556] produced antibodies against a protein moiety of incompletely melanized melanosomes.
Other immunologic markers are lacking. No consistent abnormalities of
skin testing [39], lymphocyte transformation with antigens extracted from lymph
node metastases of malignant melanoma or human hair melanin [573], or lymphocyte typing [574] have been demonstrated.
Serum immunoglobulins are usually normal in vitiligo [308,394,395,575].
Gatti [396] did report IgA deficiency in five patients with vitiligo, and Bader

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et a1. [397] also reported an eight-year-old female with vitiligo and a dysglobulinemia characterized by absent 19A, very low IgG, and normal IgM with an
intact T-cell system. However, Ruiz-Maldonado et al. [398] found normal 19A
levels in 45 Mexican children with vitiligo. Furthermore, Pottgen et al. [248]
and Ortonne [39] found normal IgA, IgM, and IgG in their patients with vitiligo.
Complement levels (C, C3, C3Pa, C4) are normal [159,574]. Attempts to identify
immunoglobulins and complement deposition in vitiliginous skin have also
been unsuccessful [39,159,197,198,441].
Immunologic inactivation of tyrosinase could also cause vitiligo. Although
antityrosinase antisera with T1 and T2 specificity have been produced in rabbits
using extracts of Harding-Passey melanoma, active sites of tyrosinases were
not improved by immunochemical reaction [576-578]. Owen and Market [579]
prepared antisera from rabbits by injecting them with tyrosinase extract of plant
(Glomerella cirgulata) cultures. Subsequent addition of the antisera produced
a marked, rapid inhibition of in vitro tyrosinase activity and a slower specific
precipitation of tyrosinase.
The balance of evidence seems to support the immune theory of vitiligo
yet there is no compelling argument available to substantiate this theory. Probably at whatever level the immunologic mechanism interacts, melanocytes are
destroyed (or tyrosinase inhibited or tyrosinase synthesis blocked) via action
of the Langerhans cells serving as antibody receptors and as effector cells.
Neural Hypothesis of Vitiligo

The neural hypothesis of vitiligo suggests that vitiligo results from the
accumulation of some neurochemical mediator which causes decreased melanin production [29]. Both melanocytes and nerve cells are of neuroectodermal
origin and both utilize tyrosine to produce an end product, melanin or catecholamines. The similarity of the structures of dopa and catechols suggests that
a translation error of receptor sites controlling melanogenesis may be the aberration in vitiligo. Abundant and conflicting observations have been advanced
to support this hypothesis.
Clinical Evidence
Segmental vitiligo, a localized leukoderma that appears to follow one or
more dermatomes, is a well-recognized entity [580-583a]. A patient with hypopigmentation confined to the distribution of the trigeminal nerve [584] and
another with small macules of hypopigmentation along the distribution of the
sacral nerves [11] have been described. One recent study has demonstrated
decreased physostigmine-induced sweating in segmental vitiligo macules [129].
Numerous clinical observations have been reported in which vitiligo patients became white in cutaneous areas corresponding to areas of neurologic
damage or in whom pigment loss was spared in a neurologically compromised
part of the body. A patient with transverse myelitis and paralysis from the
waist down developed vitiligo of the face and upper portion of the body but
not below the level of cord damage [29]. The patient underwent a hysterectomy
and no depigmentation occurred in or near the surgical scar. Another patient

[29] developed vitiligo several years after contracting poliomyelitis which had
left a unilateral neuropathy. Less depigmentation occurred over the leg with
nerve damage. A patient with extensive vitiligo and diabetes repigmented macules where she developed a severe diabetic neuropathy [584]. In a child with
viral encephalitis, unilateral vitiligo and poliosis appeared over areas innervated by both the trigeminal and upper cervical nerves [585]. Although these
are all striking observations, there are no studies that purport to show the
incidence of leukoderma in patients having cerebrovascular accidents or other
neurologic disorders.
A woman, after right cervical sympathectomy, noted more gray hair on the
left than on the right side [586]. Gray hair has been observed on the skin over
the distribution of a nerve affected with peripheral neuritis [587].
Onset of vitiligo after anesthesia and nerve injury has been reported. Tremittera [588], in 1927, reported vitiligo developed in one patient after spinal
anesthesia. Costea et al. [589] observed a 31-year-old patient who, upon developing traumatic paralysis of the right brachial plexus, exhibited ipsilateral
macules of vitiligo at the level of the upper arm, chest, buttock, sacrum, and
scrotum. The authors suggested the phenomenon of "sympathetic repercussion" resulted in widespread leukoderma; irritation of the sympathetic nerve
endings of the Cs and Dl roots induced a series of reflexes which resulted in
depigmentation exceeding the area innervated by the brachial plexus. However,
this explanation seems doubtful as their patient had insular canities prior to
the accident and showed a predisposition to dyschromia.
Vitiligo has been reported in patients with syringomyelia [590], von Recklinghausen disease [426], medullar tumor [591], multiple sclerosis with Horner
syndrome [592], poliomyelitis [29], neuritis [584,587], encephalitis [159,585]'
myelitis [29], or following peripheral nerve injury [589,593]. A patient with
encephalitis was observed to develop rapid graying of hair and total vitiligo
[594].
Vitiligo is sometimes observed to begin after severe emotional trauma such
as death of a parent or spouse, loss of a job, financial reversal, or severe fright.
A young girl, nearly struck by gunfire in the war, became suddenly aware of
having vitiligo [72]. An hysterical woman who complained of low back and
right thigh pain developed urticaria and vitiligo after electromyographic needle
insertions [595]. It was suggested that these cutaneous responses resulted from
neurohormonal changes induced by some psychic stimulus of the examination
procedure. Some reports mention an increased incidence of vitiligo in psychiatric patients [78,596-598]. History is replete with tales of sudden whitening
of hair following significant events. All such reports suggest a role of the CNS
in the pathogenesis of vitiligo.
Leukoderma occurring in a hypesthetic leprous macule has also been interpreted to favor the neurogenic hypothesis of leukoderma. But since there is
some evidence to suggest direct action of Mycobacterium Jeprae on melanocytes, the nervous system need not be implicated.
Several early authors have noted cerebrospinal fluid (CSF) abnormalities
in several vitiligo patients. CSF lymphocytosis and CSF cytologic abnormalities
have been described [599,600]. Increased CSF glucose in one patient has been
reported [601]. However, many of these patients had concomitant lues; in fact,

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these observations actually were invoked to support the syphilitic pathogenesis

of vitiligo. Skull x-rays, carotid angiograms, and pneumoencephalograms of
three vitiligo patients were reported to show minimal anatomic abnormalities
unrelated to the disease [602].
Histologic and Electron Microscopic Evidence
The reported histologic and electron microscopic abnormalities in the nerve
apparatus around macules of vitiligo [457,603] have been held in support of
the neurogenic hypothesis. Recent studies have also shown direct anatomic
contact between nerve fibers and melanocytes [604].
Pathophysiologic Evidence
Local physiologic abnormalities reflecting possible neuromediated aberrations have been reported in patients with vitiligo, but these physiologic studies have had such discordant results that drawing any conclusions has been
difficult.
Lerner [29] suggested increased adrenergic nerve ending activity in macules
of vitiligo. Chanco-Turner and Lerner [529] interpreted the increased temperature in the vitiliginous skin both before and after sweating as suggestive of
diminished sympathetic or adrenergic influence on the vasculature. Furthermore, the prolonged bleeding time and increased sweating of depigmented skin
were considered to support either increased cholinergic activity or decreased
sympathetic activity. The normal response of both normal and depigmented
skin to histamine, norepinephrine, and acetylcholine indicated that the effector
cells were intact and able to respond to stimulation. These authors concluded
that there was a dominant cholinergic influence in vitiliginous skin compared
to normal skin.
Koga [129] separated segmental from generalized vitiligo on the basis of
physostigmine-induced sweating responses. Decreased responsiveness of the
segmental type was interpreted to show an increased cholinergic influence.
(Studies of vitiligo vulgaris showed normal responsiveness.) Zebracka et al.
[531] also concluded that there was increased cholinergic activity in the vitiliginous skin. This may result from increased local acetylcholine concentration
due to either increased secretion or to delayed local clearing; or this cholinergic
activity reflects relatively decreased local epinephrine and norepinephrine levels because of decreased secretion or more rapid clearing of these sympathomimetic amines.
Although Maiti et al. [525] hypothesized increased adrenergic activity in
the vitiliginous skin, the aggregated results in the Indian studies [521,524,
532,533,605] of peripheral autonomic function in the involved skin support
the existence of an aberration of peripheral autonomic nerve function, most
likely sympathetic hypotonia.
To summarize, contradictory observations have been made, not only about
the presence of disturbances in the sensory and autonomic nerve apparatus,
but also about the nature of these disturbances. The studies of local neural
defects in vitiligo skin must be considered inconclusive.

Neural Mediators and Depigmentation in Other Animal Systems

It is apparent that pigmentation is under some degree of neural control in
many nonvertebrates. Pigment cells are under direct neural control in fish [606].
Pigment cells of fish, amphibians, and reptiles have alpha- and/or beta-adrenergic receptors. Stimulation of beta sites produces an aggregation of melanosomes and subsequent lightening. Stimulation of alpha sites brings about
dispersion of pigment granules and darkening. Where both kinds of receptors
function within a single melanophore, the alpha receptor can override the beta
[606].
Melatonin, the output of which is determined by the quantity of light to
which the animal is exposed, has a marked lightening activity on dermal
melanocytes of Rana pipiens, but has not yet been demonstrated to have any
direct action on mammalian melanocytes [606]. Melatonin does have some
effect in humans. Exogenous administration of melatonin does lead to some
pigmentary lightening [607]. Melatonin levels in humans vary from day to night
[608] and with the estrous cycle [609].
Acetylcholine darkens some fish but lightens about one out of three Rana
pipiens [606].
Fabian [610] investigated the effect of denervation on the rate of pigment
spread in guinea pigs and was able to show that the average rate of pigment
spread in the denervated skin was higher than that in the nonoperated control
sites. This suggested that peripheral nerves could playa role in regulation of
activity and behavior of melanocytes. Similar results were obtained by Voulot
[611], who concluded that an inhibitory effect of the nervous system prevails
over "pigment spread." He further observed that melatonin applied and injected
under the graft increases the inhibitory effect on pigment spread.
Laties and Lerner [612] showed ocular tyrosinase in rabbits to be dependent
on adrenergic innervation.

Abnormalities Directly Related to Neural Mediators

Depigmentation possibly attributable to acetylcholine has been reported.
Jacklin [613] observed four cases of patients with depigmentation of the eyelids
due to use of eserine ophthalmic ointment. Eserine is known to potentiate the
effect of acetylcholine.
Injection of epinephrine into rats causes local depigmentation of the pelage
[614]. But it seems likely that the depigmentation induced in animals by local
injection of epinephrine results from local vasoconstriction, as ischemic depigmentation has been produced in animals [615].
Contradictory catecholamine studies have been reported. Durneva [616]
reported increased adrenaline and noradrenaline levels in patients with vitiligo.
Lerner [29] found normal urinary catecholamine levels in five patients with
vitiligo. Suzuki [617] also found no disturbances of catecholamine metabolism.
Bamshad et al. [618] suggested abnormal inactivation of epinephrine and
norepinephrine in the vitiliginous skin. They assayed cutaneous catechol 0methyl transferase (COMT), an enzyme known to catalyze the transfer of a
methyl group from S adenosylmethionine to epinephrine to form metanephrine,

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a biologically inactive substance. They found COMT to be present in the same

concentration in the skin of normal persons and in those with vitiligo. If there
is an abnormality in the inactivation of epinephrine or norepinephrine in vitiligo, the defect is unrelated to abnormal COMT levels.
Assays of adjacent pigmented and depigmented areas from nine patients
with vitiligo revealed great variation in S-adenosylmethionine levels [619].
Although the average values were somewhat lower in depigmented skin than
in control skin, the differences were not considered significant.
Gauthier et al. [620] found decreased circulating cholinesterase activity in
vitiligo patients compared to controls. Histochemically, they found no cholinesterase activity in the vitiliginous skin in which the hair was depigmented.
They hypothesized that vitiligo is related to increased acetylcholine levels as
a result of decreased or absent cholinesterase levels. Furthermore, they reported
that monobenzylether of hydroquinone, a potent depigmenting agent, has anticholinesterase activity. No melanocytotoxic action of acetylcholine or melanocytes in vitro or in vivo has yet been observed.
Tissue histamine levels are normal in vitiliginous skin [621].
Grafting Experiments Reflecting Neurologic Environment
In humans, exchange grafts of normal and vitiliginous skin are relevant to
the question of nervous system and vitiligo. Unfortunately, experimental results
have been contradictory. Haxthausen [622] used Thiersch grafts to perform
autotransplantation experiments in three cases of vitiligo. In two of three subjects, transfer of a portion of normal skin into an area of vitiligo resulted in
loss of pigmentation after one year. Vitiliginous skin transplanted to normal
sites became completely pigmented in one case, partly pigmented in a second,
and remained unchanged in the third case. He interpreted this result as supportive of the assumption that vitiligo arises under local trophic influences,
presumably exerted through the vegetative nervous system.
Cornel [623] observed that pedicle grafts preserved their original color for
several months. Then the normal flaps lost their pigment and the vitiliginous
flaps became pigmented. Spencer [624] observed that full-thickness grafts in a
black patient retained their pigment for five months, but the vitiliginous skin
grafted to a normal area remained depigmented except for a slight repigmentation at the periphery. Similar results were observed by Spencer and Tolmach
[625] 16 months after grafts were performed. Orentreich [626] did transposition
experiments with full-thickness grafts in two white women who were followed
for more than one year. He observed "recipient dominance" in all sites in both
patients; pigmented skin transplanted to vitiligo skin became vitiliginous and
vitiligo skin transplanted to normally pigmented skin became pigmented. As
pointed out by the author, this recipient dominance may imply that, in vitiligo,
the factor responsible for the skin lesions resides in the deeper tissues of the
skin.
These results are clearly contradictory. Kato [627] suggested that the behavior of a graft is related to its thickness. So, the use of different techniques
by these several investigators may explain the variability of the results. Gopinathan [128] could not draw precise conclusions from these studies regarding

the sites of the disease process in vitiligo. He observed that in all cases where
the normal skin transplanted to the middle of a vitiliginous lesion underwent
depigmentation, a slight spread of depigmentation was seen on the previously
normal skin around the homologous pathologic grafts, and in those cases where
the vitiliginous grafts had become repigmented, a spread of pigmentation was
seen to extend onto the surrounding vitiliginous skin from the corresponding
normal skin grafts. In the latter group, the author noted signs of spontaneous
partial or complete repigmentation of many lesions on the body. He concluded
that if the vitiligo is in a progressive state, depigmentation will be the predominant change in the grafts, and if the disease is undergoing remission, then the
pathologic graft will also repigment. He found no difference in the behavior of
thick or thin grafts.
Where the Neural Hypothesis Fails
The most compelling arguments for the neural hypothesis are the dramatic
presence of segmental vitiligo and the evidence for neural control mechanisms
in fish. Recent studies demonstrating an anatomic linkage between melanocytes
and nerve cells are also fascinating. Yet there remains no direct evidence for
a primary neural defect in humans and there are several problems with this
hypothesis.
The weight of clinical observations among neurologic disorders is against
the neural hypothesis. Vitiligo is not a classical feature of denervation syndromes or of such diseases as peripheral neuritis or herpes zoster. Neural
dysfunction, is seems, is not usually associated wtih hypopigmentation. Depigmentation is not observed after sympathectomy and, conversely, sympathectomy in one vitiligo patient had no effect on the course of the disease [584].
The depigmented macules of vitiligo do not usually assume the true dermatomal pattern of known lesions of the peripheral nervous system. This quasidermatomal distribution of vitiligo also occurs in piebaldism or in nevus depigmentosus, in which neural factors are not usually implicated.
It is difficult, especially in vitiligo universalis, to explain on the basis of
inhibitory neurochemical mediators the absence of pigment inhibition in the
uveal pigmentary cells, since the iris is richly endowed with melanin, unless
one hypothesizes that the iris is somehow protected. Iris pigmentary lightening
has been reported in vitiligo but its occurrence must be rare [61]. No definite
reproducible pathophysiologic or biochemical abnormality has been demonstrated in vitiliginous skin.
Szcepanski [628] found no changes in the cerebrospinal system in 18 cases
of vitiligo. Furthermore, chronaximetry revealed no autonomic dysfunction.
Exchange transplant studies are beset with many technical difficulties [128];
several factors may influence the skin grafts (circulatory changes, pigment spread
phenomenon, scar formation) and explain the diverse results.
Serri and Cerimele [629] observed an anatomic association of cholinesterase-positive nerve endings and dendritic cells in the human fetal skin, and
Mori [446] obtained findings that might suggest a connection between the vegetative nerves and melanocytes mediated by the taste cells in the papillary
dermis. A recent report [456] has shown an anatomic relationship between

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nerve cells and melanocytes. Yet more observations must be made before it can
be concluded that there is functional control of melanocytes by the nervous
system.
The role of the nervous system in the pathogenesis of vitiligo is ill defined,
and although some observations suggest that loss of sympathetic innervation
precipitates changes in pigmentation, this must not be regarded as firmly established. The problems with the hypothesis, simply distilled, are that most of
the observations on fish, etc., may not apply to mammals, particularly humans,
that the clinical evidence is circumspect, and that no functional association
has yet been made between melanocytes and neural cells.
Self-Destruct Hypothesis of Vitiligo

The self-destruct theory of vitiligo suggests that there is an intermediate

or metabolite in the melanin synthesis pathway which, unchecked, leads to
apparent disappearance of melanocytes, or that an aberration of the normal
mechanism of melanosome destruction results in melanocyte dysfunction or
death. This implies there is a physiologic control mechanism which becomes
autonomous and unchecked. It is clear that this hypothesis is not necessarily
separate and discrete from the other two.
Pathak et al. [630] and Bleehen et al. [631] suggested destruction of melanocytes resulted from free-radical formation in phenolic compounds. In 1970,
Riley [632] suggested that an abnormal phenolic metabolite is produced in
individuals with the vitiligo gene. This compound may reach a critical level
in some region of the upper dermis and destroy melanocytes.
In 1971, Lerner [263] postulated that melanocytes have an inherited protective mechanism that leads to the successful elimination of toxic melanin
precursors, synthesized by the melanocytes and toxic to them. In vitiligo, this
labile protective process is disrupted. There is an accumulation of melanocytotoxic products and subsequent destruction of pigment cells.
In 1972, Brun [633] suggested a slightly different hypothesis. Vitiligo might
be due to the inhibitory action on the tyrosine-tyrosinase system of a phenolic
derivative which may be a degradative product of a normally occurring component in melanin synthesis. This chemical disrupts melanogenesis, possibly
by competitive inhibition and, after several days, leads to melanocyte death.
Some localized and temporally limited event may precipitate this progress.
There is some evidence to support this hypothesis. Graham et al. [516] have
shown that dopachrome is a significantly toxic metabolite in melanin biosynthesis.
Clinical Evidence
Lerner [263] pointed out that the areas of skin that most frequently lose
their pigment are those that are normally deeply pigmented. There seems to
be a correlation between the melanogenic activity of melanocytes and their
vulnerability; the greater the pigment-producing activity of melanocytes, the
less likely are their chances of survival. This observation had been made previously as early as 1864 by Beigel [7]. The occurrence of vitiligo in Addison

disease is consistent with this observation. The increased output of MSH increases the levels of cyclic AMP in the melanocytes; increased cyclic AMP
increases tyrosinase synthesis, melanogenesis, and thereby accumulation of a
melanocytotoxic product. Lerner's theory [263] implies that vitiligo would be
more frequent in people with dark skin and dark hair; but an increased incidence of vitiligo in blacks or those with black hair cannot be considered established.
Ultrastructural and Experimental Evidence
Catechols or phenolic derivatives, which selectively destroy melanocytes,
may induce vitiligo-like cutaneous depigmentation in humans or in animals.
Frenk [634] reported the ultrastructure of chemically induced depigmentation
to be similar to that of vitiligo. Some of these depigmenting agents show a
striking structural similarity to tyrosine or dopa. Brun [633] observed two tyrosine derivatives, p-hydroxycinnamic acid and p-hydroxyphenylpyruvic acid,
to be strong inhibitors of melanogenesis. Tyrosine, dopa, and tryptophan show
a selective toxicity towards melanotic cells. Treatment of cells with phenylthiourea, a selective inhibitor of tyrosinase activity, completely protects the
cells from the toxicity of the melanin precursors [350].
For most of these depigmenting agents, the precise mechanism of melanocytotoxicity is unknown. Riley [632] suggested that hydroxyanisol depigmentation is brought about by the synthesis of semiquinone free radicals. These
compounds diffuse out of the melanosomes to initiate the chain of lipid peroxidation. This causes damage to cellular organelles and ultimately the selective destruction of melanocytes. However, neither such semiquinone-free radicals, nor increased levels of the two tyrosinase inhibitors described by Brun
[633] have been found in vitiliginous skin.
Where the Self-Destruct Hypothesis Fails
The major failing of the self-destruct hypothesis is that it does not embrace
the immunologic or neurologic theories. As an inhibiting or precipitating factor,
it is attractive but, alone, it leaves too many observations unexplained.
The Composite Hypothesis

The three accepted theories of vitiligo pathogenesis must not be considered

to be mutually exclusive. An immunologic event may be secondary to cutaneous
injury, or neural stimulation may lead to stimulation of melanocytes with
overproduction of toxic precursors or destruction of a few melanocytes, subsequent leakage of antigenic material into the dermis, and stimulation of an
aggressive immunologic process destructive to melanocytes or to early components of the melanogenesis pathway.
Alternatively, melanin formation and destruction may be seen as a physiologically precariously balanced process with a metastable equilibrium in
those genetically so disposed. Overstimulation of neural elements, trauma,

257

GENETIC AND
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DISORDERS

258

CHAPTER 1

sunburn, etc., may upset this homeostasis in favor of melanin destruction, again
with incontinence of antigenic material and resultant immunologic melanocyte
destruction or inhibition.
Finally, it cannot be excluded that the primary event is a deficit in feedback
control from keratinocytes to melanocytes such that whatever mechanism genetically limits the number and packaging of melanosomes in keratinocytes
becomes defective and dominant so as to "turn off" melanocytes completely.
This too could implicate neural, immunologic, and self-destruct factors.

Diagnosis
Establishing a diagnosis of most types of vitiligo is usually not difficult.
History of an acquired progressive depigmentation excludes piebaldism, Woolf
syndrome, Waardenburg syndrome, Ziprkowski-Margolis syndrome, and nevus depigmentosus. The hypopigmented macules of tuberous sclerosis and of
tinea versicolor are not amelanotic and the latter usually are raised, scaling,
and sometimes have hyperpigmented margins. Postinflammatory hypomelanoses are likewise not amelanotic and require a history of an antecedent cutaneous eruption. Chemically induced depigmentation may be indistinguishable from vitiligo clinically and histologically; a history of industrial chemical
exposure (especially phenols) can usually be elicited and confetti white macules are usually present clinically.
When the clinical diagnosis is unclear, Thiersch biopsies for split dopa
and electron microscopy should be done. Absence of melanocytes in a biopsy
from a fully depigmented macule is required for diagnosis. A biopsy should
also be taken from clinically normal skin for comparison.
The observation of Harsoules et a1. [268] that 19 of 85 vitiligo patients (ages
4 to 78) had thyroid disease or diabetes mellitus and our observation that nearly
half of a small sample of vitiligo patients over the age of 50 have a thyroid
disease diathesis [191] make it imperative that vitiligo-associated conditions
be excluded. When the diagnosis is established, every patient should be screened
for diabetes mellitus, thyroid disease, and pernicious anemia. Addison disease
seems to be infrequent enough that laboratory screening can be reserved for
the patient who is symptomatic or has other evidence for autoimmune disease.
Probably in older patients with vitiligo, laboratory tests should be repeated
every few years indefinitely.
For those patients who wish some form of treatment, photographs prior to
therapy will later prove useful for comparison.

Treatment
There are several options for the approach to treatment of vitiligo. Simple
reassurance that the condition is not infectious or cancerous may be all the
patient requires. But for many patients the goal is to be again one color, preferably their normal constitutive skin color.

Cosmetic coverup may be adequate to satisfy the patient's needs. Vita dye
(Elder), Dy-O-Derm (Owen), dihydroxyacetone-containing quick-tanning agents,
and opaque cosmetics are satisfactory for some (Fig. 86). These must be applied
carefully to produce good camouflage but there are limitations. They gradually
wash off and must be reapplied to the vitiligo macules every few days. Unfor-

FIGURE 86. a: Patient with bilaterally symmetrical vitiligo of the dorsal hands obtains excellent
coverup match with Dy-O-Derm. b: This patient uses Vitadye to camouflage vitiligo of the chin.

259

GENETIC AND
CONGENITAL
DISORDERS

260
CHAPTER 1

tunately, a perfect match to normal skin color cannot be achieved in most

patients. Of the options, opaque cosmetics such as Covermark seem to hide the
vitiligo best in many patients; those living near large cities may find excellent
"salons" staffed by technicians who can help the patient find a good match
and teach the patient proper application techniques. With practice, some patients can completely hide their vitiligo. For very fair-skinned individuals,
Types I or II, use of a high-SPF broad-spectrum UVNUVB blocker (Total Eclipse,
Super Shade 15, PreSun 15) may prevent enough tanning so little contrast is
apparent.
Oral beta-carotene [635 J combined with topical sunscreen has also proved
helpful. For Skin Type I and II, the contrast is less apparent but xanthoderma
is also apparent on normally pigmented areas of skin, particularly the palms.
The remaining option is to attempt to effect a more permanent solution to
the cosmetic disfigurement. This may be achieved by repigmentation of the
vitiliginous macules or by depigmentation of the remaining normally pigmented skin.
Repigmentation of the Vitiliginous Macules

The ancients had some success with herbal therapy of vitiligo. In an 1880
compilation of ancient Indian medicine (Ashfangahridaya, Bombay, Krishna
Sarma, 1880), Vaghbhata summarized the nineteenth century status of therapeutic success: "The lesions where hairs have not turned white, which are not
associated with swellings, which have not become confluent, are of recent
origin, and do not follow burns are curable. The lesions which show characteristics contrary to this should be discarded (not treated). The lesions that
occur on the genitalia, hands and feet and lips, even if of recent origin should
be discarded." One hundred years later, this is not so far afield; there are still
some limits to our expected success. That so many different treatment modalities have been attempted attests to the lack of complete and ready success of
any of the methods. The list includes surgical procedures (Thiersch grafts [636],
dermabrasion, vibropuncture [637], and tattooing), vitamin therapy, hormonotherapy (MSH) [374], copper therapy [70], tyrosinase [638], p-aminobenzoic
acid [639], mepacrine [640], and chloroquine [641]. Recently L-dopa, Lamprene,
quinacrine, corticosteroids (topical, intralesional, and oral), and ACTH have
been reported to induce repigmentation. The most successful current therapy,
however, involves the use of oral (trioxsalen, methoxsalen) or topical (methoxsalen) psoralens and subsequent exposure to long-wave ultraviolet radiation
(320-400 nm) from sunlight or from high-intensity artificial sources. This is at
present the only treatment modality with a reasonable hope of achieving repigmentation of vitiliginous macules.
Psoralens and Ultraviolet Radiation
History of Psoralen Therapy
The Hindus of India in the ancient Ayurvedic system of medicine used
psoralen, the active ingredient of the seeds of Psoralea corylifolia L., for repigmentation of vitiligo. The treatment of leukoderma (vitiligo) with the plant

vasuchika or bavachee (Psora1ea corylifo1ia) was described in the Indian sacred

book Atharva Veda (1400 B.C. or earlier) and also stressed the need for solar irradiation exposure. Since the thirteenth century, Ammi majus L., a plant
that grows abundantly in the Nile Valley, has been used by the Egyptians
to treat vitiligo. Ibn EI Bitar, in his famous book, Mofradat e1 Adwiya, described the treatment of baras (vitiligo) with sunlight and the seeds of atrillal
(Ammi majus 1.).
Psoralens were first isolated from plants in 1911 [642). Psoralen research
began in 1941 in Egypt and by 1947 Fahmy and Abu-Shady [643) had isolated
from the powder of Ammi majus L. three crystalline compounds: ammoidin
(8-methoxypsoralen), ammidin (8-isoamyleneoxypsoralen), and majudin or
bergapten (5-methoxypsoralen). El Mofty [644) was the first physician to treat
vitiliginous lesions with psoralens and to report successful repigmentation of
the vitiligo macules after oral administration of 8-methoxypsoralen.
Structure and Occurrence of Furocoumarins
The furocoumarins, certain isomers of which are called psoralens, belong
to a group of heterocyclic compounds derived from coumarin (benzo-a-pyrone
or 1,2-benzopyrone) (Fig. 87). Although the furan ring can be condensed with
a coumarin molecule in 12 different ways, most of the natural furocoumarins
are derivatives of two furocoumarin molecules, psoralen or isopsoralen. More
than 30 different natural furocoumarins have been isolated. Natural psoralens
are found in the following plant families:
Umbilliferae (e.g., parsley, parsnip, celery, fennel, Ammi majus L.).
Rutaceae (e.g., bergamot fruits, lime, gas plant, cloves, citrus fruits).
Leguminosae (e.g., bavachee or Psoralea corylifolia, xanthoxylum flavum,
Coronilla species).
Moraceae (e.g., figs, Ficus carica L., and other Ficus species).
Of these, 8-methoxypsoralen (xanthotoxin, methoxsalenJ, 5-methoxypsoralen
(bergapten), trimethylpsoralen, and psoralen have been found to be cutaneous
photo sensitizers and to induce pigmentation; psoralen, 8-methoxypsoralen,
and 4,5',8-trimethylpsoralen have been used in the clinical repigmentation of
vitiligo.
Absorption and Action Spectra of Psoralens
The absorption spectrum of psoralen, 8-methoxypsoralen (8-MOP), and
4,5'8-trimethylpsoralen (TMP) ranges from 210 to 330 nm (Fig. 88). However,
the action spectra of these compounds are not in the region of maximal ab-

OCH3

r('o~0'f0
(a)

Ll~
(b)

CH3

rW
I

"""

I.&".&"

CH3

(c)

FIGURE 87. Structure of psora len (a). 8-methoxypsoralen (b), and 4,5' ,8-trimethylpsoralen (c)
(x 27).

261

GENETIC AND
CONGENITAL
DISORDERS

1.0

262
CHAPTER 1

....>-

iii

c::
~ 0.5

,"

iij

i
o

200

300
Wavelength mp

400

FIGURE 88. Absorption spectra of var= Psoraious psoralen compounds. len; - - - = 5-methoxypsoralen; - - - = 8methoxypsoralen; ..... = 5,8-dimethoxypsoralen.

sorption (Le., below 320 nm). Experimental studies show that action spectra
lie between 320 and 380 nm (UVA) and that peak of the action spectra for
8-MOP and TMP is at about 340 to 360 nm.
Pharmacology of Psoralens

Recently, considerable experimental evidence about psoralen pharmacology has accumulated. Pathak et al. [645] studied the rate of absorption, excretion, and the time at which maximum photosensitivity is elicited after oral
administration of psoralen, 8-MOP, and TMP. In humans, mice, and guinea
pigs, the maximum concentration of the photosensitizing drug in blood is found
two to three hours after oral ingestion of a single dose; this usually correlates
with the time course of maximal cutaneous phototoxicity. In not all cases does
the minimal phototoxic dose correlate with 8-MOP levels, skin type being a
factor [646]. Since the limiting factor is usually phototoxicity of amelanotic
vitiliginous skin, blood levels not skin type are the critical difference in these
patients. Blood levels may be affected by the mode of ingestion. Studies of
Ehrsson et al. [647] have shown higher blood levels when 8-MOP was ingested
with food, but absorption rate and half-life were unaffected. Cutaneous sensitivity is low or minimal in the first hour after psoralen ingestion and peak
levels occur in one-and-one-half to three hours. Likewise, four hours after
ingestion, skin has begun to lose its sensitivity to UVA. Comparative studies
have shown not all capsule forms are similar, one type (Hoffmann-La Roche,
Inc., Nutley, New Jersey) giving consistently higher blood levels than the other
(Elder Co., Bryan, Ohio). A tablet form with one-hour postingestion maximal
bioavailability was described by Thune [648] (pills supplied by Nyegaard &
Co., A/S, Oslo). Some patients have been shown to absorb 8-MOP poorly; this
occurs with either formulation.

Over 90% of the administrated psoralen is excreted within the first 12

hours in urine and feces and the rest is eliminated within the next 12 hours.
Primary detoxification occurs in the liver in mice and guinea pigs. Psoralens are excreted in urine either as hydroxylated products (hydroxylation at
the 3 position) or in the form of a glyceranate. Sixty percent of 14C-8-MOP is
excreted in the urine as seven metabolites of 8-MOP-four major and three
minor; one of these is also a photosensitizer [649].
Action of Psoralens
Photosensitization. Psoralens, in the presence of long-wave ultraviolet
radiation (320-400 nm) induce a reversible dose-related cutaneous photosensitivity response characterized by an augmented sunburn reaction with erythema, edema, desquamation, and subsequent hyperpigmentation. Erythema,
however, need not be present for melanogenesis to occur.
8-Methoxypsoralen is the most potent currently available psoralen photosensitizer. Psoralen and methyl-substituted psoralen derivatives (substitution
at the 4,4', 5', and 8 position have been found also to be effective photos ensitizers. Orally administered 8-MOP is more phototoxic than either oral TMP
or unsubstituted psoralen.
Certain furocoumarin bonds are particularly important to biologic responses to light. It appears that it is the 3 position of the psoralen molecule
that is involved in biologic photosensitization processes. The role of the 3
position or the 4' and 5' positions in the psoralen-ring system appears to be
related to binding of the molecule to the DNA at the 5 and 6 positions of the
pyrimidines [650]. Methyl substitution at the 3 position, hydrogenation at 4'
and 5', and substitution by N(CH 3 Jz, CN, NH 2 , or groups at the 8 position of
the psoralen molecule results in complete loss of photosensitizing potency.
Psoralen can intercalcate between two DNA base pairs and give interstrand
cross-linkages upon irradiation [651-654] (Fig. 89).
Reactivity of psoralens is apparently due to intersystem crossing of the
photo excited psoralen molecule from the singlet to the highly reactive metastable triplet state. The triplet state of psoralen is usually relatively long-lived

FIGURE 89. Psoralens form thymine dimers in DNA (covalent bonds) (x 30).

263

GENETIC AND
CONGENITAL
DISORDERS

264
CHAPTER 1

(10-3 seconds) and plays a major role in the transfer of energy and the initiation
of biologic photosensitization.
In vitro studies of the photoreactivity of psoralens with pyrimidines and
the photoreactivity of psoralens with the purines (adenine and guanine) are of
fundamental importance to an understanding of the process of psoralen-induced cutaneous photosensitivity. From spectroscopic data, Pathak et a1. [650]
concluded that psoralen and thymine or psoralen and uridine form a nonfluores cent C4 -cycloaddition product; the 3,4 double bond of the pyrone ring of
psoralen attaches to the 5,6 double bond of the pyrimidine (e.g., thymine).
Bonding may also be induced at the 4' ,5' double bond of the furan ring to
produce another type of C4 cycloadduct of psoralen and pyrimidine. The photoreaction of TMP with DNA has also been documented in vitro.
Methyl-substituted psoralens at the 4 or 4' position (e.g., 4,5',8-trimethylpsoralen) have a very low capacity to form cross-links with DNA. It has been
suggested that the formation of bifunctional ad ducts is probably more important
than monofunctional adducts in photosensitization and in lethality of cells
[655]. There is a very effective DNA repair process operating in normal mammalian skin [656]. In yeast cells it appears that the damage due to monofunctional ad ducts is more easily repaired than that due to bifunctional adducts
which form interstrand cross-linking [657].
To elucidate the nature of in vivo cutaneous photosensitivity, Pathak et
a1. [650] applied 3H-labeled TMP to sensitized guinea pig skin which was then
exposed to 365-nm ultraviolet radiation. TMP formed photoadducts primarily
with DNA and to a lesser extent with RNA. The changes in DNA preceded
other biochemical cellular or vascular changes. The formation of a C4 -cycloaddition product of TMP with DNA during irradiation appeared to be primarily
responsible for epidermal cell damage and cutaneous photosensitivity. Impaired duplication, transcription, and translation have been found to be the
main mechanisms of psoralen photosensitization [658].
Increased Melanogenesis. Topical or oral psoralens and subsequent exposure to ultraviolet radiation (320-400 nm) cause increased melanogenesis in
normal skin [659-663]. During psoralen-induced pigmentation, the following
events take place in normal skin [650] (Figs. 90, 91):
The number of functional melanocytes increases three- to fivefold as the
result of proliferation and/or activation of melanocytes. Melanocytic hypertrophy and increased arborization of melanocytic dendrites may accompany this
increase.
Tyrosinase activity increases as tyrosinase is synthesized in proliferating
melanocytes.
The number of melanosomes (Stages I to IV) in melanocytes increases as
a result of increased synthesis.
The number of melanosomes in keratinocytes increases because of increased transfer.
The melanosome packaging in Caucasoid skin changes, possibly secondary
to increased melanosome size. Whereas in normal unexposed skin of a lightskinned Caucasian the melanosomes are packaged as aggregates of smaller
melanosomes (1 IJ.), topical psoralen and UVA results in the formation of larger
melanosomes (1-2 IJ.) packaged as singles (nonaggregated), as in the normal

265

GENETIC AND
CONGENITAL
DISORDERS

1l7345

19301-104

130855

190345

FIGURE 90. Increase in melanocyte population in normal human skin after exposure to longwave ultraviolet radiation in the presence of 8-methoxypsoralen. a, b: Unirradiated skin. expressed in melanocytes per mm 2 S.E. c. d: Five days after a single exposure to solar radiation,
expressed in melanocytes per mm 2 S.E. Split-dopa preparation (x 28).

skin of blacks and Australian aborigines. The persistent hypermelanosis observed with the psoralen reaction appears to be correlated with the presence
of large single or nonaggregated melanosomes.
The mechanism of psoralen photoactivation melanogenesis is unclear. Ultrastructural studies [664] of human skin suggest that the keratinocyte may be
the reactive site of photoaddition products of TMP and DNA. But how this
translates into activation of melanogenesis is unclear.
Microscopic Appearance of Repigmentation of Vitiliginous Macules. Repigmentation of vitiliginous macules following oral or topical psoralen therapy
usually begins with the appearance of discrete macules of pigment within the
macule or at the periphery (Fig. 92). Studies of Pegum [665] suggest that follicular melanocytes colonize vitiliginous skin; the epidermis of vitiliginous
skin containing pigmented hairs was demonstrated to show follicular repigmentation in some patients. Migration of melanocytes from follicular reservoirs
has been demonstrated with scanning electron microscopy [666] (Fig. 93). Autoradiographic techniques with 3H-thymidine labeling has shown concentrated
activity at margins of vitiligo macules and in perifollicular array [667,668]. It
appears that follicular repigmentation is not the only mechanism. Some macules repigment not from around hair follicles but from lesional margins which
mayor may not be hyperpigmented; some of these may be from marginal
follicular reservoirs, however. Also, macules of repigmentation resembling those
observed around hair follicles may develop in the amelanotic skin of the palm,
sole, and mucosal surfaces, where the absence of hair follicles precludes the
possibility of a follicular cell-mediated process [669].

266
CHAPTER 1

FIGURE 91. Electron microscopy before and after topical TMP and long-wave UV A exposure.
1a: Melanocyte before exposure. 1b: Increase in melanosomes after TMP administration and UV A
exposure. 2a: Melanosomes in keratinocytes before exposure. Aggregates are noted. 2b: Increase
in melanosomes. now singles. after TMP and UVA exposure.

The exact mechanism by which psoralen and ultraviolet radiation induce

repigmentation of vitiliginous skin remains unknown. EI Mofty [6] summarized
various hypotheses as follows: Psoralens may
(a) induce migration of active melanocytes from the surrounding normal
epidermis and/or hair follicles;
(b) reactivate "inactive melanocytes" in the vitiliginous macules;
(c) correct the structural abnormalities in the "melanocytes" of vitiliginous
skin;
(d) release an inhibited tyrosinase enzyme;
(e) increase tolerance to ultraviolet radiation or solar exposures and thereby
allow stronger stimulation of the "melanocytes."
The issue centers on whether or not melanocytes are mitotically active. In
one study hypertrophic melanocytes were observed in the center of repigmenting perifollicular macules in four patients treated with 8-MOP but there

267

GENETIC AND
CONGENITAL

DISORDERS

FIGURE 92. PUVA-induced repigmentation of vitiligo of the forearm; after 20 treatments, myriads
of perifollicular macules of repigmentation occurred. Such macules gradually coalesce to repigment
fully a vitiligo macule.

were no mitoses. The melanosomes were slightly increased in size but keratinocyte packaging was unaltered. This suggests a repigmenting follicular reservoir [670] but does not demonstrate the mechanism. In another study, it was
concluded that the early stage of repigmentation occurs in the outer root sheath
between the infundibulum and the hair bulb [670a] and that both activation
of inactive melanocytes and their subsequent proliferation are involved in the
process of repigmentation. Evidence that mitotic activity of melanocytes must
be capable of inducing macroscopic changes arises from the observation that
Thiersch biopsy sites generally repigment fully even though the melanocytes
of the dermal-epidermal junction have been shaved away. In normal patients
many laceration scars repigment. Melanin synthesis must be arising in these
areas from melanocytes in hair bulbs, eccrine sweat glands, or in sebaceous
glands. Miyazaki et al. [474] reported evidence suggesting activation of indeterminate cells; in hairless mice indeterminate dendritic cells represent two
cell populations, one of which belongs to the melanocyte line and is thereby
an amelanogenic melanocyte. No enzyme inhibitors or melanocyte structural
aberrations have been identified. The question of the mechanism of photopharmacology of PUV A-induced melanogenesis remains.
Clinical Use of Psoralens (Table 76)
Patient Selection, Instructions, and Precautions. The well-motivated patient may wish to repigment with psoralens and UV radiation. Patient selection
dictates certain exclusions at the outset, namely:
(a) History of photosensitivity or photomediated disorders
(b) History of Grenz-ray or x-ray therapy

268
CHAPTER 1

FIGURE 93. Split-dopa and scanning EM of psoralen-induced repigmentation of a vitiligo macule.

a: Melanocyte (M) migrating along hair follicle (HF). b: Higher magnification of highly dendritic
(dd) melanocyte from outer root sheath. c: Marked dopa-positive reactivity at base of hair follicle.
Note intensely reactive areas along hair follicle. suggesting migration of melanocytes from hair
bulb reservoir.

(c) History of cutaneous malignant tumors

(d) Pregnancy
(e) Lactation
(f) Age under 12
In compelling cases, criteria other than (d) and (e) may be considered relative
and the patient treated if the potential acute or chronic risks are well explained,
and understood and accepted by the patient and the physician.
Psoralen photochemotherapy for vitiligo is a slow, tedious process. Among
the best responders, 20 to 40 treatments are required before visible repigmentation develops, and 100 to 300 treatments before full repigmentation is achieved.

269

GENETIC AND
CONGENITAL
DISORDERS

c
FIGURE 93 (Continued)

270

CHAPTER 1

TABLE 76.

Indicators of Response to Psoralen Therapy in Vitiligo

Distribution
Areas that respond well: face, neck, trunk, proximal arms and legs
Areas that respond poorly: mucosa, dorsal hands and feet, fingers and toes, palms and soles
Clinical Pattern
Presence of multiple perifollicular macules is a favorable prognostic sign
Presence of marked leukotrichia in a macule may be a poor prognostic sign for that macule
Variables of Treatment
Drug
TMP preferable to 8-MOP for treatment not under direct physician
supervision. Relative effectiveness of 8-MOP, TMP, and psoralen not well
established. Relative responsiveness individually variable.
At least 0.3 mg/kg 8-MOP or 0.6 mg/kg TMP (increasing increments of dosage
Dose
cannot necessarily be expected to give proportionately better results).
Sunlight or high-intensity long-wave UV radiation (UVA) equally effective.
UV radiation
UVB (290-310 nm, sunburn spectrum) ineffective.
source
Optimal signal dose exposure not established. Persistent erythema of vitiligo
Dosimetry of
patches not necessarily required. Severe sunburn reactions may cause more
UV
depigmentation (Koebner phenomenon) in the normal skin and should be
radiation
avoided.
At least twice weekly, but not two days in a row. Probability of sunburn
Frequency of
increases with treatment frequency, particularly with 8-MOP.
treatment
Twelve months or more for best results, as continuously as possible.
Duration
Fully repigmented macules stay filled in; subtotal repigmentation may
Permanence
undergo reversal if treatments are discontinued.

Since the period for successful repigmentation is very long, only those patients
who are highly motivated should undertake therapy. During the course of the
treatment, the normally pigmented areas become markedly tanned, so that the
cosmetic disfigurement is enhanced while the vitiligo macules are repigmenting
(Fig. 94). Showing the patient the contrast of his skin under the Wood's light
is an effective means of demonstrating the potential contrast that will occur
with psoralen therapy. The importance of patient compliance cannot be overemphasized to the patient.
Patients must be instructed in which psoralen to use, when to take it, how
to expose to light, and how frequently to treat.
The treatment regimen for repigmentation consists of the oral administration of 0.6 to 1.2 mg/kg of 4,5' ,8-trimethylpsoralen (TMP), 0.3 to 0.6 mg/kg of
8-methoxypsoralen (8-MOP), or a combination of these. 8-MOP is manufactured
as 10-mg capsules (Elder Co., Bryan, Ohio); TMP is available in 5-mg tablets
(Elder Co., Bryan, Ohio). Neither unsubstituted psoralen nor 5-methoxypsoralen is commercially available in the United States. The tablets/capsules should
be ingested in a single dose two hours before anticipated exposure. Artificial
long-wave ultraviolet radiation (UVA) or midday sun can be used. Treatments
are given two or three times weekly, preferably not two days in a row. A careful
record should be kept of each treatment exposure.
Selection of psoralen derivative for use is not completely arbitrary. We
usually select TMP for outdoor therapy because it is in most cases much less
erythemogenic on normal skin [6711 and is less likely to cause severe phototoxic

271

GENETIC AND
CONGENITAL
DISORDERS

apy. The vitiligo is a small

FIGURE 94. a: Vitiligo prior to institution of psoralen photochemother
of psoralen photochemweeks
several
After
b:
t.
apparen
ely
moderat
only
and
liability
cosmetic
heightened. Normal sun
is
contrast
the
that
so
ally
otherapy, the normal skin has tanned dramatic
markedly.
so
not
but
contrast
the
te
accentua
also
would
s
psoralen
exposure without

272
CHAPTER 1

to have catastrophic results. In a controlled therapeutic environment 8-MOP

alone or with TMP may be used safely. Patients using TMP can sometimes
safely be treated more frequently than two or three times per week, rarely true
with 8-MOP. More frequent therapy may not markedly increase response rate.
Either sunlight or artificial UVA may be used. When sun is used as the
source, the initial exposure time must not exceed 10 minutes and should be
taken at times of the greatest UVA flux, namely between 11:00 a.m. and 2:00
p.m. The duration of treatment may be gradually increased by three- to fiveminute increments per exposure until persistent erythema or a total of approximately 45 minutes' exposure per exposure site is reached.
Until the mid 1970s, the only practical and effective exposure source for
the psoralen reaction was the sun. In the early 1970s Parrish et al. [135] used
a fluorescent lamp system containing 48 four-foot fluorescent bulbs mounted
in a horizontal plane to provide uniform exposure over an area 7 ft by 4 ft.
This source emitted a continuous spectrum of high-intensity radiation between
320 and 390 nm, with a peak emission of 365 nm. A plastic sheet (Mylar filter)
was inserted just below the bulbs to filter out radiation below 320 nm. The
irradiance at 365 nm at a distance of 3 to 12 cm from the plastic sheet was 5.6
mW/cm 2
This method of treating vitiligo using a high-intensity UVA source offered
several advantages over the use of sunlight. The output of UVA of the lamp
was equal to or greater than that of the sun. The entire body, including areas
not easily exposed to the sun, could be treated. Year-round and evening treatments were made possible. The output of the system is constant (not weather
dependent), and a large part of the sunburn and infrared spectra is eliminated.
Since that study, more intense commercially manufactured walk-in units have
become available, and many of these have an output of 15 mW/cm 2 within the
first 100 hours of usage. Proliferation of these units in the United States and
Europe has put indoor psoralen therapy conveniently within reach of those
living near major urban medical center areas.
Although it has been claimed that an inflammatory response is necessary
for repigmentation [31], some patients repigment well in the absence of erythema. Erythema may in fact not be the desired end point of therapy for it is
clearly not required for repigmentation; while patients who are pushed to
persistent erythema (5 to 20 joules) may repigment slightly or moderately faster
than those who receive minimal ultraviolet radiation (0.5 to 2 joules) per treatment, we have no comparative data on the use of high suberythemal UVA
dosages. Even the occasional patient who reports repigmentation after a blistering phototoxic exposure should not be pushed to erythema because the
morbidity of a burn and the risk of a Koebner reaction do not justify these
exposure dosages.
Sunglasses that do not transmit UVA must be worn outside at least 24
hours after pill/capsule ingestion. Once the treatment time has lapsed, the
patient must avoid further sun exposure by going indoors, covering up with
clothing, or applying a UVA or broad-spectrum sunscreen to sun-exposed skin.
Protecting normal skin with a broad-spectrum, high-SPF sunscreen also may
help prevent some of the heightened contrast resulting from delayed tanning
of normal skin.
Results of Oral Psoralen Therapy (Figs. 95, 96, 97). Repigmentation usu-

273

GENETIC AND
CONGENITAL
DISORDERS

FIGURE 95. Psoralen-induced repigmentation of the low back of a young Caucasian male. Areas
of repigmentation are not so intensely melanized as previously uninvolved skin. a: Before treatment.
b: After treatment.

274

CHAPTER 1

ally occurs as perifollicular dots which enlarge progressively, though there may
also be gradual concentric spread of the pigment from the peripheral border.
This repigmentation usually begins to appear one to four months after the
beginning of treatment, and a very definite cosmetic improvement takes 12 to
24 months of two or more treatments per week (100 to 300 treatments). An
occasional accelerated responder will have hundreds to thousands of tiny perifollicular dots within 10 treatments.
Fortunately, the face and neck, which are the most important from a psychosocial viewpoint, respond best; 60% to 70% of patients who persist will fill
these areas in completely. The arms, legs, and trunk do nearly as well. Vitiligo
on the digits, volar wrists, palms, dorsal feet, soles, and glans penis respond
so poorly that treatment of these areas alone is rarely indicated. The lips may
or may not respond. Hair depigmentation may be associated with poor prognosis, but we have seen patients who have white hair in macules obtain good
results. Lesions of recent onset have been claimed to do better with psoralen
and ultraviolet radiation than older lesions, but this cannot be considered
established. Dramatic results have been observed in vitiligo present over 10
years. The extent of vitiligo has little bearing on the response rate.
Many workers have reported experience with psoralen photo chemotherapy
of vitiligo. Psoralens result in acceptable repigmentation in about 70% of those
treated [3,645]. Using 8-MOP, Sidi et a1. [35] observed partial or complete
repigmentation in 73% of their patients, and El Mofty [6] in nearly 90% of his
75 patients. Similar results were reported by Elliott [672] and Kenney [673].
Fitzpatrick et a1. [31] reported that more than 70% of 84 patients treated with
TMP showed marked repigmentation in vitiliginous areas. The best results were
obtained with 30 to 50 mg TMP in persons treated for more than two years.
Bleehen [42] also reported a significant cosmetic improvement in 15 of 22
patients with vitiligo, although he used smaller doses of TMP (15 to 20 mg).

FIGURE 96. Caucasian male with vitiligo of the chest and neck. a: Before therapy. b: After 40
treatments with 40 mg TMP plus artificial UV A. Many macules of repigmentation are apparent. c:
After 100 treatments, almost complete repigmentation is apparent. Small macules of vitiligo remain
at the base of the neck.

275

GENETIC AND
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DISORDERS

FIGURE 96 (Continued)

276

CHAPTER 1

FIGURE 97. Psoralen therapy

of a black woman with vitiligo.
a: After 20 treatments a few perifollicular macules had appeared.
b: Intermediate stage of therapy;
many macules of repigmentation
are hyperpigmented. c: Several
areas have completely filled in.

Many others have reported good results with psoralen therapy of vitiligo [674-679]
(Table 77). Those who repigment one area will usually do well elsewhere;
dramatic differences in repigmentation rate of the face and trunk should raise
the question of inadequate exposure of the nonresponding site or of chronic
phototoxicity.
Annamalai et al. [680] treated 200 patients with 10 mg TMP but found
topical TMP was required for satisfactory results. They found the 60 diabetics
and 40 myxedema patients to be responders; those without thyroid disease or
diabetes were poor responders as were those with amebiasis. We have not been
able to separate responders from nonresponders by the presence or absence of
any of the associated diseases.
Seghal [681] compared responses of 89 patients treated with TMP, psoralen,
or 8-MOP (10 mg of each-37, 29, and 23 patients, respectively). Although more
patients on 8-MOP repigmented completely (13%) on treatment for 26 weeks
or less, overall results were better with psoralen or TMP. One of the patients
on psoralen developed granulocytosis which reversed when the psoralen was
discontinued [681]. This study involved use of very low dosages of psoralens
used.
In a long study of 365 East Indian vitiligo patients, of those treated over
26 months with psoralens and sunlight nearly half of the patients repigmented
over 50% of their vitiligo when treated with 60 mg TMP, 20 mg 8-MOP, or 20
mg 8-MOP plus 40 mg TMP; between 38% and 45% fully repigmented the face.
In limited follow-up, increasing the TMP severalfold did not appear to increase
overall responsiveness. The relative responsiveness as measured by facial repigmentation is shown in Table 78. This suggests, although the numbers are
limited, that 0.3 mg/kg 8-MOP, 8-MOP plus TMP (0.3 mglkg plus 0.6 mglkg),
and high-dose TMP (1.8 mg/kg) may be equally effective. The concerns about
acute and chronic phototoxicity make it advisable to use the lowest-dosage
psoralens effective-0.3 mg 8-MOP or 0.8 mg TMP. Poor responders to 8-MOP
may respond to TMP and vice versa.
In a study using an artificial UVA source [135], among 26 patients treated

TABLE 77.

Author
Sidi et al. (1957) [35]
El Mofty (1968) [6]
Fulton et al. (1969) [688]
Africk and Fulton (1971)
[668]
Bleehen (1972) [42]
Fitzpatrick et al. (1974) [31]
Parrish et al. (1976) [135]
a

Topical.

Response to Psoralen Therapy in Vitiligo

Type of
treatment
8-MOP
8-MOP
8-Mopa
(indoor)
TMpa
TMP
TMP
TMP and 8-MOP
(indoor)

Induced
repigmentation
(%)

Total no.
of patients

73
61
93

219
75
15

91

20

47
70
70

32
84
26

277
GENETIC AND
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DISORDERS

12 to 18 months with 40 mg 8-MOP (13 patients) and 40 mg TMP (13 patients),

73% improved. In none was complete repigmentation observed but there was
over 75% improvement in four of the 13 TMP-treated patients and two of the
13 8-MOP group. These results are similar to those obtained when patients
were treated with similar doses of TMP or 8-MOP and sun exposure.
The relative responsiveness of patients to 8-MOP or TMP is unsettled. For
some patients and some investigators one drug is clearly superior to the other;
but there is no way to predict which patients are most likely to respond best
to which psoralen derivative.
Psoralen-induced repigmentation has been reported to be permanent [673].
Any macule completely filled in should remain repigmented indefinitely. However, if less than full repigmentation occurs, a macule may lose all or much of
the regained pigment once therapy has been discontinued. This pigment loss
may be trivial or dramatic. We have one patient who repigments 75% each
summer and regresses completely when treatments must be discontinued over
the winter months. For such patients summer therapy alone is fruitless and
should be undertaken only if there is an available facility to continue therapy
indoors over the winter.
Topical Psoralens. Both 8-MOP [254,682-685] and TMP [668,676] have
been used topically to treat vitiligo, particularly small areas of skin (less than
10 cm2 ). The use protocol is similar: one-and-one-half to three hours after
application of 0.1% 8-MOP solution the area is exposed to artificial UVA radiation, but for only 30 to 60 seconds, and increased by 30 seconds per everyother-day therapy. The problems with use are considerable. Topical psoralens
are extremely phototoxic, but the degree is a function of concentration [686].
As little as 2.5 IJ.g/sq in. of TMP applied topically can produce a phototoxic
reaction when the skin is exposed to several joules of long-wave ultraviolet
radiation. Since there is very little margin between exposure time required for

278
CHAPTER 1

TABLE 78. Vitiligo Patients Treated 16 to 26 Months

Facial
repigmentation

Overall
repigmentation

(%)

No. of
patients

18
15

66.7
26.6

36
24

47.2
29.2

60 mg
125 mga
250 mga

16
28
24

37.6
35.7
58.3

23
57
42

47.8
19.3
35.7

Psoralen

40 mg
80 mg

13
5

23.1
40.0

30
7

16.7
28.6

8-MOP

20 mg
25

64.0

47

53.2

Drug
8-MOP

TMP

TMP
a

Dosage170 kg
individual

No. of
patients

20 mg
40 mg

40 mg

Treated under 15 months at this dosage, plus 12 months on 40-60 mg TMP.

(%)

melanogenesis and for severe phototoxicity, inadvertent or casual sun exposure

can cause severe blistering. Topical psoralen phototoxicity has been shown to
persist for 24 hours after application [687] and up to several days in our experience unless these agents are washed off. Furthermore, casual application
of the topical psoralen will cause melanogenesis of the margin of the vitiligo
macule. The white macule of vitiligo is thus highlighted by a deeply melanized
artifactual ring that further accentuates the cosmetic disfigurement.
Because of the high phototoxic potential of these compounds topically,
careful monitoring and constant-output light sources are required. This is obviously not easily obtained with sunlight.
Several studies have attested to the success of topical psoralen therapy
despite the difficulties. Fulton et al. [688] used topical 8-MOP 0.1% and longwave ultraviolet radiation once weekly in 15 patients of whom 14 improved.
Delayed erythema was observed but severe adverse reactions were not observed.
Africk and Fulton [668] used TMP lotion and sunlight exposure to repigment
19 of 20 patients. The TMP was incorporated in a vehicle containing a UVB
sunscreen, benzyl salicylate, to help prevent blistering from the sunburn spectrum of light. Severe erythema occurred in two patients but none experienced
severe blistering.
It is possible that UV A treatment centers will allow use of psoralens topically. Regardless, after treatments the psoralen compound should be washed
off and a topical UV A sunscreen applied.
In patients with only small areas of vitiligo, even if they accept oral or
topical psoralens, cosmetics can be applied daily or stains can be applied every
several days. We have observed one patient who was able to repigment with
psoralens and UVA while she covered the macules with Dy-O-Derm. But if the
dyes are not fully removed prior to phototherapy treatment, mild to marked
impairment of repigmentation will occur.
Acute Side Effects of Psoralen Therapy. In therapeutic doses, psoralens
are well tolerated by most individuals. However, in some instances, pruritus,
mild epigastric discomfort, nausea, insomnia, nervousness, fatigue, and drowsiness have been observed. Nausea and pruritus appear to be more common
with 8-MOP than with TMP. The nausea may last only several hours after
ingestion and may be diminished by split dosage (ingestion of half the dosage
one-half hour after the first), ingestion with food or milk, or concomitant use
of nonphototoxic antiemetics, such as trimethobenzamide HCI (Tigan). The
pruritus may be more intractable and persist well after the treatment time. If
emollients do not provide adequate relief, use of oral hydroxyzine (Atarax,
Vistoril) is usually successful.
Chronic Side Effects of Psoralen Therapy. Cutaneous chronic phototoxicity is common with repeated use of oral 8-MOP, more than with TMP or
psoralen in equivalent dosages. These changes include erythema, lichenification, desquamation, and telangiectasia. The changes usually are reversible once
the treatments are discontinued. Freckling of normal skin also occurs; the
reversibility of this is not yet established.
There are three unresolved concerns of chronic toxicity of psoralens plus
ultraviolet radiation:
1. Carcinogenesis. Both squamous cell carcinoma and fibrosarcoma have

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GENETIC AND
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CHAPTER 1

been found to develop in mice that receive large doses of 8-MOP and intense
ultraviolet radiation [689,690], particularly if the drug was administered intraperitoneally [691]. It is the question of probability of tumors in humans that
troubles many. Certainly in experimental situations PUVA is capable of causing
inhibition of DNA synthesis, mutations, chromosomal aberrations, and cell
transformations [692,693]. Some patients with xeroderma pigmentosum developed skin tumors within a month of initiation of therapy and one patient
developed a lymphatic leukemia. Stern et al. [694] reported an increased formation of squamous cell carcinomas in psoriatics treated over two years with
PUVA, a finding not confirmed by Roenigk et al. [695] who found no increased
incidence. No increase in the number of melanomas or basal cell carcinomas
was reported by either group. Whether PUVA may act as an inducer or a
promoter in animals or humans is unsettled. However, in one study in which
ultraviolet-induced tumors were transplanted to syngeneic mice, tumors grew
in those treated with PUVA but not in the untreated mice [696]. This suggests
that immunosuppression may be important and that, as suggested by Bridges
and Strauss [697], the immune surveillance concept may be viable for skin.
Nevertheless, the paucity of reports of tumors in PUVA-treated vitiligo
patients is curious in light of the long history of its use. It may be that PUVA
is a promotor and that in the absence of use of therapeutic modalities common
to psoriatics (tar plus UVB) or of x-ray therapy, the risk is minimal. Nevertheless, we recently have seen two Type III patients with actinic keratoses. Both
patients had lesions on the legs; one had developed a squamous cell carcinoma
in one of these lesions. Both patients had also received large amounts of UVB
in their early lives.
In a 54-month follow-up study of 230 East Indian patients treated with
sunlight and 8-MOP (0.3-0.6 mg/kg), TMP (0.8-3.6 mg/kg), or psoralen (10.6-1.2
mg/kg), 13% developed discrete lesions in remaining vitiligo areas, particularly
on the lower legs. Seven percent had actinic keratoses but there were no squamous cell carcinomas, basal cell carcinomas, or melanomas [698]. None of these
lesions had been present at two-and-one-half-year follow-up. The occurrence
of these lesions cannot be clearly attributed to PUVA, UVB, or both, but it does
make it imperative that all patients be examined routinely during and after
therapy. Furthermore, there should be a UVA cumulative dosage limit such as
3,000 to 5,000 J/cm2/lifetime/person.
2. Ocular Toxicity. Because of the optical properties of the anterior segment
of the eye, UVA is absorbed by the lens. There is experimental evidence linking
psoralens and UVA to effects of ocular photosensitization. Guinea pigs fed 88
mg/kg 8-MOP were found to have photosensitization injury, particularly in the
320 to 340 nm range. Animal model system differences were demonstrated in
that the injury threshold was 25 mg/kg for guinea pigs, but 200 mg/kg for rabbits
[699].
Although cataract formation has been reported in albino mice [700], albino
guinea pigs, and rabbits [699] following administration of very high doses of
8-MOP and exposure to ultraviolet radiation, the doses of 8-MOP and ultraviolet
radiation used in these ocular experiments were more than 100-fold greater
than those currently in therapeutic use in humans. Intraperitoneal injection of
8-MOP in rats is followed by phosphorescence of the lens, indicating presence

of 8-MOP in the lens as early as two hours but not beyond 24 hours after
injection. That the phosphorescence emission is decreased by ultraviolet exposure suggests 8-MOP is metabolized in the lens [701]. Furthermore, the visible/ultraviolet radiation-induced increased fluorescence at 440 nm is enhanced
by prior intraperitoneal injection of 8-MOP.
Pigmented rats fed oral 3H-8-MOP were found to have high levels of radioactivity in the retina, ciliary body, and iris within an hour of ingestion.
Levels were detected in the cornea but little was found in the lens [702].
Incubation of whole lens in 8-MOP-containing medium followed by UVA
exposure is followed by diffuse nuclear labeling of lens epithelial cells [703].
Such unscheduled DNA repair synthesis may result in abnormal macromolecular and membrane synthesis, abnormal cell differentiation, and crystalline
production, all potentially with a resultant decrease in visible light transmission [704]. Other agents, such as ionizing radiation and alkylating agents, which
similarly damage DNA in lens epithelium, cause cataracts, but there is evidence
such effects may be reversible by repair mechanisms [705,706]. Because of
anatomic considerations and lens epithelial cell kinetics, there may be considerable delay in development of lens opacities following the ultraviolet insult.
Methoxsalen also interacts with lens protein in another fashion. The triplet
psoralen state may be quenched by various amino acids, namely tryptophan
[707]. 8-MOP also forms stable cyclobutane photo ad ducts with lens protein in
vitro; such extracellular binding may be relatively long-lasting [708].
Dosimetry clearly is an important consideration. Doses of UV A and 8-MOP
that do not result in acute or chronic phototoxic reactions to the skin do not
appear to change the lens. Guinea pigs administered 0.5 mg/kg 8-MOP intraperitoneally and exposed to 10 hours of F40 BLB (UVA) at 10 inches had no
ocular abnormalities (based on gross ophthalmologic examination, slit-lamp
examination, and histology) [709].
In another study, four groups of female Dutch belted rabbits were fed 12
mg/kg 8-MOP or placebo and exposed to two or eight hours of UV A five times
weekly for 18 months. All animals showed signs of acute and chronic phototoxicity. No cataracts were observed on repeated examinations of these animals
[710].
In a study of 1000 psoriatics treated with PUV A for two years, there was
no increased incidence of cataracts (R.S. Stern, personal communication). One
report of cataracts in a 42-year-old woman treated with oral 8-MOP is seriously
marred by the absence of baseline ophthalmologic examination; since the lens
opacities were not causing visual symptoms and the patient had no prior examination, it is impossible to exclude antecedent presence [711]. There are no
other reports of cataract formation in patients with vitiligo who have been
treated with large doses of psoralens [650]. One study from Scandinavia has
shown no cataracts among 13 vitiligo patients treated with 8-MOP for up to 12
years [712]. Another study [713] also showed no abnormalities in 15 patients
aged 20 to 40 treated five to 23 years. No eye protection had been used by either
group.
3. Lymphocyte Function. Studies of Morison and Parrish [714] have shown
PUVA caused localized and systemic suppression of delayed hypersensitivity
in guinea pigs; both induction and elicitation were affected.

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GENETIC AND
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282
CHAPTER 1

Increased vascular permeability with albumin leakage has also been demonstrated after short-term PUVA therapy [715].
Laboratory Abnormalities. Extensive clinical studies over the past 25
years have found orally administered 8-MOP and TMP to be virtually nontoxic
in humans [716]. Extensive clinical use of these substances has produced no
evidence of hepatotoxicity [717,718]. In over 365 patients followed up to 40
months, no liver function test abnormalities were observed (personal observations).
Increase of Tolerance to Sunlight. A curious observation is that after
several PUVA treatments many patients observe that their vitiliginous macules
have developed an increased tolerance to UVB. This increased tolerance has
been observed with 8-MOP and TMP and occurs before or independent of
repigmentation of the vitiligo areas [31,684,719]. The same phenomenon has
also been observed by normal individuals [593,684,720] and by albinos [721],
but has not been scientifically studied in double-blind trials.
Electron microscopy observations [664] suggest that the combination of
ultraviolet irradiation and psoralen accelerated keratinization. It is possible,
therefore, that the protection against severe sunburn reaction and the increased
ultraviolet tolerance is due to an increased thickness of the stratum corneum
in the vitiliginous macules [6].
Topical and Intralesional Corticosteroids
The use of topical and intradermal corticosteroids has been received with
mixed enthusiasm.
Kandil [722] treated 63 vitiligo patients with 0.2% betamethasone-17-valerate in flexible collodion. Twice-daily applications resulted in complete repigmentation of some or all macules in 28 patients. Kandil [723] also used
0.1% betamethasone-17-valerate in isopropyl alcohol. Koopmans-Van Dorp et
al. [724] employed 0.2% betamethasone-17-valerate in DMSO (43%) in a cream
base in 21 patients. Both diffuse and perifollicular repigmentation was observed
in 18, none of whom repigmented 90% or more. Bleehen [725] treated 20 vitiligo
patients with either betamethasone-17-valerate (0.1%) or with clobetasol propionate (0.05%). After three months of treatment, he observed partial repigmentation in only four patients. Light and electron microscopic study of the
repigmented areas showed dopa-positive melanocytes containing many melanosomes of normal size, shape, and melanization. El Mofty and Nada [726],
using betamethasone-17-valerate in collodion, found that none of their patients
treated with topical steroids alone had any response to this therapy. Clayton
found excellent results with two of 23 patients and limited results with another
10 treated with topical clobetasol propionate for four months; all developed
dermal atrophy [727]. However, in a double-blind multicenter study Seiji et al.
[7281 found 0.05% fluocinonide cream more effective than placebo in eight of
12 weeks of therapy. But there was no difference after four months. Atrophy
occurred in three of 108 cases. According to these authors no better response
was observed in those using PUVA than in those not using it, although the
latter group was small. Prolonged use of topical steroids may result in undesirable steroid atrophy, striae, and disfiguring telangiectasia. This makes steroid

therapy using stronger preparations for facial vitiliginous lesions inadvisable.

Iatrogenic Cushing syndrome has not been reported in any of the series.
Intralesional corticosteroids have also been reported to induce repigmentation in vitiliginous macules. Kandil [729] used 10 mg weekly for five or six
weeks and found some repigmentation in most of 52 macules in 26 patients
so treated; he found over 90% repigmentation in 30 macules, satisfactory response in 15, atrophy after 10 months in four, and little progress without
atrophy in three. The atrophy observed in 17 patients lasted 10 or more months
in four of them. Curiously, Kandil noted these cases generally repigmented by
gradual increase of color; perifollicular dotting was the exception [730,731].
The mechanism for this last observation is not explained.
ACTH and oral steroids have been used. Gokhale and Gokhale [376] found
over 80% repigmentation in 16 of 27 patients treated with 25% to 40% ACTH
twice weekly for four to five weeks per course for up to four courses; several
of their patients had previously been unresponsive to psoralen photochemotherapy. Oral steroids resulted in 75% or more repigmentation in at least one
macule in six of 22 patients and 25% to 75% in another three patients; a response
was observed in four weeks and was particularly apparent on habitually sunexposed areas of skin [732]. Most of these patients had been previously treated
with psoralen, which is not nearly so effective as 8-MOP or TMP in vitiligo
repigmentation. Complete reversal of extensive vitiligo has been reported in
one patient taking 15 mg daily prednisone for polymyalgia rheumatica [733].
Use of systemic steroids has well-documented long-term side effects, many
of which are more serious than vitiligo. It is questionable whether the risk of
these side effects ever justifies the potential benefit, even in Eastern cultures.
Dopa
Attempts to treat vitiligo with L-dopa arose from the observations that dopa
is a precursor of melanin, and that Parkinson disease, in which neuromelanin
is lost from the substantia nigra, responds to L-dopa therapy. Woolfson and
Finn [734] used topical 10% to 20% L-dopa in fat alcohol/propylene glycol base
twice daily for eight to 20 weeks. Only four of the 16 patients treated with
topical L-dopa showed any improvement. Mishima and Tanay [735] showed
that systemic administration of a methyl dopa increases the number of dopapositive melanocytes in ultraviolet-irradiated human skin compared with controls subjected to ultraviolet irradiation alone. Goolamali [736] and Iparraguire
[737] reported repigmentation of vitiliginous macules treated with L-dopa for
one to four months. But there was also improvement in a group treated with
L-dopa, 8-MOP, and sunlight. Gonin [738] noted finally that because of mediocre
results he has also abandoned L-dopa therapy.
Quinacrine
Gokhale [739] reported successful repigmentation of vitiligo macules with
quinacrine HCl 0.1 mg two to three times daily for eight to 12 weeks in 22
patients. He found a significant increase in the plasma cortisol levels after
therapy and attributed the repigmentation to steroid effect.

283

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284

Thiambutosine BP

CHAPTER 1

Verbov [740], in 1972, reported a trial of CIBA 1906 (Thiambutosine BP)

in five Caucasians with vitiligo. He reported results after five to 12 months of
therapy to be "disappointing" and stated that "further evaluation of this drug
in vitiligo is (not) warranted."
Clofazimine
Bor et al. [741] reported up to 80% repigmentation in seven of eight females
treated with a phenazine dye, clofazimine, and natural sunlight. In one patient
biopsied before and after therapy, curiously no melanocytes were found in
repigmented skin; the author suggested melanin migrates from border functioning melanocytes or hair follicles. This finding has never otherwise been
observed in repigmented skin and is contrary to the concept of the epidermal
melanin unit.
Permanent Depigmentation of the Remaining Normally Pigmented Skin

If more than 50% of the skin is depigmented and the patient has failed
with, cannot, or does not wish ever to undergo psoralen photochemotherapy
to repigment, a uniform color may be attained by deliberate, permanent chemical depigmentation of the normally pigmented areas; this may be done by
twice daily applications of 20% monobenzylether of hydroquinone (MBEH) in
an ointment base (Benoquin). The patient must understand that the depigmentation is irreversible. The depigmentation usually takes several months to
appear, a year to complete [742], and is effective in almost every patient. Depigmentation of eyes and hair does not occur, and the patients are usually very
satisfied with the cosmetic results. The newly depigmented skin must be protected against UVB burn by application of an effective sunscreen preparation.
The use of MBEH cream (Benoquin) has been reported in a retrospective
study of 18 patients with extensive vitiligo [742] (Figs. 98, 99). Of these 18
patients (16 Caucasian and two blacks), eight experienced complete depigmentation. Of those who depigmented fully, some hypopigmentation was first
noted within one to six months (average, under three months) of institution of
therapy, and full depigmentation was achieved in four to 12 months. All those
who depigmented fully were very pleased with their results. However, the
incidence of side effects of this therapy (subjective burning and itching, erythema or rash, dryness, contact dermatitis, and edema) was high. Only seven
patients reported no such complaints. The authors concluded that MBEH is a
useful agent for those vitiligo patients who wish to be one color and who can
accept the emotional and physical limitations of such a decision. The following
guidelines for the use of MBEH are suggested:
desire of permanent depigmentation in a patient with vitiligo;
(2) age over 40;
(3) more than 50% of the skin depigmented;
(4) willingness to accept the fact the repigmentation will no longer be
possible.
(1)

285

GENETIC AND
CONGENITAL
DISORDERS

FIGURE 98. a: This woman with very extensive vitiligo is an ideal candidate for Benoquin therapy.
Once undertaken, Benoquin therapy should be considered irreversible. b: Benoquin may give
satellite depigmentation as occurred in this patient. This is usually irreversible depigmentation
and not responsive to psoralen photo chemotherapy.

FIGURE 99. Benoquin depigmentation. a: Legs of woman with extensive vitiligo prior to institution of Benoquin therapy. b: After six months of Benoquin usage, the skin is fully amelanotic.
No obvious evidence of vitiligo remains and the skin has an alabaster color.

286
CHAPTER 1

Occasional macules of repigmentation may appear and require periodic

retreatment. We have subsequently found one patient who appears refractory
to MBEH depigmentation.
Use of another depigmenting formulation has been described. In two black
patients with extensive longstanding vitiligo, a formula consisting of 0.1%
tretinoin, 5% hydroquinone, and 0.1 % dexamethasone in hydrophylic ointment
was used to depigment the normally pigmented skin. Depigmentation was
complete in nine and 11 weeks, respectively. Both patients seemed pleased.
Although depigmentation with this therapy is temporary, not permanent [743],
particularly for Skin Types II or III, the achieved color match may be satisfactory. During sun exposure, a broad-spectrum sunscreen is required to prevent
melanogenesis which would again increase the contrast.

REFERENCES
1. Goldman L et al: White spots in Biblical times. Arch Dermatol 93:744-753, 1966
2. Kaposi M: On albinismus and leucoderma, in On Diseases of the Skin, vol III. Edited by F
Hebra, M Kaposi. London, New Sydenham Society, 1874, pp 170-177
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34:274-281, 1971
738. Gonin J: Traitment du vitiligo par la L-Dopa. Nouv Press Med 3:151, 1974
739. Gokhale BB: Vitiligo and anti-malarials (letter). Int J Dermatol17:843, 1978
740. Verbov J: Use of CIBA 1906 (Thiambutasine BP) in vitiligo. Br J Dermatol 87:81-82, 1972
741. Bor S et al: Vitiligo and its aetiological relationship to organ specific autoimmune disease.
Br J Dermatol 81:83-88, 1969
742. Mosher DB et al: Monobenzylether of hydroquinone: a retrospective study of 18 severely
affected vitiligo patients. Br J Dermatol 97:669-679, 1977
743. Kligman AM, Willis I: A new formula for depigmenting human skin. Arch Dermatolll1:40-48,
1975

PIEBALDISM
There is a painting in the Paris Museum by Le Masurier of a mulatto aged two years
with the white forelock and white spotting of partial albinism (1).

Piebaldism is an autosomal dominant congenital leukoderma characterized

by localized stable hypo melanosis of the skin and hair, and by a characteristic
distribution that involves the anterior trunk, extremities, the central portion of
the eyebrows, and the midfrontal portion of the scalp with resultant white
forelock.

Nomenclature
Piebaldism has historically been described under many different names.

It has been called "albinismus circumscriptus," "partial albinism," "local al-

binism," "albinoidism," "congenital achromia," "congenital vitiligo," "poikilochromia alba," "white spotting," and "piebaldism" [2-9]. It is now well established that this condition is not related to generalized albinism, and that the
commonly used term "partial albinism" is inappropriate. Since there is in
animals a similar inherited white spotting called "piebaldism," this term seems
most appropriate to designate this syndrome in humans.

History
Piebaldism dates from the classical Greek and Roman literature [7]. Lucian
mentioned a man from Egypt "one-half absolutely coal black and the other half
unusually snow white, the two colors evenly distributed." Philostratus, in Life
of Apponius, described an Indian woman "black from head to chest, white
from chest to feet." These two descriptions may represent the earliest reported
cases of piebaldism. Probably many persons with piebaldism were chosen as
slaves, coliseum curiosities, and gladiators during the Roman period as a direct
result of their striking pigmentary abnormality.

The first extensive work on piebaldism appears to be that of Simon [10]

in 1861, who collected 32 cases from 1698 to the mid-19th century. Most of
these cases were blacks in whom the trait was most striking. It is possible that
some cases described were, in fact, "vitiligo." In 1855, von Biirensprung [2]
reported six cases and suggested the term "partial albinism" to distinguish that
condition from vitiligo and other acquired leukodermas. In 1913, Pearson et
al. [7] reviewed the literature from the 18th and 19th centuries (Table 79). A
comprehensive history of the study of piebaldism may be found in the extensive
bibliographic studies of Pearson et al. [7] (Fig. 100), or Froggatt [4], and in the
general review of Cooke [3].
The earliest mention of familial occurrence of piebaldism may be found
in the paper of Morgan [11] who described a two-year-old mulatto with white
forelock and white spotting of the chest, abdomen, arms, and legs. This same
child was described by Arthaud [12] in 1789, and can be seen in a 1782 painting
by Le Masurier displayed in the Paris Museum. He also appears to be the subject
of a wax statuette in the Warren Anatomical Museum at the Harvard Medical
School (Fig. 101). The child's father and the father's brother and mother were
said to be similarly marked. In 1871, Berger [13] cited seven members of a
family with a white forelock. The first extensive family study was that of Rizzoli
[14] who described 38 piebalds among 111 members of five generations of the
Bianconini (literally "white lock") family. This pedigree had been recorded by
Mazzini [15].
Froggatt [4], in 1959, summarized the 31 classical piebald families reported
between 1871 and 1955 (Table 80). Among these, the pedigrees and histories
of two piebald families merit particular mention. In the family reported by
Miller in 1915 [16], it is possible that the piebald trait may have existed for
over 500 years. This family claimed descent from Elisabeth Mortimer, a granddaughter of Edward III. According to legend, Elisabeth, on hearing of the death
of her husband, Sir Harry Percy (Hotspur), at the Battle of Shrewsbury in 1403,
was so grief stricken that her child was born with a prominent white forelock.

TABLE 79. Isolated Piebald Black Cases of the 18th and 19th CenturiesO

Case
no.
1
2
3
4
5
6
7
8
9
a

Name of case

Sex

Gumilla's case
La Mathe's case
Bluemenbach's case
"Jean-Pierre"
"Adelaide"
Da Rocha's pied girl
Richardson's spotted boy
Darwin's case
Wilson's case

F
M
M
M
F
F
M
M
F

Date
reported (R)
or
born (B)
(R)
(R)
(B)
(B)
(B)
(R)

1743
1752
1774
1782
1783
1785
1808-1813
1872-1878
(R) 1878

Investigator
Pearson (1913)
Pearson (1913)
Granger (1804)
Morgan (1786)
Morgan (1786)
Arthaud (1789)
Pearson (1913)
Wilson (1878)
Wilson (1878)

Source: Froggatt P: An outline, with bibliography, of human piebaldism and white forelock. Ir J Med Sci
398:86-94, 1959. Used with permission.

311

GENETIC AND
CONGENITAL
DISORDERS

312

CHAPTER 1

FIGURE 100. Picture of a young

piebald black girl by Buffon.
(From: Pearson K et al: A Monograph on Albinism in Man: Drapers' Company Research Memoirs. Biometric Series VI, Atlas,
Part I. London, Dulau, 1911.)

Another family, the Anderson family, probably carries one of the most famous
pigment anomalies in existence. The original mutant, a black woman born in
Louisiana in 1848, married a normally pigmented black and bore 15 children,
eight piebald and seven normal. Three of the eight piebald children married
and had nine piebalds and two normal offspring. Several of the Anderson
children were exhibited in Barnum and Bailey's circus throughout America
and Europe and have been described in the medical literature of various countries. In 1896, Maass [17] was the first to attempt to establish the pedigree of
this family. Gould and Pyle [18], in 1897, illustrated three of the Anderson
children as "The Leopard Family" but labeled their condition "vitiligo." In
1901, Neveu-Lemaire [19] published a photograph of a piebald black woman
who probably is also a member of this family. Baudouin [20], in 1905, and Levi
[21], in 1909, extended and published this pedigree. Pearson et al. [7] also
mentioned this family in their monograph. A photograph of the "Three Striped
Graces" (Anderson children) was reproduced in 1910 in the British Medical

313

GENETIC AND
CONGENITAL
DISORDERS

FIGURE 101. Wax model of the piebald black girl from St. Lucia (Warren Anatomical Museum
at the Harvard Medical School, Boston, Massachusetts). (From: Pearson K et al: A Monograph on
Albinism in Man: Drapers' Company Research Memoirs. Biometric Series VI, Atlas, Part I. London,
Dulau, 1911.)

Journal by Hutchinson [22] (Fig. 102). Frassetto [23] and Simpson and Castle
[24] published further reports and photographs. The most recent pedigree of
this family was collected in 1934 by Keeler [25].
Some other papers from the 20th century mentioned classical piebalds but
the family data are minimal or absent (Table 81). Table 82 summarizes the
cases reported since 1960.

Clinical Features (Table 83)

Incidence
Piebaldism is not a common disorder. The exact incidence is unknown
but Pearson et al. [7] believed piebaldism to be as common as "total albinism."
Witkop [35] estimates piebaldism to be rarer than oculocutaneous albinism,
thus less than 1:20,000. According to Froggatt [4], this may be due to a low
mutation rate and to the probable social pressure against the heterozygote,
certainly in the dark-skinned races.

314

CHAPTER 1

TABLE 80. Classical Piebald Families Reported since 1871 and in Which Pedigrees
Have Been Publisheda
Case
no.
1
2
3
4
5
6
7
8
9
10
11

12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
Q

Family designation
Berger's family
Rizzoli's family
Baader's family
Harman's family
Florence Bay family
Cane's family
Jones' family
Cockayne's 1st Suffolk
Miller's family
Barton's family
Zsako's family
Mazzini's 2nd family
Meirowsky's family
Pardo-Costello's family
Meirowsky and
Spickernagel's family
Gunther's family
Cockayne's 3rd family
Sanders' 1st family
Anderson family
Sanders' 2nd family
Sanders' 3rd family
Cockayne's 2nd Suffolk
Frant's family
Fitch's family
Nussey's family
Sundfor's family
Cromwell's family
Cooke's 1st family
Cooke's 2nd family
Jahr's family
Smith and Schultz's family

Nationality
or race
German
Italian
Swiss
English
Negro
English
English
English
English-American
English
Hungarian
Italian
German
Spanish-Cuban
German
German
English
Dutch
Negro
Dutch
Dutch
English
Dutch
American
English
Norwegian
Mulatto
American
American
Negro
American

Investigator
Berger (1871)
Rizzoli (1878)
Baader (1883)
Harman (1909)
Stannus (1913)
Cane (1912)
Jones (1913)
Cockayne (1914)
Miller (1915)
Pearson (1920)
Zsako (1923)
Mazzini (1923)
Meirowsky (1925)
Pardo-Costello (1926)
Meirowsky and Spickernagel
(1926)
Gunther (1932)
Cockayne (1933)
Sanders (1934)
Keeler (1934)
Sanders (1935)
Sanders (1935)
Cockayne (1935)
Frant (1937)
Fitch (1937)
Nussey (1938)
Sundfor (1939)
Cromwell (1940)
Cooke (1952)
Cooke (1952)
Jahr and McIntire (1954)
Smith and Schultz (1955)

Source: Froggatt P: An outline, with bibliography, of human piebaldism and white forelock. Ir J Med Sci
398:86-94,1959. Used with permission.

Race

Piebaldism has been found in various races and in widely separated parts
of the world. No race appears to be spared, and black, Caucasian, and Mongoloid
piebalds have been reported.
Sex

Both sexes are equally affected [3]. As would be expected from an autosomal dominant inheritance pattern, among the 108 patients collectively reported by Cooke [3], Smith and Schultz [1], Comings and Odland [29], and Van
Velde [9], the overall female to male ratio was 54 to 54.

TABLE 81. Classical Piebald Families with Minimal Pedigree Information and
Individual Piebalds of the 20th Centurya
Case
no.
1
2
3
4
5
6
7
8

9
10
11
a

Designation
La Vallois' Martinique
family (19th century)
Emslies' negro family
(19th century)
The Cape Verte family
The Loyalty Islands case
The Papuan piebald
The Honduras piebald
Maynard's negro piebald
Dengler's two cases
European family
Sorsby's cases
Germeraard's family

Nationality
or race

Investigator

Mulatto

Cockayne (1933)

Negro

Cockayne (1933)

Negro
Negro
Papuan
Negro
Negro
American
European
English
Dutch

Neveu-Lemaire (1901)
Fram;ois (1901)
Seligmann (1902)
Blanchard (1910)
Maynard (1914)
Dengler (1925)
Hollander and Schmitt (1933)
Sorsby (1953)
Sorsby (1953)

Source: Froggatt P: An outline, with bibliography, of human piebaldism and white forelock . Ir ] Med Sci
398:86-94, 1959. Used with permission.

The Three Striped Graces. (From Sir J. Hutchinson, Pro Neisser, reproduced by
Pearson K et al: A Monograph on Albinism in Man: Drapers' Company Research Memoirs. Biometric
Series VI, Atlas, Part I. London, Dulau, 1911.)

FIGURE 102.

315
GENETIC AND
CONGENITAL
DISORDERS

TABLE 82. Piebald Patients Reported since 1960

316

CHAPTER 1

Number of cases

Number of
families

Generations

Total

Female

Male

1
1

4
5

6
19

3
7

3
12

24

12

12

Reference
Ansari (1960) [26]
Kugelman and Lerner
(1961) [27]
Campbell and Swift
(1962) [28]
Comings and Odland
(1966) [29]
Grupper et a1. (1970) [30]
Telfer et a1. (1971) [31]
Van Velde (1972) [9]
Funderburk and Crandall
(1974) [32]
Bonerandi et a1. (1976)
[33]
Marchand (1976) [34]

1
2 {Family A
Family B
2 {Family A
Family B
1

11

2
32
6
1

16
1

4
1

2
3
2
16
5

3
1

10

TABLE 83. Clinical Aspects of Depigmentation in

Piebaldism
Frequency
Inheritance
Age of onset
Clinical description
Distribution
Color
Topography
Skin
Hair
Mucous membrane
Size/shape/extent
Borders
Symptoms
Progression
Repigmentation
Associated dermatologic
findings
Associated eye, ear, and
neurologic
abnormalities

Rare
Autosomal dominant
Birth
Bilateral-symmetrical
Chalk white with hyperpigmented
macules in white areas
Trunk (anterior and lateral with
middorsal sparing)
White forelock; body hair or other
scalp hair may be involved
Rarely involved
Variable
Irregular, well-delineated
None
None
None
Hyperpigmented macules on areas of
normally pigmented skin
None

Age

317

Although the lesions are present at birth, occasionally the depigmentation

may not initially be apparent in fair-skinned babies. In one of the patients of
Smith and Schultz [1], the skin at birth was said to be pink and normal. Yet,
during the second week of life, depigmentation of the skin and a white forelock
were noted.

Heredity
Piebaldism is inherited as an autosomal dominant trait. Cooke [3] summarized 23 families in the literature and noted that when a parent had the trait,
it was transmitted to more than half of the 796 children (53.2%), while of the
more than 474 children of unaffected parents, only 15 (3.4%) were piebald.
Cooke concluded that among piebald pedigrees, unaffected parents generally
do not transmit piebaldism to their children. Thus, a child of an unaffected
member in a piebald family is unlikely to be affected.
Families with affected members in four [1,15,36-42]' five [8,9,14,16,31]'
or six or seven [28,29,43] generations are not uncommon (Figs. 103, 104). It is
clear that the trait is transmitted as an autosomal dominant pattern with a very
high degree of penetrance and that those descendants who are free of the
affection do not carry or transmit the trait to their offspring.
Chromosomal studies in two patients with piebaldism have been reported.
Funderburk and Crandall [32] reported a three-year-old child with piebaldism
and marked growth and mental retardation. His parents had no pigmentary
abnormalities. The authors attributed these features to a reciprocal translocation
between chromosomes 4 and 15, with a single band deletion from chromosome
4, just proximal to the site of the translocation. Although the dominant piebald
trait may be a coincidental mutational change, it may result from translocation,

o
1I!r

I!II-Gr
I

=.::=.~~~

....,........

UNltfH'tO

~ BrCil"" ft

iIW - Gr.,
...........

FIGURE 103. The pedigree of a piebald family. (From: Comings DE, Odland GF: Partial albinism.
JAMA 195:519-523,1966. Copyright, 1966, American Medical Association. Used with permission.)

GENETIC AND
CONGENITAL
DISORDERS

318

CHAPTER 1

FIGURE 104. A piebald family. The mother (left) and three affected daughters. Only the middle
subject is unaffected. (From: Telfer MA et al: Dominant piebald trait (white forelock and leukoderma) with neurological impairment. Am J Hum Genet 23:383-389.1971. Copyright. 1971. The
University of Chicago Press.)

deletion, or both. However, Telfer et al. [31] described a patient with normal
chromosomal studies.

Clinical Description
The White Forelock

The white forelock, present in 80% to 90% of the patients [3] (Fig. 105),
is the most familiar feature of piebaldism. It is present at birth and is usually
first observed at birth or soon thereafter. All the hairs of the forelock are hypopigmented as is the skin of the scalp. The hair color is reported to be white
or white-silver [30]. Therefore, in fair-haired patients, the poliosis may not be
apparent. According to Cooke [3], lack of hair pigment in scalp areas other than
midfrontal seems not to occur, but Pearson et al. [7] mentioned that a piebald
girl described by Usher had two tufts of white hair on the left side of the scalp
(parietal and occipital regions) and Telfer et al. [31] reported in one case a
small parietal tuft of white hair which, because of its small size, could possibly
have been overlooked. But in most instances where there is a white forelock,
the rest of the scalp hair is normal.
The hypopigmented area of the skin of the white forelock is well circumscribed and hyperpigmented borders have been observed [31] (Fig. 106). The
patch of skin from which the forelock arises is usually located in the midline
and is triangular, elongated, or diamond-shaped, and often symmetrical. The

319

GENETIC AND
CONGENITAL
DISORDERS

White forelock in
three patients with piebaldism.
(From: Telfer MA et al: Dominant
piebald trait (white forelock and
leukoderma) with neurological
impairment. Am J Hum Genet
23:383-389. 1971. Copyright,
1971, The University of Chicago
Press.)

FIGURE 105.

320

CHAPTER 1

FIGURE 106. Hyperpigmented

borders of hypopigmented macules. (From: Telfer MA et al:
Dominant piebald trait (white
forelock and leukoderma) with
neurological impairment. Am J
Hum Genet 23:383-389. 1971.
Copyright. 1971. The University
of Chicago Press.)

apex usually points posteriorly, and it can reach the bregma and the vertex. It
may extend forward to the root of the nose but the nose itself is rarely involved;
Grupper et al. [30], in their two cases, found the apex to be anterior and to
extend to the nose. The medial third of the eyebrows may be unilaterally or
bilaterally involved [29,31]. Involvement of eyelashes has also been reported
[29,31] .

Many authors have described patients with a white forelock under the
titles "white blaze," "poliosis circumscriptum," or "white forelock." But in
many of these cases, the clinical observations were limited to the localized
canities and the rest of the skin was not examined. Some well-known families,
for example, the Rohan family in France, were known to have a white forelock.
Some family names, like Whitlock, Horlock, Horlick, Silverlock, and Blaylock,
attest to the occurrence of this inherited white forelock. Is the white forelock
alone synonymous with piebaldism or can a classical white forelock occur
alone, as a separate genotype? Froggatt [4] quoted cases of isolated white fore-

lock in whom careful examination failed to show skin depigmentation. In the

Barton family, reported in 1920 by Pearson et a1. [7], there was no skin involvement in the two affected members examined, but a third was said to have
the classical body markings of piebaldism. Nussey [41], in 1938, reported a boy
with congenital white forelock but no skin involvement. Froggatt [4] thought
this case probably represented some variation in expression of the piebald
genotype. The fact that patients without a white forelock have been reported
supports the notion of phenotype variation [3]. However, no classical case of
isolated inherited white forelock has been reported in black-skinned people in
whom skin depigmentation, if present, is so apparent that it cannot be overlooked. Froggatt [4] thought it likely that isolated white forelock, if it exists, is
a particular phenotype expression of the piebald genotype and not a distinct
entity.
Pearson et a1. [7] reported the pedigree of a well-known family with an
occipital white lock that appeared to be carried only by females and to be
expressed in males; they noted that a family with white lock appearing apparently only in females on the left side of the head had been previously
reported in the literature. Such a trait with an inherited pattern different from
that of classical piebaldism might be considered a distinct entity.
Other Types of Hair Involvement
In the nine-year-old boy reported by Ansari [26], the scalp hair was chiefly
lighter in color but also contained a few patches of dark hair. No white forelock
was noted. His body hair was also light in color. Campbell and Swift [28]
described white hairs growing from tiny spots of depigmented skin around the
knees in one patient. White pubic hairs have been reported [29,31].
The Skin Depigmentation
Cutaneous depigmentation is usually associated with the white forelock
and it may be the only clinical finding in 10% to 20% of cases [3]. The white
macules are irregular in shape, well-circumscribed, and 1 to 5 cm in diameter
[30]. The macules are milk-white like those of vitiligo. An area of intermediate
color (like vitiligo trichrome) may border the normal amelanotic skin.
There are several features of the hypo pigmentation of piebaldism that distinguish it from vitiligo. The distribution is classically distinctive though both
conditions are often somewhat symmetrical. The anterior abdomen and the
ventral thorax (from the nipples to the iliac fossae) is the most common area
of hypopigmentation (Fig. 107), but the upper chest, from the throat extending
down over the clavicles, may be involved [3] (Fig. 108). The ventral areas of
amelanosis may extend laterally to the flank and the posterior chest wall, but
the central back classically is rarely involved [3,4,44,45] (Fig. 109). Telfer et
al. [31] and Keeler [25] each described a patient with a striking band of depigmentation girdling a large portion of the dorsal trunk, but sparing the dorsal
midline. Another patient of Telfer et a1. [31] had a dorsal leukoderma almost

321

GENETIC AND
CONGENITAL
DISORDERS

322

CHAPTER 1

FIGURE 107. Scattered lack of pigmentation on the chest. abdomen. and arms with hyperpigmented macules. (From: Telfer MA et al: Dominant piebald trait (white forelock and leukoderma)
with neurological impairment. Am J Hum Genet 23:383-389. 1971 . Copyright. 1971. The University
of Chicago Press .)

entirely restricted to the midline where three discrete areas of depigmentation

were present in a paravertebral position (Fig. 110). In one patient, Grupper et
al. [30] observed a large hypopigmented macule, oval in shape (12 by 18 cm)
on the dorsal trunk. Usually, however, the middorsal trunk is dramatically
spared.
The extremities are also commonly involved. The achromic areas occur
from mid upper arm to wrist and from midthigh to midcalf. both anteriorly
and posteriorly (Fig. 111). The hands, upper arms and shoulders, upper half
of thighs, and feet to midcalf remain normally pigmented [3]. Depigmentation
of the palms has been observed [26l. but involvement of the soles has never
been reported.

323

GENETIC AND
CONGENITAL
DISORDERS

HYPERPIGMENTED
MACUlES

FIGURE 108. Typical distribution pattern in piebaldism.

The face may show depigmentation in areas other than the white lock.
Occasionally, there is a white patch on the center of the chin [4,29,46]. The
white area over the anterior neck may extend upward to the lower part of the
chin [3].
Mucous membrane involvement has been reported. Ansari [26] described
depigmentation of the lips. Intraoral depigmentation of the anterior gingiva
may occur; these depigmented macules may be as randomly scattered as in the
hypopigmented skin [3].
Hyperpigmented Macules

Brown to dark-brown hyperpigmented macules, up to a centimeter or more

in diameter, are found within the piebald macules and on normally pigmented
skin. Smith and Schultz [1] described alternate patches of depigmentation,
normal pigmentation, and hyperpigmentation on the posterior and medial as-

324

CHAPTER 1

FIGURE 109. Classical sparing

of the central back. (From: Telfer
MA et al: Dominant piebald trait
(white forelock and leukoderma)
with neurological impairment.
Am J Hum Genet 23:383-389,
1971. Copyright, 1971, The University of Chicago Press.)

pects of the legs in one of their patients. They mentioned the occurrence of
these hyperpigmented macules in normally pigmented skin as well as in the
hypopigmented areas (Fig. 112). Grupper et al. [30] described a patient with
many hyperpigmented cafe-au-Iait macules, oval in shape, located on the dorsal
trunk; some of these hyperpigmented macules were quite large (2 by 4 em and
7 by 11 cm). Ansari [26] observed numerous darkly pigmented patches of
various size all over the body. Some of these were several centimeters in diameter. The pigmented patches were darkest on the legs, feet, neck, and dorsa
of the hands. These macules are thought to result from exposure to sunlight.
Associated Systemic Findings
Although there have been several isolated reports of associated neurologic
and ectodermal abnormalities, most patients with piebaldism are otherwise
well.
Several cases of piebaldism and heterochromia irides have been described.

325

GENETIC AND
CONGENITAL
DISORDERS

FIGURE 110. Atypical involvement with central dorsal white

macules. (From: Telfer MA et al:
Dominant piebald trait (white
forelock and leukoderma) with
neurological impairment. Am J
Hum Genet 23:383-389, 1971.
Copyright, 1971, The University
of Chicago Press.)

Cockayne [36] observed piebaldism and heterochromia irides in three members

of three successive generations of a piebald family. A case combining "albinism" of one iris (partial heterochromia), of the corresponding portion of the
eyelashes of the lower lid, of a patch of skin on the cheek, and of a tuft of hair
has been recorded by Stannius [47], and another of heterochromia of the irides
with two areas of very light head hair by Ahuja [48]. Three members of the
family reported by Comings and Odland [29] had heterochromia irides and
typical piebaldism. Other such patients were also observed by Van Velde [9]
and Duke-Elder [49].
It is difficult to appraise the significance of the combined occurrence of
only heterochromia irides and pigmentary abnormalities of the skin and hair.
Both types of abnormalities are features of the Waardenburg syndrome, and it
may legitimately be asked whether these patients have a forme fruste of Waardenburg syndrome, piebaldism associated by chance with heterochromia irides,
or a distinct genetic entity. Di George et al. [50], for example, reported as a case
of Waardenburg syndrome in a four-year-old black girl with heterochromia

326

CHAPTER 1

FIGURE 111. Involvement of the

legs with large normally pigmented
macules scattered in the hypomelanotic areas. (From: Telfer MA et al:
Dominant piebald trait (white forelock and leukoderma) with neurological impairment. Am J Hum Genet 23:383-389, 1971. Copyright,
1971, The University of Chicago
Press.)

irides, white forelock, marked circumscribed depigmentation of the skin, but

no dystopia canthorum; family history was negative except for early graying
of hair. One could alternatively call this piebaldism with heterochromia.
The same problem applies to the concurrence of deafness and piebaldism.
An eight-generation pedigree of piebaldism includes two deaf-mute piebalds
[15,40]. Comings and Odland [29] noted that occasional members of their piebald family were "hard of hearing"; however, those with slight deafness were
not necessarily affected with piebaldism. Busti-Rosner [51] also reported the
association of leukoderma and deaf-mutism, as did Campbell et al. [52], Woolf
et al. [46], and Reed et al. [53]. Some observers consider it to be unlikely that
the piebaldism and the deafness represented separate genetic defects, but suggest a distinct genetic entity with autosomal dominant inheritance [see "Piebaldism with Deafness (Woolf Syndrome)" later in this chapter].

327

GENETIC AND
CONGENITAL
DISORDERS

FIGURE 112. Hyperpigmented macules overlaying normal skin and in piebald macules.

The cases of Urbantschitsch [54] and Van Gilse [55], in which skin and
hair depigmentation was associated with heterochromia irides and deafness,
most likely represent instances of Waardenburg syndrome in which dystopia
canthorum was not expressed.
Piebaldism has also been reported in association with multiple systemic
abnormalities, particularly neurologic impairment. Franceschetti et al. [56] reported deafness and mental retardation with white forelock, depigmentation
of the forehead, trunk, and distal limbs. Funderburk and Crandall [32] reported
a four-year-old boy with mental retardation, short stature, and typical piebaldism associated with chromosomal abnormalities. Neurosensory hearing loss,
cerebellar ataxia, impaired motor coordination, and mental retardation of variable severity were described in two Pennsylvania families [31] with white
forelock in the typically affected individuals, a minute parietal white tuft in
one individual, and leukoderma of the dorsal as well as of the ventral trunk.
Unaffected individuals of these kindreds did not display hearing loss. Nonpiebald family members had neither ataxia nor impaired motor coordination.
The presence of these manifestations in only two piebalds in the family could

328

CHAPTER 1

be fortuitous. None of these patients showed dystopia canthorum, heterochromia irides, or fundus abnormalities.
In these patients, one possible explanation of the concomitant occurrence
of neurologic and cutaneous pigmentary disorders is a mutation at the neural
crest level. Such mutants are known to occur in mice, and it has been shown
that several mechanisms can lead to piebald spotting [57]. Perhaps, in these
rare patients, the mechanism of cutaneous spotting is different from that of
piebaldism without associated neurologic impairment because the mutant gene
in the latter might act at a different developmental anatomic level than the
neural crest.
Piebaldism has been reported in association with Hirschsprung disease
[57a]. This can perhaps be explained on embryologic grounds. Neural crest
cells give rise to melanocytes and intravisceral ganglia. Defective embryonic
migration of the neural crest cells could explain absence of cutaneous melanocytes, on one hand, and of ganglion cells on the other. This association could
be homologous with that noted in piebald mice with megacolon [57b].

Histology and Electron Microscopy

Light Microscopy
The Hypomelanotic Skin
Melanin is absent [28,29] from skin and hair bulbs (Fig. 113).
In the skin, the dopa reaction is negative [28,58] and no melanocytes are
found [29,58]. In early histologic studies, Kugelman and Lerner [27] observed
clear cells or melanocytes to be normal in number and in morphology at the
basal layer. Comings and Odland [29] noted a moderate increase in the number
of suprabasal clear cells or Langerhans cells. The transition between hypomelanotic and normal skin is usually distinct and readily visible [28]. However,
Grupper et al. [30] observed no clear-cut transition zone with either dopa or
silver stains; they described a succession of depigmented, hypopigmented, and
normally pigmented zones. In the clinically hyperpigmented borders observed
by Comings and Odland [29], melanocytes were present, melanin was increased, and there was a normal number of suprabasal clear cells.
The hair bulbs of the white forelock are tyrosinase-negative and contain
no dopa-positive melanocytes [58].
The Hypermelanotic Macules
In the hypermelanotic macules in the center of the hypomelanotic skin,
there is a normal number of dopa-positive melanocytes which have a welldeveloped perikaryon [58].
The Normal Skin
The normal skin has a normal melanin content [28,29]. Dopa reaction is
positive [28-30]. Melanocytes and suprabasal clear cells are present in normal
numbers [29].

329

GENETIC AND
CONGENITAL
DISORDERS

FIGURE 113. A melanocyte (MC) found in the hypomelanotic skin of a patient with piebaldism.
a: Abnormal indentation of the nucleus (N). No melanosomes were transferred into the keratinocytes. (x 4900). b: A high-power view of a melanocyte showing abnormal spherical melanosomes
(SM) and normal ellipsoidal melanosomes (EM). Both types of melanosomes are in unmelanized
stages (x 67,000). (From: Jimbow K et al: Congenital circumscribed hypomelanosis: a characterization based on electron microscopic study of tuberous sclerosis, nevus depigmentosus and piebaldism. J Invest Dermoto1 64:50-62, 1975. Copyright, 1975, The Williams & Wilkins Company.
Used with permission.)

Electron Microscopy

The Hypomelanotic Skin

Few or no melanocytes are present [59,60]. Comings and Odland [29] reported an absence of melanosomes and melanocytes in these hypomelanotic
areas. Grupper et al. [30] reported the presence of rare melanocytes. Breathnach
et al. [61] described cells with indented nuclei, diffusely granulated cytoplasm
cOhtaining a few partially melanized melanosomes, and peculiar rounded granules. These granules, almost invariably surrounded by a space, have an ill-

330

CHAPTER 1

defined internal structure. With several sections, Jimbow et al. [58] found only
one melanocyte. This melanocyte contained a remarkably indented nucleus, a
large perikaryon, and a few unmelanized ellipsoidal and spherical melanosomes; the spherical melanosomes contained unmelanized grains.
Langerhans cells are reported increased in number. Crupper et al. [30]
observed many Langerhans cells and other Langerhans-like cells without typical Langerhans granules in the basal layer and at the suprabasallevel in the
epidermis of the white macule. Comings and Odland [29] reported an increased
number of Langerhans cells in either the basal layer or in the suprabasallayer.
Breathnach et al. [61] noted very rare but normal Langerhans cells and other
abnormal Langerhans cells that showed a tendency toward nuclear-cytoplasmic separation. One of the Langerhans cells contained a granule similar to
those seen in the abnormal melanocytes of the basal layer. The number of
indeterminate cells appears increased [60]. Mast cells have been described in
the depigmented epidermis [59,62].
In studies of the progressive transition zone between depigmented and
normal skin, Crupper et al. [30] found a normal number of melanocytes containing normal premelanosomes. However, some melanocytes had abnormal
features; they were characterized by reduced size, indented nuclei, and
shrunken, vacuolar, and granular cytoplasm. Most of the melanosomes were
abnormal in one of three ways, namely, irregularity of size and shape of mature
melanosomes, presence of ill-defined material in small round melanosomes, or
degenerative changes within melanosomes containing a granular material surrounded by a clear halo. They also observed typical Langerhans cells in the
basal layer and at a high level in the epidermis as well as cells with a Langerhans
cell appearance but without Langerhans granules (indeterminate cells).
In the hyperpigmented borders of hypomelanotic macules, Comings and
Odland [29] observed melanocytes, Langerhans cells, and an increased number
of melanin granules.
A large number of hyaline bodies in the dermis and epidermis have been
discussed [59].
White Forelock
There are no melanocytes in the follicles of the white forelock [58,61], and
no melanosomes in the surrounding keratinocytes [58]. There is an abnormally
large number of typical Langerhans cells in the basal layer and in the suprabasal
layer. Cells resembling Langerhans cells but without Langerhans granules (indeterminate cells) have also been observed [61].
Hyperpigmented Macules in the Center of the Depigmented Macules
An abundance of melanosomes in the melanocytes and keratinocytes characterizes the hyperpigmented macules [59] (Fig. 114). These melanosomes are
either normal (ellipsoidal) or abnormal (spherical) in shape, the latter (about
0.5 to 0.7 f..Lm in diameter) being more prominent. The normal ellipsoidal melanosomes, whose inner matrices are composed of lamellae, show normal mel-

331

GENETIC AND
CONGENITAL
DISORDERS

FIGURE 114. The melanocyte and melanosomes in the hypermelanotic lesion in the center of a
hypomelanotic area of skin of a patient with piebaldism. a: An abundance of spherical melanosomes
(SM) with various stages of melanization. (x 28,500). b: Abnormal degradation of the melanosomes
in the keratinocytes (arrows). Spherical, granular melanosomes (SM) are present in the dendritic
process of the melanocyte (x 27,000). (From: Jimbow K et al: Congenital circumscribed hypomelanosis: a characterization based on electron microscopic study of tuberous sclerosis, nevus
depigmentosus and piebaldism. J Invest Dermato1 64:50-62, 1975. Copyright, 1975, The Williams
& Wilkins Company. Used with permission.)

anization, transfer, and degradation. On the other hand, the spherical melanosomes, whose inner matrices are also composed of lamellae, show abnormal
melanization and degradation. In the spherical granular melanosomes, melanization often seems to start from the central part of the melanosomes. When
transferred into the keratinocytes, the melanosomes undergo marked degradation and often are fused with each other in the lower epidermis [58]. Jimbow
et al. [58] consider the presence of spherical granular melanosomes to be characteristic of piebaldism.
Normal Skin of Piebalds (Distant from the Hypomelanotic Areas)
According to Comings and Odland [29], a normal complement of melanin
granules, Langerhans cells, and melanocytes is found in normal skin. But
Breathnach et al. [61] pointed out that the melanocytes in normal skin of
piebalds differ in several respects from those found in the epidermis of normal
subjects. These melanocytes show a greater degree of nuclear indentation, ir-

TABLE 84. Subcellular Characteristics of Skin and Hair in Piebaldismo

332

CHAPTER 1

Amelanotic
skin
Melanocytes
Number
Dopa reaction
Dendrites
Melanosomes
Size
Shape
Inner structure
Melanization
Number in melanocytes
Secretion
Number in keratinocytes
Keratinocytes
Distribution pattern of
melanosomes
Degradation of melanosomes

White
hair

Hypermelanotic islands
within hypomelanotic
lesions
Normal
Increased
Well-developed
Normal
Abnormal (Le .
ellipsoidal and
spherical)
Abnormal (Le . lamellar
and granular)
Increased markedly
Increased
Normal
Increased
Normal
Abnormal or increased

Source: Jimbow K et al: Congenital circumscribed hypomelanosis: a characterization based on electron microscopic study of tuberous sclerosis. nevus depigmentosus and piebaldism. ] Invest Dermatol 64:50---62, 1975.
Copyright, 1975, The Williams & Wilkins Company. Used with permission.
b None detectable.
a

regular vesicles forming in the cytoplasm. and a tendency to produce abnormal

melanosomes. An increased number of Langerhans cells is present in the basal
layer of the epidermis.
The subcellular characteristics of piebaldism are outlined in Table 84.

Pathogenesis
There are animal models for piebaldism. Gnus show a white forelock [35].
Various mechanisms have been identified to explain a white-spotting pattern
in mice. A clonal distribution of melanocytes has been observed in piebaldspotted and variegated mice [63]. In the case of the belted (bt) mutant, the skin
in the spotted areas selectively prevents the survival or differentiation of melanoblasts [64]. More specifically, the hair follicles seem to be the affected tissue,
for there are melanocytes in the skin between the pigment-free hair follicles.
In the WV mutation, the defect appears to be at the neural crest level. The
skin of the mutant genotype does not influence normal melanoblasts in any
adverse way [65]. WV/Wv melanoblasts either never enter the skin or they do
not survive because of some intrinsic factor operative immediately after colonization of the skin [66].

In the SLISL mice, the melanoblast component of the neural crest appears
to be normal [65], but the skin seems to playa determining role in the pigment
block. The skin of steel mice either prevents the differentiation of the normal
melanoblasts or inhibits their migration [66].
In the case of piebald mice (SIS), according to Mayer [57], the development
of white spotting occurs because the neural crest-derived cells seem to have a
reduced capacity to differentiate into melanocytes [57,64]. There is also evidence that the spotting pattern results from the differential resistance of certain
areas of the skin to the differentiation of melanoblasts [67].
These animal models suggest that the absence of melanocytes in hypomelanotic areas results from a failure of melanoblasts either to migrate into the
skin or to differentiate into melanocytes. The major target of involvement may
be the melanoblast in the neural crest, melanoblast migration or survival in the
skin, or both (Fig. 115). Since a very few melanocytes may overcome this hostile
embryonic environment [58], a few melanocytes may be found in hypomelanotic lesions. Abnormality of melanosomes within the melanocytes of hyperpigmented spots would also be a consequence of such hostile environmental
influences. The occurrence in some patients of concomitant neural disturbances
further supports a defect at the level from which these structures (skin and
neural tissues) both originate, i.e., the neural crest. That there are, in humans,
several pathogenic pathways resulting in the piebald phenotype is certainly
also possible.

Diagnosis
Vitiligo, which may also involve both skin and hair, is the major hypomelanosis that must be distinguished from piebaldism (Table 85). The following
features distinguish piebaldism from vitiligo: the white areas in piebaldism are

to migrate
or
failure of melanoblasts
to sUf"vive

or differentiate

FIGURE 115. Hypomelanosis in piebaldism.

333

GENETIC AND
CONGENITAL
DISORDERS

TABLE 85. Differential Features of Piebaldism and Vitiligo

334

Vitiligo

Piebaldism

CHAPTER 1
Mode of inheritance

Autosomal dominant

Autosomal dominant (30%)

Age of onset

Birth

Variable

Distribution pattern

Characteristic
White forelock
Anterior trunk
Arms and legs

Characteristic
Extensor surfaces
Sites of repeated trauma

Course

Stable
No extension
No spontaneous
repigmentation

Progressive
Extension or spontaneous
repigmentation

present from birth, usually remain constant throughout life, and show a characteristic distribution pattern with islands of normally pigmented or hyperpigmented skin.
In Waardenburg syndrome, the skin and hair depigmentation is similar to
piebaldism. However, the associated eye and ear findings differentiate Waardenburg syndrome from piebaldism. Ziprkowski-Margolis syndrome and Woolf
syndrome can be excluded by the absence of these characteristic features (see
appropriate sections in this chapter).

Treatment
The natural course of piebaldism is to remain unchanged throughout life.
Darkening of normal skin and of melanotic macules may follow sun exposure,
but the size and shape of the depigmented macules is usually fixed from birth.
Witkop (personal communication) has observed that piebald macules may vary
in size, and Davis and Verdol [68] have observed a piebald patient whose
hypopigmented macules expanded and contracted.
Several types of treatment have been attempted. Trisoralen has been used
in one patient who did not improve [28]. Bleaching normally melanized skin
of another patient with 20% mono benzyl ether of hydroquinone has been successful (unpublished observation). Cosmetic embarrassment may be diminished by cover-up, make-up, and clothing. Protection against UVB sunburn is
necessary.
Full-thickness autografts of normal skin into amelanotic areas have been
reported to result in peripheral spread of repigmentation from grafted sites
[69,70]; epidermal grafts are stable but lead to no peripheral spread [70].

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4. Froggatt P: An outline, with bibliography of human piebaldism and white forelock. Ir J Med
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15. Mazzini G: Long heredity of partial albinism (abstr). Gass Osp Milano 45:403, 1923
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22. Hutchinson J: On palaeogenic face-pattern in acroteric piebalds. Br Med J 1:1479-1481, 1910
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24. Simpson QI, Castle WE: A family of spotted Negroes. American Naturalist 47:50-56, 1913
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29. Comings DE, Odland GF: Partial albinism. JAMA 195:519-523, 1966
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35. Witkop CJ Jr: Albinism, in Human Genetics. Edited by H Harris, K Hirschhorn. New York,
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38. Fitch L: Inheritance of white forelock through five successive generations. JHered 28:413-414,
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39. Frant R: A family with albinismus circumscriptus. Ned Tijdschr Geneeskd 31:120-121, 1937
40. Mierowsky, Spickernagel: Uber Vererbung und Lokalisation der Scheckenbildung sowie ihre
Bedeutung fUr die Naevusatiologik. Arch Dermatol Syphilol (Berlin) 150:384-392, 1926
41. Nussey AM: A piebald family. Biometrika 13:65-67, 1938
42. Zsako I: Pigment loss in five generations. Z Gesamte Neurol Psychiatr 34:208-212, 1923
43. Pierard GE et al: Six generations of piebaldism. Dermatologica 158:184, 1979
44. Jahr HM, Mcintire MS: Piebaldness or familial white spotting (partial albinism). Am J Dis
Child 88:481-484, 1954
45. Sundfor H: A pedigree of skin-spotting in man. J Hered 30:67-77, 1939
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47. Stannius H: In discussion on Ellis RWB: Heterochromia of irides and hair. Proc R Soc Med
24:1057-1058, 1931
48. Ahuja YR: A human mosaic involving eye and hair color differences. Acta Genet Med Gemeilol
(Rom a) 9:427-431, 1960
49. Duke-Elder WS: Textbook of Ophthalmology, vol II. London, Henry Kimpton, 1938
50. Di George AM et al: Waardenburg's syndrome. J Pediatr 57:649-669,1960
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52. Campbell B et al: Waardenburg's syndrome. A variation of the first arch syndrome. Arch
Dermatol 86:718-724, 1962
53. Reed WB et al: Pigmentary disorders in association with congenital deafness. Arch Dermatol
95:176-186,1965
54. Urbantschitsch E: Zur Aetiologie der Taubstdummheit. Verh Dtsch Otol Ges (fena) 19:153-159,
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55. Van Gilse PHG: Gival van pigmentonomalie en doofheid. Ned Tijdschr Geneesk 70:479-480,
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56. Franceschetti A et al: Albinisme partiel, surdits, arrisration mentale. Dermatologica 106:279,
1953
57. Mayer TC: The development of piebald spotting in mice. Dev BioI 11:319-334, 1965
57a. Mahakrishnan A, Srinivasan MS: Piebaldness with Hirschprung's disease. Arch Dermatol
116:1102, 1980
57b. Bielschowsky M, Schofield GC: Studies on megacolon in piebald mice. Aust J Exp Med Sci
40:395-404, 1962
58. Jimbow K et al: Congenital circumscribed hypomelanosis: a characterization based on electron
microscopic study of tuberous sclerosis, nevus depigmentosus and piebaldism. J Invest Dermatol 64:50-62, 1975
59. Barneon G, Baldet P: Piebaldism: ultrastructural study and pathogenic interpretation. Ann
Anat Pathol (Paris) 23:143-152, 1978
60. Bonerandi JJ et al: Piebaldism. Clinical. pathological and ultrastructural study of three cases.
Ann Dermatol Venereo1105:67-72, 1978
61. Breathnach AS et al: Electron microscopy of melanocytes in human piebaldism. J Invest Dermatol 45:28-37, 1965
62. Nagao S et al: Mast cells in the epidermis of piebaldism. Arch Dermatol Forsch 251:221-226,
1975
63. Schaible RH: Clonal distribution of melanocyte in piebald-spotted and variegated mice. J Exp
Zoo1172:181-199, 1969
64. Mayer TC, Maltby EL: An experimental investigation of pattern development in lethal spotting
and belted mouse embryos. Dev BioI 9:269-286, 1964
65. Mayer TC, Green MC: An experimental analysis of the pigment defect caused by mutations at
the W" and SL loci in mice. Dev BioI 18:62-75, 1968
66. Mayer TC: A comparison of pigment cell development in albino steel and dominant spotting
mutant mouse embryos. Dev BioI 23:297-309, 1970
67. Mayer TC: Temporal skin factors influencing the development of melanoblasts in piebald mice.
J Exp ZooI166:397-404, 1967
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Hum Genet 34:163-170,1976

69. Selmanowitz VJ: Pigmentary correction of piebaldism by autografts. II. Pathomechanism and
pigment spread in piebaldism. Cutis 24:66-71, 1979
70. Selmanowitz VJ et al: Pigmentary correction of piebaldism by autografts. I. Procedures and
clinical findings. J Dermatol Surg Oneol 3:615-622, 1977

WAARDENBURG SYNDROME
The mother has heterochromia ... the family name is Whitlock (white-lock),
and ... records dating back to the middle of the 18th century (show) an inherited
white forelock from which the family name originated [1).

Waardenburg syndrome is a rare autosomal dominant disease characterized

by lateral displacement of the inner canthi and of the inferior lacrimal puncta,
prominence of the root of the nose and of the medial portions of the eyebrows,
congenital deafness, white forelock, and heterochromia irides.
Incomplete forms of classical Waardenburg syndrome are common among
reported cases; the "penetrance" and "expressivity" of each of these features
are variable. Arias [2] and Hageman and Delleman [3] have separated Waardenburg syndrome into Type I and Type II, based on the presence or absence
of dystopia canthorum.

History
Although Waardenburg's name has been appended to this syndrome, review of the medical literature reveals many cases that may represent earlier
examples of this disease.
In 1905, Hammerschlag [4] reported a ten-year-old boy with deaf-mutism
associated with clear blue eyes, albinoid fundus, white forelock, craniofacial
dysostosis (narrow forehead, prominent jaw, high-arched palate), ataxia, mental
retardation, and unilateral undescended testicle. In 1910, Urbantschitsch [5]
and later Van Gilse [6] observed the association of partial albinism, heterochromia irides, and deaf-mutism. van der Hoeve [7], in 1961, described monozygotic twin girls with blue eyes, deaf-mutism, ankyloblepharon, lateral displacement of the inferior lacrimal puncta, and blepharophimosis. Mende [8],
in 1926, published a pedigree with affected individuals in four generations
with white forelock, discoloration of eyebrows and eyelashes, patchy whiteness
of the trunk and limbs, deaf-mutism, persistent lanugo hair of the neck, and a
mongoloid facial appearance probably due to lateral displacement of the inner
canthi. The combination of heterochromia irides with lateral displacement of
the inner canthi was observed in 1931 by Leonardi [9] and in 1934 by John
[10]. In 1947, Goedbloet [11] presented a case at the Netherlands Ophthalmological Society with the association of deaf-mutism and lateral displacement
of the medial canthi. Walsh [12] in 1947, in his textbook of clinical neurophthalmology, showed the picture of a brother and sister with deaf-mutism,
white forelock, and lateral displacement of the medial corner of the eyelids
and of the inferior lacrimal points. In the same year, Klein [13] presented to
the Genetics Society of Switzerland a ten-year-old girl with the following features: partial albinism of the skin and hair, bilateral slate blue irides, blepharo-

337
GENETIC AND
CONGENITAL
DISORDERS

338

CHAPTER 1

FIGURE 116. Klein's patient with hypomelanosis of skin and hair and multiple associated abnormalities. (From: Klein D: Albinisme partiel (leucisme) avec surdimutite, blepharophimosis et
dysplasie myo-osteo-articulaire. Helv Paediatr Acta 5:38-58, 1950. Copyright, 1950, Schwabe and
Co, Basel. Used with permission.)

phimosis with "hypertelorism" and hypertrichosis of the eyebrows, bilateral

labyrinthine deafness, amyoplasia and stiffness of the joints limited to the upper
part of the body, skull abnormalities with absence of the nasofrontal angle and
retrognathism of the lower jaw, faulty implantation of the upper incisors arranged in two rows, high-arched palate, dysplastic bones (aplasia of the first
two ribs, lack of differentiation of the small carpal bones, and cystic formation
of the sacrum), cutaneous union of the thorax and humerus, and bilateral
cutaneous syndactyly (Fig. 116).
In 1947, Waardenburg saw a 72-year-old patient with deaf-mutism, chronic
tearing, progressive impairment of the vision, pale blue irides, marked peripapillary hypoplasia, and lateral displacement of the medial canthi of the eyes
and of the inferior lacrimal puncta. This patient was presented in 1948 to the
Ophthalmology Society of Utrecht [14]. Waardenburg [15,16] then undertook
a study of the inmates of five Dutch institutions for the deaf. He examined a
total of 1050 patients and found 13 with the eyelid abnormality. Waardenburg
defined the disease as a combination of the following six main features (Fig.
117):

1. Dystopia canthi medialis latera versa (lateral displacement of the medial

canthi) combined with dystopia of the lacrimal puncta and blepharophimosis

2. Hyperplasia radei nasi (prominent broad root of the nose)
3. Hyperplasia supercili medialis (medial fusion of the eyebrows with
hyperplasia of their medial portion)

339

HETEROCHROMIA IRIDES
DYSTOPIA CANTHORUM AND
BROAD ROOT OF THE NOSE

CUTANEOUS DEPIGMENTATION

FIGURE 117.
syndrome.

Waardenburg

4. Leucismus pilorum and poliosis (white forelock)

5. Heterochromia iridum totalis sine partialis (different color irides)

6. Surditas congenitas (deaf-mutism or incomplete uni- or bilateral deafness)
He noted the various degrees of penetrance of each of these features and
concluded that the syndrome is inherited as an autosomal dominant trait with
variable expression.
This disease came to be known as the Waardenburg syndrome, the
Klein-Waardenburg, or the Waardenburg-Klein syndrome; it has been extensively reviewed by Amini-Elihou [17) and in the monograph, Light-Eyed Negroes and the Klein-Waardenburg Syndrome, by Soussi Tsafir [18).

Animal Models
Some animals appear to have Waardenburg syndrome. Wolff [19], in 1942,
noted that there had been many earlier reports describing this syndrome, particularly in Persian cats, and reported deafness in three generations of white
cats. Deaf white cats with blue irides have been observed [20). Wilson and

GENETIC AND
CONGENITAL
DISORDERS

340
CHAPTER 1

Kane [21] described heterochromia irides in a totally deaf white cat. Hereditary
deafness in association with white hair color is also known to occur in bull
terriers, Sealyhams, dalmations [22], dachshunds, and collies [18]. A horse
with white coat, deafness, and heterochromia irides has also been reported
[23].

Clinical Features
Incidence

Waardenburg [16] estimated the incidence of Waardenburg syndrome to

be 1:212,000 in the Netherlands and in the general population, and 1.43%
among Dutch with congenital deaf-mutism. The incidence among deaf mutes
has otherwise been reported to be 0.9% to 2.8% [23-26].
Race

Any race may be affected. For a long time this disease was thought to
involve only the Dutch; in fact, in 1961 an article was subtitled "Report of a
Case in a Non-Dutch Family" [27]. And while the original cases concerned
only Caucasoids, Waardenburg syndrome has also been observed among most
European nationalities, Americans, Mongoloids, Japanese [28-30], Chinese [31],
North American blacks [23,32], and African blacks [18,33]. The syndrome shows
no particular geographic distribution.
Sex
Males and females are equally affected.
Heredity

As Waardenburg [16] concluded, this is an autosomal dominant disease.

Although Arnvig [34] hypothesized gene linkage, because he had noted similar
features among respective members of three pedigrees, this notion is not widely
accepted. It is generally agreed that Waardenburg syndrome is autosomal dominant, somewhat variable in penetrance and in expression.
Waardenburg [16] noted that expression of the defect was not bilaterally
symmetrical and suggested "some kind of somatic genetic segregation." It could
represent true mosaicism or varied expression of a defect among different cells
[35].

Not all cases are familial. Isolated cases do occur, and as Waardenburg
suggested, spontaneous mutations must occur [16,25,36]. The mutation could
occur in the generation of the proband's parents and escape detection because
of variable expression or penetration. One case has been attributed to 40 x-ray
examinations performed on the father of the patient [37].
Any theory of inheritance for Waardenburg syndrome must also explain
the occasional presence of musculoskeletal defects [13,38,39]' cleft lip, and
cleft palate [8,16,24,26,40-43]. A disturbance of gene reparation, deletion, or

some other gene disturbance may be responsible [13]. Or perhaps these cases
are new mutations or represent homozygous presence of an autosomal recessive
gene (related to consanguinity or incidental occurrences).
Arias [2] suggested possible genetic heterogenicity in Waardenburg syndrome, and this was demonstrated in a review of 1319 such patients. One family
has been reported in which none of its members has dystopia of the inner
canthi or lower puncta, while four siblings have the combination of hyperopia-estropia-amblyopia and foveal hypoplasia; iris translucency dramatizes
this heterogeneity [44]. Two distinct autosomal dominant entities have been
described as follows: Type I with dystopia canthorum, and Type II without
dystopia canthorum. Type II also has a greater incidence of bilateral deafness
[3]. Among 30 patients from Kenya, 18 were Type I and 12 Type II [45].
There have been no other reported markers for Waardenburg syndrome.
No chromosomal abnormalities have been found [13,25,39,46,47] in those with
Waardenburg syndrome. Although six patients of blood group A have been
reported as a series [48], there is no evidence that Waardenburg syndrome and
ABO blood groupings are correlated [47]. HLA typing performed on six patients
has been reported to be inconclusive [48]. Dermatoglyphics are usually normal;
however, one case with a transverse palmar fold has been reported [49].

Abnormalities in Waardenburg Syndrome (Table 86)

Pigmentary Abnormalities (Table 87)

Both cutaneous and ocular melanocytes are affected.

While the white forelock was first recognized as a feature of Waardenburg
syndrome, premature graying of scalp hair and of the eyebrows or cilia has
been considered a variant of the hair involvement [16,23].
Cutaneous pigmentary abnormalities seem to be a variable feature of Waardenburg syndrome. Waardenburg himself noted depigmented and hyperpigmented macules in some of his patients [16]. Enough cases with this "dappled
TABLE 86. Prevalence of Characteristic Features in Waardenburg Syndromea

Characteristic feature
Dystopia canthorum
Partial albinism (white forelock, other white
spots, and early graying)
Heterochromia irides
Bilateral isohypochromic irides
Congenital deafness
Hyperplasia of nose root
Hyperplasia of eyebrows

Waardenburg

Later
publications

Reed et a\.

(161)b

(181)b

(24)b

99%
17%

(159)
(27)

77.9%
43.6%

(141)
(79)

69%
60%

25%

(41)

20%
78%
45%

(32)

21.5%
14.9%
37.5%

(39)
(27)
(68)

28%
28%
100%
69%

Source: Reed WB et al: Pigmentary disorders in association with congenital deafness. Arch Dermato195:176-186,
1967. Copyright. 1967. American Medical Association. Used with permission.
b Numbers in parentheses indicate number of patients.
a

341

GENETIC AND
CONGENITAL
DISORDERS

342

TABLE 87. Pigmentary Disturbances in Waardenburg Syndrome

CHAPTER 1

Hair

White forelock
Early graying of hair
Hypomelanosis of eyebrows. eyelashes. or body hair

Skin

Hypopigmented macules with hyperpigmented macular islands

Hyperpigmented macules on normally pigmented skin

Eyes

Heterochromia irides
Bilateral isohypochromia irides
Fundus pigmentary abnormalities

appearance" have been described to justify inclusion of "patchy skin" as a

typical feature of Waardenburg syndrome [23,26,37,41,46].
Heterochromia of the iris is one of the classical features of Waardenburg
syndrome. Abnormal pigmentation of the fundus has also been described.
Frequency of Pigmentary Abnormalities (Table 88)
The white forelock seems to be the most constantly and frequently observed
cutaneous pigmentary abnormality in Waardenburg syndrome; incidence figures range from 17% to 58.4% [16,26,41]. Prematurely gray scalp hair has been
observed in 7% of one series [41]. Early disappearance of the white forelock,
scant pigmentary dilution, and artificial hair coloring may contribute to variable
or underreporting of white or gray hair.
Cutaneous depigmentation is observed in 8.3% to 50% of patients with
Waardenburg syndrome [26,41].
White Forelock
The white forelock is a classical and prominent feature of Waardenburg
syndrome (Fig. 118). It may present either as a few strands of white hair in the
midline scalp or the eyebrows or as a large white or gray lock in or near the
midline. In these areas, the scalp hair is gray or completely white, and the
medial eyebrows and eyelashes may be white. An extensively involved case
had a white forelock extending posteriorly to the vertex and anteriorly over

TABLE 88. Frequency of Pigmentary Abnormalities in Waardenburg Syndrome

Author

White
forelock

Waardenburg (1951) [16)

Goldberg (1966) [41)
Reed et al. (1967) [26)
Soussi Tsafira [18)

17%
50%
58.4%
43.5%

Series of 23 black patients.

Premature
graying
scalp

Cutaneous
hypomelanosis

No. of
cases
161

7%

50%
8.3%

24
23

343

GENETIC AND
CONGENITAL
DISORDERS

FIGURE 118. White forelock

and lateral displacement of the
inner canthi. (Courtesy of W. B.
Reed, M.D.)

the forehead to involve both medial eyebrows [23]. A few patients have had
white hair in areas other than the frontal region. Involvement of the frontoparietal scalp [17] and of the posterior scalp has been reported [36]. The skin
beneath the white forelock mayor may not also be amelanotic [23].
The white forelock may be present at birth or may appear very soon thereafter or even later [50]. This white forelock may persist throughout life or
become less prominent and even disappear in the first months or years of life.
A typical case is that of a baby with a white forelock, 4 to 5 em wide, which
began to disappear after the first two weeks, and with depigmentation involving
two-thirds of her left eyebrow and eyelashes, both of which remained depigmented. At three years seven months of age, none of the initial white forelock
remained [51]. In another case, the congenital white forelock had disappeared
by six weeks of age except for a few white hairs and had not returned by one
year of age [52]. However, the authors are aware of one black child in whom
the white forelock had disappeared at the end of the first year of life and
reappeared at the age of 10 years.
Not all forelocks of Waardenburg syndrome are white; patches of red,
brown, and black have been observed [13,26]. One blond patient had a parietooccipital patch of red hair. Another had a bright red forelock in a field of
auburn hair, red hair at one side of the neck, auburn on the other, and eyelashes
that were bright red medially and dark brown laterally. In another, a sharply
demarcated patch of black hair on the right side of the scalp contrasted with
the fair hair of the left scalp [53]. It is reasonable to ask whether the fair color
of most of the scalp hair represents a hypomelanotic variant of the white forelock or whether the dark patch is in fact abnormal, that is, hyperpigmented
[18].

344

Premature Graying of the Hair

CHAPTER 1

Many patients with Waardenburg syndrome have become prematurely gray.

The exact incidence of premature graying is unknown, but Goldberg [41] observed it in only one of 14 patients. In 1951, Waardenburg [16] noted nine
cases with premature graying of hair and speculated that this may represent
the equivalent of a white forelock in some individuals (Figs. 119, 120). One
patient had a white forelock as a child and turned completely gray at 23 [25].
Another patient [47] had a white forelock which disappeared in the first years
of life; when she was seen at the age of 29, she had diffuse graying but no
evidence of the white forelock. The gray hair and the forelock seem to be
separate processes.
Premature graying can involve the scalp, eyebrows, cilia, and body hair.
Beard and arm involvement has also been observed [23,54]. Onset may be as
early as the teens.
Premature graying of the scalp hair is seen not only in the affected individuals, but also in apparently unaffected relatives. Two mothers of involved
children had gray hair which developed from early childhood to age 20 [23].
The maternal grandmother of one of these involved children is also said to
have developed gray hair in childhood and to have had completely white hair

FIGURE 119. Premature graying of hair. (From: Amer M, El Shazly M: The association of familial
hyperbetalipoproteinemia with Waardenburg's syndrome. Br J Dermatol 90:255-262, 1974. Copyright, 1974, Blackwell Scientific Publications. Used with permission.)

345

GENETIC AND
CONGENITAL
DISORDERS

FIGURE 120. Premature graying of hair and hyperplasia of the

eyebrows. (From: Ortonne J-p et
al: Le syndrome de Waardenburg-Klein associe a une maladie de Hodgkin. Ann Dermotol
Syphiligr (Paris) 103:245-256.
1976. Copyright. Masson et Cie.
Paris. Used with permission.)

by the age of 46. None of these three individuals had other evidence of Waardenburg syndrome.
Skin Depigmentation

Waardenburg [16] observed generalized white spotting in several patients.

The skin from which the white forelock arises is depigmented.
but hypomelI
anosis of the skin anatomically distinct from the white forelock is certainly
characteristic of Waardenburg syndrome (Fig. 121).
Hypomelanosis may in fact be the predominant feature of Waardenburg
syndrome. A 17-year-old boy had white forelock, mild deafness, and a macule
of white skin on the abdominal wall, but no other features of Waardenburg
syndrome. However, he had prematurely gray hair and other family members
had features of Waardenburg syndrome [25]. One patient was reported to have
Waardenburg syndrome and extensive "vitiligo" over most of her body and on
her face and hands [55]. Many additional cases of Waardenburg syndrome with
cutaneous hypopigmentation have been observed (see Table 89). Such hypopigmentation has also been seen in blacks [18,23,50,56].
The exact incidence of white macules in Waardenburg syndrome is unknown, but the incidence figures vary from 8.3% to 50%. The overall prevalence
among reported cases is in the range of 14% to 15% [18,26,41].
Many different patterns of hypomelanosis have been described. Hypopigmentation localized to the upper part of the body [13], "patchy skin" [37], and
cutaneous hypo pigmentation scattered over both arms or on the abdominal
wall [23] have been noted.
Usually, the hypopigmented macules, which may resemble those of pie-

346
CHAPTER 1

FIGURE 121. Hypomelanotic

macules with islands of sparing.
(From: Amer M, El Shazly M: The
association of familial hyperbetalipoproteinemia with Waardenburg's syndrome. Br J Dermotol 90:255-262, 1974.
Copyright, 1974, Blackwell Scientific Publications. Used with
permission. )

TABLE 89. Skin Depigmentation in

Waardenburg Syndrome
Author

Year

Mazzini [57J
Mende [8J
Klein [13J
Waardenburg [16J
Fisch [37J
Partington [25J
Di George et al. [23 J
Borbolla et al. [58J
Grimaud et al. [59]
Partsch [60J
Campbell et al. [lJ
Calinkos [56J
Houghton [61J
Wilbrandt and Amman [62J
Hansen et al. [50]
McDonald and Harrison [55J
Goldberg [41 J
de Haas and Tan [46J
Boniface and Fontaine [63J
Reed et al. [26]
Fregonese et al. [64 J
Amer and El-Shazly [65J
Soussi Tsafir [18J
Ortonne et al. [47J
Parry et al. [66J
Amon and Abdurrahman [67J

1924
1926
1950
1951
1959
1959
1960
1961
1961
1962
1962
1963
1964
1964
1965
1965
1966
1966
1966
1967
1969
1974
1974
1976
1978
1979

baldism, are present at birth or are noted soon thereafter. The white macules
are usually circumscribed with sharply defined but irregular borders. The color
is dull white, and Wood's light examination shows a complete absence of
pigment (3 + hypomelanosis). Hyperpigmented macules are scattered randomly
within the larger hypomelanotic macules. The extent of the hypopigmentation
varies; it may be localized or scattered all over. Symmetry occurs in some cases
(Fig. 122). The hypomelanosis is usually found on the face and the forehead
next to the white forelock, but also may be on the neck, anterior chest and
abdomen, and the limbs, particularly on the anterior knees and arms. Both the
anterior and posterior arms may be involved and in many cases the dorsal
hands are amelanotic. Lip involvement has been observed [18]. The macules
usually do not increase in size and do not repigment. Body hair within the
white patches is usually white (Fig. 123). The hypopigmentation is asymptomatic.
Pedigrees with white spotting and familial patterns have also been described. A four-generation pedigree, all with hypopigmentation of the trunk
and limbs, has been reported [8]. The grandmother and the mother of one patient
with extensive involvement [23] had white spots on the dorsal wrists. In a five-

FIGURE 122. Bilateral involvement of calves. (From: Ortonne

J-p et al: Le syndrome de Waardenburg-Klein associe a une maladie de Hodgkin. Ann Dermato!
Syphiligr (Paris) 103:245-256,
1976. Copyright, Masson et Cie,
Paris. Used with permission.)

347

GENETIC AND
CONGENITAL
DISORDERS

348
CHAPTER 1

FIGURE 123. Depigmentation of body hair on the hypomelanotic macules. (From: Ortonne J-p
et al: Le syndrome de Waardenburg-Klein assode a une maladie de Hodgkin. Ann Dermatol
Syphiligr (Paris) 103:245-256, 1976. Copyright, Masson et Cie, Paris. Used with permission.)

generation pedigree, 13 members had a white forelock and hypopigmentation

of the face, chin, neck, trunk, and lower limbs [58].
Hyperpigmentation or scattered brown macules are also noted [13] on
normal as well as on hypopigmented skin. Involvement may be extensive [16]
and the macules may be varied in size and color intensity. Familial occurrence
of the hyperpigmentation has been observed [37].
Histopathology and Electron Microscopic Findings
The histology of the depigmented skin is normal except for fewer dopapositive cells in the depigmented skin compared to the normal skin [46].
Ultrastructural observations have made it possible to classify Waardenburg
syndrome among leukodermas with an absence or reduced number of melanocytes. Anton-Lamprecht et al. [68] found in hypopigmented skin a dramatic
reduction in the number of melanocytes. These melanocytes contained poorly
melanized melanosomes. In the achromic skin, Perrot et al. [69] found no
melanocytes or indeterminate cells, no melanosomes in the keratinocytes, and
a normal number of Langerhans cells distributed throughout the epidermis.
The dermal-epidermal junction was normal and there were very few dense
hyaline bodies in the upper dermis at a distance from the basement membrane.
On the edge of the lesions melanocytes were reduced in number and had
numerous cytoplasmic nuclear abnormalities (Figs. 124, 125). The melano-

349

GENETIC AND
CONGENITAL
DISORDERS

FIGURE 124. Skin from the edge of a hypomelanotic macule: melanocyte (M); colloid bodies
(CB); basement membrane (MB); vacuole (V); melanosomes (ME); mitochondria (MI); tonofibrils
(TF) (x 13,700). (From: Perrot H et al: Ultrastructural study of leucodermic skin in Waardenburg-Klein syndrome. Acta Derm Venereol (Stockh) 57:195-200, 1977. Copyright, 1977, Society
for the Publication of Acta Dermatoveneriologica. Used with permission.)

350
CHAPTER 1

FIGURE 125. Skin from the edge of hypomelanotic macule. Indeterminate cell in the basal part
of the epidermis: keratinocyte (K) ; indeterminate cell (IC) (x 18.000). (From: Perrot H et al: Ultrastructural study of leucodermic skin in Waardenburg-Klein syndrome. Acta Derm Venereol
(Stockh) 57:195-200. 1977. Copyright. 1977. Society for the Publication of Acta Dermatoveneriologica. Used with permission.)

somes were diminished in number and were sometimes found inside vacuoles
surrounded by a clear halo. Some had normal structure, but others were granular. Numerous melanosomes were found in keratinocytes.
In normal skin. distant from the lesions, many melanocytes appeared normal, many others had poorly formed dendrites and contained abnormal melanosomes characterized by an irregular outline, rounded shape, small size, and
granular inner structure (Fig. 126). Thus, in Waardenburg syndrome there are
few or no melanocytes in achromic skin and there is a disturbance in melanosome synthesis in clinically normal skin distant from the achromic patches.
This suggests biopsy of normal skin may help distinguish piebaldism from
Waardenburg syndrome.
Ocular Pigmentary Abnormalities
Isohypochromic Eyes
Goldberg [41] found bilateral iris hypochromia in 42% of his 14 patients;
in other series, an incidence of 14.9% to 28% is reported [26].
In 1961, Waardenburg [70] stated that bilateral pale blue eyes should be
regarded as a sign of his syndrome. Originally, Waardenburg [16] did not include pale blue eyes (isohypochromia) in Waardenburg syndrome because he
thought that blue-eyed individuals simply had blue eyes which somehow were

351
GENETIC AND
CONGENITAL
DISORDERS

(ME); vacuole (V); keratinFIGURE 126. Normal skin: melanocyte with abnormal melanosomes
mic skin in Waarleucoder
of
study
ocyte (K) (x 30,000). (From: Perrot H et al: Ultrastructural
ht, 1977, Society
Copyrig
.
00,1977
57:195-2
(Stockh)
l
Venereo
Derm
denburg-Klein syndrome. Acta
on.)
permissi
with
Used
ogica.
veneriol
Dermato
Acta
of
ion
Publicat
for the

became a
a genetic marker for inability to express heterochromia. Blue eyes
had
part of the clinical findings in Waardenburg syndrome once Waardenburg
eyes
blue
d
assume
he
me;
syndro
enburg
observed blue-eyed blacks with Waard
[18]
not to be a normal genetic trait of blacks (Fig. 127). But Soussi Tsafir
several
found
she
when
ct
showed Waardenburg's assum ption to be incorre
since the
cases of blue-eyed blacks withou t Waardenburg syndrome. However,
ual
individ
"an
low,
incidence of bilateral blue eyes in blacks is exceptionally
owes
eyes
blue
showing at least one other sign of Waardenburg syndrome with
noted that
his blue eyes to the Waardenburg genotype" [18]. Thorkilgaard [71]
George et
Di
and
hypoplasia of the iris may result in blue eyes. Both he [71]
enburg
Waard
of
a1. [23], who considered bilateral blue eyes to be a feature
Thorkme.
syndro
syndrome, includ ed iris hypopl asia as part of Waardenburg
since
ion,
definit
ilgaard [71] suggested the latter replace heterochromia in the
is
asia
hypopl
iris
unilateral hypopl asia of the iris gives a blue eye. When
te
comple
in
result
bilateral, both eyes are blue, but unilateral hypoplasia can
heterochromia irides with eyes of different colors.
Heterochromia Irides
hyIn total or complete heterochromia irides, the presence of unilateral
ghypopi
The
colors.
nt
differe
of
popigmentation (Fig. 128) gives rise to irides
heteroPartial
color.
blue
h
mented iris has a characteristic intense whitis

352
CHAPTER 1

FIGURE 127. Blue eyes in a

black with Waardenburg syndrome.

chromic irides refers to the condition in which one or both irides have a sector
that is differently colored from the rest of the iris. Heterochromia, partial or
complete, was found in 21% to 28% [16,18,26,41] of cases from the literature.
Hypopigmentation of the iris in one form or another was reported [18] in 87.5%
of 24 black patients and in 87% of 24 blacks collected from the literature.
Among 96 Caucasoid patients with Waardenburg syndrome, 81.3% of the cases
showed one or another form of iris hypopigmentation [18] . Thus, Negroids and
Caucasoids seem equally affected and iris hypopigmentation is a common feature of Waardenburg syndrome. Unilateral hypoplasia of the iris stroma may
be observed by slit-lamp examination.
The possibility that heterochromia irides results from unilateral hyperpigmentation is very remote [70].
Fundus Pigmentary Abnormalities
Abnormalities of fundus pigmentation have been noted in several cases of
Waardenburg syndrome. Although their exact incidence is unknown, retinal

353

GENETIC AND
CONGENITAL
DISORDERS

FIGURE 128. Heterochromic

irides in mother and child. Lateral displacement of the inner
canthi is apparent in the child.

pigmentary abnormalities must be considered as a feature of the disease and

may be related to irides hypoplasia.
As early as 1951, Waardenburg [16] stated that in a few cases "the fundus
seemed to take part in the pigment defect in minor degree." Couteau-Lagarde
and Collier [72] noted very fine snuff-like macular pigmentation of the fundus.
Di George et al. [23] observed in several patients a peculiar pigment mottling,
especially in the periphery of the fundus; one patient had retinal pigmentary
changes only in the eye with the blue iris but another patient with heterochromia irides had both retinas affected. Scott and Van Beukering [73] also
observed fundus pigment migration. Calinikos [56] and Hansen et al. [50] added
further examples, and the latter observed albinotic fundi in one case. Goldberg
[41], who noted fundus pigmentary abnormalities in several patients, considered it an integral part of the disease. de Haas and Tan [46J observed seven
cases of retinal depigmentation, in some instances located in the periphery and
in some other cases involving all of the retina except the macula. Reed et al.
[26] performed funduscopic examinations on 19 patients and observed pigmentary changes in about one-half. In general, two types of defects were ob-

354
CHAPTER 1

served. First was a generalized decrease in retinal pigment and, secondly, a

pigment mottling, particularly in the periphery. Such fundus pigmentation
abnormalities are usually not correlated with reduced visual acuity or with
abnormal electroretinography [41].
Dystopia Canthorum
Waardenburg [16] used the term "dystopia canthi medialis et punctorum
lacrimalium, lateroversa" to define the markedly increased distance between
the inner angles of the eyelids. This is found in 99% of the cases reported in
the initial description of the disease and, when present, must always strongly
suggest a diagnosis of Waardenburg syndrome. The markedly increased distance between the inner angles or medial canthi of the eyelids is accompanied
by an increased distance between, or lateral displacement of, the inferior lacrimal points, which are thus situated in front of the cornea (Fig. 129). The
interpupillary and outer canthal distances lie within normal limits so that there
is a shortening in the length of the palpebral fissure (blepharophimosis) (Fig.
130). Thus, there is reduced visibility of the medial sclera. The dystopia is
usually symmetrical, but may be asymmetrical.
Dystopia canthorum differs from hypertelorism. In the latter condition
there is no lateral displacement of inferior lacrimal points and the medial part
of the sclera is as visible as the temporal part. In hypertelorism the distances
between the pupils as well as the distance between the outer canthi are increased so that there is no blepharophimosis.
Waardenburg [16] considered "dystopia canthorum" to be pathognomonic
of this syndrome and later Partington [25] stated that the diagnosis of Waardenburg syndrome should be made with caution in patients without this sign.
But, in fact, the reported prevalence figures in various series show that
dystopia canthorum is not a constant feature of Waardenburg syndrome. Reed

FIGURE 129. Lateral displacement of the inner canthi and heterochromic irides.

355

GENETIC AND
CONGENITAL
DISORDERS

FIGURE 130. Demonstration of the interocular distances used to determine the presence of lateral
displacement of the inner canthi. (From Adams RD, Reed WB: Neurocutaneous disorders, in
Dermatology in General Medicine. Edited by TB Fitzpatrick et al. McGraw-Hill, New York, 1971,
p 1409. Copyright, 1971, McGraw-Hill Book Company. Used with permission.)

et al. [26] suggested that the correct incidence of dystopia canthorum in Waardenburg syndrome is lower than that reported by Waardenburg [16] and is
probably between 70% and 80%. A range of incidences of 41.2% to 77.9% has
been reported [18,26,74]. Numerous cases of Waardenburg syndrome without
dystopia canthorum have been described [1,16,23,37,49,60,61,75]. Soussi Tsafir
[18] established that dystopia canthorum is not as regular a feature of the disease
in families of black or deeply pigmented origin as it is in Caucasoids but was
unable to provide an explanation for this. She noted also that the incidence of
this feature in black and deeply pigmented individuals is nearly the same in
males (47.4%) and in females (52.6%).
Hageman and Delleman [3] separated Waardenburg syndrome into two
genetically distinct types: Type I has dystopia canthorum, and Type II does
not. A quarter of Type I and a half of Type II also experience eventual deafness.
Broadened Nasal Root

The hyperplasia of the root of the nose was thought by Waardenburg [16]
to be one of the characteristic features of the disease. He suggested that the
medial frontal process and portions of the two medial and lateral processes
have grown hyperplastic during embryonic development. In 1959, Fisch [37]
said that the dystopia canthorum may create the illusion of a wide nasal bridge
and that the nasal bridge, which is frequently depressed, is not necessarily
abnormally wide. As emphasized by Amini-Elihou [17], it is difficult to separate
these two hypotheses. Regardless, the impression of a broadened nasal root is
part of Waardenburg syndrome.
The incidence of broad nasal root is reported by Waardenburg [16] to be
78%. The reported incidence ranges from 17.6% to 54.5% [18,74]. In black or

356
CHAPTER 1

other deeply colored patients, the incidence is nearly the same in males (46.7%)
and females (53.3%) [18].
Soussi Tsafir [18] concluded, as there are no precise quantitative data on
normal widths of nasal roots and as this feature is difficult to assess in very
young individuals or in blacks, that the value of this feature in the diagnosis
of Waardenburg syndrome,particularly in blacks, is doubtful.
Medial Eyebrow Hyperplasia
Hypertrichosis of the medial eyebrows is characteristic of Waardenburg
syndrome. In some individuals the eyebrows are confluent (synophrys) and
these confluent hairs are usually of normal color. The incidence of hyperplasia
of the eyebrows is 17.6% to 69% [16,18,26,74]. Males and females are equally
involved.
Soussi Tsafir [18] concluded that the abnormal gene penetrates only in the
presence of at least moderate hairiness, as is more likely to be found in persons
with some Caucasoid ancestry.
Congenital Deafness
Fisch [37] observed the following two distinctive patterns of audiographs
in Waardenburg syndrome:
Type I: Almost total deafness with little residual hearing at the lower
frequencies.
Type II: Moderate degree of deafness with uniform hearing loss in the
lower and middle frequencies with a remarkable improvement in the higher
frequencies.
Fisch stated that Type I is rare and usually unilateral and that he never
observed Type II to be bilateral. These types are not correlated with those of
Hageman and Delleman [3].
Almost any combination of types of hearing loss may occur in the same
family and a combination of both types may be present in the same individual.
Partsch [60] stated that, as all possible combinations of types-bilateral or
unilateral, severe or moderate--may occur, there is no audiogram characteristic
of Waardenburg syndrome.
The incidence of deafness in Waardenburg syndrome is variably reported.
Waardenburg [16] found 20% to have hearing defects but a range of 9% to 37.5%
has been reported (Fig. 131). The latter figure arises from a study conducted
in a school for the congenitally deaf. Audiograms were not performed in all
patients, so it is possible in the initial reports that some cases of mild deafness
have been overlooked. Fram;ois et al. [74] observed in the cases with unilateral
deafness associated with unilateral iris depigmentation, that the involved ear
is on the same side as the blue eye.
Soussi Tsafir [18] found a comparatively high incidence of deafness, 62.5%
of her 24 black patients and 45.8% of blacks in the literature (54.6% in these
two combined series), and concluded that the relative high incidence of deafness among blacks exemplifies the difference in the expression of Waardenburg

357

GENETIC AND
CONGENITAL
DISORDERS

FIGURE 131. Deafness in Waardenburg syndrome. (Courtesy of

W. B. Reed. M.D.)

syndrome in different racial groups. She also noted that deafness in black
patients was much more prevalent among males than females.
Friedman and Fisch [76] reported the histopathology of the ear of a threeand-one-half-year-old girl with Waardenburg syndrome (who died of a respiratory infection). Findings included fully developed inner ears (utricle and
saccule), normal semicircular canals, absent organs of Corti, and obvious atrophy of the spiral ganglion and nerve. Pathologic examination of the cerebral
cortex in this same patient showed no involvement of the central auditory
pathway. Deafness was attributed to a defect in the organ of Corti and in the
8th cranial nerve. An absent organ of Corti and reduction of nerve fibers have
been seen in a cat with heterochromia irides.

Pathogenesis
Several theories have been advanced to explain all the features of the
Waardenburg syndrome. Any theory must be consistent with electron microscopic studies, which show an absence of melanocytes in the depigmented
skin and abnormalities of melanocytes in the clinically normal skin [69].
The "Deficient Neural Crest" Theory
In 1959, Fisch [37] suggested that a developmental abnormality of the
neural crest may give rise to Waardenburg syndrome.

358

Neural Crest Deficiency Can Induce Deafness

CHAPTER 1

Experiments involving extirpation of the neural crest in animals [77-79]

have shown that the neural crest is involved in the complex process of formation
of ear vesicles.
Neural Crest Deficiency Can Induce Skin and Hair Depigmentation
In all vertebrates, melanoblasts arise from the neural crest [80,81]. In mice
it has been shown that melanoblasts normally migrate from the neural crest to
all areas of the skin during days 8 to 12 of embryonic development. Experimental work in mutant mice with white spotting have shown that the neural
crest is implicated in the pathogenesis of depigmentation [82-84]. It has
been suggested that neural crest deficiency can affect skin and hair pigmentation by the following mechanisms: lack of appearance of melanoblasts at the neural crest levels, failure of melanoblasts to migrate from the
neural crest, or failure of melanoblasts to differentiate or survive in the skin
to which they migrated. The failure of differentiation or survival could result
from an abnormality within the melanoblasts resulting in increased fragility
and decreased resistance to hostile environmental influences. While all the
theories could explain total depigmentation, only the third mechanism can
explain the findings in Waardenburg syndrome. It is possible that melanoblasts
in this disease are altered during embryonic development of the neural crest
so that the sensitive melanoblasts can differentiate or survive in a favorable
environment but still have structural abnormalities, whereas, in the skin where
the environment is hostile, the melanoblasts do not survive or differentiate into
melanocytes. The common topography of hair and skin depigmentation in
piebaldism and in Waardenburg syndrome does suggest that some areas of the
skin represent a hostile environment for melanoblasts and melanocytes.
Pigmentary Disturbances Induced by Neural Crest Deficiency
Zimmerman and Becker [85] concluded from their observations on black
fetuses that the neural crest cells, which have been shown to be derived from
the primary optic vesicles, probably form the pigment of the iris, ciliary body,
and choroid.
An interesting case reported by Goldberg [41] further supports the neural
crest deficiency theory. A four-year-old girl was observed with Waardenburg
syndrome and congenital aganglionic megacolon (Hirschprung disease). It has
been demonstrated that the intrinsic innervation of the lower bowel originates
from cells in the cervical region of the neural crest [86,87] which migrate during
the embryonic life. Hirschprung disease has been reported in association with
congenital deafness [88,89] or with deafness and heterochromia irides [90]. In
mice, lethal spotting (ls) mutation is characterized in homo zygotes by extensive
white spotting and megacolon related to a defect in the development of the
neural crest [91]. Megacolon may also occur with the piebald mutant (s) [92].
An abnormality in neural crest development can explain many of the features observed in Waardenburg syndrome. However, some other signs (dystopia

canthorum, facial asymmetry) are difficult to explain with this hypothesis.

Probably the neural crest is involved by the pathogenic process, but other factors
probably also playa role.
Fisch [37] also suggested another possible relationship between the neural
crest and the heterochromia of Waardenburg syndrome. As the neural crest is
believed to be the source of sympathetic elements, and as unilateral paralysis
of the cervical sympathetic nervous system is known to be a possible cause of
heterochromia, neural crest deficiency may induce abnormalities in the sympathetic system. This results in heterochromia irides. But since other signs
expected to result from abnormalities of the sympathetic nervous system are
not observed in Waardenburg syndrome, this theory is difficult to accept.
Waardenburg Syndrome as a Part of the First Arch Syndrome
In 1958, McKenzie [93] included a case of Waardenburg syndrome in the
group of first arch syndromes. Stephens [32] hypothesized that a deficiency in
the embryologic blood supply can give rise to the first arch syndrome. The first
visceral arch is that region which later develops into the head and neck. During
the third to fifth weeks, the blood supply of this area depends on the three
following embryonic vessels in succession: the first aortic arch, the stapedial
artery, and the external carotid artery. In Waardenburg syndrome, the defect
is purported to concern the stapedial artery.
Soussi Tsafir [18] discussed this hypothesis and pointed out that pigmentary abnormalities similar to those in the Waardenburg syndrome rarely occur
with the other first arch syndrome conditions. McKenzie [93] explained white
forelock and heterochromia irides on the basis of poor nutrition. This is, in
fact, difficult to explain on an experimental basis, and Campbell et al. [1] agreed
that Waardenburg syndrome is a variant of the first arch syndrome and suggested that the gene defect that results in the first arch syndrome is next to or
near the locus of the gene controlling pigmentation.
Soussi Tsafir [18] also noted that the congenital deafness in the first arch
syndrome is secondary to cranial bone abnormalities, not identified with the
perceptive deafness in Waardenburg syndrome.
Furthermore, she noted that McKenzie [93] considers hypertelorism to be
a feature of the first arch syndrome. But this author described dystopia canthorum as hypertelorism in the patient that he reported with Waardenburg
syndrome. Since dystopia canthorum has nothing to do with the first visceral
arch, this observation simply produces confusion.
Thus, it seems highly unlikely that Waardenburg syndrome could be regarded as one of the first arch group. However, Soussi Tsafir [18] suggested a
possible connection between the first arch theory and the deficient neural crest
theory. Animal experiments suggest that a neural crest defect could cause
abnormal development of the first arch. Soussi Tsafir [18] hypothesized a "neural
crest syndrome" to include Waardenburg syndrome and some of the first arch
syndromes in which the time of the occurrence of the abnormality in the neural
crest, its site, and its degree differ. However, there is little evidence to support
this concept.

359

GENETIC AND
CONGENITAL
DISORDERS

360

Connection of Waardenburg Syndrome with Status Dysraphicus

CHAPTER 1

Waardenburg [16] in 1951, and later Pirodda et al. [42] in 1961, suggested
that Waardenburg syndrome might be related to status dysraphicus. Pirodda
et al. [42] hypothesized a mechanism to explain defective development of the
cervical region, alterations in the bone of the nasal roots, etc. Some patients
with Waardenburg syndrome have signs suggesting dysraphism, namely, patent
metopic suture [12,23,37,94]' cleft lip, or cleft palate (see Table 90). Heterochromia irides have also been described in patients with status dysraphicus
[42]. However, Passow [108] stated that uncomplicated heterochromia irides,
which is the type most encountered in patients with Waardenburg syndrome,
are not found in status dysraphicus. On an embryogenic basis, this hypothesis
is conceivable, as the mesenchymal cords forming the solid core of the frontonasal process are derived from neural crest cells [109] (closing anterior neuropore). So an abnormality in this region could explain a neural crest disturbance as well as facial developmental abnormalities; and neural crest abnormalities
induce the pigmentary abnormalities in the skin and hair. However, Pirodda
et al. [42] concluded that this mechanism should not be regarded as more than
a hypothesis. In fact, signs of dysraphism are not common in Waardenburg
syndrome.

TABLE 90. Other Features Associated with Waardenburg Syndrome

Central nervous system abnormalities
Mental retardation [49,61,64)
Seizures of EEG abnormalities [59,94,95)
Psychic disturbances [74)
Little's disease [49)
Skeletal and muscular abnormalities
Acrocephaly [96)
Macrocephaly [64)
Microcephaly [66)
Growth retardation [97)
Multiple abnormalities of the joints with or without amyoplasia [13,49,62,98)
Aplasia or hypoplasia of the ribs [13,64)
Osseous cysts of the sacrum and elbows [13)
Supernumerary pair of ribs [38)
Irregularity of the lumbosacral region and supernumerary lumbar vertebra [38)
Sprengel's deformation and Klippel-Feil syndrome [98)
Syndactyly [13,42,46,49,60,98,99)
Limb or extremity skeletal abnormalities [42,49)
Thorax skeletal deformity or pectus excavatum [42,46,64)
Absence of mastoid bone [100)
Spina bifida [13,34,42)
Myelocele [38,100,101)
Harelip [16,41-43,50,74,101)
Cleft palate or palatoschisis [8,16,24,26,40-43,49,50,67)
Absent uvula [12)
Decreased joint mobility [66)
High-arched palate [67)
(Continued)

TABLE 90.

(continued)

Skin and hair abnormalities

Localized abnormal growth of hair (nose, face, back) (Mende) [13,16,46,49,71,75,96]
Palmoplantar hyperkeratosis [17,47,61]
Thoracohumeral pterygion [13]
Cutaneous fibroma [13]
Tuberous xanthoma [65]
Miscellaneous
External auricular abnormalities [50,100,102]
Tooth abnormalities [13,24,97]
Hemophilia [103]
Esophageal atresia [37]
Anal imperforation [101]
Hirschsprung disease [41,104]
Cardiac interventricular communication [17,41,105]
Aortic stenosis [74]
Hodgkin disease [47]
Hand-Schiiller-Christian syndrome [31]
Familial periodic paralysis [43]
Familial hyperbetalipoproteinemia [65]
Osteosarcoma [66]
Hypogonadism [66]
Eye abnormalities
Glaucoma [16,106]
Unilateral microphthalmia [16]
Nystagmus [12]
Palpebral ptosis [26]
Cornealleukomas [100]
Chorioretinal atrophy, embryotoxin, and lacrimal fistula [97]
Ocular muscle paresthesia [42]
Lacrimal duct abnormalities (chronic dacryocystitis by stenosis or increased length
of ducts [7,12,16,63,71,106]
Epicanthus [74]
Antimongoloid palpebral fissure [13,63]
Ankyloblepharon [13,62]
Cataracts [66]
Retinal pigment mottling [67]
Hypopigmented fundus [67,107]
Strabismus [107]

The "Intrauterine Necrosis" Theory

Soussi Tsafir [18] noted that there is a striking similarity between some
signs of Waardenburg syndrome and some of those observed in Bonnevie-Ullrich syndrome and suggested that a similar pathogenesis might be responsible for both.
Bonnevie, in 1932, described a mutant mouse (my) characterized by head
and extremity abnormalities related to aggregation (blebs) of cerebrospinal fluid
migrating about the body [110]. The affected animals showed narrowing of the
palpebral fissures and sometimes microphthalmia, facial asymmetry, and de-

361
GENETIC AND
CONGENITAL
DISORDERS

362
CHAPTER 1

formation of the ears and limbs. Some skin areas to which blebs had migrated
were deficient in pigment. In these animals, it was found that excess cerebrospinal fluid collected below the epidermis in the neck regions of 7- to 8-mm
embryos and stagnated in concave areas. These blebs disrupted formative processes at critical phases. Substrains of these mice were obtained in which only
the head defects occurred related to a concentration of modifying genes which
reduced the probability of blebs migrating to the trunk region.
Ullrich [111] suggested a similar mechanism to explain some human congenital abnormalities of the head and extremities. A patient with Bonnevie-Ullrich syndrome showed facial asymmetry, broad nose, unilateral narrowing of the palpebral fissure, one iris darker than the other, and gray hair
interspersed with normally pigmented hair in the midfrontal region. Some of
these features are often observed in Waardenburg syndrome.
Soussi Tsafir [18] discussed the mechanism by which wandering blebs can
generate the features of Waardenburg syndrome. She suggested that areas of
skin or hair depigmentation might be the site of migration of a wandering bleb
and that heterochromia irides could result from the pressure exerted by a bleb
on the sympathetic nerve supply or blood supply to one eye. Soussi Tsafir also
hypothesized that the wandering cerebrospinal fluid blebs may affect the neural
crest and induce modifications in both melanoblasts and cells responsible for
auditory vesicle reduction.
Four pathogenic hypotheses have been discussed. None explains all the
features in Waardenburg syndrome. The most logical mechanism seems to be
a neural crest deficiency, a hypothesis supported by much experimental evidence. But these hypotheses are not mutually exclusive. It seems likely that
the defect in Waardenburg syndrome involves not only the neural crest, but
also other neighboring structures closely related to it during the embryonic life.
The nature of this defect is unknown.

Other Features Associated with Waardenburg Syndrome

Facial Appearance
Waardenburg [16] recognized a characteristic facial appearance in some of
these patients but he attributed this largely to the ocular abnormalities. Fisch
[37] observed in his patients a massive lower jaw associated with a relative
flatness of the nasal bridges. Fisch also stated that undoubtedly a typical configuration of the skull is part of the syndrome. Di George et al. [23] noted a
particular facial appearance with a prominent jaw in addition to ocular abnormalities. They described a typical appearance of the nose, which appears
thin because of the decreased flare of the alae nasae. The tip of the nose they
noted to be rounded and slightly upturned so that the columella is usually
easily visible. They also described full lips with a pronounced "cupid's bow"
and a shortened distance between the corners of the mouth. Soussi Tsafir [18]
found a massive jaw in two patients, but none of these other features in her 24
black patients. Waardenburg [16] also observed facial asymmetry in six of his
patients; others have made similar observations [1,25,72]. Retrognathism has
been described in some patients [13,24,94,112]. Waardenburg [16] observed, in

some cases, a faintly marked furrow in the forehead extending to the tip of the
nose. Fisch [37] also observed this in one of his patients.
In some cases, skull x-ray abnormalities have been reported. Patent metopic
suture has been observed. Occipitoparietal hyperostosis and frontal bossing
have been described [43,59].
Most of these features have been reported in only isolated cases.
Other Features
Various other abnormalities have been described in patients with Waardenburg syndrome. These are listed in Table 90.

Diagnosis and Differential Diagnosis (Table 91)

In the typical cases of Waardenburg syndrome in which the classical features are apparent, the diagnosis of Waardenburg syndrome is clear. Unfortunately, not all cases express the complete syndrome. For example, several
patients without eyelid abnormalities [1,16,23,37,49,60,75] have been reported
as having Waardenburg syndrome. What constitutes minimal expression of the
syndrome is unsettled. Waardenburg [16] thought that the presence of any
feature or combination of features in the first detected carrier was adequate for
diagnosis. Thereby, any subject with only one of the classical features could
be regarded as having a "forme fruste" of Waardenburg syndrome. Certainly,
if one or more relatives carry one or more of the features of Waardenburg
TABLE 91. Clinical Features of the Skin and Hair Pigmentary
Dilution in Waardenburg Syndrome
Mode of inheritance
Sex distribution
Age of onset
Course
Skin
Degree of dyschromia
Borders
Distribution
Extent
Course
Local symptomatology
Hair
Degree of dyschromia
Distribution

Associated findings

Autosomal dominant
MIF

Birth or soon after birth

Usually stable but white forelock may disappear
Achromia with islands of hyperpigmentation
Irregular, sharp margins
Forehead, anterior trunk, limbs
Variable
Stable-no spontaneous repigmentation
None
Hypochromia or achromia
White forelock
Early graying of scalp hair
Hypomelanosis of body hair, eyebrows,
eyelashes
Heterochromia or bilateral isohypochromia irides
Congenital deafness
Broad root of the nose
Dystopic canthorum

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364
CHAPTER 1

syndrome, the diagnosis is readily established. Yet, diagnosis in some cases

remains difficult to establish.
When there are only a few signs of Waardenburg syndrome, the family
history is essential. One of the other family members often bears another feature
of the disease.
Piebaldism is the first diagnosis to eliminate. Although in this disease the
pigmentary disturbances in skin and hair are strikingly similar to Waardenburg
syndrome, usual absence of auditory and ocular involvement helps to make
the correct diagnosis.
The other syndromes with pigmentary disorders and congenital deafness
have been described. But the pigmentary disorder in skin and hair is generalized
and the mode of inheritance is autosomal recessive. Furthermore, such cases
are quite rare. The syndrome of recessive vitiligo, congenital deafness, muscle
wasting, and achalasia has been described in only two patients and the suggested mode of inheritance is autosomal recessive. Partial albinism with deafness is sex-linked; some of the patients have heterochromia irides. Deaf-mutism
with albinism is of doubtful autonomy.
Fisch [37] described a "new syndrome" with early and pronounced graying
of the hair and congenital deafness. Some individuals (13 of 21) of the reported
pedigree showed partial heterochromia irides. The relationship of this autosomal dominant syndrome to Waardenburg syndrome is not clear, but Soussi
Tsafir [18] believes this to be a distinct entity. The same may be said of bilateral
progressive deafness of high-tone type associated with gold and silver hair and
steely-blue eyes.

Treatment
None is available. Early diagnosis permits appropriate treatment of the
deafness.

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48. Simpson JL et al: Analysis for possible linkage between the loci for the Waardenburg syndrome
and various blood groups and serological traits. Humangenetik 23:45-50, 1974
49. Sachs R: Dystopie du canthus interne associee a une forme fruste du syndrome de
Rocher-Sheldon. Ann Ocul (Paris) 197:672-683, 1964
50. Hansen AC et al: Waardenburg's syndrome: a report of a pedigree. J Natl Med Assoc 57:8-12,
1965
51. Pryor HB: A case of Waardenburg's syndrome. Am J Dis Child 122:177-178, 1971
52. Feingold M et al: Waardenburg's syndrome during the first year of life. J Pediatr 71:874-876,
1967
53. Ellis RWB: Heterochromia of irides and hair. Proc R Soc Med 24:1057-1058, 1931
54. Zelig S: Syndrome of Waardenburg with deafness. Laryngoscope 71:19-23, 1961
55. McDonald R, Harrison VC: The Waardenburg syndrome. Clin Paediatr (Phila) 4:739-744,
1965
56. Calinikos J: Waardenburg's syndrome. J Laryngol Otol 77:59-61, 1963
57. Mazzini G: Albinismo parziale ereditario a lunga discendenza. Riv Bioi 6:413-439, 1924
58. Borbolla L et al: Sindrome de Waardenburg. Rev Cubana Pediatr 33:161-170,1961
59. Grimaud R et al: Le syndrome de Waardenburg. J Fr OtorhinolaryngoI10:351-355, 1961
60. Partsch CJ: Hereditare Taubheit beim Syndrom nach Waardenburg-Klein. Z Laryngol Rhinol
Otol 41:752-762, 1962
61. Houghton NI: Waardenburg's syndrome with deafness as the presenting symptom. Report of
two cases. NZ Med J 63:83-89, 1964
62. Wilbrandt HR, Amman F: Nouvelle observation de la forme grave du syndrome de
Klein-Waardenburg. Arch Klaus-Stift Vererbungsf 39:80-92, 1964
63. Boniface L, Fontaine G: Le syndrome de Waardenburg (a propos de cinq observations). Ann
Pediatr (Paris) 13:788-793, 1966
64. Fregonese B et al: La syndrome di Waardenburg-Klein. Descrizione di due casi. Minerva
Pediatr 21:1513-1519, 1969
65. Amer M, El-Shazly M: The association of familial hyperbetalipoproteinemia with Waardenburg's syndrome. Br J Dermatol 90:255-262, 1974
66. Parry DM et al: Waardenburg-like features with cataracts, small head size, joint abnormalities,
hypogonadism, and osteosarcoma. J Med Genet 15:66-69, 1978
67. Amoni SS, Abdurrahman MB: Waardenburg's syndrome: case reports in two Nigerians. J
Pediatr Ophthalmol Strabismus 16:172-175, 1979
68. Anton-Lamprecht I et al: Zur Ultrastruktur der Haut beim Klein-Waardenburg Syndrom.
Hautarzt 23:462-473, 1972
69. Perrot H et al: Ultrastructural study of leucodermic skin in Waardenburg-Klein syndrome.
Acta Derm Venereol (Stockh) 57:195-200, 1977
70. Waardenburg PJ: Genetics and Ophtalmology, vol 1. Oxford, Blackwells, 1961
71. Thorkilgaard 0: Waardenburg's syndrome in father and daughter. Acta Ophthalmol (Kbh)
40:590-599, 1962
72. Couteau-Lagarde JM, Collier M: La meche frontale blanche et la myopie comme facteurs
"indicateurs" du syndrome de Waardenburg-Klein. J Genet Hum 12:146-153, 1963
73. Scott FP, Van Beukering JA: Waardenburg's syndrome: report of an abortive case. S Afr Med
J 36:299-300, 1962
74. Fram,ois Jet al: Syndrome de Waardenburg-Klein. Acta Genet Med Gemellol (Roma) 14:353-375,
1965
75. Diallinas NP: Les alterations oculaires chez les sourd-muets. J Genet Hum 8:225-262, 1959
76. Friedman I, Fisch L: Deafness as part of an herditary syndrome. J Laryngol Otol 73:355-382,
1959

77. Arey LB: Developmental Anatomy, 6th ed. Philadelphia, Saunders, 1954
78. Horstadius S: The Neural Crest. Oxford, Oxford Univ Press, 1950
79. Jacobson AG: The determination and positioning of the nose, lens, and ear. J Exp Zool
154:273-283, 285-291, 1963
80. Rawles ME: Origin of melanophores and their role in development of color patterns in vertebrates. Physiol Rev 28:383-408, 1948
81. Rawles ME: Origin of pigment cells from the neural crest in the mouse embryo. Physiol Rev
20:248-266, 1947
82. Mayer TC: The development of piebald spotting in mice. Dev BioI 11:319-334, 1965
83. Mayer TC, Green MC: An experimental analysis of the pigment defect caused by mutations
at the Wand SL loci in mice. Dev BioI 18:62-75, 1968
84. Mayer TC: A comparison of pigment cell development in albino, steel, and dominant-spotting
mutant mouse embryos. Dev BioI 23:297-309, 1970
85. Zimmerman AA, Becker SW: Precursors of epidermal melanocytes in the Negro fetus, in
Pigment Cell Biology. Edited by M Gordon. New York, Academic, 1959, pp 159-170
86. Okamoto E, Ueda T: Embryogenesis of intramural ganglia of the gut and its relation to Hirschsprung's disease. J Pediatr Surg 2:437-443, 1967
87. Yntema CL, Hammond WL: The orgin of intrinsic ganglia of trunk viscera from vagal neural
crest in the chick embryo. J Comp NeuroI101:515-541, 1954
88. Bodian M, Garter CO: A family study of Hirschsprung's disease. Ann Hum Genet 26:261-271,
1962-1963
89. Skinner R, Irvine D: Hirschsprung's disease and congenital deafness. JMed Genet 10:337-339,
1973
90. McKusick VA: Mendelian Inheritance in Man, 3rd ed. Baltimore, Johns Hopkins Press, 1970
91. Lane P: Quoted in Mayer MC: The development of piebald spotting in mice. Dev BioI 11:319-334,
1965
92. Bielchowsky M, Schofield GC: Studies on megacolon in piebald mice. Aust J Exp BioI Med
Sci 40:395-404, 1962
93. McKenzie J: The first arch syndrome. Arch Dis Child 33:477-486, 1958
94. Mouraux JM: Le syndrome de Waardenburg. These, Nancy, 1962
95. Porot M, Filiu S: Un deuxieme cas de surdi-mutite avec heterochromie irienne et epilepsie.
Rev Otoneuroophtalmol 31:481-483, 1959
96. Keizer DPR: Een niuewe vorm van congenitale doofheid (syndroom van Waardenburg). Ned
Tijdschr Geneeskd 96:2541-2543, 1952
97. CalmeUes L et al: Syndrome de Waardenburg-Klein avec fistules lacrymales borgnes. Bull
Soc Othtalmol Fr 81:144-155, 1968
98. Stoller FM: A deaf mute with two congenital syndromes. Arch Otolaryngol 76:42-46, 1962
99. Gedda L, Magistretti SB: Sulle anomalie pigmentarie dell'occhio deUe "albinismo oculare"
ed ancora sopra il caso delle gemelle monozigotiche albine descritte da Hanhart. Acta Genet
Med Gemellol (Rom a) 10:21-47, 1961
100. Bwibo NO, Mkono MD: Waardenburg's syndrome in an African child. Hum Hered 20:19-22,
1970
101. Roux C et al: Le syndrome de Waardenburg; une observation familiale sur 4 generations et
23 sujets. Ann Genet (Paris) 13:125-128, 1970
102. Robinson GC et al: Waardenburg's syndrome. The risk of recurrence of congenital deafness
in a kindred. J Pediatr 67:491-494, 1965
103. Basile R: A pedigree of binocular heterochromia iridis associated with other anomalies (Waardenburg-Klein syndrome). J Genet Hum 14:87-92, 1965
104. Omenn GS, McKusick VA: The association of Waardenburg syndrome and Hirschsprung
megacolon. Am J Med Genet 3:217-223,1979
105. Ray DK: Waardenburg's syndrome. Br J Ophthalmol 45:568-569, 1961
106. Walsh FB, Hoyt WF: Clinical Neuro-ophthalmology, 3rd ed. Baltimore, Williams & Wilkins,
1969
107. Delleman JW, Hageman MJ: Ophthalmological findings in 34 patients with Waardenburg
synclfome. J Pediatr Ophthalmol Strabismus 15:341-345, 1978
108. Passow A: Hornersyndrom, Heterochromie und Status dysraphicus, ein Symptomen komplex.
Arch Augenheilk 107:1-51, 1933
109. Wits chi E: Prenatal development, in Congenital Anomalies of the Face and Associated Structures. Edited by S Pruzansky. Springfield, Ill, Thomas, 1961, p 103

367

GENETIC AND
CONGENITAL
DISORDERS

368

110. Bonnevie K: Zur Meckanik der Papillarmusterbildung: Anomalien der menschlichen Finger-

CHAPTER 1

und Zehenbeeren, nebst Diskussion tiber die Natur der hier wirksamen Epidermispolsten.
Arch Entwicklungsmeckanik Organ 126:348-372, 1932
111. Ullrich 0: Turner's syndrome and status Bonnevie-Ullrich. Am J Hum Genet 1:179-202,
1949
112. Delmarcelle Y, Pivont A: Heterochromie familiale associee a des malformations oculaires et

somatiques: syndrome de Waardenburg-Klein. Bull Soc BeIge Ophtalmol 118:380-390,

1958

FIGURE 132. a-d: Hypomelanosis involving head, arms, and chest in brother of patient in Fig.
133; both have hereditary piebaldism and congenital deafness syndrome. (From: Woolf CM et al:
Congenital deafness associated with piebaldism. Arch Otolaryngol 82:244-250, 1965. Copyright,
1965, American Medical Association. Used with permission.)

PIEBALDISM WITH DEAFNESS (WOOLF SYNDROME)

Woolf et al. [1,2] reported two Hopi Indian brothers with piebaldism and
deafness. These two patients, eight and 12 years of age, had similar patterns
of hypopigmentation. Cutaneous hypopigmentation involved the entire head
and the hair, as well as a strip across the upper chest and over the arms; the
remainder of the skin, including the back and legs, had normal pigmentation
(Figs. 132, 133). Small pigmented macules were scattered within the depig-

FIGURE 132 (Continued)

369

GENETIC AND
CONGENITAL
DISORDERS

370
CHAPTER 1

mented areas. These cutaneous pigmentary abnormalities were present at birth

and changed little during the developing years. Both brothers had blue irides
and were deaf mutes. Caloric vestibular testing was normal. They had normal
parents and one normal sibling.
Two similar cases have been recorded by Reed et al. [3], who reported a
six-year-old girl and a 21-year-old man, both with deafness, white forelock,

FIGURE 133. a-d: Hypomelanosis involving head, arms, and chest in brother of patient in Fig.
132; both have hereditary piebaldism and congenital deafness syndrome. (From: Woolf eM et al:
Congenital deafness associated with piebaldism. Arch Otolaryngol 82:244-250, 1965. Copyright,
1965, American Medical Association. Used with permission.)

and symmetrical white macules over the arms, legs, and abdomen. Di George
et al. [4] reported piebaldism and deafness in a young black female.
Reed et al. [3] concluded that it is unlikely that piebaldism and deafness
had occurred together in these patients as separate genetic defects, and Konigsmark [5] suggested that it is likely that this syndrome is transmitted as an
autosomal recessive trait.

FIGURE 133 (Continued)

371

GENETIC AND
CONGENITAL
DISORDERS

372

CHAPTER 1

REFERENCES
JHum Genet 17:23-35,
1965
Woolf CM et al: Congenital deafness associated with piebaldness. Arch OtolaryngoI82:244-250,
1965
Reed WB et al: Pigmentary disorders in association with congenital deafness. Arch Dermatol
95:176-186, 1967
Di George AM et al: Waardenburg's syndrome. J Pediatr 57:649-669,1960
Konigsmark BW: Hereditary childhood hearing loss and integumentary system disease. JPediatr
80:909-919, 1972

1. Woolf CM: Albinism among Indians in Arizona and New Mexico. Am

2.
3.
4.
5.

FIGURE 134. a, b: Three children with large macules of hyperpigmentation, particularly in inguinal and buttock areas, on a hypomelanotic background, in the Ziprkowski-Margolis syndrome
of sex-linked pigmentary abnormalities and congenital deafness. (From: Ziprkowski E et al: Partial
albinism and deaf mutism due to a recessive sex-linked gene. Arch Dermatol 86:530-539, 1962.

Copyright, 1962, American Medical Association. Used with permission.)

ZIPRKOWSKI-MARGOLIS SYNDROME
In 1962, Ziprkowski et al. [1] and Margolis [2] reported a syndrome affecting
14 males in an Egyptian Jewish family. The syndrome consisted of deaf-mutism,
heterochromia irides, cutaneous and hair depigmentation, and localized hyperpigmentation. Since all the affected individuals were male and in all cases
the transmission was through a female carrier, this syndrome was considered
to be X-linked recessive. No "forme fruste" was discovered among the healthy
family members, including the carriers. This syndrome has been referred to as
"partial albinism" with deafness.

FIGURE 134 (Continued)

373

GENETIC AND
CONGENITAL
DISORDERS

374

CHAPTER 1

In the affected individuals, the skin was congenitally whitish pink in appearance. Later, hyperpigmented spots appeared, mainly on the extremities,
trunk, and rarely on the scalp, in a bilateral or roughly symmetrical distribution.
The macules were either round, oval, polycyclic, or geographical in shape, from
a few millimeters to several centimeters in size, and from light yellow-brown
to brown-black in color (Fig. 134). The presence of widespread depigmentation
and localized hyperpigmentation gave a leopard appearance. In all the patients,
the gluteal and scrotal regions were congenitally light to dark gray-brown in
color.
The hair in most cases was completely white, even over the pigmented
macules of the scalp, but in one of the patients the hair was straw colored.
Eyebrows and eyelashes were achromic.
Heterochromia irides and possibly isochromia were observed in several
patients, none of whom has nystagmus, photophobia, dystopia canthorum, or
hyperplasia of the base of the nose.
All patients were congenital deaf mutes. From audiometric examination,
it was apparent that the deafness was of the perceptive type. Caloric tests
indicated vestibular dysfunction.
Histologic studies of the hyperpigmented skin showed a strong dopa-positive reaction, as opposed to the weak reaction in the hypopigmented skin.
There was no obvious difference in the number of melanocytes in the hyperpigmented and the depigmented skin. This clearly distinguishes Ziprkowski-Margolis syndrome from piebaldism, Waardenburg syndrome, and vitiligo.
Another patient, reported by Campbell et al. [3], may be an example of
this disorder. This six-year-old white male, born of normal parents, had congenitally white hair and skin, blue eyes, and bilateral nerve deafness. At the
age of two, hyperpigmented macules appeared all over his body and a large
dark macule appeared on the sacrum. Nystagmus, photophobia, dystopia canthorum, and enlargement of the nasal root were not observed. However, because
of the negative family history, and because histologic examination of the depigmented skin was not performed, this child cannot be said definitely to have
the Ziprkowski-Margolis syndrome.
Histologically, in Ziprkowski-Margolis syndrome melanocytes are present
in the hypochromic skin; further electron microscopic studies are required to
characterize the subcellular abnormalities. Ziprkowski-Margolis syndrome appears to be a distinct entity. The mode of inheritance, the clinical and histologic
picture, and the course differ from all other depigmentary syndromes associated
with congenital deafness. It has been suggested to arise from an abnormality
of the neural crest.

REFERENCES
1. Ziprkowski L et al: Partial albinism and deaf-mutism due to a recessive sex-linked gene. Arch
Dermatol 86:530-539, 1962

2. Margolis E: A new hereditary syndrome-sex-linked deaf-mutism associated with total albinism.

Acta Genet (Basel) 12:12-19, 1962
3. Campbell B et al: Waardenburg's syndrome: a variation of the first arch syndrome. Arch Dermatol
86:718-724, 1962

TUBEROUS SCLEROSIS
... if infants have the typical white macules at birth, it is probable that tuberous
sclerosis is present [1].

Tuberous sclerosis is an uncommon neurocutaneous syndrome affecting the

nervous system, skin, eyes, and, less often, the heart, lungs, kidneys, and bones.
Although tuberous sclerosis is commonly expressed by the triad of adenoma
sebaceum, seizures, and mental retardation, these findings are preceded by
white macules. In fact, the diagnosis may initially be made by the dermatologist
who appreciates the significance of the white macules in a neonate or by the
physician who thinks to examine with a Wood's light the infant with infantile
spasms or mental retardation.
The general frequency of tuberous sclerosis has been estimated to be one
in 150,000 in Northern Ireland [2], one in 100,000 in the United States [3], and
one in 300,000 in England [4]. Tuberous sclerosis accounted for one in 20,000
of the registrations at the Mayo Clinic [5]. It accounts for 0.33% of epilepsy
and 0.66% of mental retardation [3].
Genetic studies [6,7] suggest an autosomal dominant pattern of inheritance
but spontaneous mutation appears to be responsible for most of the cases. Nevin
and Pearce [8] reported a 75% spontaneous mutation rate, Bundey and Evans
[9] 80% to 90%, and Ponsot and Lyon [10] 83%. Males and females are equally
affected and no race appears to be spared.

History of Awareness of Cutaneous Hypopigmentation

in Tuberous Sclerosis
Although tuberous sclerosis was initially described by Bourneville [11] in
1880, it was not until 1932 that leukoderma was appreciated as a feature of the
disorder; Stewart and Bauer [12] described hypopigmented macules on the

nasolabial fold of a black girl with tuberous sclerosis. In the same year, Critchley
and Earl [13] observed a case of segmental hypopigmentation and two cases of
"patches of abnormal whiteness," that were the same size and shape as cafeau-lait spots. Another of their patients had, on the lateral half of one eyebrow,
a localized patch of canities. Hopwood [14], in 1937, observed innumerable
small white macules or "pale" freckles, mostly from 1 to 3 mm in size, scattered
over the skin of patients with tuberous sclerosis. In 1938, Jones and Prior [15]
reported three cases of tuberous sclerosis in one family; all had macules of
leukoderma on unexposed areas of skin. Later, in 1941, Butterworth and Wilson
[16] also noted hypopigmented macules in those with tuberous sclerosis. In
1947, Combe et al. [17] reported "vitiligo patches" all over the body of a 30month-old girl with tuberous sclerosis but called it "nevus anemicus." Debre
et al. [18], in 1952, reported three cases of tuberous sclerosis with depigmented
patches. Goodgred [19], discussing two patients presented by Friedman [20] in
1948, suggested depigmentation to be part of the disease. Chao [21], in 1959,
stated that while these areas of depigmentation were more common than cafeau-Iait spots, they were not diagnostic for tuberous sclerosis and called them
vitiligo. In 1962, Nickel and Reed [22] found leukoderma or poliosis in 40 of

375

GENETIC AND
CONGENITAL
DISORDERS

376
CHAPTER 1

61 patients with tuberous sclerosis but considered these to be coincidental or

but minor features of tuberous sclerosis and of no diagnostic value. Becker [23]
too thought leukoderma in tuberous sclerosis represented vitiligo.
The diagnostic value of the leukoderma may have been first appreciated
by Gold and Freeman [24] who observed seven patients with depigmented nevi
and convulsions. They postulated that depigmentation may be the initial cutaneous manifestation of tuberous sclerosis; biopsy of the depigmented lesions
showed a lack of melanin pigment. Crichton [25] then, in 1966, found nine of
174 cases with infantile spasms to have depigmented nevi and observed that
most of these patients had tuberous sclerosis. In 1966, Aicardi et al. [26] found
hypomelanotic macules in 15 of 42 patients with tuberous sclerosis. Harris and
Moynahan [27], in 1966, reported two cases of tuberous sclerosis who presented
with hypopigmented macules that had been observed within the first year of
life; although they called this "vitiligo" they commented that leukoderma was
the earliest manifestation of tuberous sclerosis and noted the presence of depigmented macules in half of 38 cases of tuberous sclerosis. Moynahan [28]
reported the presence of hypopigmented macules in 1000 patients with tuberous sclerosis and suggested that such macules occur in no other condition at
birth and, that in the presence of convulsions, are pathognomonic for tuberous
sclerosis. Fitzpatrick et al. [1] first described the leaf-shaped white macules (or
mountain ash-leaf spots) probably to be pathognomonic for tuberous sclerosis;
they noted these macules may be the sole cutaneous feature of tuberous sclerosis. Later work by Tilgen [29] and Jimbow et al. [30] has shown the white
macules to have distinctive electron microscopic features.

Clinical Features (Fig. 135)

The incidence of white macules in tuberous sclerosis is reported to be 15%
to 75% [31], but specific incidences of 50% [14], 61% [8], 67% [22], 77% [32],
78% [33], 87% [33a], 90% [34,35], and 96% [36] have been reported in the
literature. The wide range of incidence figures may result from failure to examine patients with the Wood's light so that lesions inapparent to the unaided
eye also were overlooked. In a survey utilizing Wood's light, Soter et al. [37]
found hypomelanotic macules in 64 of 65 patients with tuberous sclerosis, but
the high incidence figure may be an artifact of referral selection.
Hypomelanotic macules are usually apparent at birth [8,21,31,33] or in the
neonatal period [38]. In fact, all lesions are probably present at birth but may
on occasion be inapparent, particularly in fair-skinned individuals, until the
skin is exposed to ultraviolet tanning rays or the patient is examined with a
Wood's light [1].
Soter et al. [37] summarized the clinical features of these hypomelanotic
macules from the evaluation of 64 tuberous sclerosis patients in whom these
were observed (Table 92).
The number of lesions varies from one to over 100 per patient. In the series
of 64 tuberous sclerosis patients with white macules, seven had only a single
white macule, six only two, and 51 had three or more white lesions [37]. The

377
GENETIC AND
CONGENITAL
DISORDERS

POLYGONAL
---'>-III""-of--i HYPOPtGMENTED
MACULES

IUCUlES

HYPOPIGIIENTATION

IN OERIIATOIIAL
DlSTRIBUTlON

FIGURE 135. Hypopigmentation in tuberous sclerosis.

great majority of patients have one to 20 macules, with 50% having fewer than
five and 50% having six or more macules (Fig. 136). Lesions may be lanceovate, "thumbprint," confetti, or segmental. Of the 18 patients with tuberous
sclerosis examined by Hurwitz and Braverman [33], 10 had hypomelanotic
macules. Of these lesions only 18% were lance-ovate; the white macules were
usually oval, round, or polygonal, the latter being the most common (Fig. 137).
The most characteristic but not the most frequent configuration of hypopigmented macules of tuberous sclerosis is the lance-ovate or mountain ash-leaf
spot described by Fitzpatrick et al. [1] (Figs. 138, 139). In five of 64 patients,
Soter et al. [37] noted a dermatomal distribution of depigmented macules (Fig.
140); this pattern was also observed by Critchley and Earl [13] and Zeremba
[32]. A confetti pattern has also been observed in three of the 18 patients
reported by Hurwitz and Braverman [33], and in two of the 64 patients of Soter
et al. [37] (Figs. 141, 142).

378

10

CHAPTER 1

"'
'E

.S!

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(;j

'0
CD

::I

r-- .

"

n-t.

f--

"

t--

r2

H }11

I I I ,{

11
10 12 13 14 15 16 17 18 19 20 22 27 106

Number of Hypomelanotic Macules

FIGURE 136. Number of hypo pigmented macules per patient in each of 52 patients.

FIGURE 137. Several types of hypomelanotic lesions in a single patient (segmental, lance-ovate,
and small thumbprint macules). Same patient as in Figure 140.

TABLE 92. Clinical Features of Hypomelanotic Maculesu

GENETIC AND
CONGENITAL
DISORDERS

Number
1 to 100
Distribution Frequency
Trunk
Posterior trunk
(including buttocks)
Anterior trunk
Lower extremities
Upper extremities
Head and neck

56.3%
35.7%
20.6%
32.5%
6.4%
4.8%

Shape
Common
Polygonal
Lance-ovate (ash leaf)
Rare
Dermatomal
Confetti
Size
Polygonal
Ash-leaf (long axis)
Confetti
o

379

0.5-2.0 cm
3.0-4.0 cm (range 1.0-12.0 cm)
Hundreds of 0.1-0.3 cm macules

Source: Soter NA et al: Hypomelanotic macules in tuberous sclerosis. A study of

65 patients (in preparation). Used with permission.

FIGURE 138. Lance-ovate macules (double arrow); thumbprint macules (single arrow).

380

CHAPTER 1

FIGURE 139. The Eastern mountain ash leaf. Each leaflet is the shape of lance-ovate macules of
tuberous sclerosis.

Dermatomal hypomelanosis in tuberous sclerosis. (From: Adams RD. Reed WB:

Neurocutaneous disorders. in Dermatology in General Medicine. Edited by TB Fitzpatrick et al.
New York. McGraw-Hill. 1971. p 1391. Copyright. 1971. McGraw-Hill Book Company. Used with
permission.)

FIGURE 140.

381

GENETIC AN[
CONGENITAl
DISORDER~

FIGURE 141. Confetti-like hypomelanosis on the legs in mother and son with tuberous sclerosis.
(From: Adams RD, Reed WB: Neurocutaneous disorders, in Dermatology in General Medicine.
Edited by TB Fitzpatrick et al. New York, McGraw-Hill, 1971, p 1391. Copyright, 1971, McGraw-Hill Book Company. Used with permission.)

FIGURE 142. Close-up view of confetti-like hypomeianotic macules.

382
CHAPTER 1

Hypopigmented macules usually are found on the trunk, particularly posteriorly, but may be present on any cutaneous surface except the hands, feet,
and genitalia [37] (Fig. 143). Hypopigmented macules may involve, in descending order of frequency, the lower extremities, the upper extremities, and the
head and neck [37]. On the lower extremities, hypopigmented macules are
more common above rather than below the knees and occur with equal frequency on the flexor and extensor surfaces.
The long axis of the lance-ovate (ash-leaf) macules is predominantly in the
cephalocaudal direction on the extremities and in the transverse direction on
the trunk [37] (Fig. 144).
Hurwitz and Braverman [33] found the length of the hypopigmented lesions
to be from 4 mm to 7 cm, with the average length from 1 to 3 cm (Fig. 145).
The size of the polygonal lesions ranges from 0.5 to 2.0 cm, and the lance-ovate
(ash-leaf) lesions from 1.0 to 12 cm (usually 3 to 4 cm) in length [37].

'*

'I'..-'.

:~
.'

.::.' ;:"../

."
.. .::

t (

..'....... . ...
"..

~:.

/"'

~,

""

o.

FIGURE 143. Anatomical distribution of hypomelanotic macules in 42 patients with tuberous

sclerosis. (From: Soter NA, Hori Y, Fitzpatrick TB: Unpublished data. Used with permission.)

383

GENETIC AND
CONGENITAL
DISORDERS

Lance-ovate macules in tuberous sclerosis are most

commonly oriented transversely
on the trunk.
FIGURE 144.

FIGURE 145.

Unusually large hypomelanotic macule in tuberous sclerosis.

384
CHAPTER 1

These macules are a dull white (hypo melanotic) , not the "pure white"
(amelanotic) of vitiligo. Since the lesions are not pure white, on casual examination of fair skin they may be inapparent. Wood's light examination reveals
only partial depigmentation.
The margins of the lesions are usually smooth but may be irregular [33].
The relative size and the number of the white macules does not change
with age and spontaneous disappearance does not occur. Bundey and Evans
[9] suggested that hypomelanotic macules occur most frequently in patients
under 10 years of age. They found hypomelanotic macules to be present in
82% of patients under 10, and 37% of patients over 10 years of age. However,
Hurwitz and Braverman [33] found, with Wood's light examination, that hypomelanotic macules were present in 89% of patients under 10 and in 71% of
patients over 10 years of age. The series of Bundey and Evans [9] and Soter et
al. [37] confirm that hypomelanotic macules persist unchanged through life.
There is no support for the hypothesis of Wilson [39] that with advancing
age hypomelanotic macules of tuberous sclerosis become cafe-au-Iait spots. The
striking differences between the melanosomes of the hypomelanotic macules
of tuberous sclerosis [30] and the giant granules in cafe-au-Iait spots of neu-

FIGURE 146. Hypomelanosis of hair (poliosis) in a patient with tuberous sclerosis. (From: Jimbow
K et al: Congenital circumscribed hypomelanosis: a characterization based on electron microscopic
study of tuberous sclerosis, nevus depigmentosus and piebaldism. J Invest Dermatol 64:50-62,
1975. Copyright, 1975, The Williams & Wilkins Co. Used with permission.)

rofibromatosis [40,41] or the larger than normal melanosomes in cafe-au-lait

spots in normal people [42,43] militate against this hypothesis.
Hurwitz and Braverman [33] have reported several instances of perifollicular sparing of pigment loss within several lesions. We have seen one patient
with many such lesions, most being of the "thumbprint" variety.
The white macules of tuberous sclerosis may become erythematous with
irritation or sunburn. Although the macules tan poorly, Hurwitz and Braverman
[33] reported one patient with depigmented macules that tanned partially. The
hypo melanotic macules have normal cutaneous sensation. Stroking produces
a normal flare. Sweating in the hypomelanotic areas is normal.
There may be white hair within the white patches. Poliosis occurring in
the eyebrows, eyelashes, and scalp has been reported in tuberous sclerosis
[13,22,37,44] (Fig. 146). In 61 patients with tuberous sclerosis, nine had leukoderma and poliosis and two had poliosis alone [22]. Soter et al. [37] observed
poliosis of the scalp in five of their 65 patients (Fig. 147). In four children, one
or more patches of depigmented scalp hair were observed at birth; in one case
it is said the characteristic white macules, however, were not apparent until
months later [38].

FIGURE 147. Depigmentation of hair may be subtle.

385

GENETIC AND
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Iris pigmentation is usually normal although one patient with a depigmented iris sector has been described [45].Fundal white macules like the ashleaf spots have been described [45a].

Histology and Electron Microscopy of White Macules

There have been several histopathologic studies of the white macule in
tuberous sclerosis. Gold and Freeman [24] reported the white macules to be
devoid of melanin. Degos et al. [46] reported decreased tyrosinase activity.
Fitzpatrick et al. [1] noted decreased melanocyte count. decreased dopa reaction. and decreased melanosome size and melanization. Tilgen [29]. in 1973.
reported a marked decrease in the number of mature melanin granules. and
the presence of immature melanin granules in only a few lysosomal complexes
of adjacent keratinocytes.
Electron microscopy findings. according to Jimbow et al. [30]. are summarized in Table 93 (Figs. 148. 149. 150). Hypomelanosis in tuberous sclerosis
does not appear to result from a reduction in the number of melanocytes but
rather from decreased size. impaired synthesis. and poor melanization of melanosomes. According to Jimbow et al. [30]. tuberous sclerosis is distinctive
from other circumscribed congenital hypomelanoses in that it alone is characterized by decreased melanosome size. Furthermore. regardless of racial background. most of the melanosomes in the keratinocytes are distributed in the
complexes. Some experimental studies suggest that keratinocyte packaging of
TABLE 93. Electron Microscopy Features of the Hypomelanotic Macule in
Tuberous Sclerosisa
Hair

Skin
Melanocytes
Number
Dopa reaction
Dendrites

Normal
Normal or decreased
Poorly developed

Normal
Normal or decreased
Poorly developed

Melanosomes
Size
Shape
Inner structure
Melanization
Number in melanocytes
Secretion
Number in keratinocytes

Decreased
Normal (ellipsoidal)
Normal (lamellae)
Decreased markedly
Decreased
Normal
Decreased

Decreased
Normal
Normal
Decreased markedly
Decreased
Normal
Decreased

Normal in Caucasoids;
abnormal in
Negroids (Le., in
aggregates)
Normal

Normal

Keratinocytes
Distribution pattern of melanosomes

Degradation of melanosomes
Q

Source: Jimbow K et al: Congenital circumscribed hypomelanosis: a characterization based on electron microscopic study of tuberous sclerosis, nevus depigmentosus, and piebaldism. J Invest Dermatol 64:50-62, 1975.
Copyright, 1975, The Williams & Wilkins Company. Used with permission.

387
GENETIC AND
CONGENITAL
DISORDERS

FIGURE 148. Hypomelanotic skin and normal control skin ina Caucasoid with tuberous sclerosis.
a: Normal unexposed back skin. The melanocyte (MC) contains melanizing melanosomes (arrows)
and a large perikaryon. The keratinocyte (KG) surrounding this melanocyte contains a large number
of melanosome aggregates (x 3900). b: Melanocyte containing many melanosomes (arrows) in
various stages of melanization (x 12,000). c: Hypomelanotic skin in tuberous sclerosis. Note the
reduction in the number of melanosomes in the melanocyte (MC). All the recognizable melanized
melanosomes are in the keratinocytes (KC). The number of these melanosomes is apparently decreased. The perikaryon of the melanocyte also is smaller (x 4000). d: All the melanosomes
(arrows) in the melanocytes are in unmelanized stages and appear to be smHller (x 12,000). (From:
Jimbow K et al: Congenital circumscribed hypomelanosis: a characterization based on electron
microscopic study of tuberous sclerosis, nevus depigmentosus and piebaldism. J Invest Dermatol
64:50-62, 1975. Copyright, 1975, The Williams & Wilkins Co. Used with permission.)

388

CHAPTER 1

FIGURE 149. Hypomelanotic skin and normal control skin in a Negroid with tuberous sclerosis.
a: Normal control skin. The keratinocyte (KC) contains a large number of melanosomes. The
melanocyte (MC) contains many melanized melanosomes. (x 4,400). b: A high-power view of the
melanosomes in the keratinocytes of the normal control skin. Note the single distribution of the
melanosomes. (x 8,000). c: Hypomelanotic skin. Note the reduction in the number of melanosomes
in the melanocyte (MC) and keratinocytes (KC). Compared with the normal skin, the skin has fewer
and less melanized melanosomes in the melanocytes. (x 4,100). d: A high-power view of the
melanosomes in the keratinocytes of the hypomelanotic skin. Note that all the melanosomes form
a complex. (x 7,000). (From: Jimbow K et al: Congenital circumscribed hypomelanosis: a characterization based on electron microscopic study of tuberous sclerosis, nevus depigmentosus and
piebaldism. J Invest Dermato! 64:50-62, 1975. Copyright, 1975, The Williams & Wilkins Co. Used
with permission.)

HYPOPIGMENTED
HAIR

NORMAl HAIR

. 21'.

SIZE

309..,.

..

~52!>-i

P(o.0005

DIS1RIBUTlDN
IN
KERATINOCYTE

FIGURE 150. Compared to normal skin, melanosomes are decreased in size in hypopigmented
hair and skin in tuberous sclerosis. (Courtesy of K. Jimbow and T. B. Fitzpatrick.)

melanosomes may be a size-dependent phenomenon; the aggregated pattern of

melanosomes in keratinocytes of blacks in tuberous sclerosis may be secondary
to the decreased size of these organelles. However, in another study, the size
of melanosomes did not show a significant difference between hypo- and normomelanotic skin [46a]. The authors found a decrease in the number of Stage
III and IV melanosomes and an increase of Stage II melanosomes in the hypomelanotic macules. They concluded that it is possible to characterize hypomelanosis in tuberous sclerosis reliably, which may have diagnostic importance.

Other Cutaneous Features

Adenoma sebaceum has been reported in 53% [33a], 74% [33], 83% [5],
83.3% [8], 90% [13,32]' and 100% [4] of cases (Fig. 151). These lesions are
usually multiple and appear most often at two to five years of age, although
lesions may appear up to puberty or later [6]. They are dome-shaped, pink to
red nodules that occur symmetrically on the nasolabial fold, cheeks, chin,
forehead, and scalp; the upper lip is spared except centrally inferior to the
nose. One patient with hypopigmented macules at birth and angiofibroma of
the lower eyelid has been observed [47]. In 33% of the patients of Lagos and
Gomez [5], adenoma sebaceum was the only cutaneous feature of tuberous
sclerosis. But typical tuberous sclerosis can occur without adenoma sebaceum
[48]. In 12 cases of tuberous sclerosis diagnosed early, the leukoderma and the
epilepsy were apparent before the angiofibromas were clinically evident [36].
In 20 of 30 cases of Debard et al. [34], the diagnosis was established from
epilepsy and achromic macules, again before the adenomas were apparent. The
term "adenoma sebaceum" is a misnomer as the histopathology is that of an
angiofibroma.

389
GENETIC AND
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DISORDERS

390
CHAPTER 1

FIGURE 151. Adenoma sebaceum.

Shagreen patches are found in 21% [5], 47% [32], 48% [33], and 83% [8]
of patients with tuberous sclerosis; they are present as white collagenous plaques
1 to 20 mm in size and are usually located on the lower back and less often
on the scapular region or extremities (Fig. 152). The spectrum of appearance
of the lesions ranges from white "pigskin" or "gooseflesh" with horizontal
wrinkling to flesh-colored or violaceous cauliflower-like lesions which may be
discrete or coalescent. Time of onset corresponds to that of adenoma sebaceum.
Periungual and subungual fibromas that emerge from the nail bed groove
and lie on the nail plate have been reported in 17% [5], 30% [33], and 39% [8].
They are more frequent in females than males, occur after puberty, and are

FIGURE 152. Shagreen patches.

found on toes more than fingers. Nail plate grooving may result. These fibromas
may be associated with renal hamartomas.
Intraoral fibromas occur in 9% [33] to 55% [32]; they usually are located
between the upper front incisors or between the incisors and bicuspids, but
rarely also on buccal mucosa, hard palate, and tongue. Subcutaneous fibromas
occur in 10% [5] to 16% [8], and scalp tumors in 5%. Fibromas are usually first
seen at puberty.
A few other abnormalities have been mentioned. Diffuse bronzing has been
described [13]. Cafe-au-Iait macules are reported in 7% [5], 15% [32], 26% [33],
and 27% [8] (Fig. 153). Cervical skin polyps or acrochordons are reported in
39% [8].

Systemic Manifestations
Neurologic abnormalities are the most important serious manifestations of
tuberous sclerosis. These include seizures, mental retardation, and, perhaps
more commonly than once suspected, tumors.
Convulsions occur in up to 93% [5,33a] of patients with tuberous sclerosis;
these may be infantile spasms, petit mal, or grand mal seizures and usually
begin before age five. Lagos and Gomez [5] noted the seizures to be present an
average of five years before the diagnosis of tuberous sclerosis was established.
Mental retardation is reported in 61% [8],62% [5], and 75% [33a]. Lagos
and Gomez found all patients with retardation to have seizures, whereas 69%
of those with normal mentality had convulsions. The former seemed to develop
convulsions earlier in life than those with normal mentality. Ventricular dilatation on CT scanning tends to suggest mental retardation [33a] although the
degree of retardation does not necessarily correlate with ventricle size.

FIGURE 153. Cafe-au-lait spots,

confetti spots, and thumbprint
spots in a patient.

391

GENETIC AND
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DISORDERS

392

CHAPTER 1

Abnormal EEGs have been found in 87% [5].

Calcification of the brain is noted at puberty in 51% [5]. CT scanning was
found in one series of 18 patients to be the single most useful diagnostic
technique for early detection of intracranial calcification, and thereby for confirmation of the disorders in the presence of congenital hypomelanotic macules
[33a].
Alema and Pansini [50] found 28 cases of brain tumors reported in tuberous
sclerosis from 1913 to 1953. Nodules, which are usually calcified during infancy
and often located in the subependymal region or within the parenchyma, may
be visualized on CT scanning [33a] and tumors may be identified or verified
before they are clinically apparent [50a]. In the latter series of 18 patients, two
were found to have intraventricular giant cell astrocytoma. Hence, CT scanning
may be useful to identify cortical atrophy, ventricular dilatation, dysgenesis,
or transformation of tumors into gliomas.
Phakomas, white refractile tumor masses of mulberry appearance on the
fundus, have been reported in 4% [49], 53% [5], 54% [33a], and 69% [8]. Bilateral
papilledema, optic atrophy, and disc pallor have been reported [51].
Fibroadenomas of the kidney, rhabdomyomas of the heart, cystic lung
defects, honeycomb lung, and pneumothorax may also be found. Bone findings
include cystic bone defects, particularly of metacarpal and metatarsal bones,
as well as periosteal thickening. Hamartomas of adrenals, hypothalamus, liver,
pancreas, testes, and thyroid have been reported [51,52].

Diagnosis (Table 94)

The incidence of the white macules in normal infants is not known at
present but it must be quite low. Of 4412 newborns examined for congenital
anomalies during the first 48 hours of life, Marden et al. [53] noted no hypomelanotic macules.
On the other hand, Debard and Richardet [54] found 71 (0.73%) of 9737
babies to have one or more hypomelanotic macule. All of the 60 children
(0.62%) who showed only one white spot had normal psychomotor development and no features of tuberous sclerosis. Of the eight (0.08%) who had two
white spots, only one had seizures. All of the three patients with three or more
hypomelanotic macules had mental retardation. In one there was a family
history of von Recklinghausen disease and in the two others the diagnosis of
tuberous sclerosis was made. However, these patients were not examined with
Wood's light, a significant omission because Wood's light examination will
reveal hypopigmented macules not obvious in visible light (Fig. 154).
Of 100 neurologically normal children examined with a Wood's light,
Hurwitz and Braverman [33] found only one to have a hypomelanotic macule.
No follow-up on that 16-month-old patient is available. The significance of
finding a single hypomelanotic macule in a normal child of normal parents is
unclear, but Soter et al. [37] suggested that such an individual should have
long-term follow-up. In their series [37], 10.9% of tuberous sclerosis patients
had only a single white macule. One lesion alone does not exclude tuberous
sclerosis.

TABLE 94.

Clinical Features of Hypomelanotic Macules in Tuberous

Sclerosis

Sex
History
Prevalence
Number
Size
Distribution
Shape

Color
Wood's light
Margin
Spontaneous repigmentation
Hair involvement
Diagnostic value
Associated dermatologic abnormalities
Associated systemic abnormalities

F:M = 1
Present at birth
Number and size unchanged with age
50% to 98% of cases of tuberous
sclerosis
1 to 100 (circumscribed)
Average, 10
0.1 to 12 em
Usually 3.0 to 4.0 em
Trunk and upper and lower
extremities
Face and neck
Lance-ovate (ash leaf-like)
"Thumbprint"
Polygonal
Rarely dermatomal or confetti
Dull white
Partial decrease of pigment
Smooth or irregular
Moderately sharp
No
May occur (eyelashes, eyebrows, scalp)
Yes (earliest sign)
Frequent (adenoma sebaceum,
shagreen patches, and periungual
fibromas are most common)
Frequent (mental retardation and
seizures are most common)

Zaremba [32], in a survey of 1013 patients in an institution for the mentally

retarded, found hypomelanotic macules in 3.3% of patients without tuberous
sclerosis. As the diagnoses of these patients were not recorded, perhaps there
were indeed patients with unrecognized tuberous sclerosis. On the other hand,
with Wood's light examination, Hurwitz and Braverman [33] found no hypomelanotic macules in 55 neurologically handicapped children without tuberous
sclerosis.
It appears that if an infant has three or more white macules at birth, a
diagnosis of tuberous sclerosis should be seriously entertained; when the combination of white macules and seizures is observed, it becomes much more
likely that tuberous sclerosis is present. The presence of only one or two white
spots in an otherwise well newborn does not, however, completely exclude
tuberous sclerosis, but the likelihood would seem to be markedly diminished.
Studies are in progress to attempt to ascertain the prognostic importance of
isolated white macules.
It may be that a white macule in a normal patient is a marker for a heterozygote for tuberous sclerosis. Bundey and Evans [9] observed that the father
of one of their "sporadic cases of tuberous sclerosis" had a congenital 6 by 6
cm white nevus on his back clinically similar to the typical hypomelanotic
macules seen in patients with tuberous sclerosis. This individual did not have

393

GENETIC AND
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CHAPTER 1

b
FIGURE 154. a: Hypopigmented macules in an infant with tuberous sclerosis examined with
room lighting. b: Examination of the same patient with Wood's lamp reveals many hypopigmented
macules not previously noted.

either adenoma sebaceum or other unequivocal evidence of tuberous sclerosis.

Soter et al. [37] also observed hypo melanotic macules in the mother of patients
with tuberous sclerosis. Apart from the presence of hypomelanotic macules,
this woman appeared normal. We have also seen confetti macules on the mother
of a patient with frank tuberous sclerosis. Further studies are needed to determine whether there is an increased incidence of white macules among normal
parents of these "sporadic cases of tuberous sclerosis."
The other visible signs of tuberous sclerosis usually do not appear until
the patient is over the age of two years, or may never appear at all [48]. Soter
et al. [37] concluded that the presence of any of the four shapes of hypomelanotic macules (polygonal, lance-ovate, dermatomal, confetti) in a patient
with seizures or mental retardation should suggest the diagnosis of tuberous
sclerosis. Bundey [55] attempted to imply that the various shapes of the hypomelanotic macules carry differing diagnostic weight, but this seems unlikely.
Differential diagnosis includes the conditions in which circumscribed hypopigmentation may be present at birth or soon thereafter. Lance-ovate hypopigmented macules are almost pathognomonic for tuberous sclerosis, particularly if three or more are present. Polygonal hypopigmented macules or
hypopigmented macules of various shapes are features of many disorders, the
most frequent of which is vitiligo. However, the typical distribution pattern of
vitiligo and the pure white color of the vitiliginous lesions easily differentiate
these two conditions. Depigmentation from physical or chemical agents is easily
differentiated by the history and physical exam. Nevus anemicus is readily
distinguished from the hypomelanotic macules of tuberous sclerosis; rubbing
the lesions vigorously or applying ice results in erythema in the hypopigmented
area of tuberous sclerosis but not in nevus anemicus. A few hypomelanotic
macules have been observed in ataxia-telangiectasia and in histidinemia. The
whorled pattern of hypopigmented macules in incontinentia pigmenti achromians or in incontinentia pigmenti is not seen with the hypopigmented macules
of tuberous sclerosis. A dermatomal distribution of hypopigmentation may also
be observed in nevus depigmentosus and in vitiligo; history of changes in the
pigmentary aberration usually distinguishes vitiligo. Idiopathic guttate hypomelanosis must be distinguished from the confetti pattern in tuberous sclerosis;
idiopathic guttate hypomelanosis is acquired whereas the white macules of
tuberous sclerosis are not.
Tuberous sclerosis can also present as poliosis. Clinically, however, it is
generally easy to distinguish piebaldism and Waardenburg syndrome from the
white lock in a patient with tuberous sclerosis.
In conclusion, the diagnostic value of three or more hypomelanotic macules
in tuberous sclerosis is clear [33,56], so that the traditional triad of seizures,
mental retardation, and adenoma sebaceum should be expanded to include
hypomelanotic macules observed during infancy. In up to 80% of cases CT
scanning may confirm the diagnosis.
Importance of the Diagnosis

The importance of establishing the diagnosis of tuberous sclerosis lies in

genetic counseling and in anticipating special needs for the afflicted child.
Parents and siblings of those diagnosed as having tuberous sclerosis should be

395

GENETIC AND
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CHAPTER 1

examined with a Wood's light; presence of hypopigmented macules in another

family member strongly suggests familial tuberous sclerosis and a one-in-two
risk of affliction of any newborn [55]. If no white macules are found among
siblings or parents and if no family member has seizures or retardation, the
affected child should be considered a new mutation. The risk to the parent of
having another child with tuberous sclerosis then should be quite small.
Recent advances in CT scanning suggest that this technique should also
be considered in patients suspected of having tuberous sclerosis-to confirm
the diagnosis before other features are manifest, and to identify early asymptomatic tumors. CT scanning may also prove useful to identify occult tuberous
sclerosis in apparently unaffected family members, particularly when the troublesome question of familial or mutant tuberous sclerosis must be resolved
[57].

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50. Alema G, Pansini A: Quoted by Randazzo SD: La Malattia di Bourneville-Pringle. Barcelona,
Ed Tipografica dell-Universita di Cantania, 1958
50a. Konishi Y et al: Tuberous sclerosis: early neurologic manifestations and CT features in 18
patients. Brain Dev 1:31-37, 1979
51. Mosher DB et al: Abnormalities of pigmentation, in Dermatology in General Medicine, 2nd
ed. Edited by TB Fitzpatrick et al. New York, McGraw-Hill, 1979, p 595
52. Adams RD: Neurocutaneous diseases, in Dermatology in General Medicine, 2nd ed. Edited by
TB Fitzpatrick et al. New York, McGraw-Hill, 1979, p 1214
53. Marden PM et al: Congenital anomalies in the newborn infant including minor variations. A
study of 4412 babies by surface examination for anomalies and buccal smear for sex chromatin.
J Pediatr 64:357-371, 1964
54. Debard A, Richardet JM: Signification des taches achromiques chez Ie nourrisson (letter). Nouv
Presse Med 4:2404, 1975
55. Bundey S: The significance of a white macule on the skin of child. Dev Med Child Neurol
12:805-806, 1970
56. Maleville J et al: Taches achromiques: signe precoce et frequent de la sclerose tubereuse de
Bourneville: donnes anatomo cliniques. Bull Soc Fr Dermatol Syphiligr 76:455-458, 1969
57. Burkhart CG, El-Shaar A: Computerized axial tomography in the early diagnosis of tuberous
sclerosis. Am Acad Dermatol 4:59-63, 1981

NEVUS DEPIGMENTOSUS
Nevus depigmentosus is an uncommon, congenital, stable, localized leukoderma. The first case of nevus depigmentosus was reported by Lesser in 1884
[1] in the Handbuch der Hautkrankheiten. Gebert [2] presented a case to the
Berlin Dermatology Society in 1889. Sporadic cases have been since reported
(Table 95).

Clinical Features
Nevus depigmentosus is probably not so uncommon as has been suggested
by the paucity of cases reported in the literature. Because case reports are rare,
true male-female incidence is difficult to establish, but males and females
appear equally affected. No familial cases have been reported. All races are
affected [22,23]. Nevus depigmentosus is present at birth, but may sometimes
be discovered within the first few weeks or, particularly in fair-skinned individuals, a few months later. Cases of late onset seem doubtful and probably,
in fact, represent segmental vitiligo [24-26]. In one such case reported as nevus
depigmentosus, the lesion was first apparent at the age of two; the father and
maternal grandfather were said to have vitiligo [24].

Clinical Description (Fig. 155)

Nevus depigmentosus is a hypomelanosis characterized by unilateral, nevoid or quasidermatomal macules of varied size, of pale white color, and with
discrete, regular, or occasionally serrated margins. Hyperpigmented borders
have been noted [9] (Figs. 156, 157).

TABLE 95. Nevus Depigmentosus: Location of Macules

in Reported Cases
Series reported by Coupe [11]
Onset: birth, constant with age
Lesser [1]
Hutchinson [3]
Gebert [2]
Harmon [4]
Smith [5]
Romagna-Manoia [6]
Remenowsky [7]
Schulmann and Gallerand [8]
Gareiso and Alvarez [9]
Bessone [10]
Coupe [11]
Onset: within 18 months or less
of birth
Siemens [12]
Pinetti [13]
Onset: unknown or not
specified
Blaschko [14]
Jadassohn [15]
Kuhlmann et al. [16]
Meirowsky [17]
Meirowsky and Leven [18]
Gougerot [19]
Series reported by Sugarman and
Reed [20]

F
M

Right lower abdomen

Right arm and leg, right trunk,
anterior, inferior
F
Left abdomenlbuttock, left anterior
thigh and shin
F
Left forehead and neck
M
Right abdomenlback
FRight abdomenlback, thigh
Left thorax
M
Abdomenlback
M
Right trunk/ arm/leg
M
Left arm
M
Right neck/armlback

M
F

M
M
M
M
F
F

Left face
Eight cases, details not given

Series reported by Jimbow et al.

[21]
Series reported by Berg and
Tarnowski [22]

Right thorax
Left back/abdomen/thigh

Left neck/arm/chest

The color of the involved skin is uniformly hypomelanotic or off-white.

No hyperpigmented macules are scattered within the hypomelanosis. Hair in
the macules may be hypo pigmented [10]. This is more striking where nevus
depigmentosus involves an area such as the pubis [7] or eyebrows [18]. The
contrast between the involved skin and the normal surrounding skin is enhanced by Wood's light examination. There are no other epidermal changes.
Nevus depigmentosus is asymptomatic. Sensation is normal; vigorous
stroking, heat, and cold exposure normally induce erythema.
The trunk, lower abdomen, and the proximal extremities are the most
common sites, but nevus depigmentosus may also involve the face and neck.
Most commonly there is a single, large white macule extending continuously
over several areas, but sometimes there are several separate and distinct areas

399

GENETIC AND
CONGENITAL
DISORDERS

400

CHAPTER 1

ISOLATED PATTERN

DERMATOMAL PATTERN

WHORLED PATTERN OF

OF HYPOMELANOSIS

HYPOPIGMENTATION

OF HYPOPIGMENTATION

FIGURE 155. Clinical patterns of nevus depigmentosus.

FIGURE 156. Nevus depigmentosus. An isolated pattern of hypomelanosis. (From: Jimbow K et

al: Congenital circumscribed hypomelanosis: a characterization based on electron microscope study
of tuberous sclerosis, nevus depigmentosus and piebaldism. J Invest Dermatol 64:50-62, 1975.
Copyright, 1975, The Williams & Wilkins Co. Used with permission.)

401

GENETIC AND
CONGENITAL
DISORDERS

FIGURE 157. a, b: Nevus depigmentosus. Typical dermatomal patterns of hypomelanosis.

(From: Jimbow K et al: Congenital circumscribed hypomelanosis: a characterization based on
electron microscope study of tuberous sclerosis, nevus depigmentosus and piebaldism. J Invest Dermotol 64:50-62, 1975.)
Copyright, 1975, The Williams &
Wilkins Co. Used with permission.)

402

CHAPTER 1

FIGURE 158. a-d: Nevus depigmentosus. Extensive involvement.

403
GENETIC AND
CONGENITAL
DISORDERS

FIGURE 159. a, b: Nevus depigmentosus. Atypical dermatomal patterns in which hypomelanosis

resembles an artificial splash of white paint. (From: Jimbow K et al: Congenital circumscribed
hypomelanosis: a characterization based on electron microscope study of tuberous sclerosis, nevus
depigmentosus and piebaldism. JInvest Dermoto1 64:50-62, 1975. Copyright, 1975, The Williams
& Wilkins Co. Used with permission.)

404
CHAPTER 1

of involvement. Although segmental lesions do not usually cross the midline,

Meirowsky [17] observed one exception in whom slight extension over the
midline was seen.
The lesions enlarge in proportion to body growth, so that the percentage
of cutaneous involvement remains unchanged. Cases with progressive hypomelanotic spread [24-26] probably do not represent nevus depigmentosus.
Spontaneous repigmentation does not occur.
Three patterns of nevus depigmentosus have been described: an isolated
circular, rectangular, or nevoid macule of hypomelanosis, which is most likely
to occur on the trunk but may be seen anywhere; a dermatomal or quasidermatomal pattern of hypomelanosis (Fig. 158); or an irregular or bizarre, dermatomal, sharply angulated streak that resembles artificially splashed white
paint or hypomelanotic whorls (Figs. 159, 160, 161).
Usually patients with nevus depigmentosus are in good health. However,
there have been several patients with mental retardation and seizures [9,20].
Tay [27] also described a 15-year-old Malay boy with multiple systemic abnormalities (seizures, oligophrenic congenital hemiplegia with porencephaly,
hypertelorism, strabismus, nystagmus) and a congenital segmental cutaneous
depigmentation of the right lower abdomen and the right lower limb. This
probably represented nevus depigmentosus.

FIGURE 160. a-c: Nevus depigmentosus. Whorls of hypomelanosis. (From: Jimbow K et al: Congenital circumscribed hypomelanosis: a characterization based on electron microscope study of
tuberous sclerosis. nevus depigmentosus and piebaldism. J Invest Dermotol 64:50-62. 1975. Copyright. 1975. The Williams & Wilkins Co. Used with permission.)

405

GENETIC AND
CONGENITAL
DISORDERS

FIGURE 160 (Continuedl

406
CHAPTER 1

FIGURE 161. a: Segmental hypomelanosis from right T 10 to L2 Abrupt transition zone at midline
is apparent. b: Bilateral nasofrontal mucoceles, fully inflated by blowing the nose. (From: Tay CH:
Porencephaly, nasofrontal mucocoeles, hypertelorism and segmental vitiligo. Report of a new
neurocutaneous disorder. Singapore Med J 11:253-257, 1970. Copyright, 1970, Andre Publications.
Used with permission.)

Histology and Electron Microscopy (Figs. 162, 163)

Early reports incorrectly showed dopa-negative skin and an absence of
melanin in achromic skin [9]; also, gold impregnation studies showed no Langerhans cells in achromic skin as opposed to positive controls [11].
Dopa reaction is decreased and the number of melanocytes is usually decreased. Mishima [28] found one-quarter to one-half the normal melanocyte
density. Other electron microscopic studies [23] also revealed a decreased melanocyte density, an increased alpha-dendritic cell population, and a normal
number of Langerhans cells. In the affected melanocytes, there was a decreased
number of premelanosomes and melanosomes but the melanocyte-keratinocyte
transfer appeared normal. Mishima [28] also found a slightly increased number
of alpha-dendritic cells but a normal number of Langerhans cells.
Jimbow et al. [21] (Table 96) later found a diminished dopa reaction, but
no alteration in the number of melanocytes (Fig. 163). Melanocytes were found
to be poorly developed with stubby dendrites and melanosomes were normal
in size, shape, and internai structure. The number and melanization of mel a-

407

c&-..

of melanosomes
in kerat.nocytes

abnormal melanosome t ransfer

- - me lanosomal autophagy
w ithin melanocytes

FIGURE 162. Hypopigmentation in nevus depigmentosus.

nosomes were normal or decreased. In contrast to Takaiwa and Mishima [23].

Jimbow et al. [21] found abnormal melanosome secretion with decreased numbers of melanosomes in keratinocytes. The melanosomes within the melanocytes were occasionally aggregated within membrane-limited vacuoles. In these
vacuoles. the melanosomes showed degradation and were associated with myelin bodies and some electron-dense fine grains. They concluded that in nevus
depigmentosus the synthesis and transfer of melanosomes is impaired and that
TABLE 96. Subcellular Characteristics of Nevus
Depigmentosus
Q

Melanocytes
Number
Dopa reaction
Dendrites

Normal or decreased
Normal or decreased
Poorly developed and stubby

Melanosomes in melanocytes
Number
Size
Shape
Structure
Melanization
Secretion

Normal or decreased
Normal
Normal
Normal
Normal or decreased
Abnormal (autophagosomes)

Melanosomes in keratinocytes
Number
Distribution
Degradation

Decreased
Normal
Normal

From: Jimbow K et al: Congenital circumscribed hypomelanosis: a characterization based on electron microscopic study of tuberous sclerosis. nevus
depigmentosus. and piebaldism. J Invest Dermalol 64:50-62. 1975. Copyright. 1975. The Williams & Wilkins Company. Used with permission.

GENETIC AND
CONGENITAL
DISORDERS

408

CHAPTER 1

aggregation of melanosomes in the melanocytes is also a characteristic feature

of nevus depigmentosus. Although it could not be concluded that the intramelanocytic aggregation of melanosomes results in hypomelanosis in nevus
depigmentosus, it seemed reasonable that intramelanocytic aggregation of melanosomes interferes with the transfer of melanosomes from the melanocytes to
the keratinocytes in nevus depigmentosus.

Pathogenesis
Since nevus depigmentosus is congenital, nonfamilial, and unilaterally
localized, it seems likely that it represents an embryonic developmental defect [11].

Diagnosis (Table 97)

Coupe [11] summarized the following criteria for diagnosis: unilateral hypomelanosis in a localized or systematized distribution, appearance at birth or
soon after, and life-long stability of distribution of the hypopigmented areas.

Differential Diagnosis
Nevus depigmentosus may be distinguished from localized or segmental
vitiligo, usually by history of stability from birth and by presence of melanocytes
on histologic sections. Patients with tuberous sclerosis will most often have
thumbprint or lance-ovate macules and will develop other cutaneous findings
and neurologic features not seen with nevus depigmentosus. Nevus anemicus
should be included in the differential diagnosis. Wood's light examination
accentuates nevus depigmentosus, whereas nevus anemicus disappears. Nevus
anemicus blanches with dioscopy, but nevus depigmentosus does not. Melanocytes are normal in nevus anemicus .

..

FIGURE 163. Various features of the melanocyte in patients with nevus depigmentosus. a: Hypomelanotic skin from a Caucasoid. At least nine melanosomes are recognizable in the large
aggregate (two arrows) of melanosomes. There is another vacuole (one arrow) aggregated with some
membranous organelles in the cytoplasm of the melanocyte (x 22,000). b: Hypomelanotic skin
of a Negroid. The melanocyte contains a well-developed Golgi apparatus (GA) and melanosomes
in various developmental stages. This melanocyte also contains two vacuole-like structures (VS)
aggregated with some electron-dense materials. There is no change in the size of the melanosomes.
The melanosomes (arrows) in the keratinocytes are present as a single unit (x 19,000). c: Hypomelanotic skin of a Caucasoid. There is a huge aggregate of melanosomes (MA) within the
cytoplasm of the melanocyte (x 48,000). d: Hypomelanotic skin of a Caucasoid. There is a vacuolelike structure aggregated with the melanosomes and myelin granules (arrows) in the melanocyte.
MS = melanosomes in melanizing stage (x 47,500). (From: Jimbow K et al: Congenital circumscribed hypomelanosis: a characterization based on electron microscope study of tuberous sclerosis,
nevus depigmentosus and piebaldism. J Invest Dermatol 64:50-62, 1975. Copyright, 1975, The
Williams & Wilkins Co. Used with permission.)

409

GENETIC AND
CONGENITAL
DISORDERS

TABLE 97. Clinical Features of Hypomelanosis in Nevus

Depigmentosus

410

CHAPTER 1

Age of onset
Sex prevalence
Color
Shape

Border
Distribution
Course
Local symptomatology
Associated systemic findings

Birth
Unknown: both males and females reported
White
Three patterns
Isolated circular or rectangular area of
hypomelanosis
Dermatomal pattern
Whorled pattern
Regular or occasionally serrated
Lower abdomen, trunk, proximal part of
extremities; less commonly the face and
neck
Stable
None
Usually none

Since the same whorled pattern of hypopigmented macules may be observed in both nevus depigmentosus and incontinentia pigmenti achromians,
some investigators have considered these to be the same entity. However, the
autosomal dominant pattern of inheritance of incontinentia pigmenti achromians, the clinical progression over time, and the association with neuroectodermal defects differentiate incontinentia pigmenti achromians from nevus
depigmentosus.

Treatment
Nevus depigmentosus is of cosmetic importance only; rare attempts at
repigmentation are reported. Psoralens plus ultraviolet radiation failed to repigment nevus depigmentosus in one unusual case that had undergone some
spontaneous repigmentation [29; M. A. Pathak, personal communication, 1976].

REFERENCES
1. Lesser E: In von Ziemssen H: Handbuch der Hautkrankheiten, Bd 2. Leipzig, Vogel, 1884, p
183
2. Gebert E: Krankenvorstellung Berliner dermatologischen Gesellschaft, March 7, 1899. Dermatol
Z 6:367-368, 1899

3. Hutchinson
1895

J: A Smaller Atlas of Illustrations of Clinical Surgery. London, West, Newman,

4. Harmon BN: Case quoted by Pearson K et al: A Monograph on Albinism in Man: Drapers'
Company Research Memoirs, Biometric Series VI, VIII, IX. Department of Applied Mathematics, University College, University of London. London, Dulau, 1911-1913
5. Smith G: Case quoted by Pearson K et al: A Monograph on Albinism in Man: Drapers' Company
Research Memoirs, Biometric Series VI, VIII, IX. Department of Applied Mathematics, University College, University of London. London, Dulau, 1911-1913
6. Romagna-Manoia A: Un caso di albinismo parziale. Atti Soc Rom Antrop 15:387-391, 1910

7. Remenowsky F: Case presented to the Wien dermatologische Gesellschaft, February 28, 1924.
Zbl Haut Geschlkr 12:240, 1924
8. Schulmann E, Gallerand L: Un cas de naevus achromique II disposition metamerique. Bull
Soc Fr Dermatol Syphiligr 37:1304-1306, 1930
9. Gareiso A, Alvarez G: Nevus acromino unilateral en bandas en un oligofrenco. Rev Asoc Med
Argent 52:158-160, 1938
10. Bessone L: Nevo acromico lineare. G Ital Dermatol 82:118-131, 1941
11. Coupe RL: Unilateral systematized achromic naevus. Dermatologica 134:19-35, 1967
12. Siemens HW: Zur Kenntnis des systematisierten Naevus pigmentosus mit Bemerkungen uber
die formale Genese der Naevi. Dermatol Z 42:65-75, 1925
13. Pinetti P: Albinismo parziale e disposizione metamerica unilaterale (nevo acromico). G Ital
Dermatol 78:1143-1154, 1937
14. Blaschko A: Die Nervenverteilung in der Haut, in ihrer Beziehung zu den Erkrankungen der
Haut (Paper presented to the Deutsche dermatologische Gesellschaft, May 28-30,1901). Quoted
by Coupe RL: Unilateral systematized achromic nevus. Dermatologica 134:19-35, 1967
15. Jadassohn J: Case presented to Med-Pharm Bezirksver, July 21, 1910. Quoted by Coupe RL:
Unilateral systematized achromic nevus. Dermatologica 134:19-35, 1967
16. Kuhlmann et al: Case presented to the Strassburgen dermatologischen Gesellschaft June 19,
1913. Arch Dermatol Syphilol (Berlin) 117:889, 1913
17. Meirowsky E: Uber die Entstellung der sogenannten kongenitalen Missbildungen der Haut.
Arch Dermatol Syphilol (Berlin) 127:1-192, 1919
18. Meirowsky E, Leven L: Tierzeichnung, Menschenscheckung und Systematisation der MuttermaIer. Ein Beitrag zur vergleichenden Morphologie der Haut. Arch Dermatol Syphilol (Berlin)
134:1-79, 1921
19. Gougerot H: Illustration in Darier Jet al (eds): Nouvelle Pratique Dermatologique, Paris, Masson
6:454,1936
20. Sugarman GI, Reed WB: Two unusual neurocutaneous disorders with facial cutaneous signs.
Arch Neurol 21:242-247, 1969
21. Jimbow K et al: Congenital circumscribed hypomelanosis: a characterization based on electron
microscopic study of tuberous sclerosis, nevus depigmentosus, and piebaldism. J Invest Dermatol 64:50-62, 1975
22. Berg M, Tarnowski W: Nevus depigmentosus. Arch Dermatoll09:920, 1974
23. Takaiwa T, Mishima Y: Quantitation of epidermal dendritic cells by electron microscopy:
nevus depigmentosus. Jpn J Clin Elect Microsc 3:651-652, 1970
24. Caro-Paton T: Vitiligo unilateral sistomatizado 0 nevus acromico. Actas Dermosifiliogr41:717-723,
1950
25. Leri A, Lamy L: Vitiligo zoniforme du flane droit, sclerodermie en bande avec atrophie en
masse du membre inferieur gauche. Bull Soc Fr Dermatol Syphiligr 30:127-130, 1923
26. Scholz JR, Williamson C: Vitiligo in (apparent) dermatomal distribution. Arch Dermatol
64:366-369, 1951
27. Tay CH: Porencephaly, nasofrontal mucocoeles, hypertelorism and segmental vitiligo. Report
of a new neurocutaneous disorder. Singapore Med J 11:253-257,1970
28. Mishima Y: Congenital and non-congenital depigmentation, in Modern Problems in Paediatrics, vol 20, Pediatric Dermatology: Internal and External. Edited by R Ruiz-Maldonado.
Karger, Basel, 1978, pp 18-37
29. Hewitt J et al: Naevus hypochromique unilateral en jet d'eau; repigmentation instable par Ie
soleil et les rayons UV. Bull Soc Fr Dermatol Syphiligr 5:521-522, 1955

INCONTINENTIA PIGMENTI ACHROMIANS

... the following questions have occurred to us: (1) Is incontinentia pigmenti achromians truly an entity with definable criteria? (2) Is it a variant of incontinentia pigmenti, a systematized nevus, piebaldism, or is it a separate syndrome? [1]

A Japanese woman with bizarre, bilateral, and irregularly shaped depigmented patches on the trunk and extremities was reported in 1952 by Minor

411

GENETIC AND
CONGENITAL
DISORDERS

412
CHAPTER 1

Ito as a variant of "nevus depigmentosus systematic us bilateralis" [2]. Because

of the striking resemblance between the pattern of the hypopigmentation and
the hyperpigmentation occurring in incontinentia pigmenti (Bloch-Sulzberger
syndrome), he called the disorder "incontinentia pigmenti achromians." Since
then 46 patients have been reported and we have seen a number of others.
Incontinentia pigmenti achromians is probably not rare.

Clinical Findings
Race

The first six cases reported were Japanese; incontinentia pigmenti achromians occurs in all races, however.
Sex

In the analysis of the first 17 reported patients, Jelinek et al. [1] found a
female to male ratio of four to one. If the 46 patients mentioned in the literature
through 1979 are included, the ratio appears to be over two to one.
Age on Onset
Although among the reported cases the patients when first seen ranged
from two months to 23 years of age, onset is usually at birth or early childhood.
Among 40 of the 46 reported cases, the depigmented macules were first noted
at birth (26 cases), during infancy (eight cases), or in childhood (six cases). The
oldest reported age of onset is 12 [3].
Familial History
Two European families with incontinentia pigmenti achromians have been
reported; in one there were four affected females and in the other, a black infant
girl, her two brothers, her father's aunt, and her paternal uncle were affected.
The paternal great aunt of the patient reported by Jelinek et al. is thought to
have had incontinentia pigmenti achromians.
The father-to-son transmission reported by Rubin [4] excludes X-linked
inheritance; an autosomal dominant pattern seems more likely (Fig. 164). Consanguinity has been reported [5].
Hellgren [6] described a patient with incontinentia pigmenti achromians
whose mother, sister, and brother had brown hyperpigmented macules on the
left halves of their bodies.
Another family report is less straightforward. Pifiol-Aguade et al. [7] reported incontinentia pigmenti in the daughter of a woman with inc 0 ntinenti a
pigmenti achromians; this was characterized by a congenital amelanotic zosteriform macule on the left leg and no other abnormalities apart from a bullous
reaction to heat. Jelinek et al. [1] point out that this description is insufficient
for a diagnosis of incontinentia pigmenti achromians. Furthermore, the eldest

413

GENETIC AND
CONGENITAL
DISORDERS

II

III
2

Uninvolved male

[J Partially involved male

II

o
e

Uninvolved female
Propositus

Male with fuiliPA

FIGURE 164. Pedigree of a family with incontinentia pigmenti achromians. (From: Rubin MB:
Incontinentia pigmenti achromians. multiple cases within a family. Arch Dermatol105:624....a25.
1972. Copyright. 1972. American Medical Association. Used with permission.)

daughter is said to have had erythematous and bullous lesions that became
verrucous and later became depigmented. This description is less characteristic
of incontinentia pigmenti achromians than of incontinentia pigmenti, which
can show late-onset depigmentation. The diagnosis of incontinentia pigmenti
in this family is strengthened by the fact that another daughter had typical
clinical incontinentia pigmenti and that the mother had one spontaneous abortion of a male fetus. This family probably should not be included in a review
of incontinentia pigmenti achromians.

Clinical Description
Incontinentia pigmenti achromians appears as a negative image of the
hyperpigmented swirls of incontinentia pigmenti. The hypopigmented macules
are randomly distributed and have a bizarre, whorled, or streaked "marble cake"
configuration (Fig. 165). They do not correspond to any particular dermatome
or peripheral nerve distribution. In most instances the lesions are bilaterally
distributed but an asymmetrical pattern and two unilaterally distributed cases
have been reported [3,8]. Rubin [4] noted that the depigmented lesions on the
trunk generally assumed a parallel pattern, did not cross the inidline, and
tended to follow the long axes of the extremities. Their distribution on the back
resembled an inverted Christmas tree.
Any part of the body including the face may be involved. Among 27 patients, the following areas of involvement, in order of decreasing frequency,
were noted: trunk (20 patients), extremities (15 patients), face (3 patients),
shoulders (1 patient), and hip (1 patient). Involvement of the scalp, palms,
soles, and mucous membranes has not been reported.

414

CHAPTER 1

415
GENETIC AND
CONGENITAL
DISORDERS

FIGURE 165. a-c: Asymmetric hypomelanotic macules in a whorled or marble-cake configuration

in a patient with incontinentia pigmenti achromians. Note that on the trunk. back. and upper
abdomen the hypomelanotic macules seem to originate and swirl or sweep from the midline. On
the limbs the lesions tend to follow the long axis of the extremities. (From: Rubin MB: Incontinentia
pigmenti achromians. multiple cases within a family. Arch Dermatol105:624-625. 1972. Copyright.
1972. American Medical Association. Used with permission.)

The lesions are, in most instances, present at birth, but may appear after
birth, during infancy, and rarely during childhood. In many instances the depigmentation appears to be progressive [1,2,4,8-14]. However, in several cases
the hypopigmentation tended to revert to normal before or after one year of
age. In three cases described by Grosshans et al. [10], the maximal contrast
between involved and normal skin was observed at three years of age. In the
four-and-one-half-year-old girl described by Grosshans et al. [10], the depigmentation had already begun to fade. Afaint irregular hypopigmentation was
also observed in her affected mother.

416
CHAPTER 1

The macules are irregular in shape and variable in size. Borders of the
lesions are serrated and blurred or sharply outlined [9] (Fig. 166). Hyperpigmented borders have been reported in one case [10] (Fig. 167).
The lesions have normal sensation (touch, temperature, pin-prick) [9] and,
in contrast to nevus anemicus, vigorous stroking does not produce any cutaneous changes [4,9].
Neither verrucous changes nor inflammation precede the depigmentation.
The daughter of the woman reported by Piftol-Aguade et al. [7] probably had
incontinentia pigmenti and not incontinentia pigmenti achromians. The patient
of Griffiths and Payne [15] showed, at birth, diffuse erythema and, later, verrucous lesions on the axillae and neck, around the mouth, in the groin, popliteal
spaces, and in the natal cleft. This case also seems most likely to represent
incontinentia pigmenti.

FIGURE 166. The hypomelanotic macules contrast dramatically with the normal skin. (Courtesy
of T. Hood and T. B. Fitzpatrick. unpublished data. Used with permission.)

417

GENETIC AND
CONGENITAL
DISORDERS

FIGURE 167. Multiple hypo pigmented areas interspersed with hyperpigmented areas. (From:
Griffiths A, Payne C: Incontinentia pigmenti achromians. Arch Dermatol111:751-752, 1975. Copyright, 1975, American Medical Association. Used with permission.)

418
CHAPTER 1

Other Cutaneous Findings

See Table 98.
Systemic Findings
Among the 46 cases reported in the literature, a large number of systemic
abnormalities have been reported (see Table 99). The majority of patients have
a musculoskeletal or neurologic defect. Such a common association led Nordlund et al. [29], in fact, to suggest that incontinentia pigmenti achromians may
exist as a cutaneous or a neurocutaneous disorder. In the latter, a phenotypic
pigmentary abnormality may reflect a biochemical defect found in other neuroectodermally derived tissues.

Laboratory Investigations
No consistent laboratory abnormalities have been documented. Eosinophilia has been reported in two cases [8,12]. Chromosomal analysis and dermatoglyphics are normal. No linkage is found between the disease and the ABO
blood groups or HLA antigens [10].
TABLE 98. Cutaneous Abnormalities Associated with
Incontinentia Pigmenti Achromians
Type of abnormality

Number of patients

Skin ............................................................... 9
Diminution of capillary resistance [2,8,12)
3
Decreased sweating response to pilocarpine [2,11,12)
3
1
Relative hyperhidrosis of hypopigmented area [4)
Verrucous epidermal nevi [1,3)
2
Hyperkeratotic follicular papules running in a linear
1
fashion (flexural aspect of upper and lower
extremities) [1)
Mongoloid spots [16]
1
Facial hemiatrophy [3)
1
Mucous membrane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 2
Thickening of lips [5,7)
2
Hair ............................................................... 5
Diffuse alopecia [11)
Facial hypertrichosis [11)
General hirsutism [14)
Unilateral coarse and curly hair [6)
Traumatic bilateral parietal alopecia [16)
Widow's peak [14)

1
1
1
1
1
1

Teeth .............................................................. 6
Pointed crowns [5,21)
4
Irregularly spaced teeth (17)
1
Hypoplasia of primary incisors, canines [18)
1

TABLE 99. Systemic Abnormalities Associated with Incontinentia

Pigmenti Achromians
Type of abnormality

Number of patients

Central nervous system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 19

Mental retardation [1,8,10,14,17,19-21]
8
Seizures [1,14,19,21,22]
7
EEG abnormalities [10,17,19,23,24]
4
Subcortical atrophy [10]
1
4
Hypotonicity [1,10]
Upper motor neuron signs [10]
3
Hyperextensibility and permanent flexure deformities [10]
3
1
Auditory conduction defect [3]
1
Hyperactivity [14]
1
Language retardation [24]
1
Ataxia [24]
Hydrocephaly [24]
1
Musculoskeletal system ................................................. 18
Growth retardation [14,25]
2
Delayed epiphyseal closure [14]
1
High-arched palate [17]
1
Cleft palate and lip [26]
1
2
Macrocephaly [14]
Microcephaly [25]
1
Bradycephaly [15]
3
Retrognathism, saddle nose, stubby fingers and toes,
3
increased height of lumbar vertebrae [10]
Atrophy of right fifth digit [13]
1
Hypotrophy of right lower extremity [3]
1
1
Congenital luxation of the coxae [11]
Hypertelorism [1,10,14,21]
5
Poorly formed ears [1,10,25]
2
Shortening of the fourth metacarpals [21]
1
Club feet [6]
1
2
Different leg lengths [14]
2
Bilateral genu valgus [24]
Ectrodactyly [26]
1
1
Denodactyly [14]
Diastosis recti (14)
1
Spina bifida occulta (14)
1
Scoliosis [14,27]
2
Eyes ................................................................... 11
Microphthalmia [14]
1
Nystagmus [14]
1
1
Epicanthal fold [21,25]
Strabismus [1,10,11,13,14,21,25]
6
3
Myopia [1,11,21,25]
Retinal pigmentary abnormalities [28]
1
1
Pigmented spot on the iris [6]
Tessellated fundus [11]
1
1
Ptosis and pupillary dislocation [3]
Opaque cornea [1]
1
1
Irides heterochromia [14]
Hypertelorism [25]
1
(Continued)

419

GENETIC AND
CONGENITAL
DISORDERS

TABLE 99. (continued)

420

CHAPTER 1

Type of abnormality
Miscellaneous. . . . . . . . . . . . . . . .
Unusual facies [14]
Diabetes mellitus [19]
Hypoplasia of the breasts [2,21]
Concave breast [8]
Congenital hydronephrosis [4]
Eosinophilia [8,12]
Dacryostenosis [24]

Number of patients
. . . . . . . . . . . . . . . . . . . . . . .. . .. . .. .
3

. .... . 7 . .

1
2

1
1
2

Histology of the Hypopigmented Skin

Epidermis
In most of the reports, silver stain shows only a decreased number of
melanin granules [9,10,28). The number of dopa-positive melanocytes is decreased [1,7,10,28) and the dopa reaction is weaker in depigmented skin than
in normal skin [9) (Fig. 168). Grosshans et al. [10) found the dopa-positive
melanocytes to be smaller in size and to have smaller dendrites in the hypo-

FIGURE 168. Compared to the control portion of the epidermis there is an almost complete lack
of melanin pigment corresponding to a depigmented streak. There is only a small amount of melanin
in the upper dermis. (From: Grosshans EM et al: Incontinentia pigmenti achromians II. Dermatologica 142:65-78, 1971. Copyright, 1971, S. Karger A.G. Used with permission.)

pigmented areas than in normal skin. Numerous Langerhans cells have been
demonstrated in the epidermis [24].
Although keratinocytes are usually normal, orthokeratotic hyperkeratosis
[10], epidermal atrophy, disorganization of the basal layer with nuclear edema,
and perinuclear vacuolization in keratinocytes have been reported [2,8,10,12].
Grosshans et al. [10] described architectural modifications of the epidermis and
disturbances in keratinization; they observed large clear cells that may represent
either pathologic Langerhans cells or dyskeratotic cells. Some mitotic figures
were present.
Dermis
Pigmentary incontinence is unusual [1,9,10,28] and the number of dermal
melanophages is not increased [6,10]. There are no inflammatory changes [9,28].
Some reports have mentioned the following dermal abnormalities: dermal
edema [12], endothelial swelling with capillary congestion, and slight cicatricial reorganization of the connecting tissue [2]. Grosshans et al. [10] observed
glomerular atrophy of the eccrine sudoral adnexae and dysmorphic changes of
the pilosebaceous apparatus.
Electron Microscopy Findings
Stoebner and Grosshans [30] did extensive ultrastructural studies of the
lesions of incontinentia pigmenti achromians; their findings are summarized
in Table 100. Their studies showed a decreased number, but not total absence,
of melanocytes and a quantitative decrease in melanin production. Stage I
melanosomes were scarce. Mature melanosomes, though small and few, were
normally pigmented and normally distributed among the keratinocytes. Morohashi et al. [22] described melanocyte destruction in the basal and lower
malpighian layers; melanocytes had cytoplasmic vacuolization, melanosome
aggregations, autophagic vacuoles, fatty degeneration, and pyknosis or homogeneous axoplasmic degeneration. Nerve fibers were also found approximating
normal and degenerating melanocytes.
Stoebner and Grosshans [301 also found an apparent increase in the number
of Langerhans cells that appeared to be losing their dendritic processes. Indeterminate cells were also observed. Dyskeratosis was associated with these
quantitative and qualitative modifications of the dendritic cells. In the papillary
dermis, many small nerve fibers were in close contact with keratinocytes. Deeper
in the dermis there was a great number of mast cells containing giant mast cell
granules.
Pathogenesis
Possibly the pigmentary changes are secondary to functional abnormalities
of keratinocytes observed in incontinentia pigmenti achromians. In incontinentia pigmenti achromians, where keratinocyte damage is less evident than

421

GENETIC AND
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DISORDERS

422

CHAPTER 1

TABLE 100. Cellular and Subcellular Characterization of

Hypopigmented Skin in Incontinentia Pigmenti Achromiansa
Melanocytes
Number
Dopa reaction
Dendrites

Decreased
Decreased
Decreased

Melanosomes in melanocytes
Number
Size
Shape
Structure
Melanization
Secretion

Decreased
Decreased
Ellipsoid
Transversely striated
Normal
Normal

Melanosomes in keratinocytes
Number
Distribution
Degradation

Decreased
Decreased numbers in complexes
No data

Langerhans cells
Indeterminate cells
Other changes

Increased number
Present (quantitative data)
Dyskeratosis
Mastocytosis
Pilosebaceous apparatus abnormalities
Mildly decreased number of
melanophages

Source: Stoebner P, Grosshans EM: Incontinentia pigmenti achromians (Ito). Etude

ultrastructurale. Arch Klin Exp Dermatol 239:227-244, 1970. Copyright, 1970, SpringerVerlag. Used with permission.

with incontinentia pigmenti, the hypomelanosis may result from transfer block
as in nevus depigmentosus, in which there are melanosome complexes in the
keratinocytes. But there is also a direct effect on melanocytes, as evidenced by
the presence of few mature melanosomes and evidence of melanocyte destruction.
There are still unresolved questions concerning the concept of this disease
and its relationship to other syndromes such as incontinentia pigmenti and
nevus depigmentosus. Is incontinentia pigmenti achromians in fact an entity
sui generis?
Incontinentia Pigmenti and Incontinentia Pigmenti Achromians (Table 101)
Ramos e Silva [31] and Kitamura [23] believe that incontinentia pigmenti
achromians is a clinical variant of incontinentia pigmenti. Grosshans et a1. [10]
suggest that incontinentia pigmenti achromians represents a variant of the
Bloch-Sulzberger form in which the late stage is characterized by hypomelanosis. Hamada et a1. [11] postulated an identical pathogenesis for these two
dermatoses. It is true that there are similarities between the two conditions.

Both have the same distribution of lesions, are diseases of infancy and childhood, have a tendency later to remit, and are associated with ocular, dental,
hair, musculoskeletal, neurologic, and mental abnormalities. Some histologic
features are common to both diseases. Grosshans et al. [10] found both incontinentia pigmenti achromians and incontinentia pigmenti to have disturbances
of keratinization and malformation of skin appendages.
Furthermore, depigmentation may occur late in incontinentia pigmenti. In
studying a patient considered to have incontinentia pigmenti achromians, Braverman [32] found reflectance readings of the face and the hypopigmented skin
to be identical; he concluded that the "hypopigmented" skin was in fact normal;
therefore, the actual pigmentary abnormality was hyperpigmentation. Incontinentia pigmenti achromians, therefore, is identical with incontinentia pigmenti. This notion is not generally accepted.
But the genetic, clinical, and histologic differences between the two conditions are more numerous than their similarities. Incontinentia pigmenti is
most likely transmitted as an X-linked dominant trait lethal to males, whereas
the incontinentia pigmenti achromians female to male ratio of two to one is
not compatible with this mode of inheritance. Incontinentia pigmenti achromians appears to be transmitted as an autosomal dominant trait.
TABLE 101. Comparison of Incontinentia Pigmenti and Hypomelanosis of Ito (Incontinentia
Pigmenti Achromians)O
Features

Incontinentia pigmenti

Inheritance

Probably X-linked dominant

Sex
Age of onset
Stages preceding
pigmentary change
Pigmentation

F:M = 98:2
Birth or early infancy
Vesiculobullous. verrucous

Distribution

"Marble cake," generalized,

hyperpigmented; rarely
hypopigmented areas
Asymmetrical. any part of body

Prognosis

Hyperpigmentation tends to lessen

Histologic findings

Degeneration of basal layer;

increased pigment-containing
cells in dermis; vacuolization of
keratinocytes
Yes (60%)
Affected frequently
Affected frequently
Affected occasionally
Affected occasionally
Affected occasionally

Ectodermal abnormalities
Eyes
Teeth
Hair
Musculoskeletal system
Neurologic and mental

Hypomelanosis of Ito
Uncertain; possibly autosomal
dominant
F:M = 2:1
Birth, infancy, or childhood
None
"Marble cake." generalized.
hypopigmented
Asymmetrical or symmetrical
involvement but not mirror
images, any part of body
Hypopigmentation tends to
return to normal
Basal layer normal; decrease
of numbers of pigment
cells; vacuolization of
keratinocytes
Yes (43%)
Affected frequently
Affected occasionally
Affected occasionally
Affected occasionally
Affected occasionally

Source: Jelinek JE et al: Hypomelanosis of ito. incontinentia pigmenti achromians. Report of three cases and review of the
literature. Arch Dermatol107:596...u01. 1973. Copyright. 1973. American Medical Association. Used with permission.

423

GENETIC AND
CONGENITAL
DISORDERS

424
CHAPTER 1

Furthermore, incontinentia pigmenti achromians depigmentation, unlike

incontinentia pigmenti, is never preceded by vesiculobullous and verrucous
changes. The only case with this succession was reported by Griffiths and Payne
[15] and the main argument for the diagnosis of incontinentia pigmenti achromians was that their patient was a male. Although uncommon, incontinentia
pigmenti in'males has been reported, so it seems likely that the case of Griffiths
and Payne [15] was really incontinentia pigmenti. For reasons previously discussed, the cases reported by Pifiol-Aguade et al. [7] of occurrence of both
disorders in the same family are also doubtful. Cases with vesiculobullous and
verrucous changes represent incontinentia pigmenti.
Histologically, degeneration of the basal layer, pigmentary incontinence,
and dermal inflammation, which have been considered characteristic findings
of incontinentia pigmenti, are constantly absent in incontinentia pigmenti
achromians. When depigmentation appears in incontinentia pigmenti, it appears much later than in incontinentia pigmenti achromians. Based on the
differences cited, we agree with Jelinek et al. [1] that incontinentia pigmenti
and incontinentia pigmenti achromians are probably separate entities.
Incontinentia Pigmenti Achromians and Nevus Depigmentosus (Table 102)
Ito [2] considered his case to be a nevus depigmentosus distributed along
Blaschko's lines. Several features distinguish this entity from incontinentia
pigmenti achromians. Nevus depigmentosus is an embryologic mutation and
is not transmitted as an autosomal dominant trait. Nevus depigmentosus is not
usually associated with neural and ectodermal disorders, unlike incontinentia
pigmenti achromians. Nevus depigmentosus is stable and permanent and does
not show a tendency to progression and repigmentation as does incontinentia
pigmenti achromians. While none of these observations may be conclusive or
convincing alone, coupled with electron microscopic differences, they suggest
incontinentia pigmenti achromians and nevus depigmentosus are not the same
process.
It appears that, as noted by Jelinek et al. [1], incontinentia pigmenti achromians represents an entity sui generis. The authors point out that the term
incontinentia pigmenti achromians is illogical as there is no pigmentary in-

TABLE 102. Comparison of Nevus Depigmentosus and

Incontinentia Pigmenti Achromians
Nevus depigmentosus
Not hereditary
Congenital
Stable-permanent
No repigmentation
Rarely associated with
neuroectodermal disorders

Incontinentia pigmenti achromians

Possibly autosomal dominant
May appear up to age 12
Progression
Late repigmentation
Neuroectodermal disorders often
associated

continence and the term is self-cancelling, and they proposed the name "hypomelanosis of Ito."

Diagnosis (Table 103)

The clinical picture is characteristic enough to suggest the diagnosis. The
hypomelanosis must be distinguished from normal macules surrounding hypermelanotic skin. Differential diagnoses of incontinentia pigmenti and nevus
depigmentosus are discussed above and summarized in Tables 101 and 102.
Segmental vitiligo can usually be excluded by history (pure-white macules,
acquired, and progressive). Lichen striatus, which may resolve with postinflammatory hypomelanosis, is usually accompanied by typical epidermal changes
observed by oblique lighting. The observation of incontinentia pigmenti achromians depigmentation should trigger a search for possible associated abnormalities. Histology is characteristic enough to be a worthwhile pursuit in doubtful cases.

Treatment
None is available.

TABLE 103. Clinical Aspects of Hypomelanosis in Incontinentia

Pigmenti Achromians (Ito)
Incidence
Inheritance
Sex
Age of onset
Clinical description
Color
Distribution
Skin
Hair and mucous
membranes
Configuration
Size (extent)
Borders
Local symptomatology
Progression
Neural and ectodermal
abnormalities

Rare (26 mentioned cases)

Uncertain: possibly autosomal dominant
F:M = 17:9

Birth, infancy, or childhood

Hypopigmented (lighter than normal skin)
Asymmetrical, usually bilateral
Trunk, extremities; rarely the face, shoulder,
hip; palms and soles not involved
Not reported
"Marble cake" or bizarrely whorled
Variable
Irregular, imprecise, blurred
None
In the first years of life, then
hypopigmentation tends to reverse to
normal
Yes

425

GENETIC AND
CONGENITAL
DISORDERS

426

CHAPTER 1

REFERENCES
1. Jelinek JC et al: Hypomelanosis of Ito (Uincontinentia pigmenti achromians"). Report of three
cases and review of the literature. Arch Dermatoll07:596-601, 1973
2. Ito M: Studies on melanin, XI: Incontinentia pigmenti achromians, a singular case of nevus
depigmentosus systematicus bilateralis. Tohoku J Exp Med 55(suppl):57-59, 1952
3. Koga M: Incontinentia pigmenti achromians (Ito). Opn J Dermatol 79:300, 1969). Quoted by
Jelinek JC et al: Hypomelanosis of Ito (Uincontinentia pigmenti achromians"). Report of three
cases and review of the literature. Arch Dermatoll07:596-601, 1973
4. Rubin MB: Incontinentia pigmenti achromians. Multiple cases within a family. Arch Dermatol
105:424--425, 1972
5. Masumizu T: Incontinentia pigmenti achromians (Ito). OpnJ DermatoI73[B):303, 1963). Quoted
by Jelinek JC et al: Hypomelanosis of Ito (Uincontinentia pigmenti achromians"). Report of
three cases and review of the literature. Arch Dermatoll07:596-601, 1973
6. Hellgren L: Incontinentia pigmenti achromians (Ito). Acta Dermatol (Kyoto) 55:237-240,1975
7. Piiiol-Aguade Jet al: Considerations sur l'incontinentia pigmenti achromians d'lto. A propos
de deux nouveaux cas. Bull Soc Fr Dermatol Syphiligr 16:553-555, 1969
8. Nohara N, Tasaka S: Incontinentia pigmenti achromians. Acta Dermatol (Kyoto) 56:130-133,
1961
9. Aram H: Incontinentia pigmenti achromians (Ito). Cutis 6:197-201, 1970
10. Grosshans EM et al: Incontinentia pigmenti achromians (Ito). Etude clinique et histopathologique. Dermatologica 142:65-78, 1971
11. Hamada T et al: Incontinentia pigmenti achromians (Ito). Arch Dermatol 96:673-676, 1967
12. Kato T et al: Incontinentia pigmenti achromians. Jpn J Dermatol Ural 8:214-217, 1954
13. Okuwa H, Kitamura S: Incontinentia pigmenti achromians. Jpn J Dermatol 76[A):606-618,
1966
14. Schwartz MF et al: Hypomelanosis of Ito (incontinentia pigmenti achromians): a neurocutaneous syndrome. J Pediatr 90:236-240,1977
15. Griffiths A, Payne C: Incontinentia pigmenti achromians. Arch Dermatolll1:751-752, 1975
16. Cordero AA, Woscoff A: Incontinentia pigmenti achromians (Ito). Med Cutan Iber Lat Am
4:497--499, 1970
17. Maize JC et al: Systematized hypochromic nevus. Incontinentia pigmenti achromians of Ito.
Arch Dermatoll06:884-885, 1972
18. Browne RM, Byrne JPH: Dental dysplasia in incontinentia pigmenti achromians (Ito); an unusual form. Br Dent J 140:211-214,1976
19. Cohen SR et al: Case report. New England Dermatological Society, New Haven, April, 1976
20. Hood A et al: Case presentation. New England Dermatological Society, Boston, Massachusetts,
1975
21. Lambert WC: Case report. New England Dermatological Society, New Haven, April, 1976
22. Morohashi M et al: Ultrastructural studies of vitiligo, Vogt-Koyanagi syndrome, and incontinentia pigmenti achromians. Arch DermatoI113:755-766, 1977
23. Kitamura K: Dber Incontinentia pigmenti. Mit Erinnerungen an A. Franceschetti. Hautarzt
20:492--494, 1969
24. Peiia L et al: Incontinentia pigmenti achromians (Ito's hypomelanosis). Int J DermatolI6:194-202,
1977
25. Ortonne J-p et al: Hypomelanosis of Ito: report of one case. Ann Dermatol Venereoll06:47-50,
1979
26. Stewart RE et al: A malformation complex of ectrodactyly, clefting and hypomelanosis of Ito
(incontinentia pigmenti achromians). Cleft Palate J 16:358-362, 1979
27. Happle R et al: Das Ito Syndrom (Incontinentia pigmenti achromians). Hautarzt 27:286-290,
1976
28. Piiiol-Aguade Jet al: Incontinentia pigmenti achromians (Ito). Med Cutan Iber Lat Am 3:287-290,
1968
29. Nordlund JJ et al: Hypomelanosis of Ito. Acta Derm Venereol (Stockh) 57:261-264, 1977
30. Stoebner P, Grosshans EM: Incontinentia pigmenti achromians (Ito). Etude ultrastructurale.
Arch Klin Exp Dermatol 239:227-244, 1970

31. Ramos e Silva J: Incontinentia pigmenti. Dermatologica 115:623-632, 1957

32. Braverman I: Skin Signs of Systemic Disease. Philadelphia, Saunders, 1970, p 411

INCONTINENTIA PIGMENTI
Incontinentia pigmenti or Bloch-Sulzberger syndrome is an uncommon,
sex-linked, dominant genodermatosis that usually affects female infants. Characteristically, at or shortly after birth there is an erythematous eruption with
linear vesiculation. The children afflicted, despite profound leukocytosis and
eosinophilia, do not appear toxic or generally unwell. Verrucous growths follow
after weeks to months but then resolve spontaneously to leave atrophy, hypomelanosis, or both. The final stage involves irregular macules, streaks, whorls,
or splotches of brown to slate-gray pigmentation asymmetrically distributed
over the trunk but also occasionally over the extremities. This gradually fades
as adulthood is approached. Although hyperpigmentation is the most common
residue of incontinentia pigmenti, hypomelanosis was found by Carney [1] in
13%. Other possible features include alopecia, partial anodontia, nail dystrophy, pegged teeth, ocular abnormalities (blindness, cataracts, retinitis proliferans, retrolental fibroplasia, metastatic ophthalmia, chorioretinitis, uveitis,
pseudoglioma, retinal detachment, optic nerve atrophy), and central nervous
system abnormalities (spastic or paralytic disorders, cerebellar ataxia, congenital hearing loss, hemiplegia, diplegia, psychomotor retardation, mental retardation, microcephaly, hydrocephalus, cerebral cortical atrophy, seizures, abnormal EEG).
Male cases are rare; only 16 of the 653 cases reviewed by Carney were
males. Pregnancies with affected male fetuses usually end in spontaneous abortions.

Hypopigmented Lesions in Incontinentia Pigmenti (Table 104)

Hypopigmentation is considered an uncommon but certain cutaneous feature of incontinentia pigmenti. Kleinhans [2] reported the occurrence of atrophic
and hypopigmented macules in a typical case of incontinentia pigmenti. Wiley
TABLE 104. Distribution of Cutaneous Lesions of Incontinentia

Pigmenti

Erythema
Verrucae
Pigmentation
Depigmentation
Atrophy
o

Torso
only

Extremities
only

Torso and
extremities

6
0
73
2
1

80
120
21
20
28

157
10
176
2
9

Total
243
130
270
24
38

Source: Carney RG: Incontinentia pigmenti: a world statistical analysis. Arch Dermatol11:535-542. 1976. Copyright. 1976. American Medical Association. Used with
permission.

427
GENETIC AND
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DISORDERS

428

CHAPTER 1

and Frias [3] observed streaked hypopigmented macules on the posterior lower
legs of the mother of their patient (Fig. 169). "Incontinentia pigmenti et achromians" was the name Mittal et a1. [4] gave to the condition affecting a twoyear-eight-month-old girl with typical hyperpigmented lesions of incontinentia
pigmenti and with a hypopigmented, linear, irregular, "splash" pattern of lesions occurring at sites apparently separate from the hyperpigmented patches
(Fig. 170). Hypopigmentation involved mainly the back, but was also noted on
the abdomen and the proximal upper and lower limbs (Fig. 171). Apart from
nail dystrophy, no other congenital anomaly was detected in this patient. Since
the histologic appearance of the hyperpigmented macules of this patient was
consistent with incontinentia pigmenti, this case certainly represents incontinentia pigmenti with hypo pigmented macules and not incontinentia pigmenti
achromians.
From his survey of the world literature, Carney [5] could himself satisfactorily identify 24 cases with such hypopigmented lesions. Hypomelanosis has
been observed in children [1,6,7] and in adults [6,8,9] with other features of

FIGURE 169. Depigmented lesions in incontinentia pigmenti. (From: Wiley HE, Frias JL: A useful
diagnostic sign. Am J Dis Child 128:546-547, 1974. Copyright, 1974, American Medical Association. Used with permission.)

429

GENETIC AND
CONGENITAL
DISORDERS

FIGURE 170. Hyperpigmented lesions on axillae, cubital fossae, wrists, groin, and abdomen, and
hypopigmented lesions on abdomen. (From: Mittal R et al: Incontinentia pigmenti et achromians.
Dermatologica 150:355-359, 1975. Copyright, 1975, S. Karger A.G. Used with permission.)

incontinentia pigmenti [1,6,7] or as an isolated finding [6,8,9]. In three families,

this has been reported to be the predominant form of the disease in the obligatory carrier [6,8,9]. Hypopigmented lesions in incontinentia pigmenti appear
as linear streaks on the posterior aspect of the calves [6,8]. Depigmented macules
may also occur on the arms [1,9]' thighs [6,10]' and trunk [7]. Among 24 cases,
the trunk alone was involved in two cases, the extremities alone in 20 patients,
and both the trunk and extremities in two cases [5]. The lesions are not totally
amelanotic and Wood's light examination confirms the persistence of some
background pigmentation [3]. Atrophy is occasionally observed.
The histologic picture of hypopigmentation in incontinentia pigmenti is
poorly defined. Mittal et al. [4] reported epidermal acanthosis, spongiosis, and
decreased basal layer pigment.
The pathogenesis is not understood. It has been suggested that the hypomelanosis may follow earlier vesiculobullous and hyperkeratotic lesions [6].
Carney [5] also concluded that it seems reasonable that the inflammatory stages
(erythema, blisters, verrucae) may result in postinflammatory hypopigmentation as well as postinflammatory hyperpigmentation. This conclusion is unsatisfactory for it fails to explain how early lesions of incontinentia pigmenti
and the late hypopigmentation may occur in totally different areas of the skin.

430

CHAPTER 1

FIGURE 171. Hypopigmented lesions on back and adjoining parts of limbs. and hyperpigmented
lesions over buttocks and wrists. (From: Mittal R et al: Incontinentia pigmenti et achromians.
Dermatologica 150:355-359. 1975. Copyright. 1975. S . Karger A.G. Used with permission.)

Associated Features
Incontinentia pigmenti is most often characterized by an erythematous
eruption with linear vesiculation that is first observed at birth or shortly thereafter. Later verrucous growths usually resolve with hyperpigmentation, whichgradually fades so that it is most often inapparent by adulthood.
The cutaneous syndrome is usually associated with various abnormalities
of hair (alopecia), teeth (partial or complete anodontia, pegged teeth), eyes,
central nervous system, and development. These have been recently reviewed
by Carney [5] (Tables 105, 106, 107).

Diagnosis
The course of the disease, the family history, and the clinical picture are
usually helpful. Under certain circumstances, and even in the absence of other
dermatologic findings, the presence of typical hypopigmented lesions may confirm the diagnosis of incontinentia pigmenti. A search for such lesions, with
the help of Wood's light examination, is potentially useful in the genetic counseling of involved families [3].

TABLE 105. Central Nervous System Abnormalities in 142 Cases of

Incontinentia Pigmenti

Type of abnormality
Spastic paralysis
Motor retardation
Mental retardation
Microcephalus
Cerebral cortical atrophy
Hydrocephalus
Convulsive disorders
Cerebellar ataxia
Congenital hearing loss
Unspecified disorder
Abnormal EEG
Q

No. of
patients
affected b

Percent
of
patients
affected

53
35
57
22
7
6
62
2
3
7
30

11.4
7.5
12.3
4.7
1.5
1.3
13.3
0.4
0.7
1.5
6.5

Percent of general
population
affected

0.403
0.1
0.293
0.3

Source: Carney RG: Incontinentia pigmenti: a world statistical analysis. Arch Dennatol

112:535-542, 1976. Copyright, 1976, American Medical Association. Used with permis-

sion.

b Quite

often individual patients had more than one type of disorder.

TABLE 106. Ocular Anomalies in 160 Cases of Incontinentia Pigmenti

Type of anomaly
Strabismus
Blindness
Cataracts
Retinal detachment
Microphthalmus
Optic nerve atrophy
Pseudoglioma
Retrolental fibrosis
Retinitis proliferans
Chorioretinitis
Metastatic ophthalmia
Uveitis
Optic nerve glioma
Retinal telangiectasia and ectasia
Vitreous hemorrhage
Avascular retina
Retinal pigmentation
Glial strands
Retinal depigmentation
Unspecified abnormalities
Glaucoma"
Blue sclerae"
Retinitis pigmentosa"

No. of
patients
affected b

Percent
of
patients
affected

83
34
18
13
13
18
16
7
2
4
2
6
1
10
4
6
18
5
2
14
4
7
1

18.2
7.5
4.0
2.9
2.9
4.0
3.5
1.5
0.4
0.9
0.4
1.3
0.2
2.2
0.7
1.3
4.0
1.1
0.4
3.1
0.9
1.5
0.2

Percent of general
population
affected
3.07
0.2
0.0004
0.025

0.9

Source: Carney RG: Incontinentia pigmenti: a world statistical analysis. Arch Dermatol 112:535-542, 1976.
Copyright, 1976, American Medical Association. Used with permission.
b Quite often individual patients had more than one type of anomaly.
"Considered to be unrelated to incontinentia pigmenti and, therefore, not included in the group of 160 cases.
Q

431

GENETIC AND
CONGENITAL
DISORDERS

TABLE 107. Development Anomalies in 60 Cases of Incontinentia

Pigmentia

432

CHAPTER 1

Type of anomaly
Skull deformities
Dwarfism, small stature
Clubfoot
Spina bifida
Cleft palate or cleft lip, or both
Ear anomalies
Hemiatrophy
Congenital dislocated hip
Chondrodystrophy

No. of
patients
affected b
9
7
6
6
5

5
4
3
2

Percent
of
patients
affected
2.1
1.6
1.4
1.4
1.1
1.1
0.9
0.7
0.5

Percent of general
population
affected

0.57
0.43
0.28

0.71
0.025

Source: Carney RG: Incontinentia pigmenti: a world statistical analysis. Arch DennatoI112:535-542,
1976. Copyright, 1976, American Medical Association. Used with permission.
b Quite often individual patients had more than one type of anomaly.
a

Differential Diagnosis
Depigmented macules in incontinentia pigmenti are similar to the cutaneous lesions of incontinentia pigmenti achromians. We believe that incontinentia pigmenti and incontinentia pigmenti achromians are distinct and separate entities (see Table 101). Unlike incontinentia pigmenti achromians, the
torso is relatively free of hypomelanosis in incontinentia pigmenti. The other
differences between the two entities have been summarized by Jelinek et al.
[11] (see section on "Incontinentia Pigmenti Achromians" in this chapter).

Treatment
The primary defect in incontinentia pigmenti is unknown and no treatment
is available.

REFERENCES
1. Carney RG: Incontinentia pigmenti: a report of five cases and review of the literature. Arch
Dermatol 64:126-135, 1951
2. Kleinhans D: Incontinentia pigmenti mit multiplex Fehlbildungssymptomatik bei einer Erwachsenen. Hautarzt 21:133-136, 1970

3. Wiley HE III, Frias JL: Depigmented lesions in incontinentia pigmenti-a useful diagnosis sign.
Am J Dis Child 128:546-547, 1974
4. Mittal R et al: Incontinentia pigmenti et achromians. Dermatologica 150:355-359, 1975
5. Carney RG: Incontinentia pigmenti. A world statistical analysis. Arch Dermatol112:535-542,
1976

6. Cramer JA, Schmidt WJ: Incontinentia pigmenti: report of six cases. Arch Dermato171:699-702,
1955
7. Gordon H, Gordon W: Incontinentia pigmenti: clinical and genetical studies of two familial
cases. Dermatologica 140:150-168, 1970

8. Cantu-Garzu JM, Ruiz-Barquin E: On the inheritance of incontinentia pigmenti. Dermatologica

143:190-197, 1971
9. Rubin L, Becker SW Jr: Pigmentation in the Bloch-Sulzberger syndrome (incontinentia pigmenti). Arch Dermatol 74:263-268, 1956
10. Godin RJ, Anderson JA: The characteristic dentition of incontinentia pigmenti. JPediatr 57:7S-a5,
1960
11. Jelinek JE et al: Hypomelanosis of Ito, "incontinentia pigmenti achromians." Arch DermatoI
107:596-601, 1973

ATAXIA-TELANGIECTASIA
Ataxia-telangiectasia is an autosomal recessive neurocutaneous disease
characterized by cerebellar ataxia, chorioathetosis, ocular and cutaneous telangiectasia, and recurrent pulmonary infections with bronchiectasis, presumably related to hypogammaglobulinemia (usually IgA) resulting from hypoplasia of the thymus.
Hypomelanosis in Ataxia-Telangiectasia
In patients with ataxia-telangiectasia, two types of hypomelanosis have
been described, namely, premature graying of hair and hypomelanotic macules.
Utian and Plit in 1964 [1] reported depigmented areas scattered over the
trunk and back of a nine-year-old girl with ataxia-telangiectasia. Karpati et al.
[2] later observed a one-year-old boy with ataxia-telangiectasia, depigmented
macules on the sacral area, and premature graying of the scalp hair. Reed et
al. [3] noted hypomelanosis in eight of 22 patients. The depigmented macules
were larger than 1.5 cm in diameter. In one of these patients the depigmentation
involving the back and extremities was very extensive. The hypomelanotic
macules were present at birth and did not enlarge with age. Diffuse premature
graying of scalp hair was noted in young patients, none of whom had the typical
white forelock of piebaldism [3]. McFarlin et al. [4] found premature graying
of scalp hair in 14 of 17 patients with ataxia-telangiectasia. Most of their patients
were under 12 years of age. Hypomelanosis, described as vitiligo-like, was also
observed in several of their cases. Macules may rarely assume a dermatomal
distribution [5].
There are few reports on the histology of the pigmentary changes in ataxiatelangiectasia, but Karpati et al. [2] reported pigmentary incontinence in two
of their patients. Whether it was the hyperpigmented or hypopigmented macules that were biopsied is not specified. No electron microscopic study of the
white macules of ataxia-telangiectasia is available.
Other Cutaneous Features
Telangiectases or dilated venules are present over sun-exposed areas and
areas subjected to frequent friction. Cafe-au-Iait spots, pigmented nevi, and
sclerodermoid changes are not infrequent. Eczema, seborrhea, impetigo, and

433
GENETIC AND
CONGENITAL
DISORDERS

434
CHAPTER 1

psoriasis have been reported. Clubbing of nails is frequently observed. Cyanosis

reflects pulmonary dysfunction.

Other Clinical Features

See Table 108.
TABLE 108. Systemic Abnormalities in Ataxia-Telangiectasia
General

Growth retardation

Pulmonary

Chronic bronchitis; bronchiectasis

Ocular

Telangiectasia (conjunctival)
Strabismus
Nystagmus
Oculomotor dyspraxia

Neurologic

Mental retardation
Cerebellar dysfunction
Choreoathetoses
Myoclonus
Decreased deep tendon reflexes
Distal weakness
Babinski's sign
Decreased sensation (vibration, position, and touch)

Gastrointestinal

Nausea
Jaundice
Diarrhea
Steatorrhea
Melena
Food intolerance

Malignancies

Lymphomas
Lymphosarcoma
Leukemia
Hodgkin disease
Astrocytoma
Medulloblastoma
Ovarian dysgerminoma
Gastric carcinoma

Endocrinopathies

Abnormal glucose tolerance test including frank

diabetes mellitus
Insulin resistance
Decreased 17-ketosteroid excretion

Immunologic

Decreased tonsillar tissue

Absent or reduced IgA
Increased IgM
Decreased or absent 19E
Absent thymus
Altered cellular immunity

Clinical Course
The diagnosis usually is first apparent when the neurologic abnormalities
appear in early life. The typical course is marked with frequent infections, and
death from respiratory tract infection is not uncommon. The more severe the
immunologic abnormality, the more serious and frequent are the infectious
episodes. Many patients succomb to malignancies.

REFERENCES
1. Uti an HL, Plit J: Ataxia telangiectasia. J Neural Neurasurg Psychiatry 27:38-40, 1964

2. Karpati G et al: Ataxia telangiectasia: further observations and report of 8 cases. Am JDis Child
110:51-63, 1965
3. Reed WB et al: Cutaneous manifestations of ataxia telangiectasia. JAMA 195:746-753, 1966
4. McFarlin DE et al. Ataxia telangiectasia. Medicine (Baltimore) 51:281-314, 1972
5. Berg M, Tarnowski W: Nevus depigmentosus. Arch Dermatoll09:920, 1974

XERODERMA PIGMENTOSUM
Xeroderma pigmentosum is a recessive hereditary disorder clinically characterized early in life by photophobia and persistent erythema, and later by
hyper- and hypopigmentation, scarring, premature aging of the skin, and development of epithelial tumors and, less frequently, melanomas. In xeroderma
pigmentosum, there is a defect in excision repair of ultraviolet damage to DNA
[1,2].

Hypopigmented macules of both sun-exposed and unexposed skin have

been described in xeroderma pigmentosum [3-6] (Fig. 172). These hypopigmented macules are not uncommon and appear early in life. Sadeghi [6] observed hypo pigmented macules in 10 of 22 patients with xeroderma pigmen-

FIGURE 172. Comparison between skin exposed to sunlight (left forearm) and the unexposed buttock. Freckling is
apparent on the forearm but absent on the buttock where,
on the contrary, the multiple white macules are clearly
visible. (From: Cesarini JP et al: Hypopigmented macules
of sun-unexposed skin in xeroderma pigmentosum. An
electron microscopic study. J Cutan Pathol 2:128-139, 1975.
Copyright, 1975, Munksgaard International Publishers, Copenhagen. Used with permission.)

435
GENETIC AND
CONGENITAL
DISORDERS

436

CHAPTER 1

FIGURE 173. Higher magnification of the buttock. Macules are irregular in size and shape. The circle indicates the
location of the punch biopsy (x 5). (From: Cesarini JP et
al: Hypopigmented macules of sun-unexposed skin in xeroderma pigmentosum. An electron microscopic study. J
Cuton Pothol 2:128-139, 1975. Copyright, 1975, Munksgaard International Publishers, Copenhagen. Used with permission.)

FIGURE 174. Buttock: hypopigmented macule (center). A

Langerhans cell (L) is present in the basal layer of the epidermis. Melanosomes are not detectable in keratinocytes
(K) , whatever their level. BM = basement membrane (x
8000). (From:Cesarini JP et al: Hypopigmented macules of
sun-unexposed skin in xeroderma pigmentosum. An electron microscopic study. J Cuton Pothol 2:128-139, 1975.
Copyright. 1975 . Munksgaard International Publishers. Copenhagen. Used with permission.)

437
FIGURE 175. Buttock: hypo pigmented macule. Melanocyte
containing melanosomes of a lamellar type (~) or granular type
(.) as well as normal-looking melanosomes (x 30,000). (From:
Cesarini JP et al: Hypopigmented macules of sun-unexposed
skin in xeroderma pigmentosum. An electron microscopic study.
J Cutan Patho12:128-139, 1975. Copyright, 1975, Munksgaard
International Publishers, Copenhagen. Used with permission.)

tosum (Fig. 173). The macules are 1 to 5 mm in diameter. In fair-skinned

individuals, the hypomelanotic macules may be difficult to find unless the
patient is examined with a Wood's light.
No melanocytes are present in the center of the lesions, and the number
of dopa-positive melanocytes at the margins of the hypopigmented macules is
decreased. An ultrastructural study (3) of hypopigmented macules in areas not
normally exposed to sunlight showed an absence of melanocytes and an increased number of Langerhans cells in the basal layer of the epidermis (Figs.
174, 175, 176). At the margins of the lesions there were a few melanocytes
exhibiting structural abnormalities (bizarre nuclei) with giant melanosomes,
and melanosomes aggregated in autophagic vacuoles as well as normal-shaped
melanosomes. Some of these melanosomes also showed abnormal melanin
deposition. Basal layer keratinocytes contained no melanosomes and only a
few melanosome complexes were present in the upper epidermis of the margins.
In the hypopigmented macules of sun-exposed skin, similar changes were observed.

FIGURE 176. Buttock: hypopigmented macule. Melanocyte (M) with indented nucleus. The cell contains few
melanosomes (arrows) (x 11,000) . (From Cesarini JP et
al: Hypopigmented macules of sun-unexposed skin in
xeroderma pigmentosum. An electron microscopic study.
J Cutan Pathol 2:128-139, 1975. Copyright, 1975,
MUnksgaard International Publishers, Copenhagen. Used
with permission.)

GENETIC AND
CONGENITAL
DISORDERS

438

CHAPTER 1

Hypopigmentation in xeroderma pigmentosum reflects an absence of melanocytes. Cesarini et al. [3] suggested that the abnormalities of melanocytes
at the margins of the hypopigmented macules must be independent of sun
exposure because lesions may occur in skin not habitually exposed to sun.
This suggests that xeroderma pigmentosum is characterized by a generalized
cutaneous pigmentary abnormality. The presence of pigmentary abnormalities
in a DNA repair defect disorder and the relationship of psoralen DNA adducts
to melanosome structure [7] and psoralen-induced UVA repigmentation suggest
some unknown relationship between DNA structure and melanosome morphology.

REFERENCES
1. Cleaver JE: Defective repair replication of DNA in xeroderma pigmentosum. Nature 78:652-656,
1968

2. Cleaver

JE:

DNA damage and repair in light sensitive human skin disease. J Invest Dermatol

54:181-195, 1970

3. Cesarini JP et al: Hypopigmented macules of sun exposed skin in xeroderma pigmentosum. An

electron microscopic study. J Cutan Pathol 2:126-139, 1975
4. Guerrier CJ et al: An electron microscopical study of the skin in 18 cases of xeroderma pigmentosum. Dermatologica 146:211-221, 1973
5. RoIlier MP: Aspects cliniques et histologiques des r6gions cutan6es non iso16es dans les xeroderma pigmentosum. Bull Soc Fr Dermatol Syphiligr 3:280-283,1957
6. Sadeghi N: Le xeroderma pigmentosum. Aspects anatomocliniques et traitement. Thesis V, Ed
AGEMP, Paris, 1964
7. Toda K et al: Alteration of racial differences in melanosome distribution in human epidermis
after exposure to ultraviolet light. Nature 236:143-145, 1972

NEUROFIBROMATOSIS
Neurofibromatosis is an autosomal dominant disorder appearing in childhood or adolescence and characterized by cafe-au-Iait spots and multiple peripheral nerve tumors. Poliosis has been reported in association with neurofibromas (Fig. 177). Rarely a segmental hypomelanosis may occur [1].
IIi 1968, Kaplan and Shapiro [2] reported a 19-year-old, generally healthy
male with a 15-year history of a slowly enlarging asymptomatic neurofibroma
of the scalp; gray hair localized to the same area had been present for seven
years. Masson-Fontana silver stain revealed some hairs with large quantities
of melanin pigmentation and others with none.
Bradley et al. [3], in 1974, reported in three members of one family the
occurrence of neurofibromatosis, peroneal muscular atrophy, congenital deafness, partial albinism, and the Axenfeld defect. The mother (Fig. 178) had gray
scalp hair. Her two daughters had golden-white hair, pale skin, and numerous
freckles. One daughter also had ocular albinism. The father had premature
whitening of the scalp hair and the investigators suggested he had piebaldism
which his daughters inherited as an autosomal dominant trait. The mother and
one of the daughters had cutaneous signs of neurofibromatosis and the father
was said to have a possible cafe-au-Iait spot on his hip. There was no obvious

439

GENETIC AND
CONGENITAL
DISORDERS

FIGURE 177. Hypomelanosis of the hair and of the face in a child with neurofibromatosis.

FIGURE 178. This 58-year-old woman with typical neurofibromatosis had two daughters with
piebaldism. (From: Bradley WG et al: The familial association of neurofibromatosis. peroneal
muscular atrophy. congenital deafness. partial albinism. and Axenfeld defect. Brain 97:521-532.
1974. Copyright. 1974. Oxford University Press. Used with permission.

440
CHAPTER 1

common pathogenesis for the abnormalities of Schwann cells, melanocytes,

cochlear and vestibular ganglia cells, and motor and sensory neurons of the
peripheral nervous system.

REFERENCES
1. Berg M, Tarnowski W: Nevus depigmentosus. Arch Dermatol109:920, 1974

2. Kaplan BS, Shapiro L: Poliosis overlying a neurofibroma. Arch Dermatol 98:631-633, 1968
3. Bradley WG et al: The familial association of neurofibromatosis, peroneal muscular atrophy,
congenital deafness, partial albinism and Axenfeld's defect. Brain 97:521-532, 1974

DYSCHROMATOSIS SYMMETRICAj DYSCHROMATOSIS

UNIVERSALIS HEREDITARIA
Dyschromatosis is a rare pigmentary disorder initially described in the
Japanese and characterized by spotted hyperpigmentation mingled with patches
of hypopigmentation. Two types of dyschromatosis have been reported. Both
types have a similar primary lesion but vary in the extent of the cutaneous
involvement. Localized dyschromatosis, also known as "dyschromatosis symmetrica," or "acropigmentation of Dohi," was first reported by Matsumoto [1]
in 1923 as "a leucopathia punctata and reticularis symmetrica" and later by
Komaya [2] in 1924 under the title "Symmetrische Pigmentanomalien der Extremitaten." Widespread dyschromatosis was first reported in 1933 by Toyama
et al. [3] as "dyschromatosis universalis hereditaria."
The status of dyschromatosis as an entity does not seem well established.
That dyschromatosis symmetrica and dyschromatosis universalis hereditaria
are different clinical expressions of the same pathogenic process is not fully
dismissed. Ito [4] suggested in 1950 that from the genetic point of view, dyschromatosis symmetric a belongs to the same category as freckles and xeroderma
pigmentosum. Furthermore, it is possible that "Safu" of Truk Island [5] and
the 23 cases of leukomelanoderma among natives of the islands of Palau and
Saipan [6] represent examples of dyschromatosis symmetrica [7].

Clinical Features
Incidence
Both types of dyschromatosis are apparently rare; only a few cases have
been reported. Ito [4] found in his clinic between 1925 and 1944 only 16 cases
of dyschromatosis symmetric a, but Costa [8] stated that the disease is frequent
in Brazil.
Race
Although most of the initial cases were reported in Japanese, dyschromatosis has been reported among Europeans [9] and South Americans [8].

Sex

Both types of dyschromatosis appear to affect males and females equally.

Among the 16 cases of dyschromatosis symmetric a studied by Ito [4], seven
were males and nine were females. Dyschromatosis universalis hereditaria [8]
also occurs equally among males and females.
Heredity

Both forms of dyschromatosis have been observed to be familial [1], but

many sporadic cases have been noted. Fifty-two percent of the Japanese cases
reported are familial. Suenaga [10] also observed this disease in five generations
in the same family. Ito [4], however, observed a 38.8% incidence of dyschromatosis in siblings of patients if one parent was affected, and 35.7% if neither
parent was affected. Of those with dyschromatosis, 30.7% were born of consanguinous marriages.
Tay et al. [11], in 1971, reported a case of dyschromatosis symmetrica in
a Chinese boy from Singapore. The boy also had the 47 XYY syndrome but
lacked excessive height or criminal tendencies. The family pedigree was not
reported, but the authors suggested dyschromatosis symmetric a could be a
clinical marker of the XYY genotype.
Inheritance is probably autosomal dominant. Toyama and Omori [12] reached
this conclusion for dyschromatosis symmetrica. Toyama et al. [3], who found
dyschromatosis universalis hereditaria in seven members of two families, also
suggested an autosomal dominant pattern of inheritance. Ito [4] proposed a
polymeric dominant pattern with recessive lethal factor.
Precipitating Factors

Although precipitating factors are unknown, that dyschromatosis symmetrica is localized to sun-exposed areas suggests a role of ultraviolet radiation.
But dyschromatosis universalis hereditaria is frequently most prominent on
the abdomen and back; while the face may be affected, it is less commonly
involved and, if so, less severely than elsewhere. Thus, light alone is not the
etiologic agent for all dyschromatoses.

Clinical Findings
Onset

Dyschromatosis symmetrica usually appears in infancy or in early childhood. In the young boy reported by Tay et al. [11] the abnormal pigmentation
was initially noted at the age of two. In two cases reported by Sugai et al. [13]
the disease began very soon after birth in one patient and at the age of seven
in the other; both cases could, however, represent vitiligo. Costa [8] reported
two patients in whom the condition was first noted at ages 18 and 22 years.
Ito [4] found the age at which patients were first examined to range from 16 to
40 years.

441

GENETIC AND
CONGENITAL
DISORDERS

442
CHAPTER 1

Dyschromatosis universalis hereditaria usually appears within the first two

years of life. In the two patients described by Suenaga [10], the condition was
first noticed one year after birth.
The Typical Lesions
The typical lesions are the same in both types of dyschromatosis (Table
109). Both hyperpigmented and hypopigmented macules are described. The

hyperpigmented macules are numerous, but usually small and discrete. They
range in size from "a grain of rice," to "a pea" or "a bean," and vary in color
from light to dark brown. The hypomelanotic macules may be similar. The
macules assume a round or irregularly patchy pattern. These lesions are irregularly clustered and closely intermingled so that a mottled appearance results.
Hyperpigmented macules are sharply demarcated from hypopigmented lesions.
There seems to be no seasonal variation in the intensity of pigmentation, which
curiously appears not to be stimulated by sun exposure. There are no other
epidermal changes and the lesions are asymptomatic. There is no pruritus,
localized anesthesia, anhidrosis, scaling, scarring, atrophy, inflammation, lichenification, or hyperkeratosis.
The lesions of dyschromatosis symmetrica are symmetrically distributed
TABLE 109. Clinical Features of Dyschromatoses
Dyschromatosis symmetrica

Dyschromatosis
universalis hereditaria

Inheritance

Autosomal dominant

Autosomal dominant

Age of onset

Early childhood or infancy

Usually first two years of life

Elementary lesion

Hypo- and hyperpigmented

macules
"Grain of rice" to a "bean"
Usually round
Well delineated
Mottled appearance

Hypo- and hyperpigmented

macules
"Grain of rice" to a "bean"
Usually round
Well delineated
Mottled appearance

None
Extremities of limbs
Dorsa of hands and feet
Sometimes face
Palms and soles usually
spared
Symmetrical
Variable

None
Generalized
Palms and soles usually
spared

Variable

Associated
abnormalities

None

None

Course

Stationary
Benign

Stationary
Benign

Size
Shape
Borders
Grouping
Local symptomatology
Distribution

Extent

over the extremities, particularly the distal hands and feet where spotted hyperpigmentation is mingled with hypopigmentation, and also over the arms
and legs. Occasional involvement of the face with small pigmented macules
resembling freckles has been described. Palms and soles are usually not involved.
In dyschromatosis universalis hereditaria, the lesions are distributed all
over the body, particularly the trunk, abdomen, and limbs. In some cases the
face is involved but usually only slightly and then only in the periauricular
regions. Palms and soles are usually spared, but Suenaga [10] reported involvement of the palms with a few light brown macules in two patients and involvement of the sole in one. The extent and severity of the involvement is
extremely variable.
Neither type of dyschromatosis is progressive, although both do seem less
prominent in younger patients.
Dyschromatosis does not affect the general health of the patient. Nails,
eyes, teeth, and hair are usually normal and there are no neurologic abnormalities. Only isolated patients have been reported to have systemic abnormalities. Suenaga [10], for example, reported a child with dyschromatosis universalis hereditaria, caries of the dorsal spine, coxa vulgae, and signs of nerve
root compression. There is one case of dyschromatosis symmetrica in a patient
with an atypical 47 XYY syndrome. But any significant relationship between
the dermatosis and any of these features is unsubstantiated.

Pathologic Findings
In hyperpigmented skin, Tay et al. [11] found increased melanin pigmentation in the basal layer of the epidermis and a strongly positive dopa reaction.
No comprehensive study of the hypopigmented macules in dyschromatosis
has been done. Sugai et al. [14] studied the hypopigmented macules in one of
their patients and noted decreased melanin pigmentation. Dopa reaction was
negative and there was a sharp demarcation between unmelanized and melanized areas. There were also many clear basal cells considered to represent
inactive epidermal melanocytes [13]. Saunders and Hu [15] suggested, and it
seems likely, that the latter cases represented vitiligo because depigmentation
was present without any hyperpigmented macules and because clinically the
periungual hypomelanosis was characteristic of vitiligo.
Electron microscopy studies of dyschromatosis are not available.

Diagnosis
The clinical presentation and the hereditary pattern suggest the diagnosis.
However, pigmentary lesions of dyschromatosis may simulate ephelides, xeroderma pigmentosum, and various leukomelanodermas characterized by both
hyperpigmentation and hypopigmentation (arsenic dermatosis, incontinentia
pigmenti, Fanconi anemia, vagabond's leukomelanoderma, piebaldism, vitiligo,

443
GENETIC AND
CONGENITAL
DISORDERS

444
CHAPTER 1

and various poikilodermatoses). Relevant history and careful examination can

exclude most other disorders.

Treatment
No effective treatment is available.

REFERENCES
1.

2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.

Matsumoto S: (Acta Dermatol (Kyoto) 2:191, 1923). Quoted by E Meirowski, in Handbuch der
Haut- und Geschlechtskrankheiten. Edited by J Jadassohn. Berlin, Julius Springer, 1933
Komaya G: "Symmetrische Pigmentanomalien" der Extremitiiten. Arch Dermatol Syphilol
(Berlin) 147:389-393, 1924
Toyama I et al: A previously undescribed anomaly of pigmentation: dyschromatosis universalis
hereditaria. Jpn J Dermatol Urol 34:360-364, 1933
Ito M: Dyschromatosis symmetrica. Tohoku J Exp Med 55(suppI1):77-78, 1952
Matsunaga M: Quoted in Ito M: Dyschromatosis symmetrica. Tohoku J Exp Med 55(suppl
1):77-78, 1952
Ikegami Y, Hashiguchi M: On a peculiar depigmentary condition in the islets of Palau and
Saipan, South Sea Islands (abstr). Acta Dermat01 (Kyoto) 11:100, 1928
Ito M: Dyschromatosis symmetrica on the extremities. Tohoku J Exp Med 53:69-75, 1950
Costa OC: Leucopathie symmetrique progressive des extremites. Ann Dermat01 Syphiligr (Paris)
78:452-454, 1951
Siemens HW: Acromelanosis albo-punctata. Dermat010gica 128:86-87, 1964
Suenaga M: Genetical studies on skin diseases VII: Dyschromatosis universalis hereditaria in
5 generations. Tohoku J Exp Med 55:373-376, 1952
Tay CH et al: Dyschromatosis symmetrica in a Chinese with 47-XYY syndrome. Int J Dermat01
11:134-139, 1972
Toyama I, Omori H: (Jpn J Dermatol). Quoted by M Ito: Dyschromatosis symmetrica on the
extremities. Tohoku J Exp Med 53:69-75, 1950
Sugai T et al: Reply to comments on "symmetric acroleukopathy in mother and daughter."
Arch Dermatol 94:252, 1966
Sugai T et al: Symmetric acroleucopathy in mother and daughter. Arch Dermat01 92:172-173,
1965
Saunders TS, Hu F: Symmetric acroleukopathy or vitiligo (letter). Arch Dermatol 93:261, 1966

HYPOPIGMENTED MARKINGS IN DARK-SKINNED PEOPLE:

PIGMENTARY DEMARCATION LINES
Pigmentary demarcation line refers to a discrete, dramatic, and sharp contrast between pigmented and adjacent hypopigmented skin (Fig. 179). Sometimes a line of demarcation between the two areas is clearly visible [1]; other
times it is subtle. Included in this section is a discussion of various types of
pigmentary demarcation lines and also hypopigmented chest-wall macules.
Pigmentary demarcation lines must be distinguished from those disorders
in which there are hyperpigmented macules on normally pigmented skin, e.g.,
melasma and postinflammatory hyperpigmentation. In those conditions the

A Group

Type

445

GENETIC AND
CONGENITAL
DISORDERS

Type II
Type I
C Group

Type I
Type n

Type III

8 Group

FIGURE 179. Demarcation lines of pigmentation (feathered and hyphenated) found in Japanese.
after Miura. Ventral axial lines of inner thigh. to which Group B may correspond. are usually
shown in posterior view. (From: Selmanowitz VJ. Krivo JM: Pigmentary demarcation lines. Br J
Dermatol 93:371-377. 1975. Copyright. 1975. Blackwell Scientific Publications. Used with permission.)

defect lies in the darker area of skin, whereas in pigmentary demarcation lines
the lighter areas are abnormal.
Pigmentary demarcation lines were first described in 1913 [2] among Japanese and have generally been observed in dark-skinned people, particularly
Japanese and blacks. Pigmentary demarcation lines have been found to involve
various areas of the body. In 1953, Kisch and Nasuhoglu [3] described "a
mediosternal depigmentation line" in a great percentage of black patients. Having observed pigmentary demarcation lines in siblings and in several generations of a family, they concluded the condition must be hereditary. In 1965,
Weary and Behlen [4] reported an "unusual familial hypopigmentary anomaly"
in five members of a black family; all showed sharply outlined areas of hypopigmentation in approximately symmetrical locations just inferior to both
clavicles. In 1973, Selmanowitz and Krivo [5] studied these two kinds of hypopigmented markings in blacks and called them "pigmentary demarcation
lines." Miura [6] proposed the following classification of pigmentary demarcation lines based upon the location of the pigmentary disturbance:

446
CHAPTER 1

Subgroups

Location

Group
A

Arms

Legs
(mid perineum straight to
inner popliteal fossa)

Sternum

Back
(downward on either side
of midline)

Chest
(linear from nipples
toward midline)

Mid inner upper arm to upper axilla

and downward and toward the
midline across pectorales
muscles; may extend to flexor
elbow and even to radial aspect
of waist.
II. Similar to I but passing horizontally
from upper axilla toward
midline.
III. Similar to I and II, but pectoral
portion dips inferiorly, then
moves again in superior
direction to the midline to join
line from other side.
IV. Terminus a vaguely defined white
wedge pointed toward upper
axillary border.
I.

Upper sternum medial to linea

sternales to stomach;
symmetrical.
II. Upper sternum, then lines diverge
inferiolaterally between
mammary and inframammary
regions.
I.

Clinical Findings
Incidence
Pigmentary demarcation lines are common, particularly in dark-skinned
peoples. A mediosternal depigmentation line has been reported in nearly 40%
of 112 investigated blacks [3]. In a study of 100 blacks [5], a mediosternal

TABLE 110. Hypopigmented Markings in a Study of 100 Black Patientsa

Number of patients
by age and sex

Number (and %) with

mediosternal line

Number (and %) with

bilateral hypopigmented
chest macules

100 Patients
aged 6 mo. to 72 yr.
26 Patients aged 6
mo. to 13 yr.
74 patients aged
13 yr. to 72 yr.

38

(38%)

16

(16%)

18

(69%)

12

(46%)

20

(27%)

(5%)

52 Males
48 Females

22

(42%)

16

(33%)

11
5

(10%)

(21%)

From: Selmanowitz JV, Krivo JM: Hypopigmented markings in Negroes. Int J DermatoI12:229-235,
1973. Copyright, 1973, J. B. Lippincott Co. Used with permission.

depigmentation line was present in 38% and bilateral hypopigmented chest

macules in 16% (Table 110).
Sex
Both males and females may be affected. A mediosternal hypopigmentation
line has been found in 42% of 102 male Negroes and 35% of 110 females [3,5].
Bilateral hypopigmented chest macules were found in 21% of 52 black males
and 10% of 48 black females [5] (Table 110).
Race
The hypopigmented markings have been obser'led only in dark-skinned
people, principally Negroes, Japanese, and Spanish-Americans. They also exist
in Caucasoids but, because the contrast is faint, the pigmentary demarcation
lines are less apparent.
Age
The time of onset is unknown; in fact, in most of the cases these markings
were not noted by the patient initially. The incidence between six months and
13 years is greater than that between 13 and 72 years of age for both mediosternal
lines and bilateral hypopigmented chest macules [5]. Thus, there seems to be
a progressive disappearance of these hypopigmented markings during growth
and development of the individual. The observation that in a given family these
features are less apparent in parents than in their children reinforces this observation.
Heredity
The inheritance pattern of hypopigmented macules of the anterior chest
in five members of the same family strongly suggests autosomal dominant

447

GENETIC AND
CONGENITAL
DISORDERS

448
CHAPTER 1

inheritance [4]. Mediosternal depigmentation lines have been seen in a mother,

her two children, and also her two sisters [3]. However, because of the high
incidence of such hypopigmented markings, coincidental occurrence in several
individuals of the same family has to be considered.

Clinical Description
Chest Hypopigmented Macules
The principal lesion is a small hypopigmented but not totally amelanotic
macule, about 1 cm in size. The margins of the lesions are ill defined. The
epidermis is otherwise normal. Hair growth, sweating, and sensation are not
disturbed. In anyone patient there may be from several to 10 macules that may
vary in size and shape. These hypopigmented macules are always bilateral and
usually symmetrical, but there is sometimes an asymmetrical distribution of
lesions (Fig. 180).
Mediosternal Hypopigmentation Lines and Chest Hypopigmented Markings
Chest-wall markings have been variously characterized as "broad and slightly
curved ribbon-like markings with irregular margins and blunt ends," "narrower
markings with tapered ends, somewhat leaf-shaped," and "longer streaklike

FIGURE 180. Bilateral hypopigmented macules (arrows) and mediosternal line (broad arrow).
Right: Periareolar hypopigmented macules. The two macules indicated by arrows have leaf-shaped
configurations. The cause of the mediosternal line (broad arrow) is described in the text. (From:
Selmanowitz VJ. Krivo JM: Hypopigmented markings in Negroes. lnt JDermato112:229-235. 1973.
Copyright. 1973. J. B. Lippincott Co. Used with permission.)

hypopigmentation." Lesions are usually located in the preareolar areas but have
also been observed just below the mid portion of the clavicles, midway between
the clavicles and nipples, and sometimes in a linear fashion from the nipples
toward the midline. The latter were described as Group E pigmentary demarcation lines by Selmanowitz and Krivo [7].
Mediosternal hypopigmentation lines are located on the midline of the
sternum and may extend longitudinally onto the abdominal skin (Figs. 180,
181). In some patients, the hypopigmented band may involve the suprasternal
area with a slight curvature of the band to one side. Sometimes also the hypopigmentation line is not strictly located to the midline but arches away,
sometimes taking a second change in direction. Selmanovitz and Krivo [7]
identified this latter as consistent with the pigmentary demarcation lines of
Group C (Fig. 182) described by Miura [6]. Both types of mediosternal lines
and chest macules can occur in the same individual.

FIGURE 181. Arrows indicate the hypo pigmented streaks. The mediosternal line extends into
the abdominal midline skin (broad arrows). (From: Selmanowitz VJ, Krivo JM: Hypopigmented
markings in Negroes. lnt J Dermato112:229-235, 1973. Copyright, 1973, J. B. Lippincott Co. Used
with permission.)

449

GENETIC AND
CONGENITAL
DISORDERS

450

CHAPTER 1

Other pigmentary demarcation lines have been described. Anterobrachial

demarcations (Group A of Miura) have been described among blacks [5,8,9]
and Japanese [6] (Fig. 182). They may extend in a transpectoral direction. It is
not clear from the literature whether these pigmentary demarcation lines can
appear as a hypopigmented streak, but a picture reported by Selmanowitz and
Krivo [7] seems to show an area of hypopigmentation related to Group A pigmentary demarcation lines. Group B (ventral axial lines of the inner thigh) [7]
and Group E (posteromedian demarcation lines) [7] have also not been related
to hypopigmentation in the literature.
These hypopigmented markings are not associated with other conditions
and the individuals who bear them are usually in good health. There are no
other associated dermatologic findings. Pigmentary demarcation lines is a relatively stable condition; the markings do not seem to extend and, in some
instances, they may progressively disappear with age [5]. No histologic or
electron microscopic studies of these hypopigmented markings are available.

FIGURE 182. The arrow points to a pronounced typical brachial demarcation line of pigmentation
(Group A). A prominent line is also seen on the other arm. The ends of the "V" on the chest abut
a Type II mediosternal line (Group C) which arches from xiphisternal midline and returns to
midline superiorly. (From: Selmanowitz VJ. Krivo JM: Pigmentary demarcation lines. Br J Derrnatol
93:371-377. 1975. Copyright. 1975. Blackwell Scientific Publications. Used with permission.)

Diagnosis
In some individuals the markings are so clear as to cause little doubt of
their presence to an aware physician. However, sometimes even in dark-skinned
individuals they are very faint and can easily be overlooked. In the latter case,
Wood's light examination may be useful.
As pointed out by Selmanowitz and Krivo [5], the mediosternalline is not
likely to be confused with anything else.
In a patient with hypopigmented chest macules, relevant history and the
absence of other cutaneous lesions help to exclude postinflammatory hypopigmentation. The presence of normal sensation on the hypopigmented macules
excludes Hansen disease. Tuberous sclerosis also may be present with a similar
ash leaf-shaped macule, but in tuberous sclerosis the depigmentation is usually
not an isolated finding and the depigmented patches are more numerous, widely
distributed, and not bilaterally symmetrical.

Significance
It is most probable that pigmentary demarcation lines are a dominantly
inherited trait [1,4,5] and represents, as suggested by Selmanowitz and Krivo
[7], a duality in the population of melanocytes.
These demarcation lines cause very slight cosmetic disfigurement and require no treatment.

REFERENCES
1. Ito K: The peculiar demarcation of pigmentation along the so-called Voigt's line among the
Japanese. Dermatologia Internatl 44:45-47,1965

2. Matzumoto S: Ober eine eigentumliche Pigmentverteilung in den Voigtshen Linien (Beitrag zur
Kenntnis der Voigtschen Grenzen). Arch Dermatol Syphilol (Berlin) 118:157-164, 1913
3. Kisch B, Nasuhoglu A: A mediosternal depigmentation line in Negroes. Exp Med Surg 11:265-267,
1953

4. Weary PE, Behlen CH: Unusual familial hypopigmentary anomaly. Arch Dermatol 92:54-55,
1965

5. Selmanowitz VI. Krivo JM: Hypopigmented markings in Negroes. Int J Dermatol12:229-235,

1973

6. Miura 0: On the demarcation lines of pigmentation observed among the Japanese, on inner
sides of their extremities and on anterior and posterior sides of their medial regions. Tohoku J
Exp Med 54:135-140, 1951
7. Selmanowitz VI. Krivo JM: Pigmentary demarcation lines-comparison of Negroes with Japanese. Br J Dermotol 93:371-377, 1975
8. Fletcher PH: A peculiarity of pigmentation of the upper arm of Negroes. Science 88:570-571,
1938

9. Vollum DI: Skin markings in Negro children from the West Indies. Br J Dermotol 86:260-263,
1972

451

GENETIC AND
CONGENITAL
DISORDERS

452

OTHER MISCELLANEOUS SYNDROMES

CHAPTER 1

Darier-White Disease
Darier-White disease is an uncommon autosomal dominant disorder of
keratinization characterized by small hyperkeratotic papules usually located
on the face, extremities, chest, and back. Palms and soles, nails, and mucous
membranes may be involved. Spontaneous mutation is responsible for many
cases. Electron microscopic studies show a structural defect in the tonofilament-desmosome complex.
There are only a few scattered reports of leukoderma in Darier-White
disease [1]. Goodall and Richmond [2], in 1965, reported a 24-year-old woman
with many macules of leukoderma on the upper extremities and trunk; it is
possible that these represented postinflammatory changes. Cornelison et al. [3],
in 1970, described guttate leukoderma associated with Darier-White disease.
Based on the presence of these widespread white macules among three of 15
patients with keratosis follicularis, Cornelison et al. [3] concluded that guttate
leukoderma with keratosis follicularis is more common than the scant attention
afforded it in the literature would indicate. These patients, two males and one
female, respectively aged 21, 49, and 32, had had depigmented lesions since
childhood. None had a positive family history for the disease. In all three
patients, the white macules were numerous, 1 to 5 mm in diameter, asymptomatic, and randomly distributed around as well as between the hair follicles
on the trunk and extremities. None of the white macules occurred on the face.
According to the patients, no other lesions preceded the appearance of the
white macules. Dystrophic nail changes and characteristic keratotic papules in
the typical distribution were also noted. Histologic examination of white macules of two patients revealed decreased to absent epidermal melanin. However,
the typical histologic features of the disease, namely dyskeratosis, corps ronds
or grains, were absent in these sites.
Cattano [4] reported a postinflammatory leukoderma in keratosis follicularis. Histologic studies showed epidermal thinning, atrophy, and flattening of
rete ridges. Dopa-silver nitrate stain revealed a virtual absence of melanocytes.
Many hyperpigmented hyperkeratotic papules were present in this
patient.

Autosomal Recessive Deafness Associated with Vitiligo (Rozycki

Syndrome)

Rozycki et al. [5] described a syndrome of congenital deafness with profound sensorineural hearing loss, muscle wasting, short stature, hyperreflexia,
achalasia, and vitiligo in two children of parents who were also first cousins.
In both, depigmented patches are described on their necks and trunks. Both

453

GENETIC AND
CONGENITAL
DISORDERS

FIGURE 183. a: Small hypomelanotic macules scattered over the lateral neck. (Courtesy of D. L.
RozyckL) b, c: Small hypomelanotic macules scattered over the lateral neck. (Courtesy of D. L.
RozyckL)

454

CHAPTER 1

c
FIGURE 183 (Continued)

Muscle wasting involving the hands (a) and feet (b) of affected individuals. (From:
Rozycki DL et al: Autosomal recessive deafness associated with short stature. vitiligo. muscle
wasting and achalasia. Arch Otolaryngol 93:194-197. 1971. Copyright. 1971. American Medical
Association. Used with permission.)

FIGURE 184.

455

GENETIC AND
CONGENITAL
DISORDERS

~I..n
ot M - IIIItJ 't

"'''' -''11
"t OIfO "'l I~ '

o
T

I-Ill

DIAD
( MIIl o-t ...

S4!1 .... ~

!tt 1 ~~ ""-'. ~tC)wN

00 ... ..,""'.

FIGURE 185.

Pedigree of the affected family. (From: Rozycki DL et al: Autosomal recessive

deafness associated with short stature. vitiligo. muscle wasting and achalasia. Arch Otolaryngol
93:194-197. 1971. Copyright. 1971. American Medical Association. Used with permission.)

FIGURE 186.

Barium swallow demonstrating dilatation of esophagus compatible with achalasia.

(From: Rozycki DL et al: Autosomal recessive deafness associated with short stature. vitiligo. muscle
wasting and achalasia. Arch Otolaryngol 93:194-197. 1971. Copyright. 1971. American Medical
A~~nr.i"tinn. Used with nermission.l

456

CHAPTER 1

also had abnormal EEGs, slightly elevated beta and gamma globulins, decreased
alpha globulins, and abnormal cephalin flocculation and thymol turbidity tests
(Figs. 183, 184, 185, 186).

Focal Dermal Hypoplasia Syndrome

Focal dermal hypoplasia is a rare congenital meso ectodermal syndrome
which includes small stature, mental deficiency, and skeletal, ocular, oral and
dental, and soft tissue defects. The focal dermal hypoplasia syndrome predominantly occurs in females but may also involve males. Hypopigmentation of
the skin and hair may be one of the cutaneous features of this rare disorder.
In several patients, hyper- or hypopigmented areas of the skin have been observed to be linear or reticular [6]. A nine-year-old black girl showed multiple
areas of hypopigmentation, hyperpigmentation, and anetoderma distributed
over the face, buttocks, legs, and thighs [7] (Figs. 187, 188). Poliosis has also
been reported in focal dermal hypoplasia [8].
Additional cutaneous features include atrophy and linear hypermelanosis.
Abnormalities of dentition include hypodontia, oligodontia, and microdontia,
dysp,lastic fragile enamel, delayed tooth eruption, and malocclusion. Accompanying features of this syndrome include, characteristically, groups of linear
yellow-red nodules and papillomas of mucosal surfaces, particularly the lips,
but also of other periorificial skin-anus, eyes and genital region. Localized fat
deposits are seen in addition to small, thin, and dystrophic nails, and sparse,
brittle hair accompanying patchy alopecia.
Muscular skeletal abnormalities include small stature and slender habitus
with triangular facies marked by prominent ears, small rounded skull, and
pointed chin. Arms and legs may be asymmetrical. Absence of a digit, syndactyly and polydactyly are common.
Ocular defects may include, most commonly, strabismus or coloboma and
infrequently keratoconus.
Diagnosis of focal dermal hyperplasia is usually readily apparent in a
Caucasian female with multiple characteristic findings. A few cases in males
have been reported, however, When the clinical expression, which may be
highly variable, renders the diagnosis difficult, biopsy may be helpful. Histopathologic studies show focally marked reduction in dermal thickness so that
the epidermis is seated almost directly on subcutaneous fat. The papillomas
show only marked acanthosis and a vascular connective tissue. Radiologic
studies of long bones may also be useful-osteopathia striata or radioopaque
metaphyseal stripes are found in many such cases of focal dermal hypoplasia.
Histopathologic studies, including split dopa and electron microscopy of
the melanocytes in the abnormally melanized cutaneous areas, are not yet
available.

Hypopigmentation with Punctate Keratosis of the Palms and Soles

An 18-year-old man has been described with hypopigmented keratotic
papules and irregular macules with varied degrees of hypopigmentation [9].

457

GENETIC AND
CONGENITAL
DISORDERS

FIGURE 187. Multiple areas of anetoderma and hypopigmentation of buttocks, legs, and thighs
at birth. (From: Gottlieb SK et al: Focal dermal hypoplasia. Arch Dermatol 108:551-553, 1973.
Copyright, 1973, American Medical Association. Used with permission.)

458
CHAPTER 1

FIGURE 188. Multiple areas of anetoderma, hypopigmentation of posterior thighs and knees at
age nine. (From: Gottlieb SK et al: Focal dermal hypoplasia. Arch Dermatol108:551-553, 1973.
Copyright, 1973, American Medical Association. Used with permission.)

The macules varied from 1 to 16 mm in diameter and from brown to light tan
in color. None of the macules depigmented totally. The macules, which had
sharply demarcated borders, were scattered over most of the body, but were
sparse or absent on the acral portions of the body, including the head, neck,
nipples, elbows, knees, genitalia, hands, and feet (Fig. 189). Fontana-Masson
silver stain showed melanin granules in the hypopigmented epidermis with
occasional small collections of melanophages in the upper dermis.
Hair, mucous membranes, and irides were normally pigmented. In addition, flat-topped hypopigmented keratotic papules were present on the palms,
soles, and dorsolateral fingers and toes. This patient also had a G6PD deficiency.
Other members of the family (maternal grandfather, mother, and three
brothers) all also had the same dermatologic features. The authors suggested
an autosomal dominant pattern of inheritance.

459

GENETIC AND
CONGENITAL
DISORDERS

FIGURE 189. Sharply demarcated irregular hypomelanotic macules that were scattered all over
the body in a patient with punctate keratosis of the palms and soles. (From: Cole MLA: Hypopigmentation with punctate keratosis of the palms and soles. Arch Dermatol112:998-1000. 1976.
Copyright. 1976. American Medical Association. Used with permission.)

460
CHAPTER 1

Hypomelanoses in Possible Ectodermal Dysplasia Syndromes

Freire-Maia et al. [10] reported a seven-year-old girl with trichodysplasia,
hypohydrosis, normal teeth, onychogryposis, psychomotor and growth retardation, dry and warm skin with follicular hyperkeratosis, bilateral nuclear
cataracts, a peculiar facies (frontal bossing, depressed bridge of the nose), partial
alopecia of the scalp, absence of eyebrows and body hair, and scarce eyelashes.
This girl had hyperpigmented macules on her feet, knees, arms, neck, and
forehead and large hypopigmented macules on the anterolateral front forearm.
It was suggested that she had a genetic condition which may be a new form of
ectodermal dysplasia. But since the history of the onset and stability of these
features is unknown, the depigmentation may in fact have been nevus depigmentosus.
Berlin [11] also described a congenital familial anomaly which he suggested
may represent a special, unusual, incomplete and mixed type of ectodermal
dysplasia. The disorder, observed in two sons and two daughters of healthy
parents, was characterized by a widely generalized leukomelanoderma especially involving the extremities and sparing only the scalp. The mottled dyschromia exhibited the appearance of a leopard skin. There were multiple abnormalities which included the following: stunted growth, thinness ofthe body,
especially the legs (bird legs); mental retardation; and sexual underdevelopment
in the males (hypospadia, small penis and scrotum, atrophy of the testes, absence of secondary sex signs). The appearance of the face was striking (sparse
eyebrows, saddle-shaped nose, thick lips, wrinkling around the eyes and mouth).
The eruption of the deciduous and permanent teeth was delayed and the pilosebaceous apparatus was underdeveloped. In addition to the pigmentary abnormalities, the skin was thin, fine, and dry; there were also anetopoikilodermatous lesions, atrophic scars, and palmoplantar hyperkeratosis.

REFERENCES
1. Cohen-Hadria M: Maladie de Darier (premier cas publie en Afrique du Nord); debut tras
precoce; lesions zoniformes; leukodermie residuelle. Bull Soc Fr Dermotol Syphiligr
46:1478-1481, 1939
2. Goodall JWO, Richmond QMS: A case of Darier's disease. Br J Clin Proct 19:475-476, 1965
3. Cornelison RL et al: Guttate leukoderma in Darier's disease. Arch Dermotol102:447-450, 1970
4. Cattano AN: An unusual case of keratosis follicularis. Arch Dermotol 98:168-174, 1968
5. Rozycki DL et al: Autosomal recessive deafness. Arch Otoloryngol 93:194-197, 1971
6. Goltz RW et al: Focal dermal hypoplasia syndrome. Arch Dermotol101:1-11, 1970
7. Gottlieb SK et al: Focal dermal hypoplasia. Arch Dermotol108:551-553, 1973
8. Marchionini A, Besser F: Ober Poikilodermia atrophicans vascularis Uacobi). Arch Dermotol
Syphilol (Berlin) 165:431-442, 1932
9. Cole LA: Hypopigmentation with punctate keratosis of the palms and soles. Arch Dermotol
112:998-1000, 1976
10. Freire-Maia N et al: A syndrome of hypohidrotic ectodermal dysplasia with normal teeth,
peculiar facies, pigmentary disturbances, psychomotor and growth retardation, bilateral nuclear cataract and other signs. J Med Genet 12:308-310, 1975
11. Berlin C: Congenital generalized melanoleukoderma associated with hypodontia, hypotrichosis, stunted growth, and mental retardation occurring in two sisters. Dermotologico
123:227-243, 1961

SECTION 4. DISORDERS AFFECTING HAIR PIGMENTATION

WITHOUT AFFECTING SKIN PIGMENTATION
PREMOLAR APLASIA, HYPERHIDROSIS, AND CANITIES
PREMATURA
In 1950, Book [1] described 18 patients with a new autosomal dominant
syndrome with complete penetrance but somewhat variable expression and
characterized by bicuspid aplasia, premature whitening of the hair, and hyperhidrosis.
Early whitening of the hair was found in all 18 cases. Hair whitening began
in 14 patients before or at the age of 14 years, but onset varied from six to 23
years. The whitening was uniform and never patchy. The progression of whitening was usually slow, and in the older patients was always complete. The scalp
hair was most constantly affected but in six of the 18 cases. there was conspicuous whitening of axillary (five cases) and genital (six cases) hair and the
eyebrows and cilia (two cases). In 16 cases, the original hair color was specified
(seven were blond, four light brown, three dark brown, one red blond, and one
black). The hair was otherwise completely normal. No depigmentation of the
skin was observed. The author examined 63 members of this family and found
premature graying of the hair in seven who lacked other features of the syndrome. All 18 patients had blue irides, but this is such a common trait in
Sweden that this observation may represent only coincidence. Two-thirds of
the patients had a definite functional palmoplantar hyperhidrosis. The most
striking feature was the involvement of the bicuspid teeth. In nine patients, all
eight bicuspids were missing and no anlage could be detected by x-ray. The
other patients were missing one to seven bicuspids. In most cases, there was
a posterior displacement of the canines. Deciduous teeth were present in all
cases.
General health is unimpaired. The pathogenesis is unknown. No treatment
is available.

FANCONI SYNDROME
Fanconi syndrome is vitamin-D-resistant rickets or osteomalacia with hypophosphatemia, glucosuria, generalized aminoaciduria and generally chronic
acidosis, hypouricemia, and hypokalemia. It may occur early (infantile form)
or later (adult form) in life.
Fanconi syndrome may be idiopathic or associated with cystinosis, Lowe
syndrome, or tyrosinemia. In a series of 24 patients reported by Cowie [2], 19
patients had cystinosis, four had cirrhosis and no cystinosis, and one had
neither. Both groups of patients were found to have significantly fairer hair
electrospectrophotometrically than their siblings or than age-matched controls.
Schneider and Seegmiller [3] noted that although these patients with increased intracellular cystine often have blond hair and are significantly fairer
than their parents, they have much less tendency to sunburn than would be
expected for their degree of pigmentary dilution.

461

GENETIC AND
CONGENITAL
DISORDERS

462
CHAPTER 1

The mechanism of hypopigmentation is unknown but may relate to cystine

binding of sulfhydryl-requiring enzymes.

ROTHMUND-THOMSON SYNDROME
Rothmund-Thomson syndrome is a rare, autosomal recessive disease which
is characterized by acquired erythematous patches that develop atrophy, telangiectasia, hypo- and hyperpigmentation, and sometimes warty keratosis [4,5].
Other features include alopecia, photosensitivity, bilateral cataracts, short stature, small skull, sometimes with birdlike features, and hypogonadism. Life
expectancy appears to be normal. Premature canities is an inconstant feature
of Rothmund-Thomson syndrome; it sometimes appears in adolescence and
progresses rapidly.

DYSTROPHIA MYOTONICA
Canities occurring in the second or third decade may be seen in dystrophia
myotonica [6], an entity that was first described in 1909 by Steinert [7]. This
rare disorder, which is inherited as an autosomal dominant disease, usually
appears in the second or third decade and is characterized by myotonia, severe
muscle wasting, cataracts, premature frontal baldness, and characteristic lugubrious physiognomy. Testicular atrophy, various disorders of ovarian function, and low basal metabolic rate are frequently observed. Few of these patients
survive beyond the sixth decade and death is often attributed to aspiration
pneumonia or to cardiac conduction defects.

PREMATURE AGING SYNDROMES

Two of the premature aging syndromes, Werner syndrome (pangeria) and
Hutchinson-Gilford syndrome (progeria), are characterized by premature graying of hair.

Werner Syndrome (Pangeria)

Werner syndrome, which is a rare autosomal recessive disorder, was first
described in 1904 in the thesis "Uber Kataract in Verbindung mit Sklerodermie"
(Cataract in Combination with Scleroderma) by Otto Werner [8]. Werner gave
a detailed description of four siblings with cataracts and sclerodermatous changes
as well as a senile appearance and graying beginning at about the age of 20.
Males and females are equally affected. The nature of the fundamental defect
responsible for the disease is unknown.
Pigmentary Disturbances
Graying of hair is one of the earliest characteristic signs of the disease.
From a survey of 125 cases, Epstein et al. [9] established that gray hair is first
seen at about 20 years of age, while the mean age of onset is 25.3 years for

alteration of the voice, 30 years for detection of cataract formation, 33 years

for skin ulcers, and 34.2 years for diabetes mellitus. Premature graying of hair
is rarely present before eight years of age.
The graying generally first affects the temples and eyebrows, may require
from five to 20 years for maximal loss of pigment, and often progresses to
complete whiteness. Baldness follows graying of the hair by several years.
Other Clinical Features

Patients with Werner syndrome have a characteristic habitus with a beakshaped nose, stocky trunk with slender extremities, and short stature first apparent in adolescence. A weak, high-pitched voice is characteristic. The skin
and subcutaneous tissues are atrophic with circumscribed hyperkeratosis. Indolent ulcers often develop over malleoli of ankles, Achilles tendon, heels and
toes. Most of the patients develop juvenile cataracts. Hypogonadism and diabetes mellitus are frequently observed. Generalized arteriosclerosis, osteoporosis, calcifications of ligaments, tendons, and subcutaneous tissues may develop prematurely. The incidence of malignancy is increased and the life
expectancy is decreased.
Diagnosis

The combination of the prematurely aged appearance, the other physical

features, the scleroderma-like skin changes, and the cataracts establish the
diagnosis [10]. The other premature aging syndromes (metageria, acrogeria, total
lipodystrophy, and progeria) have a different clinical picture [11]. Sclerosis of
the skin does not usually accompany Rothmund-Thomson syndrome. Observation of early graying may alert the physician to other possible features.

Hutchinson-Gilford Syndrome (Progeria)

This autosomal recessive disease was first described in 1886 by Hutchinson
[12] who reported a boy who had been bald since infancy and whose skin was

atrophic and wrinkled. This child and another patient were subsequently reported by Gilford [13], who first used the name "progeria."
Progeria is a rare condition occurring equally in both sexes. The primary
defect responsible for the disease is unknown.
Pigmentary Disturbances

In progeria, the hair is sparse and prematurely gray. DeBusk [14] noted
that sparse, downy blond or white fuzz was present even if the original hair
was black.
Other Clinical Features

Patients with this disease usually appear normal at birth. During the first
year of life there is a profound failure to meet normal growth markers and

463

GENETIC AND
CONGENITAL
DISORDERS

464
CHAPTER 1

during the second year of life the characteristic facies (plucked-bird appearance
with craniofacial disproportion, micronathia, and prominent eyes), alopecia,
loss of subcutaneous fat, stiffness of joints and bones, skeletal abnormalities
(pyriform thorax, coxa valga), cutaneous changes (diminution of subcutaneous
fat and sclerodermatous skin), and abnormal dentition become apparent. Motor
and mental development is normal. There is insulin resistance and increased
basal metabolic rate. Early death results from severe generalized arteriosclerosis.
Diagnosis

Progeria with its remarkably constant phenotypic expression can easily be

distinguished from other premature aging syndromes. Graying of the hair, when
present, appears sooner than in Werner syndrome. Cockayne syndrome differs
from progeria by the presence of light sensitivity, disproportionate dwarfism,
and absence of alopecia.
No treatment is available.

FISCH SYNDROME
Fisch [15] described a family with deafness and early, pronounced graying
of the hair. Among 21 members of this family, two of the 10 who had early
graying also had deafness. Two other young children had only deafness and
two others partial heterochromia irides. Fisch observed similar cases and believed this a genetically distinct syndrome. Soussi Tsafir [16], arguing that none
of the 13 affected members of this family had dystopia canthorum, drew the
same conclusion and distinguished this condition from Waardenburg syndrome, which has a penetrance of 40% to 99%. Other possible cases include
those of Ballantyne [17] who noted that many of his patients with progressive
high-tone deafness, among them a father and daughter and a brother and sister,
had strikingly light blond hair and light blue eyes.

KAPPA CHAIN DEFICIENCY

Bernier et al. [18] reported a young girl with recurrent respiratory infections, diarrhea, white hair, extremely long white eyelashes, and very pale skin.
This was associated with a decreased concentration of immunoglobulins of
one light chain type (kappa). Radiolabeled kappa and lamda type molecules
survived equally well, suggesting that the synthesis of molecules bearing kappa
chains was decreased.

HEREDITARY PREMATURE CANITIES

Premature graying of hair in individuals who are otherwise normal has
been reported as an hereditary autosomal dominant trait. Among six generations

in one family, nine individuals were involved. In these cases, graying of scalp
and body hair appeared during the second decade or earlier, but did not affect
the eyebrows and eyelashes [19].

BIRD HEADED DWARFISM (SECKEL SYNDROME)

Bird-headed dwarfism is a rare autosomal recessive form of dwarfism characterized by a bird-head profile, trident hands, skeletal defects, hypodontia,
and pancytopenia with hypersplenism. Brown pigmentation with white macules has been reported in one Japanese infant [20] and premature senility has
been described in several patients with this disease [21]. Fitch et al. [21] reported premature graying of scalp hair that began at age 18 in one patient.
Though premature graying is most characteristic, hypo melanotic macules have
also been described.
In 1974, Tay et al. [22] reported such a recessive disorder in two Indian
teen-aged sisters from West Malaysia. The disease, probably inherited as a
recessive autosomal trait, was characterized by microcephaly, triangular-shaped
face, prominent eyes, hypoplastic alae nasi, small pinched nose, tiny mouth
and large pegged-shaped incisors, abnormal limbs characterized by trident hands,
hypoplastic transverse palmar creases, and large big toes and stubbed short
toes. One girl had a large number of cafe-au-Iait spots and depigmented lesions
on the shins, knees, extensor surfaces of the arms, and upper chest wall that
appeared at the age of nine. At the same time, hairs of the scalp, eyebrows,
eyelashes, and of the limbs turned prematurely gray. The skin biopsy of the
hypopigmented patches resembled vitiligo. The second patient showed similar
premature canities and depigmented macules, though fewer and less extensive.
In addition, these two girls had liver involvement with fatty infiltration and
hepatic cirrhosis with hypersplenism, raised serum immunoglobulins, and hyperaminoaciduria, mainly of taurine, beta-aminoisoleutyric acid, and glycine.
As there is a striking similarity between these cases and patients with "birdheaded dwarfism," the authors suggest that these cases may represent a variant
of the latter.

TREACHER COLLINS SYNDROME, PIERRE ROBIN SYNDROME,

HALLERMAN-STREIFF SYNDROME, DOWN SYNDROME,
CHROMOSOME FIVE PSYNDROME
Lopez et al. [23] included Treacher Collins syndrome, Pierre Robin syndrome, and Hallerman-Streiff syndrome in the group of hereditary disorders
associated with hypomelanosis of the skin and hair. Porter and Lobitz [24] also
mention fine, light-colored hair in Pierre Robin syndrome and light-colored
hair in tyrosinemia and in Down syndrome (trisomy 21). However, these are
only isolated reports.
Several adult patients with chromosome five p-syndrome (cri-du-chat syndrome) have prematurely gray hair [25].

465

GENETIC AND
CONGENITAL
DISORDERS

466
CHAPTER 1

PROLIDASE DEFICIENCY
Prolidase deficiency, a very rarely reported inborn error of metabolism,
has important and severe dermatologic manifestations, especially ulcers of the
lower extremities. Poliosis or premature graying of hair has been found in
several of these patients [26].

REFERENCES
1. Book JA: Clinical and genetical studies of hyperdontia. I. Premolar aplasia, hyperhidrosis and
canities prematura. A new hereditary syndrome in man. Am J Hum Genet 2:240-263, 1950
2. Cowie V: Hair colour in the infantile Fanconi syndrome. Ann Hum Genet 21: 170-176, 1956
3. Schneider JA, Seegmiller JE: Cystinosis and the Fanconi syndrome, in Metabolic Basis of
Inherited Disease, 3rd ed. Edited by JB Stanbury et al. New York, McGraw-Hill, 1972, pp
1581-1604
4. Rook A, Wells RS: Genetics in dermatology, in Textbook of Dermatology. Edited by A Rook
et al. London, Blackwell, 1969, pp 57-60
5. Tannhauser SJ: Werner's syndrome (progeria of the adult) and Rothmund's syndrome: two
types of closely related heredofamilial atrophic dermatoses with juvenile cataracts and endocrine features. A critical study of five new cases. Ann Intern Med 23:559-626, 1945
6. Touraine A: (Progres Medical 73:47, 1945). Quoted in Ebling EJ, Rook A: Premature canities,
in Textbook of Dermatology. Edited by A Rook et al. London, Blackwell, 1969, pp 1413-1414
7. Steinert H: Myopathologische Beitrage I. Dber das klinische und anatomische Bild des Muskelschwunds der myotaniker. Dtsch Z Nervenh 37:58-104, 1909
8. Werner 0: Dber Katarakt in Verbindung mit Sclerodermie. Doctoral Dissertation, Kiel University. Kiel, Schmidt and Klaunig, 1904
9. Epstein DJ et al: Werner's syndrome. Medicine (Baltimore) 45:177-221, 1966
10. Rook A: Disorders of connective tissues, in Textbook of Dermatology. Edited by A Rook et al.
London, Blackwell, 1969, pp 1287-1288
11. Gilkes JJH et al: The premature aging syndromes. Br J Dermatol 91:243-262, 1974
12. Hutchinson J: Congenital absence of hair and mammary glands. Medico-Chirurg Trans 69:473,
1886. Quoted by Gilkes JJH et al: The premature aging syndromes. Br J Dermatol 91:243-262,
1974
13. Gilford H: Progeria: a form of senilism. Practitioner 73:188-217,1904
14. DeBusk FL: The Hutchinson-Gilford progeria syndrome. J Pediatr 80:697-724, 1972
15. Fisch L: Deafness as part of an hereditary syndrome. J Laryngol Otol 73:355-382, 1959
16. Soussi Tsafir J: Light-Eyed Negroes and the Klein-Waardenburg Syndrome. London, MacMillan, 1974
17. Ballantyne JC: Deafness. London, Churchill, 1960
18. Bernier GM et al: Kappa chain deficiency. Blood 40:795-805, 1972
19. Hare HJH: Premature whitening of hair. J Hered 20:31-32, 1929
20. Seckel HPG: Bird-Headed Dwarfs. Basel, S Karger, 1960
21. Fitch N et al: A form of bird-headed dwarfism with features of premature senility. Am J Dis
Child 120:260-264, 1970
22. Tay CH et al: A recessive disorder with growth and mental retardation, peculiar facies, abnormal
pigmentation, hepatic cirrhosis and aminoaciduria. Acta Paediatr Scand 63:777-782, 1974
23. Lopez B et al: Trastornos de la pigmentaci6n, in Actas Del VI Congresso Ibero-Latino Americano
de Dermatologia (Barcelona, Spain, 1967). Barcelona, Editorial Cientifico Medica, 1970, pp
157-179
24. Porter PS, Lobitz WC: Human hair: a genetic marker. Br J Dermatol 83:225-241, 1970
25. Breg WR: Abnormalities of chromosomes 4 and 5, Endocrine and Genetic Diseases of Childhood
and Adolescence. Edited by 11 Gardner. Philadelphia, Saunders, 1975, pp 1505-1515
26. Der Kaloustian VM et al: Prolidase deficiency: an inborn error of metabolism with major
dermatological manifestations. Dermatologica 164:293-304, 1982

2
Hypomelanoses Associated with
Nutritional and Metabolic Disorders
KWASHIORKOR
Kwashiorkor is a result of dietary deficiency of protein in the weaning and
early postweaning stage of childhood. In underdeveloped nations it remains a
significant cause of death among children from one to four years of age.
Credit for the first description of kwashiorkor is generally given to Williams
[1], who, in 1953, reported five "Gold Coast children," four of whom died. The
origin of the term "kwashiorkor" is not precisely known.
Kwashiorkor has been reported in every part of Africa, and also in China,
India, Malaya, Indonesia, Fiji, the Philippines, Caribbean Islands, Hungary,
Italy, and various parts of South America. Henington et al. [2], in 1958, reported
four cases from Louisiana. The general prevalence of kwashiorkor is 0.5% to
1.5% in various community surveys [3]. It is said to be much higher in primitive
cultures.

Depigmentation in Kwashiorkor
Clinical Description

Depigmentation, according to Williams [1] may precede by weeks other

dermatologic features of kwashiorkor. It may present in the early stages of the
disease-before the rash is well circumscribed. The hypopigmentation of
kwashiorkor usually first involves the face and, after the appearance of a shiny
epidermis, resembles a background of fair skin on a red baby. As the eruption
evolves over one to two days, except on the face, red raised plaques gradually
darken until they take on a shiny black appearance.
Exfoliation is followed by depigmentation. Enamel-plaque areas or ulcerations develop to suggest the de pigmented skin is readily predisposed to destructive processes. These depigmented macules do later repigment, often with
hyperpigmentation. Lesions most typically occur on pressure points.

467

468

CHAPTER 2

Banerjee and Dutta [4] noted that there may be generalized pallor with
extensive hypo- and hyperpigmentation, the latter mostly in the diaper area,
buttocks, back, thighs, and elbows-as opposed to the sun-exposed areas of
pellagra.
Dyschromic hair is a common feature of kwashiorkor. Mukherjee and Jelliffe [5] found the changes minimal in India compared to those seen in Africa,
where hypochromotrichia is pronounced. Others [6] reported only 13% with
hair discoloration, yet Jelliffe [7] reported as high as 82% among African infants
in Jamaica. In the latter, curled jet black hair is replaced by sparse dry hair
varying from red-brown to gray in color.
Henington et al. [2] noted golden to reddish coloration at the ends of
normally black hair in their four black patients. There is often such minimal
dilution of color-a fringe effect-and the color may be brown, red, golden,
gray, or white. The "signe de bandera" or "flag sign"-which is striped hairmay represent a recurrence. Thinning of eyebrows or loss of the outer thirds
may occur. The hair also becomes dry, thin, and brittle and may be removed
painlessly with little effort [8]. Partial or total alopecia may result. Hair production is 59 /-Lm 3 per follicle in kwashiorkor vs. 514 /-Lm 3 for controls [9].
Cystine levels are also reduced but return to normal after therapy.
Histology of Depigmentation

Sims [9] compared the epidermis of 10 Zulu infants with kwashiorkor to

five unaffected infants. He reported decreased thickness of the epidermis and
normal cell volumes and concluded there were changes in the kinetics of cell
migration. Desmosomes were found to be shorter than controls, and this may
explain the epidermal fragility.
Pathogenesis of Depigmentation

Protein deficiency in hair, infection, and multiple nutritional deficiencies

have been invoked to explain the pigmentary abnormality. Rao and Gopalan
[10] found no correlation between hair color and amino acid content. Nor could
hair color or cystine content be correlated with severity of clinical disease.
Bradfield and Jelliffe [11] emphasized that tuberculosis and malnutrition may
coexist in underprivileged populations and that the two together cause greater
loss of skin and hair pigment than does either alone. Partial de polymerization
of melanin has also been suggested. Riboflavin or pantothenic acid deficiency
and deficiency of sulfur or of sulfur-containing amino acids have been implicated [10]; this fits with the observation that cystine and glutathione as well
as other reducing enzymes affect the conversion of tyrosine to melanin by
inhibiting tyrosinase and by regulating the oxidation reduction potential of
melanocytes [12]. That the pigment in the discolored hair behaves chromatographically like oxidized melanin [13], coupled with the above observation,
supports the theory that lowering the SH concentration in melanocytes accelerates the conversion of tyrosine to melanin; further oxidation of melanin to a
brown or colorless product results.

TABLE 111. Kwashiorkor: Associated Findings

Skin

"Crazy-pavement" dermatitis
Bullae, ulceration
Purpura

Mucous membrane

Angular stomatitis
Cheilosis

Nails

Thinning, softening, ridging

Eyes

Xerophthalmia
Bitot's spots
Blepharitis, conjunctivitis, photophobia

Systemic changes

Growth retardation
Psychic disturbances and mental retardation
Muscle wasting
Edema
Gastrointestinal disorders (anorexia, diarrhea)
Hepatomegaly

Laboratory findings

Hypoalbuminemia
Anemia
Hypovitaminosis

Associated Clinical Findings

See Table 111.

Diagnosis
Leukoderma is not a primary or essential feature of kwashiorkor, the diagnosis of which is based on the history of malnutrition in an infant from an
endemic area plus the presence of the many clinical features noted. Bands of
de pigmented or dyschromic hair may correspond to relapses and those of repigmentation to treatment. Other nutritional deficiency syndromes may also
be present.

Treatment
Kwashiorkor responds to dietary protein and the skin is said to repigment
slowly [4].

GENERALIZED DYSCHROMIA IN A MALNOURISHED INFANT

Petrozzi [14] reported a 20-month-old black girl who presented several
months after birth with multiple episodes of infectious diarrhea associated with
febrile seizures. At the age of two months, she developed asymptomatic, small,

469

HYPOMELANOSES
ASSOCIATED
WITH
NUTRITIONAL
AND METABOLIC
DISORDERS

470
CHAPTER 2

hypopigmented macules in the diaper area, upper legs, and lower abdomen.
During the next two months, similar lesions continued to appear on the trunk
and spread to the distal extremities. No inflammation preceded the hypopigmented eruption but the father and an older sister had a history of infantile
eczema.
Examination revealed a generalized mottling of the skin which had irregularly scattered hyperpigmented and hypopigmented macules.
As poor dietary intake and recurrent diarrhea had been present in the first
months of life, the author suggested that the dyschromia may result from malnutrition. However, amino acid, copper, and vitamin B12 studies were not done.

PIGMENTARY CHANGES IN THE HAIR OF PATIENTS WITH

NEPHROSIS, ULCERATIVE COLITIS, OR EXTENSIVE RESECTION

OF THE GUT

As in kwashiorkor, chronic protein loss may result in pigmentary changes

of the hair [15]. This can be observed in nephrosis [16] and also in malabsorption
syndromes [16].
Mellinkoff [17] reported a 26-year-old Caucasian with ulcerative colitis
whose hair turned red with malnutrition and returned to its normal dark brown
color after he had gained weight. Silverblatt and Brown [16] observed a kwashiorkor-like syndrome with change of the hair from black to red associated with
"burning feet" in a 45-year-old black male in whom, 10 years after a gastrectomy
for intractable duodenal ulcer, progressively severe diarrhea and pronounced
malnutrition developed.

SEVERE IRON DEFICIENCY

Tasker and Polunin [18] reported a 10-year-old aboriginal Malayan male
with extremely severe iron deficiency anemia (hemoglobin level of 0.7 g per
100 ml). This boy had light brown hair, a very unusual feature among the
usually dark brown-haired peoples of Malaya. As the plasma protein values
were grossly normal, the authors attributed the pigmentary disturbance to severe iron deficiency. Treatment with intravenous iron oxide did not alter the
hair color. Clinical features of copper deficiency were not present in this patient
but blood copper levels were not obtained.

COPPER DEFICIENCY
Acquired copper deficiency is discussed with Menkes kinky hair syndrome
(see "Copper Deficiency" in Chapter 1).

VITAMIN B12 DEFICIENCY (PERNICIOUS ANEMIA)

Pernicious anemia is associated with vitiligo in a significant number of
cases (see "Vitiligo" in Chapter 1). Premature graying is also a clinical feature
of pernicious anemia [19].
Dawber [20] found premature graying of the hair to be more frequent in
patients with pernicious anemia than in controls. Among 125 patients with
pernicious anemia, 14 (11.2%) had graying of the hair before the age of 20,
compared to only three out of 132 controls (2.2%). Furthermore, early graying
of the hair (between 20 and 50 years of age) was more frequent in pernicious
anemia. Thirty-eight of the 132 controls (20.8%) and 69 out of 125 patients
with pernicious anemia (55.2%) had early graying of the hair. In the same group
of pernicious anemia patients, blond hair and blue eyes seemed common.
A family with premature graying of the hair and pernicious anemia has
been reported. One member of this family had both pernicious anemia and
premature graying of the hair. Another had only pernicious anemia, and three
others only premature graying of the hair. Another had diabetes mellitus and
an autoimmune hemolytic anemia in addition to premature graying of the hair.
Several family members with or without premature graying had antinuclear
antibodies [21].

REFERENCES
1. Williams CD: Kwashiorkor. JAMA 153:1280-1285, 1953
2. Henington VM et al: Kwashiorkor. Arch Dermatol 78:157-170, 1958

3. Ebrahim GJ: The skin in malnutrition, in Essays on Tropical Dermatology. Edited by J Marshall.
Amsterdam, Excerpta Medica, 1972, vol 2, pp 124-128
4. Banerjee BN, Dutta AK: Malnutrition in the tropics: dermatoses in nutritional disorders, in
Clinical Tropical Dermatology. Edited by 0 Canizares. Oxford, Blackwell, 1975, pp 273-277
5. Mukherjee KL, Jelliffe DV: Clinical observations on kwashiorkor in Calcutta. J Trop Pediatr
1:61-66, 1955

6. Venhalachalam PS et al: Clinical features of nutritional edema syndrome in children. Indian

J Med Res 42:555-568, 1954
7. Jelliffe DV: Hypochromotrichia and malnutrition in Jamaican infants. J Trop Pediatr 1:25-33,
1955
8. Scrimshaw NS, Behar M: Protein malnutrition in young children. Science 133:2039-2047,
1961

9. Sims RT: The ultrastructure of depigmented skin in kwashiorkor. Br J Dermatol 80:822-832,

1968
10. Rao BS, Gopalan C: Some aspects of the hair changes in kwashiorkor. Indian J Med Res
45:85-93, 1957
11. Bradfield RB, Jelliffe DB: Hair-colour changes in kwashiorkor (letter). Lancet 1:461-462, 1974
12. Lerner AB, Fitzpatrick TB: Biochemistry of melanin formation. Physiol Rev 30:90-126, 1950
13. Nagchandhuri J, Platt BS: Malnutrition in African mothers, infants and young children, in

Report of the Second Inter-African [CCTA) Conference on Food and Nutrition, Gambia. London, Her Majesty's Stationery Office, 1954, p 215
14. Petrozzi JW: Unusual dyschromia in a malnourished infant. Arch Dermatol103:515-519, 1971
15. Rook A: Nutritional, metabolic, and chemical influences of hair colour, in Textbook of Dermatology. Edited by A Rook et al. London, Blackwell, 1969, pp 1631-1632

471

HYPOMELANOSES
ASSOCIATED
WITH
NUTRITIONAL
AND METABOLIC
DISORDERS

472

CHAPTER 2

16. 8ilverblatt CW, Brown HE: "Kwashiorkor-like" syndrome, associated with burning feet syndrome, in one adult male. Am J Med 28:847-854, 1960
17. Mellinkoff 8M: Temporary redness of the hair in ulcerative colitis. Am J Dig Dis 2:738-739,
1957
18. Tasker P, Polunin I: Extreme anaemia with recovery associated with pigmentary changes in
the hair (case report). Br Med J 2:465, 1954
19. Wintrobe MM: Pernicious anemia and related macrocytic anemias, in Clinical Hematology,
6th ed. Philadelphia, Lea & Febiger, 1967, pp 502-576
20. Dawber RPR: Integumentary associations of pernicious anemia. Br J Dermatol 82:221-223,
1970
21. Wintrobe MM: Pernicious anemia and related macrocytic anemias, in Clinical Hematology.
London, Kimpton, 1967, p 509

3
Hypomelanosis Associated with
Endocrine Disorders
HYPERTHYROIDISM

The association of vitiligo with hyperthyroidism has been discussed (see

"Vitiligo" in Chapter 1). Premature graying of hair may also accompany hyperthyroidism [1].
HYPOPITUITARISM

Decreased or absent skin pigmentation occurs in panhypopituitarism. This

clinical finding may help distinguish primary Addison disease from secondary
Addison disease due to hypopituitarism [2]. In hypopituitarism, there is an
increased sensitivity to sunburn with reduced melanin content and delayed
tanning [1]. Decreased MSH and ACTH production is probably responsible.
ADDISON DISEASE

The association of vitiligo and Addison disease has been discussed (see
"Vitiligo" in Chapter 1).
CUSHING SYNDROME

Brooks and Richards [3] reported depigmentation in two black women with
Cushing syndrome. In both patients, depigmentation occurred on the exposed
areas (extensor surfaces of the hands and feet) but returned to normal after
adrenal surgery.
The authors suggested the depigmentation may be due to suppression of
melanocyte-stimulating hormone (MSH) by high circulating levels of cortisol.
But as only two cases are reported, any association must be considered tentative.
473

474

HYPOGONADISM

CHAPTER 3

Male eunuchs have pale skin [4]. One eunuch who failed to tan after sun
exposure has been reported. Five months later, after administration of testosterone, deep pigmentation developed in the normally sun-exposed areas [5].
This suggests that testosterone deficiency decreases melanin pigmentation and
decreases the capacity of the melanin pigmentary system to respond to solar
stimulation. However, while orchidectomy has been reported to decrease melanin pigmentation of the skin in men [6], there are experimental results which
suggest that testosterone has no effect on the melanin pigmentation of the skin
[4].

HYPOPARATHYROIDISM, ADDISON DISEASE, AND CHRONIC

MUCOCUTANEOUS CANDIDIASIS
There are several reported cases of a syndrome of hypoparathyroidism,
Addison disease, chronic mucocutaneous candidiasis, and vitiligo [7,8]. (See
"Vitiligo" in Chapter 1.)

GOITER AND PARATERTIARY BUTYLPHENOL

DEPIGMENTATION
Two reports from Germany [9,10] mention the occurrence of thyroid abnormalities in workers with vitiligo-like depigmentation attributed to exposure
to paratertiary butylphenol. (See Chapter 5.)

REFERENCES
1. Freinkel RK, Freinkel N: Dermatologic manifestations of endocrine disorders, in Dermatology

in General Medicine. Edited by TB Fitzpatrick et al. New York, McGraw-Hill, 1971, pp 1434-1459
2. Sheehan HL: Simmond's disease due to post-partum necrosis of the anterior pituitary. Q JMed
8:277-309, 1939
3. Brooks VEH, Richards R: Depigmentation in Cushing's syndrome. Arch Intern Med 117:677~80,
1966
4. Lorincz AL: Pigmentation, in Physiology and Biochemistry of the Skin. Edited by S Rothman.
Chicago, Univ of Chicago Press, 1954, pp 515-563
5. Hamilton JB, Hubert G: Photographic nature of tanning of the human skin as shown by studies
of male hormone therapy (letter). Science 88:481, 1938
6. Edwards EA et al: Cutaneous vascular and pigmentary changes in castrate eunuchoid men.
Endocrinology 28:119-128, 1941
7. Fields JP et al: Hypoparathyroidism, candidiasis, alopecia and vitiligo. Arch Dermatol
103:687-689, 1971
8. Fisher M, Fitzpatrick TB: Candidiasis, vitiligo, Addison's disease and hypoparathyroidism.
Arch Dermatol102:110-111, 1970
9. Goldmann PJ, Thiess AM: Berufsbedingte Vitiligo durch para-tertiar Butylphenol, eine Ames
Trias von Vitiligo, Hepatose und Struma. Hautarzt 27:155-159, 1976
10. Rodermund DE, Wieland H: Vitiligo, Hepatosplenopathie und Struma nach Arbeit mit paratertiiirem Butylphenol. Dtsch Med Wochenschr 100:2216-2222, 1975

4
Hypomelanosis Secondary to
Irradiation and Physical Trauma
Melanocytes are vulnerable to nonspecific trauma. In animals or in humans,
dark skin or hair may lose pigment in areas exposed to various types of injury
(x-rays and ionizing radiations, ultraviolet rays, thermal burns, freezing, physical traumas) (Fig. 190).
X-rays have long been known to cause changes in melanin pigmentation.
In animals, x-ray exposure causes depigmentation of feathers [1,2] or hair [3-6].
In humans, cutaneous depigmentation with atrophy may follow x-ray therapy
[7]. Human hair color changes following x-radiation were reported just after
the turn of this century [8,9]. Regrowth of white hair has been observed in
white or black children [10,11] following epilating doses of x-rays for the treatment of tinea capitis.
X-ray depigmentation results from a loss of functioning melanocytes. Straile
[12] observed that x-ray irradiation decreases the number of melanocytes in
the hair follicles of mice. Other changes included alterations of the length of
the dendrites, decrease in the transfer of pigment granules, alteration in the
distribution of melanin in the hair, and changes in the color of melanin granules.
However, the mechanism by which follicular melanocytes seem to disappear
after irradiation is unknown.
The epithelium target theory suggests that x-rays alter the epithelium of
the hair follicle [13]; subsequently, there is either a failure of the induction of
follicular melanogenesis or a disturbance in the regulation of the differentiation
of the secretory melanocytes at the beginning of the hair growth cycle. Cohen
[14] suggested from studies of tissue culture of irradiated growing feathers
and transplant experiments that the action of x-rays is upon the melanoblast-ectoderm relationship. Chase et al. [6] observed radiation effects remote
from the site of original exposure; depigmentation was delayed until the second
growth cycle after irradiation. They concluded that there is an indirect effect
of x-rays on melanocytes.
The melanocyte theory suggests that melanocytes are individually and
directly killed or inactivated by x-rays [13].
Still another theory is that proposed by Straile [12], who suggested a more

475

476
CHAPTER 4

FIGURE 190. Top: Clip in position on the shaved back of the rat. Bottom: One month after
application of the clip. the hair in the previously ischemic area is white and longer than in the
surrounding areas where regeneration after shearing is irregular and slow. (From: Selye H: Ischaemic depigmentation. Experientia 23:524.1967. Copyright. 1967. Birkhauser Verlag. Used with
permission.)

complicated mechanism. In his view, x-ray-induced depigmentation results in

part from a complete block in the differentiation of the melanoblasts, possibly
related to an injury to the follicular epithelium, and also from direct or indirect
destruction or inactivation of the melanocytes on an individual basis.
Gamma and neutron radiation from atomic weapons also alters the melanin
pigmentation, and depigmentation induced in animals by these radiations has
been used for biologic radiation dosimetry [15].
Nonionizing radiation and photosensitization may lead to pigment loss; a
single PUVA (psoralen plus UVA) reaction was observed to lead to depigmentation of an exposed square in a Dutch belted black rabbit U. A. Parrish, unpublished observations).
Thermal burns which cause severe epidermal damage may destroy melanocytes to leave a depigmented scar. Freezing can be followed by cutaneous
depigmentation, and, with the increased use of liquid nitrogen in dermatologic

practice, this phenomenon is increasingly observed. Taylor [16] observed in

black rats that hair growing from skin treated by cryotherapy lacked pigmentation and also noted that in skin that survived freezing the melanocytes were
selectively destroyed. This suggested the increased vulnerability of melanocytes to freezing.
Experimental ischemia of the skin, produced by compression of a skin fold
in rubber-covered umbilical clamps for eight hours in rats [13], resulted in longstanding depigmentation of the hair.
Physical trauma also often leaves depigmentation which is most apparent
in dark-skinned patients.
The reason for the increased sensitivity of melanocytes to a wide variety
of injuries is unknown. The low-density, self-perpetuating melanocyte population in the skin may be responsible. Furthermore, cells are most sensitive to
trauma in mitosis and the turn-over rate of melanocytes is probably very low
[17].

REFERENCES
1. Cole LJ, Finley HE: Production of somatic mutations in the pigeon with x-rays. Anat Rec
[Suppl] 81:48-49, 1941

2. Espinasse PC: The responses of some developing feathers to x-ray. J Embryol Exp Morphol
7:165-172, 1959

3. Chase HB: Graying of hair. I. Effects produced by single doses of x-rays on mice. J Morphol
84:57-80, 1949
4. Chase HB: Number of entities inactivated by x-rays in graying of hair. Science 113:714-716,
1951

5. Chase HB, Raugh H: Graying of hair. II. Response of individual hairs in mice to variations in
x-irradiation. J Morphol 87:381-392, 1950
6. Chase HB et al: Evidence for indirect effects of radiation of heavy ions and electrons on hair
depigmentation. Ann NY Acad Sci 100:390-399, 1963
7. Ladanyi E: Nach Riintgenbestrahlung entstandene, "White Spot Disease." Hautarzt 21:328-330,
1970
8. Danysz J: De I'action du radium sur les differents tissus. C R Acad Sci (Paris) 136:461-464,
1903
9. Ellinger F: Medical Radiation Biology. Springfield. Ill. Thomas. 1907. p 173
10. Hazen H: Results of repeated epilation with roentgen rays in tinea tonsurans. Arch Dermatol
56:539-540, 1947

11. Zeligman I: Graying of hair following epilating doses of x-rays. Arch Dermatol 66:627-628,
1952
12. Straile WE: A study of the hair follicle and its melanocytes. Dev Biol10:45-70, 1964
13. Selye H: Ischemic depigmentation. Experientia 23:524, 1967
14. Cohen J: The nature of the effect of x-irradiation in depigmentation. Ann NY Acad Sci 100:400-412,
1963
15. Moshman J, Upton A: Depigmentation of hair as a biological radiation dosimeter. Science
119:186-187, 1954
16. Taylor AC: Survival of rat skin and changes in hair pigmentation following freezing. J Exp
2001110:77-112, 1949

17. Jimbow K et al: Mitotic activity in non-neoplastic melanocytes in vivo as determined by

histochemical. autoradiographic and electron microscopic studies. JCell Bio166:663-671, 1975

477

HYPOMELANOSIS
SECONDARY TO
IRRADIATION
AND PHYSICAL
TRAUMA

5
Chemical Hypomelanosis

A large number of chemical compounds induce depigmentation in humans

and in experimental animals (Fig. 191, Table 112). Cutaneous chemical depigmentation, which often resembles vitiligo in clinical appearance, may result
from direct contact or from systemic exposure (ingestion or particularly inhalation) to various phenol derivatives, sulfhydryl compounds, and others (Fig.
192). Some of these compounds have also purportedly been found in commercially available consumer products, and accidental exposures have occurred historically in the course of many industrial processes. Both careful
research discovery and serendipity seem to increase the growing list of known
chemical depigmenting agents. There are likely important and common depigmenting agents yet to be revealed.
Leukoderma has been attributed to the mono benzyl ether of hydroquinone
contained in rubber-covered wire-disk trays [1,2]' adhesive tape [3,4], hat bands
[3], contraceptive diaphragms [2], rubber finger cots [3,], rubber clothing [5],
rubber aprons [3], powdered rubber condoms [6,7], rubber dolls [8], neoprene
(a synthetic rubber) [9], fabric-lined rubber gloves [10], and shoes (rubber cement) [11].
Paratertiary butyl phenol is used as an intermediate in the processing of
varnish and lacquer resins, as an ingredient in motor oil demulsifier, as a soap
antioxidant, as a plasticizer for cellulose acetate, as a rubber antioxidant, as an
intermediate in synthetic oil, and as an ingredient in insecticides, deodorants,
commercial detergents, germicidal disinfectants, writing ink, and latex adhesives [12].
Paratertiary amyl phenol is used in the manufacture of oil-soluble resins,
and as a plasticizer, commercial germicide, and fumigant [12].
The germicidal phenolic detergents in Tables 113 and 114, which contain
paratertiary butyl phenols and paratertiary amylphenols, are potential depigmenting agents.
Ortho-benzyl-para-chlorophenol (chlorophene) is used widely as a disinfectant, cleaner, and preservative. Ortho-phenylphenol is used as a germicide
and as an intermediate in the production of dyes [12].
479

480
CHAPTER 5

0
0
OH

0
OH

OH

Hydroquinone

OOH
OH

CH. C CH.
CH.
p-tertiary
Butylcatechol

CH,

Monobenzylether
of
Hydroquinone

0
OH

CH.
Monomethylether
of
Hydroquinone

0
OH

CH. C CH.
CH.

p-tertiary
Butylphenol

0
OH

CH. C CH.
CH,
CH.

p-tertiary
Amylphenol

COMPARED TO

o
OH

CH,
NH, CH COOH
Tyrosine

FIGURE 191. Structures of some depigmenting phenol derivatives.

TABLE 112. Chemicals Implicated

in Induction of Leukoderma in
Humans
Paratertiary butylphenol
Paratertiary butylcatechol
Paratertiary amylphenol
Alkyl phenol
Monobenzylether of hydroquinone
Hydroquinone
Dihydroxyphenylmethane
Butylated hydroxytoluene
Heavy metals (mercury, bismuth, zinc)

FIGURE 192. Extensive depigmentation attributed to industrial exposure to monobenzylether of

hydroquinone.

481

CHEMICAL
HYPOMELANOSIS

TABLE 113. Germicidal Phenolic Detergents Containing

Para tertiary Amylphenolo

482
CHAPTER 5

Product
Bactophene
Beaucoup
Chlorocide
Galahad
Listophene
Matar
Microphene
Phenocide
Phenomycin
Staphene
i-Stroke Vesphene
Tergisyl
Tri-Kem
Ves-Phene
Ves-Phene 0
a

Manufacturer
Sanfax Corporation
Huntington Laboratories
Center Chemicals
Puritan Chemical
Enterprise Paint Manufacturing
Huntington Laboratories
Sanfax Corporation
Center Chemicals
Franklin Division of Purex
Vestal Laboratories
Vestal Laboratories
Lehn and Fink Division, Sterling Drug
Airwick Industries
Vestal Laboratories
Vestal Laboratories

Source: Fisher AA: Vitiligo due to contactants. Cutis 17:431--437,1976. Copyright, 1976, Donneley Publishing Corporation. Used with permission.

PHENOLIC COMPOUNDS
The basic structural requirements for a depigmenting phenolic compound
seem to be hydroxylation of the benzene ring, particularly in the para-position,
and a nonpolar side chain in the one position [13]. The presence of an ether
link at the 1 position increases the effective depigmenting potency [13]. Many
of these phenol derivatives resemble tyrosine or dihydroxyphenylalanine in
their molecular structure.

Clinical Features
The leukodermas arising from chemical exposure are clinically similar.
Chemical exposure of as little as two weeks' duration may cause depigmentation, but four to six months is a more commonly cited exposure period.

TABLE 114. Germicidal Phenolic Detergents

Containing Paratertiary Butylphenolo
Product
Bactophene
Microphene
O-Syl
Penocide
a

Manufacturer
Sanfax Corporation
Sanfax Corporation
Lehn and Fink Division, Sterling Drug
Center Chemicals

Source: Fisher AA: Vitiligo due to contactants. Cutis 17:431--437, 1976.

Copyright, 1976, Donneley Publishing Corporation. Used with permission.

483

CHEMICAL
HYPOMELANOSIS

FIGURE 193. Leukomelanoderma after application of monobenzylether of hydroquinone.

Contact dermatitis may precede whitening but is not necessary for development
of depigmentation. Depigmentation begins as confetti-like or small, round to
oval macules which may be more or less grouped in a particular anatomic
region. Predisposed sites are a function of direct occupational contact, so that
the hands, forearms, perioral skin, neck, and lower legs are among the first to
depigment. Satellite lesions (Fig. 193) may occur in areas not directly exposed
to the chemical. In extensive cases, which certainly resemble vitiligo, genital
and perianal skin may be affected. Extensive and symmetrical depigmentation
of the trunk may also occur. A leukomelanoderma may result. Graying of scalp
and body hair is rare. Eye color is unchanged. Repigmentation may occasionally
occur from the margins or from hair follicles after the chemical is withdrawn,
but more often depigmentation is permanent.

Monobenzylether of Hydroquinone (MBEH)

In the late 1930s, the rubber industry began to use a phenol derivative,
monobenzylether of hydroquinone (MBEH), as an antioxidant. Oliver et al. first

484
CHAPTER 5

reported in 1939 [14] depigmentation of skin occurring among factory workers

exposed for several months to rubber gloves containing an antioxidant, "Agerite
Alba." The leukoderma occurred mainly on the hands and half-way up the
forearms, often with a sharp cut-off line corresponding to areas outlined by the
heavy gauntlet type of gloves worn. Other areas of the face and trunk were also
involved. This depigmentation was attributed to direct contact with the antioxidant. About 50% of the workers were affected and the severity was a
function of the duration of exposure. Patch tests confirmed that MBEH caused
the depigmentation in the affected workers. McNally [15] at the same time
reported the same phenomenon in 34 black employees in a tannery. Leukoderma observed at remote sites was attributed to accidental direct contact with
the gloves. A mild inflammatory reaction and hair loss in the depigmented
macules was observed in one patient. Yet, the occurrence of leukoderma in
only nine of 200 workers exposed to oil droplets containing the antioxidant
material suggested that exposure alone was not the sole factor required for
depigmentation to occur [16].
These observations precipitated attempts to induce depigmentation with
MBEH. Application of MBEH to guinea-pig skin induced cutaneous depigmentation, whereas oral feedings over five months did not [17]. Later, production of depigmentation from oral feedings was observed by another group of
investigators [18] who attributed the different results to a different strain of
guinea pigs or to a higher dosage of MBEH.
Clinically, MBEH was reported to cause pigmentary lightening in melasma
[18-22], postinflammatory hyperpigmentation [22], benign acanthosis nigricans
[22], idiopathic melanoderma [22], congenital eyelid melanosis [22], pigmented
nevi [22,23], Riehl melanosis [24], cafe-au-Iait spots [22], generalized lentigines
[22], senile lentigines [22], seborrheic keratoses [22], berloque dermatitis [22],
hyperpigmented scars [21], and normally melanized skin in vitiligo patients
[22].

Monomethylether of hydroquinone (4-hydroxyanisole) is also a potent depigmenting agent [25].

The histology of MBEH-induced total depigmentation is identical to that
of vitiligo; the epidermis is normal except for an absence of identifiable melanocytes. The dopa reaction is negative. Electron microscopy reveals a total
absence of melanosomes.
Most chemical depigmenting agents appear to act by destroying melanocytes rather than by mere inhibition of melanin formation [26]. Studies in guinea
pigs have shown that MBEH inhibits melanogenesis. The number and size of
melanocytes is decreased. The content of melanocytes and keratinocytes is
diminished. The effect was observed to last four weeks after application. Prolonged application would be expected to cause irreversible loss of all melanocytes. Snell [27], like Peck and Sobatka [17], found no change in melanin
content of hairs and suggested MBEH may not penetrate skin so far as the
follicular melanocytes. Patients bleached with MBEH generally are permanently depigmented but may on occasion develop perifollicular repigmentation; these observations suggest that at least the potential for perifollicular
melanocyte activation may remain.

Hydroquinone (HQ)
Oettel [28], in 1936, noted that black-haired cats developed reversible graying of hair after six to eight weeks of hydroquinone (HQ) feedings. Martin and
Ansbacher [29] noted that achromatrichia developed after four to 20 weeks of
oral HQ in mice. HQ fed to guinea pigs did not cause depigmentation, whereas
subcutaneous injection resulted in depigmentation at the injection sites [18].
Workers exposed to large amounts of HQ do not develop depigmentation, but
depending on the length of exposure may develop a reddish discoloration of
hair and exposed skin, particularly on the palms and soles [30]. This may result
from oxidation and polymerization of absorbed HQ [30] or from conversion of
HQ to a melanin-like product similar to that in the conjunctivae in ochronosis
[31]. HQ has also been found to be a quite effective de pigmenting agent but,
unlike MBEH, it does not cause satellite depigmentation and the depigmentation is usually reversible once application of HQ is discontinued (Fig. 194).
Furthermore, total depigmentation has never been reported. Large quantities
of HQ creams have been used in Africa for over 15 years; no reports of vitiligolike depigmentation have been reported despite annual sales of several million
dollars.
Jimbow et al. [32] found evidence of destruction of melanocytes with HQ;
there was decreased formation of melanosomes, alteration of internal structure,
increased melanosome degradation, and destruction of membranous organelles.

Paratertiary Butylphenol (PTBP) and Paratertiary Amylphenol

(PTAP)
In 1962 Russian researchers [33] observed depigmentation in 23 of 52
factory workers exposed to paratertiary butylphenol (PTBP) and paratertiary
amyl phenol (PTAP) formaldehyde resin. The depigmentation was symmetrical
and resembled vitiligo. Three of the cases occurred after a year of exposure.
Forty percent of those exposed for more than two years were depigmented. The
exposure was attributed to inhalation of various phenol vapors in combination
with formaldehyde and to exposure to the resin dust.
Daily injection of PTBP into black rabbits also induced graying of hair
[34,35]. The observation that daily application of PTBP in propylene glycol
caused capillaritis suggested depigmentation remote to directly exposed areas
could be secondary to a generalized capillaritis [36]. Subcutaneous and oral
administration also caused depigmentation in C-57 black mice [37,38].
Five housekeeping employees in a Denver hospital developed depigmentation of the hands and forearms after six months' use of O-Syl, a PTBP-containing detergent disinfectant [12].
Rodermund and Wieland [39] reported three men with vitiligo-like skin
changes, hepatosplenomegaly, and diffuse goiter (grade III), all of which developed after one to two years' work in a factory producing PTBP. Liver function
tests showed BSP elevation and a slight increase in the SGOT and SGPT levels.
Liver biopsy showed polymorphism of the hepatocytes, disintegration of the

485

CHEMICAL
HYPOMELANOSIS

486

CHAPTER 5

FIGURE 194. a: Patient with melasma before treatment with hydroquinone. b, c: Same patient
during and after treatment. The hypomelanosis is much less apparent.

487

CHEMICAL
HYPOMELANOSIS

FIGURE 194 (Continued)

cytoplasm, and, in two of the workers, disseminated fatty degeneration. In

addition, TSH levels were increased and antithyroid antibodies were present.
The triad of vitiligo-like depigmentation, hepatosplenomegaly, and thyroid
struma was attributed to PTBP and suggested that an immunologic process
followed simultaneous PTBP-induced damage to cells of different organ systems. Goldmann and Thiess [40] also observed thyroid struma in eight and BSP
abnormalities in nine of 12 patients with occupational PTBP-Ieukoderma.
In another industrial survey [41], of 198 employees exposed to PTBP, 54
had leukoderma (in seven cases this was obvious only with Wood's light examination). Only two of those with leukoderma had been exposed less than
five years. Exposure was attributed to dust and vapor and the sites of involvement suggested systemic absorption. The degree of leukoderma correlated with
the extent and duration of PTBP exposure. None of those with leukoderma had
positive family histories or histories of associated diseases. Among studies
performed-ANA, smooth muscle antibodies, thyroid antibodies, and aspartate
aminotransferase (AAT)-only the latter was abnormal more commonly in those
affected than in the 144 unaffected. In the six patients with abnormal AAT
levels, all had abnormal liver histology characterized by moderate to severe
fatty changes, and one had frank cirrhosis. This too suggests systemic effects
of PTBP exposure.
A similar chemical, paratertiary butylcatechol (PTBC), was responsible for
depigmentation among another cluster of factory workers [42]. These four tap-

488

CHAPTER 5

pet plant workers had had a dermatitis on their upper arms prior to the appearance of depigmentation. Leukoderma appeared following a few months' to
four years' chemical exposure. The amelanotic macules were confined to the
hands and forearms in only one patient, whereas the others also had remote
areas involved. One worker was 75% depigmented. Patch testing gave positive
results in three of four patients, one of whom subsequently developed an area
of depigmentation at the site of patch testing.
Another worker exposed to PTBC was studied. It was observed that patch
tests to 0.01% and 0.5% PTBC were both positive, but only with the 0.5% did
depigmentation occur. This developed two weeks after patch testing. The same
worker was also patch test-positive to PTBP but depigmentation did not occur.
Histologic studies show decreased melanin, a decreased number of dopa-positive melanocytes, and melanophages in the dermis. After three years, improvement was noted but some depigmentation remained. Phase contrast and electron microscope studies of guinea-pig ear melanocytes treated with PTBC show
the changes in more detail. These changes included decreased melanocyte size,
a beaded dendritic pattern, and some melanocytes rounded-up in shape; many
of these changes were reversible once PTBC was washed out. PTBC exposure
also caused transition from smooth melanocyte contour to irregular outlines
and melanin pigmentary clumping. In cell culture, half the cells were killed,
but among remaining cells, no lightening occurred. Thus, cell killing would
appear to be the mechanism for PTBC depigmentation. An alternative mechanism for depigmentation is inhibition of tyrosine oxidation as has been observed in vitro [43].
In another industrial investigation in a Dutch factory, inhalation was implicated. Patch testing of 16 of these workers to multiple phenol derivatives
including PTBP revealed universally negative results and no depigmentation
at sites of application of the testing materials. Wild-type colored guinea pigs
and black cats fed up to 10 months a tube feeding mixture of phenols, including
PTBP, PTBC, and others did not develop hypomelanosis of hair [44a].
Depigmentation of hands and arms occurred in seven employees of a Denver hospital [12] who were exposed to Vesphene, a PTAP-containing disinfectant. PTAP was observed to cause depigmentation in the absence of an antecedent dermatitis. In some patients and test subjects, the depigmentation
disappeared in six months, whereas in others it persisted more than one year.
PTBP-depigmented skin lacks melanin granules and contains only occasional melanocytes with few melanosomes [44]. In four of five patients in
another series, no melanocytes were identified in the involved skin and the
rare melanocytes found contained swollen mitochondria, many vacuoles, and
premelanosomes with "an abacus" type of pigment distribution [44a].
Occupational leukoderma from the alkylphenols has also been reported
[38,45].
4-Isopropylcatechol (4-IPC)

One of the most potent depigmenting agents is 4-isopropylcatechol (4-IPC).

Topical4-IPC consistently produces depigmentation of epliated and unepilated
skin of black guinea pigs [46]. Only rare melanocytes could be found in 4-IPC-

exposed areas. The few melanocytes identified contained fewer electron-dense

melanosomes, imperfectly melanized melanosomes, vacuoles, swollen mitochondria, and sometimes electron-dense round or oval bodies with double
membranes. Other cells resembling melanocytes without characteristic organelles were observed, but could not be characterized as melanocytes, histiocytes,
or Langerhans cells; these had well-developed rough endoplasmic reticulum
and a lobate nucleus, but no Langerhans granules, premelanosomes, melanosomes, or desmosomes. Only occasional keratinocytes had melanosomes which,
in the few instances in which they were observed, appeared normal. The number, morphology, and distribution of Langerhans cells were normal.

Dihydroxydiphenylmethane
Depigmentation due to adhesive tape has been attributed to contact with
a natural rubber-base adhesive containing a derivative of dihydroxydiphenylmethane [4].

p-Cresol
A compound in laundry ink, p-cresol, has been shown to induce permanent
hair depigmentation in CBA/J mice [47]. p-Cresol appeared to be toxic to melanocytes during the early anagen phase of the hair cycle. Superficially the coat
appeared pigmented until the hair was parted to reveal depigmentation of 90%
of the hair, which in fact retained pigment only at the tips. The area of depigmentation corresponded to the area of application of p-cresol.

Butylated Hydroxytoluene
Vollum [48] found two black children who developed hypopigmentation
at the site of application of a polyethylene film containing an antioxidant,
butylated hydroxytoluene. After four weeks one showed no signs of repigmentation; the other had repigmented in eight weeks.

Mechanism of Action
Bleehen et al. [46] suggested seven possible mechanisms for exogenous
depigmentation with an agent such as 4-IPC:
1. Selective action on the melanocyte-as metabolic antagonists or respiratory inhibitors-through formation of free radicals that disrupt melanocyte
function
2. Competitive inhibition with tyrosinase
3. Block of enzymatic oxidation of tyrosine to dopa, for example, by reduction of dopaquinone to an orthodihydroxyphenol compound, which may
then inhibit melanin pigmentation

489

CHEMICAL
HYPOMELANOSIS

490
CHAPTER 5

4. Interference with biosynthesis of premelanosomes or melanosomes (disorganization of the matrix)

5. Interference with tyrosinase synthesis by combining with ribosomes in
melanocytes
6. Interference with transfer of melanosomes from melanocytes to keratinocytes by inhibition of arborization of melanocytic dendrites or by intercellular
edema of keratinocytes
7. Reduction of melanin present in melanosomes
Hydroquinone was found to inhibit the oxidation of tyrosine to dopa, but
dopa oxidation itself was not inhibited [18]. Others found inhibition in the
conversion of dopa to melanin [49]. It was also suggested that hydro quinone
could function as a reducing agent [18].
The mechanism of MBEH, 4-hydroxyanisole (4-HA), and PTBP depigmentation is not understood. Denton et al. [18] suggested MBEH may be converted
to hydroquinone, which they found to inhibit the enzymatic oxidation of tyrosine to dopa. The hydroquinone hypothesis is not consistent with clinical
experience-if hydroquinone were an intermediate step in the final pathway
of MBEH depigmentation, MBEH should behave clinically as hydroquinone.
The mechanism must differ in order to explain the irreversible and remote
depigmentation seen with MBEH but not with hydroquinone.
Iijima and Watanabe [49] suggested direct tyrosinase inhibition. Studies
suggest various germicidal phenols may induce depigmentation by such direct
inhibition of tyrosinase [50]. Yet, MBEH appears to have no action in vitro on
the enzymatic oxidation of tyrosine or dopa to melanin [51]. Denton et al. [18]
found the O2 uptake of the tyrosine-tyrosinase MBEH reaction mixtures to be
greater than that of control tyrosine-tyrosinase preparations; O2 uptake of the
dopa-tyrosinase reaction was also increased. Although they could not relate
this to the mechanism of action of MBEH, they suggested that MBEH may be
converted to hydroquinone, which inhibits the formation of dopa from tyrosine.
Or it may act directly as a reducing agent causing melanin reduction (lightening).
It may be suggested that 4-HA blocks the synthesis of tyrosinase in the
melanocytes. If the enzyme substrate tyrosine is also an inducer of tyrosinase
synthesis, then perhaps tyrosine analogs could inhibit tyrosinase synthesis by
binding the inducer site [13]. Supportive of this is the observation that a 10:1
molar ratio of tyrosine and 4-HA delays the appearance of 4-HA-induced depigmentation [52]. Furthermore, tyrosine applied to guinea-pig ear skin causes
increased pigmentation [13]. However, there is no evidence in humans that
tyrosine is an inducer of melanocyte tyrosinase [13].
An attractive variant hypothesis is that the chemical similarity of these
compounds to tyrosine makes them competitive inhibitors of tyrosinase activity. However, the negative dopa reaction makes this untenable [13]. Furthermore, Riley [53] has suggested that 4-HA in vitro stimulates tyrosine oxidation.
Also, other possible competitive inhibitors, 4-hydroxyphenylpyruvate, adrenaline, and noradrenalin, which are all rapidly oxidized in vitro by mushroom
tyrosinase, do not cause depigmentation [13].
That 4-HA may act as a tyrosinase substrate is supported by the observation

that tritiated 4-HA uptake into melanosome-rich melanocytes and distribution

of labeled compound is similar to that of dopa reaction product in control cells.
These labeled granules then appear in surrounding keratinocytes [54]. This 4HA effect has been shown to be dose-dependent on cultured cells and to be
selective for melanocytes in mixed cell cultures.
Similar results, according to Riley [54], have been obtained for l-isopropyl3,4-catechol, l-tertiary-butyl-3,4-catechol, 4-HA, and 3-tertiary-butyl-4-hydroxyanisole. These are all toxic substances, whereas the nontoxic substances 2HA and 3-HA proved to be poor substrates.
Thus, melanocytotoxicity results from a reaction product of tyrosinase
oxidation of a particular phenolic compound. This is further supported by the
protection generally afforded by the copper-binding tyrosinase inhibitors and
by "free radical scavengers" such as ascorbate and ubiquinone [54].
A dialyzable free radical oxidation product can be formed from a mixture
of 4-HA and mushroom tyrosinase and with other nonpolar tyrosinase substrates, but not with polar ones. Riley [13] suggests this contributes to diffusability and that greater lipid solubility may contribute to initiation of lipid
peroxidation.
A third suggestion, which Denton et al. [18) noted was not supported by
other studies, was that MBEH is a sylfhydryl antioxidant; it prevents sulfhydryl
oxidation so that more sulfhydryl groups are available to inhibit tyrosinase.
Becker and Spencer [9] suggested an inflammatory reaction was the primary
event in chemical depigmentation-increased cell permeability occurs, MBEH
enters the melanocyte, and an antigenic substance is formed, attaches to melanin granules, and enters the dermis where antibodies are produced. If a certain
level of antigenic stimulation is produced, remote positive patch testing may
result. The latter seems a reasonable postulation. It may be that clinical or
subclinical inflammatory reaction accompanies MBEH use. Membrane disruption permits MBEH to enter the melanocyte to bind with substrate to form an
antigenic complex which leaks into the dermis. Antibody production could
thus be initiated against an antigenic component of normal melanocytes.
It has been demonstrated that 4-HA in vitro is toxic to RNA and protein
synthesis systems, as well as to mitochondrial respiration, with secondary
inhibition of cellular capacity to manufacture melanin [53).
Possibly reduction of a quinone intermediate produces semiquinone free
radicals which diffuse out of melanosomes to initiate the chain reaction of lipid
peroxidation with resultant damage to cellular organelles and melanocyte destruction. RBC hemolysis in vitro with these substances with or without tyrosinase is increased compared to unsubstituted phenol alone [53). It has been
demonstrated that tritiated 4-HA is selectively taken up by melanocytes in
tissue culture [54] and that a new electron spin resonance signal is generated
in black guinea-pig skin treated with topical 4-HA [54]. This supports the
concept of new free radical formation and suggests the depigmentation results
from synthesis of diffusible free radicals.
4-HA has been observed to cause membrane damage in RBC suspensions,
and also to melanocytes [53]. It is not known whether this effect relates to lipid
peroxidation.
Riley [13] notes that other effects of phenolic cmpounds may be relevant.

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4-HA was noted to produce keratinocyte pseudopods into the dermis, whereas
nontoxic 2-HA and 3-HA had no, or a much slower, effect, respectively. This
effect is reversed once application is discontinued.
The mechanism of PTBP is not understood, but it induces changes in the
cresolase activity of tyrosinase [37,55]. McGuire and Hinders concluded that
paratertiary butylphenol depigmentation may result from competitive inhibition of tyrosinase [50].

Diagnosis and Differential Diagnosis

In most cases of chemical depigmentation, except with hydroquinone, the
typical clinical presentation resembles vitiligo. Clusters of small round, oval,
or confetti-like depigmented macules are highly suggestive. A history of exposure to known depigmenting agents and industrial clustering of cases should
be pursued in such incidences. The distribution of lesions on exposed areas
is also suggestive. Mode of spread may be helpful-a history of gradual coalescence of small discrete macules, rather than development of large macules with
perifollicular sparing suggests chemical leukoderma. For this reason a work
history of those with leukoderma is essential. It is also important to know
whether others at work have any evidence of leukoderma.
Hydroquinone, however, leads to a uniform lightening over the area of
application and not to focal pigmentary lightening or leukoderma.

Prevention and Treatment

Preventing occupational leukoderma involves constant vigilance for the
offending agent. Ideally, direct contact with the depigmenting agent should be
avoided and adequate ventilation to prevent inhalation should be present [44].
With most agents, spontaneous repigmentation may occasionally occur,
but often the depigmentation persists [56]. The hypermelanosis which usually
accompanies chemical leukoderma is most often permanent.
Topical or systemic psoralens and UVA may stimulate repigmentation.
The hospital orderly with depigmentation attributed to O-Syl detergent exposure was treated with methoxsalen applied to the dorsum of one hand, and
subsequent black-light exposure. Perifollicular repigmentation was observed
after six treatments. The left hand, which was untreated, did not repigment
[57]. In another case, no repigmentation was observed with similar therapy
[12].

Therapeutic Use of Phenolic Depigmenting Agents

Hydroquinone and monobenzylether of hydroquinone (MBEH) have been
employed in the treatment of various pigmentary disorders.
The only rational use of MBEH is for total removal of normal pigmentation
in patients with extensive vitiligo (Fig. 195). In 18 of our patients with severe
vitiligo, seven of eight who applied Benoquin (20% MBEH) once or twice a

493

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HYPOMELANOSIS

FIGURE 195. Monobenzylether of hydroquinone. Leukoderma resulting from exposure to

MBEH.

day for over four months achieved complete depigmentation [58]. An average
of only two to three months of therapy was required to notice any change. After
completely depigmenting, two patients observed small macules of repigmentation; these macules were readily erased with further applications of Benoquin.
All patients who depigmented fully were very pleased with the results.
Side effects of MBEH therapy are not uncommon. Dermatitis, burning [59-61],
and pruritus [7] are the most frequent complaints. Contact dermatitis, varying
from mild asymptomatic erythema to a painful vesicular eruption, has been
reported in 13% of treated patients; in some of these cases dermal or epidermal
hyperpigmentation resulted [22]. In 3816 patch tests on 578 subjects (200 Indians, 316 Zulus, and 62 mixed whites and blacks) with 1% to 75% hydroquinone or MBEH, reactions varied from erythema to vesiculation as a function
of concentration. Hyperpigmentation, never depigmentation, followed [62].
Two-thirds of the 18 patients treated at the Massachusetts General Hospital
complained of burning or itching, erythema, dryness, or warm sensation. One
patient developed a contact dermatitis and was unable to use Benoquin [58]
and one of the authors has since observed another such patient.
Other pigmentary abnormalities, including leukomelanoderma, satellite
depigmentation (Fig. 196), and hypermelanosis, may occur. Hyperpigmentation
with MBEH-containing Neoprene has been reported [8], and such hyperpigmentary responses tend to be permanent [63]. According to a study of Becker

494
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FIGURE 196. Hypomeianosis of the dorsum of the hand

remote from the sites of application of monobenzyiether of
hydroquinone.

and Spencer [9], among 25% of patients responding to 1% to 20% MBEH application, the response was unpredictable in extent and degree. Among Japanese women using MBEH, a vitiligo-like leukomelanoderma developed remote
from the sites of direct application [59]. Development of completely depigmented macules outside the treated area was noted in two South American
patients [23]. Total depigmentation was common among blacks and Asiatics
but not among Caucasians [23]. Curiously, in another 185 patients, neither
hyper- nor hypo pigmentation was noted; this suggested possible patient misuse
or careless transfer by fingers [22] was responsible for the satellite depigmentation reported by others. The variation in reactions to patch testing of 43 normal
black males [2], one of whom discontinued MBEH because of a disseminated
eczematous eruption, confirms a spectrum of MBEH reactions. Twenty-three
developed inflammation at the site of MBEH application, and after four months
26 had leukoderma. Five, in fact, developed leukoderma within the time of
application, and in seven the leukoderma continued to progress for six months
after application. Four years after application had been discontinued, nine
subjects continued to be depigmented. MBEH depigmentation is, however, not
necessarily permanent. But a few months to years may be required for repigmentation to occur. Such repigmentation may be partial or complete. In two
of seven volunteers who underwent 30-day patch testing with 10% to 30%
MBEH, perifollicular repigmentation was observed a month after the end of
the experiment [18]. Another group of Caucasians treated with MBEH did not
develop leukoderma, but the test sites would not tan for several years.
Other effects are rarely reported. A halo nevus has been reported to develop
in an MBEH-treated patient [64J. Hair loss has been observed in one case [3J.
While the incidence of side effects is high, these do not usually limit the
proper use of Benoquin. The only clinical use of MBEH is for those vitiligo
patients who wish, above all, to be one color and who can accept the emotional
and physical limitations of being totally amelanotic. Once therapy has resulted
in hypomelanosis, irreversible depigmentation (amelanosis) should be expected to follow and remain. And, after full depigmentation, the patient must

be constantly aware of the possibility of sunburn and must use an effective

UVB sunscreen. Attempts to repigment Benoquin-induced depigmentation with
oral psoralens have generally been unsuccessful. MBEH should never be used
as a hypo pigmenting agent for melasma or postinflammatory hyperpigmentation because the end point of hypopigmentation cannot be reliably predicted
or controlled, and satellite depigmentation may occur.
For nearly 15 years hydroquinone has been used to bleach various hypermelanoses. Hydroquinone in 2% to 4% concentration is a useful hypopigmenting agent for hypermelanoses of epidermal origin. Pigment loss must be
considered temporary and reversible. Arndt and Fitzpatrick [65] used 2% to
5% hydroquinone in 54 patients with melasma, vitiligo, idiopathic hyperpigmentation, postinflammatory hyperpigmentation, and ephelides. Cosmetically
acceptable results were obtained in 67% to 90% of patients treated for a month
or more. Complete disappearance of hypermelanosis did not usually occur.
Nevi did not respond. One patient developed an equivocal leukoderma.
A later report [7] showed overall improvement to be 63.5% of 93 patients
with pigmentary disorders. No differences were noted in the reactivity between
blacks and Caucasians.
In addition to the treatment of hypermelanoses, hydro quinone may be used
to "feather" the area of normal pigmentation into an area of vitiligo to make
the contrast less dramatic. The use of such a temporary hypopigmenting agent
also leaves open the option for repigmentation should the patient decide on
such a course at a future date. For effective therapy, an opaque sunscreen must
be used daily before sun exposure.
In simulated use tests, 1.5% to 2% hydroquinone has been found to be
remarkably free of side effects [66]. Among 98 patients with pigmentary disorders, hydro quinone produced hypopigmentation in 45% and irritation and
sensitization in none. Yet, hydro quinone is a mild primary irritant and may
provoke sensitivity and contact dermatitis in those previously exposed. Thirtytwo percent of 93 patients using 5% hydroquinone developed erythema and
tingling at the site of application, whereas only 8% had reactions to the 2%
concentration [40]. In another study, patch testing with hydroquinone revealed
essentially no reaction to a concentration of less than 3%, 11% reactivity to
3.5% hydroquinone, and 35% reactivity to 7% hydroquinone [67]. The most
frequently observed adverse reaction was hyperpigmentation, either with or
without preceding erythema. Increasing the concentration of hydroquinone to
10% increases its effectiveness but also its irritancy [68]. Temporary brown
discoloration of the fingernails attributed to binding of hydroquinone to keratin
and oxidation may occur [40].
The combined use of hydroquinone, retinoic acid, and dexamethasone
augments the hypopigmenting effect of hydroquinone [68]. Retinoic acid alone
seems to cause pigment granule dispersion in keratinocytes, interference with
pigment transfer, and accelerated pigment loss because of increased epidermal
turnover. Complete depigmentation of normal skin of more than 100 adult black
males followed daily application of five to seven weeks of a mixture of 0.1%
T retinoin, 5% hydroquinone, and 0.1% dexamethasone. Pigment loss was
blotchy at first and the follicles were the last to depigment. Erythema and
desquamation usually preceded depigmentation, although after one month significant hardening had occurred such that little or no irritation was present.

495

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No satellite depigmentation occurred. One to two weeks after treatment was

discontinued, repigmentation from the borders and from hair follicles began
and was generally complete after three to four months. Biweekly exposure to
2 MEDs (minimal erythema doses) of ultraviolet radiation markedly retarded
the rate of depigmentation. Omission of one or two of the ingredients significantly lessened the hypopigmentary potency [68]. Depigmentation seems to
take a longer time and to be less satisfactory in fair-skinned individuals than
in blacks.
In clinical usage, 67% to 88% of 45 patients with melasma, ephelides, and
postinflammatory hyperpigmentation achieved satisfactory response. None of
the seven patients with senile lentigines responded to treatment.
However, the long-term complications of fluorinated corticosteroid usage
on the face makes use of this combination not practicable. Substitution of
hydrocortisone for dexamethasone circumvents this problem but likely decreases therapeutic responsiveness.

SULFHYDRYL COMPOUNDS
Depigmentation has been found to occur with 2-mercaptoethylamine (MEA),
N-(2-mercaptoethyl)-dimethylamine (MEDA), cystamine dihydrochloride, 3mercaptopropylamine hydrochloride, and sulfanolic acid. Sulfhydryl compounds were first observed to cause depigmentation in goldfish [69]. Topical
application of these compounds was later found to depigment mammalian skin
[46,70].
With black guinea pigs, MEDA was found to be a more potent depigmenting
agent than MEA, and sulfanilic acid, like hydroquinone, was found to induce
barely perceptible hypopigmentation [71]. In MEDA-treated epidermis, only
rare melanocytes could be identified. Those present contained many vacuoles,
swollen mitochondria, and imperfectly melanized melanosomes. Some small
vacuoles resembled coated vesicles; larger ones containing electron-dense material resembled malformed melanosomes. The depigmented skin contained
some normal melanosomes similar to those in the untreated epidermis [71], a
normal complement of Langerhans cells, and unidentified cells lacking desmosomes, melanosomes, or Langerhans granules. Although sulfhydryl-induced
depigmentation has not been clearly documented in humans, several patients
ingesting sulfhydryl-containing compounds have developed hypopigmentation. Depigmentation was observed in a black patient treated with thiouracil
for hyperthyroidism [72]. Chronic administration of BAL (2,3-dimercaptopropanol) is said to cause graying of hair [73].
It was concluded that MEDA is a cytotoxic agent which alters or blocks
the formation of melanin by tyrosinase inhibition. The selective action on
melanocytes suggested that thiol compounds attach to the melanocyte components by both covalent and ionic bonds, such that functional activity is
disrupted. These thiols may interfere directly with enzymes, including tyrosinase, and may attach to microsomal particles thought to be templates for
protein synthesis. Riley [13] suggested sulfhydryl compounds may decrease
the cellular capacity to inactivate a potentially harmful free radical.

CINNAMIC ALDEHYDE
Several cases of perioral leukoderma simulating vitiligo from use of a
toothpaste containing cinnamic aldehyde have been observed [73a].

METALS
Mercurials have been widely used as depigmenting agents. However, use
of mercurials has been banned because cutaneous absorption of mercury may
cause nephrotoxicity [67].

HYDROGEN PEROXIDE
Hydrogen peroxide is a very popular topical bleaching agent for hair. Keratin is irreversibly altered by oxidation of combined cysteine. The cysteic acid
formed causes a significant change in the distribution of electrostatic crosslinks [74]. Electron microscopy studies of bleached human scalp hair reveal
that bleaching is associated with destruction and dissolution of the melanin
granules. There were no premelanosomes in bleached hair [75]. There is no
evidence for a depolymerization of the melanin polymer.
Benzoyl peroxide contained in antiacne preparations can also bleach hair.

GUANONITROFURACIN
Cutaneous depigmentation was observed in Japan after the use of a topical
solution or ointment containing 5-nitro-2-furfurylidene aminoquaridine (guanonitrofuracin) for the treatment of conjunctivitis and blepharitis. One to eight
months after cessation of the therapy, depigmentation of the eyelid and eyelashes occurred in about 20% of the cases; in some, cutaneous depigmentation
remote from the sites of application of the compound was also observed. Halo
nevi have been reported. No patients had a history of preceding inflammatory
changes [76]. The involved skin was normal except for the absence of melanin;
dopa reaction was negative.
Absence of sweating in the leukodermatous macules has been described
and is said to precede appearance of the depigmentation. This observation has
led to the hypothesis that guanonitrofuracin-induced leukoderma is precipitated by some neuropathic process. The eccrine sweat glands are histologically
normal.
Guanonitrofuracin has been shown to interact with several components of
the melanogenesis pathways. Guanonitrofuracin inhibits potato tyrosinase. This
inhibition can be reversed by the addition of copper; it has been demonstrated
spectrophotometrically that guanonitrofuracin interacts with cupric sulfate.
However, guanonitrofuracin does not inhibit the dopa reaction of normal human skin, and has only a 10% inhibitory effect on human melanoma tyrosinase.
But according to Ito [77], since guanonitrofuracin is a competitive inhibitor of

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CHAPTER 5

substrates in the dopa reaction, high concentrations of these substrates may

mask an inhibitory effect of guanonitrofuracin. It has also been suggested that
guanonitrofuracin not only interacts with the tyrosinase copper, but also induces changes in the sulfhydryl metabolism of the skin so that increased sulfhydryl compounds are present to inhibit tyrosinase. Animal experiments in which
there is a slight increase in the sulfhydryl content of red blood cells support
this hypothesis. These changes are slow to develop and impossible to reproduce
by dopa technique. None of these hypotheses, however, is totally satisfactory.

MEPHENESIN CARBAMATE
Mephenesin, an aromatic glycerol ether, a,~-dehydroxY-"Y-(2-methylphen
oxy)propane, which has been used for the treatment of multiple sclerosis, exerts
a depressant effect on synoptic transmission at spinal, brain stem, and subcortical levels and in addition possesses anesthetic and anticonvulsant properties. Spillane [78] reported depigmentation of scalp hair in six patients (four
females and two males) using this drug. Five were suffering from multiple
sclerosis and one from a posttraumatic hemiplegia. The degree of depigmentation seemed proportional to the dosage of the drug and to the duration of the
treatment. In the most striking cases, in which the patients were taking 10 g
daily, the hair turned from dark brown to blond in three months. The mechanism of this depigmentation is unknown. No cutaneous depigmentation was
observed.

TRIPARANOL (MER-29)
Triparanol (MER-29), 1-[p-(~-diethylaminoethoxy)phenyl]-1-(p-tolyl)-2-(p
chlorophenyl)ethanol, a drug that principally blocks the conversion of demosterol to cholesterol [79], was, for a short time, employed therapeutically to
reduce cholesterol levels. Change of hair color was one of the complications
noted with use of MER-29. Achor, Winkelmann, and co-workers [80,81] reported loss of hair color in two males, and Minton and Bounds [82] observed
in one of 12 patients treated by MER-29 that the hair changed from dark brown
to light brown. Winkelmann et a1. [81] observed two patients in whom examination of the hair shaft showed abrupt color change. Alopecia, ichthyosis,
and cataracts were other undesirable side effects of this drug. Since MER-29
is known to disturb the formation of the horny layers in rat epidermis, it is
likely that the pigmentary changes are secondary to disturbed keratinization
which results from interference with cholesterol synthesis [83].

DINITROCHLOROHENZENE (DNCH)
Holzegel [84] observed two patients with permanent depigmentation on
the sites of an epicutaneous test with DNCB (dinitrochlorobenzene). Grosshans
et a1. [85] also observed several instances of such depigmentation. Holzegel
[84] found this depigmentation could not be differentiated clinically or histologically from vitiligo.

The depigmentation in sites of epicutaneous testing with DNCB may be

postinfiammatory, may result from selective inhibition of melanogenesis, or
may arise from selective destruction of melanocytes. The existence of DNCB
depigmentation suggests that an immunologic mechanism may cause leukoderma.

ARSENIC
Chronic arsenical ingestion [86,87] can induce a cutaneous leukomelanoderma which may occur without an antecedent dermatitis and may develop
several to many years after arsenical use. The hyperpigmentation may be diffuse, but more frequently the presence of small depigmented macules gives a
freckled or "raindrop" appearance. The hypopigmented macules vary in size
from several millimeters to a few centimeters, are round to oval, usually not
confluent, and asymptomatic.
Diagnosis is made by the history of therapeutic or industrial use of arsenic,
by the association of the other clinical signs of the disease, namely, loss of
hair, transverse whitish discoloration ofthe fingernails (Mees' lines), and, later,
keratotic lesions of palms and soles which can evolve into skin tumors, and
by the finding of elevated arsenic levels in urine, hair, and nails.
The mechanism of the hypopigmentation is unknown.

NITROGEN MUSTARD AND THIOTEPA

Boyland and Sargent [88] found intradermal injection of nitrogen mustard
to be followed by regrowth of white hair in mice. Several cases of depigmentation, localized to areas of topical application of thiotepa have been reported
[88a]. By light and electron microscopy, melanocytes were apparently absent
in the depigmented area.

CORTICOSTEROIDS
Depigmentation can follow either topical or intralesional injection of corticosteroids.
Kestel [89] first reported hypopigmentation associated with the use of corticosteroid tape. The tape alone (without the steroid preparation) did not produce the hypopigmentation, which was restricted to the sites of use of the
corticosteroid tape. In this case, the skin remained hypopigmented for about
one week, then slowly repigmented. Another patient applied flurandrenolide
tape to the side of her neck two times for 10 to 12 hours each. Approximately
one month later, hypopigmentation appeared in the area of previous application
and remained unchanged for five months. A 21-year-old female found herself
unable to tan in sites where triamcinolone acetonide cream had been applied
three times a day for one month. Arnold et al. [90] found topical depigmentation
to be fairly rapid, incomplete and reversible. Amelanosis does not occur.
Hypopigmentation may also complicate corticosteroid injections [91,92].

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Cutaneous depigmentation appeared four weeks after injection of 1 ml of

methylprednisolone for tennis elbow [93]. The complete depigmentation was
postage-stamp in size and persisted at least 12 weeks after the injection. Depigmentation after injection of different corticosteroids has been noted to involve relatively fair-skinned as well as the dark-skinned peoples [94].
The course of the hypomelanosis induced by intralesional triamcinolone
diacetate or acetonide was monitored in six black patients [95]. Four months
after developing hypopigmentation, two of these patients had experienced repigmentation while two others had shown no signs of repigmentation. None
had developed atrophy. The inescapable conclusion was that in some cases
hypopigmentation may be permanent. Others [96,97] observed hypopigmentation several days to months after intra- or periarticular injection of corticosteroids (triamcinolone acetonide). In these cases the hypomelanosis was generally accompanied by alopecia and slight atrophy of the skin. In most cases,
repigmentation occurred within one year after the injections had been discontinued.
The relative hypopigmenting potential of repeated application of several
topical corticosteroid preparations was studied on guinea pigs by Arnold et al.
[90]. Triamcinolone acetonide and betamethasone valerate 0.1% were found to
be potent depigmenting agents; desoxydecamethasone and hydrocortisone did
not depigment. The degree and rate of depigmentation may be a function of
concentration. Glick [94] suggested, and it seems reasonable, that the more
potent and longer-acting corticosteroids are most likely to produce depigmentation.
Electron microscopy suggests that the leukoderma secondary to corticosteroid injection is related to a transfer block [98]. Guinea pig studies [90] show
a decreased number of melanocytes in the epidermis, infundibulum, and external root sheath. The melanocytes present are swollen, have short, thick
processes, and appear overloaded with melanin. Arnold et al. [90] noted the
microscopic changes within the first several days are too limited to explain so
rapid and intense a depigmentation; a mechanism other than, or in addition
to, a transfer block must be involved.
Cutaneous hypopigmentation must be considered one of the possible sequelae of topical or intralesional steroid therapy, particularly in dark-skinned
patients. But considering the great frequency of usage of topical and intralesional corticosteroids, hypomelanosis is not commonly reported and must
therefore be an unusual complication. Discontinuation of the topical corticosteroid usually results in repigmentation.

BUTYROPHENONE
Butyrophenone
(4-(3-azaspiro/5 ,5/undec-3/yl)-4' -fluorobutyrophenone),
which has been used as an antipsychotic agent, may induce depigmentation
of hair. Simpson et al. [99] observed hair color changes in four of 10 patients
receiving large doses of butyrophenone (45 to 300 mg daily) for two or three
weeks. During treatment, these four Caucasoid patients developed a peculiar

501

eyelashes. eyebrows. beard. and pubic hair. None of the three black patients
or the two Puerto Ricans of this group was affected.
All these disturbances proved reversible once butyrophenone was discontinued. Although the exact mechanism of this depigmentation is unknown. it
seems likely that it is related to disturbances in keratinization. probably induced
by an interference of the drug with cholesterol metabolism. Decreased cholesterol blood levels were found in several of these patients during the treatment.

CHLOROQUINE DIPHOSPHATE
Amelanosis of hair following the administration of chloroquine was first
reported by Alving et al. [100] in 1958 (Fig. 197). This phenomenon occurred
in blond subjects taking 0.3 g daily. Another subject developed the same changes
on a weekly dose of 0.5 g; the decreased hair color reversed spontaneously
when the dosage was reduced. In three blond patients with lupus erythematosus
treated with 0.5 to 0.75 g of chloroquine diphosphate daily. decreased hair

FIGURE 197. Localized depigmentation of hair following the

administration of chloroquine 500
mg a day. This patient had light
brown hair. (From: Saunders TS
et al: Decrease in human hair color
and feather pigment of fowl following chloroquine diphosphate. JInvest Dermato133:87-90,
1959. Copyright, 1959, The Williams & Wilkins Co. Used with
permission.)

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HYPOMELANOSIS

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CHAPTER 5

color occurred from three to seven weeks after the treatment was instituted;
not only the scalp but also the eyebrows were involved in some patients. Lanugo
hair was unaffected. The hair returned to normal color about three weeks after
treatment was discontinued. Other similar cases have been reported [101-104].
Although chloroquine-induced hair depigmentation occurs mainly in patients with blond hair, Schoch [104] observed it in a brown-haired woman. He
later mentioned a young woman who was blond until age 20, when her hair
spontaneously darkened; while taking chloroquine, her hair again became blond.
Sharvill [105] also reported a brown-haired patient in whom the scalp hair and
the eyebrows turned white. Depigmentation of the hair of red-haired individuals has also been reported [106]. Saunders et al. [107] reported 10 cases of
dilution of reddish or blond hair color following chloroquine diphosphate
therapy. Similar alteration of hair color has been reported in patients ingesting
hydroxychloroquine sulfate [108].
Hypopigmentation of the skin as well as of the hair has been observed in
one patient [109] ingesting chloroquine.
The mechanism by which chloroquine diphosphate induces pigmentary
changes in the hair is unknown. Chloroquine has been found to have little or
no in vitro effect on mammalian tyrosinase. Although there was a significant
lengthening of the induction period for tyrosine oxidation, this could not account for the observed clinical effects [107]. Chloroquine feedings to flies or
to guinea pigs failed to produce any color changes. However, instillation of
chloroquine into the yolk sac [107] depigmented feathers of the Rhode Island
Red chick. No change in the pigmentation in the Black Minorca chick could
be induced by the same procedure [107]. The latter results suggest that chloroquine diphosphate induces a block in the synthesis of pheomelanins but not
in the eumelanin pathway. The exact site of the block in the metabolic pathway
is unknown.

ESERINE
Four cases of depigmentation of the eyelids due to use of eserine ophthalmic
ointment have been reported [110]. A possible potentiation of the effect of
acetylcholine may be responsible, but the mechanism of the depigmentation
is unknown.

EPINEPHRINE
Injection of epinephrine into pigmented rats caused a local alopecia areata
and subsequent regrowth of white hair [111]. Epinephrine must have an effect
on melanin production; in rats, when hair had been plucked prior to injection
of epinephrine, the regrown hairs were amelanotic [112].
It has also been suggested that an oxidation product of epinephrine is the
inhibitor of melanogenesis [111]. Since ischemia has been shown to induce
depigmentation in animals [113], it is possible that epinephrine-induced vasoconstriction destroys hair bulb melanocytes.

503
CHEMICAL
HYPOMELANOSIS

FIGURE 198. a. b: Leukomelanoderma on sun-exposed skin in a patient on tetracycline. (From:

Tanioku K, Ono K: Phototoxic and photoallergic problems in Japan, in Sunlight and Man: Normal
and Abnormal Photobiologic Responses. Edited by MA Pathak et al. Tokyo, Univ of Tokyo Press,
1974, pp 483-493. Copyright, 1974, University of Tokyo Press. Used with permission.)

PHOTOTOXIC DRUGS
In Japan, leukomelanoderma frequently occurs in patients treated with
chlorothiazide. The pigmentary abnormalities occur mainly on exposed skin.
As chlorothiazide is a well-known phototoxic and photoallergic agent, it is
possible that this leukomelanoderma is a phototoxic reaction and that the
pigmentary changes are postinflammatory.
Tetracycline, another phototoxic drug, has been reported to induce pigmentary changes (Fig. 198). Tanioku and Ono [114] reported a 36-year-old
female patient who, three days after tetracycline administration, developed a
phototoxic eruption which resolved in seven days. One month later, she developed leukomelanoderma on the face and dorsa of the hands and feet.

REFERENCES
1. Spencer GA: Pigmentogenesis and the Negro. J Natl Med Assoc 36:43-45, 1944
2. Spencer GA: Leukoderma produced by antioxidants. Arch Dermatol SyphiloI58:215-219, 1948
3. Klander JV, Kimmick JM: Occupational leukoderma with report of cases. Indust Med Surg
22:106-110, 1953
4. Frenk ME, Kocsis M: Depigmentation due to adhesive tape: ultrastructural comparison with
vitiligo and vitiliginous depigmentation associated with a melanoma. Dermatologica 148:276-284,
1974

504

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5. Lockhart H, Lowenthal LJ: Occupational leukoderma: a report of six cases observed in a South
African factory. S Afr Med J 23:867-868,1949
6. Fisher AA: Case presentation: Bronx Dermatological Society. Contact dermatitis due to rubber.
Arch Dermatol SyphiloI64:797, 1951
7. Fitzpatrick TB et al: Hydroquinone and psoralens in the therapy of hypermelanosis and vitiligo.
Arch Dermatol 93:589-600, 1966
8. Bernstein ET, Sachs PM: Pigmentary disturbance following exposure to monobenzylether of
hydroquinone. Arch Dermatol Syphilol 59:542-548, 1949
9. Becker SW Jr, Spencer MC: Evaluation of monobenzone. JAMA 180:279-284, 1962
10. Botvinick I: Dermatitis and secondary leukoderma due to fabric-lined gloves. Arch Dermatol
Syphilol 63:334-335, 1951
11. Fisher A: Contact Dermatitis, 2nd ed. Philadelphia, Lea & Febiger, 1973

PHENOLIC COMPOUNDS
12. Kahn G: Depigmentation caused by phenolic detergent germicides. Arch Dermatoll02:177-187,
1970
13. Riley PA: Pathological disturbances of pigmentation, in The Physiology and Pathophysiology
of the Skin. Edited by A Jarrett. London, Academic, 1974, vol 3, pp 1167-1197
14. Oliver EA et al: Occupational leukoderma: preliminary report. JAMA 113:927-928, 1939
15. McNally WD: A depigmentation of the skin. Indust Med 8:405--410, 1939
16. Zakon SJ, Goldberg AL: Occupational leukoderma from rubber dust and debris. Arch Dermatol
Syphilol 64:441--443, 1951
17. Peck SM, Sobotka H: Effect of monobenzyl hydroquinone on oxidase systems in vivo and in
vitro. J Invest Dermatol 4:325-329, 1941
18. Denton CH et al: Inhibition of melanin formation by chemical agents. JInvest DermatoI18:119-135,
1952
19. Fisher AA: Case presentation: Bronx Dermatological Society. Treatment of chloasma with
monobenzylether of hydroquinone. Arch Dermatol Syphilol 64:645-646, 1951
20. Forman L: A note on the depigmentary properties of monobenzylether of hydroquinone. Br J
Dermatol 65:406-409, 1953
21. Kelly EW: Pigmented skin lesions-treatment with monobenzylether of hydroquinone. JMich
Med Soc 55:303-304, 1956
22. Lerner AB, Fitzpatrick TB: Treatment of melanin hyperpigmentation. JAMA 152:577-582,1953
23. Canizares 0 et al: Leukomelanoderma: subsequent to the applications of monobenzylether of
hydroquinone. Arch Dermatol 77:220-223, 1958
24. Pollock JH: Hyperpigmentation improved by treatment with monobenzylether of hydroquinone. Arch Dermatol Syphilol 61:873-875, 1950
25. Brun R: Contribution a l'etude de la depigmentation experimentale. Bull Inst Natl Genevois
61:1-18, 1961
26. Frenk ME: Depigmentation par agents chimiques. Bull Soc Fr Dermatol Syphiligr 78:153-156,
1971
27. Snell RS: Monobenzylether of hydroquinone. Arch DermatoI90:63-70, 1964
28. Oettel H: Die Hydrochinonvergiftung. Arch Exp Pathol PharmacoI183:319-362, 1936
29. Martin GJ, Ansbacher S: Confirmatory evidence of the chromotrichial activity of p-aminobenzoic acid (letter). J BioI Chem 138:441,1941
30. Ahuja YR: Berufsschiidigung des Auges bei Arbeitern in Hydrochinon Betrieben. Klin Monatsbl
Augenheilkd 113:177, 1948
31. Anderson B: Corneal and conjunctival pigmentation among workers engaged in manufacture
of hydroquinone. Arch Ophthalmol 38:812-826, 1947
32. Jimbow K et al: Mechanism of depigmentation by hydroquinone. JInvest DermatoI62:441--449,
1974
33. Chumakov NN et al: Vitiliginoid dermatoses in workers of phenol-formaldehyde resin works.
Bull of Dermatol No.4, 3-8, State 1962. Publishing firm of Medical Literature, Moscow

34. Babanov GL, Chumakov NV: Etiology and pathogenesis of occupational "vitiligo." Vestn Dermotol Venero140:44, 1966. Quoted in Malten KE et al: Occupational vitiligo due to paratertiary
butylphenol and homologues. Trans St Johns Hosp 57:115-131, 1971
35. Okumura Y, Shirai T: Vitiliginous lesions occurring among workers in a phenyl derivative
factory (English summary). Jpn J Dermotol 72:618, 1962
36. Hara I, Okumura Y: Unpublished data, quoted in Malten KE et al: Occupational vitiligo due
to paratertiary butylphenol and homologues. Trans St Johns Hosp 57:115-131, 1971
37. Hara I, Nakajima T: Studies on the leucoderma caused by alkylphenols. Quoted in Malten KE
et al: Occupational vitiligo due to paratertiary butyl phenol and homologues. Trans St Johns
Hosp 57:115-131, 1971
38. Hara I, Uda K: Pathological studies of leucoderma caused by alkylphenols I: Subcutaneous
injection experiments (abstr in Japanese). Jpn J Indust Heolth 8:211, 1966
39. Rodermund OE, Wieland H: Vitiligo, Hepatosplenopathie und Struma nach Arbeit mit paratertiiirem Butylphenol. Dtsch Med Wochenschr 100:2216-2222, 1975
40. Goldmann PJ, Thiess AM: Berufsbedingte Vitiligo durch para-tertiar Butylphenol, eine Trias
von Vitiligo, Hepatose und Struma. Houtorzt 27:155-159, 1976
41. James 0 et al: Occupational vitiligo induced by p-tertiary butyl phenol. a systemic disease?
Lancet 2:1217-1219,1977
42. Gellin GA et al: Depigmentation from 4 tertiary butyl catechol-an experimental study. J Invest
Dermotol 55:190-197, 1970
43. Mansur JD et al: Effects of 4-tertiary butyl catechol on tissue cultured melanocytes. J Invest
Derm 70:275-279, 1978
44. Van de Staak WJBM: Quoted in Malten KE et al:; Occupational vitilito due to paratertiary
butyl phenol and homologues. Trans St Johns Hosp 57:115-131, 1971
44a. Malten KE et al: Occupational vitiligo due to paratertiary butylphenol and homologues. Trans
St Johns Hosp 57:115-131, 1971
45. Calnan CD: Occupationalleukodermas from alkyl phenols. Proc R Soc Med 66:258-260, 1973
46. Bleehen SS et al: Depigmentation of skin with 4-isopropylcatechol, mercaptoamines and other
compounds. J Invest Dermotol 50:103-117, 1968
47. Shelley WB: p-Cresol: cause of ink-induced hair depigmentation in mice. Br JDermatoI90:169-174,
1974
48. Vollum 01: Hypomelanosis from an antioxidant in polyethylene film. Arch DermotoI104:70-72,
1971
49. Iijima S, Watanabe K: Studies on dopa reaction. II. Effects of chemicals on the reaction. J Invest
Dermotol 28:1-4, 1957
50. McGuire J, Hinders J: Biochemical basis for depigmentation of skin by phenol germicides. J
Invest Dermotol 57:256-261, 1971
51. Lorincz AL: Studies on inhibition of melanin formation. J Invest DermotoI15:425-432, 1950
52. Riley PA: Hydroxyanisole depigmentation: in vivo studies. J Pothol 97:185-206, 1969
53. Riley PA: Hydroxyanisole depigmentation: in vitro studies. J Pathol 97:193-198, 1969
54. Riley PA: The mechanism of hydroxyanisole depigmentation. J PothoI101:163-169, 1970
55. Nakajima T, Hoh K: The effect of alkylphenols on the potato tyrosinase, in Proceedings of the
Osaka Prefect Institute of Public Health (Editions of Industrial Health), No 5, 17. Quoted in
Malten KE et al: Occupational vitiligo due to paratertiary butylphenol and homologues. Trans
St Johns Hosp 57:115-131, 1971
56. Dorsey CS: Dermatitic and pigmentary reactions to monobenzylether of hydroquinone. Arch
Dermatol 81:245-248, 1960
57. Ehrenfeld 10: Depigmentation due to phenolic detergent germicide treated with methoxsalen
and blacklite. Arch DermatoI104:216-217, 1971
58. Mosher DB et al: Monobenzylether of hydroquinone: a retrospective study of 18 severely
affected vitiligo patients and a review of the literature. Br J Dermatol 97:669-679, 1977
59. Ito M: Monobenzylether hydroquinone leukomelanoderma. Tohoku J Exp Med 65(suppl 5):
64-75, 1957
60. Saperstein DB: Hyperpigmentation of face: 1, Benoquin induced? 2, Dermatitis induced? Arch
Dermatol 79:123, 1959
61. Sidi E, Bourgeois-Spinasse J: Traitement par les derives hydroquinones. Presse Med 69:2369-2372,
1961

505

CHEMICAL
HYPOMELANOSIS

506

CHAPTER 5

62. Bentley-Phillips B, Bayles MAH: Acquired hypomelanosis: hyperpigmentation following reaction to hydroquinones. Br I Dermotol 90:232-233, 1974
63. Becker SW Jr: Hyperpigmentation: variations in type and therapy. I Indion Med Assoc 4:1837-1839,
1957
64. Combleet T et al: Acquired halo-nevus like formation from Benoquin. Arch DermotoI78:276-277,
1958
65. Arndt KA, Fitzpatrick TB: Topical use of hydroquinone as a de pigmenting agent. lAMA
194:965-967, 1965
66. Spencer MC: Hydroquinone bleaching. Arch Dermotol 84:131-134, 1961
67. Bentley-Phillips B, Bayles MAH: Cutaneous reactions to topical application of hydroquinone:
results of a 6-year investigation. S Afr Med 149:1391-1395, 1975
68. Kligman AM, Willis I: A new formula for depigmenting human skin. Arch Dermtool111:40-48,
1975

SULFHYDRYL COMPOUNDS
69. Chavin W, Schlesigner W: Some potent melanin depigmentary agents in the black goldfish.
Noturwissenschoften 53:413-420, 1966
70. Pathak MA et al: Cutaneous depigmentation. Clin Res 14:272-278, 1966
71. Frenk E et al: Experimental depigmentation: selective action of mercaptoethylamines on melanocytes in mammalian skin. Arch Dermotol 97:465-477, 1968
72. Hellerstein HK: Personal communication to AB Lerner and TB Fitzpatrick, in Biochemistry of
melanin formation. Physiol Rev 30:91-126, 1950
73. Lerner AB, Case JD: Pigment cell regulatory factors. I Invest Dermotol 32:211-221, 1959

CINNAMIC ALDEHYDE
73a. Mathias CGT et al: Perioral leukoderma simulating vitiligo from use of a toothpaste containing
cinnamic aldehyde. Arch Dermotol 116:1172-1173, 1980

HYDROGEN PEROXIDE
74. Wolfram LJ et al: The mechanism of hair bleaching. I Soc Cosm Chern 21:875-900, 1970
75. Mahrle G, Orfanos CE: Haarfarbe und Haarpigment. Elektronenmikroskopische Untersuchungen am natiirlichen und gebleichten Haarpigment. Arch Dermoto! Forsch 248:109-122, 1973

GUANONITROFURACIN
76. Yamada M: Studies on guanonitrofuracin leukoderma of eyelids, Part I. I Dermotol Venereol
65:187-202, 1955
77. Ito M: Guanonitrofuracin leukoderma, studies on melanin II. Tohoku I Exp Med 65(suppl
5):76-85, 1957

MEPHENESIN CARBAMATE
78. Spillane JD: Brunette to blonde: depigmentation of human hair during oral treatment with
mephenesin. Br Med J 1:997-1000, 1963

TRIPARANOL (MER-29)
79. Goodman OS et al: The metabolism of demosterol in human subjects during triparanol administration. J Clin Invest 41:962-971, 1962
80. Achor RWP et al: Cutaneous side effects from use of triparanol (MER-29). Preliminary data in
ichthyosis and loss of hair. Proc Mayo Clin 36:217-228, 1961
81. Winkelmann RK et al: Cutaneous syndromes produced as side effects of triparanol therapy.
Arch Dermatol 87:372-377, 1963
82. Minton LR, Bounds GW Jr: Ectodermal side effects of MER-29. Am J Ophthalmol55:787-791,
1963
83. Clayton RB et al: The skin sterols of normal and triparanol-treated rats. JLipid Res 4:166-176,
1963

DINITROCHLOROBENZENE (DNCB)
84. Holzegel K: Vitiligo als Dauerfolge von Epikutantestungen. Dtsch Gesundheitsw 28:133-136,
1973
85. Grosshans E et al: Criteres du diagnostic clinique du vitiligo. Bull Soc Fr Dermato! Syphiligr
81:519-526, 1974

ARSENIC
86. Cannon AB, Karelitz MB: Vitiligo from arsphenamine dermatitis and from arsenic of unknown
origin. Arch Dermato! Syphilo! 28:642-681, 1933
87. Jeghers H: Pigmentation of the skin. N Eng! J Med 231:122-136, 1944

NITROGEN MUSTARD AND THIOTEPA

88. Boyland E, Sargent S: The local graying of hair in mice treated with x-rays and radiometric
drugs. Br J Cancer 5:433-440, 1951
88a. Harben OJ et al: Thiotepa induced leukoderma. Arch Dermatol105:973-974, 1979

CORTICOSTEROIDS
89. Kestel JL Jr: Hypopigmentation following the use of Cordran tape. Arch Dermato!103:460-461,
1971
90. Arnold J et al: Depigmenting action of corticosteroids. Dermatologica 151:274-280, 1975
91. Di Stefano V, Nixon JE: Steroid-induced skin changes following local injection. Clin Orthop
82:254-256, 1972
92. Morris WJ: Undesirable side effects following intralesional corticosteroid therapy. Calif Med
116(1):55, 1972
93. Bloomfield E: Depigmentation from corticosteroid (letter). Br Med J 3:766, 1972
94. Glick EN: Depigmentation from corticosteroid (letter). Br Med J 4:300, 1972
95. Cahn BJ, Drowns BV: Leukoderma acquisition: secondary to intralesional steroid injection.
Cutis 9:509-512, 1972
96. Dupre A, Fournie A: Leucodermies secondaires 11. des injections de corticoides. Bull Soc Fr
Dermatol Syphiligr 80:616-618, 1973

507
CHEMICAL
HYPOMELANOSIS

508

CHAPTER 5

97. Rimbaud P et al: Complications dermatologiques locales second aires aux injections cortisonees.
Nouv Presse Med 3:665-668, 1974
98. Bioulac P, Beylot C: Hypopigmentation localisee apres injection d'un corticoide intraarticulaire. Presented at XV'eme Congres de l'Association des Dermatologistes et Syphiligraphes de
Langue Fran"aise. Ajaccio, 1976

BUTYROPHENONE
99. Simpson GM et al: Cutaneous effects of a new butyrophenone drug. Clin Pharmacol Ther
5:310-321, 1964

CHLOROQUINE DIPHOSPHATE
100. Alving AS et al: Studies on the chronic toxicity of chloroquine. J Clin Invest 27:60-64, 1958
101. Fuld H: Chloroquine and bleaching of hair (letter). Br Med J 2:300, 1956
102. Payne RS: Personal communication to the authors, in Saunders TS et al: Decrease in human
hair color and feather pigment of fowl following chloroquine diphosphate. J Invest Dermatol
33:87-90, 1959
103. Schoch AB: Bull Assoc Milit Dermatol 4:16, 1955. Quoted in Saunders TS et al: Decrease in
human hair color and feather pigment of fowl following chloroquine diphosphate. J Invest
Dermatol 33:87-90, 1959
104. Schoch AG: Personal communication to the authors, in Saunders TS et al: Decrease in human
hair color and feather pigment of fowl following chloroquine diphosphate. J Invest Dermatol
33:87-90, 1959
105. Sharvill DF: Bleaching of hair by chloroquin. Br Med J 1:1035, 1950
106. Tye MJ et al: Chronic discoid lupus erythematosus. Treatment with Daraprim and chloroquine
diphosphate (Aralen). N Engl J Med 251:52-55, 1954
107. Saunders TS et al: Decrease in human hair color and feather pigment of fowl following
chloroquine diphosphate. J Invest Dermatol 33:87-90, 1959
108. Scherbel AL et al: Further observations on the use of 4-aminoquinoline compounds in patients
with rheumatoid arthritis or related diseases. Cleve Clin Q 25:95-111,1958
109. Marriott P, Borrie PF: Pigmentary changes following chloroquine. Proc R Soc Med 68:535-536,
1975

ESERINE
110. Jacklin HN: Depigmentation of the eyelids in eserine allergy. Am J Ophthalmol 59:89-92,
1965

EPINEPHRINE
111. Munam LP: Depigmentation of hair by oxidized adrenaline solutions (letter). Lancet 1:600,
1953
112. Selye H: Ischemic depigmentation. Experientia 23:524, 1967
113. Shelley WB, Ohman S: Epinephrine induction of white hair in AcI rats. J Invest Dermatol
53:155-158, 1969

PHOTOTOXIC DRUGS
114. Tanioku K, Ono K: Phototoxic and photoallergic problems in Japan, Sunlight and Man:
Normal and Abnormal Photobiologic Responses. Edited by MA Pathak et al. Tokyo, University
of Tokyo Press, 1974, pp 483-493

6
Hypomelanosis Associated with
Inflammation

Hypomelanosis resulting from a wide variety of inflammatory dermatoses (Fig.

199) is a common problem in dark-skinned people [1] but may occur in many
skin types. The most frequent causes of postinflammatory hypopigmentation
include discoid lupus erythematosus, atopic dermatitis, eczematous dermatitis,
chronic guttate parapsoriasis, lichen striatus, and probably pityriasis alba. The
primary defect may be a pathologic change in the malpighian cells or increased
keratinocyte turnover. A disturbance of transfer of melanosomes from melanocytes to keratinocytes is probably responsible for the pigmentary dilution.
Sarrat and Nouhouayi [2] observed that the characteristic pigment cell
response to inflammatory skin conditions includes both melanocyte hyperplasia and hypertrophy. They also concluded that increased melanocyte density
and activity as reflected by the dopa reaction may be unrelated to the clinical
pigmentary intensity, but a positive dopa reaction does not reveal the true
activity of a melanocyte. Dopa-positive melanocytes may have no melanosomes,
only tyrosinase on the smooth and rough endoplasmic reticulum.
ECZEMATOUS DERMATITIS AND ATOPIC DERMATITIS

Pinkus et a1. [3] observed, in eczematous black skin, prominent melanocyte

dendrites and edematous malpighian cells with very few or no melanin particles. Edematous keratinocytes in an environment of abundant dendrites were
apparently unable to accept or ingest melanosomes (Fig. 200).

LUPUS ERYTHEMATOSUS
Hypopigmentation with or without marked cutaneous atrophy is frequently
observed in sites of resolving discoid lupus erythematosus (Fig. 201). Depigmentation can also be observed in systemic lupus erythematosus; Tuffanelli
and Dubois [4] found localized depigmentation in 4.8% of 520 patients with

509

510
CHAPTER 6

FIGURE 199. Postinflammatory hypo pigmentation.

spongiosis
and edema

~J

decreased secretion
of melanosomes
re lated to structural
alterations in
kerat inocytes

FIGURE 200.

Mechani m of hypomelanosis in eczema,

511

HYPOMELANOSIS
ASSOCIATED
WITH
INFLAMMATION

FIGURE 201. a, b: Hypopigmented macules in two patients with discoid lupus erythematosus.
Lesions are atrophic.

512
CHAPTER 6

systemic lupus erythematosus. The depigmentation was most commonly postinflammatory. The mechanism is unknown but may be a transfer block.
ACHROMIC GUTTATE PARAPSORIASIS
Achromic guttate parapsoriasis, first described by Lortat-Jacob and Fernet
[5], is not uncommon. The lesions are small, white, round macules 1 ern in
diameter, scattered on the neck, trunk, and limbs (Fig. 202). Sometimes they

are associated with typical lesions of parapsoriasis (reddish brown, slightly

infiltrated papules). There may be a slight scaling but no atrophy. Itching is

FIGURE 202. a, b: Small hypo pigmented

macules in a patient with pityriasis lichenoides chronica.

almost invariably absent. This is a chronic disease that lasts from several months
to five to 10 years with occasional remissions of variable duration.
Since the hypo pigmentation occurs only in sites involved with or previously involved with typical papules of guttate parapsoriasis, the depigmentation in achromic guttate parapsoriasis is likely postinflammatory.
In the presence of hypopigmentation and typical lesions diagnosis is easy.
When hypopigmentation is the only cutaneous finding, history of the disease
is helpful but leukoderma of secondary syphilis, achromic tinea versicolor, and
other postinflammatory hypomelanoses must be excluded.
No effective treatment is available.

PSORIASIS
Three types of hypo pigmentation have been seen with psoriasis. These
include postinflammatory hypomelanosis, vitiligo, and Woronoff's ring.
Postinflammatory hypopigmentation, which is the most common, appears
after the disappearance of the typical psoriatic plaque (Fig. 203). Increased
keratinocyte turnover may interfere with the transfer of melanosomes from
melanocytes to keratinocytes (Fig. 204). More recent views of the role of cyclic
AMP, both in epidermal turnover and in melanogenesis, may give further in-

FIGURE 203. Postinflammatory hypomelanosis in a patient with psoriasis. Woronoff's ring may
be seen on the left arm.

513
HYPOMELANOSIS
ASSOCIATED
WITH
INFLAMMATION

514

CHAPTER 6
CONVEYOR BELT -

- - - ff.

(proliferating epidermal cells)

abnormal
melanosome transfer

..
,
'
.-.-.
.-

FACTORY

(melanocyte)

increased speed
of conveyor belt
(increased turnover
of kerat inocytes)

FIGURE 204. Diagrammatic representation of mechanism of hypomelanosis

in association with psoriasis.

sight into this problem. It is also possible that the depigmentation may, at least
in part, result from topical steroid therapy.
Vitiligo has been reported in patients with psoriasis. Both are, of course,
common problems, but in some patients the vitiligo and the psoriasis involve
the same skin surfaces; or different areas may be involved . This problem has
been discussed (see "Vitiligo" in Chapter 1).
In 1926, Woronoff [6] described hypomelanotic halos surrounding indi-

FIGURE 205. Appearance of psoriatic lesions and hypo pigmented halos (arrow points to most
prominent one) prior to treatment. (From: Koplon BS et al: The Woronoff ring of psoriasis: study
of a patient. Int J Dermato1 10:235-238, 1971. Copyright, 1971, J. B. Lippincott Co. Used with
permission.)

515
HYPOMELANOSIS
ASSOCIATED
WITH
INFLAMMATION

FIGURE 206. In black children.

the contrast between the depigmen ted skin and the normal surrounding skin is often striking and
the transition zone is feathered.

vidual ultraviolet radiation-treated psoriatic lesions (Figs. 205, 206). Penneys

et a1. [7] observed that these white rings have an approximately uniform width
around the psoriatic plaques. regardless of the size and shape of the psoriatic
plaque; furthermore, the white area did not develop erythema during ultraviolet
radiation and coal tar therapy. It is uncertain whether this phenomenon represents blanching (vasoconstriction) or decreased melanin pigmentation. Although some experimental work suggested that, in fact. Woronoff's ring is not
a true hypomelanosis but rather a vascular abnormality [8,8a], Koplon et a1. [9]
found normal blood vessels beneath the halo, normal vascular reactivity to
histamine phosphate and methacholine chloride, and decreased melanin content in both psoriatic and halo epidermis. Thus Woronoff's ring appeared to
be a true hypomelanosis. However, the prostaglandin E2 level in the hypopigmented ring is one-third that of the involved skin from either psoriatics or
normal controls. Extracts from psoriatic tissue inhibit the dioxygenase that
catalyzes the first step in the pathway of prostaglandin synthesis, and an in-

516
CHAPTER 6

hibitor of prostaglandin synthesis has been found during ultraviolet radiation

therapy on the normal-appearing skin surrounding psoriatic plaques. Vessels
in the hypopigmented ring show a normal reactivity after injection of PGE 2 [7].
This suggested that the white ring that surrounds ultraviolet-treated psoriatic
plaques results from a local inability to synthetize PGE 2 in response to ultraviolet radiation; this results from the presence of an inhibitor of prostaglandin
synthesis and is manifest as reduced erythema because of less vasodilatation.
Warin and Greaves [9a] concluded that another mechanism must be operative because the Woronoff ring has been found around both PUVA- and
UVB-induced erythema even though the former is not associated with prostaglandin metabolism. These investigators suggested superficial edema may
explain the apparent hypopigmentation.

PITYRIASIS ALBA
Pityriasis alba is a common entity consisting of slightly scaling, round to
oval, often poorly circumscribed macules of mild to moderate (1 to 2 + hypopigmentation).

History
The initial cases of pityriasis alba described by Fox [10,11] involved partial
depigmentation of the face of several black children [10-12]. In 1924, PardoCostello and Dominguez [13] described a similar but more extensive dermatosis,
"achromia parasitaria," from which Aspergillus was isolated in six of 36 cases.
The various names that have been used to describe the disease include pityriasis
streptogenes, pityriasis corporis, pityriasis simplex facei, erythema streptogenes [14], pityriasis impetigo furfuracia, chronic impetigo, pityriasis sicca
facei, pityriasis alba facei, and achromatous pityriasis facei. The name "pityriasis alba" suggested by O'Farrell [15] was thought by Wells et al. [16] to be most
suitable, for the name is morphologically appropriate and etiologically noncommittal.

Clinical Features (Table 115)

Incidence
Pityriasis alba probably is a very common condition. Bassaly et al. [17]
found that 40% of the children in an Egyptian school health clinic had facial
lesions typical of pityriasis alba. Wise [18] suggested that if all black children
in New York City were adequately examined, most would be found to have
this type of lesion.

TABLE 115. Clinical Features of Hypomelanosis in Pityriasis Alba

Incidence

Common

Sex

Female = male

Age of onset

Infancy and adolescence; adults may be affected

Elementary lesion
Color
Shape
Size
Borders
Local symptomatology

Pale pink and scaly

Variable (round, oval, or irregular)
5 to 30 mm; larger lesions may occur
Ill-defined
None

Distribution

Most commonly face; less commonly neck,

trunk, back, limbs, scrotum

Course

Usually, but not always, spontaneous remission

at puberty

Race
Pityriasis alba occurs in all races. Although it may involve whites [18,19],
it is considered more frequent in blacks [16]. However, as the disease is primarily of cosmetic importance, and as a depigmenting process is more visible
in dark-skinned people, this increased incidence among blacks may be more
apparent than real. That all 67 cases collected at the Mayo Clinic over 10 years
were Caucasoid is hardly surprising because the Mayo Clinic population at
large is 99% white.
The disease is found worldwide; series are reported from North America
[16], South America [13], Europe [20], and Africa [17].
Sex
Both sexes are probably equally affected. Of 67 cases, 37 were females and
30 males [16]. A marked male prevalence of up to 78% has been reported [17,21].
Age
Pityriasis alba is a disease of childhood and adolescence. Among 200 patients with pityriasis alba [17], 90% were between six and 12 years and about
10% between 13 and 16 years of age. Wells et al. [16] noted a predominance
of the condition among children in the prepuberal age group. However, adults
may also be affected [16]; onset at 39 and 41 years of age has been reported.
Precipitating Factors
Various seasonal and climatic factors have been reported to influence pityriasis alba. O'Farrell [15] observed that pityriasis alba becomes more apparent

517
HYPOMELANOSIS
ASSOCIATED
WITH
INFLAMMATION

518

CHAPTER 6

FIGURE 207.

a, b: Typical lesion of pityriasis alba. The surface of the macules has a filmy, scaly,
or whitish, dry, powdery appearance, sometimes with slightly raised borders.

in summer and tends to fade in winter; he proposed seasonal variation and

solar exposure as major etiologic factors. Bassaly et al. [17] in Egypt observed
in most of their cases that the lesions improved or disappeared in Mayor June
only to recur in the former sites in November and December, when the relative
humidity is highest, the temperature the lowest, and sunshine the least. However, Wells et al. [16] noted the effects of the sun exposure to be variable; in
some patients sun exposure made the lesions more apparent because the surrounding skin tanned, while in others the lesions became less apparent. They
concluded that excessive dryness of the skin, whether from winter wind or
summer sun, precipitated or aggravated the lesions.

Clinical Description
The primary lesion is a pale pink, round, oval, or irregular, scaling macule
with ill-defined borders (Figs. 207, 208). The lesions usually vary in size from
5 to 30 mm, but larger lesions may occur. Usually, there are only two or three
lesions; however, there may be from one to 20 lesions or more. The early lesions
are erythematous; after a few weeks the erythema fades and the cutaneous
surface assumes a whitish, dry, powdery appearance, sometimes with slightly
raised, pink or reddish borders. The scale is characteristically fine or powdery.
The face is the most frequent site of involvement. In 20 cases, the following
sites of facial predilection predominated: midforehead, 64%; malar ridge, 56%;
angles of the mouth, 37%; lateral periorbital area, 35%; paranasal area, 18%;
and lateral supraorbital area, 14%. Macules of pityriasis alba occur less commonly on other parts of the body, namely the neck, trunk, back, limbs, and
scrotum. In 200 cases [17], involvement of the legs was noted in four patients
and involvement of the extensor surfaces of the arms and forearms in two

FIGURE 208. a: A child with a few hypomelanotic macules on the face. The contrast between
the involved skin and the normal surrounding skin is subtle and the borders poorly defined. b:
Large hypomelanotic macules distributed on the arm of another patient.

519

HYPOMELANOSIS
ASSOCIATED
WITH
INFLAMMATION

520

CHAPTER 6

patients. In another series of 67 patients [16], generalized lesions occurred in

eight patients, five of whom were postpubescent. The dermatosis was asymptomatic in most of the cases, but some patients complained of itching and
burning.
With Wood's light examination more lesions may be apparent than with
room light alone. Wood's light examination also demonstrates that the lesions
of pityriasis alba are not totally amelanotic.
Once the erythema has disappeared, peripheral spread is unlikely and the
patch of hypo pigmentation remains stationary and unchanged for several years
[19]. Early repigmentation may occur. In most instances, the lesions clear spontaneously at puberty but the fact that typical lesions of pityriasis alba may
persist into adulthood at least suggests that spontaneous remission is not a
universal rule [15].

Histology
Histologic examination [15] shows a nonspecific dermatitis. There are varying degrees of hyperkeratosis and parakeratosis. Silver stain shows reduced
pigment in the basal layer of the epidermis. There is a moderate dilatation of
the vessels in the superficial dermis, a slight perivascular lymphocytic infiltrate,
and edema of the upper dermis. Appendages are normal. Split-dopa and electron microscopy studies have not been reported.

Pathogenesis
Although pityriasis alba has been said to arise from lack of cleanliness
[22], vitamin deficiencies [23], or unknown nutritional factors [24], the etiology

remains unknown. Pityriasis alba has also been considered a form of seborrhea,
eczema [25], or an abortive form of impetigo. Search for microbial or fungal
agents has been unrewarding. Dobes and Jones [19] noted cultured J3-hemolytic
streptococcus from five of seven patients. On the other hand, Wells et al. [16]
found Staphylococcus aureus in only one case and nonpathogenic staphylococci in two cases. Bassaly et al. [17] consistently found negative bacterial
cultures in 68 cases.
Aspergillus has been reported to cause pityriasis alba [13], but Wells et al.
[16] and Bassaly et al. [17] found fungal studies consistently negative. Bassaly
et al. [17] did find several fungi (Aspergillus-Trichophyton spadix) in a small
number of their cases but considered this fortuitous contamination. No bacteria
or fungi can be implicated in the pathogenesis of pityriasis alba.
The pathogenesis of the primary lesion remains unknown. O'Farrell [15]
concluded that pityriasis alba is eczematous dermatosis of complex etiology.
Wells et al. [16] consider pityriasis alba to originate from a nonspecific erythema
with a mild dermal inflammatory infiltrate which somehow results in localized
hypopigmentation, possibly because of ultraviolet screening by the hyperkeratotic and parakeratotic epidermis. Bassaly et al. [17] observed that in Egypt
pityriasis alba seemed to disappear in Mayor June and then reappear in the

same areas in November or December, and they speculated that hot summer
sun stimulated seborrheic and sudoriparous activity and cleared pityriasis alba.

Diagnosis
In a young patient, the presence of hypomelanotic slightly scaling macules
with poorly defined margins suggests a diagnosis of pityriasis alba. Lesions are
usually larger than those of tinea versicolor, which can be excluded by a scraping for fungus. Trichrome vitiligo usually has discrete margins and is accompanied by typical amelanotic lesions elsewhere. Postinflammatory hypomelanosis must be excluded by history.
Treatment
No effective treatment is available. Topical hydrocortisone combined with
exposure to ultraviolet radiation may be effective. Emollients seem to be as
effective as anything else [16,17].

REFERENCES
J Invest Dermatol
45:465-474, 1965
Sarrat H, Nouhouayi Y: Les modifications du pigment melanique cutane rencontrees chez
l'Africain au caves de diverses dermatoses. Int J Dermatoll0:44-60, 1971
Pinkus H et al: The symbiosis of melanocytes and human epidermis under normal and abnormal
conditions, in Pigment Cell Biology. Edited by M Gordon. New York, Academy, 1959, pp
127-138
Tuffanelli DL, Dubois EL: Cutaneous manifestations of systemic lupus erythematosus. Arch
Dermatol 90:377-386, 1964
Lortat-Jacob L, Fernet P: Quoted by Degos R: Dermatologie, Dyschromies. Paris, Editions Medicales Flammarion, 1953, pp 126-127
Woronoff DL: Die peripheren Veriinderungen der Haut urn die Effloreszcizen Psoriasis vulgaris
und Syphilis corymbosa. Dermatol Wochenschr 82:249-257,1926
Penneys NS et al: Pathogenesis of Woronoff ring in psoriasis. Arch Dermatol 112:955-957,
1976
Bettman S: Kapillarmikroskopishe Untersuchungen bei Psoriasis. Derm Wschr 83:1223, 1926
Herrmann F, Kanof ND: The flourescein pattern of dermatoses. J Invest Derm 8:421-432, 1947
Koplon BS et al: The Woronoff ring of psoriasis: study of a patient. Int JDermatoll0:233-236,
1971
Warin AP, Greaves MW: Woronoff's rings with PUVA therapy. Arch Dermatol115:105, 1979
Fox H: Partial depigmentation of the face of a Negro. Arch Dermatol Syphiloll0:78-79, 1924
Fox H: Partial depigmentation of the face and arms. Arch Dermatol Syphilol12:753-754, 1925
Fox H: Partial depigmentation; chiefly on the face in Negro children. Arch Dermatol Syphilol
7:268-269, 1923
Pardo-Castello V, Dominquez M: Achromia parasitaria. Arch Dermatol Syphilo19:82-95, 1924
Weidman F: Quoted by Dobes WI, Jones J: Erythema streptogenes. Arch Dermatol Syphilol
53:107-114, 1946
O'Farrell MM: Pityriasis alba. Arch Dermatol 73:376-377, 1956
Wells B et al: Pityriasis alba: a ten year survey. Arch Dermatol 82:183-189, 1960
Bassaly M et al: Studies on pityriasis alba. Arch Dermatol 88:272-275, 1963

1. Papa CM, Kligman AM: The behavior of melanocytes in inflammation.

2.
3.
4.
5.
6.
7.
8.
8a.
9.
9a.
10.
11.
12.
13.
14.
15.
16.
17.

521
HYPOMELANOSIS
ASSOCIATED
WITH
INFLAMMATION

522

CHAPTER 6

18. Wise F: In discussion of Fox H: Partial depigmentation; chiefly on the face in Negro children.
Arch Dermatol Syphilol 7:268-269, 1923
19. Dobes WI, Jones J: Erythema streptogenes. Arch Dermatol Syphilol 53:107-114, 1946
20. Pautrier LM: Quoted in Brand A, Tas J: Pityriasis simplex faciei (dartre volante). Dermatologica
105:145-153, 1952
21. Gaul LE, Underwood GB: Relation of dew point and barometric pressure to chapping of normal
skin. J Invest Dermatol19:9-19, 1952
22. Brand A, Tas J: Pityriasis simplex faciei (dartre volante). Dermatologica 105:145-153, 1952
23. Bacarini I, Diniz 0: Dartre volante: an account of its etiology and treatment (abstr). Excerpta
Medica 5:414, 1951
24. Tas J: Pityriasis simplex (dartre volante). Dermatologica 108:202-208, 1954
25. Unna PG: Quoted by Tas J: Pityriasis simplex (dartre volante). Dermatologica 108:202-208,
1954

7
Infectious and Parasitic
Hypomelanosis
LEPROSY
Leprosy is a chronic and contagious human disease that mainly affects the
skin and the peripheral nervous system, but which may also involve the mucous
membranes of the upper respiratory tract, the eye, the superficial lymph nodes,
the testes, and other organs. Hypopigmentation is one of the main cutaneous
features of leprosy (Figs. 209, 210).

Clinical Features
Etiology and Epidemiology

Leprosy is caused by a gram-positive bacillus, Mycobacterium leprae, which

with carbo I-fuchsin staining resists discoloration with weak acids and alcohol.
The infection occurs only in humans. Lepromatous leprosy is considered to be
the principal source of contagion.
Geographic Distribution

The disease is widespread in tropical and subtropical countries and endemic in some temperate zones.
Race

No race is spared.
Sex

Lepromatous leprosy is usually twice as frequent in males as in females.

The tuberculoid type affects both sexes equally [1].

523

524

CHAPTER 7

FIGURE 209.

Hypomelanosis in a patient with leprosy.

FIGURE 210.

chella.)

a-c: Lepromatous macules in three patients with leprosy. (Courtesy of S. L. Mos-

525

INFECTIOUS AND
PARASITIC
HYPOMELANOSIS

FIGURE 210 (Continued)

526

Age

CHAPTER 7

In endemic areas, leprosy is usually contracted in childhood but exposure

in adult life may lead to infection.

Heredity
There may be a genetic predisposition in leprosy.

Classification
The current classification of leprosy is based on the degree of host resistance
[2].

Lepromatous leprosy is characterized bacteriologically by the presence of

abundant M. leprae in lesions, histologically by a characteristic infiltrate of
Virchow cells containing globi of bacilli, and immunologically by a negative
lepromin test which indicates lowered host resistance.
Tuberculoid leprosy is characterized histologically by tuberculoid or occasionally sarcoidal structures, bacteriologically by the rarity or absence of
bacilli, and immunologically by a positive lepromin test.
Indeterminate leprosy is characterized clinically by involvement of only
skin and nerves, bacteriologically by a few or no bacilli, histologically by a
nonspecific inflammatory reaction, and immunologically by a lepromin test
which may be positive or negative.
Tuberculoid and lepromatous leprosy are stable polarized types, whereas
indeterminate and borderline leprosy are unstable types.

Hypopigmentation in Leprosy (Table 116)

Clinical Features

Dating from antiquity, depigmented macules have been considered one of

the most important clinical signs of leprosy. In 1929, Henderson [3] described
five types of depigmented lesions in leprosy. The first or "perifollicular type"
was characterized by pinhead-like hypochromic macules associated with hyperkeratosis. The second and third types, flat uniformly depigmented macules,
were thought to represent further development of the first type. The fourth type
represented a transition stage between the true depigmented and the erythematous lesions, and the fifth or "mottled" type was characterized by perifollicular
repigmentation of the white macules. Later, other authors described and classified lepromatous hypopigmentation clinically and histologically according to
the old classification of leprosy. Cochrane [4], in 1964, applied the modern
classification of leprosy and it became apparent that hypopigmentation might
be observed in all the forms of the disease.

Many bacilli

Tuberculoid or
occasionally
sarcoidal
structure
None-a few during
reaction
Positive

Nonspecific
inflammatory
reaction

Absent or few

Positive or negative

Unstable-regress
or progress into
more definite
types

Histopathology

Bacilli

Lepromin test

Course of the
disease

Stable

None. or as in
tuberculoid
leprosy
Association of
tuberculoid and
lepromatous
structures

Dryness-slight
scaling or atrophy

Negative or weakly
positive
Unstable

Stable to
progressive

Negative

Lepromatous
infiltrate with
Virchow cell
(foamy
macrophages)
Abundant bacilli

None

None

Variable
Variable

None

None

Pronounced
anesthesia
Alopecia

Hypesthesia

Sensory
changes
Alteration of
hair
Other skin
changes

Asymmetricwidespread

Asymmetricexposed areas

Multiple

Macules

Lepromatous

Variable
Large
Ill-defined.
indistinct
Symmetricextremities.
buttocks. face.
sparing of
warmer regions
Slight anesthesia

Distribution

Variable
Small
Ill-defined

Variable
Small
Well-defined with
raised borders
Asymmetricextremities. back.
buttocks. face

Usually single or a
few
Variable
Small
Ill- or well-defined

Number

Shape
Size
Borders

Macules

Macules or infiltrated
plaques
Multiple

Borderline or
dimorphous

Macules or
infiltrated plaques
Single to few

Tuberculoid

Hypopigmented Lesions in Leprosy

Type

Indeterminate

TABLE 116.

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o
tEl
E!::'"tIQ
tEl:> ......

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.'"tI. :

en
N
"'I

528

Lepromatous Leprosy

CHAPTER 7

Hypopigmented macules may be the earliest expression of lepromatous

leprosy (Fig. 211). The lesions are usually small, multiple, and ill defined with
very vague, indistinct borders. They may be difficult to recognize, particularly
in light-skinned people. Although the lesions may cover the whole body, they
are usually observed symmetrically on the face, extremities, and buttocks and
usually spare the warmer parts of the body. They show little or no anhidrosis
or loss of sensation. Later, plaques, nodules, or diffuse infiltration of the skin
appear.
Tuberculoid Leprosy
Hypopigmented macules in tuberculoid leprosy are different from those
of the lepromatous type (Fig. 212). Involvement can be extensive and the macules have discrete edges and may be quite large, up to 30 cm in diameter.
Sometimes there is a central flat macule surrounded by raised borders or the
lesions may be uniformly infiltrated or present a characteristic pebbled appearance. The surface of the macules may be slightly scaly, dry, or faintly
atrophic. The lesions are asymmetrically distributed on the posterolateral aspects of the extremities, back, buttocks, and face. Hypopigmentation is associated with a loss of tactile and heat sensations. Alopecia and anhidrosis of
the macules is present.
Borderline (Dimorphous) Leprosy
Plaques or annular lesions are more common than hypopigmented macules.
The hypopigmented macules, if present, have very ill-defined borders (Figs.
213, 214, 215). A characteristic and common lesion has a "swiss cheese" appearance with the erythematous annular lesions and discrete hypopigmented
areas all bounded by vague outer borders.

FIGURE 211. Lepromatous leprosy with hypopigmented macules. (Courtesy of S. G. Browne.)

529
INFECTIOUS AND
PARASITIC
HYPOMELANOSIS

FIGURE 212. a: Moderate tuberculoid

leprosy with active margin. b: Minor tuberculoid leprosy. (Courtesy of S. G. Browne. )

Indeterminate Leprosy
In indeterminate leprosy, the macules are usually hypopigmented but may
also be erythematous. There is usually a single lesion, but there may be more.
The lesions are asymmetrically distributed, mostly on the exposed areas, but
also on the trunk, limbs, or buttocks. The borders, which are well- or ill-defined,
are flat and not infiltrated; the hair is normal. The macules may be hypesthetic
or anesthesic and the histamine test may show sympathetic dysfunction. These
lesions may regress spontaneously or may evolve into one of the more definite
types of leprosy.
Histology

Early histologic studies of the hypopigmented macules showed loss of

epidermal pigment to be the only significant histologic change. Henderson [3]
concluded erroneously that there is much more depigmentation in the recent

530

CHAPTER 7

FIGURE 213. Borderline leprosy. (Courtesy of S. G. Browne.)

than in the older macules. In the epidermis of tuberculoid or lepromatous

leprosy, Ishibashi [5] found an extreme irregularity in the distribution of epidermal pigment with a resultant mosaic in which some epidermal cells possess
abundant pigment while adjacent cells have little or no pigment and tend to
lose pigment with the progression of the dermal granuloma. No inflammatory
epidermal changes were described in lepromatous leprosy and there was no
correlation between the degree of hypomelanosis and the presence or absence
of M. leprae . In tuberculoid leprosy the epidermal depigmentation was related
to the intensity of liquefaction degeneration of the basal layer.
Breathnach et al. [6] reported a slightly decreased dopa reaction. Nayer
and Job [7] studied split-dopa preparations from 20 patients with macules of
hypopigmentation secondary to tuberculoid, indeterminate, and dimorphous
types of leprosy. Decreased melanocyte counts were present in 13, to a statistically significant degree in nine. Increased density of melanocytes was noted
in six, but in only three cases was the difference statistically significant. The
intensity of the dopa reaction was reduced in six cases, increased in five, and
unchanged from normal in nine patients. In 16, there was a slight increase and
in one a slight decrease. The length and branching of the dendrites was normal
in 14 cases, reduced in two, and increased in four. These authors concluded
that the majority of the lesions studied showed a reduction in melanogenic

531

INFECTIOUS AND
PARASITIC
HYPOMELANOSIS

FIGURE 214.

Macular dimorphous leprosy. (Courtesy of S. G.

Browne.)

FIGURE 215.

Resolving reactional with features of dimorphous leprosy. (Courtesy of S. G.

Browne.)

532

CHAPTER 7

activity but they were unable to identify the cause of this alteration in the
melanocyte.
Electron Microscopy Studies
Breathnach et al. [6] observed that melanocytes appeared ultrastructurally
normal in nine patients with leprosy. In two cases of hypopigmented lesions
of indeterminate leprosy studied by Job et al. [8] the number of melanocytes
was greatly reduced. Some of these cells showed vacuolization or atrophy,
fewer showed mitochondria and a dilated endoplasmic reticulum. In some
others, the number of melanosomes was decreased, the endoplasmic reticulum
was reduced, and the Golgi apparatus barely apparent. Retraction of the cytoplasm of some melanocytes from adjacent keratinocytes was observed and
the space thus provided was filled with a granular material. Folding and replication of the basement membrane were found in areas of contact with several
basal melanocytes. Job and Mathan [9] also noted that melanosomes were poorly
melanized. Various findings have been reported concerning Langerhans cells.
Breathnach et al. [6] found normal numbers. Richter [10] found that, in early
cases of leprosy, the number of Langerhans cells was greatly reduced and most
showed degenerative changes. Job et al. [8] reported an increased number of
Langerhans cells, which generally were of normal appearance, although some
were atrophic or also showed a retraction of the cytoplasm.
Pathogenesis of Hypomelanosis
The mechanism of hypopigmentation in leprosy is unknown.
Having observed no histologic or ultrastructural alterations in the melanocytes, Breathnach et al. [6] concluded that hypopigmentation in leprosy is
probably just a postinflammatory hypomelanosis. This does not explain the
histologic and electron microscopic findings reported by Job et al. [8].
Shira saki [11] concluded that the depigmentation of the epidermis could
be considered a direct sequela of the invasion of lepra bacilli at the melanocyte
level or the peripheral nerve. Shirasaki suggested that melanocytes and peripheral nerves, because of their common neuroectodermal origin, show a peculiar susceptibility to lepra bacilli.
Prabhakaran et al. [12-16] observed that M. leprae contains an enzyme
similar to the tyrosinase of melanocytes. Like plant phenolases and unlike
mammalian tyrosinases, this M. leprae enzyme was able to act on catechols
and dopa. With fairly purified concentrates of M. leprae from lepromatous
nodules, in vitro oxidation of dopa to indole-5,6-quinone was observed. The
investigators suggested that the lepra bacillus converts dopa to a quinone, so
that dopa is unavailable for melanin production. However, there is no correlation between the degree of hypomelanosis and the presence or absence of M.
leprae [17]. The palest areas of skin often have remarkably few bacilli present,
whereas lepromatous nodules with many bacilli frequently show no pigmentary
changes.

Seghal [18] suggested that, in leprosy, there is a reduction in the cutaneous

vascular supply which leads to atrophic changes in the melanocytes and hypomelanosis.

Associated Findings
Various features of leprosy may be associated with the cutaneous hypopigmentation.
In indeterminate leprosy, hypopigmented macules are the only cutaneous
finding. There is usually no associated nerve enlargement.
In lepromatous leprosy, hyperpigmented or erythematous macules may be
associated with the achromic ones and are usually the earliest manifestations
ofthe disease. As the disease progresses, plaques, nodules, or diffuse infiltration
appear. Hypopigmentation usually does not persist to this stage.
In tuberculoid leprosy, erythematous plaques may be associated with the
hypopigmented lesions. Enlarged superficial nerves are present, sometimes in
the vicinity of the lesions.
In borderline or dimorphous leprosy, erythematous macules, nodules, or
plaques, which are succulent with a smooth surface and a brownish or a violaceous hue, may be associated with the hypopigmented lesions.

Diagnosis
The diagnosis of leprosy is based on the history (endemic area or familial
exposure to leprosy), on the clinical appearance and the demonstration of
hypesthesia of a skin lesion, and by the presence of enlarged, hard, and tender
nerve trunks at the sites of predilection or near a hypopigmented area of the
skin.
M. leprae can be demonstrated in a skin smear or stained by the Ziehl-Nielsen
method. The diagnosis can be made by biopsy of a skin lesion which may show
typical granuloma or M. leprae on Ziehl-Nielsen stain. Enlarged lymph nodes
may contain M. leprae. In the presence of skin lesions, nerve biopsy is usually
not necessary. The histamine test or sweat test (pilocarpine) is helpful. The
lepromin skin test (Mitsuda) has no diagnostic value but is useful for classification.

Differential Diagnosis of Hypomelanosis in Leprosy

Hypochromic lesions in leprosy may be mistaken for vitiligo, nevus anemicus, pityriasis alba, tinea versicolor, morphea, postinfiammatory leukoderma,
pinta and other trepanematoses, onchocerciasis depigmentation, and post-kalaazar dermatosis. However, all of these lack hypesthesia.

533

INFECTIOUS AND
PARASITIC
HYPOMELANOSIS

534

Treatment

CHAPTER 7

Reversal of the hypomelanosis is not possible without treatment of the

disease. The drugs of choice are the sulfones (particularly diaminodiphenylsulfone, DDS) and rifamipicin. Other drugs (thioureas, B-663 [Geigy], Lamprene, long-acting sulfonamides, Isoniazide [INH] , and ethionamide) may be
used. Treatment usually results in repigmentation of the hypopigmented macules but residual depigmentation may remain.

YAWS
Yaws is a treponematosis caused by Treponema pertenue and found in
impoverished isolated areas, particularly in Central Africa, where warm humid
conditions prevail. The World Health Organization estimates that 50 million
people over the world are afflicted. Yaws is most common in childhood and
among men more than women.
The disease is acquired through direct contact with fomites or an infected
carrier, usually through an open wound; occasional transmission is attributed
to the Hippelates fly.

Clinical Description
The primary stage, called "protopianoma," "bubo madre," or "mamanpian"
develops at the site of inoculation. An asymptomatic, erythematous, infiltrated
plaque is formed; this ulcerates and may be covered by yellow exudate. The
lesion enlarges centrifugally or by satellites or forms a raised, rounded ulcer
or a raspberry-like vegetation. Fever, malaise, arthralgias, or adenopathy may
occur. After two to six months, the ulcers leave large atrophic and depressed
scars with hypochromic or achromic centers, sometimes surrounded by a dark
halo.
An uncommon presentation of the second stage involves lenticular or hypochromic macules considered to be an id reaction. These are called "babides,"
"framboesides," or "pianides." Headache, fever, bone and joint pain, and generalized adenopathy may occur.
Tertiary yaws features hyperpigmentation, shininess, and chronic thickening of the skin. Because the leukoderma usually follows tertiary yaws, treatment of the latter prevents development of leukoderma. Untreated, the hyperpigmentedskin develops macules of hypopigmentation (Fig. 216). These macules
enlarge until an entire area becomes depigmented. There are no other epidermal
changes.
Browne [19] found depigmentation to be uncommon among those with
yaws-affecting 686 of 45,035, none of whom were under nine and only six of
whom were between 10 and 19 years of age. Of those under 30 years of age,
0.11 % of males and 0.13% of females had leukoderma as opposed to 4.42% of
males and 9.63% of females over 50. Browne suggested the female prevalence

535

INFECTIOUS AND
PARASITIC
HYPOMELANOSIS

FIGURE 216. a, b: Patchy hypomelanosis following tertiary yaws and involving the hands. (Courtesy of S. G. Browne.)

may relate to the fact that the female who is less hairy than the male may have
embryologically different follicular melanocytes that are more susceptible to
treponemal toxins.
There is a characteristic pattern of involvement. Lesions are usually symmetrically placed. The most commonly affected areas are the anterior wrists
(40%), often having a triangular macule the apex of which points inferiorly;
dorsal hands (21 %); and metacarpophalangeal and interphalangeal joints (17%).
Involvement of the feet and legs is much less common (Fig. 217).
Mottled palmar dyschromia is often associated with typical frambesial
hyperkeratosis and contracture, especially of the fourth and fifth digits. Pigment
loss over the dorsal hand is usually patchy and irregular, although it may be
complete over small bony prominences. The olecranon process may be depigmented as may be the fibular head, either side of the tibial crest, anterior ankle,

536

CHAPTER 7

FIGURE 217. Depigmentation of the foot is not as

common as of the hands. (Courtesy of S. G. Browne.)

and occasionally large areas of the leg and thigh. Normally deeply pigmented
areas, such as female areolae, scrotum, and penis, may be affected if general
pigment loss is severe. There are only a few affected sites in anyone patient.
In 87 patients, 137 locations were found [19].
Two examples of generalized achromia of limbs have been reported to
follow widespread secondary yaws.

Histology and Laboratory Studies

The epidermis is normal except for flattening of the rete pegs and absence
of melanin in the basal layer. No spirochetes can be identified.
The serology (Wasserman) is positive in early hyperpigmented stages but
often negative in the later achromic stages.

Treatment
Penicillin is the treatment of choice. Treatment prior to the tertiary stage
prevents the development of leukoderma.

PINTA
Pinta, also called "mal del pinto," "carate," "cute," or "cativa," is a chronic,
non venereal treponematosis, caused by Treponema carateum and characterized by partial or complete loss of pigment.
The causative agent, T. carateum, is microscopically identical to the treponemas of syphilis and yaws. Penetration occurs usually through a minute
abrasion or wound.

Pinta is endemic in South America but also occurs in isolated areas of

Central America. The disease shows no sex or racial predilection and occurs
essentially in infancy, childhood, and adolescence.
The clinical course of the disease is divided into early and late pinta, but
these frequently overlap so that there is also an intermediate stage in which
early and late lesions occur simultaneously.

Cutaneous Depigmentation in Pinta

The primary lesion, at the site of inoculation, may be variably pigmented
so that hypochromic and achromic areas coexist. The healed lesions are usually
hypopigmented (Fig. 218). The primary lesions are usually located (listed in
decreasing frequency) on the lower limbs (legs, dorsa of the feet, ankles, knees,
and buttocks), face, neck, arms, chest, loins, and abdomen.
One month to one year [20] or more after inoculation, the secondary lesions
appear. These "pintides," which are initially erythematous, "copper colored,"

FIGURE 218.

Typical involvement of the wrists in late pinta.

537

INFECTIOUS AND
PARASITIC
HYPOMELANOSIS

538

CHAPTER 7

and, after some time, "slate blue," show gradations of depigmentation throughout, around the periphery, or in small areas. The presence of alternating macules
of erythema, pigmentation, and leukoderma may give the pintides a mottled
appearance (Fig. 219). Finally, they may become completely depigmented (Fig.
220). Pintides may occur at the same site as the primary lesion but extensive
dissemination may be observed. Although depigmentation occurs in most cases
six months to one year after the appearance of pintides, it may be seen within
two or three months. Leukoderma, or "white pinta," is characteristic of the late
stage of the disease. The occurrence of leukoderma in a patient with pinta
reflects the rate of regression of the lesions rather than the duration of the
disease [21]. Some patients may develop achromic lesions within a few months
(late pinta) while others may require many years to develop depigmented macules (intermediate stage).
The depigmented macules in late pinta may be localized or generalized
and vary in size, shape, and distribution. Near total cutaneous depigmentation
may occur. Depigmented macules are seen on the bony prominences such as
the knuckles, elbows, knees, and ankles. Involvement of the flexor wrist is
common [22,23]. Bilateral symmetry is the rule. The contours of the lesions
are irregular but well defined and are marked by peripheral brownish hyperpigmentation. The color may be white. Sometimes there is also an intermingling
of all varieties of dyschromia, hypochromia, and achromia. Usually, this variant
is extensive and found on the back and extremities. Sometimes, on the flexor
aspect of the upper extremities, especially the forearms, reticulated areas are
observed mixed with pinhead-sized depigmented macules and brownish hy-

FIGURE 219. Mottled pigmentation and depigmentation of the dorsa of the hands of a patient
with pinta. (From: Canizares 0 (Ed): Clinical Tropical Dermatology. London. Blackwell. 1975.
Plate 9. Copyright. 1975. Blackwell Scientific Publications . Used with permission.)

539
INFECTIOUS AND
PARASITIC
HYPOMELANOSIS

FIGURE 220. Late achromic lesions in pinta with peculiar bilateral and symmetric distribution.
(From: Marquez F: Pinta, in Clinical Tropical Dermatology. Edited by 0 Canizares. London, Blackwell, 1975, p 91. Copyright, 1975, Blackwell Scientific Publications. Used with permission.)

perpigmented or bluish puncta. Pea- or bean-sized hyperpigmented spots are

often randomly scattered in areas of depigmentation. Peripheral extension of
the depigmented lesions has been observed.
In many cases, the skin is otherwise normal. However, in long-standing
pinta, atrophic lesions with thinning, wrinkling, alopecia, and dryness of the
skin due to suppression of sweating and sebaceous secretion may be observed,
particularly on the dorsa of the hands, knees, thighs, and anterior legs (Fig.
221).

Focal pruritus or discomfort is minimal or absent.

Histology
In newly developed primary or secondary lesions, there is spongiosis,
migration of lymphocytes into an acanthotic and spongiotic epidermis, liquefaction degeneration of the basal layer, and loss of melanin. In the papillary

540
CHAPTER 7

FIGURE 221. a-c: Hypopigmentation is associated with thinning. wrinkling. alopecia. and dryness of the involved skin.

dermis there are numerous melanophores and a moderately dense infiltrate of

plasma cells, lymphocytes, and some histiocytes and neutrophils. In these early
stages, the pigmentary disturbance is minimal.
In old hypochromic or achromic lesions, there is a decrease or absence of
melanocytes and of melanin granules in the basal layer of the epidermis. The
epidermis is atrophic and there is no inflammatory infiltrate. There is an accumulation of melanophores in the hyperchromic areas.
Treponemas are demonstrable by silver impregnation in early and recent
lesions, but not in old lesions.

Mechanism
The hypomelanosis in pinta may be postinflammatory. In light of the fact
that hypopigmentation is associated with many treponematoses, it must also
be postulated that treponemas may have an inhibitory effect on melanocytes.

541

INFECTIOUS AND
PARASITIC
HYPOMELANOSIS

FIGURE 221

(Continued)

542

CHAPTER 7

Other Clinical Features

Other cutaneous features of pinta include atrophy and hyperkeratosis. Inguinal, epitrochlear, and cervical adenopathy may occur in late pinta. However,
the disease affects only the skin and there is no visceral, cardiovascular, or
central nervous system involvement.

Diagnosis and Differential Diagnosis

The diagnosis, which must be based upon epidemiologic and clinical features, may be confirmed by the isolation of T. carateum and from lymph obtained from any cutaneous lesion except an old achromic one.
Serologic reactions (Kahn-VDRL, Kline, Kolmer, Wasserman, Reiter immobilization test, immunofluorescence) become positive from two to three months
after the onset of the disease. No serologic reaction can distinguish pinta from
other treponematoses.
Clinically the lesions may mimic piebaldism and vitiligo. However, the
history is directive. Furthermore, the presence of T. carateum and a positive
serology distinguish pinta from other hypomelanoses.

Treatment
Either PAM or benzathine penicillin given intramuscularly is the treatment
of choice. Primary or secondary dyschromic lesions disappear after treatment
in four or six months without the occurrence of hypochromia. Rein et al. [21]
observed that penicillin therapy resulted in a complete repigmentation of leukoderma of short duration except for macules over bony prominences. In these
areas, there was only a spotty repigmentation or a reduction in the size of the
patches of leukoderma. In patients with long-standing achromic lesions, repigmentation is rarely observed.

ENDEMIC SYPHILIS
Bejel or endemic nonvenereal syphilis is a treponematosis said to affect
about a million people in the world, particularly in certain districts of Central
America, Ghana, Nigeria, the Middle East, Lower Mongolia, and Tibet. Bejel
affects poverty-striken regions where hygiene is poor. Bejel appears usually in
children over the age of two but may also be seen in adolescents and adults.
There is no racial predisposition and girls are more frequently affected than
boys.
The disease tends to be familial and is usually acquired by nonvenereal
childhood contact from infected children or from articles in daily use and is
transmitted subsequently to adolescents and adults. Most authors think that
the infective agent is Treponema pallidum.

Clinical Description
Hypomelanosis

Depigmentation occurs in the late stage of endemic syphilis. Csonka [24]

found pigmentary changes, consisting of depigmentation and pigmentary macules in 49 of 3507 patients with bejel. The depigmentation in this disease is
similar to that of pinta. The hypopigmented macules are usually bilaterally
symmetrical and have well-defined borders. The peripheral extremities, genitalia, shoulders, areolae, and the trunk are most commonly involved. Pigmented
macules may be randomly scattered throughout the hypopigmented ones. Csonka
[24] also noted that penicillin given early induced satisfactory repigmentation.

Other Features

Tuberous or nodular syphilide and gummas may occur in these patients.

Skeletal lesions (periostitis exostosis or eburnations) occur in the long bones.
Extensive destruction of the central face can lead to hideous mutilation. A few
cases of aortitis, aortic aneurysm, and meningovascular lesions have been reported [25].

Diagnosis
Epidemiology, other cutaneous features, skeletal lesions, and serologic tests
with treponemal antigens distinguish bejel from pinta, vitiligo, and piebaldism.

Treatment
Treatment is intramuscular penicillin.

LEUKODERMA IN SECONDARY SYPHILIS

First described by Hardy in 1854 [26], leukoderma syphiliticum is an occasional clinical finding of secondary syphilis.

Clinical Features
Leukoderma syphiliticum, found frequently on the lateral neck of women,
has been called the "necklace of Venus." It occurs about three months after
infection when roseola is fading, but may be seen sometime later within the

543

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544

CHAPTER 7

first year. Whereas in some patients this hypopigmentation is easily detected,

in most cases it is so subtle that a careful examination, often with a Wood's
light, is necessary.
The clinical picture is a leukomelanoderma. Small round or oval macules,
only slightly hypopigmented, I to 2 cm in diameter, well-defined, not confluent,
are randomly scattered on a darker grayish or brownish background. The lesions
are usually bilateral and nearly symmetrical. The hyperpigmentation is ill delineated. The combination of the hypopigmented macules and of the slightly
hyperpigmented background presents a reticulated pattern. There is no scaling
or itching. Most lesions are on the side of the neck, sometimes with extension
to the shoulder, upper trunk, and axillae. Involvement of the abdomen, inguinal
region, and proximal part of the limbs may occur.
Leukoderma syphilitic urn regresses with treatment and usually disappears
totally within several months, but up to a year may be required for full resolution.
Since this type of leukoderma is always preceded by an erythematous
macular syphilide [27,28], it is considered to be postinflammatory; but since
varying degrees of hypo pigmentation are associated with the various treponematoses, one may raise the question of a more specific link between the
treponemas and pigmentary disturbances.

Diagnosis and Differential Diagnosis

Diagnosis is generally easily established. Degos [26] considered the lesion
to be pathognomonic and characteristic of syphilis. In association with the skin
hypopigmentation, the other clinical features of secondary syphilis (papular
ham-colored lesions of the palms and soles, "moth-eaten" alopecia, erosion of
the mouth and the tongue, moist, wartlike lesions in the anogenital region,
regional or generalized adenopathy) make the diagnosis inescapable. Furthermore, at this stage of the disease, the serology is always positive.
Achromic tinea versicolor or postinflammatory hypopigmentation may be
considered in the differential diagnosis. History of a primary chancre, other
cutaneous findings, and a positive serology establish the diagnosis.

Treatment
Resolution follows treatment with intramuscular penicillin.

HERPES ZOSTER

A tuft of white hair can mark the site of herpes zoster of the scalp. McCarthy

[29] shows a picture of localized graying of the hair that followed herpes zoster

of the supraorbital nerve.

TINEA VERSICOLOR
Tinea versicolor, a disease which may cause marked hypopigmentation of
the skin, is a chronic, mild, usually asymptomatic infection of the stratum
corneum and is caused by a lipophyllic yeast, Pityrosporum orbiculare, formerly known as Malassezia furfur.

History
Tinea versicolor was first described in 1846 by Eickstedt [30] and in 1847
by Shuyter [31]. Hypopigmentation in tinea versicolor was first described by
Ehrmann [32] in 1908. Later, in 1929, Gougerot et al. [33] found the achromia
of tinea versicolor to be particularly frequent after sunlight exposure. About
this time, many reports of such cases accumulated in the European and American literature [34-38]. That the hypochromia reflected true hypopigmentation
and not a pseudoachromia or contrast phenomenon was clearly established by
Gougerot et al. [39-41] and by Wise and Sulzberger [42], who observed that in
North African or in black patients the involved skin became much lighter and
contained less pigment than the normal surrounding skin.
Several hypotheses were proposed to explain the hypopigmentation.
Wertheim [43], in 1923, studied the role of ultraviolet radiation. In 1927, Kistiakovsky [44] and, in 1936, Lewis and Hopper [45] suggested that hypopigmentation results from obstruction of ultraviolet radiation by the fungus so that
delayed tanning does not occur. On the other hand, in 1933 Ruete [46] suggested
that the depigmentation in tinea versicolor results from some direct interaction
between the fungus and melanocytes.

Clinical Features (Table 117)

Tinea versicolor is a very common disease, particularly in tropical and
temperate climates. It is found in all races and in all parts of the world. The
disease presents from childhood to old age but is most commonly seen in young
adults.
That P. orbiculare has been shown to be a common endogenous saprophyte
of the normal skin suggests that other factors must playa role in the overgrowth
of this organism. Genetic predispositon and increased endogenously produced
or exogenously administered corticosteriods [47,48] have been reported as precipitating factors. There may also be an increased incidence among those frequenting swimming pools or the seashore. Tinea versicolor may also be contagious; numerous conjugal cases have been observed.

Hypopigmentation in Tinea Versicolor

The primary lesion is a round or oval hypopigmented macule from several
millimeters to 1 to 3 em or more in diameter. These macules are tan to dull

545

INFECTIOUS AND
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546

CHAPTER 7

TABLE 117. Clinical Features of Hypomelanosis in Tinea

Versicolor
Incidence

Frequent

Sex

FIM

Age of onset

Usually young adulthood

Clinical description
Configuration
Color
Size
Border
Surface
Distribution

Symptoms
Course
Associated cutaneous
findings

1:1

Macules usually round or oval, often

confluent
Tan-white (hypopigmented); grayish
with Wood's light
Usually several millimeters to 1 to 2
cm
Irregular, sharp
Slightly scaly; may be raised
Upper trunk (front and back), proximal
portion of extremities; less
commonly, lower abdomen, gluteal
regions, penis, face, and neck
Usually none
Chronic
Sometimes pink to brown scaly
macules

white so that the involved skin appears moderately hypopigmented but not
totally depigmented (Figs. 222, 223). While the contrast between the hypopigmented infected skin and the surrounding normal skin is striking in darkskinned patients, in light-skinned people Wood's light examination may be
required to locate the lesions. The borders of macules are usually sharp to
slightly fuzzy. The scaling may not be very apparent on casual inspection but
may be obvious with a hand lens or when the involved skin is scratched with
a glass slide. Depigmentation without any scaling may remain for months after
spontaneous remission of the actual scaling lesions. Occasionally the lesions
appear slightly raised. Although the lesions are usually asymptomatic, some
patients complain of mild pruritus.
Most commonly, the hypopigmented macules are distributed randomly
over the upper anterior and posterior trunk (Fig. 224). However, involvement
of the proximal extremities, the lower abdomen, and the neck and face may
occur [49] (Fig. 225). Jelliffe and Jacobson [50] described white, depigmented,
scaly, circumscribed macules on the face and perineal and gluteal regions of
black infants with tinea versicolor. A blotchy, somewhat rounded island of
depigmentation, extending as a scattered archipelago onto the abdominal wall
anteriorly and onto the lower back posteriorly was observed in these patients.
Blumenthal [51] reported multiple hypopigmented scaly macules on the penis
in a 63-year-old black man. Palms and soles are never affected.
These macules, once established, do not change. In winter the macules

547

INFECTIOUS AND
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HYPOMELANOSIS

FIGURE 222. Characteristic lesions in achromic tinea versicolor. There are multiple punctate
scaly hypomelanotic macules.

seem to disappear on light-skinned individuals. Following sun exposure, the

macules are again more apparent (Fig. 226). The disease is chronic but 8e1limited.

Histology
El Gothamy et al. [52] used histochemical techniques to study melanin
formation in the involved skin of tinea versicolor. In seven patients, although
there was no hypo pigmentation clinically, there was decreased density of melanin granules in keratinocytes and a decreased dopa reaction. Split-dopa preparations of hypopigmented epidermis in another study [53] showed no change
in the density of dopa-positive melanocytes, but the melanocytes appeared
larger and more intensively stained than those of uninvolved areas (Fig. 227).

548

CHAPTER 7

FIGURE 223. a, b: Close-up view of hypomelanotic macules in tinea versicolor. The contrast
between the involved and the normal skin is not striking in fair-skinned patients.

549

INFECTIOUS AND
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HYPOMELANOSIS

FIGURE 224. a: Extensive involvement of the chest, one of the most commonly affected sites in
tinea versicolor. b: Close-up view of raised margin of affected and normal skin.

550

CHAPTER 7

FIGURE 225.

Tinea versicolor of the face in a black child.

FIGURE 226. The contrast between hypomelanotic macules of tinea versicolor and normal skin
increases after sun exposure.

551

INFECTIOUS AND
PARASITIC
HYPOMELANOSIS

FIGURE 227. Top: Involved skin: Keratinocytes showing paucity of melanosomes within the
cytoplasm. N = nuclei. (x 4500) Bottom: Involved skin: stratum spinulosum melanin aggregation
within dendrite of melanocyte. K = keratinocyte. (x 4500) (From: Charles CR et al: Hypopigmentation in tinea versicolor: a histochemical and electromicroscopic study. Int J Dermato112:43-53,
1973. Copyright, 1973, J. B. Lippincott Co. Used with permission.)

The keratinocyte turnover time did not differ significantly from that of normal
uninvolved skin.

Electron Microscopic Studies (Table 118)

In the involved epidermis, Charles et al. [53] noted decreased pigmentation.
Melanosomes were smaller than those in normal skin. The number of melanosomes in melanocytes in involved skin was markedly reduced. The dendrites

552
CHAPTER 7

TABLE 118. Cellular and Subcellular Characterization of Hypopigmented

Skin in Tinea Versicolor"
Melanocytes
Number
Dopa reaction
Dendrites

Normal
Normal or decreased
Marked "melanin loading" with melanosomes

Melanosomes in melanocytes
Number
Size
Shape
Inner structure
Melanization

Increased
Decreased
Normal (ellipsoidal) and abnormal (round)
Normal (lamellar) and abnormal (granular)
Decreased

Melanosomes in keratinocytes
Number
Distribution pattern
Degradation

Decreased
Variable: no melanosomes in some, complexes in
others
Possibly increased

Transfer of melanosomes to
keratinocytes

Decreased

Other abnormalities

Increased size of intercellular spaces; close

contact between lymphocytes and melanocytes

From: Charles CR et al: Hypopigmentation in tinea versicolor; a histochemical and electromicroscopic

study. Int J Dermatol 12:48-58, 1973, and Grupper CH et al: Pityriasis versicolor achromiant. Etude
ultrastructurale i\ propos de 3 cas. Bull Soc Fr Dermatol Syphiligr 82:114-117,1975.

of these cells also showed marked "melanin loading" compared to the dendrites
in normal skin. Melanosomes were irregularly distributed within keratinocytes.
While some of these cells, scattered in the basal and spinous layers, were
overloaded with melanosomes, others showed little or no melanin uptake.
Melanosome packaging was different from normal uninvolved skin; melanosomes were aggregated rather than dispersed. Dark collapsed cells were also
observed scattered throughout the stratum spinulosum. There was a suggestion
that "melanin loaded" cells observed in the basal and spinous layers became
the dark collapsed cells of the upper spinous layer and at the same time lost
their melanosome complexes. The extracellular glycogen granules described
by Keddie [54] were not found.
On the basis of their electron microscopic findings, Charles et al. [53]
suggested the following interpretation of the cellular and subcellular events
that result in hypopigmentation in tinea versicolor: production of abnormally
small melanosomes; partial block in melanosome transfer to keratinocytes; and
possible increased melanosome degradation in lysosomal complexes resulting
in degeneration of keratinocytes,
Similar electron microscopic findings of affected hypopigmented epidermis were observed by Grupper et al. [55] who also found decreased or absent
melanin synthesis, aggregation of mature melanosomes, and structural abnor-

malities of stage I melanosomes (small size, rounded shape, granular matrix).

There was a loss of contact between melanocytes and keratinocytes, with an
increased intercellular space which contained a granular material and mononuclear cells. Contact between melanocytes and inflammatory cells was observed and no melanosomes were found in those melanocytes close to the
inflammatory cells. Grupper et al. [55] also concluded that there was a disturbance in melanin synthesis, in melanosomes, and in melanosome transfer.

Pathogenesis of Hypopigmentation in Tinea Versicolor

That many patients first note their hypopigmented macules after sun exposure suggested ultraviolet reaction as an important etiologic factor. One of
the first hypotheses was that the hypopigmentation resulted from mechanical
screening of the sun's rays by the fungus. In 1927, Kistiakovsky [44] concluded
that the fungal spores contain a yellowish pigment which strongly refracts light.
The spores, and possibly the mycelium, act as an ultraviolet filter, so that the
skin affected by fungus does not tan. However, this fails to explain the occurrence of hypopigmentation on covered, unexposed areas [50,51]. In 1936, Lewis
and Hopper [45] also suggested a purely mechanical basis for the hypopigmentation. Histochemical and electron microscopic findings indicate, in fact,
that there is a disturbance in the melanogenesis. It is likely that in tinea versicolor, as well as in many other depigmented disorders, the ultraviolet radiation merely unveils an already present skin condition.
Beare et al. [56] suggested that a failure of the transfer of melanin granules
and increased keratinization result in hypopigmentation in tinea versicolor.
While electron microscopic findings seem to support such a transfer block, the
hypomelanosis cannot result from just disordered kinetics, as Charles et al.
[53] found no evidence of increased keratinocyte turnover in involved skin.
Wilson and Plunkett [57] considered the hypo pigmentation a result of
thinning of the stratum corneum and resultant loss of the melanin granules
contained within the affected areas. Neither does this help explain the apparent
transfer block evident on electron microscopy.
Ruete [46] suggested a direct interaction between the fungus and melanocytes, and in the light of electron microscopic findings, this seems a reasonable postulate. Hildick-Smith et al. [58] observed tinea versicolor hypopigmentation to occur in the absence of a history of sun exposure and suggested
that the fungus itself may alter the normal mechanism of pigmentation of the
skin. El Gothamy et al. [52], quoting the work of Ito and Tanaka [59], suggested
that the fungus may interfere with the metabolism of tyrosine.
Grupper et al. [55] observed close contact between lymphocytes and melanocytes without melanosomes and suggested that hypopigmentation in tinea
versicolor may involve cellular immunity (Fig. 228). They suggested the following three possibilities: the fungus may secrete a factor toxic to melanocytes
and induce modifications in their antigenicity; some factor of the fungus may
absorb specifically at the surface of melanocytes to change their antigenicity;
or the fungus may have a cross-antigenicity with melanocytes. The mechanism
has been clarified by Porro and Passi [60] who have isolated azelaic acid lib-

553

INFECTIOUS AND
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554

CHAPTER 7

erated by M. furfur and now established as a depigmenting agent. M. furfur

appears to elaborate an enzyme that catalyzes production of a C9 dicarboxylic
acid from C14 to C18 fatty acids; it is the dicarboxylic acid that seems to be the
depigmenting agent in tinea versicolor.

Other Cutaneous Features

Usually hypopigmented macules are the only cutaneous finding. However,
it is also possible to find other cutaneous lesions of tinea versicolor in a patient
with typical hypopigmented tinea versicolor. These macules have the same
morphologic characteristics as the hypopigmented lesions but are fawn to yellow-brown or dark brown in color. Wood's light examination shows a golden
yellow-chartreuse fluorescence, usually covering an area slightly larger than
that of the apparent lesions.

Diagnosis and Differential Diagnosis

In typical cases in which hypopigmented macules are associated with pink
to brown scaly lesions, a clinical diagnosis can be made with great assurance.

FIGURE 228. a, b: Electron microscopy shows decreased melanin synthesis with abnormal first
stage melanosomes (small, round, with granular matrix.) I = indeterminate cell; M = melanocyte;
mb = basement membrane. (From: Grupper C et al: Pityriasis versicolor achromiant. Etude ultrastructurale. Note preliminaire a propos de 3 cas. Bull Soc Fr Dermatol Syphiligr 82:114-117,1975.
Copyright, 1975, Masson & Cie, Paris. Used with permission.)

In whitish macules, Wood's light examination shows the skin to be only hypopigmented. In pink to brown macules, the golden-green fluorescence is characteristic. The diagnosis of tinea versicolor may be confirmed by histologic
examination of the scrapings of any of the lesions regardless of their color. The
hyphae seen in epidermal scales are 2.5 to 4 (.Lm in diameter, short, curved and
bent, rarely branching. They are associated in clusters with spherical cells
which have rather thick walls and may reach a diameter of 8 (.Lm. However,
the hyphae may be difficult to demonstrate in old lesions or in the patient who
has been using a fungicide.
Achromic tinea versicolor may be confused with vitiligo, postinflammatory
hypopigmentation, or chronic parapsoriasis. However, history, Wood's light,
and examination of the scales with potassium hydroxide readily differentiate
the hypopigmentation of tinea versicolor from that of other hypomelanoses.

Treatment
There is no one specific drug that will clear the lesions of tinea versicolor
and prevent recurrence of the infection. Sulfur, salicylic acid, or a combination
of both will clear the skin temporarily. Sodium hyposulfite 25% solution or
5% selenium sulfide lotion applied to the skin for five to 15 minutes once daily
for two to four weeks is satisfactory. Clotrimazole and miconazole are also said
to be effective.
To treat the hypomelanosis, EI Gathamy et al. [52] used meladinine (three
tablets, each composed of amoiden 0.01 g and amiden 0.005 g) in a single dose
two hours before exposure to ultraviolet radiation and after local application
of sodium thiosulfate. The incidence of hypo pigmentation was 54.5% in 33
patients treated with this combination, whereas it was 56% in 25 treated with
sodium thiosulfate and ultraviolet radiation alone and 66.7% in 21 patients
treated with sodium thiosulfate only. Hence, the addition of 8-methoxypsoralen to the treatment regimen produced minimal improvement in results.
The authors suggested that the small dose of 8-methoxypsoralen given to the
patients and the fact that the psoralen therapy was administered at the same
time as the specific treatment for the fungus may explain these poor results.
One of our patients treated with PUV A for six weeks failed to respond until
antifungal therapy was given. The role of psoralens is in accelerated tanning
once the fungal infection has been effectively treated. Successful melanogenesis
with natural sunlight alone or with psoralen therapy implies the tinea versicolor
has been adequately treated. Recurrences, however, are not at all unusual.

ONCHOCERCIASIS
Onchocerciasis or blinding filarial disease is caused by Onchocerca volvulus and transmitted to humans by black flies. It most typically affects the
skin, subcutaneous tissue, and the eye.
Onchocerciasis is endemic to sectors of Africa (Senegal to Ethiopia, Angola,
Tanzania), Yemen, the Sudan, and America (Guatemala, Dominican Republic,
Mexico, and Columbia).

555

INFECTIOUS AND
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556

Depigmentation

CHAPTER 7

Most typically the depigmentation is a late manifestation associated with

atrophy and wrinkling and is so speckled as to cause a leopard appearance
[61,62]. While the threat to the general health of the patient results from other
features of onchocerciasis, the economic and social impact of the leukoderma
may be dramatic.
Incidence
Browne [62] studied a population of the Sudan and found the general
incidence of onchocerciasis to be 31.41% in men, 21.19% in women, and 3.00%
in children (total population 7781) with 6.2%, 1.2%, and 0.2%, respectively,
of the cases having clinically apparent depigmentation.
The age of appearance of depigmentation best correlated with duration of
habitation in hyperendemic areas; 302 of the 317 cases with depigmentation
also occurred in hyperendemic foci occupied by fewer than half the population.
Male predominance was attributed to increased opportunity for exposure.
Clinical Picture
The most common site of depigmentation was the pretibial region, usually
the middle third of the lower leg (470 of 549 sites) and, in the majority (374
cases), involvement was bilateral (Fig. 229). The inguinal region was involved
in 22 cases, Scarpa's triangle in 24 cases, and the anterior superior iliac spine
in 25 cases, none bilaterally. The skin overlying the greater trochanter was
involved in three, over the iliac crest in one, and the paraaxillary pectoral
region in four (who were extensively involved-including back, buttocks and
thighs).
Depigmented scars of the lower extremities, the scrotum, and penis were
observed more commonly in those with onchocerciasis than in those without.
Hanging groin [62], often with overlying depigmentation, was common and
associated with advanced degree of pretibial achromia (Fig. 230). Depigmentation of Scarpa's triangle was associated with the presence of sclerosing and
hypertrophic inguinal lymph nodes and in severe cases to multiple long-standing nodules and retinal degeneration; 42% of those with ocular lesions ascribable to onchocerciasis had depigmentation.
Clinical Course
Depigmentation is first seen as one or more punctate or small, round,
yellow-brown islets typically located from the middle third of the tibia medial
to the tibial crest. This mottled area enlarges progressively and irregularly and
the macules coalesce until complete achromia is present. Then the process
usually begins on the contralateral tibia. Later the macules enlarge centrifugally
to involve the lateral surface of the lower leg.

557

INFECTIOUS AND
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HYPOMELANOSIS

FIGURE 229. a: Typical bilateral depigmentation of the anterior mid tibial region in a patient with
onchocerciasis. b: Symmetrical depigmentation of the chest. (Courtesy of S. G. Browne.

Finally, islets of normal pigmentation with discrete borders remain; should

repigmentation occur, these borders become indistinct. It is in this stage that
"hanging groin"-senile, atrophic, inelastic, inguinal skin draped over densely
fibrotic matted glands-occurs.
The following factors correlate with the presence of depigmentation: repeated bites, greater numbers (about five) of palpable onchocercomata, longer
duration of onychocercomata, and larger than average size of tumors.

FIGURE 230. Hanging groin with

overlaying depigmentation in a man
with onchocerciasis. (Courtesy of S.
G. Browne .)

558

Histology

CHAPTER 7

Early Lesions
Many microfilariae are found close to rete pegs, and nearby melanoblasts
of the germinal layer may be slightly disturbed. The moderate round cell dermal
infiltrate does not seem directly related to the microfilariae.
Late Stage
Rete ridges become flattened and micro filariae more numerous. Acanthosis
and hyperkeratosis may appear. Cells of rete pegs may be normal or have a
shrivelled appearance and pyknotic nuclei. Melanocytes may have disappeared, have abnormally shaped melanin granules, or normal granules abnormally distributed. Increased transport of melanin from the basal to the reticular
layer is apparent. The only identifiable melanin present may be at the tips of
the rete ridges.
Final Stage
This is marked by the absence of melanin, thinned epidermis, dermal
fibrosis with increased elastic tissue and collagen, near or complete absence of
microfilariae, total flattening of rete ridges, and a slight lymphohistiocytic infiltrate.
Mechanism

The mechanism of depigmentation remains unknown. There is no evidence

to suggest these patients are more than normally susceptible to other types of
depigmentation. Browne [62] notes that no fungi or spirochetes can be identified
in stained preparations. A direct effect of the black fly bite is unlikely as the
depigmentation commonly occurs in areas not predominantly bitten by the
black fly. Furthermore, the depigmentation may occur a long time after the
patient has been in the hyperendemic area. Browne [62] suggests a hypersensitivity phenomenon by which the adult filaria produces a circulating factor
which affects skin, nodes, and eye.

Other Clinical Features

After a year of incubation, transient, pruritic, edematous lesions or nodules
develop on the face or trunk and are accompanied by fever and arthralgias. An
erythematous reaction accompanies the bite. Pruritus is also seen at bite sites.
A rare erysipelas-like condition may occur on the face or elsewhere.
"Gale filarienne" or "craw-craw" or onchodermatitis is characterized by
marked pruritus, lichenification, excoriation, and sometimes secondary bac-

terial infection. This is most common over the trunk, hips, shoulders, and
extensor thighs and arms.
"Mal morado" are localized, nonpitting, violaceous, edematous, oval plaques
associated with massive dissemination from gravid females.
Cutaneous papillomas, regional lymphadenitis, scrotal nodules, hydrocele,
and elephantiasis may occur.
Nodules, which begin as subcutaneous infiltrations, may be movable or
adherent to deeper structures, even within muscle, and vary from several millimeters to 2 to 5 cm in diameter. These firm, painless lesions are found most
commonly on affected Africans, where the trunk is primarily involved, whereas
in Americans the lesions are usually scant in number and localized to the head.
Nodules, which may be calcified, have been reported on scrotal skin.
Microfilariae in the anterior chamber of the eye are diagnostic of onchocerciasis. Chamois iris, acute or chronic iritis, posterior synechiae with secondary glaucoma, punctate keratitis, and tigroid retina have been described.

Diagnosis
Patients from endemic areas with the ocular and cutaneous findings described should have slit-lamp examinations to identify micro filariae in the
anterior chamber of the eye. Mazzotti's test is positive in 92% of parasitologically confirmed cased [63]. Swimming microfilariae may be identified on Tiersch
skin biopsy suspended in saline on a glass slide.

Treatment
There is little to suggest that leukoderma responds to any treatment except
excision of onchocercomata. Browne [62] found that in one-third of those in
whom all onchocercomata were removed, repigmentation occurred from the
margins of normally pigmented skin. The failure of others to repigment may
occur because a depigmenting agent remains in undetected extranodular or
unencapsulated adult filariae or because such a factor has permanently suppressed melanocyte function.
Antitreponemal therapy and oral or topical 8-methoxypsoralen are generally ineffective in repigmenting onchocerciasis, although Browne [62] did
notice slight repigmentation of smaller macules (not the larger dead-white ones)
with the latter.

POSTKALAAZAR DERMATOSIS
Post-kala-azar dermatosis, a post-kala-azar dermal leishmaniasis, may present with hypopigmented macules.
Post-kala-azar dermatosis occurs in patients with untreated or incompletely

559
INFECTIOUS AND
PARASITIC
HYPOMELANOSIS

560
CHAPTER 7

treated chronic kala-azar and may appear one to five years after the initial
infection. The causative agent is the parasite Leishmania donovani, which
infests the skin to produce insidious, nonulcerative granulomas containing the
protozoa. 1. donovani is transmitted by the sandfly.
Post-kala-azar dermatosis is found commonly in India and Bangladesh,
less frequently in the Sudan and East Africa, rarely in China, and virtually
never in Mediterranean countries or South America, despite the fact that kalaazar itself occurs in all these regions. Attempts to eradicate the sandfly have
decreased the incidence of post-kala-azar dermatosis in the world [64].

Hypopigmentation in Post-Kala-Azar Dermatosis

Clinical Picture

Post-kala-azar dermatosis was well described by Acton and Napier [65].

Hypopigmentation, which is the initial stage of the process, may precede or
occur with dermal nodular lesions. The lesions appear simultaneously on various parts of the body and not in successive crops. Lesions begin as small
pinpoint macules which increase in size but usually do not exceed 1 cm.
Lesions are usually singular and discrete but occasionally they coalesce to
involve large areas such as entire limbs [66]. In these cases, they produce a
map like appearance with irregular but well-defined borders. These hypopigmen ted macules are bilateral and often symmetrically distributed. They appear
more commonly on the chest and back, arms, front of the thighs, neck, and
less commonly on the face. The waist-belt area in "dhoti" wearers is conspicuously spared even when the whole body surface is involved [67]. The lesions
are hypopigmented and not totally amelanotic (Fig. 231). There is no loss of
pigment or dyschromia of the hair over the lesions. The depigmentation is not
progressive and complete depigmentation does not occur. There is usually no
local itching or discomfort and no other epidermal changes. No sensory abnormalities, nerve thickening, or disturbances of sweating are observed.
The hypopigmented lesions that constitute the prenodular stage of the
disease are initially flat macules and later become slightly raised. The hypopigmented macules representing the first stage of the dermatosis may be the
only cutaneous finding. However, erythematous macules or nodules that are
later stages of the disease may be observed at the same time.
Histology

Sen Gupta and Bhattacharjee [68] described the histology of these hypopigmented macular lesions. A slight decrease in basal layer pigmentation was
the only epidermal change. In the dermis, there is an infiltrate of histiocytes,
lymphocytes, and a few plasma cells in the upper dermis around proliferated
blood vessels and deeper around hair follicles, sebaceous glands, and sweat
ducts. Leishmanias are present in small number and are difficult to demonstrate
within histiocytes. Biopsy of another patient [64] showed a dense bandlike
infiltrate in the upper dermis with histiocytes, plasma cells, and lymphocytes.

561
INFECTIOUS AND
PARASITIC
HYPOMELANOSIS

FIGURE 231. Post-kala-azar dermal leishmaniasis. Hypomelanotic lesions (patient of Dr. Lahiri).
(From: Banerjee BN. Dutta AK: The cutaneous manifestations of kala-azar and post-kala-azar dermatosis. in Clinical Tropical Dermatology. Edited by 0 Canizares. London. Blackwell. 1975. Plate
17. Copyright. 1975. Blackwell Scientific Publications. Used with permission.)

Histologic changes are more marked in erythematous and nodular lesions.

Pigment loss is more pronounced in erythematous lesions and maximal in
nodules, as is the intensity of the dermal cellular infiltrate. L. donovani are
more numerous in the erythematous type and most numerous in the nodular
type of lesion.

Other Features
The two other cutaneous features include erythematous macules and yellow to pink nodules. A butterfly erythema of the face involving the nose and
cheeks as well as the chin and the perioral skin may also extend to other parts
of the body, particularly those areas that typically become hypopigmented. The
yellowish pink nodules, often compared to xanthoma and varying from pinhead
to plum size. either replace the earlier lesions of hypopigmentation or erythema
or may appear de novo. The face, earlobes, trunk, and genitalia are frequently
involved. Involvement of palms and soles, as well as mucous membranes, may
also be observed. When these nodules disappear, they do not scar or leave
pigmentation abnormalities.

562
CHAPTER 7

Otherwise, patients are healthy, afebrile, and without any sign of visceral
involvement.

Diagnosis and Differential Diagnosis

The diagnosis of post-kala-azar dermatosis must be based upon a history
of treated or untreated kala-azar, clinical features, and demonstration of L.
donovani in skin lesions.
Eosinophilia is the only abnormal blood finding. Serologic tests are negative except for complement fixation which is positive only in a few cases. The
parasite may be demonstrated by slit-scraping of the erythematous or nodular
lesions but is difficult to find in hypochromic macules. Animal (hamster) inoculation may be helpful.
Hypopigmented macules can be differentiated from leprosy, tinea versicolor, pityriasis alba, postinfiammatory hypopigmentation, tuberous sclerosis,
idiopathic guttate hypomelanosis, and leukodermic syphilis on the basis of
associated clinical findings, presence of L. donovani, histology, and the absence
of other focal epidermal changes. Absence of anesthesia and M.leprae exclude
the diagnosis of leprosy.

Treatment
Systemic treatment with antimonials or diamidines (especially pentamidine-Iomidaine) is effective. Patients with mild disease and few organisms in
lesions may respond better to therapy and tend less to relapse than those with
severe disease and many organisms. Post-kala-azar dermatosis must be treated
with pentavalent antimonials. It is almost impossible to obtain total repigmentation of hypopigmented areas.

TUBERCULOSIS

Hypochromia has been reported by Pearson [69] to occur in many cases

of pulmonary tuberculosis in Nigeria. With the use of colorimetry he found
hypomelanosis, which was obviously subtle clinically, in many with about a
10% reduction in mean colorimetric readings. The hypomelanosis may be generalized and subtle or occasionally be more apparent on isolated areas, such
as the cheeks. This is slightly more marked in males than females. The pathogenesis is unclear but several postulates, namely malnutrition and anemia,
seem not to apply. In this study most patients repigmented, as measured by
colorimetry, following treatment with streptomycin 1 g daily for two months
and isoniazid 300 mg plus thiacetazone 150 mg daily for 18 months. The author
observes that failure to repigment often signifies poor therapeutic response and
resistance to first-line drugs.

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1. Canizares 0: Leprosy, in Clinical Tropical Dermatology. Edited by 0 Canizares. London,
Blackwell, 1975, pp 109-133
2. Ridley DS, Jopling WH: Classification of leprosy according to immunity. Int J Leprosy
34:255-273,1966
3. Henderson JM: The depigmented patch in leprosy: a clinical and pathological study. Indian
J Med Res 17:33-39, 1929-1930
4. Cochrane RG: Leprosy in Theory and Practice. Bristol, John Wright and Sons, 1964, pp 251-279
5. Ishibashi Y: Histopathological studies on the skin lesions in leprosy with special reference to
the histological changes of pigmentation. Jpn J Dermatol [BJ 74:44-60, 1964
6. Breathnach AS et al: Observations on Langerhans cells in leprosy. Br J Dermatol 74:243-253,
1962
7. Nayer A, Job CK: A study of epidermal melanocytes in hypopigmented patches of leprosy.
Indian J Med Res 58:187-193, 1970
8. Job CK et al: Electron microscopic study of hypopigmented lesions in leprosy. A preliminary
report. Br J Dermatol 87:200-212, 1972
9. Job CK, Mathan M: Personal communication quoted by Nayer A, Job CK: A study of epidermal
melanocytes in the hypopigmented patches of leprosy. Indian J Med Res 58:187-193, 1970
10. Richter R: Studien zur Neurohistologie der nervosen vegetativen Peripherie der Haut bei verschiedenen chronischen infectiosen Granulomen mit besonderer Beriicksichtigung der Langerhansschen Zellen. Arch Klin Exp Dermatol 202:466-555, 1956
11. Shirasaki Y: Quoted by Ishibashi Y: Histopathological studies on the skin lesions with special
reference to the histological changes of pigmentation. Jpn J Dermatol [BJ 74:44-60, 1964
12. Prabhakaran K: Oxidation of 3-4 dihydroxyphenylalanine (dopa) by Mycobacterium leprae.
Int J Leprosy 35:42-51,1967
13. Prabhakaran K: Properties of phenoloxidase in Mycobacterium leprae. Nature 218:973-974,1968
14. Prabhakaran K et al: Oxidation of phenolic compounds by Mycobacterium leprae and inhibition
of phenolase by substrate analogues and copper chelators. J Bacteriol 95:2051-2053,1968
15. Prabhakaran K et al: Effect of inhibitors on phenoloxidases of Mycobacterium leprae. J Bacteriol
100:935-938, 1969
16. Prabhakaran K: Unusual effects of reducing agents on O-diphenoloxidase of Mycobacterium
leprae. J Bacterioll07:787-789, 1971
17. Editorial: Leprous leukoderma. Trans St Johns Hosp Dermatol Soc 59:129-130, 1973
18. Seghal VN: Hypopigmented lesions in leprosy (Letter). Br J Dermatol 89:99, 1973
19. Browne SG: Treponemal depigmentation, with special reference to yaws. S Afr Med J 50:442--445,
1976
20. Marquez F: Pinta, in Clinical Tropical Dermatology. Edited by 0 Canizares. London, Blackwell,
1975, pp 86-92
21. Rein CR et al: Repositary penicillin therapy of pinta in the Mexican peasant. A clinical and
serologic survey. J Invest DermatoI18:137-145, 1952
22. Fox H. Carate (pinta) as observed in Colombia, South America. Arch Dermatol Syphilol
18:673-691, 1928
23. Fox H: White pinta or vitiligo in Yucatan. Arch Dermatol Syphilol 36:534-535, 1937
24. Csonka GW: Clinical aspects of bejel. Br J Vener Dis 29:95-103, 1953
25. Marquez F: Endemic syphilis, in Clinical Tropical Dermatology. Edited by 0 Canizares. London, Blackwell, 1975, pp 92-96
26. Degos R: Dyschromies, in Dermatologie. Paris, Editions Medicales Flammarion, 1953, pp 125-126
27. Milian G: Le vitiligo est consecutif a une syphilide erythemateuse fruste. Bull Mem Soc Med
Hop Paris 45:731-732, 1921
28. Milian G et al: Syphilis et vitiligo: erytheme previtiligineux. Bull Mem Soc Med Hop Paris
54:631-635, 1930
29. McCarthy L: Diagnosis and Treatment of Diseases of the Hair. St. Louis, Mosby, 1940
30. Eickstedt: Quoted in Emmons CW et al: Medical Mycology. Philadelphia, Lea & Febiger, 1970,
pp 156-161
31. Shuyter: Quoted in Emmons CW et al: Medical Mycology. Philadelphia, Lea & Febiger, 1970,
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32. Ehrman: Quoted in Uber Lichtwirkung and Leukoderma bei Pityriasis versicolor. Dermatol
Wochenschr 38:343-347,1923
33. Gougerot H et al: Achromies "parasitaires" ou mieux epidermomycoses (pityriasis versicolor)
achromiantes. Action decolorante, action antipigmentaire protectrice des epidermomycoses
ou mieux difference de resistance ala pigmentation. Bull Soc Fr Dermatol Syphiligr 36:1028-1029,
1929
34. Barney RE: Pseudoachromia post parasitaria-tinea versicolor. Arch Dermatol Syphilol
25:1167-1168,1932
35. Bechet PE: Vitiligo? Tinea versicolor? Arch Dermatol Syphilol 32:960, 1935
36. Fox H. Pityriasis rosea followed by apparent depigmentation. Arch Dermatol SyphilolI5:751-753,
1927
37. Lewis GM: Tinea versicolor (white). Arch Dermatol Syphilol 31:911-913, 1935
38. Throne B: Acromia cutis postparasitaria. Arch Dermatol SyphilolI8:146, 1928
39. Gougerot H et al: Un cas d'achromie parasitaire nord-africain du "pityriasis versicolor." Bull
Soc Fr Dermatol Syphilogr 37:110-111,1930
40. Gougerot H et al: "Pityriasis versicolor" achromiant. Achromie parasitaire chez un Tunisien.
Bull Soc Fr Dermatol Syphiligr 38:1296-1297, 1931
41. Gougerot H et al: Pityriasis versicolor achromiant chez une negresse. Bull Soc Fr Dermatol
Syphiligr 40:420-421, 1933
42. Wise F, Sulzberger MB: Comments on one case, in Yearbook of Dermatology. Chicago, Year
Book, 1932, p 29
43. Wertheim L: Ueber Lichtwirkung und Leukoderma bei Pityriasis versicolor. Dermatol Wochenschr 77:1155, 1923
44. Kistiakovsky EV: Pityriasis versicolor and ultraviolet rays. Arch Dermatol SyphilolI5:685-689,
1927
45. Lewis CM, Hopper ME: Pseudoachromia of tinea versicolor. Arch Dermatol Syphilol 34:850-864,
1936
46. Ruete AE: Zur Frage der depigmenterienden Pityriasis versicolor. Dermatol Wochenschr
96:333-336, 1933
47. Boardman CR, Malkinson FD: Tinea versicolor in steroid-treated patients. Arch Dermatol
85:44-52, 1962
48. Jung EG, Truniger B: Tinea versicolor and Cushing syndrom. Dermatologica 127:18-22, 1963
49. Bumgarner FE, Burke RC: Pityriasis versicolor: atypical clinical and mycologic variations. Arch
Dermatol Syphilol 59:192-195, 1949
50. Jelliffe DB, Jacobson FW: The clinical picture of tinea versicolor in Negro infants. J Trop Med
Hyg 57:290-292, 1954
51. Blumenthal HL: Tinea versicolor of the penis. Arch Dermatoll03:461-462, 1971
52. EI Gothamy Z et al: Tinea versicolor hypopigmentation: histochemical and therapeutic studies.
Int J DermatoI14:510-516, 1975
53. Charles CR et al: Hypopigmentation in tinea versicolor: a histochemical and electromicroscopic
study. Int J Dermatol12:48-58, 1973
54. Keddie FM: A novel cellular reaction caused by tinea versicolor: extracellular glycogen deposits. J Invest Dermatol 53:363-372, 1969
55. Grupper CH et al: Pityriasis versicolor achromiant. Etude ultrastructurale a propos de 3 cas.
Bull Soc Fr Dermatol Syphiligr 82:114-117, 1975
56. Beare JM et al: Pityriasis versicolor, in Textbook of Dermatology. Edited by A Rook et al.
Oxford, Blackwell, 1968, pp 752-755
57. Wilson JW, Plunkett OA: The Fungous Diseases of Man. Berkeley, Univ of California Press.
1965, pp 252-258
58. Hildick-Smith G et al: Fungus Diseases and Their Treatment. London, Churchill, 1964, pp
5-11
59. Ito K. Tanaka T: Amino acid metabolism of fungi: decomposition of L-tyrosine by fungi. in
Dermatology Proceedings of the XN International Congress, 1972. Edited by F Flarer et al.
New York, American Elsevier, 1974. p 735
60. Porro MN. Passi S: Identification of tyrosinase inhibitors in cultures of genus Pityrosporum.
in Proceedings of the 10th International Pigment Cell Conference, Cambridge, Mass. 1977. vol
4. Biologic Basis of Pigmentation. Basel.S Karger, 1979

61. Browne SG: Onchocercal depigmentation. Trans R Soc Trop Med Hyg 54:325-334,1960
62. Browne SG: Onchocerciasis and the skin. S Afr Med J 50:301-304,1976
63. Convit J: Onchoceriasis, in Clinical Tropical Dermatology. Edited by 0 Canizares. Oxford,
Blackwell, 1975, pp 220-225
64. Girgla HS et al: Post-kala-azar dermal leishmaniasis. Br J Dermatol 97:307-311,1977
65. Acton HW, Napier LE: Post-kala-azar dermal leishmaniasis. Indian J Med Res 15:97-106,
1927-1928
66. Napier LE, Das Gupta CR: A clinical study of post-kala-azar dermal leishmaniasis. Indian Med
Gaz 65:249-257,1930
67. Banerjee BN, Dutta AK: The cutaneous manifestations of kala-azar and post kala-azar dermatosis, in Clinical Tropical Dermatology. Edited by 0 Canizares. Oxford, Blackwell, 1975,
pp 197-205
68. Sen Gupta PC, Bhattacharjee B: Histopathology of post-kala-azar dermal leishmaniasis. J Trop
Med Hyg 56:110-116,1953
69. Pearson CA: Hypochromia as a clinical sign of tuberculosis in the tropics. Tubercle 59:111-119,
1978

565

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8
Leukoderma Acquisitum Centrifugum:
Halo Nevus and Other
Hypomelanoses Associated with

Neoplasms

The partial or complete regression of benign and malignant tumors is of interest for
it is evident that if on rare occasions forces within the human organism can bring
about spontaneous regression of a tumor, the intellect will some day master the
mechanism of the process.
Rohdenburg, 1927 [1]

The term "leukoderma acquisitum centrifugum" is a somewhat generic one

commonly used synonymously with "halo nevus" but applicable to various
tumors, including primary or secondary melanomas, surrounded by leukoderma (Table 119). This entity has been described as "leukopigmentary nevus"
[2], "perinevoid vitiligo" [3], and "perinevoid leukoderma" [4]. While leukoderma acquisitum centrifugum applies to all nevi surrounded by a macule of
leukoderma, the term "halo nevus" is restricted to nevus cell nevus.

HALO NEVUS
Halo nevus [5], also referred to as "Sutton's nevus" or "Sutton's disease,"
is the most common form of leukoderma acquisitum centrifugum. Halo nevus
can be defined as a benign nevus cell nevus undergoing spontaneous resolution
and surrounded by leukoderma (Fig. 232).

History
The first description of halo nevus was not found in the medical literature
but rather was painted by Grunewald, a 16th century artist [6]. On a panel of

567

TABLE 119. Leukoderma Acquisitum Centrifugum

568
CHAPTER 8

A. Halo nevus: depigmented halo around a benign nevus cell nevus

B.

Perineuroplastic halo or leukoderma surrounding other neoplasms

of the skin: depigmented halo around a central tumor other than
a benign nevus cell nevus
1.
Blue nevus
2.
Neurotized nevus
3.
Garment nevus
4.
Neurofibroma
5.
Spitz nevus
6.
Primary or secondary melanoma
7.
Dermatofibroma

the Isenheimer Altar ("The Temptation of Saint Anthony"), one of the demons
has numerous colored spots surrounded by light areas typical of Sutton nevi.
The first mention in the medical literature of the phenomenon of a macule
of depigmentation surrounding a preexisting pigmented nevus was in an 1874
textbook by Hebra and Kaposi [7], who called this "vitiligo." Additional repdrts
did not appear until the early 20th century. Hyde [8], in 1906, presented a case
of "vitiligo with a central mole." Cases of halo nevus were recorded in 1910
by Rolleston [9] in a jaundiced patient with abdominal carcinomatosis and in
1915 by Almkvist [10], who used the term "nevus anemicus" to describe the
depigmented halo. However, it was Sutton, in 1916 [11], who first recognized
"depigmentation around a brown center resembling a pigmented nevus" as a
distinct entity; he named this "leucoderma acquisitum centrifugum." Stokes
[12], in 1923, first recognized the central tumor to be a nevus cell nevus. The
natural course was elaborated by Kuske [6] who noted that in some enlarging
lesions, the central nevus seems to be gradually obliterated. Gougerot and
Carteaud [13] observed complete disappearance of the central mole. Sutton
recognized the presence of an infiltrate of cells histologically, which he interpreted to be endothelial in nature. Shelmire [14] and Bunch [15] later made
similar observations. There has been much discussion about the nature of the
depigmented macule surrounding the central nevus. Feldman and Lashinsky
[16] suggested the achromic area to be a nevus anemicus and proposed the term
"halo nevus" to describe what they considered to be a nevoid entity composed
of two components, namely, nevus anemicus and nevus cell nevus.
Many others have considered this condition to be a variant of vitiligo.
Montpellier [3] and Petges [17] used the term "perinevoid vitiligo" and Narducci [2] that of "perinevic vitiligo" to emphasize that vitiligo may coincidentally surround moles. In fact, Weber [18] suggested that vitiligo tends to form
around preexisting nevi. Crawford [19] based his assertion that this entity was
a variant of vitiligo on the observation that both presented with hyperpigmented
borders, an observation not confirmed by later studies. Leider and Cohen [4]
concluded that "vitiligo, perinevic vitiligo, leukoderma associated with
syphilis, and psoriasis have a common physiochemical mechanism of inhibition of pigment formation." Leider and Fisher [20] followed the disappearance

569

LEUKODERMA
ACQUISITUM
CENTRIFUGUM

FIGURE 232. a, b: Typical halo nevi composed of a central pigmented nevus surrounded by a
depigmented halo.

570

CHAPTER 8

of the central mole and postulated the nevus also could be involved in a
"vitiliginizing" process. But Poor [21] felt that the presence of islands of pigment
in the epithelium of the halo area differentiate the disease from vitiligo, in
which he considered depigmentation to be total. Kuske [6] also agreed that
there were important clinical differences between the two conditions. Even
today this issue is not well resolved. Many authors consider halo nevus as an
entity sui generis. Stokes [12] believed that central nevus may play an important
role in the pathogenesis of depigmentation, which may result from physiochemical inhibition of melanogenesis. Niles [22] removed the central nevus
and observed no changes in the surrounding halo. He concluded erroneously
that the halo is nevoid in character.
Rohdenburg [1] first suggested an immunologic basis for halo nevus. There
is now considerable evidence to support this hypothesis.

Incidence
Frequency (Tables 120, 121)
Halo nevus does not appear to be uncommon, but its exact frequency has
never been reported. Since over 20% of vitiligo patients (1% to 2% of population) have halo nevi and many have halo nevi without vitiligo, the general
incidence of halo nevus must be about 1% or greater.
Sex

There is no convincing evidence that either sex is favored. Graham et al.

[35], in their review of the literature, found halo nevus to be equally common
in males and females. However, the series of Findlay [36], Frank and Cohen
[23], and Kopf et al. [24] showed female prevalence (75%, 64.3%, and 55.8%,
respectively). Conversely, Copeman et al. [25] and Wayte and Helwig [5] reported a male prevalence (65.2% and 66%, respectively), but it should be noted

that the latter study from the Armed Forces Institute of Pathology (A.F.I.P.)
would be expected to be biased towards males.

TABLE 120. Incidence of Vitiligo in Patients with Halo Nevus

Author
Frank and Cohen, 1964 [23)
Kopf et aI., 1965 [24)
Wayte and Helwig, 1968 [5)
Copeman et aI., 1973 [25)
Gauthier et aI., 1975 [26]

No. of patients
with halo nevus

% with Vitiligo

14
35
100
23
7

21.4
25.7
1.0
47.8
42.8

TABLE 121. Incidence of Halo Nevus in Patients with Vitiligo

Author
Chorazak and Rzempoluch,
1968 [27)
EI Mofty, 1968 [28)
Bor et aI., 1969 [29)
Lerner, 1972 [30)
Perrot et aI., 1973 [31)
Copeman et aI., 1973 [32)
Ortonne, 1974 [33)
Schnitzler et aI.. 1974 [34)

No. of patients
with vitiligo

% with Halo nevus

62

3.2

545
62

2.9
6.4
50
0.5
14
1.0
10.0

200
348
100
30

Race
Cases have been reported from all parts of the world. No race is spared.
All the 100 patients of Wayte and Helwig [5] were Caucasoids, but this appears
to reflect the A.F.I.P. population which is predominantly Caucasoid. There are
numerous reports concerning halo nevus in black patients [35,37,38]. In the
Kopf et a1. series [24], the black to white ratio of 1:16 shows an insignificant
black predominance compared to the general clinic ratio of 1:19.
Age

Halo nevi have been observed to arise in patients from three to 50 years
of age. In the series of Wayte and Helwig [5], the age of male patients varied
from five to 50 and that of females from eight to 40, the average age being 17
and 18, respectively. The patients of Frank and Cohen [23] were from five to
37 years of age, and those of Kopf et a1. [24] from three to 42 years of age. The
peak incidence is in the second decade-44% [5], 40% [24], and 42.8% [23].
Seventy-five percent of the eight patients of Findlay [36], 86.9% of the patients
of Copeman et a1. [25], and 71.4% of the 14 patients of Frank and Cohen [23]
were under the age of 20. In two series, 85% [5] to 92.8% [23] of halo nevi
occurred within the first three decades of life. No congenital halo nevi have
been reported.
Familial History
Familial cases have been noted but they are uncommon. Kopf et a1. [24]
noted halo nevi among sisters. Another girl with halo nevus and vitiligo has a
sister with multiple halo nevi (personal observation of the authors). Two of the
100 patients reported by Wayte and Helwig [5] had a positive family history
for halo nevus. One of the patients of Kopf et a1. [24] had a positive family
history of vitiligo.
Kopf and Petratos [39] reported a patient's father to have developed premature graying of the hair by 17 years of age and his sister to have a solitary
macule of leukoderma and a caUi-au-Iait spot.

571
LEUKODERMA
ACQUISITUM
CENTRIFUGUM

572

Clinical Features

CHAPTER 8

The Typical Lesion

The typical halo nevus is composed of a central pigmented nevus and a
surrounding depigmented halo.
The halo is a ring of pale white hypomelanosis, usually round or oval in
shape. The diameter of the depigmented lesion varies from 1 to 5 cm [5].
Generally, the peripheral margin is regular in outline and has sharply defined
edges. In fair-skinned individuals, the halo may not be apparent without Wood's
light examination. Centrally, or occasionally eccentrically, placed within the
depigmented macules is a 4- to 5-mm, round, brown-red papule which occasionally resembles a hemangioma [5]. There is no apparent relationship between the size of the central nevus and the size of the halo (Fig. 233). Halo
congenital giant nevus cell nevus has been reported [40,41]. The hypochromic
halo may be discernible around only a portion of very large nevi [40] and the
halo may become erythematous with sun exposure [23,40].
Pigmented, white, and coarse hairs may be seen arising from a single nevus
[40]. Boardman [42] observed pigmented nevi of the scalp surrounded by patches
of white hairs in an eight-year-old white boy.
Number of Lesions
More than one halo nevus is not uncommon. Graham et al. [35], in a survey
of the literature in 1963, found more than two-thirds of the 46 reported patients
to have more than one halo nevus (Fig. 234). The incidence of multiple lesions
has been reported in other surveys to be 25% [23], 26% [24], and 50% [5] among
those with halo nevi.
In various series [5,23,24] patients with more than one halo nevus had up
to seven, eight, or 10 lesions. Stegmaier et al. [43] reported a patient with 17
lesions and Graham et al. [35] reported a black with 90 halo nevi. Stegmaier
et al. [43] stressed that not all the nevi in patients with halo nevi are involved;
in their patients with multiple halo nevi, numerous brown macular and slightly
elevated nevi and lentigines were not surrounded by leukoderma.
Anatomic Site
The most common site of involvement is the trunk, particularly the back,
but the face, extremities, and axillae may also be involved [5,23,24] (Fig. 235).
Lesions of the palms and soles have not been reported.
The distribution of halo nevi seems to be no different than the distribution
of pigmented nevi in general [23]. Wayte and Helwig [5] noted that the distribution of halo nevi is in no way characteristic of that of vitiligo.
Signs and Symptoms
In general, the lesions are asymptomatic. One of the 100 patients of Wayte
and Helwig [5] complained of "irritation" at the site of the nevus. Pruritus,

FIGURE 233. a, b: There is no apparent relationship between the size of the central nevus and
the size of the halo.

cmllllllll 1IIIP111JII Ipl 11

1
2 , -3

scaling, and erythema may follow sunburn but otherwise do not occur. The
depigmented macules do not tan. Most patients are otherwise healthy.

Natural History of a Halo Nevus

There are three stages in the evolution of halo nevus, namely, the appearance of the halo, the disappearance of the nevus, and finally the disappearance
of the halo.

573

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574

CHAPTER 8

a, b: Multiple halo nevi. Note that not all the nevus cell nevi are surrounded by a
halo of depigmentation.

FIGURE 234.

575
LEUKODERMA
ACQUISITUM
CENTRIFUGUM

FIGURE 235. Anatomic distribution of 108 halo nevi. (From: Wayte DM, Helwig EG: Halo nevus.
Cancer 22:69-90, 1968. Copyright, 1968, J. B. Lippincott Co. Used with permission.)

The Nevus

Most patients with halo nevi specifically observed the involved nevi had
been present many years prior to the development of the halo. In some instances, the nevi are congenital [24,40,44,45]. Never does the nevus develop
in a preexisting macule of leukoderma; in the 100 cases reported by Wayte and
Helwig [5], none observed the pigmented nevus to have developed at the same
time as or after the halo. However, in one of Sutton's two original cases, the
patient's mother stated that the central spot had not been present before the
onset of depigmentation, but this observation is open to question.
Halo Formation

In most cases the patient suddenly becomes aware of a depigmented ring

around a nevus and has little knowledge of the dynamics of its development.

576
CHAPTER 8

Although the term "leukoderma acquisitum centrifugum" implies that there

is an enlarging ring of depigmentation around a central mole, only an occasional
patient is reported to have observed this evolutionary change [5]. Most patients
become aware of the lesion once it is fully developed and little change is noted
thereafter. One vitiligo patient noticed a trichrome-like subaxillary macule with
a central brown tuberous nevus; this lesion was surrounded from the center
outward by an achromic area, a hypochromic area with brown speckles, and
then the normal surrounding skin [46] (Fig. 236). This appearance suggests an
evolutionary process analogous to trichrome vitiligo.
The rate of depigmentation is unknown. Frank and Cohen [23] reported a
patient in whom a halo nevus appeared over a three-month period. But, since
most patients and physicians describe only the abrupt appearance of a white
macule of a fixed size, the clinical transition from normal perinevic to leukodermic perinevic skin remains unknown (Figs. 237, 238).
In most patients, the central nevus is unchanged during the period of the
appearance of the depigmented halo. In seven of 34 halo nevus patients observed by Frank and Cohen [23], the central nevus changed from brown-red to
red or red-violaceous. In one patient, crusting, scaling, and elevation accompanied halo formation [23].

FIGURE 236. Trichrome hypopigmented halo around a pigmented nevus. (From: Dupre A et al: Une variante
du vitiligo trichrome de Fitzpatrick. Bull
Soc Fr Dermatol Syphiligr 81:530-532,
1974. Copyright, 1974, Masson & Cie,
Paris. Used with permission.)

577

LEUKODERMA
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FIGURE 237. Early stage of formation of the halo depigmentation.

Disappearance of the Central Nevus

Typically the nevus gradually disappears, leaving an area of pale white
depigmentation called "resolved halo nevus." In four patients followed by
Frank and Cohen [23], a total of nine halo nevi spontaneously disappeared; in
their series the incidence of this phenomenon was at least 50% and the nevus
required from five months to eight years to disappear (Fig. 239). Three of the
100 patients reported by Wayte and Helwig [5) observed disappearance of halo
nevi over several months to two years. In one patient, Stegmaier et al. [43)
reported a six-month period between the first patient visit and the disappearance of the central pigmented portion.
Seven patients of Wayte and Helwig [5) were observed to have, in addition
to halo nevi, localized macules of satellite depigmentation varying in size from

FIGURE 238. Later stage in the formation of the

halo of depigmentation.

578
CHAPTER 8

FIGURE 239. Resolved halo

nevus. In this lesion, the central
nevus almost completely disappeared leaving a white macule.

1 to 2 cm and resembling the halo nevi in shape and color, but without the

central pigmented nevus. These macules of hypo pigmentation resemble those

remaining after the resolution of the central nevus [4,5,20,22,23,47].
Striking resolution of a giant nevocellular nevus has also been reported by
Ridley [41].
Repigmentation of the Halo

The course of repigmentation is unpredictable. The depigmented halo may

finally repigment so that no evidence of the nevus or the halo remains (Fig.
240). Wayte and Helwig [5] noted complete repigmentation of a resolved-halo
nevus over eight months in one of their patients. Two of the 14 patients of
another series [23] also demonstrated halo repigmentation. Frank and Cohen
[23] observed one case in which the halo remained unchanged for six years,
whereas another case repigmented within five years. On the other hand, in
others the halo nevus has remained unchanged (15 of 71) for periods of 14
years and 30 years [23J.
The mode of repigmentation is unknown and neither the time of onset nor
the duration of perinevic leukoderma or the resolved halo nevus is predictive
of repigmentation.

Precipitating Factors
For the majority of patients, no obvious precipitating cause is apparent.
Sunlight, chemical exposure, and familial predisposition have all been suggested.

579

LEUKODERMA
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FIGURE 240.

Spontaneous repigmentation in the depigmented halo may occur.

Wayte and Helwig [5], noting that the majority of their cases often were
first seen during the months of July and August, suggested solar irradiation to
be a significant factor in the pathogenesis of halo nevi. Four patients of Kopf
et al. [24] and six of the 100 of Wayte and Helwig [5] reported a sunburn
preceding the onset of halo nevus. Another 14-year-old patient first became
aware of his perinevic depigmentation after a severe sunburn sustained while
he was water skiing [43]. However, the broad geographic distribution of the
occurrence of halo nevus makes the relationship of halo nevus to a specific
environmental factor, such as sunlight, extremely difficult to evaluate. It is
likely that sunlight, tanning the normal skin and burning the unmelanized
halo, causes patient awareness.
Chemical exposure may be a significant factor in some cases. Acquired
halo nevi-like lesions attributed to Benoquin [37] and Guanofurocin [48] have
been reported.
There is scant evidence to suggest halo nevus is a genetic disorder. Although most patients have no family history of halo nevus or of other pigmentary disturbances, several observations raise the question of a genetic predisposition. Chisa [49] reported two siblings in whom multiple halo nevi appeared
at nearly the same age. Fitzpatrick and Mihm [50] also observed two siblings
with halo nevus without vitiligo.

580

CHAPTER 8

FIGURE 241.

a, b: Vitiligo-like depigmentation in a patient with halo nevus.

Associated Disorders

581
LEUKODERMA
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Vitiligo

Vitiligo and halo nevus occur in the same patient with significant frequency. Between 1% and 47.8% of patients with halo nevus are reported to
have vitiligo, and between 0.5% and 50% of patients with vitiligo are reported
to have concomitant halo nevus (Fig. 241). This concomitant vitiligo is not
thought to represent resolved halo nevi, although the latter are clinically, histopathologically, and ultrastructurally [32] indistinguishable from ordinary vitiligo. The exact sequence of appearance of these two dermatoses varies; the
halo nevus may occur before, during, or after the appearance of the vitiligo.
There are also examples of the occurrence of vitiligo and halo nevus in different
members of the same family.
The relationship between vitiligo and halo nevus (Table 122) is controversial. Halo nevus was initially considered to be a peculiar variety of vitiligo;
some early authors considered halo nevus only the incidental occurrence of
vitiligo around a preexisting mole. Lerner [51] still considers the halo nevus
to be a form of vitiligo. To support his thesis, he cites the seeming scarcity of
nevi other than halo nevi in vitiligo patients, the similar histology in the two
conditions, and the greater occurrence of halo nevi in patients with generalized
vitiligo.
Ito and Yoshida [52] suggested that in vitiligo there is dysfunction in the
region of spinal ganglia; the depigmentation has a corresponding symmetrical
or unilateral quasidermatomal array. But in Sutton disease the neural disturbance is limited to the area of the nevus, resulting in a circumscribed perinevic
lesion with little tendency to extension.
A number of observations support the concept of halo nevus and vitiligo
as separate and distinct entities. Vitiligo and halo nevus certainly do not always
coexist. Those nevi present in vitiligo patients rarely become inflamed and do
not undergo the specific retrogressive inflammatory changes characteristic of
TABLE 122.
Evidence for
Both are pure-white in color.
The histology is similar.
There is an increased incidence
of halo nevi in patients with
generalized vitiligo.

Is Halo Nevus Actually Vitiligo?

Evidence against
Lymphocytic infiltrate is always present in halo nevi,
but is unusual in vitiligo.
Inflammatory nevi in vitiligo are rare.
Jaundice is not seen in vitiligo patches, but is in halo
nevi.
There is no pigmented margin in halo nevi.
There are no retrogressive inflammatory changes in
vitiligo.
Pigmented nevi are often present in long-standing
vitiliginous areas.
Cross-transplantation studies show no typical
inflammatory response when nevi are implanted
into vitiliginous areas.

582

CHAPTER 8

halo nevi. Pigmented nevi may even exist in long-standing vitiliginous areas.
Stegmaier [53] found no vitiligo in his 11 cases of halo nevus. The lymphocytic
infiltrate seen in halo nevi usually is absent in vitiligo. Halo nevi lack a hyperpigmented border that may be seen in vitiligo. The course of vitiligo may
occasionally be marked by repigmentation, which is rarely adequate, but halo
nevi do not repigment before resolution of the nevus. In cross-transplantation
studies, no specific resolution or typical inflammatory response could be found
in nevi transplanted into a macule of leukoderma [43].
More recently, Copeman and co-workers [25,54] have suggested that vitiligo
associated with halo nevus is different from ordinary vitiligo and results from
an immune phenomenon directed against both nevus cells and normal melanocytes. But there is no clinical evidence that vitiligo with halo nevus is any
different from that not associated with halo nevus.
In summary, the association between halo nevus and vitiligo appears to
be statistically significant, but concrete evidence to support a common pathogenesis remains elusive.
Leukotrichia
Graying of hair may be observed in the white macule or in the nevus cell
nevus [55]. Graying of hair remote from the site of the halo nevus also occurs
(Fig. 242). Premature graying of the entire scalp has been reported [39]. Several
patients with the triad of leukotrichia, vitiligo, and halo nevus have been reported [42,56].
Melanoma
True halo nevus may accompany melanoma. This is separate and distinct
from the halo occasionally reported around the melanoma itself. Epstein et al.
[57] reported the appearance of multiple prominent halo nevi in five patients
who had undergone surgical excision of a primary melanoma. Clark et al. [58]
also observed multiple halo nevi to occur randomly, unrelated to the site of
the primary or of recurrent metastatic melanoma. The prognostic significance
of this phenomenon is unknown.
Donaldson et al. [59] noted a patient to develop halo nevus, vitiligo, and
uveitis following BCG vaccination immunotherapy for metastatic melanoma.
However, since no skin biopsy was performed, that the central tumor of the
"halo nevus" was a metastatic melanoma cannot be excluded.
Chorioretinitis
Chorioretinitis has been reported in one patient with halo nevus [3].
Pernicious Anemia
Among 125 cases of pernicious anemia, Dawber [60] found four with halo
nevus; one of these also had vitiligo. In all four cases, the central nevus was

583

LEUKODERMA
ACQUlSITUM
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FIGURE 242. Nevus cell nevus of the scalp with white hair arising in the depigmented halo.

clinically a benign pigmented nevus. No cases of halo nevus were found among
132 controls. The association between pernicious anemia and halo nevus seems
statistically significant.

Histologic Findings
The histopathology of halo nevus is that of a dermal or compound nevus
in an epidermis with reduced or absent melanin content. The appearance of
any given biopsy is a function of the stage at which the biopsy is taken [61,62)
(Fig. 243).
Halo Epidermis

The major change observed in the halo epidermis is a reduction or absence

of epidermal melanin content. Dopa reactivity is reduced or absent and the
number of melanocytes is reduced or absent. In a fully developed halo, melanocytes are absent and the dopa reaction is negative. Dopa-negative dendritic
cells, which have been interpreted as amelanotic melanocytes [5,24,62)' have
been observed at the dermal-epidermal junction as well as at higher levels of
the epidermis. The number of these cells has been reported to be increased
[5,24,63)' or decreased [62]. Lymphocytes may be present in the epidermis.

:>
:;:>'

PRIMARY
FACTOR

7J UNKNOWN

,.::- 0:-'~[!)

i!)0 0

~~~

<i)

FIGURE 243.

\_
f)G>

ey@e 6
o (9C1
G

80
(5::)

DH

8(%.
6) ' .

cD

(!)

IV. Destruction and disappearance of the

nevus cell nevus

II. Development of the depigmented halo (DH I

DH

'--y-----J

Evolutionary stages of halo nevus.

III. Massive Iymphomacrophagic infiltration

around and within the nevus

~:~J.

('J

@(;e{5), ~_

;~.q;;

,:;'i

~ (;), ~e 0

~__~(9:CD~

Initial stage of inhibition of both the

melanocytes and the nevus cells

LYMPHOCYTES
AND
MACROPHAGES

I.

0>

:;0

~
~

en

Epidermis Overlying the Central Nevus

The thickness of the epidermis overlying the nevus may be normal, decreased, or increased [5,24,36]. Acanthosis is often associated with nevus cells
at the dermal-epidermal junction [24,35]. Keratinocytes are normal in number
and appearance. According to Wayte and Helwig [5], hyperkeratosis and follicular plugging are frequently observed.
Wayte and Helwig [5] reported that there is no exocytosis or migration of
nevus cells into the upper levels of epidermis. Findlay [36] reported a case
with a thick gelatinous basement membrane, but the basement membrane is
usually normal. The melanin content in the region of the nevus is usually
normal or increased. The dopa reaction may be strongly positive [24,40,43],
but later negative [24]. Few lymphocytes may be seen [43].
Epidermis Surrounding the Depigmented Skin

The transition between the depigmented halo and the surrounding normal
epidermis is histologically abrupt. There is no increased melanogenesis at the
border [5,24] of normal and depigmented skin.
The Central Nevus

The central nevus is a dense nevus cell nevus in the superficial dermis
with deeper extension perpendicular to the involved surface of the skin. Rare
perifollicular extension has been observed. Melanin and tyrosinase activity are
usually found only in the uppermost cluster of epithelioid cells [36] and the
dopa reaction decreases with the depth of the nevus; dopa-negative nevus cells
are located in the mid and lower dermis.
The nevus may be junctional, dermal, or compound but Wayte and Helwig
[5] and Stegmaier et al. [43] found all the nevi to be compound nevi. Nests of
nevus cells are most commonly found in the most superficial areas of the nevus
[5] and isolated small nests in the deepest parts. In the late resolution stage,
nevus cells disappear [23,36].
The morphology of the nevus cells is a function of their location. The most
superficial tend to be polygonal and relatively large (type A nevus cells) [43],
but in the deeper areas the cells are epithelioid or fusiform in shape.
The nevus cells show intense diphosphopyridine nucleotide diaphorase,
lactic, and succinic dehydrogenase activity [5] only in the upper part of the
nodule. Hexokinase and G-6-PD (glucose-6-dehydrogenase) [5] and cholinesterase [43] are negative. Histiocytes within the tumor show maximal acid phosphatase activity.
The nevus cells are not markedly hyperchromic. Pleomorphism and mitotic
figures are unusual [5,24]. Although Wayte and Helwig [5] and Stegmaier et
al. [43] observed no structural changes in the nevus cell nevus, Findlay [36]
described cytologic damage and impending cell death. Kopf et al. [24] also
observed various degrees of nevus cell damage. Nuclear changes including
swelling, chromatin clumping and condensation, pyknosis, and karyorrhexis
vacuolization have been described. Cytoplasmic changes include intracellular
edema, basophilia, and vacuolization [24].

585

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586

CHAPTER 8

There is usually a dense lymphocytic infiltrate around and between the

nevus cells, but a mild to absent inflammatory response has occasionally been
described in early halo nevi or in long-standing halo nevus [26,40]. The infiltrate
is usually composed of histiocytes and of lymphocytes which are likely the
same small dark cells described by Tanaka [62] and Kopf et al. [24]. Plasma
cells and mast cells are seen but less commonly [24,62]. Multinucleated giant
cells are occasionally seen. Polymorphonuclear leukocytes or eosinophils are
not present. Melanophages occur predominantly in the upper dermis [5,24].
There is a fine network of connective tissue between the cells. Edema may
be present. Reticular fibers and acid mucopolysaccharides are not increased.
Collagen and elastic fibers are thinned [35] and reduced in number [5]. In some
nevi, there is a marked increase in vascularity. The blood vessels may be
morphologically normal or have thickened walls with endothelial hypertrophy
and proliferation [5,24]. Wayte and Helwig [5] described the "river delta" distribution of the vasculature with a central core extending from the deep dermis
and branching out at the base of the nevus into multiple tortuous vessels. Nerve
fibers penetrate the periphery of the nevus but are not identifiable among the
closely packed central nevus cells [5]. However, in some instances, the nevus
cells seem to be in direct contact with the cutaneous nerves [24].
Adnexae are generally normal, but occasionally there are melanophages in
close proximity to the outer root sheath, particularly in resolved halo nevi [5].
Lipid is occasionally present in the nevus cells [5].
The dermis surrounding the nevus appears normal.
Resolved Halo Nevus
In resolved halo nevus, apart from a complete lack of melanin [5], there
are no obvious changes demonstrable in the epidermis or dermis. Occasional
melanophages or a patchy infiltrate of lymphocytes may be the only remaining
features of the process. Dermal vasculature appears normal. No nevus cells are
present.

Electron Microscopy
Halo Epidermis
Melanocytes
Although Stegmaier et al. [43] reported the same number of melanocytes
in the halo as in the normal epidermis, melanocytes are decreased in number
[40,64,65] or totally absent [40,63,66,67]. In the remaining melanocytes, the
number of melanosomes is usually decreased and these are mainly stage I
melanosomes [40,66,68].
Hashimoto [65] observed a decreased number of basal melanocytes and a
number of degenerated melanocytes in the upper epidermis in the progressively
depigmented area surrounding a compound nevus. These cells were observed
even in the granular layer and showed various degenerative changes such as

vacuolization, coagulation, segregation of part of the cytoplasm, and autophagocytosis of melanosomes. Serial sections did not show any anatomic connection of these "high level melanocytes" to the basal layer (Figs. 244, 245).
Gauthier et al. [26] noted an abundance of cytoplasmic filaments around the
nucleus in some melanocytes, but the significance of this finding is unknown.
At the ultrastructural level, the depigmentation appears to result from an absence of melanocytes or a markedly reduced number of melanocytes and impaired production of melanin in the remaining melanocytes.

FIGURE 244. Melanocyte M, shows severe vacuolar and coagulation degeneration. M2 also contains many vacuoles and remains in the same position between M, and Langerhans cell L2. It does
not extend toward the basal layer. L2 contains a large number of L cell granules (arrow in inset).
Keratohyaline granule (K) containing granular cells, and horny cells (H) are just above these cells.
Not only the intercellular edema but also severe degenerative changes (*) are seen in malpighian
cells. The rectangle at L2 indicates the area enlarged in the inset. N2 = nucleus of L2 (x 8,000).
Inset x 61,000. (From: Hashimoto K: A case of halo nevus with effete melanocytes. Acta Derm
Venereol (Stockh) 55:87-95, 1975. Copyright, 1975, Society for the Publication of Acta DermatoVenereologica. Used with permission.)

587

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CHAPTER 8

FIGURE 245. Pyknotic nucleus (N) is visible in the same cell (Md shown in Fig. 244. A part of
the cytoplasm is enlarged in the inset and broad arrows in both pictures point to the same area.
Melanosomes in various stages of maturation are seen (broad arrows). Many immature ones appear
to be degenerating in vacuoles. Coagulation necrosis (cn) or dense homogenization of the cytoplasm
is enlarged in the inset. This melanocyte is located among granular cells which contain cytoplasmic
(kJ and intranuclear (thin arrows) keratohyaline granules (x 1200). (Inset x 60,000) (From Hashimoto K: A case of halo nevus with effete melanocytes. Acta Derm Venereol (Stockh) 55:87-95,
1975. Copyright, 1975, Society for the Publication of Acta Dermato-Venereologica. Used with
permission.)

Langerhans Cells
An increased number of Langerhans cells has been observed at the basal
layer [40,63,65,67,69,70]. Studies of Mishima et al. [67] show the total number
of Langerhans cells in the entire epidermis is normal. Usually the Langerhans
cells appear normal. However, Hashimoto [65] observed a few vacuolated cells.
Cesarini et al. [64] described Langerhans cells with "feather-like bodies" (considered to be debris of melanosomes or of Langerhans cell-specific granules),
stage IV melanosomes, and dense vesicles containing pseudomyelin structures,
limited by a unit membrane, perhaps of lysosomal origin. Ebner and Niebauer
[69] observed melanin granules in the cytoplasm of Langerhans cells.
Indeterminate Cells
Zelickson and Mottaz [68] observed the same number of "indeterminate
cells" in the hypopigmented epidermis as in normal epidermis, but Mishima
et al. [67] found an increased number. Well-established older halos may have
no indeterminate cells.
Keratinocytes
Except for pigmentary changes, the keratinocytes are normal. Usually the
number of melanosomes in keratinocytes is decreased [40,63,66] or totally
absent. Stegmaier et al. [43] observed that keratinocytes contained a normal
number of melanosomes and melanosome complexes. Hashimoto [65] described degenerative changes in the keratinocytes. A few lymphocytes have
also been observed in the hypopigmented epidermis [66].
Epidermis Overlying the Nevus
Melanocytes
Melanocytes in the epidermis overlaying the nevus are usually normal in
number and contain numerous melanized melanosomes [40,64]. Tyrosinase
activity is slightly increased [40]. Hashimoto [65] described vacuolated and
shriveled pigmented cells in the upper layers of epidermis, but could not
determine whether these high-level effete cells originated from normal melanocytes or from nevus cells (Fig. 246).
Langerhans Cells
Langerhans cells are normal in number [40,64] and in morphology.
Keratinocytes
Keratinocytes are usually unaffected, except that they may be overloaded
with pigment and contain many melanosomes or melanosome complexes

589

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590

CHAPTER 8

FIGURE 246. Advancing border of depigmentation. No nevus cells forming a nest are seen.
Transferred melanin pigment is visible in the basal cells and lower malpighian cells but not in
clear cells. Several shrunken clear cells (*) are present near the granular cell layer. Some of the
basal clear cells are vacuolated (x 400). (From: Hashimoto K: A case of halo nevus with effete
melanocytes. Acta Derm Venereol (Stockh) 55:87-95, 1975. Copyright, 1975, Society for the Publication of Acta Dermato-Venereologica. Used with permission.)

[40,64,66]. Cesarini et al. [64] observed a thinning of the epidermis with significant intercellular edema and Jacobs et al. [71] described disruption of some
keratinocytes.

The Nevus

The nevus cell population is often somewhat heterogenous. Nevus cells,

usually in clusters, may be observed in the basal layer of the epidermis [63,65].
Swanson et al. [63] observed also in the epidermis "small lymphocyte-like
cells," and although these authors could not determine the type of these cells,
it is likely that they are lymphocytes. Some of these showed degenerative
changes. The nevus cells are epithelioid or Type A nevus cells [40,64]. Gauthier
et al. [26] observed, in the most superficial nests of nevi, light Type A nevus
cells surrounded by many darker Type B nevus cells, present sparsely or in
clusters. In the deep dermis, the nevus cells are intimately entwined with the
inflammatory cells.
The histologic dynamics of halo nevus evolution are well described by
Jacobs et al. [72] who classified the inflammatory changes into four stages. Stage
I (erythema and edema) showed an edematous papillary epidermis with vasodilatation, early mononuclear infiltration of the reticular dermis, and intact
nevus cells. Lymphocytes and monocytes were present next to and within the
nevus cell nests (Fig. 247). An electron-dense material was noted at the plasma
cell-nevus cell junction where cell membranes were thickened. Electron-dense
flocculent material was also present between contacting cell membranes of
lymphocytes and nevus cells. In stage II (erythematous, raised nevus with faint
halo formation), loss of melanin became apparent and there was minimal in-

591
LEUKODERMA
ACQUISITUM
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FIGURE 247. Nest of nevus cells

with inflammatory infiltrate. Nevus cells of Type A (A) and Type
B (B) are seen. Among them are
a macrophage (Ma) and a lymphocyte-like cell (Ly) (x 4500).
(From: Gauthier Y et al: Ultrastructure of halo nevi. J Cutan
Patho12:71-81, 1975. Copyright,
1975, Munksgaard International
Publishers, Copenhagen. Used
with permission.)

flammation of junctional nests of nevus cells, marked inflammation in the

reticular dermis, and degenerative nevus cells with pyknotic nuclei and vacuolated cytoplasm. The vacuoles, apparently derived from endoplasmic reticulum, were filled with electron-dense granular material. Other nevus cells
contained large electron-lucid vacuoles. Stage III (flat, with established halo
formation) showed complete depigmentation (except less so overlaying the
nevus) and fewer inflammatory or nevus cells. Occasional melanophages containing phagocytized portions of nevus cells were present. Phagocytized cytoplasm contained electron-lucid vacuoles and degenerated organelles. In this
stage, nevus cell destruction was widespread with nuclei separated from vacuole-laden cytoplasm. Vacuolated nevus cells in junctional nests appeared
necrotic. Basal melanocytes were rounded with vacuolar cytoplasmic changes.
Keratinocytes also displayed vacuolar changes but only in the region of the
packaged melanosomes, and those keratinocytes with large vacuoles had no
melanin. In stage IV (hypopigmented macule without nevus), the histology
resembled vitiligo; keratinocytes had no vacuoles and there was no melanin.

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The dermis contained only occasional nevus cells, disrupted mast cells, lymphocytes, and pigment-laden macrophages.
The inflammatory infiltrate is predominantly lymphocytic (Fig. 248). Swanson et al. [63] observed small lymphocyte-like cells, particularly in the deeper
portions of the nevus, and suggested these cells could also represent Type B
nevus cells. Gauthier et al. [26] distinguish the lymphocyte-like cells from the
Type B nevus cells, as only the former have very dense chromatin and unipolar
mitochondria. Although Jacobs et al. [71] considered most inflammatory cells
infiltrating the nevus to be antigenic ally activated lymphocytes, Gauthier et al.

FIGURE 248. Advanced clinical stage. Infiltrate in the deeper dermis. Different types of cells can
be observed: lymphocyte-like cells (Ly), macrophages (Ma), mast cells (Me), and fibroblasts (Fi)
(x 2000). (From: GauthierY et al: Uitrastucture of halo nevi. J Cutan Pathol 2:71-81, 1975. Copyright, 1975, Munksgaard International Publishers, Copenhagen. Used with permission.)

[26] noted that only a few of the inflammatory cells showed ultrastructural

features associated with antigenic stimulation (numerous cytofilaments, many

cytoplasmic polyribosomes, absence of organized endoplasmic reticulum).
Contact between lymphocytoid cells and nevi or melanocytes has been
observed in three cases of "halo" compound nevi [26] (Fig. 249). Mononuclear
cells abutting abnormal nevus cells have also been observed [57] (Fig. 250).
The latter contained dilated and distorted mitochondria and small, dense,
lamellated bodies in the cytoplasm, which were called "melanolysosomes,"
corresponding to autophagocytosis. As noted earlier, Jacobs et al. [72] ob-

FIGURE 249. Superficial nest of nevus cells in the epidermis [Ep). Nevus cells [Nc) are seen in
contact with several lymphocyte-like cells [Ly) (x 9000). (From: Gauthier Y et al: Ultrastructure
of halo nevi. J Cuton Potho12:71-81, 1975. Copyright, 1975, Munksgaard International Publishers,
Copenhagen. Used with permission.)

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FIGURE 250. Close contact between a small mononuclear cell with a deeply clefted nucleus (N)
and a fibroblast-like cell (Fi) (x 25,000). (From: Gauthier Y et al: Ultrastructure of halo nevi. J
Cutan Pathol 2:71-81, 1975. Copyright, 1975, Munksgaard International Publishers, Copenhagen.
Used with permission.)

served that when lymphocytes and nevus cells are in contact, the involved
cells have thickened cell membranes with small ruptures along the points of
contact.
Other types of cells observed include numerous melanophages, some plasma
cells, and a few mast cells. Langerhans cells have been observed in the dermal
infiltrate of halo nevus [70].
Gauthier et al. [26] described multiplication of the basement membrane
and a swollen unmyelinated nerve close to the epidermis, similar to vitiligo.

HALO PHENOMENA AROUND LESIONS OTHER THAN NEVUS

CELL NEVUS
Halos of hypopigmentation may occur around a variety of pigmented lesions, including neurofibroma, flat warts, neurotized nevus, blue nevus, garment nevus, Spitz nevus, and melanoma (primary tumor or cutaneous metastases). However, in such cases resolution does not occur. Wayte and Helwig
[5], among 105 nevi examined, noted one to have features of an epithelioid
and spindle cell nevus.

Neurofibroma
Leszczynski [73] first described halos around multiple neurofibromas in a
healthy 48-year-old woman. Kopf et al. [24] also reported that in one of their
cases the central tumor was not a nevus cell nevus but was a neurofibroma. A
patient with multiple halo neurofibromas and probably Recklinghausen disease
has been reported [74].
The histology surrounding the neurofibroma is essentially that of the halo
of a nevus cell nevus.

Flat Warts
Two patients with depigmented halos around involuting flat warts have
been described [75]. The warts had been unresponsive to three-and-one-half to
five months of topical salicylic acid-propylene glycol gel (Keralyt) usage before
the depigmentation appeared. In both cases all warts with depigmentation
regressed in three to eight weeks. In one of the patients depigmentation appeared around only three of the warts and these were the only warts to disappear. Patch testing with Keralyt applied to normal skin for four to six months
did not induce any depigmentation.
Histologic studies of one lesion showed mononuclear cell infiltrate in the
central lesion with exocytosis of mononuclear cells into the epidermis. Necrosis, spongiosis, and hyalinized epithelial cells were prominent in the epidermis.
The upper epidermis showed lymphocytic infiltration around subpapillary blood
vessels, few histiocytes, edema, dilated papillary and subpapillary vessels, and
focal hemorrhage. Masson silver stain demonstrated absence of melanin in the
halo epidermis.

Neurotized Nevus
Kopf et al. [24] observed two cases in which the central tumor was a neuroid
nevus; most of the nevus cells closely resembled neuroid structures. In both
cases, the tumor within a protruding area of the papillary dermis was amelanotic

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FIGURE 251. Halo of depigmentation around giant congenital nevus.

and entirely intradermal in location. No functional nevus cell theques were

present and the tumor elements were almost entirely composed of long, palestaining fascia of neuroid structures. Small dark cells, probably lymphocytes,
were present, although sparsely so. Argentaffin stain revealed a total absence
of melanin pigment in the epidermis directly overlaying the tumor as well as
in a broad zone surrounding it.

Blue Nevus
Kopf et al. [24] observed a halo around a lesion that had the typical histologic features of a blue nevus. Apart from a mild perivascular leukocytic
infiltrate in the upper dermis outside the tumor area, the lesion was remarkably
free of inflammatory infiltrate. Iijima and Kanazawa [76] described a similar
case and noted that blue nevus cells were dopa-positive whereas the epidermis
was not.

Garment Nevus
Ridley [41] reported a case of giant congenital nevus that underwent considerable spontaneous resolution (Fig. 251). In the chronically depigmented
skin, there were no residual nevus cells and no inflammation. The dermis
contained some melanin-containing macrophages. Berger and Voorhees [40]
also described a middle-aged woman with a giant pigmented nevus with a wellmarked halo.

Melanoma
Several types of cutaneous depigmentation have been associated with cutaneous melanomas (Table 123). They may occur at the site of the tumor (Fig.
252) or its metastases or at sites distant from the tumor or its metastases.
There are many reports of appearance of the halo phenomenon around a
primary melanoma or cutaneous metastases. Merklen and Pelbois [77] pre-

TABLE 123. Types of Depigmentation Associated with

Melanoma
At sites of the tumor or its metastases
Spontaneous partial or complete regression of the primary
Leukoderma acquisitum centrifugum around primary or metastatic
lesion.
Remote from the tumor or its metastases:
Halo nevi around preexisting moles
Vitiligo-like depigmentation
Vogt-Koyanagi-Harada-like syndrome
Nonspecific depigmentary phenomenon

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FIGURE 252. Circumscribed area of depigmentation within a primary malignant melanoma. Lesion has been encircled with ink. (From: American Academy of Dermatology Melanoma Home
Study Program. Compiled by TB Fitzpatrick et al. Copyright, 1974, Syntex Laboratories, Palo Alto,
California. Used with permission.)

sen ted a case first thought to represent a benign halo nevus but subsequently
found to be a halo around a melanoma [78). Champion [79) reported as "malignant Sutton's nevus" a central nodular melanoma surrounded by a pale zone
which in turn was almost completely encircled by a zone of senile lentigines.
Stehlin [80) observed a primary melanoma of the foot with a surrounding halo
which appeared after the limb was perfused with chemotherapeutic agents.
Several months later, other pigmented lesions appeared on the patient's back
and depigmented halos developed around these also. Kopf et al. [24) followed
an elderly man with disseminated melanoma who developed depigmented
halos around many of his cutaneous metastases; thereafter, spontaneous resolution of the metastases ensued so that only macular areas of depigmentation
remained. Shapiro and Kopf [81) reported a nine-year-old girl who developed
widespread lymphadenopathy, visceral metastases, and a depigmented halo
around a pigmented cutaneous tumor; histologic studies of the cutaneous tumor
and axillary metastases suggested melanoma. Goldman et al. [82) observed
perilesionalleukoderma appearing suddenly around metastatic melanomas in
many areas of the skin. Other cases have also been recorded [5,58,59,83,84).
The frequency of occurrence of partial or complete halos of depigmentation
around primary or metastatic melanoma has not been firmly established; examination of melanoma patients with a Wood's light may assist in revealing
subtle examples of this phenomenon [82,85).
Depigmentation may be observed at the sites of spontaneous, total or partial
regression of the primary melanoma. In some patients with metastases, cir-

cumscribed macules of depigmentation occur. They have been interpreted as

sequelae of the involution of the primary melanoma [84,86-88].
Of the 3% to 8% of melanoma patients whD present with metastatic melanoma and no demonstrable primary lesions [86,87], some have small macules
of depigmentation which may be the equivalent of a "resolved halo nevus" and
may, in fact, represent the site of a primary tumor that underwent spontaneous
and complete resolution.
Das Gupta et al. [89] found that 37 of 992 melanomas had metastatic lesions
but cryptic primary sites. Two of these 37 cases had macules of leukoderma
of which histologic examination revealed focal melanophages and minimal
chronic inflammatory infiltrate, but no tumor cells-the same histologic picture
reported in end-stage halo nevus. Sumner [88], and later Sumner and Foraker
[90], observed a woman who had on the ankle a mole that became "infected
and dropped off" to leave an area of depigmentation; three years later, she
appeared with disseminated melanoma. Everson[91] reported a man who experienced spontaneous resolution of a multiple cutaneous metastases. The cutaneous sites of the previous melanoma tumors were described as "bone white
depigmented" scars. Such patients with metastatic melanoma of unknown origin should be examined with Wood's light to elicit a potential primary site.
Biopsy of many of these depigmented areas may resemble that of halo
nevus, namely lymphocytic infiltrate with absence of pigment and melanocytes
[92]. It appears that melanocytes may be absent or reduced in number. In
another more recent study [93], large (two to three times normal size) but
reduced numbers of dopa-positive melanocytes were found in depigmented
macules remote from the primary melanoma. These differences must reflect
varied degrees or stages of melanoma-associated depigmentation. Clinically,
such patients have hypomelanotic, but not amelanotic, macules.
Partial or complete halos of depigmentation have been observed around
primary melanomas [24,83] or their metastases [58,92] (Fig. 253). Halo nevi
around preexisting moles have been reported to occur following removal of
melanomas [57] or prior to treatment [58].
A vitiligo-like depigmentation and a nonspecific depigmentation phenomenon have been observed in patients with melanoma (see "Vitiligo" in Chapter
I) (Figs. 254, 255). As with other melanoma-associated leukodermas, studies
have shown both absence of melanocytes and abnormal dendritic melanocytes
[93]. Autophagic vacuoles containing melanosomes within the melanocytes in
the depigmented epidermis have also been described [94].
A Vogt-Koyanagi-Harada-like syndrome with uveitis and vitiligo-like depigmentation has been observed in two melanoma patients with melanomas
following BCG therapy [59] (Fig. 256) and in one melanoma patient not subjected to immunotherapy [85] (Fig. 257).

PATHOGENESIS
Over time, halo nevus has been considered to be a neurotrophic, postinflammatory, or an immunologic disorder.
That the leukoderma surrounding a nevus results from a neurotrophic

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FIGURE 253. Malignant melanoma with hypomelanosis on the dorsum of the foot. remote from
the site of the tumor. (From: Frenk E: Depigmentation vitiligineuse chez des patients atteints de
melanome malin. Dermatologica 139:84-91. 1969. Copyright. 1969. S. Karger A.G. Used with
permission. )

disturbance is a hypothesis favored by scanty evidence. Gauthier et al. [26]

observed some changes in the unmyelinated nerves of the superficial dermis
in the depigmented skin of halo nevi, but these abnormalities were probably
secondary to, and not the cause of, halo nevus.
Depigmentation in halo nevus is not merely a postinfiammatory change.
Most authors consider halo nevus to result from an immunologic mechanism
in which nevus cells and the embryologically related melanocytes are destroyed. Many clinical and laboratory observations support such an immunologic basis for halo nevus. Depigmented halos may appear around preexisting
nevi in patients with malignant melanoma [57]; lymphocytes from these patients display cellular immunity toward melanoma cells. Halo nevi have been
observed distant from the site of guanonitrofuracin-induced [48] or Benoquininduced [37] depigmentation. The appearance of multiple halo nevi in a 23year-old white woman being treated with oxymetholone for severe hypoplastic
anemia [95] suggested an oxymetholone-induced alteration in immune surveillance, so that a mutant clone of B- and/or T-Iymphocyte precursor cells
developed. Or there may have been an oxymetholone-induced alteration in the
cell surface antigen of the nevus cell, or a reconstitution of immune surveillance
by repopulation of the bone marrow. It is possible of course that, in this case,
the development of halo nevi may have been purely coincidental.

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FIGURE 254. Vitiligo-like depigmentation on the dorsa of the

hands and arms in a patient with
a malignant melanoma of the right
foot.

FIGURE 255. Hypomelanosis in a patient with subcutaneous metastasis of a malignant melanoma.

(From: Donaldson RC et al: Uveitis and vitiligo associated with BCG treatment for malignant
melanoma. Surgery 76:771-778, 1974. Copyright. 1974. The C. V. Mosby Company. Used with
permission.

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CHAPTER 8

FIGURE 256. Vitiligo-like depigmentation in a patient treated by immunotherapy.

Sinclair swine probably represent an animal model for halo nevus. Millikan
et al. [96] observed that a large number of melanocytic nevi occur in Sinclair
swine (Fig. 258). The pathology of these lesions and the organ distribution of
metastases mimics human melanomas [97]. Some of these tumors regress dramatically. Regression accompanied by depigmented halos around the tumors
begins with an inflammatory infiltrate and leads to depigmentation and fibrosis.
Ultrastructurally, regressed lesions show an almost complete absence of melanocytes.
The inflammatory infiltrate, which is predominantly lymphocytic in nature, seems to be composed of antigenically activated lymphocytes [26,71]. In
situ immunocytochemical identification by antihuman T or B lymphocyte antigens show that most of the inflammatory cells are T lymphocytes [97a]. Contact
between these cells and degenerating nevus cells or melanocytes has been
observed [57]. Reed et al. [98] suggested that atypical nuclear changes commonly seen in halo nevi prove the existence of melanocytic dysplasia. They
further concluded that the halo reaction more likely results from an abnormal
clone of melanocytes than from the action of an abnormal clone of lymphocytes
against nevus cell nevus.
A number of studies have attempted to demonstrate the presence of a
circulating factor in those with halo nevi. Sumner and Foraker [90] transfused
whole blood from a patient with spontaneously regressing primary and metastatic melanoma into a man with similar lesions. Thereafter, all of the lesions
of the latter disappeared and, following regression of a scalp tumor nodule, the
overlying hair became depigmented while the rest of his hair remained black.
Melanoma-specific protein, immunologically related to altered nevus cell

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FIGURE 257. Vitiligo-like depigmentation involving face and neck as well as circumscribed areas
of otherwise normal skin surrounding each pair of BCG vaccination scars in both deltoid areas in
a patient with metastatic malignant melanoma. There is a halo of depigmentation around an
intradermal lesion in the left supraclavicular area.

cytoplasm has been detected not only in melanoma patients but also in patients
with actively developing halo nevi [99]. Although Kopf et al. [24] were unable
to detect prefixed or 7S gamma globulin antibodies directed against tumor cells
in halo nevi, Copeman and coworkers [25,54] found circulating antibodies
against the melanoma cell cytoplasm in 15 of 23 patients with halo nevi. Antibody cound be detected while the nevi were actively regressing cytologically,
but usually disappeared after this stage so that the halo itself could be present
for some time after the cytoplasmic antibody could no longer be detected. This
antigenic link between halo nevus and melanoma raised the possibility that
benign halo nevus, although all other clinical and histopathologic features
suggest it is benign, may be a manifestation of a seldom seen interim stage of
rejection of an early melanoma arising in such a nevus. The halo nevus must
be just an exaggerated expression of a natural protective mechanism in which
the entire nevus tumor mass rather than perhaps just a few selected cells
undergoes a dramatic, rapid, and massive rejection.

604
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FIGURE 258. In many of the Sinclair swine. the first sign of regression of pigmented tumors is
the appearance of depigmented hair around the lesions. These changes in the hair coat allow one
to look deep into the hair to find an involuting lesion. Here we can see some whitening and
keratosis of this lesion. This could be considered as the animal model of human leukoderma
acquisitum centrifugum. (From: Millikan LE et al: Gross and ultrastructural studies in a new
melanoma model: the Sinclair swine. Yale JBiol Med 46:631-645.1973. Copyright. 1973. Academic
Press. Inc. Used with permission.)

Presence of a cytopathic cytoplasmic antibody suggests that in those with

halo nevi the vitiliginous depigmentation distant from the tumor results from
the same process. This presumes an antigenic link not only between melanoma
cells and nevus cells but also between nevus cells and normal epidermal melanocytes. Several objections may be raised. Whimster [100] noted that there
is no conclusive proof that these antibodies are associated with malignancy or
that malignancy can be implicated in cases of halo nevi. Furthermore, the
presence of multiple halo nevi would imply that several different nevi are
undergoing malignant changes at the same time, or perhaps that only one of
these nevi had undergone malignant change but that the immune rejection
phenomenon precipitated a halo reaction around other nevi in the absence of
malignant changes. This suggests that depigmentation should surround all the
nevi in the affected individuals, but even in patients with multiple lesions, not
all the cutaneous nevi are halo nevi. Also, aside from the presence of lymphocytes, the histology of the early melanoma and halo nevus [100] have little in

common. Rather, the common factor between the two might be the processes
of involution and cell destruction and not malignancy. Apparently a primary
unknown event alters melanocytes and/or nevus cells, and initiates a progressively destructive self-limited immunologic process.
Cytotoxic lymphocytes have been noted in patients with halo nevi [101).
Roenigk et a1. [102) studied tumor immunity by cell inhibition (microcytotoxicity) assay in 11 patients with halo nevus (Fig. 259). The target cells in this
study were derived from cultured melanoma cell lines. Actively regressing halo
nevi showed a high percentage of cell inhibition, whereas inactive halo nevi
had low levels of cell inhibition and of blocking factor. With indirect immunofluorescent microscopy, tumoral antibodies against the cytoplasmic melanoma cell antigen could be demonstrated in five of 11 patients with halo nevi.
They concluded that perhaps cellular cytotoxicity against melanoma cells may
be more important than tumoral antibodies. Clark, Leung, and Mastrangelo
(unpublished data) and Mastrangelo et a1. [103) have also observed that the
lymphocytes of patients with halo nevi with or without melanoma are cytotoxic
to allogenic melanoma cell lines.
Five patients with primary melanoma and multiple halo nevi that developed after the melanoma was excised were subjected to skin testing; these
patients were found to have normal to increased cellular immunity [57). All
four cases evaluated displayed cellular immunity in at least one in vitro test
(lymphocyte stimulation, migration inhibitory factor production, or rosetteforming lymphocytes). Only two of four patients had antibodies cytotoxic to
melanoma cells. It has been demonstrated that cultured lymphocytes from
patients with halo nevi quickly attach to several different lines of cultured
human melanoma cells, after which the tumor cells swell, become vacuolated,
and die [104) .
Stegmaier et a1. [43) proposed the following hypothesis: Dermal nevus cells
become antigenic, attract lymphocytes, and a delayed hypersensitivity reaction
occurs. A soluble substance cytotoxic to melanocytes is produced and attaches
to the nevus cells and to epidermal melanocytes in areas not protected by nevus
cells. There is progressive destruction of nevus cells, active epidermal melanocytes above the nevus cells, and inactive melanocytes beyond the nevus.
60
c:

.2
-:;
:;
FIGURE 259. Comparison of percent
of cell inhibition in patients with halo
nevus (regressing and persisting) and
normal controls scoring greater than 40%
cell inhibition against melanoma target
cells. (From: Roenigk HH Jr et al: Microtoxicity and serum blocking factors
in malignant melanoma and halo nevus .
Arch Dermatol 111:720-725, 1975.
Copyright, 1975 , American Medical Association. Used with permission.)

c.
o

40

11.

'0
'E

e
CD

20

11.

o
5
Normal

Halo Nevus

Halo Nevus

Regressing

Persisting

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From their electron microscopy study of halo nevi in different stages of

regression, Jacobs et al. [72] proposed a sequence of events. The earliest change
in the lesion is a migration of lymphocytes and monocytes into the tumor mass.
The nevus cells, in both the dermis and the epidermis, are separated and
surrounded by the inflammatory cells. Reactivity of inflammatory cells against
nevus cells causes focal nevus cell membrane destruction. A diffusible lymphotoxin is released and this causes necrosis of both melanocytes and nevus
cells.
However, Gauthier et al. [26] noted that the inflammatory infiltrate does
not seem to appear early in the stages of involution but rather comes later.
They suggested an initial stage (lymphocytes absent) of inhibition of both melanocytes and nevus cells may be responsible for the development of the depigmented halo. The later lymphocyte phase (lymphocytes present) is responsible only for the destruction of the nevus. Thus, the halo nevus phenomenon
is a two-step process [40]. Step one results in the disappearance of the melanocytes as in vitiligo. There is no dermal cellular participation at this level.
Step two requires massive lymphomacrophagic intervention and results in the
destruction of the nevus.
Further serial studies should resolve this issue.

DIAGNOSIS
The diagnosis of leukoderma acquisitum centrifugum is based on identification of a nevus or tumor with a perilesional hypomelanotic halo. There is
no other clinical entity that is characterized by a central pigmented tumor
surrounded by a symmetrical halo of depigmentation. However, particularly
in fair-skinned individuals, Wood's light examination may be required to detect
those lesions that are inapparent under ordinary light. Macules of depigmentation around senile verruca [105], papular sarcoid [12], vascular nevus [72],
dilated pores [106] and comedones (personal observation by the authors) have
also been noted.
The appearance of a halo of hypo pigmentation around any pigmented
tumor should always lead to a careful clinical scrutiny of the central lesion
(Table 124). The only clinical problem is to be certain the central tumor is not
a melanoma and this distinction is usually not difficult. The age of the patient
TABLE 124. Features of Leukoderma Acquisitum
Centrifugum That May Be Associated with Melanoma
Eccentric placement of tumor
Irregular margin of halo
Pruritus of lesion
Bleeding of lesion
Growth of tumor
Red, white, and blue color of tumor
Appearance in older adult
Note: The primary melanoma may anatomically be elsewhere


Benign Halo Nevus

FIGURE 260. The "halo" surrounding

benign and malignant pigment-cell neoplasms.

-tumor centrally placed

-halo round or oval and
regularly shaped

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Halo surrounding tumor

suspected of being
malignant
- tumor eccentrically placed
- halo irregularly shaped

is helpful. Halo nevi typically occur in the young, especially in adolescents,

and are unusual later in life. The occurrence of halos of hypopigmentation
around pigmented lesions in middle life or later life should at least suggest the
presence of leukoderma acquisitum centrifugum around a melanoma or a halo
nevus appearing in the course of an unrecognized melanoma. The occurrence
of "active changes" in the nevus may be very distressing. Irregular, enlarging,
pruritic, and red, white, and blue nevoid lesions suggest melanoma [107].
A "halo nevus" that bleeds should be considered malignant. Clark and
Mihm [108] noted that hypopigmented halos around benign moles and other
benign lesions are quite symmetrically round or oval in shape, and that the
benign tumor is placed centrally in the depigmented macule. Halos around
melanomas tend to be irregular in shape and the malignant lesion lies eccentrically in the hypopigmented area [108,109] (Fig. 260). Hence, the presence of
an irregular halo around a pigmented lesion that is eccentrically placed within
the white macule should lead to the biopsy of the pigmented lesion. In all
patients with halo nevus, particularly older patients, complete examination of
the skin to exclude melanomas is indicated.

TREATMENT
Patients and particularly the parents of young involved children will need
to be reassured the lesions are not malignant. Typical halo nevi require no
treatment. The natural course is for spontaneous resolution, although this sometimes requires years. In all the cases where there is a clinical suspicion of
melanoma, removal of the entire nevus for histologic examination should be
performed. Patients with one halo nevus are probably at increased risk of
developing more and of developing vitiligo.

REFERENCES
1. Rohdenburg GL: Spontaneous recession of multiple pigmented moles. Arch Pathol Lab Med
4:528-529, 1927

2. Narducci F: Sui neo leucopigmentario et sulla vitiligine perinevica. Arch Ital Derm Vener
1:271-273,1925

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3. Montpellier J: Vitiligo a debut perinaevique. Bull Soc Fr Dermotol Syphiligr 29:81-83, 1922
4. Leider M, Cohen TM: Leukoderma acquisitum contrifugum. Arch Dermotol SyphiloI57:380-386,
1948
5. Wayte DM, Helwig EB: Halo nevi. Cancer 22:69-90, 1968
6. Kuske H: Ober Leukoderma acquisitum centrifugum (Sutton). Dermotologico 88:282-290,
1943
7. Hebra F, Kaposi M: In On Diseases of the Skin, Including the Exanthemata. Edited and
translated by W Tay. London, New Sydenham Society, 1874, pp 180-182
8. Hyde IN: Vitiligo, a rare form of. J Cuton Dis 24:84-85, 1906
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1910
10. Almkvist J: Fall von eigentumlichen Naevi. Dermotol Wochenschr 60:74, 1915
11. Sutton RL: An unusual variety of vitiligo (leukoderma acquisitum centrifugum). J Cuton Dis
34:797-800, 1916
12. Stokes JH: Clinical note on leukoderma acquisitum centrifugum (Sutton). Arch Dermotol
Syphilol 7:611-618, 1923
13. Gougerot H, Carteaud A: Maladie de Sutton avec regression d'un naevus pigmentaire pendant
l'accroissement de l'achromie. Bull Soc Fr Dermotol Syphiligr 41:1526-1527, 1934
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15. Bunch JL: White spot disease and vitiligo. Br J Dermotol 30:203-207, 1918
16. Feldman S, Lashinsky 1M: Halo nevus-leukoderma acquisitum centrifugum (Sutton): leukopigmentary nevus. Arch Dermotol Syphilol 34:590-604, 1963
17. Petges M: Naevus achromique (ou vitiligo perinaevique). Bull Soc Fr Dermotol Syphiligr
28:302-304, 1921
18. Weber FP: A law regarding the distribution of the depigmented (leucodermic) patches of
vitiligo, when they are superadded to mole-like nevi. Br J Child Dis 21:202-206, 1924
19. Crawford S: Leukoderma acquisitum centrifugum (case report). Arch Dermotol SyphiloI9:394,
1924
20. Leider M, Fisher AA: Fate of central nevus in leukoderma acquisitum centrifugum. Arch Belg
Dermotol Syphiligr 60:1160-1166, 1949
21. Poor FV: Ober Leucoderma acquisitum centrifugum (Sutton). Dermotol Wochenschr 80:401-405,
1925
22. Niles HD: Leukoderma acquisitum centrifugum. Arch Dermotol Syphilol 43:357-360, 1951
23. Frank SB, Cohen HJ: The halo nevus. Arch Dermotol 89:367-373, 1964
24. Kopf AW et al: Broad spectrum of leukoderma acquisitum centrifugum. Arch DermotoI92:14-35,
1965
25. Copeman PWM et al: Immunological associations of the halo nevus with cutaneous malignant
melanoma. Br J Dermotol 88:127-137, 1973
26. Gauthier Y et al: Ultrastructure of halo nevi. J Guton Pothol 2:71-81, 1975
27. Chorazak T, Rzempoluch E: Etiopathogenesis of vitiligo in the light of our studies. Pol Med
J 7:494-500, 1968
28. El Mofty AM: Vitiligo and Psoralens. New York, Pergamon, 1968
29. Bor S et al: Vitiligo and its etiological relationship to organ specific autoimmune disease. Br
J Dermotol 81:83-88, 1969
30. Lerner AB: Vitiligo. Prog Dermotol 6:1-6, 1972
31. Perrot H et al: Vitiligo, thyreopathies et autoimmunite. Lyon Med 230:325-331, 1973
32. Copeman PWM et al: Biology and immunology of vitiligo and malignant melanoma, Recent
Advances in Dermatology. Edited by AJ Rook. London, Churchill Livingstone, 1973, pp
245-258
33. Ortonne JP: Le vitiligo: maladie ou syndrome. These Medecine, Lyon, 1974
34. Schnitzler L et al: Vitiligo et associations pathologiques: resultats de quelques explorations
biologiques sur une periode de 2 ans. Bull Soc Fr Dermotol Syphiligr 81:542-545, 1974
35. Graham JH et al: Multiple nonpigmented nevi in a Negro child. Arch Dermotol 88:313-319,
1963
36. Findlay GH: Histology of Sutton's naevus. Br J Dermotol 69:389-394, 1957

37. Cornbleet T et al: Acquired halo-nevus like formation from Benoquin. Arch DermotoI78:276-277,
1958
38. Cornbleet T et al: Observations on leukoderma acquisitum centrifugum. Arch Dermotol
82:1011-1012, 1960
39. Kopf AW, Petratos M: Leukoderma acquisitum centrifugum, leukotrichia, and leukoderma
areata. Arch Dermotol 93:624-625, 1966
40. Berger RS, Voorhees JJ: Multiple congenital giant nevocellular nevi with halos. Arch Dermotol
104:515-521, 1971
41. Ridley CM: Giant halo nevus with spontaneous resolution. Trans St Johns Hosp Dermotol
Soc 60:54-58, 1974
42. Boardman CR: Perinevoid vitiligo (leukoderma acquisitum centrifugum). Arch Dermotol
85:554-555, 1962
43. Stegmaier OC et al: Multiple halo nevi: histopathological findings in a 14 year old boy. Arch
Dermotol 99:180-189, 1969
44. Brownstein MH et al: Halo congenital nevus. Arch Dermotol113:1572-1575, 1977
45. Garcia RL, Gano SE: Halo congenital nevus. Cutis 23:338-339,1979
46. Dupre A, Christol B: Cockade-like vitiligo and linear vitiligo, a variant of Fitzpatrick's trichrome vitiligo. Arch Dermotol Res 262:197-203, 1978
47. Netherton EW, Curtis GH: Leukoderma acquisitum centrifugum. Arch Dermotol Syphilol
39:163, 1939
48. Yamada M: Studies on Guanofuracin leukoderma. Jpn J Dermotol VenereoI65:187-202, 1955
49. Chisa N: Multiple halo nevi in siblings. Arch Dermotol 92:404-405, 1965
50. Fitzpatrick TB, Mihm MC Jr: Abnormalities of the melanin pigmentary system, Dermotology in General Medicine. Edited by TB Fitzpatrick et al. New York, McGraw-Hill, 1971,
p 1614
51. Lerner AB: Vitiligo. J Invest Dermotol 32:285-310, 1959
52. Ito M, Yoshida Y: Malignant melanoma. Tohoku J Exp Med 55(suppll):60-71, 1952
53. Stegmaier OC: Transplantation of melanocytic nevi into vitiliginous skin. J Invest Dermotol
36:47-54, 1961
54. Lewis MG, Copeman PWM: Halo nevus: a frustrated malignant melanoma. Br Med J 2:47-48,
1972
55. Kawamura T et al: Gray hair on the nevus cell nevus. Jpn J Dermotol [B] 73:305-308, 1963
56. Perlman HH: Vitiligo, leukoderma acquisitum centrifugum, nevus pilosus, premature graying.
Arch Dermotoll0l:123-124, 1970
57. Epstein WL et al: Halo nevi and melanoma. lAMA 225:373-377, 1973
58. Clark WH et al: The developmental biology of primary human malignant melanomas. Semin
Oncol 2:83-103, 1975
59. Donaldson RC et al: Uveitis and vitiligo associated with BCG treatment for malignant melanoma. Surgery 76:771-778, 1974
60. Dawber RPR: Integumentary associations of pernicious anemia. Br I Dermotol 82:221-223,
1970
61. Fitzpatrick TB: Quoted in Stegmaier OC et al: Multiple halo nevi: histopathological findings
in a 14 year old boy. Arch Dermotol 99:180-189, 1969
62. Tanaka H: Studies of pigmentation in nevoid neoplastic and other diseases of skin. Jpn I
Dermotol 68:59-64, 1958
63. Swanson JL et al: Ultrastructure of halo nevi. I Invest Dermotol 50:434-450, 1968
64. Cesarini JP et al: Le halo-naevus (naevus de Sutton): etude structurale. Ann Dermotol Syphiligr
(Poris) 95:505-512, 1968
65. Hashimoto K: A case of halo nevus with effete melanocytes. Acto Derm Venereol (Stockh)
55:87-95, 1975
66. Hori Y: Quoted in Smith WE, Moseley JC: Multiple halo neurofibromas. Arch Dermotol
112:987-990, 1976
67. Mishima Y et al: Dendritic cell dynamics in progressive depigmentations. Arch Dermotol
Forsch 243:67-87, 1972
68. Zelickson AS, Mottaz JH: Epidermal dendritic cells: a quantitative study. Arch Dermotol
98:652-659, 1968

609

LEUKODERMA
ACQUISITUM
CENTRIFUGUM

610
CHAPTER 8

69. Ebner H, Niebauer G: Elektronenoptische Befunde zum Pigmentverlust beim Naevus Sutton.
Dermatologica 137:345-357, 1968
70. Kurosumi K, Suzuki K: Langerhans cell, Kisohifukagaku (Basic Science in Dermatology).
Edited by M Seiji et al. Tokyo, Asakura Shoten, 1973, pp 265-279
71. Jacobs JB et al: Halo nevus: a fine structural study of a host rejection phenomenon (abstr).
Fed Proc 32:870, 1973
72. Jacobs JB et al: Ultrastructural evidence for destruction in the halo nevus. Cancer Res 35:352-357,
1975
73. Leszczynski R: Dber Suttonsche Krankheit (Leucoderma acquisitum centrifugum). Dermatol
Wochenschr 82:575-578, 1926.
74. Smith WE, Moseley JC: Multiple halo neurofibromas. Arch Dermatol112: 987-990,1976
75. Berman A: Depigmented haloes associated with the involution of flat warts. Br J Dermatol
97:263-265, 1977
76. Iijima S, Kanazawa T: The relationship between blue nevus and vitiligo. Tohoku J Exp Med
57:144, 1953
77. Merklen FP, Pelbois F: Cas type de maladie de Sutton vraie: leucodermie centrifuge acquise
geometriquement centree sur un naevus pigmentaire. Bull Soc Fr Dermatol Syphiligr 56:12,
1949
78. Merklen FP, Pelbois F: Maladie de Sutton a elements multiples plus au moins typiques avec
taches achromiques circulaire sans centre naevi que clinique apparent. Bull Soc Fr Dermatol
Syphiligr 56:244-245, 1949
79. Champion RH: Unusual melanoma: "malignant Sutton's naevus." Br J DermatoI76:347, 1964
80. Stehlin JS: In Discussion of Spoor HJ: Effect of topical hormones and other dermatologicals
on melanin pigmentation. Ann NY Acad Sci 100:57, 1963
81. Shapiro L, Kopf AW: Leukoderma acquisitum centrifugum: an unusual case. Arch Dermatol
92:64-68, 1965
82. Goldman L et al: Perilesional leucoderma in metastatic melanoma. Acta Derm Venereol
(Stockh) 47:369-372, 1967
83. Happle R et al: Spontamegression und Leukoderm beim malignen Melanom. Hautarzt
26:120-123, 1975
84. Maurer LH et al: Spontaneous regression of malignant melanoma: pathologic and immunologic study in a ten year survivor. Am J Surg 127:397-403, 1974
85. Sober AJ: Immunology and cutaneous malignant melanoma. Int J DermatoI15:1-18. 1976
86. Milton GW et al: Malignant melanoma with an occult primary lesion. Br J Surg 54:651-658,
1967
87. Smith JL Jr, Stehlin JS Jr: Spontaneous regression of primary malignant melanomas with
regional metastases. Cancer 18:1399-1415, 1965
88. Sumner WC: Spontaneous regression of human melanoma. Cancer 6:1040-1043, 1953
89. Das Gupta T et al: Malignant melanoma of unknown primary origin. Surg Gynecol Obstet
117:341-345, 1963
90. Sumner WC, Foraker AG: Spontaneous regression of human melanoma: clinical and experimental studies. Cancer 13:79-81, 1960
91. Everson TD: Spontaneous regression of cancer. Ann NY Acad Sci 114:721-735, 1964
92. Kopf AW: Host defense against malignant melanoma. Hospital Practice 6(10):116-124, 1971
93. Takahashi M et al: Vitiligo-like leukoderma in patients with metastatic malignant melanoma,
in Proceedings of the 10th International Pigment Cell Conference, Cambridge, Mass, 1977,
vol 4, Biologic Basis of Pigmentation. Basel, S Karger, 1979
94. Perrot H et al: Vitiliginous achromia with malignant melanoma. Tyrosinase activity and
ultrastructural study of achromic and normal skin. Arch Dermatol Res 257:247-253, 1977
95. Jhung JW et al: Multiple halo nevi developing after oxymetholone treatment of "aplastic
anemia." Cutis 12:56-61, 1973
96. Millikan LE et al: Gross and ultrastructural studies in a new melanoma model: the Sinclair
swine. Yale J BioI Med 46:631-645, 1973
97. Oxenhandler RW et al: Malignant melanoma in the Sinclair miniature swine: an autopsy
study of 60 cases. Am J Pathol 96:707-720, 1979
97a. Schmitt D et al: Halo nevus and halo melanoma: Immunocytochemical study of the inflammatory cell infiltrate, Pathology of Malignant Melanoma. Edited by AB Ackerman. New York,
Masson, 1981, pp 333-340

98. Reed RJ et al: Common and uncommon melanocytic nevi and borderline melanomas. Semin
Oncol 2:119-147,1975
99. Cooke KB et al: Melanoma specific protein: occurrences in the urine of patients with halo
naevus and vitiligo. Br J Dermotol 98:663-668, 1978
100. Whimster IW: The halo nevus and cutaneous malignant melanoma. Br JDermotol 90:111-113,
1974
101. Krebs JA: Halo nevus, competent surveillance of potential melanoma. 33rd Annual Meeting
of the American Academy of Dermatology, Chicago, 1974
102. Roenigk HH Jr et al: Microcytotoxicity and serum blocking factors in malignant melanomas
and halo nevus. Arch Dermatoll11:720-725, 1975
103. Mastrangelo MJ et al: Cutaneous depigmentary phenomena in patients with metastatic melanoma. International Pigment Cell Conference, 9th, Houston, Texas, January 1975
104. Terry W: Quoted in Jacobs JB et al; Ultrastructural evidence for destruction in the halo nevus.
Cancer Res 35:352-357, 1975
105. Poor FV: Uber Leucoderma acquisitum centrifugum (Sutton). Dermatol Wochenschr 80:401-405,
1925
106. Nelson LM: Acquired depigmentation around a dilated pore. Arch Dermatol 74: 549-551,
1956
107. Mihm MC Jr et al: Early detection of primary cutaneous malignant melanoma. N Engl J Med
289:989-996, 1973
108. Clark WH Jr, Mihm MC Jr: Moles and malignant melanomas, Dermatology in General Medicine. Edited by TB Fitzpatrick et al. New York, McGraw-Hill, 1971, pp 491-511
109. Mihm Me Jr et al: The clinical diagnosis, classification and histogenetic concepts of the early
stages of cutaneous malignant melanomas. N Engl J Med 284:1078-1082, 1971

611

LEUKODERMA
ACQUISITUM
CENTRIFUGUM

9
Miscellaneous Hypomelanoses
SARCOIDOSIS
Sarcoidosis is an idiopathic systemic granulomatous disease that frequently presents with cutaneous manifestations of which leukoderma is one
of the less commonly observed. Although sarcoidosis was first described in
1875 by Hutchinson [1], the associated leukoderma was first mentioned by
Mayock et al. [2] in 1963. It was later described by Harmon and Peterson [3]
in a patient with asthma and generalized lymphadenopathy, by Kotler and Zwi
[4] in a review from South Africa, and by Cornelius et al. [5] in four additional
patients. A series of eight cases was assembled by Clayton et al. [6] who also
performed ultrastructural studies.
The general incidence of sarcoidosis is estimated to be from 20:100,000
(Great Britain) to 200:100,000 [7]. Sarcoidosis in general involves females more
than males and is especially predominant among blacks but is not uncommon
among Caucasians from the southeastern United States or Scandinavia. Peak
incidence is in the third or fourth decade.

Hypomelanosis
Clinical Picture (Fig. 261)

The true incidence of leukoderma in sarcoidosis is unknown, but the observation of hypo pigmentation in 6% of the series of Mayock et al. [2] suggests
it must not be rare. Yet, in the patients of eight series [1,8-14] there is no
mention of hypo pigmentation. Emphasis on systemic involvement and on other
cutaneous features may have led to underreporting in earlier series.
Analysis of seven cases of hypopigmentation associated with sarcoidosis
(six from the literature and one presented to the New England Dermatology
Society, November 12, 1975) [15] (Table 125) makes it possible to characterize
these lesions. All patients were in the third or fourth decade when first seen;
in two of five the hypopigmented macules were the presenting complaint and
in another two the macules appeared within two years after the diagnosis ot

613

614

CHAPTER 9

FIGURE 261.

Hypopigmented macules in sarcoidosis; margins are usually indiscrete.

sarcoidosis was established. All patients were black, and the female to male
ratio was 5:2, both features probably reflecting the general sarcoidosis population. The lesions are described as circumscribed or poorly marginated macules or plaques that vary from 1 to 3 cm in diameter and mayor may not be
indurated. Two patients had papules within the white macules and one had
raised borders with a central violaceous hue. Lesions were most common on
arms and legs but also occurred on the face in two patients and on the trunk
in one. The lesions have no epidermal component other than hypo pigmentation
and are asymptomatic. Spontaneous repigmentation is reported in one case.
This generally agrees with the report of Clayton et ai. [6] who described
eight black patients with hypopigmented lesions of sarcoidosis. The female to
male ratio was 5:3. Six patients had dermal nodules surrounded by hypopigmentation and four had hypopigmented macules, both mostly located on the
thighs and upper arms. The nodules were dark red-brown centrally and light
tan peripherally. Most were 1 to 6 cm in diameter. Margins were indiscrete,
sometimes with perifollicular macules of pigmentation. None were symptomatic but some nodules were tender.
The hypopigmented macules appear to carry no specific prognostic significance. In one case, the white macules were the only feature of sarcoidosis.
However, in four patients with hypomelanotic macules, all had hilar adenopathy, three had pulmonary abnormalities, and two had arthritis or arthralgias
(Table 125). Clayton et ai. [6] were unable to correlate the cutaneous lesions
with any systemic features of sarcoidosis. Several patients developed the lesions while on oral corticosteroid therapy.
Histopathology

Cornelius et ai. [5] found noncaseating granulomas in the hypomelanotic

macules in all of their patients but no granulomas in surrounding normalappearing skin. Clayton et ai. [6] found sarcoid granulomas in all six patients
examined but only in one of two hypopigmented macules. In two patients
studied in detail by Cornelius et aI., dopa-positive melanocytes were observed
in the basal cell layer but only sparsely in the malpighian and horny layers.
Melanocyte counts were the same in normal and hypopigmented skin. This
was confirmed by Clayton et ai. [6] and Hulber [16]. The epidermal turnover
rates of normal and abnormal skin were the same, 23 days.
The convalescent stage, as uveitis begins to abate, is marked by vitiligo,
poliosis, and alopecia which occur from three to nine months after the onset
of the disease. Rosen [55] found 90% with poliosis, 73% with alopecia, and
63% with vitiligo, but none, one, two, or all of these may be seen in anyone
patient (Fig. 268).
The histopathology of the sarcoid granuloma in a macule of leukoderma
seems no different from a granuloma in normally pigmented skin. While the
mechanism of depigmentation is unknown, it clearly is not related to decreased
melanocyte population or to altered keratinocyte turnover. Since the granulomatous process is not in direct contact with the basal melanocyte-containing
layer, some other dermal-epidermal interaction must be responsible for a block
in melanogenesis.

615

MISCELLANEOUS
HYPOMELANOSES

Mlblackl31

Flblackl33

Mlblackl32

Harmon and
Peterson
[3]

Cornelius
et al. [5]

Cornelius
et al. [5]

Series

Sex/race/
age at
diagnosis

Knees, anterior
thighs

Cheeks, arms,
trunk, legs (7)

Pretibia, thighs (5)

Nonindurated,
"slightly"
depigmented

Circumscribed
macules, some
indurated
with eruptive
papules and
nodules

Indurated

Morphology of
hypopigmented
lesions

Nodules
upper
eyelids, left
nasal alae

Other
cutaneous
features

Calcified nodes,
interstitial fibrosis,
cardiomegaly with
congestive heart
failure, pulmonary
hypertension

Anterior uveitis and 2

glaucoma, arthritis,
hilar adenopathy

Asthma, pulmonary
infiltrates, hilar
adenopathy,
generalized
lymphadenopathy,
hepatosplenomegaly

Noncutaneous
features

Summary of Seven Cases of Leukoderma Secondary to Sarcoidosis

Site of
hypomelanotic
lesion
(duration in yrs)

TABLE 125.

Treated with
40-60 mg
prednisone but
no mention of
cutaneous
response

Topical steroids
flattened
nodules but
resulted in no
repigmentation

Skin lesions,
pulmonary
functions
markedly
better on 3week trial of
60mg
prednisone
q.d.

Comment

CD

..==

Flblackl37

Flblackl30

Flblackl22

Flblackl34

Cornelius
et al. [5)

Cornelius
et al. [5)

Rhodes [15)

Hubler [16)
Arms

Arms. legs (1)

Arms. thighs (1)

Nose. cheeks. and

forehead (1 1 / 2 )

Upper arms
bilaterally
enlarged to 3
cm

Circumscribed
macules or
plaques with
irregular
borders and
1-3 cm
violaceous
center

Multiple 1- to
15-cm poorly
marginated
patches. some
mildly
indurated

Patches. some
with 2--4
papules

Nodule on
nose

Hypertrophic
scar

Hilar adenopathy

History of arthralgias.
increased
pUlmonary markings

Hilar adenopathy.
mediastinal
adenopathy at aortic
arch

Iron deficiency anemia

C/)C/)

ell

"'I

@O
t<:IC
...

Z~

~~

~~

~~

Treated with
Plaquenil but
no comment
about response
of
hypomelanosis

No therapy.
some
spontaneous
clearing

No therapy

Papules
responded to
intralesional
triamcinolone.
chest x-ray
normal. biopsy
of skin
showed
sarcoidal
granulomas

618

Electron Microscopy

CHAPTER 9

Clayton et al. [6] examined two patients. Although some melanocytes appeared normal, others had abnormalities which included cytoplasmic vacuolation, marked dilatation of rough endoplasmic reticulum, and degenerative
changes of mitochondria. Melanosomes appeared morphologically normal. The
number of melanosomes in keratinocytes was decreased; those observed were
packaged as singles. Intercellular fluid and intracellular vacuolation were observed in one patient. Examination of the dermis showed melanin-laden macrophages, granulomatous infiltration, mast cells, and some Schwann cells with
ingested melanosomes. Dilated lymphocytes and exudate in the region of the
dermal-epidermal junction were observed in one patient.

Diagnosis
The presence of macules of leukoderma on arms or legs, particularly in
association with somewhat indurated plaques in a black patient with uveitis,
hilar adenopathy, and peripheral adenopathy, should suggest a diagnosis of
sarcoidosis.
Certain laboratory studies may be helpful. Sarcoidosis may be associated
with hypochromic and microcytic anemia, eosinophilia, leukopenia, and hypergammaglobulinemia. The sedimentation rate is elevated in two-thirds of the
patients and, if present with erythema nodosum, may rise and fall as the erythema no do sum exacerbates and remits. Alkaline phosphatase levels may rise
with or without clinical granulomatous invasion of bone or liver. Hypercalcemia, hypercalcuria, and increased hydroxyproline excretion may be noted
in some patients. IgA may be very elevated and IgG somewhat elevated. Delayed
hypersensitivity is often impaired. A positive Kveim test has been reported in
75% of patients with sarcoidosis [18].
In difficult cases in which the diagnosis of sarcoidosis is entertained, careful examination of the patient (with a Wood's light in Caucasians) may reveal
the presence of hypopigmented macules, the biopsy of which will establish
the diagnosis and obviate the need for biopsy of nodes, liver, muscles, nerves,
or bronchial mucosa.

Prognosis and Treatment

From analysis of the six cases reported, it is impossible to attach any
prognostic significance to the presence of hypopigmented macules in a patient
with sarcoidosis. The prevalence of hilar adenopathy and of pulmonary involvement seems to be representative of the sarcoidosis population at large.
Only one patient was reported to show spontaneous clearing of the hypopigmented macules. It is said to be unusual for sarcoid skin lesions to improve with steroids, but in one case there was dramatic improvement after three
weeks of oral prednisone; no changes were mentioned in the description of the

macules of another patient treated with similar dosages. None of the lesions

TABLE 126. Sarcoidosis: Cutaneous and Systemic Features

Cutaneous
Erythema no do sum
Lupus pernio
Plaques
Scarring alopecia
Flesh-colored papules and plaques
Violaceous-yellow macules and papules
Nodules
Hypertrophic scars
Psoriasiform plaques
Generalized erythroderma
Ulceration
Hypopigmentationlhyperpigmentation
Thickening of the nails
Pruritus

Systemic
Intrathoracic
Mediastinal or hilar adenopathy
Parenchymal changes with or
without adenopathy
Uveitis
Peripheral lymphadenopathy
Splenomegaly
Bone cysts
Arthritis
Coronary, CNS, renal abnormalities

observed by Clayton et al. [6] repigmented with oral, topical, or intralesional

corticosteroids. Improvement in papules with intralesional or topical steroids
does not necessarily imply repigmentation. That spontaneous repigmentation
may occur as lesions resolve should make one cautious in evaluating the value
of any therapy in inducing repigmentation. One patient with an immune defect
was reported to show improvement in macular lesions after treatment with
transfer factor.

Other Features of Sarcoidosis

See Table 126.

IDIOPATHIC GUTTATE HYPOMELANOSIS

The entity named "idiopathic guttate hypomelanosis" by Cummings and
Cottel [19] in 1966 was probably first described by Arguelles-Casals [20] as
"leukoderma lenticular disseminata" in 1954, and in 1965 by McDaniel and
Richfield [21] as "macular hypopigmentation of the legs in women."

Clinical Findings
Incidence
Despite the fact that in two years McDaniel and Richfield [21] observed
only 17 patients with idiopathetic guttate hypomelanosis, it appears to be a
very common disorder. In a survey of 452 randomly selected patients (mostly
blacks) at Charity Hospital, Louisiana, the incidence was found to be 47%;

619

MISCELLANEOUS
HYPOMELANOSES

620
CHAPTER 9

among another 500 patients, 68% were found to have idiopathic guttate hypomelanosis [22].
Race
The incidence among various races varies with the series reported. Idiopathic guttate hypomelanosis has been reported as both more and less common
among blacks compared to whites [19,23]. In one series, among 123 black males
the incidence was 58%, whereas it was only 20% in 107 white males. But the
incidence was nearly the same for black and white women, 54% of 117 blacks
and 53% of 105 whites, respectively [19]. On the other hand, Whitehead et al.
[22] reported an incidence of 74% among 322 Anglo-Saxons, 62% among 81
Northern Europeans, 69% among 36 Southern Europeans, and 30% among 30
blacks, and concluded that the condition is most common among Anglo-Saxons
and Europeans. That idiopathic guttate hypomelanosis was not observed among
the six Asiatics examined does not exclude its occurrence in Mongoloids or
other Orientals.
Hair Color, Eye Color, Skin Type
While idiopathic guttate hypomelanosis appears to occur among patients
of all hair and eye colors, there seems to be a preponderance of brown eyes
and brown hair. Among 17 patients, 10 tanned deeply, six moderately, and one
lightly [21].
Sex Distribution
Males and females are probably equally affected. Arguelles-Casals and
Gonzales [23] found no sex predominant. However, McDaniel and Richfield
[21] reported all of their patients were women. Cummings and Cottel [19] found
the incidence of idiopathic guttate hypomelanosis to be higher in women (53%
vs. 20%) among whites, and slightly higher in men (58% vs. 54%) among blacks.
Among 339 patients, Whitehead et al. [22] found an incidence of 44.2% in
males and 55.8% in females. It seems doubtful that idiopathic guttate hypomelanosis is more common in females; the apparent increase reported probably
results from the increased cosmetic disfigurement perceived by women compared to men.
Age
Idiopathic guttate hypomelanosis is a disease of adulthood and senescence
[23] and is probably more prevalent with increasing age. However, onset as
young as five years of age has been reported [22]. The age of patients in McDaniel
and Richfield's series [21] ranged from 14 to 63, and peak incidence was in the
thirties and forties. Whitehead et al. [22] observed only two cases below age
10, and found the disease usually appearing after age 30. The data of Cummings

32
37
30
39
62
78
93

81

010

1020

2030

3040

4050

5060

6070

70+

I!

10

20
30

40
50

80

70
80

90
100

FIGURE 262. Incidence of idiopathic guttate hypomelanosis in white and black. male and female patients (452 cases). This
demonstrates increased prevalence with age. (From: Cummings K. Cottel W: Idiopathic guttate hypomelanosis. Arch Dermatol
93:184-186. 1966. Copyright. 1966. American Medical Association. Used with permission.)

Number of Patients
Screened

Age Group

Percent of Patients Found to Have Idiopathic Guttate Hypomelanosis

0000

@O
t'lC

Z~

t'"t'"

~~

21 a:::

"'t:J00

...
Cl
N

622

CHAPTER 9

and Cottel [19] support an increased incidence of the condition with age (Fig.
262).

Etiology and Precipitating Factors

The etiology is unknown. Trauma has been suggested. McDaniel and Richfield [21] first thought idiopathic guttate hypomelanosis was induced by shaving with a safety razor; this was thought to cause a localized impairment in
the functional ability of the melanocytes. But since many patients used only
depilatories or electric shavers, this hypothesis seems too narrow in scope. Nor
could it explain the localization of the disease on the arms, or trunk, areas not
commonly shaved, or its occurrence in males.
Since there is an increased incidence with age and the lesions tend mostly
to occur on sun-exposed areas of skin, ultraviolet radiation may be implicated
[19,21,22]. Most patients appeared to be enthusiastic sunbathers and the majority of them were from the sunny regions of the United States. The unfolding
of the keratin layer observed in areas of the hypopigmentation supports this
hypothesis, but the precise pathogenesis of the unfolding of the keratin layer
is unclear. Since some lesions may occur in areas never exposed to the sun,
there must be other significant factors.

Clinical Description
The typical lesion is a small, discrete, smooth, depigmented macule of
porcelain-white color (Fig. 263). Sometimes small black dots are irregularly
distributed in the white macules [23]. The shape of the macules may be round
(guttate) or angular [22], and they may be delineated by the skin furrows. They
vary from 0.2 to 6 mm, with occasional larger lesions [22]; the average size is
0.5 cm. Once present, these lesions do not change in size. Multiple lesions
(several to 10 and sometimes more than 50) are a frequent occurrence and the
number of macules increases with age. The borders are very sharply defined,
as if pasted on, and there is no peripheral hyperpigmentation (Fig. 264). The
macules are not confluent. The surface of the lesions is smooth, not infiltrated,
and without scarring or atrophy. One patient with a slight hyperkeratosis detachable by scratching has been described [24].
The lesions are most common on the sun-exposed areas of the skin, particularly on the anterior surface of the lower extremities and the lower abdomen.
Whitehead et al. [22] found that male subjects had an increased percentage of
lesions on the arms (Table 127). Facial involvement has also been described;
Whitehead et al. [22] found involvement of preauricular skin in some patients
and McDaniel and Richfield [21] observed a depigmented macule around the
mouth of one patient. Involvement of normally sun-protected skin may occur.
The lesions are totally asymptomatic. Uninvolved skin is normal and patients with this disorder are usually in good health.
Idiopathic guttate hypomelanosis is a slowly progressive disorder. Usually
the lesions do not increase in size, but their number increases with age (Table
128). No spontaneous repigmentation has been observed.

623
MISCELLANEOUS
HYPOMELANOSES

FIGURE 263. Idiopathic guttate hypomelanosis. Lesions on

the leg of a black. (From: Fitzpatrick TB et al (Eds): Dermatology
in General Medicine. New York,
McGraw-Hill, 1971, Plate XXVII,
4a. Copyright, 1971, McGrawHill Book Company. Used with
permission. )

FIGURE 264. Close-up of lesions in which the sharp margins of the hypomelanosis are evident.
(From: Fitzpatrick TB et al (Eds): Dermatology in General Medicine. New York, McGraw-Hill,
1971, Plate XXVII, 4b. Copyright, 1971, McGraw-Hill Book Company. Used with permission.)

TABLE 127. Distribution of LesionsG in Idiopathic Guttate

Hypomelanosis"

624
CHAPTER 9

Number of lesions
1-10

11-50

Over 50

Males
Arms
Legs
Arms and legs
Face
Face, arms, and legs

39
11
14
1
3

12
3
13
0
0

8
3
14
0
3

Females
Arms
Legs
Arms and legs
Face
Face, arms, and legs

27
11
14
0
5

0
3
20
0
7

7
5
35
6
9

Distribution of idiopathic guttate hypomelanotic lesions in 124 males and 149 females
in whom the distribution was recorded.
b Source: Whitehead WJ et al: Idiopathic guttate hypomelanosis. Arch Dennatol
94:279-281, 1966. Copyright, 1966, American Medical Association. Used with permission.
a

Pathology
Except for decreased melanin the skin is usually normal. Generally the
epidermis is normal in thickness, but an increased thickness of the keratin
layer of the depigmented patches has also been reported [24]. The dopa reaction
in the hypopigmented macules is decreased [21, N. Soter, Y. Hori, T. B. Fitzpatrick, unpublished data]. Only a few melanocytes are seen in the hypopigmented macules. Usually there is no dermal change, pigmentary incontinence,
or inflammation. When thickening and fibrosis of the papillary dermis have
been observed in lesions of idiopathic guttate hypomelanosis, similar changes
TABLE 128. Age and Number of LesionsG in Idiopathic
Guttate Hypomelanosis"
Number of lesions
0

1-10

11-50

Over 50

Males
No. of patients
Average age

97
19.2 yr

83
31.8 yr

32
40.0 yr

35
57.4 yr

Females
No. of patients
Average age

64
14.0 yr

72

29.7 yr

47
42.4 yr

70
53.5 yr

Males (247) and females (253) grouped by age and number of lesions.
Source: Whitehead WJ et al: Idiopathic guttate hypomelanosis. Arch Dennatol
94:279-281,1966. Copyright, 1966, American Medical Association. Used with
permission.

FIGURE 265. Melanocytes are present in the hypomelanotic macules. They contain melanosomes with a reduction in the amount
of melanin deposition in comparison with the melanosomes in the control skin. (From: Soter NA. Hori Y. Fitzpatrick TB:
Unpublished data. Used with permission.)

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tr:IC:

Otr:l

ZZ

tr:I r
r
r

a:::R

o~

"'-

'"en

626

CHAPTER 9

also have been found in normally pigmented skin [19]. In one case, there was
a slight suggestion of some edema between the basement membrane and the
immediate subjacent epidermis. Some investigators [19] have noted a mild
perivascular infiltrate of chronic inflammatory cells.
At the electron microscopic level, the melanocytes contain melanosomes
that are not fully melanized (Fig. 265). Another study suggests that there is a
progressive loss of epidermal melanocytes in a later stage of this disorder [24a].

Diagnosis
The diagnosis can usually be readily established on the basis of characteristic morphology, distribution, and clinical course of the lesions (Table 129).
The small size, porcelain-white surface, and sharp margins are usually diagnostic.
The differential diagnosis may include such hypopigmentary disorders as
vitiligo, lichen sclerosis et atrophicus, atrophie blanche en plaque, leukodermic
guttate parapsoriasis, tinea versicolor, tuberous sclerosis, achromic planar warts,
tinea alba, leprosy, syphilis, chemical depigmentation, and postinflammatory
hypopigmentation.
TABLE 129. Clinical and Histologic Features of Idiopathic Guttate
Hypomelanosis
Incidence

Common (47% to 68%)

Sex

More frequently reported in women

Age

Rare before 10; incidence tends to increase with age;

more common in adult or old age

Clinical features
Configuration
Shape
Color
Size
Number
Border
Localization

Progression
Local symptoms
Repigmentation
Pathologic features
Number of melanocytes
Dopa reaction
Melanization of
melanosomes

Macular
Round or angular
Dull-white or porcelain-white
0.2 to 6 mm (average about 5 mm). occasionally larger
Usually multiple (several to 10); may be 50 or more
Very sharply circumscribed
Sun-exposed areas
Extremities
Lower abdomen
Face (preauricular)
Increase in number but not usually in size with age
None
Usually none
Decreased
Decreased
Decreased

Treatment
No treatment is available. McDaniel and Richfield [21] treated one patient
with 20 mg 8-methoxypsoralen daily for two months and observed an estimated
two-thirds repigmentation. However, no further improvement occurred and
with cessation of therapy a gradual loss of pigment again was observed.
In general, the cosmetic disfigurement is usually mild. As sunlight may be
a precipitating factor, sunbathing should be discouraged and use of topical
sunscreens encouraged.

MACULAR TROPICAL HYPOCHROMIA

Browne [25] described macular tropical hypochromia and found it to be
fairly common in tropical countries. It is characterized by groups of small
macules, all the same size, often symmetrically distributed (forearms, upper
arms, deltoid area), and often localized to a single area of the body (scapular
region, buttocks). There is no erythema or desquamation. The condition is
intractable but not progressive. Bacteriologic studies are negative. Antimycotic
therapy is ineffective.
Macular tropical hypochromia is clearly unrelated to leprosy, yaws, or
fungi. The etiology is obscure and multiple causative factors have been suggested.

VOGT-KOYANAGI-HARADA SYNDROME
Vogt-Koyanagi-Harada syndrome (VKHS) is a rare multisystem disorder,
the most consistent feature of which is uveitis, and the variable features of
which include alopecia, poliosis, vitiligo, and dysacousia.

Historical Background
Although Vogt [26], in 1906, described a case of idiopathic atraumatic
uveitis, poliosis, and alopecia, earlier descriptions of what would later become
known as VKHS had been made. The 12th century physician Mohammed al
Ghafigi regarded eyelash poliosis as a disease. In 1873, Schenkl [27] reported
a case of silvery-white eyelashes associated with sympathetic ophthalmia. One
year later, Jacobi [28] reported a similar patient with canities of the upper and
lower eyelids. Similar cases were observed by Tay [29], Bock [30], and Nettleship [31], who considered the concurrence of white eyelashes and sympathetic
ophthalmia no mere coincidence. Peters [32] reported in 1912 six cases of
sympathetic ophthalmia associated with deafness. In 1892, in the course of the
presentation of a case of eyelash poliosis and severe deafness, Hutchinson [33]
referred to another patient with atraumatic destructive uveitis, partial hair loss,
and poliosis of scalp and axillary hair. Cramer [34], in 1913, described a case
that evolved following extraction of a luxated lens.

627

MISCELLANEOUS
HYPOMELANOSES

628

CHAPTER 9

In 1911, Komoto [35] presented his first case of the syndrome but recalled
that some seven years earlier at an ophthalmologic meeting he had presented
a case of sympathetic ophthalmia with circumscribed vitiligo of the forehead.
In the same periodical is another case consistent with VKHS characterized by
vitiligo, poliosis, and chronic nontraumatic choroidal inflammation [36]. Erdmann [36] considered this a type of heterochromic inflammation and attributed
the vitiligo to a similar process.
Gilbert [37], in 1910, observed a patient who developed the concomitant
onset of vitiligo and bilateral optic neuritis resulting in iridocyclitis. He attributed this to ocular herpes; 20 years later he implicated endocrine factors.
Harada [38], in 1926, described five cases of bilateral posterior uveitis and
retinal detachment. Severe headaches and CSF pleocytosis were also frequently
present. A similar disorder was described by Tagami [39] in 1931.
In 1914 Koyanagi [40] reported a syndrome of uveitis and poliosis; in 1929
[41] he completed the description of what has become known as the VKHS.
The features described in his 16 cases included headache, fever, dysacousia,
vitiligo, poliosis, alopecia, and bilateral anterior uveitis with occasional exudative retinal detachment.
The first review in the English literature was that of Parker [42] in 1931;
he associated the syndrome with both idiopathic uveitis and sympathetic
ophthalmia.
Although Ogawa [43] used the names of Vogt and Koyanagi to refer to the
syndrome of "idiopathic uveitis with poliosis and leukoderma," it was Babel
[44] who first called this syndrome the "Vogt-Koyanagi syndrome."
The terms "uveoencephalitis" [45], "oculocutaneous syndrome" [46], "idiopathic neuraxitis" [47], and "uveomeningoencephalitis" [48] have also been
used to describe VKHS.

Classification
For a long time, Vogt-Koyanagi syndrome and Harada disease were considered separate entities. Idiopathic uveitis with leukoderma and poliosis was
classified as either Harada type, Vogt-Koyanagi type, or transitional type (Harada progressing to Vogt-Koyanagi type), mainly on the basis of the ophthalmologic findings [49].
The criteria for the diagnosis of Harada disease included bilateral retinal
detachment beginning in the macular area, hyperemia of the optic disc, inflammation of the vitreous and aqueous humors, and ocular "sunset glow fundus" or cutaneous depigmentation. It was later suggested that Vogt-Koyanagi
syndrome might represent Harada disease in its late, chronic stage.
In the Vogt-Koyanagi type, the uveitis was considered anterior in location
and retinal detachment did not occur, while in Harada disease the uveitis was
posterior and accompanied by retinal detachment.
Most recent authors have been aware that alopecia and poliosis are not
features of Vogt-Koyanagi syndrome alone and that retinal detachment may
occur following any anterior uveitis, not just that of Harada disease. Since these

two types seem to represent varied manifestations of a single disease process,

the name Vogt-Koyanagi-Harada syndrome is appropriate.

Incidence
VKHS is a rare disorder. By 1953, only 116 cases had been reported in the
world literature [50].
Any race may be affected. All the initial cases were among Japanese. Reed
et al. [51] and Aita [52] suggested VKHS is a disease of pigmented races, particularly blacks and Orientals (Fig. 266). But, as cases have also been reported
from the United States, the West Indies, Mexico, South America, Egypt, Europe,
and China, it appears that no race is spared [53,54].
Males and females are equally affected [54]. In one series there were 25
males and 20 females [53], and in another 23 males and 24 females [55].

FIGURE 266. Vogt-Koyanagi-Harada syndrome. Uveitis and hypomelanosis in a black. (From:

Fitzpatrick TB, Mihm MC Jr: Abnormalities in the pigmentary system, in Dermatology in General
Medicine. Edited by TB Fitzpatrick et al. New York, McGraw-Hill, 1971, pp 1591-1637. Copyright,
1971, McGraw-Hill Book Company. Used with permission.)

629
MISCELLANEOUS
HYPOMELANOSES

630
CHAPTER 9

VKHS seems to be most frequent in the third decade [56] or between the
ages of 30 and 40 [53], but occurrence in patients from 10 [57] to 57 [58] years
of age has been reported. The average age of onset in one series was 30.3 years
[59]. VKHS has also been reported in children [60].
Social and hereditary factors do not seem to be important [53,59]. One
familial case has, however, been reported [61]. Consanguinity is unusual; it
has been noted in only one instance [62].

Clinical Features of the Three Stages of VKHS

The first stage is characterized by CNS involvement with meningoencephalitic signs and symptoms. This initial cephalgia occurs in 50% of patients
with VKHS [55]. Prodromata include malaise, fever, headache, nausea, and
vomiting. Papilledema and nystagmus may be observed. Nuchal rigidity may
first reflect meningeal irritation. In the acute phase, the patient may be mildly
confused, delirious, or frankly psychotic. EEG changes may suggest a diffuse
encephalitis [45].
Other signs and symptoms include hemiparesis, paraplegia, loss of sphincter control, generalized muscle weakness, slight aphasia, syncope, and unilateral convergent squint. CSF abnormalities include increased intracranial pressure, elevated protein, and pleocytosis. The histopathology is generally consistent
with an adhesive arachnoiditis [63].
The degree of involvement is highly variable and permanent defects not
uncommonly persist, particularly long tract signs, paresis, expressive aphasias,
and personality disorders [51,53,64].
The second stage, accompanying or occurring shortly after the first, is the
ophthalmic stage; it is of gradual or fulminant onset and may last 10 years or
more. Onset of uveitis is marked by rapidly decreasing visual acuity, photophobia, and eye irritation. Blurring may be the initial symptom; all nine cases
of Perry and Font [58] presented with decreased visual acuity as the primary
complaint. Rapid progression to nearly complete blindness may ensue. Progression slows and reverses after initial deterioration, but preservation of better
than 20/40 vision is uncommon. Ocular and supraorbital pain may occur at the
same time. There may be mild fever. As with any chronic uveitis, hypotony is
usual. Secondary glaucoma may also be observed. Nausea, vomiting, vertigo,
and general discomfort may accompany the onset or be noted somewhat later.
In the Harada type, posterior uveitis may be associated with retinal detachment and diffuse and diverse neurologic symptoms.
Constriction of the visual field may occur. There may be cells in the aqueous
humor, intense bulbar injection, turbidity of the media, many granulomatous
choroid precipitates, bilateral scleritis [45], often diffuse choroiditis, optic neuritis, and pronounced retinal edema (Fig. 267). In most, the fundus cannot be
visualized. Retinal detachment marks the height of the disease, but reattachment may follow as the uveitis subsides after a year or more.
Vestibular and hearing problems occur. The dysacousia, which occurs in
50% to 89% of patients [53,58], is usually bilateral, may be only transitory, and
disappears over weeks to months. Noise hyperesthesia, tinnitis, and partial

631
MISCELLANEOUS
HYPOMELANOSES

FIGURE 267. Vogt-Koyanagi-Harada syndrome. Scleral infection and poliosis. (From: Howsden
SN et al: Vogt-Koyanagi-Harada syndrome and psoriasis. Arch Dermatol 108:395-398, 1973.
Copyright, 1973, American Medical Association. Used with permission.)

deafness usually occur after the onset of the disease. The eighth nerve defect,
which is of variable degree, is in the high-pitch range and may not be apparent
to the patient. Spontaneous resolution may occur.
Seals and Rise [56] studied three patients with VKHS and hearing loss.
One patient had severe cochlear and vestibular loss. Another had no cochlear
or vestibular response on one side and a nonresponsive right vestibular labyrinth and severe sensorineural hearing loss in the other. The third patient
complained of hearing loss but had normal audiometry.
The convalescent stage, as uveitis begins to abate, is marked by vitiligo,
poliosis, and alopecia which occur from three to nine months after the onset
of the disease. Rosen [55] found 90% with poliosis, 73% with alopecia, and
63% with vitiligo, but none, one, two, or all of these may be seen in anyone
patient (Fig. 268).
Patchy or diffuse hair loss usually follows ocular symptoms by two to three
months, but in two of Koyanagi's cases the loss was seen at three weeks [41].
Early hair loss may be readily overlooked. Hair whitening is probably most
apparent once alopecia has commenced and may or may not be permanent.
Parker [59] noted seven patients who had return of normal hair color over five
to eight months.
White areas may remain scattered through the fundus and be interspersed

632
CHAPTER 9

FIGURE
268. Vogt-Koyanagi-Harada
syndrome. Symmetrical hypomelanosis of
the face with nearly complete poliosis of
eyebrows and lashes. (From: Howsden SN
et al: Vogt-Koyanagi-Harada syndrome and
psoriasis. Arch Dermatol 108:395-398,
1973. Copyright, 1973, American Medical
Association. Used with permission.

with pigment deposits. Retinal detachment, secondary glaucoma, cataracts, or

ophthesis bulbi may result.
Hearing loss is seen in 69% and usually occurs with or soon after the ocular
symptoms. The general health of the individual is usually unaffected.
The order of the involvement of various organs can be quite variable. For
example, cutaneous changes may precede the uveitis [65].

Dermatologic Features
Hypopigmentation

The first case of VKHS associated with leukoderma was reported by Gilbert
in 1910 [37]. Depigmentation in VKHS occurs classically in the third phase of
the disease and involves the skin and hair.
Poliosis occurs in 82% [53] to 90% [55] of cases, and may appear abruptly
a few weeks after the onset of the disease; involvement of the eyebrows, eyelashes, scalp, beard, and body hair, particularly in the sacral area [66], may be
patchy or diffuse (Fig. 269). Depigmentation of the eyebrows and eyelashes is
usually accompanied by ipsilateral depigmentation of the iris.

633

MISCELLANEOUS
HYPOMELANOSES

FIGURE 269. Vogt-KoyanagiHarada syndrome. Diffuse whitening and poliosis of seal phair.

Poliosis may occur with, before, or after ocular abnormalities appear. In

the cases reviewed by Carrasquillo [53], three had poliosis one to 24 months
before the eye involvement, two at the same time, and 16 from one to 12 months
afterwards; three reported no poliosis. Five were simply unaware of the temporal relationship between involvement of the two systems.
The prevalence of leukoderma in VKHS varies from 56% [58] to 79% [59].
In general, the depigmentation of the skin strongly resembles vitiligo (Figs.
270, 271). Macules tend to be symmetrically distributed [65] and may enlarge
centrifugally. Parker [59] noted depigmentation to be most common on the
head, shoulders, nape of the neck, and eyelids. But a widespread distribution
seems so common a feature of VKHS that no special pattern for the leukoderma
in this syndrome can be identified. Partial or complete repigmentation may
occur.
The leukoderma usually occurs with, but occasionally before or after, the
visual changes. Of 29 cases summarized by Carrasquillo [53], 21 had vitiligo.
Of these, in five it began from one to 15 years (average, 5.5) before the syndrome
became apparent, at the same time in one, and afterwards by one to 12 months
(average, four) in six; seven were unaware of a temporal relationship. Vitiligo
has been reported to appear up to five years after the appearance of eye symptoms of VKHS [65].
Alopecia and Other Cutaneous Abnormalities

Alopecia is said to occur in 53% to 73% of patients and may present after
the apparent onset of the disease. Usually the alopecia occurs as discrete patches
of small areas of hair loss, but the entire scalp may be involved. Regrowth may

634

CHAPTER 9

FIGURE 270. Vogt-Koyanagi-Harada syndrome. Variation in size and degree of pigment loss of
hypomelanotic macules . (From: Howsden SN et al: Vogt-Koyanagi-Harada syndrome and psoriasis.
Arch Dermatol 108:395-398, 1973. Copyright, 1973, American Medical Association. Used with
permission.)

be gray and thinner, shorter and more pointed than the former hair. Regrown
hair may remain white to gray [65]. Some general thinning of the scalp hair
may also be observed.
Massive hives and psoriasis have been reported in patients with VKHS
[67,68] (Fig. 272).

635

MISCELLANEOUS
HYPOMELANOSES

FIGURE 271. Vogt-Koyanagi-Harada syndrome. Hypomeianosis of skin and body hair.

Associated Diseases
Although VKHS usually occurs alone, it has been reported associated with
insomnia, amenorrhea, polyuria, and hypertension [69]; a hypothalmic syndrome with hyperglycemia, hypercholesterolemia, nocturia, polyuria, and diabetes insipidus [70]; pituitary dysfunction [71]; adiposogenital syndrome [72];
Frohlich syndrome [73]; Klippel-Feil syndrome with ear agenesis [67]; mandibulofacial dysostosis [71,74]; facial hemiatrophy and alopecia [75]; and progressive facial hemiatrophy [53].

Pathologic Findings
Eye
Histology
The characteristic lesion is a granulomatous uveitis but nongranulomatous
uveitis has also been observed [58]. Typically, nodular eye lesions show epi-

636

CHAPTER 9

FIGURE 272. Vogt-Koyanagi-Harada syndrome. Lesions of hypomelanosis with hyperpigmented

margins and overlapping or congruent psoriasis. (From: Howsden SN et al: Vogt-Koyanagi-Harada
syndrome and psoriasis. Arch Dermatol108:395-398. 1973. Copyright. 1973. American Medical
Association. Used with permission.)

thelioid cells containing melanin granules surrounded by a wall of plasma cells

and lymphocytes in the choroid. Many Dalin-Fuchs nodules are observed. This
and the infiltrate in the iris resemble that of sympathetic ophthalmoplegia
[45,46,76]. A later study of the eyes of five patients with VKHS showed most
change in the choroid and the ciliary body. There was proliferation of mela-

nocytes, surrounded by lymphocytes and plasma cells. Melanocytes become

swollen and lose their cytoplasmic processes. Melanocytes are converted in
time to epithelioid cells which are polygonal or spindle shaped and which
have a variable number of melanin pigment granules and a small amount of
chromatin in their acidophilic cytoplasm. One or two nucleoli are located in
the large nuclei [77]. In smear preparations of uveal tissues, epithelioid cells
are rounded and show a wide range of morphologic abnormalities. Some pigment granules are barely visible while others are closely attached to one another
to form a coarse clump of pigment [78].
Electron Microscopy
Matsuda [77] compared the electron microscopy of limbal corneal epithelium and uveal tissue of eight patients with VKHS and three patients with
sympathetic ophthalmia. In the early stage of the disease, melanocytes were
found to be in contact with lymphocytes. Later, melanocytes were observed to
lose cytoplasmic organelles engaged in the melanogenesis and to change to
epithelioid cells in the uveal tract and to dendritic cells of the limbal corneal
epithelium. Lymphoid cells showed mitotic activity. No morphologic differences between VKHS and sympathetic ophthalmia existed at the electron microscopic level. Matsuda suggested that the close relationship of lymphocytes
to melanocytes is important in the pathogenesis of the disease.
Ikui and Mimura [78] observed a few dense granules often found in a dark,
less dense area which was considered to be a lysosome. They concluded that
epithelioid cells were simply metamorphosed melanocytes.
Depigmented Skin
Histology
Usually the epidermis and dermis are normal except that melanocytes are
absent. In the dermis of involved depigmented skin, however, Garza Toba [79]
found edema, vasodilatation, vessel wall abnormalities, lymphocytic infiltrate
around adnexae, particularly sebaceous glands, and pigment incontinence with
melanophages around vessels and in the papillary dermis. In contrast, Howsden
et al. [68] found no abnormalities except for the absence of melanin.
Studies of Ikui and Mimura [78] showed the melanocytes surrounding the
involved hair bulbs had become swollen, had assumed the form of epithelioid
cells, and were surrounded by an infiltrate of lymphocytes and plasma cells.
The histologic picture of the depigmented skin was identical to that of the
uveal tract [78].
Electron Microscopy
Findings similar to those of the uveal tract in which melanocytes lose their
organelles have been reported at the electron microscopy level [80]. Morohashi
et al. [81] described melanocytes with cytoplasmic vacuolization, melanosome

637
MISCELLANEOUS
HYPOMELANOSES

638
CHAPTER 9

aggregation, autophagic vacuoles, fatty degeneration, and pyknosis or homogeneous cytoplasmic degeneration. Most of the nonmelanocytic dendritic cells
were Langerhans cells. Nerve connection to normal and degenerated melanocytes was also observed. Bazex et al. [82] identified 250 A wide particles,
probably alpha-glycogen, well-developed unmyelinated nerve endings, and
lymphoid cells closely approximating dendritic cells which contained internal
granular deposits.
Immunofluorescence
In one patient with VKHS and psoriasis, indirect immunofluorescence was
negative. Direct immunofluorescence was faintly positive with IgG; this was
confined to epidermal intercellular space. Results with IgM and C3 were negative. Sections from skin with psoriasis and vitiligo showed not only these
changes but also yellow-green fluorescence beneath the dermal-epidermal
junction. Immunization of normal or control patient skin was negative [68].

Etiology
Although the etiology of VKHS has not been established, various pathophysiologic mechanisms have been suggested; these include endocrine disturbances [41,83], vitamin deficiency [37], bacterial infection [84], neurotrophic
disturbance, viral infection, and autoimmune disturbance. Brucellosis was suggested as a cause of the uveomeningeal syndrome [48].
Hague [85] mentioned a patient with VKHS and ependymoma compressing
the third ventricle and postulated a neurotrophic factor; he suggested a lesion
of the suprachiasmic region could explain all the features of VKHS. He noted
that VKHS usually follows an upper respiratory infection and suggested as a
precipitating factor a resultant encephalitis, severe emotional trauma, or a tumor compressing the hypothalamus.
Currently only two hypotheses-autoimmune and viral-seem appropriate.
As early as 1910, Gilbert [37] suggested herpes zoster as the cause of VKHS.
Others have suggested herpes to be a neurotrophic virus [83,86-88].
Many observations have been used to support the viral hypothesis. Occurrences and recurrences after paranasal sinusitis are compatible with a viral
(or at least infectious) etiology. Mohan and Gupta [89] suggest the meningeal
phase noted in the initial stage of a majority of cases supports an infectious,
e.g., viral, agent. The presence of pleocytosis in the final stage of the meningeal
phase has been interpreted in favor of this hypothesis. The apparent involvement of the hypothalamus could be implicated in the pathogenesis of the
pigmentary disturbance. Similar significance has been ascribed to atypical epidemic cases in a small French village [90]. Yet this is only one case in the
literature in which a person in contact with a VKHS patient acquired bilateral
uveitis [45].
Japanese investigators attempted to establish a virus as the responsible
etiologic agent. Takahashi [91], in 1930, inoculated rabbit cisterna magna with

sterile vitreous from an enucleated eye afflicted with Harada disease and found
optic neuritis and generalized uveitis in two of five rabbits. Brain material from
one of these injected into normal rabbit vitreous also caused uveitis and optic
neuritis; similar injection of CSF from a VKHS patient gave like results. Tagami
[39] transferred the disease through three rabbit generations. Similar transference results were obtained by others [50,92-94]. Friedenwald and McKee [95]
produced the characteristic lesion and passed the agent from CSF serially through
rabbits, cats, and dogs.
Erbakan [96] isolated a virus from the CSF of a patient with VKHS. Suguira
et al. [97] also isolated a virus from the eyes of patients with VKHS and, with
serum of another patient with the same disease, were able to demonstrate a
positive neutralization test against this virus.
However, although particles resembling virus have also been described in
the involved skin [80], most investigators have been unable to isolate or culture
a virus from VKHS patients. For example, injection of subretinal fluid from
affected patients into the brains of mice did not induce the disease [98]. In
other patients, repeated egg embryo, mouse brain, and rabbit eye inoculations
of VKHS subretinal or spinal fluid have been unsuccessful. Thus, neither the
transfer nor isolation experiments have been completely reproducible. The
possibility exists that because the diagnosis usually was not made early, the
phase in which the virus was present and identifiable had passed when most
of these unsuccessful transfer experiments were attempted. If so, the viral
hypothesis must still be considered viable.
Considerable evidence has accumulated to support an autoimmune hypothesis. Pusey in 1903 [99] and Elschnig in 1910 [100] were the first to suggest
that an allergy was responsible for uveitis associated with pigmentary change.
Elschnig considered sympathetic ophthalmia to result from release of damaged
uveal pigment which had antigenic properties and resulted in formation of
organ-specific antibodies. Thus anaphylactic pigment destruction resulted.
Peters [32] suggested uveitis caused the destruction of choroid pigment
and dissemination of breakdown products which led to sensitization and allergic reactions in other body pigmentary structures.
There are clinical similarities between sympathetic ophthalmia and VKHS.
Sympathetic ophthalmia has been associated with alopecia, poliosis, and deafness [34] and VKHS has been observed after eye surgery [67]. The general
concept of sympathetic ophthalmia is that of a severe traumatic reaction which
causes a uveitis. Subsequent uveal degradation is followed by release of antigens which stimulate antibody formation. Once adequate titers are reached,
sympathetic uveitis occurs in the untraumatized eye. A similar mechanism
may exist for VKHS. A VKHS-like syndrome has been observed in two melanoma patients treated with BCG [101]. Furthermore, the histologic and electron
microscopic ocular and cutaneous findings are consistent with this mechanism.
Various experimental studies support the autoimmune hypothesis. Foreign
protein injected into rabbit eyes produced sensitizing reactions in the contralateral eye [102], but only in pigmented and not in albino rabbits. Friedenwald
[92] found the tissue reaction after intracutaneous injection of uveal pigment
to be similar to sympathetic ophthalmia; this is now considered compatible
with a delayed hypersensitivity response. Others have obtained similar results

639

MISCELLANEOUS
HYPOMELANOSES

640
CHAPTER 9

with VKHS and sympathetic ophthalmia [103,104]. Kahan et al. [105] were
able to correlate skin test results with activity of VKHS and sympathetic
ophthalmia. When combining antibodies were completed by Coombs serum,
uveal pigment-agglutinizing antibodies could be found in sera of patients with
VKHS or sympathetic ophthalmia. Hammer [106] found uveal pigment to stimulate lymphocyte cultures from patients with sympathetic ophthalmia or VKHS.
Furthermore, lymphocytes from patients with VKHS may show microcytotoxicity against allogenic melanoma cells in vitro [107].
Since there is much evidence that cutaneous depigmentation can result
from an immunologic mechanism (see "Vitiligo" in Chapter 1 and "Halo Nevus"
in Chapter 8), it is reasonable that the same pathogenesis may apply to VKHS.
It is further possible that these two hypotheses are not separate and discrete,
but that a viral infection may induce an autoimmune reaction.

Diagnosis (Table 130)

The association of vitiligo-like depigmentation, poliosis, ocular abnormalities, and auditory changes should suggest a diagnosis of VKHS. Vitiligo
alone is common and is frequently associated with graying of hair. As the
auditory changes in VKHS may be very subtle, a careful history of eye changes
and of neurologic changes may be required to distinguish the patient with
VKHS from one with vitiligo and gray hair.
Alezzandrini syndrome, also rare, can be readily distinguished by the presence of unilateral degenerative retinitis, facial vitiligo, and poliosis, sometimes
with bilateral perceptive deafness.
Most of the other syndromes of cutaneous depigmentation and ocular and
auditory involvement are hereditary and can be readily excluded.
TABLE 130. Clinical Features of Vogt-Koyanagi-Harada Syndrome
Age of onset

30 to 40 years most common

Sex incidence

Male

Racial incidence

Nonselective

General incidence

Rare

Clinical description of
depigmentation
Skin
Hair
Associated clinical findings
Dermatologic
Other
Course

female

Vitiligo-like depigmentation
Poliosis of eyelashes, scalp, eyebrows, body
hair
Alopecia
Uveitis, meningeal signs and symptoms,
dysacousia
Self-limited

Treatment

The effectiveness of any therapeutic modality is difficult to assess because

of the self-limited nature of VKHS. Topical or systemic steroids have been
reported to prevent blindness. Immunosuppressive agents have also been used.
Topical ophthalmic atropine may help prevent the development of synechiae.
ALEZZANDRINI SYNDROME

In 1959 and 1961, Cremona, Alezzandrini, and Casal a reported two cases
of facial vitiligo, poliosis, deafness, and tapetoretinal degeneration with lesions
of the macules and specific electroretinograms [108].
In 1964, Alezzandrini [109] reported three patients with unilateral tapetoretinal degeneration, facial vitiligo, and poliosis, all on the same side. Two
of these patients also had perceptual deafness.
Alezzandrini syndrome is probably related to the Vogt-Koyanagi-Harada
syndrome.
SENILE GRAYING OF HAIR

Canities or graying of hair is the term for the progressive replacement of

pigmented by hypopigmented hairs. Whitening of hair refers to the arne Ian otic
end stage of this process (Fig. 273).

FIGURE 273. Senile "whitening" of hair.

641

MISCELLANEOUS
HYPOMELANOSES

642
CHAPTER 9

Graying of the hair is a familiar and obvious physiologic manifestation of

the aging process. Graying of the hair was found by the Atomic Bomb Casualty
Commission of Hiroshima [110] to be the physical trait most closely correlating
with chronologic age of physiologic functions.
Pathologic canities or graying of hair associated with various pathologic
processes is discussed in separate specific sections dealing with those processes.

Clinical Features
Frequency
This phenomenon is very common and occurs to varying degrees in all
persons.
Age of Onset
The age of onset of physiologic canities seems largely hereditary, but other
factors are probably involved. Graying may begin in the twenties or early thirties, but usually is first seen in the late fourth or early fifth decade [111]. Neither
sex is spared. Keogh and Walsh [112], in an Australian population, found no
significant difference in the age of graying among men and women. They found
22.29% of 2574 men and 23.35% of 698 women between 24 and 35 years of
age had some graying and 0.25% of men and 0.15% of women in these same
populations showed a complete graying (Table 131). Burch et al. [113] noted
some gray hair in dark-haired men between 20 and 24 years of age (Table 132).
Onset as early as the second or as late as the ninth decade is also possible.
Keogh and Walsh [112] concluded from their study that at 50 years of age,
regardless of sex, 50% of people are at least 50% gray (Table 133).
Race
No race is spared, but the age of onset has been reported to vary among
several populations. According to Boas and Michelson [114], the normal age

TABLE 131. Sex- and Age-Related Graying of Hair"

Number of subjects

Any visible graying ('Yo)

Complete graying ('Yo)

Age

Males

Females

Males

Females

Males

Females

25+
35+
45+
55+

2574
2157
1493
429

698
627
553
189

22.29
61.38
88.68
94.16

23.35
66.35
88.25
96.30

0.23
2.18
12.59
29.91

0.14
1.59
9.95
29.57

Source: Keogh EV, Walsh RJ: Rate of graying of human hair. Nature 207:877-878, 1965. Copyright, 1965,
MacMillan Journals Ltd. Used with permission.

Percent graying

Dark hair
Percent graying

Age Prevalence of Graying of Hair in Malesa.b

Miscellaneous
no. with
graying

2643

202
281
306
288
288
311
353
215
233
166

503

83
111
115
77
53
28
23
8
3
2

223

0
0
5
10
23
44
60
30
36
15
95

0
0
0
0
4
2
11
16
29
33

0.0
0.0
4.2
11.5
33.8
62.2
75.5
85.2
95.6
96.0

0.0
0.0
0.0
0.0
5.0
2.7
11.7
29.6
42.6
66.0

0
6
18
81
98
150
170
112
97
26
775

119
164
167
115
93
51
42
9
5
1
766
71

0
0
0
0
1
6
8
11
19
26
0.0
3.5
10.8
41.3
51.6
75.4
80.9
93.1
95.9
98.6

0.0
0.0
0.0
0.0
0.5
2.9
3.6
8.3
15.7
37.1
6

0
0
0
2
1
2
0
0
0
1
100

0
0
1
3
10
19
25
15
16
11

104

0
0
0
0
5
9
14
14
28
34

0.0
0.0
0.0
0.0
3.5
5.5
9.3
19.1
32.6
56.0

IZlIZl

t"lC:::

a~
IZlO

5:5:

t"lr-'

~R

OIZl

"'-

~~

Two communities in the North of England. Fair hair = unaffected hair or eyebrows are blond to light. Dark hair = unaffected hair or eyebrows are brown to black.
Miscellaneous = men whose hair color could not be allocated to either the "Fair" or "Dark" categories; the "None" column of this group records men with wigs.
Partly = some gray hairs clearly seen. Completely = all hairs gray or white.
b Source: Burch PRJ et al: The age-prevalence of arcus senilis, greying of hair and baldness. Etiological considerations. J Gerontol 26:364-372, 1971. Copyright, 1971,
Gerontological Society. Used with permission.

15+

15-19
20-24
25-29
30-34
35-39
40-44
45-49
50-54
55-59
60+

All groups
Any
Any
Age
%
No. graying
No. graying
gray Completely
gray Completely
range Number
completely
gray
None Partly Completely hair
(yr) examined None Partly Completely hair
gray
None Partly Completely
gray

Fair hair

TABLE 132.

c.o

a>

TABLE 133. Age Incidence of Graying in Relationship to Hair Color"

644

Number of patients
at risk

CHAPTER 9

Percent with
any graying

Age

Fair

Medium

Dark

Fair

25+
30+
35+
40+
45+
50+
55+
60+

502
345
333
263
282
205
137

839
674
666
604
510
331
222
26
3872

454
459
444
474
406
312
198

4.6
18.0
37.2
60.5
84.0
92.7
96.4
100.0
45.3

-1
Totals

2083

2765

Percent with
complete graying

Medium

Dark

Fair

Medium

Dark

10.4
32.3
53.2
71.4
83.3
91.2
93.2
100.0
52.9

26.4
49.5
64.0
74.9
90.4
93.3
94.9
100.0
68.1

0.4
0.6
0.9
4.6
8.9
23.9
42.3
50.0
7.6

0.0
0.3
1.2
3.3
8.6
15.4
31.1
23.1
5.2

0.0
0.2
1.1
1.9
8.4
12.8
19.2
16.7
3.3

Source: Keogh EV, Walsh RJ: Rate of greying of human hair. Nature 207:877--878, 1965. Copyright. 1965.
MacMillan Journal Ltd. Used with permission.

of onset of graying in white races is 34.2 B.6 years and in blacks 43.9 10.3
years. In Japanese, canities appears on the average at 35.39 years in females
and 30.34 in males [115]. Among Bantus, gray hair is said to be uncommon
before 40 or 50 years of age [116].

Hair Color
Among Caucasoids, graying appears to begin at a younger age in the darkhaired than in the fair-haired, and more dark-haired than fair-haired subjects
show some degree of graying at a given age [112]. But more fair-haired than
dark-haired subjects appear to be completely gray. The reason for this apparent
contradiction is that the first signs of graying are more obvious against a background of dark than of fair hair and, conversely, compared to fair-colored hair
a few dark hairs will be more noticeable against gray hair background. Hence,
the dark-haired individual is the first to appear somewhat gray and the last to
appear to be totally so.
Boas and Michelson [114] concluded that dark hairs of adult Caucasians,
including a great many patients originally with light hair that darkened over
time, become gray earlier than those whose hair continued to have light hues.
Those individuals whose hair darkened most rapidly have the greatest likelihood of becoming gray at an early age. Regardless of hair color, 50% of people
will be 50% gray by the age of 50 [112].
Correlation between Age and Graying of Hair
Most studies correlate graying of hair with aging [112,117]; the relationship
of prevalence to age fits a simple biologic model of aging [113] (Tables 131,
132, 133).

Clinical Picture
Graying of hair usually becomes evident by the latter part of the fourth
decade or the early part of the fifth decade. Occasionally, hypomelanotic hairs
develop during the early part of the second decade, and in rare instances they
fail to appear except in very small numbers even in the ninth decade.
Graying appears first at the temples, extends to the vertex and, over a period
of years, slowly involves the remainder of the scalp. The rate of progression
appears to be extremely variable. Graying of the beard and of the body hair
usually, but not invariably, follows after an interval of some years. Chest, pubic,
and axillary hairs may retain their pigment even in old age. Fitzpatrick et al.
[111) , in a study of eight octogenarians, found virtually no hypomelanotic hairs
in the axillae, presternum, and pubis.
Graying of hair is ordinarily irreversible, but in certain cases reversal of
hair graying has been known to occur [118) (Fig. 274). Ronchese [119) described

FIGURE 274. Hair showing loss of pigment distally with recovery of normal pigmentation in
proximal hair shaft. (From: Comaish S: White scalp hairs turning black. An unusual reversal of
the aging process. Br J Dermatol 86:813--814, 1972. Copyright, 1972, Blackwell Scientific Publications. Used with permission.)

645
MISCELLANEOUS
HYPOMELANOSES

646
CHAPTER 9

the gradual repigmentation of white hair over the course of a long terminal
illness in a male patient who had shown gray hairs at age 38 [120]. Several
hairs plucked from his scalp showed the remarkable loss of pigment distally
and normally pigmented proximal hair and roots; the transition from black to
white was gradual over a length of nearly 6 mm.

Histologic and Electron Microscopic Findings (Table 134)

Even as early as 1921, Bloch [121], who studied the hair bulbs of six subjects
over 57 years of age, reported a gradual reduction of the dopa oxidase reaction.
In the gray hair bulbs, dopa reactivity was very weak, and in the white hair
bulbs it was absent. Bloch believed that hairs that were originally pigmented
were replaced by white hairs and that hairs did not undergo "depigmentation."
In some of his six subjects, he found clumps of melanin in the dermis, but he
was unable to ascertain whether this melanin was in melanocytes that had
migrated to the dermal papillae or whether the melanin had come from melanocytes that had disintegrated and left the pigment granules to be phagocytized
by macro phages in the papillae. His final conclusion was that physiologic
graying of scalp and beard hair was due to a gradual loss of dopa oxidase
(tyrosinase) activity.
Fitzpatrick et al. [122], using autoradiographic histochemical techniques,
were unable to detect the presence of tyrosinase in the hair bulbs of eight
subjects with gray hair.
R. E. Mitchell et al. (unpublished data) used electron microscopy to study
the fine structure of hair follicles. In the black hair follicles, there were many
apparently normal melanocytes in the dermal papillae and many melanin granules in the matrix and cortical cells. In the gray hair follicles, there were
numerous normally situated melanocytes but the cytoplasm contained large
vacuoles of unknown significance. There was a very large number of apparently
normal melanosomes, very few of which were fully melanized. A decreased
number of melanin granules was observed in the hair matrix and shaft but
those granules present were normal in size and density. After incubation with
dopa, a melanocyte in one of these gray hairs was found to contain large
numbers of very dense and fully melanized melanosomes.
TABLE 134. Cellular and Subcellular Bases for Alterations of
Pigment in Physiologic Canities
Melanocytes
Number
Morphology
Melanosomes
Size
Shape
Inner structure
Melanization
Number of melanocytes
Number of keratinocytes
Transfer to keratinocytes

Decreased
Marked vacuolization
Normal
Normal
Normal or structurally altered
Decreased
Decreased
Decreased
Normal

In white hair, melanocytes were scarce or entirely absent and there was
no pigment in the matrix and cortex. No Langerhans cells were seen in the
bulbs, but a single Langerhans cell was observed in the outer root sheath beneath
a sebaceous gland. In the papillae, melanin, melanocytes, and melanophores
were all absent. Melanin-containing melanophores were seen only in pigmented
hairs, and were located outside the glassy membrane, usually along the blood
vessel walls. Thus, the structure of gray scalp hair or pigment cells was different
from that of pigmented hair from the same region.
Orfanos et al. [123] noted white hair usually showed large quantities of
pigment debris and an occasional intact melanin granule. He suggested that
melanocytes in old people produce only a few imperfect melanin granules
which disintegrate in the hair shaft.
Herzberg and Gusek [124] found the number of melanocytes in gray hair
to be greatly reduced or totally absent. Pigment cells were markedly vacuolated;
fewer melanosomes were present and those observed had abnormal structural
changes. Pigment transfer appeared normal, however (Fig. 275).

FIGURE 275. Seventy-year-old individual with gray hair. Melanocyte shows a reduction in the
size and number of melanosomes (M). Mi = mitochondria; V = vacuoles; G = Golgi apparatus;
N = nucleus (x 14,000). (From: Herzberg 1. Gusek W: Das Ergrauen des Kopfhaeres. Arch Klin
Exp Dermatol 236:368-384, 1970. Copyright, 1970, Springer-Verlag. Used with permission.)

647

MISCELLANEOUS
HYPOMELANOSES

648

CHAPTER 9

In 1971, Kukita et al. [125] studied the dendritic cells in the matrix of
human senile white and gray hair. There were no melanocytes in white hair,
but there were Langerhans cells and cells closely resembling indeterminate
cells. In senile gray hair, melanocytes and Langerhans cells were observed, but
indeterminate cells could not be identified. Ultrastructural studies revealed
identical dendritic cell populations in both senile white hairs and white hairs
from vitiliginous macules.

Pathogenesis
The mechanism of senile graying of hair has not been established. Metchnikoff [126] suggested that phagocytosis of melanin causes natural graying of
hair.
According to Orfanos et al. [123], senile graying of hair is due not to
corpuscular color but to a constellation of impressions arising from the actual
color of the hair keratin and from the reflection of light on the boundary surfaces
and islets of infundibulary matrix.
In 1937, Yosikawa [127] compared the copper content of gray and normally
pigmented human hairs from aged individuals. In all cases, the copper content
of gray hair was lower than that of colored hair. But it seems unlikely that such
a common event as senile graying of hair could be related to a disturbance in
copper metabolism, which appears to be rare.
Fitzpatrick et al. [111] suggested a decreased number of melanocytes and
slowed melanogenesis in remaining melanocytes accounted for graying of hair.
In electron microscope studies a number of dopa-positive melanocytes with
partially melanized normal melanosomes were observed but there were no
abortive melanocytes or Langerhans cells with their characteristic granules and
lobulated nuclei. Whether melanogenesis was incomplete in these melanosomes because of a change in the rate of enzyme activity or because tyrosine
was unavailable has not been determined. The presence of melanin granules
in the cortical and medullary cells of gray hairs shows that the melanosomal
transfer mechanism continues to function when melanocytes are present. Ultrastructural findings [124] support this conclusion (Figs. 276, 277).
Animal models suggest that heredity is a significant factor. Kirby [128]
described a related graying in a population of wild-type Australian mice. This
progressive loss of hair pigmentation with aging was inherited as an autosomal
dominant trait; the time course seemed to be determined by the mother (Fig.
278). Similar genetic age-related graying has also been found in black and brown
rats, guinea pigs, rabbits, dogs, sheep, and horses.
Burch and Jackson [129] suggested age-specific prevalence of senile graying
of hair suggests some disturbance of immune tolerance. Although premature
graying of hair has in some instances been reported associated with autoimmune disorders or biologic stigmata of autoimmunity, the "immune intolerance" hypothesis is without firm foundation.

649

MISCELLANEOUS
HYPOMELANOSES

FIGURE 276. Brown hair bulb (Mishima stain. x 512) with melanocytes evident in the upper
part. (From: Herzberg J. Gusek W: Das Ergrauen des Kopfhaeres. Arch Klin Exp Dermatol 236:
368-384. 1970. Copyright. 1970. Springer-Verlag. Used with permission.)

Probably melanocytes in the hair have their own genetically determined

internal clock for development and resolution. The same process seems to occur
in the epidermis with an average loss of 10% of the melanocytes per decade.
At the end of their programmed life, functioning melanocytes are irretrievably
lost.

FIGURE 277. Gray hair (Mishima stain. x 512) . (From: Herzberg J. Gusek W: Das Ergrauen des Kopfhaeres. Arch Klin Exp
Dermoto) 236:368-384. 1970. Copyright. 1970. Springer-Verlag. Used with permission.)

<0

~
Q

=
en

651

MISCELLANEOUS
HYPOMELANOSES

FIGURE 278. Female 181 (age 8 1/2 months; genotype aa/BBIGa-) showing gray phenotype of Ga
alongside a 5-week-old progeny that shows normal black (aa/BB) phenotype. (From: Kirby GC:
Graying with age. A coat color variant in wild Australian population of mice. J Hered 65:126-128,
1974. Copyright. 1974. American Genetics Association. Used with permission.)

SUDDEN WHITENING OF HAIR

And Beauty for confiding youth
Those shocks of passion can prepare
That kill the bloom before its time
And blanch. without the owner's crime
The most resplendent hair.
William Wordsworth
"Lament of Mary. Queen of Scots"

History and folklore are replete with tales of sudden whitening of hair. For
hundreds of years the curious sudden appearance of white or gray hair as a
response to fear or grief has stirred the interest of physiologists attempting to
explain dramatic changes in a structure that has no blood supply or enervation.
Many have questioned that sudden whitening is even possible.
The term "sudden whitening" here applies to the abrupt appearance of
totally depigmented hair in contradistinction to graying, which is a gradually
developing admixture of pigmented and hypopigmented hairs. In earlier times,
premature graying was considered a result of chronic anxiety whereas "acute
shock" rendered one abruptly white.

Sudden Whitening in History and Literature

Literature is replete with references to sudden whitening of hair; the following excerpts from the literary past leave little doubt as to its occurrence or
to its relationship to important life events.

652

CHAPTER 9

Shakespeare referred to sudden blanching in King Henry N, in which Sir

John Falstaff states to Hotspur, "Worcester is stolen away tonight. Thy father's
beard is turned white with the news."
In 1781, after a night with a mulatto, a young officer in the regiment of
Touraine is said to have experienced violent spasms of the body and whitening
of the beard and hair, but only of his right side.
Smiley [130] wrote of a gambler who, in 1851, staked $1000 on a single
card and experienced sudden whitening of his hair. Although the outcome of
the game is not reported, his white locks became the eternal badge of the frown
of fortune.
Jelinek [131] remarked that while the commoner who experienced sudden
whitening was considered punished for sexual indulgence, heresy, or antiCalvinistic behavior, the patrician developed white locks only out of valor.
Jacques Orsario was a Spanish nobleman who was unfortunate enough to
fall in love with a lady in the court of King Ferdinand of Spain and then unwise
enough to climb a tree in the royal garden to pursue whatever advantage he
might have. A barking dog revealed his hiding place and he was imprisoned
and sentenced to be beheaded. His pending doom is said to have so tormented
him that he became as white-haired as a man of 80. He must have been considered adequately punished for he was subsequently pardoned by the king.
The Moghul ruler, Shah Johan, who built the Taj Mahal to immortalize his
beautiful and favorite wife who bore him 14 children and died in childbirth,
is said to have grieved so at her death that he developed white hair within two
weeks.
Henry of Navarre, after his escape from the horrors of the Massacre of St.
Bartholomew in 1572, overnight became as white as snow. It is not clear whether
his moustache whitened within hours because of his feigned adjuration of
Protestantism or from his grief over the decision of the Edict of Nemours in
1585 to bar heir-apparent Henry from succession to the French throne. Henry,
troubled by the prospects of war, after lifting his head from his hands found
his moustache to have become white.
Scholar Guareno of Verona (1370-1460) had gathered numerous Greek
manuscripts to be sent to Italy by ship; when he learned they had been lost en
route he became instantly white.
Sir Thomas More, Chancellor of England and author of Utopia, incurred
the wrath of King Henry VIII when he refused to recognize the marriage of the
king to Anne Boleyn. He was imprisoned in the Tower of London for his failure
to place the will of the king above that of the Pope and the Church. Sentenced
to be beheaded for high treason, Sir Thomas developed white hair of his scalp
and beard the night before his execution day.
Similarly, as Marie Antoinette mounted the scaffold to be beheaded, she
was observed to have white hair, not her rather characteristic auburn hair.
Some had observed her to have a fully whitened head of hair some nine months
earlier and even if the exact time of its occurrence is in doubt, writers have
suggested her whitening was sudden. Charles A. Sainte-Beuve writes:
The last ray of joy and hope she knew was at the time of the flight to Varennes Gune
21, 1791). Three days later, how different was the prospect. The moment Madame
Campan (the wife of the cabinet) met her after her return from Varennes, the Queen
removed her hat and bade her see the effect which sorrow had produced upon her

hair. In a single night it had become as white as that of a woman of seventy. She was
thirty-six.

Two years before his death, General Charles Gordon had been noted to
have dignified streaks of gray hair. Yet, during the long seige of Kartoum by
the Mahdi in 1885, Gordon is said to have been so anxious that he developed
snow-white hair.
John Libeny, convicted of the attempted assassination of Emperor Franz
Josef of Austria, and E. S. Stokes, murderer of financier and former associate
Jim Fiske, both developed dramatic changes in their hair color.
More recent and less illustrious men have been reported to blanch under
stress. The hair of a Viennese man became white one day after his mother was
killed in an air raid [132]. Seven weeks after an accident, a motorcyclist noted
blanching of his hair [133]. Sudden graying was noted in a woman who had
been shipwrecked [134]. Ephraim [135] noted he could find four cases of whitening associated with the horrors of World War I but found none related to
World War II.
Other instances of dramatically rapid graying or whitening of hair have
been reported. A soldier in the Bengalese Army, under the horror and despair
of his inquisition as a prisoner, turned completely gray in 30 minutes [136].
Holzgraefe [137] reported a 58-year-old woman whose husband had suddenly
turned white when his house caught fire and who herself turned gray overnight
after learning her two sons had been poisoned by gas. Ornsteen [138] reported
a woman who in the morning had not a single gray hair and who later in the
day and less than four hours after learning that her son had been in a serious
accident became snow white.
Rarely is sudden whitening reversible [120]. However, Canuto [139] noted
a 20-year-old woman whose hair became gray and whose hair color returned
seven months later.

Sudden Whitening and Neurologic Disorders

While details on many of these anecdotes are often sketchy, Ephraim [135]
found those cases associated with neurologic or mental disorders generally
described in greater detail. In a review of 150 years of medical literature, he
separated the development of sudden whitening into those 26 cases associated
with excitement, fear, or mental stress and the others with neurologic or mental
disorders. Landois [140], in 1866, reported a 43-year-old man hospitalized with
delirium tremens; he seemed quite frightened and awoke one morning with
completely white beard and hair. The hair on microscopic examination was
completely normal except for color. Most hairs were white from root distally,
whereas others were white only proximally, blond at the root with a gray tip,
or speckled. On the white parts were many air bubbles, expulsion of which
with water, ether, or turpentine led to return of the hair to its natural blond
color.
Raymond [141], in 1882, reported a woman who, following considerable
emotional stress, developed severe neuralgia of the head and, at the peak of
her pain, then diagnosed as meningitis, within five hours developed scalp hair
color changes. While the sides and back remained her normal black, the front

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was flame red in color and the remainder white or red-white. Two days later
her red hair became completely white and two weeks later she lost all of her
white hair, but not her normal remaining black hair.
Jelinek [131] described a 21-year-old schizophrenic woman who developed
a 3 cm-wide streak of white hair stretching from her forehead to her left side.
Four days later her hair returned to normal, but the whitening, which recurred
with exacerbation of illness, could be reversed by immersion of the hair in
water (with escape of the observed air bubbles).
In 1954, Hoff [142] reported a 40-year-old miner with chalicosis who, after
a small mine accident, developed what was diagnosed as a "grippe" marked
by chills, syncope, nausea, and increased thirst. The next night he lost much
of his blond hair so that his hair appeared to have become completely white.
Slowly his body hair turned white and his brown irides became very light in
color. With this history and the subsequent appearance of weight loss, decreased libido, decreased hearing, and development of small testes, he was
considered to have had hypothalmic trauma or encephalitis.
Gowers [143], in 1901, reported unilateral sudden whitening of a brown
beard within three days of a contralateral meningeal hemorrhage. Cases of
sudden whitening following hemiplegia, brain tumor, ataxia, and unilateral
headache have also been reported. In addition, five cases of sudden whitening
of cilia have been reported by ophthalmologists.
Ephraim [135] personally observed whitening within six weeks (possibly
as soon as two to three weeks) of an accident. His patient had graying of the
temples and a peppering of white hairs prior to a fall; yet within four weeks
of the injury his hair had become completely white except for a band of black
hair at the base of his neck. Examination of his scalp revealed very few dark
hairs. All hairs were normal on microscopic examination, except that the white
hairs were transparent and had clumps of pigment in the medulla. This patient
is said later to have developed generalized vitiligo.
The true incidence of sudden whitening is unknown, but the curiosity
surrounding its occurrence suggests it is indeed rare. There are no apparent
underlying predisposing factors, including family history. No disease associations are known. Spontaneous reversal has been reported. No therapeutic
attempts to repigment have been reported.

Pathogenesis
That sudden whitening, which is more common than sudden graying,
seems to occur is accepted by many American and British dermatologists.
However, many others have asserted sudden whitening is fictional and not
compatible with known anatomic and physiologic phenomena. von Stieda [144],
in 1910, even suggested that abrupt whitening appeared because neurologically
compromised or grief-stricken patients were no longer able to dye their hair.
Hebra and Kaposi [145] have also doubted this can be other than an evolutionary
type of natural replacement of normally pigmented hairs by gray hairs.
Yet observers cannot agree whether hair turns white throughout the entire
shaft simultaneously (if at all), from the root, or from the distal tip. Ephraim
[135] discussed this with hairdressers who stated they never noted short white

or gray hairs during physiologic graying-only long ones. Brown-Sequard [146]

for some weeks plucked all the white hairs from his beard yet found white
ones of equal length present the next morning. Given the observation that hairs
grow only 0.35 mm daily, he could not accept these as newly grown hairs and
concluded established pigmented hairs had depigmented overnight.
No paucity of theories is available to explain sudden whitening of hair
[147-149]. Vauquelin [150] thought a peculiar substance secreted under mental
stress dissolved the pigment. Metchnikoff [151], in 1901, suggested pigment
was phagocytized and carried down through the hair bulb to be deposited in
connective tissue. He called these phage cells "pigmentophages." No such cells
have ever been demonstrated. Landois [140] suggested, and others have observed, that the presence of air in the hair bulbs reversibly alters the refractive
index so that the hairs appear white. This mechanism is responsible for the
paler segments of banded hair of pili annulati. Although this is not observed
in most patients with sudden graying of hair or with physiologically gray hair,
it is probably still the most widely accepted theory. No one has explained how
a biologically inactive tissue can be altered to admit air.
It is certainly possible that pigmented hairs fall out and leave depigmented
hairs remaining. Some of the reported cases have been associated with observed
hair loss. Alopecia areata, either focal or diffuse, has often been shown to follow
psychic stimuli and nearly exclusively to involve pigmented hairs; that is, the
melanized hairs are lost and the depigmented hairs remain. When hair regrows
in areas of alopecia, it often remains achromatic. In a patient previously gray,
with even 10% of the scalp remaining pigmented, loss of many pigmented hairs
could lead to the impression of sudden whitening of the hair. The occurrence
of alopecia areata of explosive onset involving the entire scalp has been reported
to lead to the appearance of abrupt whitening of hair. For example, Helm and
Milgrom [152] reported a 45-year-old patient who complained of sudden diffuse
hair loss. Formerly his hair had been brown mingled with a few white hairs,
but in the course of three days he lost nearly all his brown hair. Since his
remaining hair was white, he seemed to have whitened overnight. As time
passed, he developed discrete patches of complete hair loss characteristic of
alopecia areata. Burton [153] reports such a case in a 55-year-old man who lost
dark hair and few white hairs over a three-week period; exclamation-point
hairs were observed. Damste [154], Klingmiiller [155], Lehnert [156], and Montgomery [157] have described similar cases.
Lerner [158] also suggested that the rapid graying of hair may appear to
occur when approximately half of the hair is gray and then diffuse hair loss
occurs, most commonly from a febrile illness or alopecia areata. Since dark
hair falls out more readily than gray hair, over a few days nearly all the black
hair but little of the gray hair may be lost. Loss of the pigmented hair results
in overall thinning, which may not be very noticeable. With only the gray hair
remaining, the patient has turned gray "overnight." Aging and positive family
history are predisposing factors.
In a case of rapid whitening of scalp hair associated with diffuse, subtotal
alopecia, immunofluorescence microscopy showed prominent IgG and IgM
deposits in the lower portion of hair follicles [158a]. Whether these findings
are of etiologic significance remains to be established.
A few cases of sudden whitening have been reported in patients with

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vitiligo [135]. Folklore and a few reported cases reveal limited insight into this
curious problem. Perhaps these cases represent vitiligo, alopecia areata, or other
leukodermas associated with canities. Critical clinical observation should provide the next clue.

ALOPECIA AREATA
Alopecia areata, which is an idiopathic, circumscribed, nonscarring alopecia, may be associated with several types of depigmentation. The hair, the
skin, or both may be involved.

Depigmentation of the Hair

Depigmentation Associated with Regrowth of Hair

During the regrowth phase of alopecia areata, new terminal hairs usually
lack melanin pigment (Fig. 279). Usually the amelanosis is transitory so that
the amelanotic hair is eventually replaced by dark, entirely normal hair [159].
In rare instances, the white hair is permanent. Van Scott [160] observed that
the dermal papillae of hair and its underlying column of connective tissue
contained variable amounts of pigment which he explained was melanin that

FIGURE 279. a, b: Regrown hairs in alopecia areata are often white.

had migrated. But the presence of pigment incontinence, which could be a

postinflammatory effect, does not fully explain the mechanism of development
of white hairs. It does suggest an analogy to postinflammatory hypomelanosis
of skin, also transitory. No electron microscopic studies of regrowing hair in
alopecia areata are available. The exact mechanism of this hypopigmentation
is unknown.
Alopecia Areata and Sudden Whitening of Hair

Klingmuller [148] reported a patient who rapidly lost all of his pigmented
hair while the gray hair persisted, presumably the result of alopecia areata
involving pigmented hair. Hoff [142] has reported a patient with sudden total
vitiligo and sudden graying of the hair, the latter of which was presumably the
result of diffuse alopecia totalis involving the pigmented hair. Lerner [158]
suggested that accounts of the rapid onset of gray hair may be explained in the
following manner: "Some gray hairs appear with age or because of familial
predisposition. When approximately half of the hair is gray, a diffuse hair loss
may occur, most commonly from a febrile illness or from alopecia areata. Since
dark hair falls out more readily than gray hair, in a few days nearly all the
black hair, but little of the gray, may be lost. Loss of the pigmented hair results
in overall thinning which may not be very noticeable. With only the gray hair
remaining, the patient has turned gray overnight." More recent studies by Ortonne et a1. [161] have confirmed this mechanism in four patients.

Depigmentation of the Skin

Alopecia Areata and Vitiligo

Alopecia areata and vitiligo occur together more commonly than would
be expected by chance alone (see "Vitiligo" in Chapter 1).
Alopecia Areata and Pallor of the Skin

Lubowe [162] reported that in a large majority of his patients with alopecia
totalis, hypomelanosis of the scalp and face was present. With corticosteroid-corticotropin therapy this pigment dilution was reversed. The patients
reported by Demis and Weiner [159] to have "alopecia universalis onychodystrophy and total vitiligo" really had more of a "generalized palor" than actual
vitiligo. In fact, one of them still retained some ability to tan. No skin biopsies
were performed in these patients.

VAGABOND'S LEUKOMELANODERMA
Vagabond's disease [163-166] is a cutaneous affliction that occurs in older
persons who are unkempt in personal habits, have pediculosis corporis, and
give a history of infrequent bathing or changing of clothes, dietary deficiency,

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CHAPTER 9

and chronic alcoholism. The description suggests a typical beggar or "vagabond." The disorder is characterized by macules and patches of diffuse lightbrown hyperpigmentation especially noticeable around the wrists and groin,
between the thighs, in the axillae, over the back of the neck, and particularly
the upper back (Figs. 280, 281). The face and the extremities usually appear
less pigmented than the trunk [167). Diffuse hyperpigmentation of the oral
mucosa has also been observed in such patients [168,169] . Vagabond's disease

FIGURE Z80. Vagabond's leukomelanoderma. (From: Grosshans E et al: La leucodermie des vagabonds. Etude anatomopathologique et ultrastructurale. Ann Dermatol Syphiligr (Paris) 99:141-166,
1972. Copyright, 1972. Masson & Cie. Used with permission.)

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MISCELLANEOUS
HYPOMELANOSES

FIGURE 281. a, b: Close-up view of the hypomelanotic macules in two patients. (From: Grosshans
E et al: La leucodermie des vagabonds. Etude anatomopathologique et ultrastructurale. Ann Dermatol Syphiligr (Paris) 99:141-166,1972. Copyright, 1972, Masson & Cie. Used with permission.)

is not a homogeneous melanoderma; the many depigmented macules observed

have been attributed to stretching, to infectious processes [166], or to pediculosis corporis bites [164].
The pathogenesis of vagabond's disease is not established. The melanoderma has variously been attributed to physical factors [170], to nutritional
deficiency [167], or to Addisonian-like changes [165,166,168,171]. However,
in most of the cases, adrenal function tests are normal [172]. It seems more

FIGURE 282. Epidermal depigmentation, spongiosis, and pigmentary incontinence. (Fontana stain, x 64) (From:
Grosshans E et al: La leucodermie des vagabonds. Etude anatomopathologique et ultrastructurale. Ann Dermatol
Syphiligr (Paris) 99:141-166, 1972. Copyright, 1972, Masson & Cie. Used with permission.)

to

=
=
0=

likely that the melanoderma in these patients is postinflammatory, related to

multiple ectoparasitic infections (Fig. 282).
There is a decreased number of dopa-positive melanocytes in the de pigmented macules. Ultrastructural examination [173], however, shows that melanocytes do not disappear but undergo degenerative changes with autophagic
vacuoles (Fig. 283). The keratinocytes contain fewer melanosomes than normal.

FIGURE 283. Melanocyte in involution in Vagabond's disease. Autophagic vacuoles (VA), multivesicular bodies (cmv), and catabolic debris scattered in the cytoplasm. Square on the upper right
shows a premelanosome. (x 28,600 and 61,000) (From: Grosshans E et al: La leucodermie des
vagabonds. Etude anatomopathologique et ultrastructurale. Ann Dermatol Syphiligr (Paris)
99:141-166, 1972. Copyright, 1972, Masson & Cie. Used with permission.)

661
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These melanosomes are normal in size and shape. Transfer of melanosomes

from melanocytes to keratinocytes appears to be normal. The number of Langerhans cells is considerably reduced and some of those remaining appear to
contain melanosomes. There are abundant pigment deposits in the upper dermis and few Schwann cells contain melanin granules.
From ultrastructural studies, Grosshans et al. [173] concluded that the
cutaneous depigmentation in vagabond's disease results from the following:
pigment incontinence with phagocytosis of the melanin granules; loss of melanocytes and loss of melanosomes in autophagic vacuoles within melanocytes;
and phagocytosis of melanosomes by Langerhans cells and resorption of melanosomes by Schwann cells.
Usually, bathing, disinfection, clean clothes, good diet, and vitamin supplements result in improvement in the pigmentary disturbance.

HETEROCHROMIA IRIDES AND HORNER SYNDROME

Heterochromia Irides
Heterochromia irides is an alteration in iris color and structure. Occurring
in many disorders, heterochromia irides may occur in one of two forms [174],
namely, a hypopigmentation of the iris with iris hypoplasia, or a hyperpigmentation with iris hyperplasia. Both eyes or only one eye may be involved.
The involvement may be partial or complete.
Gladstone [174] distinguished the following three main types of heterochromic irides: simple heterochromia which is usually benign; complicated
heterochromia which is associated with ocular disease; and sympathetic heterochromia which is associated with a neurogenic lesion of the sympathetic
nerve supply of the iris.
Simple heterochromia is congenital, either sporadic or familial, but may
also occur in diseases such as Waardenburg syndrome, status dysraphicus
(Bremer syndrome), and Romberg syndrome.
Complicated heterochromia of the hypopigmented type is seen in Fuchs
heterochromic cyclitis, Pasner-Schlassman syndrome, and is associated with
diffuse unilateral iris atrophy or with infiltration of the iris by an amelanotic
tumor. Complicated heterochromia of the hyperpigmented type may follow a
childhood eye injury, hyphema, iron foreign body, vascular abnormalities, melanosis bulbi, or malignant melanoma of the iris.

Horner Syndrome
Sympathetic heterochromia is represented by Horner syndrome which can
be congenital or acquired. The essential features of Horner syndrome are a
moderate miosis, a minimal ptosis, and narrowing of the palpebral fissure.

Other features may include anhidrosis on the affected side of the face, an
"upside down" ptosis (elevation of lower lid), conjunctival congestion, transient ocular hypotonia, and heterochromic irides in congenital Horner syndrome [175]. Heterochromia irides with congenital Horner syndrome is transmitted as an irregular dominant trait; familial cases have been reported [176,177].
Gladstone [174] pointed out that sympathetic ophthalmia permits the differentiation of congenital Horner syndrome from a more recent acute lesion.
Section of the superior cervical ganglion [178] has resulted in change in iris
color in animals. Heterochromia irides in association with Horner syndrome
has also been reported to follow excision of the superior cervical ganglion [178],
or in conjunction with neonatal trauma [179] or cervical ribs [179]. Isolated
cases of hypochromic heterochromia of the iris have also been described following a cervical sympathetic lesion or a cervical sympathectomy [180-185].
Laties and Lerner [186] observed decreased iris tyrosinase activity after decentralization of the superior cervical ganglion in mammalian systems.

HYPOMELANOSIS IN SCLERODERMA
Various disturbances of cutaneous pigmentation have been reported in
patients with localized or systemic scleroderma [187,188]. Vitiligo is not uncommon in patients with systemic or localized scleroderma [189,190]. However, some pigmentary abnormalities, including hyperpigmentation and/or hypo pigmentation appear to be more specifically related to the pathogenesis of
scleroderma [187,191]. Diffuse hyperpigmentation is quite common in patients
with systemic scleroderma and macular hypopigmentation may occur, most
frequently on the upper trunk, arms, forearms, and hands (Fig. 284a) Perifollicular sparing of the epidermal pigmentation loss is typical of these lesions
[192]. Morphea is usually hypopigmented or hyperpigmented.
On split dopa preparations, dopa-positive melanocytes are absent in depigmented skin whereas in hyperpigmented skin the melanocytes are large,
with prominent dendrites, and exhibit intense dopa oxidase activity (Fig. 284b).
In depigmented skin, ultrastructural studies confirmed the disappearance of
melanocytes. At the borders of achromic skin, the melanocytes contain few
melanosomes and show evidence of cytoplasmic degeneration (lipid vacuoles
and autophagocytosis of melanosomes) [191].
Hypomelanosis associated with scleroderma is secondary to the disappearance of melanocytes, and hypermelanosis is due to increased activity of
epidermal melanocytes.
The origin and mechanism of these melanin pigmentary disturbances in
scleroderma are unknown. The following hypothesis has been proposed [191]:
Initially and for unexplained reasons, increased melanogenesis occurs within
the epidermal melanocytes. This results in an increase in the intramelanocytic
content of cytotoxic melanin precursors. During a second stage, cellular organelles are altered, resulting in cell death.

663
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CHAPTER 9

FIGURE 284. (a) Systemic scleroderma: this patient with diffuse melanoderma shows depigmented macules on the upper chest. (b) Systemic scleroderma (split DOPA). At the border of the
depigmented macules. a few dopa positive melanocytes are observed. No melanocytes are observed
in the depigmented epidermis.

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61. Flynn GE: Bilateral uveitis, poliosis and vitiligo with an hereditary factor, Am J Ophthalmol
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62. Zentmayer W: Severe uveitis with associated alopecia, poliosis, vitiligo and deafness. Arch
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63. Leyva AV: Uveomeningitis, uveoencephalitis; Vogt-Koyanagi-Harada syndrome; intra-cranial pseudohypertension. Report of three cases. Arch Hosp Univ (Habana) 11:215-231, 1959
64. Alajouanine T et al: Sur une meningoencephalite avec uveite unilaterale et decollement de
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65. Johnson WC: Vogt-Koyanagi-Harada syndrome. Arch Dermatol 88: 146-149, 1963

667

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HYPOMELANOSES

666

CHAPTER 9

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67. Schwartz EA: Vogt-Koyanagi syndrome precipitated by lens extraction. Report of a case. Am
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68. Howsden SM et al: Vogt-Koyanagi-Harada syndrome and psoriasis. Arch Dermatoll08:395-398,
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104. McPherson SO, Wood AC: The significance of the intracutaneous test for hypersensitivity to
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105. Kahan A et al: Pigment Autoagression in der Pathogenese es Vogt-Koyanagi-Harada syndroms. Albrecht von Graefes Arch Klin OphthalmoI167:246-264, 1964
106. Hammer H: Lymphocytic transformation in sympathetic ophthalmitis and the Vogt-Koyanagi-Harada syndrome. Br J Ophthalmol 55:850-852, 1977
107. Tagawa Y: Lymphocyte-mediated cytotoxicity against melanocyte antigens in Vogt-Koyanagi-Harada disease. Jpn J Ophthalmol 22:36-39, 1978

ALEZZANDRINI SYNDROME
108. Cremona AC et al: Vitiligo, poliosis and unilateral macular degeneration. Arch Oftalmol
Buenos Aires 36:102-106, 1961
109. Alezzandrini AA: Manifestations unilaterales de degenerescence tapeto-retinienne de vitiligo,
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SENILE GRAYING OF HAIR

110. Hollingsworth JW et al: Correlations between tests of aging in Hiroshima subjects-an attempt
to define "physiologic age." Yale J BioI Med 38:11-26, 1965
111. Fitzpatrick TB et al: Age changes in the human melanocyte system, Advances in Biology of
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consideJ:'ations. J Gerontol 26:364-372, 1971
114. Boas F, Michelson N: The graying of hair. Am J Phys AnthropoI17:213-228, 1932
115. Straile WE: A study of the hair follicle and its melanocytes. Dev BioI 10:45-70, 1964
116. Wade WG et al: A study of two families with multiple autoimmune disease. Irish J Med Sci
3:463-473, 1970
117. Conrad RA: An attempt to quantify some clinical criteria of aging. J GerontoI15:358-365,
1960
118. Ebling FJ, Rook A: Hair, in Textbook of Dermatology, 2nd ed. Edited by A Rook et a1. Oxford,
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MISCELLANEOUS
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CHAPTER 9

119. Ronchese F: A comment on even whitening of senile hair. Int J Dermatol11:84-85, 1972
120. Comaish S: White scalp hairs turning black-an unusual reversal of the aging process. Br J
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121. Bloch B: Uber die Entwicklung des Haut- und Haarpigmentes beim menschlichen Embryo
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Arch Dermatol Syphilol (Berlin) 135:77-108, 1921
122. Fitzpatrick TB et al: The nature of hair pigment, The Biology of Hair Growth. Edited by W
Montagna, RA Ellis. New York, Academic, 1958, pp 255-303
123. Orlanos C et al: Das weisse Haar alterer Menschen. Arch Klin Exp Dermatol 236:395--405,
1970
124. Herzberg 1. Gusek W: Das Ergrauen des Kopfhaares. Arch Klin Exp Dermatol 236:368-384,
1970
125. Kukita A et al: The electron microscopic study on dendritic cells in the hair matrix of human
white and gray hair. Jpn J Dermatol [BJ 81:326-334, 1971
126. Metchnikoff E: Sur Ie blanchissement des cheveux et des pails. Ann Inst Pasteur Lille 15:215,
1901
127. Yosikawa H: Studies in biochemistry of copper; copper in keratinous appendages of skin.
Jpn J Med Sci II Biochem 3:267-272, 1937
128. Kirby GC: Greying with age: a coat-color variant in wild Australian populations of mice. J
Hered 65:126-128, 1974
129. Burch PRJ, Jackson D: The greying of hair and the loss of permanent teeth considered in
relation to an autoimmune theory of aging. J Gerontol 21:522-528, 1966

SUDDEN WHITENING OF HAIR

130. Smiley ER: Blanched hair from sudden emotions. Boston Med Surg J 44: 438--440, 1851
131. Jelinek JE: Sudden whitening of the hair. Bull NY Acad Med 48:1003-1013, 1972
132. Menninger-Lerchenthal E: Pliitzliches Ergrauen der Haare durch Schreck. Wien Klin Wochenschr 60:295-296, 1948
133. MacLeod JMH: A case of leucodermia and leucotrichia following motor accident. Br J Dermatol
49:437--438, 1937
134. Baelz (1908): Quoted by Ephraim AJ: On sudden or rapid whitening of the hair. Arch Dermatol
79:228-236, 1959
135. Ephraim AJ: On sudden or rapid whitening of the hair. Arch Dermatol 79: 228-236, 1959
136. Perry BC: A treatise on the Human Hair and Its Diseases. New Bedford, Tauber, 1859, pp
54-67
137. Holzgraefe A: Alopecie als Symptom neurohormonaler Erkrankungen. Nervenarzt 18:134-138,
1947
138. Ornsteen (1930): Quoted by Ephraim AJ: On sudden or rapid whitening of the hair. Arch
Dermatol 79:228-236, 1959
139. Canuto F: Quoted by Vignolo-Lutati C: Canizie precoce e psicopatie di guerra. Policlinico
25:680-685, 1918
140. Landois L: Das pliitzliche Ergrauener Haupthaare. Arch Pathol Anat Physiol 35:575-599,
1866
141. Raymond (1882): Quoted by Ephraim AJ: On sudden or rapid whicening of the hair. Arch
Dermatol 79:228-236, 1959
142. Hoff F: Akuter totaler Pigmentverlust. Dtsch Med Wochenschr 79:284-287, 1954
143. Gowers WR: A letter on metallic poisoning. Lancet 2:1173-1176, 1901
144. von Stieda L: 1st Pliitzliches Ergrauen des Haupthaares miiglich? Wien Med Wochenschr
36:1484-1487, 1910
145. Hebra Kaposi: Quoted by Ephraim AJ: On sudden or rapid whitening of the hair. Arch
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146. Brown-Sequard M: Experience demontrent que les poils pouvent passer rapidement du noir
au blanc chez l'hamme. Arch Physiol 2:442--443, 1869
147. Editorial: Sudden whitening of hair. Br Med J 1:504, 1973
148. Klingmuller G: Sudden graying of hair. Hautarzt 24:44--45, 1973
149. Ronchese F: A comment on uneven whitening of senile hair. Int J DermatolI3:84-85, 1974

150. Vauquelin: Quoted in Ephraim AJ: On sudden or rapid whitening of the hair. Arch Dermatol
79:228-236, 1959
151. Metchnikoff E: On the process of hair turning white. Proc R Soc Lond 69:156, 1901-1902
152. Helm F, Milgrom H: Can scalp hair suddenly turn white? Arch Dermatoll02:102-103, 1970
153. Burton JL: Canities of rapid onset due to diffuse alopecia. Practitioner 205:655--656, 1970
154. Damste TJ: A case of alopecia with acute pigment loss. Dermatologica 136:440, 1968
155. Klingmiiller G: Dber "plotzliches Weisswerden" und psychische Traumen bei der Alopecia
areata. Dermatologica 117:84-92, 1958
156. Lehnert W: Beitrag zur Frage des "plotzlichen Weisswerdens" von Korperhaaren. Dtsch Gesund 26:740-743, 1971
157. Montgomery PR: White overnight? (letter). Br Med J 1:300,1967
158. Lerner AB: Vitiligo. Prog Dermatol 6:1--6, 1972
158a. Guin JD et al: Immunofluorescence findings in rapid whitening of scalp hair. Arch Dermatol
117:576-578, 1981

ALOPECIA AREATA
159. Demis J, Weiner MA: Alopecia universalis, onychodystrophy, and total vitiligo. Arch Dermatol 8:195-201, 1963
160. Van Scott EJ: Morphologic changes in pilosebaceous units and anagen hairs in alopecia areata.
J Invest Dermato! 31:35-38, 1958
161. Ortonne J-p, Jeune R: Hair color and alopecia areata. Arch Dermatol114:1716, 1978
162. Lubowe II: Pigmentation in alopecia totalis. Arch Dermato! 77:593-594, 1958

VAGABOND'S LEUKOMELANODERMA
163. Bondet M: Melanodermic parasitaire. Lyon Med 70:262-264, 1892
164. Habermann R: Paratypishe Pigmentanomalien, in Toxicodermien. Edited by E Guttmann et
a1. Handbuch der Haut- und Geschlechtskrankheiten, IV 2. Berlin, Springer-Verlag, 1933,
pp 854-856
165. Pautrier LM, Levy G: Maladie des vagabonds et melanodermie generalisee. Bull Soc Fr Dermatol Syphiligr 32:172-175, 1925
166. Pautrier LM et al: Maladie des vagabonds et melanodermie generalisee (contribution a I'etude
des melanodermies). Bull Soc Fr Dermatol Syphiligr 34:249-253, 1927
167. Jeghers H: Pigmentation of the skin. N Eng! J Med 231:122-136, 1944
168. Greenhow EH: A case of vagabond's discoloration simulating the bronzed skin of Addison's
disease. Trans Clin Soc Lond 9:44-47, 1876
169. Lanzerberg MP: Maladie des vagabonds, avec pigmentation de la mugueuse buceale. Opposition avec un autre malade atteint de phtiriase et d'un autre type de melanodermie. Bull
Soc Fr Dermatol Syphiligr 39:293-295, 1932
170. Becker SW, Obermayer M: Modern Dermatology and Syphilology. Philadelphia, Lippincott,
1940, pp 3-7
171. Marie P, Guillain G: Melanodermie de cause incertaine (maladie d'Addison ou maladie des
vagabonds). Bull Mem Soc Med Hop Paris 19:198-203, 1902
172. Thiers H et al: Deux cas de melanodermie des vagabonds. Etude des epreuves de fonctionnement surrena1. Bull Soc Fr Dermatol Syphiligr 72:82-83, 1965
173. Grosshans E et al: La leucomelanodermie des vagabonds. Etude anatomopathologique et
ultrastructurale. Ann Dermatol Syphiligr (Paris) 99:141-166, 1972

HETEROCHROMIA IRIDES AND HORNER SYNDROME

174. Gladstone RM: Development and significance of heterochromia of the iris. Arch Neurol
21:184-192, 1969

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MISCELLANEOUS
HYPOMELANOSES

672
CHAPTER 9

175. Grimson BS, Thompson HS: Drug testing in Horner's syndrome, in Neuroophthalmology.
176. Calhoun FP: Causes of heterochromia irides with special reference to paralysis of the cervical
sympathetic. Am J Ophthalmol 2:255-269, 1919
177. Durham DG: Congenital hereditary Horner's syndrome. Arch Ophthalmol 60: 939-940, 1958
178. Angelucci A: Sulle alterazioni trofiche dell'occhio che nei manniferi seguono Ie estirpazione
del gangl ganglio cervicale superiore de sympatico. Arch Ottalm 1:1-100, 1893
179. Mayou MS: Heterachromia iridis associated with paralysis of the sympathetic in early life.
Trans Ophthalmol Soc UK 30:196-197,1910
180. Bistis J: Etude clinique et experimentale sur Ie r61e du sympathique dans l'etiologie de
l'heterochromie. Arch Ophtalmol 45:569-595, 1928
181. Duke Elder S (Ed): System of Ophthalmology, Vol 3. London, Harry Kimpton, 1964
182. Lazarescu D, Lazarescu E: Heterochromia neurogene de l'iris et syndrome de Claude Bernard-Horner: observation clinique et recherches experimentales. Ann Oculist 170:767-771,
1933
183. Makley TA, Abbott K: Neurogenic heterochromia; report of an interesting case. Am JOphthalmol 59:927-928, 1965
184. Waardenburg PJ: Over ongelijke iristeleur bij verlamming van den nevus sympathicus. Ned
Tijdschr Geneeskd 64:1929-1941, 1920 Quoted in Gladstone RM: Development and significance of heterochromia of the iris. Arch Neurol 21:184-192, 1969
185. Weber E: Ober einen feltenen Fall von heterochromia Iridis. Klin Monatabl Augenheilkd
106:719, 1941
186. Laties AM, Lerner AB: Iris colour and relationship of tyrosinase activity to adrenergic innervation. Nature 255:152-153, 1975

SCLERODERMA
187. Jablonska S: Cutaneous lesions in systemic scleroderma (progressive systemic sclerosis), in
Scleroderma and Pseudoscleroderma. Edited by S Jablonska. Warsaw, Polish Medical Publishers, 1975 pp 243-276
188. Jablonska S: Localized scleroderma, in Scleroderma and Pseudoscleroderma. Edited by S
Jablonska. Warsaw, Polish Medical Publishers, 1975, pp 277-303
189. Szczepanski A: Studies of rheobase and sensory chromaxy in an appraisal of the role of the
nervous system in cases of the coexistence of circumscribed scleroderma with vitiligo. Przegl
Dermatol 60:219-222, 1973
190. Szczepanski A: Clinical and etiopathological appraisal of diffuse scleroderma with skin depigmentation. Przegl Dermatol 60:323-326, 1973
191. Ortonne J-p, Perrot H: Scleroderma: ultrastructural study of the melanin pigmentary disturbances of the skin. Clin Exp Dermatol 5:13-25, 1980
192. Guillaum A et al: A propos de deux cas de sclerodermie generalisee chez l'Africain. Bordeaux
Medical 11:101-105, 1978

IV
Leukodermas without Hypomelanosis
NEVUS ANEMICUS
Nevus anemicus, first described by Vomer [1] in 1906, is a congenital
malformation characterized by macules of varying size and shape which appear
distinctly pallid compared to the surrounding skin.

Clinical Features
Nevus anemicus is rare. Piorkowski [2] observed only seven cases in 19
years. However, as the disease is asymptomatic and causes no cosmetic disfigurement, it is likely that few affected patients seek medical counseling. It is
more frequent in women [3]. The lesion is present at birth. Most patients are
generally in good health, but nevus anemicus has been reported in patients
with von Recklinghausen disease [3,4] and with multiple vascular malformations [5]. But there is no data supporting an increased incidence; the incidence
in the general population is unknown.

Clinical Description
Usually, nevus anemicus appears as a large area of pale skin with sharply
outlined irregular borders surrounded by satellite macules (Fig. 285). Sometimes it appears as a number of grouped small macules "arranged like the fronds
of a maidenhair fern" [6] (Fig. 286). Nevus anemicus is usually located on the
trunk, most commonly on the chest. However, involvement of the face and
extremities has been reported [4,7,8]. A patient with a linear nevus anemicus
on an arm has been described [2].
The epidermis appears otherwise normal and the condition is usually
asymptomatic. There are no local sensory abnormalities.
Several simple tests facilitate the diagnosis: Under the Wood's light, nevus
anemicus seems to disappear. This clearly establishes that the decreased color
of the involved skin is not secondary to decreased melanin content. Pressure
on the border of the lesion with a glass slide renders the area of the nevus

673

674

PART IV

FIGURE 285. Large area of pale skin surrounded by small satellite macules. Even with suninduced pigmentation, in the right part of the picture the nevus anemicus is still apparent.

indistinguishable from that of the blanched surrounding skin [21. Vigorous

rubbing or prolonged application of heat or cold to the affected area fails to
induce erythema in the nevus area in contrast to normal surrounding skin which
reacts with intense vasodilatation.

Histology
The histology is normal [9]. In the affected areas, hematoxylin-eosin-saffran stains reveal normal papillary and subpapillary vasculature. Alkalinephosphatase histochemical preparations show intact vasculature indistinguishable from uninvolved skin [3].

Electron Microscopy
Electron microscopy of involved skin is normal [10].

675

LEUKODERMAS
WITHOUT
HYPOMELANOSIS

FIGURE 286. a, b: Grouped small macules of pale skin with sharply outlined borders "arranged
like the fronds of a maidenhair fern. "

676
PARTlY

Pathogenesis
Nevus anemic us is a vascular phenomenon. Since no anatomic abnormalities have been identified in the vasculature of the involved skin, nevus
anemicus must result from a physiologic vascular abnormality. Nevus anemicus
is fascinating because it is a purely functional congenital disorder. Greaves et
al. [10] suggested that nevus anemicus may justifiably be called "pharmacological nevus."
Inquiry into the nature of the vascular reaction pattern anomaly has provoked some observations and studies. Vomer [1] noted that it was difficult to
produce urticaria factitia within a nevus anemicus. Piorkowski [2] concluded,
from physiologic studies of nevus anemicus, that "the cause of the disease is
a permanent tonic constriction" of the vasculature. Butterworth and Walters
[11) hypothesized that the underlying defect is in the effector cells of the
arterioles. Fleisher and Zeligman [3) noted that intralesional injection of acetylcholine, pilocarpine, histamine, or serotonin failed to produce vasodilatation
in the affected areas and concluded that the defect may be "at the motor endplate
or at the smooth muscle effector cells of the blood vessels, perhaps associated
with an increased stimulation of the vasoconstrictor fibers or of inhibition of
the vasodilator fibers of the arterioles." Greaves et al. [10] concluded that the
immediate cutaneous abnormality is sustained adrenergic vasoconstriction. Abolition of visible evidence of the nevus by a sympathetic block suggested sympathetic vasoconstriction produced the nevoid pallor. The lowered threshold
of the nevus vessels to the blanching effect of levarterenol suggested increased
sensitivity of cutaneous blood vessels to catecholamines as important to the
production of the nevoid pallor. However the possibility of increased adrenergic
sympathetic tone due to increased local catecholamine concentration in nevus
anemic us could not be excluded.
Transplant studies demonstrated donor dominance [9). Transplanted skin
biopsies retained their original characteristics and did not assume those of the
receptor site. The defect seems to be an increased sensitivity of blood vessels
to catecholamines and not increased adrenergic stimulation.

Diagnosis and Differential Diagnosis (Table 135)

The diagnosis of nevus anemicus is easily established clinically. Wood's
light examination, local reactivity after vigorous stroking, heat, or cold exposure
clearly distinguish nevus anemic us from leukoderma related to melanin abnormalities. Histologic and ultrastructural studies are not helpful.

Treatment
Fortunately, nevus anemicus induces only a slight cosmetic disfigurement,
because no effective treatment is available.

TABLE 135. Clinical Features in Nevus Anemicus

Frequency
Age of onset
Sex
Shape and size
Borders
Color
Distribution
Extent
Local symptomatology
Wood's light examination
Stroking, heat, or cold exposure
Associated findings

Rare
Birth
More frequent in females
Variable: large area with small satellite
spots; grouped small spots
Irregular, sharply outlined
Slightly paler than normal skin
Trunk, face, extremities
Localized
None
No contrast with normal skin
Absence of vasodilatation
Usually none

EDEMA OF THE SKIN

Cutaneous edema renders the skin more pallid than normal. This may
result from altered transmission through and reflection from the affected tissues
[12). Separation of the structural elements of the skin from each other because
of the presence of edema fluid results in decreased absorption of light. Possibly
intra- or extracellular edema also disturbs melanosome transfer.

ANEMIA
Decreased levels of circulating oxyhemoglobin in anemic states induce a
pallor which is most readily detected in areas where there is physiologically
less melanin (palms and soles, mucous membranes). The degree of pallor in
the skin is inversely proportional to the hemoglobin content of the blood. Pallor
also results from decreased cutaneous blood perfusion, as in Raynaud phenomenon. However, nevus anemicus is the only focal leukoderma secondary
to decreased oxyhemoglobin content of the skin that can be confused with
melanin disturbances.

REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.

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Fleisher TL, Zeligman I: Nevus anemicus. Arch Dermatol100:750-755, 1969
Naegeli 0: Naevi anaemici und Recklinghausensche Krankheit. Arch Dermatol Syphilol (Berlin) 121:742-745, 1915
Weber FP: Case of nevus anemicus. Br J Dermatol 41:119-120, 1929
Little EGG: Case of nevus anemicus. Br J Dermatol 33:25-26, 1921
Lane J: Naevus anaemicus. J Cutan Dis 34:602-604, 1916
MacKee GM: Case report presented before the Manhattan Dermatologic Society. J Cutan Dis
36:200-201, 1918

677
LEUKODERMAS
WITHOUT
HYPOMELANOSIS

678

PART IV

9. Daniel RH et al: Nevus anemicus. Arch Dermotol 113:53-56, 1977

10. Greaves MW et al: Nevus anemicus: a unique catecholamine-dependent nevus. Arch Dermotol
102:172-176, 1970
11. Butterworth T, Walters JD: Observations and pharmacologic responses of Vomer's nevus anemicus. Arch Dermotol Syphilol 66:333-339, 1952
12. Jeghers H, Edelstein LM: Pigmentation of the skin, Signs ond Symptoms, 5th ed. Edited by
eM MacBryde, RS Blacklow. Philadelphia, Lippincott, 1970

Index
Achromic guttate parapsoriasis, 512
Addison disease and vitiligo, 191
Albinism
with hemorrhagic diathesis, 75
and immunodeficiency, 87
ocular, 89
optic pathway abnormalities, 92
Albinism, oculocutaneous, 59
classification, 61
incidence, 63
tyrosinase-negative, 65
tyrosinase-positive, 69
yellow-mutant, 74
Albino, 61
Alezzandrini syndrome, 641
Alopecia areata, 656
Alpha-dendritic cells, see Indeterminate cells
Amelanosis, 37
Arsenic, 499
Ascorbic acid in vitiligo, 237
Ataxia-telangiectasia, 433
other cutaneous features, 433
systemic abnormalities, 434
Basement membrane in vitiligo, 233
Benoquin, therapeutic use in vitiligo, 284
Bird-headed dwarfism, 465
Bleeding times in vitiligo, 241
Bloch-Sulzberger syndrome, 422, 427
Butyrophenone, 500
Canities, 37
Chediak-Higashi syndrome, 79; see also
Depigmentation, chemically indiced
Chemical hypomelanosis, 479
mechanism of action, 489
Chloroquine diphosphate, 501
Clofazimine, therapeutic use in vitiligo, 284
Copper, in vitiligo, 235

Copper deficiency, 102, 470

hereditary, 103
in infants, 103
nutritional, 102
Corticosteroids, therapeutic use in vitiligo,
282
Cross-McKusick-Breen syndrome, 88
Cushing syndrome and hypomelanosis, 473
Cutaneous blood flow in vitiligo, 239
Cystathionine synthetase deficiency, 119
Darier-White disease, 452
Delayed tanning, 27
Dendritic cells in vitiligo, 227
Depigmentation, 37
chemically induced, 479
diagnosis, 492
mechanism of action, 489
treatment, 492
and corticosteroids, 499
in vitiligo, 284
Dinitrochlorobenzene, 498
Dopa
melanin precursor, 4
therapeutic use in vitiligo, 283
Down syndrome, 465
Dyschromatosis symmetrica, 440
clinical features, 440
diagnosis, 443
incidence, 440
Dyschromatosis universalis hereditaria, 440
clinical features, 440
diagnosis, 443
incidence, 440
Dyschromia, 469
Dyschromic hair, 468
Dystrophia myotonica, 462
Endocrine disorders and hypomelanosis, 473
Epidermal dendritic cells, 7

679

680

INDEX

Epidermal melanin unit, 1

Epinephrine and depigmentation, 502
Eserine, 502
Eumelanin, 3
Fanconi syndrome, 461
Fisch syndrome, 464
Focal dermal hypoplasia syndrome, 456
Furocoumarins, 261
Gastric function abnormalities and vitiligo,
195
Gastroenteropathies, 219
Guanonitrofuracin and depigmentation, 497
Hair, pigmentary changes
in Kwashiorkor, 467
in malabsorption syndromes, 470
in nephrosis, 470
in ulcerative colitis, 470
Hair pigmentation disorders, 461
Hallerman-Streiff syndrome, 465
Halo nevus, 567
clinical features, 572
electron microscopy, 586
histology, 583
incidence, 570
pathogenesis, 599
and vitiligo, 581
Halo phenomena, 595
Harada disease, 627
Hematologic disorders in vitiligo, 217
Hereditary premature canities, 464
Hermansky-Pudlak syndrome, 75
Herpes zoster, 544
Heterochromia irides, 662
Histidinemia, 107
Homocystinuria, 119
Horner syndrome, 662
Hydroquinone, therapeutic use, 284, 492
Hyperthyroidism and premature graying of
hair, 473
Hypogonadism and hypomelanosis, 474
Hypomelanoses, 467
and copper deficiency, 470
and endocrine disorders, 473
and iron deficiency, 470
and metabolic disorders, 470
and nutritional disorders, 467
in possible ectodermal dysplasia
syndromes, 460
and Vitamin B'2 deficiency, 471
Hypomelanosis; see also Leukoderma
associated with neoplasms, 567
cellular and subcellular basis for, 53
chemical, 479
circumscribed, 129
classification, 38, 60

Hypomelanosis (cont.)
and endocrine disorders, 52, 473
hereditary, 42, 60
infectious, 523
and inflammation, 509
following irradiation, 475
of Ito, 423, 425
and neurocutaneous disorders, 52
with oculocutaneous albinism, 59
parasitic, 523
pathogenesis, 54
following physical trauma, 475
of scalp hair, 39
theoretical mechanisms, 55
Wood's light examination, 49
Hypomelanotic disorders, 57
with circumscribed hypomelanosis, 129
with generalized decreased pigmentation,
102
genetic and congenital, 59
Hypopigmentation
and microphthalmia, 88
with punctate kerotosis of the palms and
soles, 458
Hypopituitarism and hypomelanosis, 473
Hutchinson-Gifford syndrome, 463
Idiopathic guttate hypomelanosis, 619
Immediate pigment darkening, 27
Incontinentia pigmenti, 422
development anomalies in, 432
diagnosis, 430
hypopigmentation in, 427
nervous system abnormalities in, 431
ocular anomalies in, 431
Incontinentia pigmenti achromians, 411
clinical findings, 412
diagnosis, 425
familial, 412
histology and electron microscopy,
420
incidence, 412
systemic findings, 418
pathogenesis, 421
Indeterminate cells, 7, 232
Inflammation and hypomelanosis, 509
Kappa chain deficiency, 464
Keratinocytes, 1
in vitiligo, 233
Koebner phenomenon, 163
Kwashirokor, 467
associated findings, 469
depigmentation in, 467
diagnosis, 469
histology, 468
pathogenesis, 468

Langerhans cells, 7, 228

Leprosy, 523
diagnosis, 533
histology, 529
Leukoderma; see also Hypomelanosis
diagnosis, 37
chemically induced, 479
eye examination, 51
histology and electron microscopy, 51
without hypomelanosis, 673
physical examination, 41
Wood's light examination, 49
Leukoderma acquisitum centrifigum, 567; see
also Halo nevus
Leukoderma lenticular disseminata, 619
Leukomelanoderma, 37
Leukopigmentary nevus, 567
Lupus erythematosus, 213, 509

Macular tropical hypochromia, 627

MBEH, see Hydroquinone
Melanin formation, 3
Melanin metabolites in vitiligo, 238
Melanin pigmentary system, 1
Melanin pigmentation, biologic basis of, 11
Melanin synthesis, inhibitors of, in vitiligo,
237
Melanization of melanosomes, 14
Melanocyte function, 24
Melanocytes
melanosome formation in, 11
origin of, 9
racial differences, 23
variation in, 20
Melanogenesis, regulation and variables, 20
Melanoprotein, 14
Melanosome formation in melanocytes, 11
Melanosome organization, 13
Melanosome-stimulating hormone, 16, 25
Melanosomes
degradation of, 19
movement within melanocytes, 15
transfer of, 16
Melatonin, 26
Menkes Kinky Hair syndrome, 103
Mephenesin carbamate, 498
Metabolic disorders and hypomelanosis, 467
Methionine malabsorption syndrome, 123
Methionine metabolism disorders, 119
MSH, see Melanosome-stimulating hormone

Neoplasms and hypomelanoses, 567

Neural crest, 9
Neurofibromatosis, 438
Neuromelanin, 6
Nevus anemicus, 37,40,673

Nevus depigmentosus, 424

clinical features, 398
diagnosis, 409
histology and electron microscopy, 406
treatment, 410
Nitrogen mustard, 499
Nutritional disorders and hypomelanoses, 467
Oasthouse urine disease, 123
Occupational leukoderma, 483
Ocular albinism, 89
Oculocerebral-hypopigmentation syndrome,
88
Oculocutaneous albinism, 59
Oculocutaneous albinoidism, 89
Onchocerciasis, 555
Pangeria, 462
Parapsoriasis, 512
Paratertiary amyl phenol and hypomelanosis,
485
Paratertiary butyl phenol and hypomelanosis,
485
Parkinson disease, 215
Perinevoid leukoderma, 567
Perinevoid vitiligo, 567
Pernicious anemia, 471
Phaeomelanin, 6
Phenolic compounds, 480, 482
Phenolic de pigmenting agents, therapeutic
use, 492
Phenylketonuria, 109
enzymatic defect in, 116
pathogenesis of melanin in, 117
pigmentary dilution in, 110
Phototoxic drugs, 503
Piebaldism, 310
with deafness (Woolf syndrome), 326, 369
diagnosis, 321, 333
distinguished from vitiligo, 321, 333
heredity, 317
histology and electron microscopy, 328
incidence, 313
pedigrees, 314
systemic findings, 324
Pierre Robin syndrome, 465
Pigmentary demarcation line, 444
Pigmentation,
genetic control of, 22
hormonal factors, 25
human, 23
mouse models, 22
neural control, 26'
nutritional and metabolic factors, 26
tissue factors in control of, 24
Pinta, 536
Pityriasis alba, 516
Poliosis, 37

681

INDEX

682
INDEX

Porphyria, 213
Post-kala-azar dermatosis, 559
Premature aging syndromes, 462
Premature graying of scalp hair, 40
and vitiligo, 207
with Waardenburg syndrom, 344
Premolar aplasia, hyperhidrosis and canities
prematura, 461
Progeria, 463
Protein deficiency, 467
Psoralens, 260
absorption spectra, 261
pharmacology, 262
photosensitization, 263
therapeutic use, 267
side effects, 279
Psoriasis, 513
Quinacrine, therapeutic use in vitiligo, 283
Rothmund-Thomson syndrome, 462
Rozycki syndrome, 452
Sarcoidosis, 613
Scleroderma, 663
Seckel syndrome, 465
Senile graying of hair, 641; see also Canities
Sensory function of skin, in vitiligo, 238
Skin temperature in vitiligo, 239
Sudden whitening of hair, 651
Sulfhydryl compounds and depigmentation,
496
Sutton's nevus, see Halo nevus
Sweat secretion in vitiligo, 240
Syphilis
endemic, 542
secondary, 543
Thiambutosine, therapeutic use in vitiligo,
284
Thiamine in vitiligo, 237
Thyroid disease and vitiligo, 182
Tietz syndrome, 123
Tinea versicolor, 545
diagnosis, 555
electron microscopy, 551
histology, 547
treatment, 555
Treacher-Collins syndrome, 465
Trichochrome, 6
Trichopoliodystrophy, 103
Triparanol. 498
Tuberculosis, 562
Tuberous sclerosis, 375
clinical features, 376
diagnosis, 392
histology and electron microscopy, 386
systemic manifestations, 391

Tyrosinase, 5
in vitiligo, 234
Tyrosinase inhibitors, 27
Tyrosine-melanin pathway, 3
Ultraviolet radiation, control of pigmentation
by, 27
Vagabond's leukomelanoderma, 657
Vesicoglobular bodies, 14
Vitamin BI2 deficiency, 471
Vitiligo
and Addison disease, 191
and alopecia areata, 205
animal models, 241
and associated disorders, 182
and atopic dermatitis, 211
auditory changes, 177
and autosomal recessive deafness, 452
biochemical studies, 234
and blood groups, 178
classification, 165
clinical features, 132, 145
composite hypothesis, 257
confusion with leprosy, 129
and diabetes mellitus, 198
diagnosis, 258
distribution of depigmented macules, 153
and dysglobulinemia, 216
familial. 135
functional abnormalities of skin, 238
and gastric function abnormalities, 195
and gastroenteropathies, 219
and hematologic disorders, 217
hepatobiliary disease, 216
histologic findings, 225
history, 129
and hypogonadism, 214
and hypoparathyroidism, 204
and hypopituitarism, 214
and idiopathic heart block, 220
immune hypothesis, 243
incidence, 132
involvement of hair in, 161
isomorphic phenomenon, 163
and lichen planus, 211
and lichen sclerosus et atrophicus, 213
and lupus erythematosus, 213
and malignancies, 217
and multiglandular insufficiency
syndromes, 200
and myasthenia gravis, 220
neural hypothesis, 250
and Parkinson disease, 215
and pernicious anemia, 194
and porphyria, 213
precipitating factors, 140
pregnancy, 144

Vitiligo (cont.)
psoralen and ultraviolet radiation therapy,
260
and psoriasis, 207
psychologic factors, 141
repigmentation, 260, 265
and rheumatoid arthritis, 215
self-destruct hypothesis, 256
and thyroid disease, 182
trauma, 143, 163
treatment, 258
Vitiligo-like leukoderma and melanoma, 208
Vogt-Koyanagi-Harada syndrome, 627
clinical features, 630
diagnosis, 640
etiology, 638
pathologic findings, 635
Waardenburg syndrome, 337
abnormalities in, 341
animal models, 339
deafness in, 356
"deficient neural crest" theory, 357

Waardenburg syndrome (cont.)

diagnosis, 363
dystopia canthorum in, 354
as First Arch syndrome, 359
histopathology and electron microscopy,
348
incidence, 340
"Intrauterine necrosis" theory, 361
ocular pigmentary abnormalities, 350
and status dysraphicus, 360
Werner syndrome, 462
White forelock in piebaldism, 318
Woolf syndrome, see Piebaldism, with
deafness
Woronoff's ring, 513
Xeroderma pigmentosum, 435
X-ray depigmentation, 475
Yaws, 534
Ziprkowski-Margolis syndrome, 373

683

INDEX