CHROMOSOMAL DISORDERS

Uncommon at birth but very common at conception

0.4% of live births - either chromosomal number or structure problem

MISCARRIAGE
~ 15% of recognised pregnancies end in miscarriage
early spontaneous abortions
o 40% have normal chromosomes
o 60% abnormal chromosomes
trisomy (30%) - trisomy 16 most common trisomy leading to miscarriage
45XO (10%)
triploid (10%)
tetraploid (5%)
other (5%)
trisomy 21
o >60% spontaneously abort
o >20% are stillborn
spontaneous abortion due to chromosomal abnormalities
o overall 50%
o early (<12/40) 60%
o late (12-20/40) 20%
o still birth 5%

CHROMOSOMAL NUMBER ABNORMALITIES
ANEUPLOIDY AND POLYPLOIDY
Haploid = 23 chromosomes, Euploid = 46 chromosomes, Polypoid = multiple of 23 eg triploid
polyploid conception do not survive
exception is mosaics
Aneuploid = cells deviating from haploid number
either extra or missing chromosome
o trisomies only 13, 18, 21 survive to term
o monosomies usually lethal
proteins are over or underproduced depending whether sensitive to dosage
most genes only need 1 chromosome to be normal (the others are extra)
ie. enzymes only need 1 copy to work (AR conditions ie. CF)
however some genes dosage is important (need 2 copies to work)

TRISOMIES
most common chromosomal number abnormality
Genetics: usually due to meiotic non-disjunction
either due to failure of homologous chromosomes to separate in meiosis I (mostly)
or sister chromotids to separate in meiosis II
account for 35% of spontaneous abortions (T16 most common)
present in all cells or in mosaics
only T21 (Down), T18 (Edwards), T13 (Patau) & sex chromosome aneuploidies compatible with life
all have incidence when maternal age >35yrs
women < 35 yrs age: offer triple screen
women > 35 yrs of age: offer CVS and amniocentesis

MONOSOMIES
only monosomy compatible with life is XO
CHROMOSOMAL STRUCTURE ABNORMALITIES

DELETION
piece chromosome missing
mostly de novo but can be inherited (therefore always karyotype parents)
usually a/w mental retardation (more severe than duplication) and malformations
1) at terminal ends = telomeres: often non-specific mental retardation + minor anomalies
subtelomeric deletions (SDs)
DNA near telomere very gene rich
if screen kids with developmental delay: 1 in 20 with SDs
top 3 causes DD: T21, fragile X and SDs (and Retts in girls)
2) within chromosome (interstitial)



Deletions vs Microdeletions
deletions are seen under routine chromosome preparations
micro-deletions are seen only with high quality protaphase preparations use FISH
effects due to monosomy of several contiguous genes
sub-micro-deletions need molecular probes

Deletion types (most common)
4p Wolf-Hirschhorn syndrome
5p Cri-du-Chat syndrome

Micro-deletion types
7q23 Williams
8q24.1 Langer-Giedion
11p13 WAGR
15q11-13 Prader Willi
15q11-13 Angelman
16p13 Rubinstein-Taybi
17p11.2 Smith Magenis
17p13.3 Miller Dieker
20p12 Alagille syndrome
22q11 22q11 microdeletion syndrome

TRANSLOCATION
= transfer chromosome material from one to another
incidence 1/500

types
Balanced (=reciprocal) translocation
have all genetic material needed (no gain or loss genetic material)
In fact ~20% of balanced translocations have gain or loss of genetic material at the break point
Germline:
10% clinically abnormal (breakpoint occurs in crucial gene causes phenotype)
risk of miscarriages and abnormal offspring who inherit extra copy of translocated chromosome & get unbalanced translocation (always
check karyotype if recurrent miscarriages)
NO cancer risk
somatic
relatively common
a/w haematological malignancies

Unbalanced translocation = gain or loss genetic material

Robertsonian
2 acrocentric chromosomes fuse near centromere
loss of non-functional truncated short arm (with no effect on individual)
usually phenotypically normal (but chromosome count 45)
risk of miscarriages and abnormal offspring






Recurrence risk
if balanced found on amniocentesis do karyotype on parents
if one parent carries translocation is safe to assume kid with translocation normal
if translocation de novo: 10% risk possible genetic disorder (due to breakage in critical gene)

INVERSIONS
occur in 1/100 liveborns!
chromosome breaks in 2 places and piece is inverted and reinserted
types: pericentric
breaks in 2 opposite arms of chromosome
involves centromere (identified by abnormal centromere location)
paracentric
only one arm of chromosome involved
usually normal but again increased risk of miscarriages and abnormal offspring or breakage in critical part of a gene (leading to
phenotype)

RING CHROMOSOMES
rare: cases involving each chromosome have been reported
due to deletion at each end of chromosomes and sticky ends joining up
phenotype depends on amount of genetic material lost
normal to nearly normal
intellectual disability and other congenital anomalies
if ring replaces normal chr results in partial monosomy
if ring in addition to normal chromosome result is partial trisomy

DUPLICATIONS
= presence of extra genetic material from same chromosome
due to abnormal segregation in carriers of translocations or inversions
sometimes referred to as partial trisomy

INSERTIONS
requires 3 breakpoints, involves one or more chromosomes
1 chromosome breaks at two points
resulting piece inserted at site of another break (same or diff chromosome)

ISOCHROMOSOME
2 identical arms of chromosome: duplication one arm and loss of the other



SEX CHROMOSOMAL ABNORMALITIES
tend to have less severe phenotype ie. Turners/ Kleinfelters/ XYY male
few important genes on Y
X inactivation most genes
Lyonisation = random inactivation of 1 X at 32 cell stage

FRAGILE SITES
= chromosome regions with increased risk separation, breakage or attenuation under particular growth conditions
ie fragile X syndrome fragile site at Xq27.3 = CGG/CCG repeats (triplet repeats)

CHROMOSOME BREAKAGE SYNDROMES
= associated with chromosomal breaks or rearrangements
may be spontaneous or induced by environmental agents
Ie. Xeroderma Pigmentosa AR = BCCs/SCCs
Fanconis Anaemia AR = leukaemia, many other malignancies
Ataxia Telangectasia - AR = lymphoma, leukaemia
Blooms - AR = lymphoma and leukaemia
Nijmegen syndrome AR = lymphoma/ leukaemia + microcephaly, facial anomalies immunodef
Werner syndrome AR = premature aging begins in teens or early adulthood
Dysplastic Naevus Syndrome - AD = melanoma

MOSIAICISM
= 2 cell lines from single zygote


somatic
variable effects - does not affect all tissues
if suspect mosacism need no of cells analysed from blood test or take skin biopsy

germ line
presence of mosaicism in germ line
suspect when > 1 offspring with genetic disorder (usually AD or chromosome) with phenotypically normal parents
risk of recurrence of disorder in subsequent children
do not look for in lymphocytes (as may not tolerate mosaic genetics) use fibroblasts
eg. Pallister-Killian syndrome = mosaicism of isochromosome 12p (ie 4 copies in some cells)
profound mental retardation
pigmented skin anomalies
coarse facies
CVS anomalies
diaphragmatic hernia
supernumerary nipples

Down syndrome

EPIDEMIOLOGY
incidence: 1/600 live births
o 75% abort spontaneously
o most common autosomal chromosomal disorder causing mental retardation
risk factors:
o maternal age (although 80% are born to mothers <35 yrs) [below: prevalence per thousand]

GENETICS
Trisomy 21 (95%)
due to non-disjunction during meiosis
o 80-90% due to maternal non-disjunction
65% Meiosis I [associated with increased maternal age]
23% Meiosis II
o 10% " paternal " nondisjunction (50/50 Meiosis I & II)
1% recurrence risk (due to small percentage 2 to gonadal mosaicism)

Unbalanced Translocation (3-4%)
50% sporadic (de novo)
50% due to a balanced translocation in one parent
o Most commonly onto chromosome 14 or 21
o chr 13,14,15,21,22 are acrocentric prone to Robertsonain translocation
o no maternal age effect
recurrence risk:
o 100% in parent with a 21:21 translocation
o 16% in mother with a 21:acrocentric chromosome translocation
o 5% in father (theoretically is 33% - real risk is probably due to miscarriages)

Mosaicism (2%)
due to non-disjunction after meiosis
may have modified phenotypes (ie. higher IQ)
mostly due to trisomic rescue

PATHOGENESIS
trisomy of the bottom 1/3 of chromosome 21 is sufficient to account for Down's phenotype
800 genes in the 21q22 band appear to be those responsible for the pathogenesis
results in a 50% "dose" of certain proteins:
SOD-1 (superoxide dismutase)
protects cells from oxygen-containing free radicals
? role in mental retardation & accelerated rate of aging
Gart (phosphoribosylglycinamide synthetase)
involved in purine synthesis
? elevated purines mental retardation
Ets-2 - oncogene
? role in AML
amyloid protein
major component of neurofibrillary plaques
? pathogenesis in Alzheimers
-A-crystallin protein
structural component of lens of eye
? role in formation of cataracts, Brushfield spots

GATA1 mutation + Down syndrome transient myeloproliferative disorder and megaloblastic leukaemia
JAK2 mutation + Down syndrome ALL

CLINICAL FEATURES

DYSMORPHIC FEATURES
General short stature
hypotonia with poor moro reflex
hyperflexible joints
Head 3
rd
fontanelle b/w anterior and posterior fontanelles (also assoc. with hypothyroidism)
false fontanelle
mild microcephaly
flat occiput
Facial widely spaced eyes
Brushfield spots = speckled iris (75% Downs, 10% normal)
slanted palpebral fissures
low set ears +/- over folded upper helix
flat facial profile with a small nose
large protruding tongue
excess skin on back of neck
Hands dysplastic 5th mid-phalanx
simian crease (50-55%)
1
st
digit polydactyly (negative association with postaxial polydactyly)
Feet sandal gap

MENTAL RETARDATION
borderline to moderate IQ range (only 5% severe)
processing problems:
o better at visual than auditory processing
o better at simultaneous than sequential processing
also:
global developmental delay milestones take twice as long
gross motor due to hypotonia
o sit by 9 months
o walk by 20 months
fine motor
speech and language delay
o 75% have an expressive language disability
behavioural problems
o aggression, depression, inappropriate
Alzheimers
may affect 15-20% of adults with Down's
mean age of onset is 51 years (range 46-57 years)

GROWTH
short stature
near the 3rd % of general population
diminished growth velocity can occur at a variety of times (i.e., adolescent growth spurt)
there are specific growth charts for Trisomy 21
obesity
especially at 2-3 years, 12-13 years, and in adult life
o a common problem
sexual maturation

normal but fertility very rare
25-50% have undescended testes
5% have hypospadias
testes may be histologically abnormal

normal sexual maturation and development
menstruation normal
fertility
o abnormal follicular development is common
o pregnancy is possible with a 50% chance of Trisomy 21 occurring in the infant

STRUCTURAL ABNORMALITIES
Cardiovascular Manifestations (40%)
Endocardial Cushion Defects
complete AV canal AVSD (40%)
VSD (20%)
ASD - secundum (15%)
ASD - primum (8%)
Others
PDA (3%)
ToF (3%)
AV valve malformation (prolapse)
aberrant subclavian artery

Gastrointestinal Manifestations (12%)
duodenal atresia most common problem (+/- polyhydramnios, double bubble)
coeliac disease (often asymptomatic)
others: TOF, annular pancreas, Meckel's diverticulum, Hirschsprung's disease, imperforate anus , gallstones

Genitourinary Manifestations
Kidney Malformation
PUJ obstruction with hydro-nephrosis
alterations in structure or maturation of parenchymal structures

External Genitalia Malformation
hypospadias (25-50% of males)
undescended testes (5% of males)
small penis and scrotum

Respiratory Manifestations
incidence of pulmonary hypoplasia + PVR [pulmonary hypertension] (+/- congenital heart defects)
may lead to risk of:
o respiratory tract infections
o acute and chronic airway obstruction
o sleep apnoea (small airways, large tonsils/adenoid, obesity)
o cor pulmonale

Musculoskeletal
cervical spine: atlantoaxial instability
o screen at 4-5yrs lateral neck Xray
o not reliable (operator dependent)
o avoid diving/ trampolining
o symptoms: easy fatiguability/ walking/ neck pain
bladder/ bowel control
incoordination & clumsiness
sensory defects
bony abnormalities of the cervical spine
subluxation or dislocation of hips/ knees
pronation of feet at ankles
pes pannus
short broad hands
short sternum
dysplastic hips

Endocrine
hypothyroidism can be congenital or acquired (usually Graves disease)
congenital - most commonly compensated (TSH with normal T3, T4)
usually normal thyroid scan
use of thyroid hormone not effective for compensated
acquired (lymphocytic) present later (>10yrs) = uncompensated
+/- DM, precocious sexual maturation, hypoPTH
infertility (almost all males, 50% females)

Eyes
congenital nystagmus or alternating esotropia [cross-eye/strabismus]
congenital cataracts and glaucoma
strabismus (60%)
refractive errors (50%)
epicanthal folds, oblique palpebral fissures
blepharitis, keratoconus, Brushfield spots


Ears
recurrent OM
75-90% have conductive hearing loss
midface hypoplasia nasolacrimal duct obstruction, OSA, sinusitis, rhinitis

Teeth
delays and alterations in the sequence of tooth eruption
malocclusion (100%)
relative macroglossia (60%)
missing teeth (50%)
37-60% with fissuring tongue, enlargement of vallate papillae

Dermatologic Manifestations
dry skin (90%) = icthyosis [means fish-like dry, scaly skin with hyperkeratosis & cornification]
with 2 itching, eczema, and infections (i.e., recurrent follicular skin infections)
syringomas
benign sweat gland tumors
> ; onset at beginning of puberty
yellow or skin-coloured, soft 2-3 mm raised papules occur-ring singly or in groups
most commonly found around eyes but also on neck and thorax, axillary, umbilical, and pubic areas
others
alopecia areata (in 10%) -- chronic inflammatory disorder causing non-scarring hair loss [T-cell mediated perifollicular inflammation]
rapid aging of skin
risk of sunburn

Neurologic Manifestations
hypotonia (100%)
at birth, in infancy, and as a toddler
may delay motor milestones but improves with age
seizures (5-10%)
generalized, myoclonic most common type
bimodal presentation (either <1yr or >30yrs)

Autoimmune Disorders
higher than average likelihood of developing:
o thyroiditis
o alopecia areata (in 10-15%)
o diabetes mellitus
o rheumatoid-type arthropathy
autoimmune haemolytic anemia

INVESTIGATIONS
Prenatal Screening/Diagnosis
USS - nuchal translucency (11-14 wks)
o most commonly a/w cardiac disease
o also skeletal dysplasia/ storage disorders
triple test
o AFP
o human chorionic gonadotropin - beta-HCG is usually elevated in pregnancies affected with DS
Should be checked at ~9-13 weeks
o unconjugated estriol (uE3)
o PAPP-A: high molecular weight glycoprotein
Levels usually LOWER in DS pregnancy
Also should be checked between 9-13 weeks
o Inhibin A: not commonly used in screening tests, but levels are elevated in DS pregnancies
+ve in 60% (but false +ve 5-7%)
chorionic villus sampling at 9-12 weeks
amniocentesis at 16-18 weeks
o indications:
advanced maternal age (>35 years)
previous child with Trisomy 21
balanced translocation in parent
prenatal U/S findings suggestive of trisomy 21
abnormal triple test

Routine Imaging Studies
cardiac
2D-Echo, chest x-ray, ECG
gastrointestinal
abdominal x-ray, barium swallow/enema
renal
renal ultrasound
skeletal X-Rays
bone age for short stature
C-spine - an atlanto-dens space > 5mm is suggestive of atlantoaxial instability

Routine Serum Studies
compensated respiratory acidosis (due to COPD)
urea, creatinine, uric acid ( creatinine and uric acid clearance)
CBC with blasts
TSH, T3, T4, thyroid antibodies
? GH stimulation tests

MANAGEMENT
Counselling
outcome
o 80% survive to age 30 or beyond
genetic counselling if plans for another child

Developmental
learning disabilities
teaching methods which emphasize visual over auditory information
developmental delay
early intervention
gross/fine motor - physiotherapy
speech/language - total communication techniques (signing or computers), speech therapy, special education
behaviour - mental health assistance, family counselling

Cardiovascular
echo within 1
st
few weeks of life
surgical correction of CHD

Gastrointestinal
surgical correction of malformations
treat functional problems, i.e., constipation
feeding team for problems

Respiratory
sleep apnoea
weight, repositioning during sleep, nasal CPAP, remove tonsils and adenoids
cor pulmonale
early surgical correction of congenital heart disease (CHD)
COPD
bronchodilators/steroids

Genitourinary
follow serum urea, creatinine, uric acid
follow uric acid and creatinine clearance rates
? role of imaging studies for screening for anomalies
surgical correction of hypospadias, undescended testes

Musculoskeletal
C-Spine
initially assessed at 2-4 years and repeated between 8-10 years
earlier assessment if indicated - neurologic findings:
o loss of motor skills
o asymmetric hypertonicity in lower limbs
o increased clumsiness or tripping
o widely-spaced stiff-legged gait
o any upper motor neuron signs
o loss of fine motor skills
o torticollis, neck pain, headaches
if abnormal then must restrict activities - tumbling, diving, butterfly, collision sports
Spinal Cord Compression
may require surgical stabilization (skeletal fixation) of cervical spine
ortho, neuro, neurosurg consults

Endocrine
thyroid
screen TFT (TSH, T3, T4) annually +/- thyroid antibodies
growth
monitor growth on charts for Down's
true GH deficiency is rare but may respond to GH supplements
obesity - caloric restriction, increase activity/exercise
reproduction
birth control & reproductive health issues need to be addressed (i.e., sterilization)

Eyes
initial screen should occur in early infancy with follow-up at
18 months and 5 and 15 years

Ears
audiologic evaluation by sound field testing or auditory brain-stem responses (ABR) should begin at 6 months and be repeated q6-
12m during the preschool years
antibiotics for recurrent OM, sinusitis, or purulent rhinitis
myringotomy tubes for recurrent otitis media (OM)

Oral and Dental
routine preventive dental care
relative macroglossia may be corrected by oral or plastic surgery if indicated

Dermatology
moisturizers, hypoallergenic creams for dry skin
steroid creams for eczema
topical or systemic antibiotics for infection
preventive measures to avoid sunburn
topical steroids, minoxidil for alopecia areata

Neurology
seizures
neurology consult, EEG, anticonvulsant medications

Autoimmune
screen for manifestations i.e., TSH, blood sugar
? role of pneumococcal and influenzae vaccines

T21 and LEUKEMIA
10-30 x risk
in newborns AML > ALL (2-4:1)
in children ALL > AML (2:1)
treatment and outcome
risk of side-effects of anti-folate chemotherapy (get very bad mucocitis with methotrexate and need lower dose)
risk of infection
remission rate & mortality with ALL
better prognosis AML than other children (>80% cure!)
Transient myeloproliferative syndrome
10% of neonates with DS have a "transient myeloproliferative syndrome" . 30% will develop AML within 3 years
= presence of a large number of blasts (megakaryoblasts) in the peripheral blood
occurs exclusively in Down's (82% in newborn period)
may even prompt the diagnosis of mosaic T21
100% spontaneous remission rate within 1st weeks of life
hepatosplenomegaly, lymphadenopathy, leukemoid reaction (WCC/ plt/ Hb)
risk of developing later M7 (megakaryocytic) AML
manage by monitoring blasts in peripheral blood

PROGNOSIS
a generation ago 2/3 of children with Down syndrome died in early childhood usually from the associated congenital abnormalities
now only about
o 20% die in the first year
o 45% of individuals with Down syndrome will survive to 60 years of age

2. Trisomy 13

Aka Patau syndrome
4
th
most common autosomal disorder, incidence ~1:10,000

TRISOMY 13
Head and
face
Scalp defects (e.g., cutis aplasia)
Microphthalmia, corneal abnormalities
Cleft lip and palate in 60%80% of cases
Microcephaly
Microphthalmia
Sloping forehead
Holoprosencephaly (arhinencephaly) e.g. cyclopia
Capillary hemangiomas
Deafness
Chest Congenital heart disease (e.g., VSD, PDA, and ASD) in 80% of
cases
Thin posterior ribs (missing ribs)
Extremities Overlapping of fingers and toes (clinodactyly)
Polydactyly (posterior)
Hypoplastic nails, hyperconvex nails
General Severe developmental delays and prenatal and postnatal growth
retardation
Renal abnormalities
Nuclear projections in neutrophils
Only 5% live longer than 6 mo







3. Trisomy 18

Aka Edwards syndrome
Low birthweight
Closed fists, IF overlaps MF, LF overlaps RF
Narrow hips, limited abduction
Short sternum
Rocker-bottom feet
Microcephaly
Prominent occiput
Micrognathia
Cardiac and renal malformations
Mental retardation
95% cases are lethal in first year of life

TRISOMY 18
Head and face Small and premature appearance
Tight palpebral fissures
Narrow nose and hypoplastic nasal alae
Narrow bifrontal diameter
Prominent occiput
Micrognathia
Cleft lip or palate
Microcephaly
Chest Congenital heart disease (e.g., VSD, PDA, and ASD)
Short sternum, small nipples
Extremities Limited hip abduction
Clinodactyly and overlapping fingers; index over 3rd, 5th over 4th;closed fist
Rocker-bottom feet
Hypoplastic nails
General Severe developmental delays and prenatal and postnatal growth retardation
Premature birth, polyhydramnios
Inguinal or abdominal hernias
Only 5% live longer than 1 year






SEX CHROMOSOME DISORDERS

Common X linked conditions:
DMD and BMD
o DMD = frame disruption from deletion
o Ends up in stop codon, and no dystrophin produced in muscle
o BMD milder version, cos IN-FRAME deletion (no disruption)
o Therefore less severe symptoms
Haemophilia A & B
Hunter disease MPSII (not hurlers!)
G6PD
Fragile X and several other kinds of MR
Chronic granulomatous disease (1 type)
Some metabolic disorders, eg. OTC, menkes
1 type of hydrocephalus (L1CAM)
also XLMR

X linked DOMINANT
quite rare but two well documented diseases:
1. vitamin D resistant rickets
2. rett syndrome where only carrier females are seen
hemizygosity for mutations in the rett gene assumed to be lethal
Lyonization ~ women inactivate one X
Can be skewed, e.g X linked immunodeficiencies SCID skewed picture

Sex Chromosome Abnormalities
DISORDER KARYOTYPE APPROXIMATE INCIDENCE
Klinefelter syndrome 47, XXY 1/5751/1,000 Males
48, XXXY 1/50,0001/80,000 Male births
Other (48, XXYY;49, XXXYY; mosaics)
XYY syndrome 47, XYY 1/8001,000 Males
Other X or Y chromosome abnormalities 1/1,500 Males
XX males 46, XX 1/20,000 Males
Turner syndrome 45, X 1/2,5001/5,000 Females
Variants and mosaics
Trisomy X 47, XXX 1/1,000 Females
48, XXXX and 49, XXXXX Rare
Other X chromosome abnormalities 1/3,000 Females
XY females 46, XY 1/20,000 Females

47,XYY.
The incidence of 47,XYY is approximately 1 in 800 to 1,000 males, with many cases remaining undiagnosed, since most affected individuals
have a normal appearance and normal fertility. The extra Y is the result of nondisjunction at paternal meiosis II (MII). Those with this abnormality
are of normal intelligence but are at risk for learning disabilities and hyperactive behavior.

47,XXX
47,XXX (also called triple X) is the most common female chromosomal abnormality [5]. Most individuals with 47,XXX are diagnosed incidentally
prenatally on genetic screening [20]. These women do not appear to be at increased risk of having chromosomally abnormal offspring [21].

A review of 155 females with 47,XXX karyotype found that 62 percent of these individuals were physically normal [22]. Thus, it is estimated that
most individuals with 47,XXX are never diagnosed [5]. 47,XXX females have a tendency to be tall, with many reaching the 80th centile by
adolescence, but with average head circumference between the 25th to 35th centile [16]. Puberty and fertility are generally the normal range,
but premature ovarian failure can occur [5,16]. Another prospective study of eleven 47,XXX females identified in a newborn survey at birth
reported that their verbal and performance intelligence quotient (IQ) scores were 15 to 20 points lower than those of their siblings [23]. Thus,
monitoring for developmental delays and psychologic problems is recommended


Triple X syndrome
- 47, XXX
- Incidence 1:1000
- Associated with maternal age
- Possible features:
o Lower mean birth weight
o Smaller head circumference, decreased brain volumes on MRI
o Delayed language development
o Accelerated growth until puberty
o EEG abnormalities common
o Motor-incoordination problems, auditory processing disordes
o incidence of scoliosis
o IQ 20 pts lower than average, especially verbal IQ
o risk of premature ovarian failure
o risk psychotic illness
1/1000 girls
Usually normal
May have menstrual irregularity and be taller than average


Turner syndrome

Incidence 1:2500

Disorder of growth/development
Short stature
Primary amenorrhoea due to early ovarian failure, therefore lack of secondary
sexual characteristics
Endocrine sequelae
o Osteoporosis and fractures
?Due to ovarian failure + haploinsufficiency for bone-related X-chr genes
o Abdominal obesity
o Insulin resistance
o T2DM
o Autoimmune endocrinopathies e.g. hypothyroidism
o May all improve with GH therapy
Malformation of lymph channel development can hydrops, congenital lymphoedema, cystic hygroma
cardiovascular mortality due to cardiac disease (see below), renal abnormalities and HTN
o Cardiac lesions in 40%: usually left sided obstructive lesions
o Coarctation in 15-20%
o Aortic valvular disease e.g. bicuspid valve in 50%, aortic stenosis
o Aortic dissection, MVP
Renal lesions common (60%)
Appearance
o Webbed neck, congenital lymphoedema, triangular face, posteriorly rotated ears
Can present at birth with webbed neck, congenital lymphoedema, or later with growth failure in childhood, failure to enter/complete
puberty, or early ovarian failure

Genetics
Almost half are 45,X, in 75% the lost X is from the paternal side
o ~90% of these conceptions are aborted
Others are mosaic for 45,X or have monosomy of the short arm of X chromosome
o Can have 45,x/46,XY mosaicism
In phenotypically female pts increased risk of gonadoblastoma, and require gonadectomy
10% of these mosaic pts will have ambiguous or male external genitalia
Turner syndrome:
- Complete or partial monosomy X
- Half have 45, X, the other half exhibit mosaicism and varied structural abnormalities of the X or Y chromosome
o Can be 45,X/46,XY mosaicism
- Maternal age is not a pre-disposing factor
- Incidence 1:5000 female births
- In 75%, the lost sex chromosome is of paternal origin (whether X or Y)
- 95-99% of 45,X conceptions are miscarried

Reasons for short stature:
- IUGR and slow childhood growth rate
- Delayed onset of puberty
- Bone maturation is delayed, so growth continues into 20s
- Adult height is 20cm shorter than their target height
- Major portion of heigh deficit occurs during the first 3 years of life
- May reflect a suppressive effect of oestrogen on growth in those retaining some ovarian function
- Much of the deficit in height is caused by haploinsufficiency of the short-stature homeobox-containing gene (SHOX) on the X-
chromosome
1

- SHOX gene belongs to a family of regulators of developmental processes


TURNER SYNDROME associations
Short stature
Congenital lymphedema
Horseshoe kidney [kidneys fuse to form a single kidney]
Patella dislocation
Increased carrying angle of elbow
Madelung deformity (chondrodysplasia of distal radial epiphysis)
Congenital hip dislocation
Scoliosis
Widespread nipples
Shield chest
Redundant nuchal skin (in utero cystic hygroma)
Low posterior hairline
Coarctation of aorta
Bicuspid aortic valve
Cardiac conduction abnormalities
Hypoplastic left heart syndrome?
Gonadal dysgenesis (infertility, primary amenorrhea) fibrosis leading to streak gonads
Gonadoblastoma (if Y chromosome material present)
Learning disabilities (nonverbal perceptual motor and visuospatial skills) [in 70%]
Developmental delay (in 10%)
Social awkwardness
Hypothyroidism (acquired in 1530%)
Type 2 diabetes mellitus (insulin resistance)
Strabismus
Cataract
Red-green colorblindness (as in males)
Recurrent otitis media
Sensorineural hearing loss
Inflammatory bowel disease
Celiac disease?


Klinefelter
syndrome

80% have 47,XXY, 20% have
higher grade of aneuploidy e.g.
(48,XXXY; 48,XXYY;
49,XXXXY), mosaicism
(46,XY/47,XXY), or structurally abnormal X chromosomes
tall stature (long legs)
hypergonadotropic hypogonadism - low testosterone & infertility (100%)
mild learning difficulties (expressive language speaking/ reading)

Epidemiology
single most common cause of hypogonadism and infertility in males
1:500 - 1:1000 males
often difficult to pick up before adolescence and many go undiagnosed

Aetiology
prezygotic meiosis error maternal and paternal (50/50)
very rarely due to a postzygotic mitotic error
maternal age is RF for maternally derived errors (not associated with paternal age)
XXY/XY mosaicism more likely to have normal testicular function
XXYY more likely to have intellectual impairment and behavioural problems (more male!)

Abnormalities
Growth
tall and slim feminine shape
mean height 75
th
centile but range from 25
th
99
th

long limbs
Hypogonadism(1 - ie hypergonadotropic)
small hard testes (fail to size with puberty) and penis
o testosterone gonadotropins fibrosis (woody testes!) of seminiferous tubules
o infertility (100%)
sometimes cryptorchidism
partial virilisation and delayed puberty
gynaecomastia in 40%
Intellect and personality
IQ 85- 90 (IQ with X chromosomes)
problems in expression and perception in language (70%)
tend to be shy and passive
ADHD, anxiety, depression
Other
5
th
finger clinodactyly/ mild elbow dysplasia/ scoliosis
diabetes (8%)/ hypothyroidism/ hypoparathyroidism
MVP (50%)
osteoporosis (due to androgen) vertebral collapse
ataxia
legs - anterior leg skin breakdown and varicose veins
Malignancy
risk of germ cell tumours of mediastinum
risk of Ca breast 7.5% of male Ca breast is XXY
risk of leukaemia and lymphoma

Investigations
karyotype
FSH/ LH/ oestrodiol but testosterone i.e. hypergonadotropic hypogonadism
echo (?MVP), DEXA (?BMD),

Outcome and management
testosterone IM (2-3x/ week) mood/ self-image, body mass, facial growth, BMD
school help - significant number reach tertiary education

1p 36 deletion syndrome

This syndrome is likely the second most common deletion syndrome in humans and likely the most frequent terminal deletion syndrome. The
pattern of malformation consists of intellectual disability, growth delays, microcephaly, seizures, a characteristic facial phenotype and heart
defects, most importantly, a cardiomyopathy. The developmental disability is notable, and most children have significant language delays. The
frequency of this condition among children with developmental delay supports the current strategy of performing CGH microarray in such
children

21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia

Disease characteristics
21-hydroxylase deficiency (21-OHD CAH)
Most common cause of congenital adrenal hyperplasia
Family of autosomal recessive disorders involving impaired synthesis of cortisol from cholesterol by the adrenal cortex.
In 21-OHD CAH, excessive adrenal androgen biosynthesis results in virilisation in all individuals and salt wasting in some individuals.
Classic form with severe enzyme deficiency and prenatal onset of virilisation
o Simple virilising form in 25%
o Salt-wasting form in 75%
o At risk of life-threatening salt-wasting crises
Non-classic form with mild enzyme deficiency and postnatal onset.
o Present postnatally with hyperandrogenism
o Females wont be virilised at birth

Feature 21-OHD CAH
Classic Non-Classic
Prenatal virilisation Present in females Absent
Postnatal virilisation Males and females Variable
Salt wasting ~75% of all individuals Absent
Cortisol deficiency ~100% Rare

Epidemiology
1:15,000 incidence (classic)
>90% due to 21-hydroxylase deficiency, but can be due to other enzyme deficiencies, e.g. 17-alpha-hydroxylase

Presentation
Females who are virilised at birth, or who become virilised postnatally, or who have precocious puberty or adrenarche (phenotypically
same for simple classic and salt-wasting classic females)
Enlarged clitoris, fused labioscrotal folds, urogenital sinus
AMH is not secreted, therefore mullerian ducts normal uterus and fallopian tubes
Hirsutism, male pattern baldness, menstrual abnormalities, fertility
Males with virilisation in childhood (i.e., pseudoprecocious puberty)
Progressive penile enlargement, small testes
Subfertility due to testicular adrenal rest tumours from aberrant adrenal tissue
Hypogonadotrophic hypogonadism [i.e. 2
o
] from LH suppression in pituitary by adrenal androgens & aromatisation products
Untreated males and females:
Rapid initial growth but potential height reduced short adult stature due to premature epiphyseal fusion
Precocious pubic and axillary hair, acne, rapid linear growth, advanced bone age
Any infant with a salt-losing crisis in the first four weeks of life
Salt-wasting form
Weight loss, anorexia, vomiting, dehydration, weakness, hypotension, hypoglycemia, hyponatremia, and hyperkalemia.
These problems typically first develop in affected infants at approximately 2 wk of age. Without treatment, shock, cardiac
arrhythmias, and death may occur within days or weeks.
Adrenal crisis = azotaemia, vascular collapse, shock, death
Non-classic form
Can present any time with symptoms of androgen excess: acne, premature pubic hair, accelerated growth, advanced bone
age, reduced adult stature (premature epiphyseal fusion)
Females will have normal genitalia, but may get hirsutism, temporal baldness, delayed menarche, menstrual irregularities,
infertility
60% have hirsutism only, 10% have hirsutism + menstrual disorder, 10% have menstrual disorder only
Increased risk PCOS
Fertility rate 50%
Males: early beard growth, enlarged phallus, relatively small testes. Usually normal sperm counts


Diagnosis/testing
Biochemical findings
o 17-hydroxyprogesterone elevated [normal to be in days 0-3 of life, so test after]
> 20,000 ng/dL for classic form, and 2000-5000 for non-classic
o Plasma renin activity raised in salt-wasting form
o Delta-4-androstenedione and progesterone raised in females and prepubertal males
o In the salt-wasting form, serum aldosterone is low relative to raised plasma renin activity
o Androstenedione and testosterone are high in females, not high in males because its normal to be high in neonates
ACTH stimulation test
o Measure 17-OHP and
4
-androstenedione before and 60 mins after injection of 250g of synacthen
o Check against nomogram. Cortisol deficiency will their ACTH
Molecular testing of CYP21A2 for 9 common mutations and gene deletions detects 80-98%
Entire gene sequencing for rarer alleles if the above fails
In the salt-wasting form:
o Low serum sodium, low serum chloride, low serum total CO2
o High serum potassium, inappropriately high urine sodium
Karyotype will be normal (can do FISH for X- and Y- chromosomes instead)
Ultrasound of pelvis and adrenals

Management
Glucocorticoid replacement
o Hydrocortisone 10-20mg/m
2
daily in 2-3 divided doses. Can use prednisone or dexamethasone in adulthood (after growth is
finished)
o Risk of Cushings
Increase dose by 2-3 X PO or IM during periods of stress
Salt-wasting form treatment needs with age
o Mineralocorticoid 9-fludrohydrocortisone therapy
o Often sodium chloride
Females who are virilised at birth may require feminizing genitoplasty and/or vaginal dilation.
Symptomatic individuals with non-classic 21-OHD CAH require treatment.

Surveillance
(1) Monitoring glucocorticoid and mineralocorticoid replacement therapy every three to four months while children are actively
growing, and less often thereafter
(2) Monitoring for testicular adrenal rest tumours in males every three to five years after onset of puberty
(3) Monitoring weight, bone mineral density, fertility, and cardiovascular risks in adults

Prevention
NBST identifies classic 21-OHD CAH by measuring concentration of 17-OHP to initiate glucocorticoid/mineralocorticoid treatment
prior to salt-wasting crisis
Measure 17-OHP (17-hydroxyprogesterone) from NBSP of at-risk siblings

Genetic Counselling
Autosomal recessive; 1% are de novo (will still need one heterozygous parent to develop the disease)
Carriers are asymptomatic (but may have slightly high 17-OHP)
Occasionally parent of proband has non-classic form
Carrier testing possible

Pathophysiology
21-hydroxylating cytochrome 450 function inadequate cortisol production pathway blocked accumulation of 17-OHP, which is
shunted into androgen pathways [androstenedione, which is converted outside of the adrenals to testosterone]
Also involved in aldosterone production, therefore aldosterone is deficient salt-wasting
Mineralocorticoid pathway only needs minimal 21-hydroxylase activity, so only severe forms of the disease lead to salt-wasting
In classic form; prenatal exposure to potent androgens such as testosterone and delta-4-androstenedione at critical stages of sexual
development virilizes the external genitalia of genetic females, often resulting in genital ambiguity at birth
Aldosterone secretion deficiency leading to insufficient sodium reabsorption in the distal tubule salt wasting
o Also causes cortisol deficiency

22q11.2 Deletion Syndrome

Basics
CHD in 74%, especially conotruncal malformations
ToF, interrupted aortic arch, VSD, truncus arteriosus
Palatal abnormalities in 69% e.g. velopharyngeal incompetence (most common), submucous cleft palate, cleft palate
o VPI: short palate, hypotonic palate, or combination
Learning difficulties in 70-90%
o Developmental delay, ASD
Immune deficiency in 77%
o Thymic aplasia reduced T cell production (rarely, function problems, or Ab production problems)
o Usually not too severe, more a problem of pharyngeal arch development than an immune problem
Craniofacial abnormalities
o Facies: distinctive tall nasal root and bridge with a bulbous nasal tip and a small mouth.
o Craniofacial findings include auricular abnormalities, nasal abnormalities, "hooded eyelids," ocular hypertelorism, cleft lip
and palate, asymmetric crying facies, and craniosynostosis
o Variable facies; may be long with malar flatness
Hypocalcaemia in 50% [worse in neonatal period]
Feeding problems in 30% [severe dysphagia]
o Dysmotility in pharyngo-oesophageal area region of 3
rd
and 4
th
pharyngeal pouches
o Reflux
Renal anomalies in 37%
o renal agenesis, hydronephrosis, multicystic/dysplastic kidneys, duplicated kidney, horseshoe kidney, absent uterus,
hypospadias, inguinal hernia, and cryptorchidism
Hearing loss (both conductive/sensorineural)
Laryngotracheoesophageal abnormalities: vascular ring; laryngeal web
GH deficiency
Autoimmune disorders
o thrombocytopenia, juvenile rheumatoid arthritis, Grave's disease, vitiligo, neutropenia, haemolytic anemia
Seizures (without hypocalcaemia)
Skeletal abnormalities
o pre and postaxial polydactyly of the hands and postaxial polydactyly of the feet, supernumerary ribs, hemivertebrae,
craniosynostosis
Psychiatric illness
CNS: cerebellar atrophy, polymicrogyria, enlarged sylvian fissures, neural tube defects, tethered cord, unprovoked seizures, and
asymmetric crying facies
o Hypotonia in infancy and learning disability is common
o The rest are all RARE
GI: anteriorly placed anus or imperforate anus, esophageal atresia, jejunal atresia, accessory spleens, umbilical hernia, diaphragmatic
hernia, intestinal malrotation, and Hirshprung disease
Increased risk of the following tumours: Hepatoblastoma, renal cell carcinoma, Wilm's tumor, and neuroblastoma
Eye problems including tortuous retinal vessels

Cardiac Finding % of Affected Individuals
Tetralogy of Fallot (TOF) 22%
Interrupted aortic arch (IAA) 15%
Ventricular septal defect (VSD) 13%
Truncus arteriosus (TA) 7%
Vascular ring 5%
Atrial septal defect 3%
Aortic arch anomaly 3%
VSD; ASD 4%
Other
1
4%
Normal 26%

Incidence
1:4000 1:6000

Diagnosis
FISH for 22q11.2 deletion (DiGeorge chromosomal region)

Investigations/Management
Neonate:
o FBC (lymphocytes)
o CMP Ca supplementation if needed
o Echo, ECG, CXR
o MRI if suspecting vascular ring or ectopic ICA (e.g. before surgery)
o Renal US
Neonate/infancy
o Feeding problems speech path, treat GORD
o Craniofacial surgery
o Early intervention for education/speech therapy (age 1)
Age 4
o Cervical spine films (five views: flexion, extension, AP, lateral, open mouth) in all individuals over age four years, the age
that the cervical spine becomes ossified
PRN
o Evaluation of children with short stature (height below the 2nd centile) by an endocrinologist for possible growth hormone
deficiency
o Evaluation in any person with evidence of anxiety, mood disorder, behavioral differences, or frank pyschoses
o Evaluation by a hematologist of any person with a history of a bleeding disorder
o Treat infections aggressively
Infants with lymphocyte abnormalities should not receive live vaccines
Rarely: prophylactic ABx, IVIG or thymic transplantation

Genetic counselling
Autosomal dominant
Deletion of contiguous genes
93% have de novo deletion; 7% inherited
??Prenatal exposure to alcohol/Accutane (Jos notes)


DDx
Smith-Lemli-Opitz syndrome (when polydactyly and cleft palate are present). Smith-Lemli-Opitz syndrome is associated with elevated
serum concentration of 7-dehydrocholesterol (7-DHC) or an elevated 7-dehydrocholesterol:cholesterol ratio. Molecular genetic testing
for mutations of the DHCR7 gene is available.
Alagille syndrome (when butterfly vertebrae, congenital heart disease, and posterior embryotoxon are present). Sequence analysis of
the JAG1 gene detects mutations in more than 70% of individuals who meet clinical diagnostic criteria. FISH detects a microdeletion
of 20p12, including the entire JAG1 gene, in approximately 5-7% of affected individuals.
VATER syndrome (when heart disease, vertebral, renal, and limb anomalies are present)
Oculo-auriculo vertebral (Goldenhar) syndrome (when ear anomalies, vertebral defects, heart disease, renal anomalies are present)

Nomenclature
22q11.2 deletion syndrome encompasses DiGeorge syndrome, VCFS (Shprintzen syndrome), conotruncal anomaly face syndrome
DGS: originally described as a developmental field defect of the third and fourth pharyngeal pouches with a conotruncal cardiac
anomaly and aplasia or hypoplasia of the thymus gland and parathyroid glands. Later, congenital heart disease was added. The
majority of individuals with DGS were identified in the neonatal period with a major congenital heart defect, hypocalcemia, and
immunodeficiency

Pharyngeal pouches: 1- tubotympanic recess
2 - tonsil
3 - parathyroid, thymus
4 - parathyroid

Branchial arches: L aortic arch
R R subclavian artery

GENOTYPE Microdeletion at 22q11.2 at the DGCR (DiGeorge Critical Region) dysmorphogenesis of 3
rd
and
4
th
pharyngeal arches defects in the heart, head, neck, thymus and parathyroid
INCIDENCE 1: 2000 - 4000
INHERITANCE 85% are sporadic, 7% are inherited as dominant, 1% as chromosomal rearrangement
FEATURES




CARDIAC: TOF, truncus arteriosis, interrupted aortic arch, right sided aortic arch
CRANIOFACIAL: micrognathia, high, broad nasal bridge, narrow palpebral fissures, long face, cleft
palate, asymmetric crying face, low set notched ears, hypertelorism, short philtrum of upper lip
THYMIC HYPOPLASIA: recurrent infections due to T-cell immunodeficiency,
hypogammaglobulinaemia and selective immunoglobulin deficiencies may be present. Higher
incidence of autoimmune diseases
HYPOCALCAEMIA: due to parathyroid hypoplasia
DEVELOPMENTAL DELAY/LEARNING DIFFICULTIES: 70-90%
BEHAVIOURAL: autistic spectrum, shyness, disinhibition, ADHD, psychosis

SCREENING Should be screened at birth for T-cell defieicney, cardiac anomaly and hypocalcaemia. Routine FBC
and CMP every few years throughout childhood.



46,XX Testicular Disorder of Sex Development

Synonyms
46,XX Testicular DSD; XX Male Syndrome. Includes: SRY-Negative 46,XX Testicular Disorder of Sex Development; SRY-Positive 46,XX
Testicular Disorder of Sex Development

Characteristics
46, XX karyotype
Male gender role and identity
Male external genitalia ranging from normal to ambiguous (20%)
Two testicles, azoospermia, absence of Mullerian structures
Infertile

Pathogenesis
80% have small Y-chromosome fragment including SRY in their genome
o i.e. translocation of normal SRY allele onto an X chromosome
Abnormal terminal X-Y exchange during paternal meiosis
o i.e. abnormal recombination from homologous loci on X and Y chromosomes (sex-specific parts)
Testicular failure leads to hypergonadotropic hypogonadism and clinical features of testosterone deficiency

Natural history
80% present after puberty with normal pubic hair, normal penile size, but small testes, gynaecomastia and sterility (from azoospermia)
o Small testes are soft but become firmer with age
o Minority have cryptorchidism and/or anterior hypospadias
o These are more likely to be SRY-positive
20% have ambiguous genitalia, typically penoscrotal hypospadias +/- chordee these tend to be SRY-negative
o Will also develop gynaecomastia
Male gender role and identity
If untreated will develop sequelae of testosterone deficiency
o Low libido
o Erectile dysfunction
o secondary sexual characteristics e.g. sparse body hair, infrequent need to shave, muscle mass
o Increased fat mass with lower muscle strength
o risk of osteopenia and depression
No intellectual/behavioural issues

Diagnosis
Clinical findings
Hypergonadotropic hypogonadism
o Secondary to testicular failure
o Basal serum LH and FSH moderately increased
o Serum testosterone concentration is usually decreased,
Typically < 300ng/dL in adults (normal is 350-1030)
o hCG stimulation test
low-to-subnormal testosterone response
little-to-no elevation of serum testosterone after IM hCG
o HPA axis preserved
Normal LH and FSH response to GnRH
Dont need to do this test for diagnosis
Cytogenetics
o 46, XX karyotype
FISH or PCR amplification for SRY
o 80% are positive (those with normal male genitalia)
o 20% negative (usually those with ambiguous genitalia)

Management
Low dose testosterone from age 14, gradually increase dose
o CI: prostate or breast Ca
Growth hormone therapy if short may need to delay testosterone therapy to maximise growth potential
Reduction mammoplasty
Treat osteopenia

Surveillance
During testosterone Rx: monitor prostate size and PSA in adults
BMD (annual DEXA) if osteopenia has been diagnosed

Genetic counselling
De novo interchange between X and Y chromosome resulting in SRY gene on X chromosome and infertility
When SRY is translocated to another chromosome, AD inheritance is seen
If fertility is preserved, AD inheritance
Prenatal Dx is possible

DDx
Rare syndromic cases of XX, testicular DSD (other genetic defects)
Klinefelter (47, XXY)
o Male with hypogonadism, small testes, gynaecomastia
o In contrast: normal/tall stature, speech delay, learning/behavioural problems
o Differentiate by karyotype
Chimerism (46,XX/46,XY)
o May present as true hermaphrodites depending on relative ratio of XY and XX cells
o Ranges from normal male to normal female
45,X/46,XY
o Often present as male, short stature, clinically indistinguishable from 46,XX DSD
o Karyotype diagnostic
o If % of 45,X is very high, phenotype is likely to be female with Turner syndrome
46,XX ovotesticular DSD
o True hermaphrodites with both testicular and ovarian tissue
Ovotestis or ovary AND testis
May have uterus or hemi-uterus
May produce oestrogen
o Conversely, 46,XX testicular DSD only have testicular tissue, no Mullerian structures
o Gonadal biopsy
21-OHD CAH
o Most common cause of CAH (AR)
o Virilised females: ambiguous external genitalia, normal uterus/ovaries
o Molecular genetic testing of CYP21A2
Prenatal exposure of an XX pregnancy to externally administered androgens e.g. danazol, or endogenous androgens from the mother
o Can produce virilisation and ambiguous genitalia

46,XY Disorder of Sex Development and 46,XY Complete Gonadal Dysgenesis

46, XY DSD:
46,XY karyotype
Ambiguous genitalia
o Mild-to-severe penoscrotal hypospadias +/- chordee
o Dysgenetic testes
Abdominal gonads are at increased risk for tumours (especially dysgerminoma), should be removed
to no sperm production
Mullerian structures ranging from absent to fully developed uterus and fallopian tubes
Raised as males or females
o May require surgery

46,XY complete gonadal dysgenesis
46,XY karyotype
Normal female external genitalia
Completely undeveloped streak gonads (should be removed risk of gonadoblastoma)
No sperm production
Normal Mullerian structures
Raised as females

Diagnosis
Clinical findings
Gonadal histology
Karyotype
Gene testing:
o SRY (deletion/sequence variant)
o Others: NR5A1, DHH, NR0B1, WNT44

Endocrine studies
Usually show the following for both 46,XY DSD and 46,XY CGD:
Hypergonadotropic hypogonadism secondary to gonadal failure:
Basal serum concentration of LH and FSH are moderately to significantly elevated (in adult males normal range for LH: 7-
24 mLU/mL; for FSH: 1.5-12.4 mLU/mL).
Serum testosterone concentration is usually decreased, typically lower than 300 ng/dL in adults (in adult males normal
range: 300-1000 ng/dL).
Human chorionic gonadotropin (hCG) stimulation test typically shows little or no elevation of serum testosterone
concentration after IM injection of hCG.
Normal hypothalamic-pituitary axis. Gonadotropin releasing hormone (GnRH) stimulation test shows a normal LH and FSH response
to an IM injection of GnRH. (Such testing is not warranted for diagnosis.)

Management
Psychosocial
Surgery if needed
o External genitalia
o Remove streak or abdominal gonads
Hormone replacement from puberty
Women (46,XY CGD) may become pregnant from zygote donation
Males (46,XY DSD) may donate games via ICSI

Surveillance
Abdominal US annually if gonads not removed

Genetic counselling
Can be autosomal dominant, autosomal recessive, X-linked, Y-linked depending on the gene
Prenatal diagnosis is possible

APC-Associated Polyposis Conditions

APC-associated polyposis conditions include
FAP
Attenuated FAP
Gardner syndrome
Turcot syndrome

FAP
Hundreds-to-thousands of precancerous colonic polyps, beginning ~age 16
By 35, 95% have polyps
Colon cancer is inevitable need colectomy
Mean age of cancer Dx is 39
Extracolonic manifestations
o Polyps of gastric fundus and duodenum
o Osteomas
o Dental anomalies
o Congenital hypertrophy of retinal pigment
o Soft tissue tumours
o Desmoid tumours
o Associated cancers

Attenuated FAP
Significant risk of colon cancer but fewer polyps (average ~30)
More proximal polyps
Diagnosis of cancer at a later age

Gardner syndrome
Colonic polyposis typical of FAP + osteomas + soft tissue tumours

Turcot syndrome
Colonic polyposis and CNS tumours

Diagnosis
All caused by mutations in APC gene
Molecular genetic testing

Management
Colectomy if >20-30 adenomas or multiple adenomas with advanced histology
NSAIDs can regress adenomas in FAP
Endoscopic/surgical removal of duodenal ademoas if polyps are dysplastic, >1cm or symptomatic
Osteomas removed for cosmesis
Desmoid tumours: NSAIDs, excision, anti-oestrogens, cytotoxics, radiation

Surveillance
Liver US for hepatoblastoma
Serum AFP until age 5 for hepatoblastoma
Sigmoidoscopy/colonoscopy from age 10-12
Annual colonoscopy once polyps detected, until colectomy
Oesophagogastroduodenoscopy by age 25 or prior to surgery
Regular examination

Genetic counselling
Autosomal dominant

Achondroplasia

Disease characteristics
Achondroplasia is the most common process resulting in disproportionate small stature.
Affected individuals have short arms and legs, a large head, and characteristic facial features with frontal bossing and midface
retrusion (formerly known as midface hypoplasia).
In infancy, hypotonia is typical
Acquisition of developmental motor milestones is often both aberrant in pattern and delayed.
Intelligence and life span are normal/near normal
Craniocervical junction compression increases the risk of death in infancy.
o Causes damage to respiratory control centres central apnoea
True megalencephaly occurs in individuals with achondroplasia and most children with achondroplasia are macrocephalic
Hydrocephalus requiring treatment, which probably occurs in 5% or fewer, may be caused by increased intracranial venous pressure
because of stenosis of the jugular foramina.
OSA
o Due to midface retrusion, hypertrophy of lymphatic ring, ?abnormal innervation
Genu varum (Bowing is actually a complex deformity arising from a combination of lateral bowing, internal tibial torsion and dynamic
instability of the knee)
Kyphosis at the thoracolumbar junction
Spinal stenosis L1-L4 in adulthood
Obsesity is common

Pathogenesis
More than 99% of individuals with achondroplasia have one of two mutations in FGFR3
Fibroblast growth factor receptor 3

Incidence: 1:26,000

Diagnosis/testing
Achondroplasia can be diagnosed by characteristic clinical and radiographic findings in most affected individuals.
Molecular genetic testing can be used to detect a mutation in FGFR3, the only gene known to be associated with achondroplasia.
Such testing detects mutations in 99% of affected individuals and is available in clinical laboratories.

Management
VP shunt for increased ICP/hydrocephalus
Suboccipital decompression if craniocervical junction compression
OSA
o Adenotonsillectomy
o CPAP
o Rarely: tracheostomy
Manage middle ear dysfunction
Genu varum: ortho surg, e.g. e.g. valgus-producing and derotational osteotomies, guided growth using 8-plates
Surgery for spinal stenosis in adults
Bracing for kyphosis
Educational support

Surveillance
Monitor height, weight, and head circumference in childhood using growth curves standardized for achondroplasia;
Evaluation of developmental milestones throughout infancy and childhood;
CT in infancy (baseline)
Polysomnography in infancy
Tympanometric and audiology assessment
Clinical assessment for kyphosis and bowed legs (genu varum), with radiographic evaluation and referral to an orthopedist, if
necessary; in adults, clinical history and neurologic examination to screen for spinal stenosis every three to five years

Agents/circumstances to avoid:
Activities in which there is risk of injury to the craniocervical junction, such as collision sports; use of a trampoline; diving from diving
boards; vaulting in gymnastics; and hanging upside down from the knees or feet on playground equipment.
Pregnant women with achondroplasia must undergo Caesarian section delivery because of small pelvic size.

Genetic counselling
Autosomal dominant
80% have de novo mutations (their parents have a low risk of having another child with achondroplasia)
Homozygous achrondroplasia is lethal

DDx
Hypochondroplasia (also usually caused by mutations in FGFR3). This distinction is sometimes the most difficult to make. In fact,
there appears to be some overlap between the radiologic and clinical phenotypes of these two conditions
Thanatophoric dysplasia
Cartilage-hair hypoplasia (metaphyseal chondrodysplasia, McKusick type)
Pseudoachondroplasia (a clinically and genetically distinct skeletal dysplasia; the similar nomenclature, however, may cause
confusion)
Other metaphyseal dysplasias

Aicardi Syndrome

Disease characteristics
Triad
o 1. Agenesis of corpus callosum
o 2. Chorioretinal lacunae
white or yellow-white, well-circumscribed, round,
depigmented areas of the retinal pigment epithelium and
underlying choroid with variably dense pigmentation at
their borders that can cluster in the posterior pole of the globe
around the optic nerve
o 3. Infantile spasms
Many other features now recognised:
o Microcephaly, polymicrogyria
o Axial hypotonia
o Appendicular hypotonia with spasticity
o Mod-severe global developmental delay, intellectual disability
o Seizures, most in infancy
o Refractory epilepsy with variety of seizures
o Characteristic facies
o GI difficulties
o Small hands
o Vascular malformations
o Pigmentary lesions of the skin
o Increased incidence of tumours
The most common tumors are choroid plexus papillomas; however, lipomas, angiosarcomas, hepatoblastomas,
intestinal polyposis, and embryonal carcinomas have also been described
o Lower growth rates after age 7
o Precocious or delayed puberty
Survival variable: mean age of death 8.3 years, median age 18.5 years

Diagnosis
No lab diagnosis. The presence of all three classic features is diagnostic for Aicardi syndrome. The existence of two classic features plus at
least two other major or supporting features is strongly suggestive of the diagnosis of Aicardi syndrome:

Major features
Cortical malformations (mostly polymicrogyria)
Periventricular and subcortical heterotopia
Cysts around third cerebral ventricle and/or choroid plexus
Optic disc/nerve coloboma or hypoplasia

Supporting features
Vertebral and rib abnormalities
Microphthalmia
"Split-brain" EEG: characteristically show burst suppression pattern, arises from each hemisphere, no hypsarrhythmia
Gross cerebral hemispheric asymmetry
Vascular malformations or vascular malignancy

Diagnosis
Eye exam: chorioretinal lacunae
MRI
o Dysgenesis of corpus callosum
o Polymicrogyria or pachygyria
o Choroid plexus papillomas
o Ventriculomegaly
o Cysts e.g. 3
rd
ventricle
o Hemivertebrae, block vertebrae, fused vertebrae, missing ribs

Genetic counselling
X-linked dominant, lethal in males
Seen only in females and 47, XXY males
Lethal in 46,XY males
Presumed de novo mutation
Risks to siblings < 1%
No gene/region identified on the X chr
No known mother-to-daughter transmission, but theoretically possible

Management
Usually need multiple AEDs
Some respond to vigabatrin, vagus nerve stimulators
Physio, OT, speech path, vision therapy

Surveillance
Dermatologic evaluation for vascular/other malignancies
Monitor for GI complications
Scoliosis

Alagille Syndrome

Alagille syndrome is characterized by the paucity of interlobular bile ducts and the following associated features:
Chronic cholestasis (approximately 90 percent)
Cardiac anomalies, most commonly peripheral pulmonic stenosis (85 to 91 percent)
Butterfly vertebrae (39 to 87 percent)
Posterior embryotoxon (prominent Schwalbe line) of the eye (61 to 88 percent)
Dysmorphic facies, consisting of broad nasal bridge, triangular facies, and deep set eyes (77 to 95 percent)


Disease characteristics
Alagille syndrome (AGS) is a complex multisystem disorder involving primarily the liver, heart, eyes, face, and skeleton.
The clinical features are highly variable, even within families.
The major clinical manifestations of AGS are:
o Cholestasis, characterized by bile duct paucity on liver biopsy
o Congenital cardiac defects, primarily involving the pulmonary arteries
o Posterior embryotoxon in the eye
o Typical facial features: triangular face
o Butterfly vertebrae.
o Renal and central nervous abnormalities also occur.
Mortality is approximately 10%, with vascular accidents, cardiac disease, and liver disease accounting for most of the deaths.

Diagnosis/testing
Clinical diagnosis
Deletion on chr 20p - jagged 1 (JAG1)
Two genes associated: JAG1 and NOTCH2
o JAG1 mutations in > 89%
o Numerous types of mutations; diagnosis is slow

Clinical
IUGR (50%)
conjugated jaundice and cholestasis (paucity of intrahepatic bile ducts)
o highly variable - no way to predict who will progress to end-stage liver disease
o hepatomegaly infrequent
typical facies (95%)-
o broad forehead
o deep-set, widely spaced eyes
o long straight nose
o underdeveloped mandible
cardiac lesions - PS, or peripheral pulmonary artery stenosis, ASD/VSD
o only reliable predictor of mortality is congenital heart disease
butterfly vertebrae
eye findings - posterior embryotoxon - anterior chamber abnormality
mild ID (15%) - may have developmental/growth delay
renal renal a stenosis/ dysplasia/ hypertension
pancreatic insufficiency
hypogonadism/ short stature

complications: absorption of Vitamins DEKA (due to bile salts for absorption)
vit E peripheral neuropathy, cerebellar ataxia, post column dysfunction
vit K risk of intracerebral bleed
xanthoma
itch

Investigations
SBR/ INR cholesterol vit DEKA

Management
most have problems with itch and xanthoma
liver transplant to relieve itch
rifampacin bile duct flow/ itch
rotating antibiotics cholangitis


Management
Choloretic agents (ursodeoxycholic acid)
Cholestyramine, rifampin, naltrexone
Partial external biliary diversion for pruritis/xanthomas
Liver transplantation in end-stage liver disease
Treat cardiac/renal/neuro complications
Prevent secondary complications
o Nutrition
o Fat soluble vitamins
o Spleen guard if splenomegaly present

Genetic counselling
Autosomal dominant
30-50% inherited; 50-70% de novo
Increased risk for recurrent even if de novo mutation, because of the possibility of germline mosaicism

Alpha1-Antitrypsin Deficiency

Autosomal recessive
Lung emphysema in adulthood
Liver cirrhosis in childhood

PATHOPHYSIOLOGY
-1-antitrypsin structure
Glycoprotein (gene on chromosome 14)
Produced by liver (some by macrophages) protease inhibitor
Acute phase protein
Faecal -1-AT levels are used to assess protein loss in the bowel (other proteins which are excreted are broken down by gut proteases)
Comprises 90% of alpha-1-globulins in blood
> 20 different alleles, only a few of which are associated with defective protease inhibitors

-1-antitrypsin production
Abnormal synthesis interferes with excretion of product (ZZ phenotype) accumulation in liver liver damage (but only in 10-20% despite
all with ZZ phenotype accumulate in liver)

Serum A1A in lung protease damage (released from dead bacteria or leucocytes) COAD

PI (protease inhibitor) SYSTEM - alleles

Phenotype Lung disease Liver disease
MM (90%) - -
SS +/- +/-
ZZ
Null/null -
Null/Z +/-
SZ +/-
MS - +/-
MZ - +/-

M normal MM commonest phenotype (90%)
Disease alleles differ from M by single base pair substitution
S slow SS 50% normal AT1 function
Z deficient ZZ 10-20% of normal AT1 production (most common abnormality)
Null none produced Null/Null no AT1 production

ZZ
Normal production AT1 abnormal transport into circulation
AT1 in hepatocytes and 20% of normal AT1 in serum
1 in 2,000 4,000
Little or no lung disease in childhood risk adulthood
80% adults develop COAD
10-20% develop neonatal cholestatic hepatitis (indistinguishable from idiopathic neonatal hepatitis)
Hence majority in childhood asymptomatic!

Null/null
No AT1
No liver disease (no PAS +ve inclusions)
?But develop lung disease

Other intermediate forms +/- liver/lung disease

HEPATIC DISEASE
10-20% neonatal hepatitis with cholestasis (with PiZZ)
Presentation often 1
st
week of life (can present later) with:
conjugated SBR usually clear by 2
nd
-4
th
month
hepatomegaly
pale stools

liver biopsy
early infancy indistinguishable other forms neonatal hepatitis
later globules of AT1 in periportal liver cells (stain +ve with PAS)
severe disease cholestasis and periportal liver damage mimic biliary atresia

other presentations
resolution but risk CLD throughout life
hepatitis may present in adolescence
5% cirrhosis and liver failure can present this way
hepatocellular carcinoma 2-3% PiZZ adults

LUNG DISEASE
panacinar emphysema

3
rd
to 4
th
decade of life
rarely pulmonary disease in kids very few early onset (wheeze, cough)
smoking risk in all phenotypes severe disease in early 30s

SKIN DISEASE
panniculitis inflammation of subcutaneous tissue cellulitis like areas or red, tender nodules on trunk or extremities (trauma stimulus in
some) number of other causes of panniculitis



treatment dapsone (steroid) or infusion of AT1 concentrate

INVESTIGATIONS
-1-antitryspin
LFTs: AST
trypsin inhibitory capacity (i.e. AT1 ability to inhibit trypsin)
Pi genotype
CXR in adults COAD
liver biopsy (confirms diagnosis) in PiZZ
cytoplasmic globular inclusions AT1 (may be absent early!)
PAS +ve and diastase resistant
EM lie within smooth (and sometimes rough) ER
globules also present in number and size in intermediate deficiency state
liver parenchyma normal, hepatitis or cirrhotic changes



MANAGEMENT
Medical
Danazol
analogue testosterone
hepatic AT1 production
only used in men
short term use only

AT1 replacement costly $$
purified blood derived human A1A
in USA ZZ and null/null
given IV

recombinant AT1 available
intra-nasal spray available

supportive
bronchodilators
pneumococcal and influenza vaccine
no smoking
prompt treatment of respiratory infections

Liver transplantation
decompensated CLD > 80% continued survival
transplanted liver produces A1A of donor type normal type and hence serum levels of A1A protects against subsequent COAD

Screening
family members
all with serum AT1 risk COAD partially related to environment (smoke, industrial fumes)

Alstrom syndrome

Rare autosomal recessive disease characterized by multiorgan dysfunction.
Childhood obesity
Blindness due to congenital retinal dystrophy
Sensorineural hearing loss
Associated endocrinologic features include
o Hyperinsulinemia
o early-onset type 2 diabetes
o hypertriglyceridemia
Thus, AS shares several features with the common metabolic syndrome, namely obesity, hyperinsulinemia, and hypertriglyceridemia.
Mutations in the ALMS1 gene have been found to be causative for AS




Red inclusions = PAS +ve A1A
Androgen Insensitivity Syndrome

Most common forms of male DSD, occurring with a presumed frequency of 1/20,000 genetic males.
Group of heterogeneous X-linked disorders is due to more than 150 different mutations in the androgen receptor gene, located on
Xq1112: single point mutations resulting in amino acid substitutions or premature stop codons, frameshift and premature
terminations, gene deletions, and splice site mutations.
Karyotype shows 46, XY

Clinical Manifestations.
Range from phenotypic females (in complete AIS) to males with various forms of ambiguous genitals and undervirilization (partial AIS,
or clinical syndromes such as Reifenstein syndrome) to phenotypically normal-appearing males with infertility.
The presence of testes and normal or elevated testosterone levels are common to all such children

Complete AIS
Appear female at birth, usually raised female
Vagina ends in blind pouch, uterus is absent
In 1/3, unilateral or bilateral fallopian tube remnants exist
Testes are intraabdominal but may to inguinal canal, largely consisting of seminiferous tubules
Puberty normal breast development, female habitus, but no menstruation or sexual hair
Adult height similar to normal males
Testes produce normal amounts of testosterone and DHT
Osteopenia
Pathophysiology
o Failure of normal male differentiation during fetal life reflects defective response to androgens at that time, but the absence
of mllerian ducts indicates normal fetal testicular production of AMH.
o The absence of androgenic effects is caused by a striking resistance to the action of endogenous or exogenous
testosterone at the cellular level.

Clues to diagnosis
Inguinal mass has testis or testis is found during hernia repair in a female (1-2% of girls with inguinal hernia have AIS)
gonadotropin levels in an infant
Amenorrhoea in an adult

DDx
XY gonadal dysgenesis
True agonadism
Leydig cell aplasia including LH receptor defects
17-ketosteroid reductase deficiency
All of these above have low testosterone levels, and failure of response to hCG

Partial AIS
Wide range of presentations from perineoscrotal hypospadias, bifid scrotum, cryptorchidism to extreme undervirilisation with
clitoromegaly and labial fusion
Reifenstein syndrome: incomplete virilisation with hypogonadism, severe hypospadias, gynaecomastia
In all cases, abnormalities in the androgen receptor gene have been identified.

Diagnosis.
Difficult to diagnose in infancy
Diminished postnatal surge of testosterone and LH in those with complete AIS
Often diagnosed at puberty when there is inadequate virilisation with lack of facial hair or voice change, and the appearance of
gynaecomastia
Azoospermia and infertility are common, as are small phallus and testes and infertility.

Treatment and Prognosis.
If sexual orientation is unambiguously female, the testes should be removed as soon as they are discovered, e.g. laparoscopically
In one third of patients, malignant tumors, usually seminomas, develop by 50yr of age. Several teenaged girls have acquired
seminomas.
Replacement therapy with oestrogens is indicated at the age of puberty.
Normal breasts develop in affected girls who have not had their testes removed by the age of puberty. In these individuals, production
of oestradiol results from aromatase activity. The absence of androgenic activity also contributes to the feminization of these women.
The psychosexual and surgical management of patients with partial AIS is extremely complex and depends in large part on the
presenting phenotype. Osteopenia is recognized as a feature of AIS.
Sex hormonebinding globulin reduction after exogenous androgen administration (stanozolol) has been shown to correlate with the
severity of the receptor defect and may become a useful clinical tool. Successful therapy with supplemental androgens has been
reported in patients with partial AIS and various mutations of the androgen receptor in the DNA-binding domain and the ligand-binding
domain.

Pathogenesis
Androgen gene receptor mutation
?Somatic mosaicism of the androgen receptor gene.
The presence of mosaicism shifts the phenotype to a higher degree of virilization than expected from the genotype of the mutant allele
alone.


Angelman Syndrome



Epidemiology
1 in 20,000
onset in 1st year of life
M = F

Genetics
gene is UBE3A on chromosome 15
large common deletion (70%)
deletion of maternal copy of UBE3A + GABRB3 gene (codes for GABA receptor)
sporadic usually without apparent increased risk in future offspring
usually diagnosed by FISH
microdeletion of maternal copy of UBE3A
can occur in several areas including imprinting centre and UBE3A gene
can be sporadic or inherited from apparent normal mum if these deletions also present in mother 50% risk
to offspring
UBE3A mutations or imprinting
mutation within putative AS gene
imprinting normally maternal gene on if imprinted methylated switched off like a mutation or
deletion
appear sporadic
if inherited from apparently normal mother risk of 50% transmission however
paternal UPD (5%)
appear sporadic with recurrence risk only 1%


Angelman syndrome
o microdeletion of the same locus as PWS (chr 15 11q)
but the origin of the deleted gene is maternal (not paternal as in PWS)
o paternal uniparental disomy of chromosome 15
rare cause of missing genetic information









genetic analysis
methylation analysis
fast and easiest; at locus D15S63
distinguish maternal from paternal origin using methylation sensitive restriction endonuclease Hpa II due to
methylation of maternal locus this test involves a southern blot (DNA)
detect 80% of AS but usually does not distinguish the mechanism maternal deletion, paternal UPD, or
imprinting mutation
deletion of maternal origin (absent 6 Kbp Hind III/Hpa III fragment)
FISH analysis - will detect deletions BUT not UPD
linkage analysis

Clinical features
growth normal
IQ - severe IQ & gross motor delay
absent speech or < 6 words
behaviour - hand clapping, tongue thrusting and mouthing, paroxysms of laughter (develop @ 3-4 years of age)
face - dysmorphism absent at birth but becomes evident by 5 years of age
brachycephaly (short/broad-headed; with cephalic index >80; cephalic index = maximum breadth of the head to its maximum
length x100)
pointed chin, maxillary hypoplasia
eyes - deep set eyes, blue eyes
ENT - macrostomia (large mouth) with prognathia, tongue protrusion, wide spaced teeth
MSK - small hands and feet
scoliosis (10%) onset by 5 years of age and progressive
skin a/w hypopigmentation and oculocutaneous albinism (OCA2)
neuro - marked truncal hypotonia
limbs (like UMN) hypertonia, flexion contracture + hyper-reflexic
ataxia (puppet-like gait) toe walking and jerky arm movements
seizures (begin in 2nd year of life)

Investigation
CT/MRI
o mild cortical atrophy and generalised ventricular enlargement

Prognosis
survival to adulthood is possible, only one known case has reproduced
severity of seizures with age

Ataxia-Telangiectasia

Autosomal recessive
Main features: ataxia, telangiectasia, immunodeficiency, increased risk of malignancy
Ataxia beginning at about age 2yr and progressing to loss of ambulation by adolescence
Caused by mutations in the ATM gene located at 11q22q23.
ATM is a phosphytidylinositol-3 kinase that phosphorylates proteins involved in DNA repair and cell cycle control.
Oculomotor apraxia of horizontal gaze, defined as having difficulty fixating smoothly on an object and therefore overshooting the
target with lateral movement of the head, followed by refixating the eyes, is a frequent finding, as is strabismus, hypometric saccade
pursuit abnormalities, and nystagmus.
Telangiectasia becomes evident by mid-childhood and is found on the bulbar conjunctiva, over the bridge of the nose, and on the
ears and exposed surfaces of the extremities.
Examination of the skin shows a loss of elasticity.
Abnormalities of immunologic function that lead to frequent sinopulmonary infections include decreased serum and secretory
IgA as well as diminished IgG2, IgG4, and IgE levels in more than 50% of patients.
50- to 100-fold greater chance over the normal population of developing lymphoreticular tumors (lymphoma, leukemia, and Hodgkin
disease) as well as brain tumors.
Additional laboratory abnormalities include an increased incidence of chromosome breaks, particularly of chromosome 14, and
elevated levels of -fetoprotein.
Death results from infection or tumor dissemination

Bardet-Biedl Syndrome

Bardet-Biedl syndrome (BBS) is characterized by rod-cone dystrophy (>90%), truncal obesity (72%), postaxial polydactyly, cognitive impairment,
male hypogonadotrophic hypogonadism, complex female genitourinary malformations, and renal abnormalities (particularly calyceal
abnormalities, and polyuria and polydipsia)

Genetics
Autosomal recessive
Marked variable expression (though eye changes seem to be consistent)

Features
Obesity
Short stature
Retinitis pigmentosa (in <10%)
o Rod-cone dystrophies characterized by progressive degeneration and dysfunction of the
retina, primarily affecting photoreceptor and pigment epithelial function
o any of several hereditary progressive degenerative diseases of the eye
o marked by
night blindness in the early stages
atrophy
pigment changes in the retina
constriction of the visual field
eventual blindness
polydactyly
hypogonadism
mental retardation

Note
Laurence Biedl Moon is quite similar
o medullary cystic disease of the kidney
o ataxia (progressive to eventual loss of ambulation)
o intellectual disability
o visual impairment
retinitis pigmentosa
progressive optic atrophy & blindness
o endocrinopathy
obesity
hypogonadotrophic hypogonadism

Prader-Willi also similar

Beal syndrome

Congenital contractural arachnodactyly
Mutations in the FBN2 gene, the gene encoding the extracellular matrix protein fibrillin-2
Autosomal dominant
Marfanoid habitus with arachnodactyly, kyphosis/scoliosis, contractures of knees and
ankles, flexion contractures of the proximal interphalangeal joints of the fingers and toes
(camptodactyly), and crumpled ears (folded upper helix)
Some individuals with this syndrome have mild enlargement of the
sinuses of Valsalva.


Beckwith-Wiedemann

Key features
overgrowth syndrome
macroglossia
omphalocele/exomphalos
macrosomia
ear creases
1. hyperinsulinism
2. predisposition to tumours

Genetics
Chr 11p15
o near this gene is the gene for IGF-2 therefore overgrowth
usually sporadic (85%), but 15% familial, M = F
o microduplication
o in normal people
maternal copy of the gene is imprinted and the paternal copy is active
o BWS
maternal imprinting with paternal disomy causes a dosage imbalance
the child gets a double dose of IGF-2
another mechanism is through chromosomal inversions and translocations
maternal copy becoming active causing overgrowth
Maternal copy Paternal copy
normal people imprinted active
BWS mechanism 1 imprinted disomy = double dose!
BWS mechanism 2 active active

Clinical features
Macrosomia (traditionally defined as height and weight >97th percentile)
Hemihyperplasia in 1/3 (asymmetric overgrowth of one or more regions of the body due to an abnormality of cell proliferation, ie
increased cell number)
o Becomes less obvious with age
o Can involve multiple body parts which may be ipsilateral or contralateral
Macroglossia
Omphalocele or exomphalos in 80%/umbilical hernia in 50%/diastasis recti
o > 10% of pts with omphalocele/exomphalos have BWS
Anterior linear ear lobe creases/posterior helical ear pits
Visceromegaly involving one or more intra-abdominal organs including liver, spleen, kidneys, adrenal glands, and pancreas
o big kidneys with renal medullary hyperplasia (97%)
o big spleen (80%)
o big liver (70%)
Embryonal tumors (eg, Wilms tumor, hepatoblastoma, neuroblastoma, rhabdomyosarcoma) in childhood
Cytomegaly of the fetal adrenal cortex when present is pathognomonic
Renal abnormalities
o medullary dysplasia, duplicated collecting system, nephrocalcinosis, medullary sponge kidney, cystic changes, diverticuli,
and nephromegaly
o even with a normal renal ultrasound, patients can develop hypercalciuria
Cleft palate (rare)
Facial nevus flammeus, other vascular malformations
Characteristic facies, including midface hypoplasia (in 80%)
o Infraorbital creases
o Prominent occiput with large fontanelles
o Microcephaly
o Macroglossia in 98%, may cause obstruction in neonates
Cardiomegaly (usually inconsequential & resolves)/structural cardiac anomalies in 1/3; cardiomyopathy (rare)
Advanced bone age
Cryptorchidism (undescended testes) or large gonads with interstitial cell hyperplasia
Development is usually normal
Pancreas
o Hyperinsulinism secondary to pancreatic cell hyperplasia
o Neonatal hypoglycaemia in 50%, can persist for first few months of life
Polycythaemia
Malignancies
o Overall risk of malignancy is 7.5%, risk is greatest in first 8 years of life
o Adrenocortical tumours
o Wilms tumours
o Less commonly: rhabdomyosarcomas, gonadoblastoma, hepatoblastoma

Natural history
Prenatal:
o Macrosomia in 90% with long cord and large placenta
o Polyhydramnios in 50%
o Prematurity in 50%
Infancy & Childhood
o Macroglossia can cause obstruction in neonates
o Rapid growth until age 7-8, then slows
if survive past infancy then prognosis generally good though there may be ID
advanced bone age tends not to persist into adolescence, adult height is upper limit of normal

Management
Neonatal period: airway and feeding issues, hypoglycaemia
Abdo US to evaluate for visceromegaly
AFP to check for hepatoblastoma
ECG and echo
Craniofacial referral if needed
Then regular screening with US and AFP

Benign Familial Neonatal Seizures

autosomal dominant condition
begins on the 2nd3rd day of life
seizure frequency of 10-20/day
Patients are normal between seizures, which stop in 16 mo.

Bloom's Syndrome

Chromosomal breakage disease associated with malignancies & with immunodeficiency
Autosomal recessive
Mutation on 15q

Features
Proportionate small stature with microcephaly [only feature present at birth SGA, IUGR]
o Not due to growth hormone deficiency, cause unknown. Children can appear
wasted or confused with dwarfism
Caf-au-lait spots or hypopigmented skin lesions, acanthosis nigricans, ichthyosis [dry
rough epidermis with fish like scales]
Predisposition to the early development of a wide variety of cancers
o 50% will develop malignancy by age 25 likely due to genomic instability +/-
immunodeficiency
o Lymphoma or leukaemia
o Carcinomas of tongue, larynx, lung, oesophagus, colon, skin, breast
o Wilms tumour
Facial anomalies and sun-sensitive facial erythema
o Telangiectatic erythema
o Butterfly distribution in 1
st
year after sunlight exposure, improves after childhood, can involve hands/forearms
o Abnormal facies: prominent ears, malar hypoplasia, defective dentition, high pitched voice
Infertility - Primary hypogonadism in males, subfertility in females and premature menopause
DM
Immunodeficiency usually not severe but sinopulmonary infections (?also contributed to by reflux)
o Recurrent OM, (check hearing), recurrent respiratory and GIT infections
Long arms, large hands and feet

Investigations
chromosomal fragility
IgM and IgA

Brugada Syndrome

Sudden cardiac arrest/sudden cardiac death
Usually due to VF from structural heart disease e.g. coronary heart disease
SCA in the normal heart accounts for 5% of cases, and causes include:
o Brugada syndrome
o Long QT syndrome
o Preexcitation syndrome
o Commotio cordis

Characteristic ECG:
pseudo-RBBB and persistent ST segment elevation in leads V1 to V3
Brugada sign: coved ST segment elevation followed by T wave inversion
Classic type 1 Brugada has ST elevation 2 mm descends with an upward convexity to an inverted T wave. This is referred to as the
"coved type" Brugada pattern.
The type 2 and type 3 patterns have a "saddle back" ST-T wave configuration, in which the elevated ST segment descends toward
the baseline, then rises again to an upright or biphasic T wave. The ST segment is elevated 1 mm in type 2 and <1 mm in type 3.

Epidemiology
Mostly affects Asians
Up to 1% prevalence in Japan
M > F (up to 9:1)
Usually diagnosed in adulthood

Pathogenesis
Factors may include RV abnormalities, mutations in cardiac sodium channel gene SCN5A, autonomic tone, use of
cocaine/psychotropics, ?fever
Autosomal dominant inheritance with variable expressivity
SCN5A mutation in up to 30% of families affected
o Loss of function mutation
o Defective myocardiac sodium channels reduce sodium inflow currents, reducing duration of normal action potentials

Manifestations
Ventricular arrhythmias
Sudden cardiac arrest

Diagnostic criteria
Appearance of type 1 ST elevation (coved type) in more than one right precordial lead (VI-V3) +/- sodium channel blocker and at least
one of the following
a) Documented ventricular fibrillation
b) Self-terminating polymorphic ventricular tachycardia (VT)
c) Family history of sudden cardiac death at <45 years
d) Type 1 ST segment elevation in family members
e) Electrophysiologic inducibility of VT
f) Unexplained syncope suggestive of a tachyarrhythmia
g) Nocturnal agonal respiration
Appearance of type 2 or type 3 ST segment elevation (saddle-back type) in more than one right precordial lead under baseline
conditions, with conversion to type 1 following challenge with a sodium channel blocker & one of the features (a-g) described above

Drug challenge
Some type 2 or 3 patients can be unmasked with sodium channel blockers

Management
AICD

CADASIL

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)
Caused by mutations in the NOTCH3 gene.
Underlying vascular lesion is a nonatherosclerotic angiopathy involving small arteries and capillaries, primarily in the brain,
characterized by the presence of electron-dense granular osmiophilic material (GOM) within the arterial media surrounding the
smooth muscle cells.

Major clinical manifestations
TIA
Ischemic stroke predominately involving small vessels
Cognitive deficits with early executive dysfunction
Migraine with aura
Neuropsychiatric disturbances

Imaging
Brain MRI shows lacunar infarcts and less well demarcated T2-hyperintensities primarily located in the subcortical white matter, but
also in the brainstem and subcortical gray matter.
White matter T2 hyperintensities in the anterior temporal lobe and external capsule are additional features suggestive of CADASIL.

Natural history
The clinical course of CADASIL is highly variable. The duration from onset to death varies between 3 to 43 years with a mean of 23
years, while the median age at death is 65 years in men and 71 years in women
No specific treatment apart from secondary prevention

Campomelic Dysplasia

Autosomal dominant
Mutation in transcription factor leading to bone dysplasia
SOX9 is a member of the SOX family of genes related to the SRY (sex-determining
region of the Y chromosome) gene

Bowing of long bones (especially lower legs) & short bones, apparent in neonates
Also develop respiratory distress, from laryngotracheomalacia in combination with a
mildly narrowed thorax.

Defects of C-spine, CNS, heart, kidneys
Several cases of sex-reversal of XY males have been reported
XR: bowing, hypoplasia of scapulae and pelvic bones

Natural history: infants may die of respiratory distress. Surviving children may have
short stature, progressive kyphoscoliosis, recurrent apnoea and respiratory infection
and learning difficulties

In pic: Note bowed femurs, which are not particularly wide as compared with the thick bowed tibiae and fibulae.

Cat Eye Syndrome

Can be the result of trisomy or tetrasomy 22q.
The name is derived from the vertical iris coloboma.
Characteristic clinical features include:
Preauricular tags and/or pits
Iris coloboma
Congenital heart disease (total anomalous pulmonary venous return [TAPVR] is the characteristic defect associated with this
condition)
Anal anomalies
Renal malformation
Skeletal abnormalities
Intellectual disability.
The clinical manifestation may vary from very mild to a full pattern and lethal outcome
Patients with cat-eye syndrome should be assessed at birth for presence of heart, biliary, and anorectal abnormalities.
Usually normal intellect

CHARGE Syndrome


Key = Midline defects
Coloboma and cranial nerves
Heart defect [septal or cono-truncal]
Atresia of choanae
Retardation somatic growth and retardation of cognition
Genital and urinary abnormalities
Ear anomalies and/or hearing loss

Epidemiology
1/10,000-1/12,000 births
=

Aetiology
sporadic (majority)
in some abnormalities of chromosome 14, 9 and 22 (remember Catch 22)
familial (uncommon)
AR or AD
recurrence risk low 1-2% (but risk if affected individual attempt to have child)

Clinical criteria
need 4 out of 7 features
including a major anomaly coloboma, atresia

Coloboma (80%)
cleft or failure to close of the eyeball
usually bilateral
keyhole shaped pupil and/or
abnormalities in the retina or optic nerve visual loss (especially upper visual field) & acuity
in severe coloboma microphthalmia, nystagmus
retinal detachment
management: glasses help with visual acuity

Cranial Nerves
CN palsy associated in some
40% have CN 7 palsy more likely to have sensorineural hearing loss
30% have CN 9/10 palsy increased risk of swallowing problems, often resolve at 7-8 years of age

Heart defect (70%)
septal defects (interventricular and interatrial)
cono-truncal abnormalities

Atresia of chonae (50%)
polyhydramnios
unilateral (in 50%) persistent nasal discharge
bilateral (in 50%) tachypnoea (poor prognosis with other complex anomalies)

Retardation of somatic growth
FTT up to 80%
IUGR in 75% (FTT common by 6 months of life)
contributing factors
o poor oral intake
o CHD
o GH and FSH/LH deficiency

Retardation of cognition
low IQ in 70%
developmental delay mild to moderate
contributing factors
coloboma (vision)
ear problems
hearing problems
abnormal vestibular function (hence affect adoption of upright posture exacerbating delay in motor milestones)
multiple hospitalisation
IQ as part of the syndrome (extent not apparent until all corrective measures for above in place)

GUT (Genitourinary tract)
70% in male
micropenis
cryptorchidism or absence of testis
30% in female
labial hypoplasia
hypogondaotropic hypogonadism secondary to pituitary/hypothalamic cause possible
renal
hydronephrosis/VUR

Ear anomalies and hearing (80%)
abnormal ears (100%)
short, wide ears with little or no earlobe
soft and floppy
hearing loss (80-85%)
mixed hearing loss
frequent ear infections

Other associated (not consistently)
GIT (atresia, tracheo-oesophageal fistula)
MSK (hemi-vertebrae, scoliosis, limb abnormalities)

Investigations
bloods
karyotype (in some abnormalities 22, 14, 9)
FISH 22q (Di George has overlapping features)
U&E
FSH and LH
IGF-1

imaging
CXR (heart size)
cranial U/S (exclude any major malformations of brain)
head CT +/- MRI scans (exclude other CNS malformations)
barium swallow (if suspect TOF)
renal U/S (for renal abnormalities)
echo & ECG (for heart defects)

specials
audiometry
visual acuity
do if possible with underlying cognitive defect
if not possible do VER and electro-retinogram
FBE/Ig testing (Di George overlap)

Management
coloboma
o ophthalmology review
o glasses
cranial nerves
o CN 7 nerve (eye drops)
heart defects
o cardiology r/v
o surgery
o medications
o antibiotic prophylaxis
atresia (surgery)
retardation of growth and cognition
o NG/PEG feeds
o maximise nutrition
early intervention programme
genitourinary abnormalities (trial of androgen therapy for penile growth)


Central Core Disease

Congenital myopathy
Mutations in gene encoding ryanodine receptor on chromosome 19q13.1
Gene product forms channel mediating calcium release in skeletal muscle
Presents in neonatal period (or infancy) with hypotonia, muscle weakness, proximal > distal
Muscle involvement ranges from undetectable to severe
Often mild facial weakness present, but no ptosis/extraocular muscles/dysphagia or respiratory involvement
DTRs present but reduced in proportion to disease severity
MSK abnormalities
o Congenital hip dislocation
o Kyphoscoliosis
o Joint contracture
o Foot deformities
Increased risk of malignant hyperthermia
Clinical course is non progressive
Ix: CK is normal, EMG may show minor myopathy, muscle biopsy confirms diagnosis:
o Cores of degenerated myofibrils in 20-100% of muscle fibres, mostly type 1
o Cores are central and may be single or multiple

Charcot-Marie-Tooth Hereditary Neuropathy Overview

Hereditary Motor sensory neuropathy
Mutations is one of several myelin genes
Defects in myelin structure, maintenance and formation

Types:
CMT 1
o Demyelinating disorder of peripheral nerves.
o Usually Autosomal Dominant but AR and X-linked forms also occur.
o Usually presents in the first decade
o Features include distal muscle weakness, loss of reflexes, pes cavus foot deformity, hammer toes. Clumsy walking due to
motor and sensory deficits.
o Distal calf muscle atrophy often occurs stalk leg deformity
o Later changes include:
Atrophy of hand and foot muscles
Palpable enlargement of peripheral nerves due to nerve hypertrophy
Kyphosis and scoliosis often occur.
o EMG shows slowing of conduction in both motor and sensory nerves to less than 60% of normal.
CMT 2:
o Mostly AD but other types of inheritance can occur
o Similar symptoms but sensory loss usually predominates over motor symptoms.
o EMG findings also usually less severe
o Usually less demyelination occurs.
o Usually presents in the 2
nd
or 3
rd
decade

Treatment:
Supportive:
o Physio and stretching exercises can slow progression of contractures and weakness
o Orthopaedic involvement for foot deformities, scoliosis may be needed
Vitamin C, Progesterone antagonists and Neurotrphin-3 have shown some benefit.

Chediak-Higashi Syndrome

Rare autosomal recessive disorder characterized by:
o Recurrent pyogenic infections
o Partial oculocutaneous albinism
o Progressive neurologic abnormalities
o Mild coagulation defects
o Lymphoma-like accelerated phase
The diagnosis of CHS can be made by examination of a peripheral smear for pathognomonic
giant cytoplasmic granules in leukocytes and platelets.
Hematopoietic cell transplantation (HCT) is the treatment of choice
Parental consanguinity is common
Mutation in the lysosomal trafficking regulator (CHS1/LYST) gene at 1q42
Nonsense/null mutations leading to aberrant fusion of vesicles and failure to
transport lysosomes to the appropriate site of action
o Therefore neutrophils & cytotoxic T cells cant release their granules
immunodeficiency
o Melanocytes cant transfer pigment oculocutaneous albinism
o Platelet storage pool deficiency and bleeding diathesis

Presentation
In infancy with oculocutaneous albinism and recurrent pyogenic infections especially
of skin, mucous membranes and respiratory tract
Usually fair/blue eyed but in darker skinned races can have mixed pigmentation
(see right)
Hair usually blond but can have a metallic sheen
Accelerated phase
o Massive lymphohistiocytic infiltration of all organ systems
o Immunodeficiency worsens
o Mild bleeding diathesis can worsen
o Hepatosplenomegaly, lymphadenopathy
Surivival to adolescence/adulthood neurological sequelae
o Neurologic defects include weakness and sensory deficits due to peripheral neuropathy, ataxia, tremors, cranial nerve
palsies, progressive intellectual decline, and seizures. Spinocerebellar degeneration, movement disorders such as
Parkinson disease, and dementia also occur. Patients who survive to the second or third decade may be confined to
wheelchair.

Investigations
Neutropenia (probably destroyed)
Reduced neutrophil and monocyte chemotaxis
B cell function preserved
Abnormal platelet aggregation and bleeding time
CT/MRI brain and spine atrophy
PBS: classic giant azurophilic granules in neutrophils, eosinophils, and other granulocytes

Chronic Granulomatous Disease

Genetics/pathogenesis
Caused by defects in phagocyte NADPH oxidase (phox) phagocytes (neutrophils, monocytes, macrophages) can phagocytose, but
then cant destroy pathogens once phagocytosed
X-linked and autosomal recessive forms exist
o Mostly X linked therefore M > F [skewed lyonisation can lead to a mild form in carrier females of X-linked CGD]
o Autosomal recessive forms are milder and have later diagnosis

Characterized by recurrent life-threatening bacterial and fungal infections and granuloma formation [granulomata especially in GIT and GU tract]
Commonly by catalase positive organisms i.e. most bacteria and all fungi
Infections frequently involve lungs, skin, lymph nodes and liver
In order of decreasing frequency:
o Pneumonia [fungal lung infections do not cavitate as they do in patients with neutropenia]
o Abscesses (skin, tissue, organs)
Especially perianal, perirectal, liver
o Suppurative adenitis
o Osteomyelitis
o Bacteremia/fungemia
o Superficial skin infections (cellulitis/impetigo
o Also common: gingivitis, stomatitis, gastroenteritis, otitis media
Most common pathogens
o Staphylococcus aureus
o Burkholderia (Pseudomonas) cepacia
o Serratia marcescens
o Nocardia
o Aspergillus

Presentation
Growth failure
Abnormal wound healing
Diarrhoea
Infected dermatitis
May have hepatomegaly, splenomegaly, or lymphadenitis
A history of recurrent or unusually severe infections

Diagnosis
Neutrophil function testing
Mutation analysis
Early diagnosis of infections, antimicrobial and immunomodulatory prophylaxis, and aggressive management of infectious
complications

Cleidocranial Dysostosis

Genetics
o Autosomal dominant
o defect in CBFA 1 gene
o responsible for initial differential differentiation of osteoblasts to form skeletal structures

Clinical
o bones
defective bone formation
clavicles - hypoplastic/aplastic, can present with shoulder dislocations
large head with delayed suture closure
narrow pelvis
spinal abnormalities
o short stature
o dental
supernumerary teeth
defective cementum formation
specialized external bony layer covering the dentin of the part of a tooth normally within the gum (also called
cement)
abnormal permanent tooth eruption
2 to defects in alveolar bone osteoclastic and resorptive activity

Treatment
o extract supernumerary teeth
o assist eruption of permanent teeth through surgery/orthodontia


Cockayne Syndrome


Remember similar to xeroderma pigmentosum, and there is a combined form

Overview
Autosomal recessive, characterised by growth failure and multisystem degeneration many types exist reflecting the stages of onset
Facial features
o Large ears, sunken eyes
Other physical cachectic dwarfism
o Short stature
o Microcephaly
o Kyphoscoliosis
o Gait defects
Neurological
o White matter demyelination with atrophy of cerebrum and cerebellum
o Retinal degeneration with pigmented retinopathy and optic atrophy, corneal opacity
o Limb ataxia
o Abnormal auditory evoked responses
o Imaging: ventricular size, white matter changes, perivascular calcifications in basal ganglia and cerebellum
Skin: sun sensitivity (to UV) but no increased risk of cancer [unlike in xeroderma pigmentosum]

Natural history
Child considered normal until 2yo

Common Variable Immune Deficiency


Heterogeneous disorder involving immune dysfunction of B and T lymphocytes and dendritic cells.
Characteristic immunologic defect is the inability of B cells to differentiate into plasma cells capable of secreting all
immunoglobulin types.

Definition CVID is defined by the following
Age specific reduction in serum concentrations of IgG, in combination with low levels of IgA and/or IgM
Presence of B cells
Poor or absent response to immunizations e.g. can develop vaccine related poliomyelitis
An absence of any other defined immunodeficiency state

Epidemiology
Usually present after puberty
25% present in childhood/adolescence
Difficult to diagnose < 6 years because of immunologic immaturity and persistence of transient hypogammaglobulinaemia of infancy

Manifestations
Small and chronically ill, often with chronic cough
Chronic URTI or LRTI with otitis, purulent rhinorrhoea, visible post-nasal drainage
May have crackles, wheezing, clubbing
Hepatosplenomegaly suggests GI or autoimmune problems
Less common: arthritis, vasculitis, vitiligo, skin infections, eczema

Most common infections
Sinusitis (75%)
OM (67%)
Pneumonia (58%)
Bronchiectasis
Chronic diarrhoea due to Giardia

Associations
Autoimmune disease e.g. ITP
Neutropenia
Allergic disease e.g. food allergy, eczema, urticarial, asthma
FTT [due to repetitive illnesses], developmental delay
GH deficiency, hypothyroidism
Malignancy in adulthood most commonly B cell lymphoma

Diagnosis
FBC: lymphopenia
B and T cell function tests
Hypogammaglobulinaemia [IgG, +/- low IgA and/or IgM]
Defective antibody formation antibody function studies
Exclude other causes
Endocrine studies

Management
IVIG
Infection prevention
Prompt treatment
Prophylactic antibiotics for refractory infections
Monitor pulmonary function and physical/emotional development

Cornelia de Lange Syndrome

Characteristics
Small IUGR and stay that way, growth retardation
Synophrys, hirsutism
Limb abnormalities with micromelia, can have oligodactyly
Dysmorphic face thin down-turning lip and anteverted nares, small widely spaced teeth
Severe mental retardation , mean IQ of 50
Autistic & self-destructive tendencies
Associated with
o Cardiac septal defects
o GI dysfunction including GORD
o Hearing loss, myopaia, cryptorchidism or hypoplastic gonads

Genetics
1 in 30 to 60,000
Mutation can be in NIPBL, SMC1A, and SMC3 - ?or others
o De novo [vast majority]
o AD
Recurrence risk
o 1-2% if parents normal [risk of gonadal mosaicism]
o 50% if a parent affected

Management
Manage GORD, may require fundoplication
Growth: may need supplementary formulas, gastrostomy
PT, OT, speech pathology
Treat hearing loss, cardiac defects, seizures, VUR and cryptorchidism

Surveillance
Annual GI evaluation
Monitor growth & psychomotor development
Routine eye & hearing evaluations
Monitor heart/kidney abnormalities


Craniosynostosis Syndromes

Sagittal 50% dolicocephaly
Coronal 22% brachycephaly
Metopic 6% trigonencephaly

Aperts:
Autosomal Dominant, mutation in FGFR2 gene on Chr
10
Most cases are sporadic
Abnormal growth of the skull base
o Bicoronal synostosis and maxillary
hypoplasia
o Hypoplastic midface can result in airway
compromise
o Protruding eyes [exorbitism] and
hypertelorism, antimongoloid slant
o Small flat nose
o High arched palate, cleft palate in 1/3
Distinct Extremity anomalies:
o Syndactyly (complex) Mitten Hands
o Feet also demonstrate syndactyly
Hearing loss
Acne Vulgaris
CNS abnormalities and ventriculomegaly (raised ICP
can occur in as many as 43% of cases and requires
urgent surgery)
Intellectual delay in >60% of patients
craniosynostosis, midface hypoplasia, broad
thumbs




Aperts syndrome:

Crouzon Syndrome
Autosomal Dominant
Mutations in FGFR2 and FGFR3 (associated with Acanthosis nigricans)
Clinical:
o Tall, flattened forehead due to bicoronal synostosis.
o Proptosis
o Midface hypoplasia.
o Cervical spine anomalies occur in up to 30%
Degree of facial deformity is milder than Aperts, the limbs are usually normal and their
IQ is also usually normal

Pfeiffer Syndrome
Autosomal Dominant but most cases are sporadic.
Mutations in FGFR1 and FGFR2
Clinical:
o Variable degrees of craniosynostosis and mid face hypoplasia
o Broad thumbs and great toes
o Syndactyly is also variable
o Type 1 - AD usually but can be sporadic
symmetric bicoronal craniosynostosis, broad thumbs and great toes, normal IQ and survival
o Type 2 - Sporadic
Clover leaf skull, severe ocular proptosis, broad thumbs and great toes, ankylosis of elbows and visceral anomalies.
Severe CNS involvement and hydrocephalus
Poor outcome
o Type 3 - Sporadic
Similar to type 2 but cloverleaf skull is absent


Carpenter Syndrome
Autosomal Recessive
Genetic Mutation has not been identified
Clinical:
o Brachycephaly and craniosynostosis of multiple sutures. coronal, sagittal, and lambdoid
craniosynostosis
o Low set and malformed ears
o Hypoplastic midface +/- maxilla
o Narrow, high arched palate.
o brachydactyly of the hands with clinodactyly, partial syndactyly, and camptodactyly
o CVS abnormalities VSD or ASD, PDA, PS, ToF, TGA
o Obesity and low IQ are common










Cri Du Chat Syndrome

Genetics
1 in 50,000
partial deletion 5p
o sporadic (85%) risk recurrence 1%
o unequal parental translocation (15%)
o Paternal origin in 80%
size deletion variable
o 5p15.2 - account for most phenotype
o 5p15.3 - critical region, responsible for high pitched cry
Progressive severity of clinical features according to size of deletion
Clinical features become less striking with advancing age
>

Clinical features
characteristic CRY (cat like from vocal cord abnormalities), resolves within months
growth
o FTT (100%)
o short stature (85%)
o low birth weight (50%)
neuro/development
o IQ (100%) IQ rarely above 35
o infantile hypotonia (80%) then hypertonic
o psychomotor delay
dysmorphism (facial)
o microcephaly (100%)
o broad based nose (85%)
o small jaw
o low set &/or malformed ears
o high and narrow or broad and flat palate
o round face
o pre-auricular tags
o eyes
hyperterlorism (95%)
epicanthic folds (90%)
downslanting or oblique palpebral fissures (85%)
CVS
o CHD (PDA most common)

Investigations
simple deletion of portion of chromosome 5 diagnostic
some patients may be mosaics

Cystic fibrosis

Genetics
Autosomal recessive
CFTR gene on 7q
o Expressed in epithelial cells of airways, GIT including pancreas, biliary system, sweat glands and genitourinary system
o Product functions as a chloride channel
o Other regulatory functions that are perturbed variably by the different mutations
Many different mutations
All lead to reduced/absent functioning of CFTR protein at the apical membrane.
Therefore unable to secrete chloride in response to cyclic AMP stimulated protein kinase A

Most prevalent mutation is deletion of single phenylalanine residue at amino acid 508 (delta 508) Class 2 mutation
This mutation responsible for high incidence of CF in northern European populations
Approx. 50% of individuals of Northern European ancestry with CF are homozygous for delta 508
>80% are heterozygous
Other mutations include W1282X, common in Ashkenazi Jews (60% of affected)

Types of mutations
Note
Endoplasmic reticulum
Contains ribosomes
Site of protein synthesis
mRNA from nucleus comes to ribosome where tRNA brings the matching anticodon for the
each mRNA codon (3 amino acids that code for a single amino acid), gradually forming a long
chain of amino acids
Golgi apparatus
Process and packages proteins prior to transport

Class I
Defective protein production
E.g. abnormal transcription in the nucleus or abnormal translation in the ER)
Leads to premature transcription termination signals during CFTR protein formation truncated or
absent protein
Results in few or no functioning CFTR chloride channels

Class II
Defective protein folding and processing in the Golgi apparatus defective transportation of CFTR to
the apical surface where it can function

Class III
Defective regulation of CFTR at the surface due to abnormal ATP gating of the Cl channel
Even though it makes it to the surface, it cant function

Class IV
CFTR makes it to the cell surface but it has poor conductance of Cl through the channel

Class V
Abnormal splicing of the CFTR protein during processing in the golgi apparatus amounts of functional protein


Dyskeratosis Congenita

Disease characteristics
Telomere disorder
Triad of dysplastic nails, lacy reticular pigmentation of upper chest and/or neck and oral leukoplakia
Associations:
o Risk of bone marrow failure, MDS, AML, SCC of head/neck, anogenital cancer
o Pulmonary fibrosis
Other possible findings:
o Abnormal pigmentation
o Eye abnormalities: epiphora, blepharitis, sparse eyelashes, ectropion, entropion, trchiiases
o Dental abnormalities: caries, periodontal disease, taurodauntism
Usually have normal psychomotor development and neurologic function
o Can have developmental delay in some variants

Genetics
Abnormally short telomeres for their age
8 known genes that are involved, 7 can be tested for
Some are AD, some AR

Management
HSCT is curative for BMF/leukaemia
Androgen therapy for BMF
Treat cancers
Supportive treatment for pulmonary fibrosis


Dystrophinopathies

DMD + genetics
Most common hereditary neuromuscular disease, incidence 1:3600 live males
Progressive weakness, intellectual impairment, calf hypertrophy, proliferation of CT in muscle
X-linked recessive
30% de novo
Female carriers are usually normal, except in cases of skewed lyonisation or those with Turner syndrome
o Female carriers can develop cardiomyopathy
Asymptomatic carriers can have CK in the hundreds/thousands, but not extreme
Can do a PCR on peripheral blood to look for carrier status
Defects can be intragenic deletions, duplications or point mutations
o 65% have deletions, typically of exons 45-71
o 7% duplications
In DMD, nonsense mutations result, while in Becker, missense mutations are responsible
Even milder form formerly called quadriceps myopathy is due to abnormal dystrophin molecule


Clinical manifestations
Infancy
o Rarely symptomatic at birth or in early infancy some are mildly hypotonic
o Early gross motor skills are met at the usual times may have poor head control
o Facial muscle weakness is late hence no distinctive facies
o Normal age of walking
Toddlers
o By 2 years, hip girdle weakness may be seen
o Lordotic posture when standing (compensates for gluteal weakness)
o Early Gowers sign by 3yo, fully expressed by 5-6yo
Childhood
o Trendelenburn gait (hip waddle
o Gowers manoeuvre
o Variable time that patient remains ambulatory most can walk with difficulty until ~10yo
Adolescence/young adulthood
o Progressive weakness
Calf pseudohypertrophy, wasting of thigh muscles
Caused by hypertrophy of some muscle fibers, infiltration of muscle by fat, and proliferation of collagen.
Next most common site of muscular hypertrophy is the tongue, followed by muscles of the forearm.
o Usually distal muscles function enough for eating, typing
o Respiratory may have weak/ineffective cough, infections, respiratory reserve
o Pharyngeal weakness can lead to aspiration/regurgitation and airy/nasal voice
o Extraocular muscle function preserved
o Rare/late: sphincter weakness leading to urinary or faecal incontinence

Complications/Sequelae
Intellectual impairment
o Occurs in all patients, 20-30% have an IQ < 70, most have mild delay, a few have profound MR [doesnt correlate with
skeletal muscle weakness]
Respiratory infections
Contractures most commonly ankles, knees, hips, elbows
Scoliosis, rapid once wheel-chair bound
o Thoracic deformity compresses pulmonary capacity and compresses heart
Cardiomyopathy
o Persistent tachycardia, myocardial failure
o 50-80% of patients
o Doesnt correlate with skeletal muscle weakness, e.g. can die of myocardial failure while still ambulant
Smooth muscle dysfunction in GIT
Slightly incidence of epilepsy
There is NO pain/myalgia/muscle spasm
Death occurs usually age 18-20, causes include:
o Respiratory failure in sleep
o Intractable heart failure
o Pneumonia
o Aspiration/airway obstruction
risk of obesity due to inactivity, depression further impairs mobility

Examination
Reduced power
Ankle DTRs well preserved until terminal stages
Knee DTR present but reduced until ~6 yo, then eventually lost
Brachioradialis reflex > biceps/triceps reflexes

CNS manifestations - pathophysiology
Dystrophin is expressed in brain, retina, striated and cardiac muscle
Level is lower in brain than in muscle
MRI will show cerebral atrophy in late stage

Becker muscular dystrophy
Essentially the same disease
Genetic defect at same locus, but missense (so amino acid chain is not disrupted)
Milder phenotype, more protracted course

Clinical manifestations
Ambulatory until late adolescence or early adulthood
Later onset of weakness
Calf pseudohypertrophy, cardiomyopathy, CK as in DMD
Learning disabilities are less frequent
Death occurs in mid to late 20s, less than half survive to 40, and these are severely disabled

DMD & BMD: Investigations
Serum
o CK, usually 15,000-35,000 IU/L (normal is < 160IU/L)
o In terminal stages there may be less muscle to degenerate hence CK elevation is less severe
o Aspartate aminotransferase, Aldolase both are lysosymal enzymes present in muscle
PCR for dystrophin gene
o If diagnostic, may deter muscle biopsy but 1/3 of cases dont show PCR abnormality
o If normal and clinical suspicion is high proceed to dystrophin immunocytochemistry on muscle biopsy
Immunohistochemical staining of frozen muscle detects differences between the rod domain, the carboxyl-
terminus (that attaches to the sarcolemma), and the amino-terminus (that attaches to the actin myofilaments) of
the large dystrophin molecule
More severe weakness occurs with truncation of the dystrophin molecule at the carboxyl- than at the amino-
terminus.
Dystroglycans and other sarcolemmal regional proteins, such as merosin and sarcoglycans, also can be
measured because they may be secondarily decreased.
Muscle biopsy
o Can do immunohistochemical staining [fluorescence or LM], Western blot
o Myopathic changes
Endomysial CT proliferation, scattered degenerating and regenerating myofibres, foci of mononucleocytes
(inflammatory reaction to muscle necrosis), mild architectural changes in still-functioning fibres and many dense
fibres
Dense fibres: hypercontracted fibres resulting from segmental necrosis, allowing calcium to enter sarcolemmal
membrane contraction
Calcifications: correlated with secondary -dystroglycan deficiency.
o When to do muscle biopsy: can avoid if there is a positive FHx (e.g. brother), and pt has typical features and high CK
o Most common locations vastus lateralis, gastrocnemius
o Classic DMD: < 3% of normal dystrophin
o BMD: 80% have molecular weight of dystrophin, some have normal size but quantity, 5% have abnormally large
protein
o DMD vs BMD: selective immunoreactivity or molecular genetics

Genetics

Figure 1. Duchenne muscular dystrophy patient muscle
biopsy characteristically revealing necrotic or degenerating
muscle fibers (arrow), often observed in clusters, surrounded
by macrophages and CD4+ lymphocytes (star). Small
immature centrally nucleated fibers are also present (double
star), reflecting muscle regeneration from myoblasts (bar =
200 m).

Management
Maximise period that the patient is ambulant
psychological benefit, and reduces risk of
scoliosis
o Orthotic bracing
o Physiotherapy
o Achilles tendon lengthening
Refer to cardiologist. Decompensation often
responds to digoxin
Treat chest infections
Nutrition
o Avoid vitamin overdose
o Adequate calcium to minimise osteoporosis to immobilised patients
o Fluoride supplements
Physiotherapy
o Delays but doesnt always prevent contractures
o Elbow contractions functionally beneficial if they prevent extension > 90 degrees prevents flail arm, pt can then
eat/write
o Limited improvement in muscle strength already using their entire reserve daily excessive exercise can
degeneration
Steroids
o rate of apoptosis of myotubes, may decelerate necrosis
o Long term sequelae
o Can be used e.g. for the 1
st
10 days of each month
o Avoid fluorinated steroids e.g. dex or triamcinolone


Ehlers-Danlos Syndromes


Overview
Diverse group of disorders with hyperextensible skin, hypermobile joints, easy bruising, dystrophic scarring, variable cardiovascular
manifestations
Abnormalities of mature collagen structures are common to all of them
Subcategorized by their predominating features and molecular
characterization.
Classic, hypermobile, vascular, and kyphoscoliotic subtypes (defined by the
Villefranche nosology) other subtypes exist

EDS classic type
Autosomal dominant
Most common form
Mutations of genes encoding for type V (COL5A1, COL5A2) and type I
collagen (COL1A1)
Dermatologic features predominate
o Soft, hyperextensible skin
Best evaluated in areas not subject to mechanical stress
Difficult to appreciate in very young children because of
subcutaneous fat stores
o Molluscoid pseudotumors
o Subcutaneous spheroids
o Piezogenic papules (small herniations of subcutaneous fat
pictured0
o Easy bruising
o Abnormal wound healing
o Atrophic scar tissue
o Hernias

EDS hypermobility type
Autosomal dominant
Joint hyperextensibility
Absence of significant involvement in other organ systems - important
negative finding.
A clear aetiology for this form has not been identified, but some affected
individuals have an associated autosomal dominant mutation of tenascin X
(TNXB) and type III collagen.
Complications
o Subluxation and dislocations- minimal mechanical forces or
spontaneously.
o Degenerative joint disease and chronic disabling and debilitating
pain can long-term complications.
Skin may have a soft or velvety texture and mild elasticity is sometimes seen
Atrophic scarring is unusual.

EDS vascular type
Autosomal dominant
Characterized by arterial aneurysm and rupture, intestinal perforation, translucent skin, easy bruising, polyarthropathies, a
characteristic facial appearance, uterine rupture, progeroid features
Facies: large eyes, thin alae nasae, thin lips
By far the most severe form of EDS, with a risk for a significantly shortened lifespan because of its associated complications.
25% of affected individuals will experience a significant medical complication by age 20.
The arterial aneurysms are particularly hard to manage surgically, as the vessels are often described as friable and not amenable to
anastomosis.
Diagnosis based on clinical findings, and confirmed by analysis of type III procollagen from cultured fibroblasts and/or identification
of mutations in COL3A1.

EDS kyphoscoliotic type
Autosomal recessive
Characterized by kyphoscoliosis, joint laxity, hypotonia, and fragility of the optic globe
Vascular involvement has also been associated, including dilation and rupture of arteries.
Caused by deficiency of the procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1 (PLOD1; lysyl hydroxylase 1)
Increased ratio of deoxypyridinoline to pyridinoline cross-links in urine on high performance liquid chromatography (HPLC).
Lysyl hydroxylase activity can be directly measured in cultured skin fibroblasts and supported by mutations found in the associated
gene, PLOD1.

Other forms
Dominant arthrocalasia type
Congenital hip dislocation
Severe hypermobility
Soft skin
Recessive dermatosporaxis type
Extreme skin fragility, sagging, and redundant skin
Recessive valvular type caused by mutations in COL1A2
Joint hypermobility
Skin hyperextensibility
Cardiac valvular defects
X-linked classic type
Others!

Other nonspecific signs & symptoms of EDS
Chronic pain sleep disturbance, fatigue, fibromyalgia, depression, headaches
Hypotonia delayed gross motor development, clumsiness
Frequent muscle cramps
Dental issues: TMJ syndrome, periodontal disease, high palate with dental crowding
Haematologic: easy bruising, prolonged bleeding despite normal bloods
GIT: reflux, HH, gastritis that can be refractory, IBS, diverticulitis, rectal prolapse
Cardiac:
MVP
Stable aortic root dilatation
Atypical chest pain
Palpitations
Orthostatic intolerance
Risk of incision, inguinal & umbilical hernias
Maternal complications: progression of aortic dilation and aneurysm, premature rupture of membranes, cervical incompetence, and
uterine rupture.

Management
PT, strength training, muscle group conditioning
Avoid injurious activities
Orthopaedics: bracing, reduction, surgery
Pain management
Psychiatry
Wound management wounds must be closed without tension, sutures to both surface and deeper tissues, leave sutures for twice
the usual time
Screen for cardiac complications
Can screen for osteopenia with DEXA
Vascular subtype: immediate medical attention for neurological symptoms, visceral or cranial pain
High risk pregnancy management

Epidermolysis Bullosa Disorders

Overview
Heterogeneous group of congenital, hereditary blistering disorders.
Characterized by induction of blisters by trauma and exacerbation of blistering in warm weather.
Categorisation
Epidermolysis bullosa simplex (EBS)
Junctional epidermolysis bullosa (JEB)
Dystrophic epidermolysis bullosa (DEB)

Epidermolysis Bullosa Simplex (EBS).
Non-scarring, autosomal dominant disorder, multiple subtypes
Defect in most types of epidermolysis bullosa simplex is in keratin 5 or 14, which makes up intermediate filaments of the basal
keratinocytes.
The intraepidermal bullae result from cytolysis of the basal cells.
Subtypes
In EBS-Koebner
Blisters are usually present at birth or during the neonatal period.
Sites of predilection are the hands, feet, elbows, knees, legs, and scalp.
Intraoral lesions are minimal, nails rarely become dystrophic and usually regrow even when they are shed
Dentition is normal
Bullae heal with minimal to no scar or milia formation.
Secondary infection is the primary complication.
Propensity to blister decreases with age, and the long-term prognosis is good.
Mx: Blisters should be drained by puncturing, but the blister top should be left intact to protect the underlying skin. Erosions may
be covered with a semipermeable dressing.
Weber-Cockayne type
Localized EBS of the hands and feet
Often presents when a child begins to walk; onset may be delayed, however, until puberty or early adulthood when heavy shoes
are worn or the feet are subjected to increased trauma.
Rarely, bullae occur elsewhere such as the dorsal aspect of the arms and the shins.
The disorder ranges from mildly incapacitating to crippling at times of severe exacerbations.
EBS-Dowling-Meara (herpetiformis) type
Grouped blisters resembling herpes simplex
During infancy, blistering may be severe and extensive, may involve mucous membranes, and may result in shedding of nails,
formation of milia, and mild pigmentary changes, without scarring.
After the 1st few months of life, warm temperatures do not appear to exacerbate blistering.
Hyperkeratosis and hyperhidrosis of the palms and soles may develop, but generally, the condition improves with age
EBS-muscular dystrophy
Rare variant associated with muscular dystrophy
Caused by mutation in plectin gene hemidesmosomal protein

Junctional Epidermolysis Bullosa Herlitz type
Autosomal recessive
Life threatening
Usually blistered at birth or in neonatal period
Areas involved: perioral, scalp, legs, diaper area, thorax
Hands and feet spared except for digits/nail plates dystrophic or lost
Mucous membrane involvement may be severe
Ulceration of GIT, GUT, respiratory tract
Delayed healing, vegetating granulomas may persist
Large, moist erosive plaques bacterial entry septicaemia, a common cause of death
Areas of recurrent blistering atrophy
Defective dentition, rampant caries, early loss of teeth
Growth retardation, recalcitrant anaemia
Cachexia, circulatory failure also cause death
Most patients die by age 3

Junctional Epidermolysis Bullosa non-Herlitz type
Heterogenous group of disorders
May have severe neonatal presentation, but usually milder
Generalized atrophic benign epidermolysis bullosa is included as a variant of non-Herlitz JEB.
Another variant is associated with pyloric atresia.

JEB - treatment
Supportive
Dietary supplementation including iron
Treat infections prompty
RBCs if pt doesnt respond to iron and EPO
Skin grafts may be required

DYSTROPHIC EPIDERMOLYSIS BULLOSA (DEB).
Mutations in collagen VII, major component of anchoring fibrils that tether the basement membrane and overlying epidermis to its dermal
foundation.
Blister is subepidermal in all types of DEB. The type and location of the mutation dictates the severity of the phenotype.
Types
Dominant dystrophic EB
Most common type
Blisters may be present at birth, often over acral bony prominences
Heal promptly with soft, wrinkled scars, milia and pigmentation abnormalities
Abnormal nails and nail loss is common
Blistering is often mild, with little restriction of activity, growth or development. Minimal MM involvement
Transient bullous dermolysis of the newborn
Self limited
Autosomal dominant
Resolved by age 2
Recessive DEB
Most incapacitating form of EB
Blisters mainly on hands, feet, elbows, knees, but can have extensive erosions and blisters from birth that impede care and
feeding
MM lesions common nutritional deprivation, growth retardation
Oesophageal erosions, strictures, scarring of buccal mucosa, flexion contractures of joints, cutaneous carcinomas, digital fusion
can all develop
Skin becomes less sensitive with age but overall prognosis is poor

Management
Avoid foods that traumatise mucosa
Oesophageal scarring semiliquid diet may be needed, oesophageal dilatation
Oesophageal stricture excision
May need gastrostomy if cant feed orally
Treat anaemia iron, epo, transufions
Intermittent antibiotics for infecitons
Surgery to release contractures [from scarring of integument]
Tissue-engineered skin grafts containing keratinocytes and fibroblasts are of some benefit.

Esophageal Atresia/Tracheoesophageal Fistula Overview

Esophageal atresia (EA)
Most frequent congenital anomaly of the esophagus
Incidence 1/4,000 neonates
>90% have an associated tracheoesophageal fistula (TEF)
Most common form of EA the upper esophagus ends in a blind pouch and the TEF is connected to the distal esophagus.
This defect has survival rates of >90%
Infants weighing <1,500 g at birth have the highest risk for mortality.
50% of infants are nonsyndromic without other anomalies while the rest have associated anomalies most often associated with the
VATER/VACTERL (vertebral, anorectal, [cardiac], tracheal, esophageal, renal, radial, [limb]) syndrome.
Usually normal intelligence.
Low concordance among twins, low incidence of familial cases, but genetic factors have a role in the pathogenesis of TEF in some
cases: Feingold syndrome (N-MYC), CHARGE syndrome (CHD7) and anophthalmia-esophageal-genital syndrome (SOX2).

Below: types of OA/TOF, in decreasing order of frequency


PRESENTATION
Frothing/bubbling at mouth and nose after birth
Episodes of coughing, cyanosis, respiratory distress, exacerbated by feeding
Regurgitation
Aspiration aspiration via distal fistula causes worse pneumonitis than aspiration from blind upper pouch
Isolated TOF can present later in life with chronic respiratory infections and refractory bronchospasm

DIAGNOSIS
In utero polyhydramnios is common with OA
Inability to pass NGT or OGT suggests OA
CXR: will show coiled feeding tube in oesophageal pouch and/or air-distended stomach which suggests TOF. Pure OA on CXR will show
an airless, scaphoid abdomen.
Isolated TOF: oesophagogram with contrast injected under pressure may demonstrate the defect. Alternatives: bronchoscopy or intubation
+ injection of methylene blue dye during forced inspiration leading to dye being seen on endoscopy

MANAGEMENT
ABC
Prevent aspiration of secretions
Prone positioning minimises gastric secretions into distal fistula
Oesophageal suctioning to minimise aspiration from blind pouch
Avoid ETT + mechanical ventilation may worsen distension of abdominal viscera
Surgical ligation of the TEF and primary end-to-end anastomosis of the oesophagus are performed when feasible
In prems: may do fistula ligation and gastrostomy tube first, then primary closure later
If the gap between the atretic ends of the esophagus is >34 cm, primary repair cannot be done; options include using gastric, jejunal, or
colonic segments interposed as a neo-esophagus.
Careful search must be undertaken for the common associated cardiac and other anomalies.
Complications of surgery
Anastomotic leak or stricture
Re-fistulisation
Other complications:
GORD due to oesophageal dysfunction, delayed gastric emptying, and can contribute to reactive airway disease
Reactive airway disease

Laryngotracheoesophageal clefts
Septum between oesophagus and trachea fails to develop fully channel between pharyngoesophagus and laryngotracheal lumen
laryngeal closure during swallowing or reflux is incompetent
Present as neonate/infant with stridor, choking, cyanosis, aspiration and recurrent LRTI
Diagnosis: endoscopic visualisation of larynx + oesophagus, or contrast radiography
Management: surgical

Familial Mosaic Monosomy 7 Syndrome

Disease characteristics
Characterized by early-childhood onset of bone marrow insufficiency/failure
Associated with increased risk for myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML)
Bone marrow failure/MDS/AML follows within a few months to years of identification of a monosomy 7 cell line in peripheral blood.
Almost universally fatal
Note: Only a minority of individuals with bone marrow failure/MDS/AML with monosomy 7 fall into the diagnostic category of familial
monosomy 7.

Diagnosis/testing
Bone marrow cytogenetic and interphase FISH studies.
A bone marrow karyotype of 45,XX,-7 in females or 45,XY,-7 in males, often mosaic with a normal cell line (i.e., 46,XX in females
and 46, XY in males), confirms the presence of a monosomy 7 cell line.
Of note, individuals with a family history of monosomy 7 (i.e., a sib) may initially have a normal karyotype in peripheral blood and/or
bone marrow and over time transition to mosaic monosomy 7 in peripheral blood and/or bone marrow.

Management
Treatment of manifestations: Urgent referral to an oncologist should be considered in those with monosomy 7 (mosaic or non-
mosaic).
Definitive therapy is bone marrow transplantation (BMT) prior to the emergence of a leukemic clone.
It is recommended that sibs who are potential bone marrow donors be evaluated with appropriate cytogenetic studies to determine
their suitability.

Fragile X Syndrome

Martin-Bell Syndrome
Fragile X Syndrome
X linked - fragile X chromosome site (Xq27.3)
= FMR-1 gene (fragile X mental retardation 1) CGG repeats
mental retardation (100%)
account for 6% of intellectually impaired males
most common cause of inherited mental retardation
3
rd
most common genetic cause (after DiGeorge/ Down)
behavioural abnormalities (autistic features, emotionally unstable)
macro-orchidism

Epidemiology
fits neither dominant or recessive x-linked inheritance patterns
prevalence
o 1:1,250 males
o 1:2,500 females
o 1: 500 carrier females
age of onset: toddler adolescence

Genetics
unstable tri-nucleotide repeats (CGG) in the 5 region of the FMR-1 gene
normal individuals = 10-50 CGG repeats
Fragile X = 200-2000 CGG repeats
promote methylation of regulatory sequences within sequence (CpG islands)
turn off of FMR-1 gene expression lack of gene product
in the karyotype
constriction followed by a thin strand = giving appearance of a fragile X
fragile sites can be demonstrated in 1/3 of intellectually normal carriers
80% penetrance in males, 30% in females
pre-mutation carriers
generally have no phenotypic manifestations (have risk of offspring with syndrome)
amplification of pre-mutation allele occurs only through female gametogenesis
gene remains stable when passed through male gametogenesis
males with a pre-mutation allele
not true pre-mutation FXATS (frag X associated ataxia & tremor synd.)
pass allele on to all daughters
most phenotypically normal
premature ovarian failure, shy (not true pre-mutation)
all of the daughters children will be at risk of having affected children
known as the Sherman paradox

number of CGG repeats affects phenotype & risk for amplification to full mutation:

Number of CGG rpts Allelle Phenotype Risk of amplification
6-60 normal allele normal phenotype no risk
60-200 pre-mutation allele normal phenotype (obligate
carrier)
ataxia & tremor
20% have
premature menopause;
shy personality
70-90 = >50% risk
>100 = 99% risk
>200 full mutation allele fragile X phenotype

Tri-nucelotide (triplet) repeat disorders
repetition of three nucleotides
o normal phenomenon
o disease caused when expanded beyond a certain threshold
o below that threshold stable in mitosis & meiosis
o beyond a certain number the repeat can be unstable

characteristics
o intergenerational instability
sex of transmitting parent important (but differs for diseases)
o anticipation
best example is myotonic dystrophy
more severe phenotype with successive generations
o pre-mutations
repeat size which is unstable but does not result in a phenotype
best example is fragile X syndrome
o gentoype-phenotype correlation
for all trinucleotide repeat disorders the larger the repeat, the earlier the onset
cannot use the repeat size to predict phenotype with accuracy

locations of trinucleotide expansions in humans
o myotonic dystrophy CTG,CTG,CTG
o Fragile X CGG,CGG,CGG
o Friedrichs ataxis GAA,GAA,GAA (only AR inherited triplet repeat disorder) (look like they are GaaGaa)
o Huntington disease CAG,CAG,CAG

Clinical features

Males
growth
somatic normal
sexual - macro-orchidism (large testicles); 80-90% of affected males after puberty; normal testicular function

intellectual disability (100%)
ranges from profound normal IQ with learning disabilities
developmental delay (usually reach early milestones and then delay)
gross motor - may be hypotonic as infant
speech/language - generalized language disability, jargon,
perseveration, echolalia
behaviour variable
autistic-like behaviour (in 5-10%) & ADHD-like behaviour
emotional instability, hand biting, tactile defensiveness
tends to improve around puberty

face
head - large, with prominent forehead
long, thin face with prominent mandible
large ears +/- low set, posteriorly rotated, poorly formed
eyes pale blue irides, stabrismus, refractive errors
hi arched palate, dental over-crowding

other
hyperextension of fingers, single palmar crease, pes planus
pectus excavatum (mild-moderate) & scoliosis
CVS - floppy mitral valve (in 80% over 18yo)
genitourinary

Females
females get it because of skewed lyonisation (normally 50% chance of switching off good gene)
intellectual disability - 50% cf 100% in males
developmental delay
behavioural shyness, emotional problems
dysmorphic features - mild craniofacial and connective tissue manifestations

Diagnosis
cytogenetics
o diagnostic
o fragile X chromosome site at Xq27.3 is induced under folic acid or thymidine-deficient culture conditions using
lymphocytes
o NOT seen in metaphase

molecular analysis
o size of CGG amplification and the degree of methylation of the associated CpG islands

Management and outcome
no treatment for underlying disorder
degree of intellectual impairment determines extent of educational, speech & language intervention
normal life span

Friedreich Ataxia

Autosomal recessive
GAA repeat expansion in the noncoding region of the gene for the mitochondrial protein frataxin
Affects spinocerebellar tracts, dorsal columns, pyramidal tracts, cerebellum and medulla
Mutations cause oxidative injury and excessive iron deposits in mitochondria
Presentation
o Onset of ataxia sometime before age 10 (later than in ataxia-telangiectasia)
o Ataxia progresses slowly, involving LL > UL
o Positive Romberg test
o Absent DTR especially Achilles
o Extensor plantar response
o Characteristic explosive dysarthric speech
o Nystagmus in most
o Intelligence preserved, but may appear apathetic
o Weakness of distal musculature of hands and feet
o Loss of vibration and proprioception due to degeneration of posterior columns and indistinct sensory changes in distal
extremities
o Skeletal abnormalities including pes cavus (high arch), hammertoes and kyphoscoliosis
Visual, auditory brainstem and somatosensory-evoked potentions are abnormal
HOCM -> intractable congestive heart failure is the cause of death for most
Management: antioxidant therapy with coenzyme Q10 and vitamin E
Goldenhar Syndrome

Oculo-auriculo-vertebral syndrome
anomalies of 1
st
& 2
nd
branchial arch
results in OMENS
o Orbits
o Mandible
o Ear
o Facial Nerve
o Soft tissue
severe end of the hemifacial microsomia spectrum
o face: hypoplasia and microsomia (tends to be
hemifacial in 70%)
o spine: hemivertebrae (tends to be cervical > thoracic,
lumbar)
o ears: microtia with tags and pits, variable deafness
o eyes: epibulbar dermoid, antimongoloid slant of
eyes, micropthalmia

Genetics
usually sporadic
some AD, AR and multi-factorial (can present in monozygotic
twins with only one affected)
recurrence in siblings 2%

Clinical features
CNS
IQ in some (85% normal)
Arnold-Chiari malformation
agenesis of corpus callosum

facial dysmorphism
small head
facial asymmetry
70% cases unilateral (R > L) hypoplasia
malar, maxillary, mandibular
small jaw, cleft lip/palate, OSA, feeding problems
macrostomia
almost always unilateral and on affected side
+/- associated agenesis parotid gland with absent/ function
ears
external ears - mild dysmorphism to small to absent; skin tags
middle ears - narrow auditory canals
inner - conductive +/- sensorineural hearing loss
eyes
microphthalmia, colobomas, retinal problems
epibulbar dermoids or lipodermoids (in 35%) - may vision

others
limbs - talipes equinovarus (clubfeet) & bifid thumbs
spine scoliosis, fused vertebrae (short neck)
lungs hypoplasia, laryngeal anomalies
CVS VSD > PDA > TOF > CoA
kidneys VUR, multi-cystic kidneys, agenesis, others
note normal growth

Differentials to consider
CHARGE given both have ear anomalies and eye colobomas
TORCH infection given both have hearing loss and microphthalmia

Treatment
cosmetic surgery

Hemophagocytic Lymphohistiocytosis, Familial

Overview
Autosomal recessive
Histiocytes = macrophages
Aka familial erythrophagocytic lymphohistiocytosis (FEL), and viral-associated hemophagocytic syndrome (VAHS)
Aggressive and potentially life-threatening disease most often affects infants from birth to 18 months of age, but cases in older children
and adults have been reported
Similar to macrophage activation syndrome, which occurs in patients with JIA or SLE
Terminology
Primary HLH = underlying genetic disorder
Secondary HLH = occurring secondary to another condition e.g. virus, autoimmune disease, lymphoma
However genetic disease can be triggered by the above factors, and in children its hard to differentiate (in adults, its usually secondary)

Incidence: 1:50,000 live births, M=F

Associations
Infections
EBV, CMV, parvovirus, HSV, VZV, measles, HHV-8 and HIV [alone or in combination]
Can occur shorted after starting HAART
Bacterial: Brucella, gram negatives, Tb
Parasites (leishmaniasis), fungal infections
Autoimmune disorders + other
Immunodeficiency, X-linked lymphoproliferative disease, CVID, renal/liver transplant patients (may accompany EBV), Kawasaki
In adults: SLE, RA, Stills, PAN, sarcoidosis, systemic sclerosis, Sjogrens
Malignancies
Leukaemias and lymphomas
Chediak-Higashi probably responsible for the accelerated phase of this disease

Familial HLH
Up to 25% are familial
Associated with parental consanguinity
Some genes may be tested for mutations perforin, syntaxin, others

Pathophysiology
Lack of perforin-dependent cytotoxicity, which is an essential function of NK and cytotoxic T cells
Normally store perforins and granzyme proteins in lysosomes, but in HLH cannot severe immune dysregulation

Presentation
Can mimic infection, PUO or hepatitis
Can also mimic multiple organ failure, encephalitis
Most common features
Fever 91 percent
Hepatomegaly 90 percent
Splenomegaly 84 percent
Neurologic symptoms 47 percent
Rash 43 percent
Lymphadenopathy 42 percent
Can have ARDS picture with alveolar-interstitial opacities + pleural effusion
US: may show GB wall thickening, hyperechoic kidneys, ascites, hepatosplenomegaly

Sequelae
Liver failure from infiltration


Pathologic findings
Result from aggressive proliferation of normal histiocytes and T-cells in various tissues
Haemophagocytosis of RBCs, other white cells or platelets in BM is the key diagnostic finding
In up to 20%, may need multiple specimens to find this
Macrophages do not have cellular atypia that is seen in malignant histiocytes, and do not resemble Langerhans cells
Damange seen to liver, BM

Diagnostic criteria
Need at least 2 of the following
Fever
Splenomegaly
Cytopaenia in at least 2 cell lines
triglycerides and/or fibrinogen
Triglycerides after liver damage
Tissue demonstration of haemophagocytosis with LN biopsy or BMA
Additional findings:
Low-absent NK activity
Ferritin
solube CD25 > 2SD above mean

Management
Immunochemotherapy on HLH-94 protocol
Dexamethasone
Etoposide
Methotrexate
Supportive care
Infection prophylaxis e.g. cotrimoxazole (antimycotic)

Hereditary Hemorrhagic Telangiectasia

- Autosomal dominant
- Aka Osler-Weber-Rendu disease
- One involved gene encodes endoglin, a membrane glycoprotein on endothelial cells that binds transforming growth factor.
- Affected children may experience recurrent epistaxis before detection of the characteristic skin and mucous membrane lesions.
o Lesions usually develop at puberty, 14 mm, sharply demarcated red to purple macules, papules, or spider-like projections,
each composed of a tightly woven mat of tortuous telangiectatic vessels.
o Nasal mucosa, lips, and tongue are usually involved; less commonly, cutaneous lesions occur on the face, ears, palms, and
nail beds. Vascular ectasias may also arise in the conjunctivae, larynx, pharynx, gastrointestinal tract, bladder, vagina,
bronchi, brain, and liver.
- Massive hemorrhage is the most serious complication and may result in severe anemia.
- Bleeding may occur from the nose, mouth, gastrointestinal tract, genitourinary tract, and lungs; epistaxis is often the only complaint,
however, occurring in 80% of patients.
- Approximately 1520% of patients with arteriovenous malformations in the lungs present with stroke due to embolic abscesses.
- Persons with hereditary hemorrhagic telangiectasia have normal levels of clotting factors and an intact clotting mechanism. In
the absence of serious complications, life span is normal.
- Local lesions may be ablated temporarily with chemical cautery or electrocoagulation. More drastic surgical measures may be
required for lesions in critical sites such as the lung or gastrointestinal tract. Anemia should be treated with iron.


Hirschsprung Disease Overview

- Congenital Aganglionic Megacolon (Hirschsprung Disease)
- Abnormal innervation of bowel beginning in internal anal sphincter and extending
proximally to variable length of gut
- Most common cause of lower intestinal obstruction in neonates
- Incidence 1:5,000 births
- M>F 4:1
- familial incidence in long segmen disease
- Associations: Down syndrome, Smith-Lemli-Optiz, Waardenburn, Ondine curse
- Also assoc. with microcephaly, MR, abnormal facies, autism, cleft palate

Pathology + Genetics
- Absent gangion cells due to arrest of neuroblast migration from proximal to distal
bowel
- Usually sporadic
- Dominant and recessive forms exist
- Limited to rectosigmoid in 75%, entire colon involved in 10%
- Total bowel agangionosis is rare
- Histologically
o Absence of Meissner and Auerbach plexus
o Hypertrophied nerve bundles with acetylcholinesterase between muscle layers and in the submucosa

Presentation
- In neonates: delayed meconium passage
o Leads to dilated proximal bowel and abdominal distension intraluminal pressure blood flow and deterioration of
mucosal barrier
o Stasis bacterial proliferation which can enterocolitis (C. difficile, S. aureus, anaerobes, coliforms), sepsis
o Bowel obstruction
o DDx: meconium plug syndrome, meconium ileus, intestinal atresia
- In children
o Chronic constipation
o Increasingly difficult to pass stools, which consist of small pellets, ribbon-like or fluid consistency [whereas in patients with
functional constipation, stools are large & there is faecal soiling
o DDx: Currarino triad [anorectal malformations- ectopic, anus, rectal stenosis; sacral bone anomalies- hypoplasia, poor
segmentation; or presacral masses- anterior meningoceles, teratoma, cysts]
- FTT, hypoproteinaemia from protein-losing enteropathy less common because it is usually diagnosed
- Worse in formula fed infants

Examination
- Normal rectal examination, normal tone
- May precipitate an explosive discharge of foul smelling faeces and gas

Diagnosis
- Rectal manometry and suction cup biopsy
- Perform biopsy no closer than 2cm to dentate line to avoid normal hypogangionosis which occurs on the anal verge
- Specimen stained for acetylcholinesterase stains positively in the hypertrophied nerve bundles of patients
- Absent ganglion cells on biopsy
- Imaging: transition zeon between normal dilated proximal colon and smaller calibre distal colon due to nonrelaxation of aganglionic
bowel
o Cant see this until 1-2 weeks age
o Funnel shaped intestine
o Can do a 24h delayed film
o Barium enema is useful to determine extent of aganglionosis before surgery

Management
- Surgery with full thickness biopsy in OT
- Can do a temporary colostomy first until 6-12 mo age
- 3 surgical options
o Excise abnormal segment, anastomose proximal bowel with rectum 1-2cm above dentate line
o Neorectum with normal bowel behind aganglionic rectum
o Endoretal pull-through- mucosa stripped from aganglionic rectum, normall innervated colon pulled through residual
muscular cuff can be done laparoscopically
- Ultrashort segment disease dysfunction limited to internal sphincter, presents similar to functional constipation
o Excise strip of rectal muscle

Holt-Oram Syndrome

1. Upper limb malformations involving radial, thenar, or carpal bones [abnormal carpal bone is in all
affected individuals and may be the only sign]
2. 75% have congenital heart disease others may have family history
1. Ostium secundum atrial septal defect (ASD
2. Ventricular septal defect (VSD), especially those occurring in the muscular trabeculated
septum
3. Cardiac conduction disease

Genetics
Autosomal dominant, variable expressivity
85% de novo
Muation in TBX5
Prenatal US may show upper limb malformations or CHD

Clinical features
Cardiac - Most common is ASD secundum (creates single ventricle)
Can also have VSD/ PDA/ PS
Skeletal problems
o upper limb defects (that can extend to the shoulder)
o thumb - absent, hypoplastic or triphalangeal
o radius - absent or hypoplastic
o other bones can be hypoplastic - ulnar, humerus, scapula, clavicle
o syndactyly between 1
st
and 2
nd
fingers
o sloping shoulders common
o absent pecs
o vertebral anomalies can occur

note on absent/hypoplastic radii
a/w 4 entities
TAR (thrombocytopaenic absent radii syndrome) 100% have CMP insensitivity
VACTERL
Fanconis anaemia
Holt Oram syndrome

Huntington Disease

- Autosomal dominant
- Trinucleotide repeat (CAG) on chromosome 4p16.3, resulting in mutations in the huntingtin protein
- Huntingtin forms abnormal inclusions in nuclei of neurons, leading to sequestration or reduction of proteins required to transcribe
other genes
- Symptom onset usually between 35-55 years, <1% in children <10 years
- Present with rigidity, dystonia, seizures
- Behavioural problems prominent in children
- Seizures: GTC common and often refractor to anticonvulsants
- 50% have cerebellar signs
- 20% have oculomotor apraxia
- In children:
o More rapid disease course
o Average time to death = 8 years
-

CT scanning, although nondiagnostic, shows the mean bifrontal : bicaudate ratio to be decreased, indicating atrophy of the caudate nucleus and
putamen. MRI shows hyperdensity of the putamen in adults with the akinetic-rigid form. There is no specific therapy for Huntington disease, but
once the diagnosis is confirmed, the pediatrician should provide genetic counseling to the family so that risks for additional cases in future
generations are understood. Molecular biologic testing (CAG trinucleotide repeat) is available but is inappropriate for children under the age of
consent. Presymptomatic adult patients who test positive respond similarly to patients with cancer when the diagnosis is confirmed.

Other causes of chorea include atypical seizures, drug intoxication (phenytoin, amitriptyline, and fluphenazine) hormonally induced seizures
(oral contraceptives, pregnancy/chorea gravidarum), Lyme disease, hypoparathyroidism, hyperthyroidism, and Wilson disease (see Chapter
354.2 ).
- DNA diagnostic test
- N also be used for presymptomatic diagnosis of family members
- Triplet repeat disorder
- Affected individuals usually have over 40 repeats
- <26 normal
- 27-36 will NOT develop HD but offspring at some risk
- 36-39 may develop HD, some will not
- 40+ predicts HD
- higher repeats = lower age of onset

- Autosomal dominant, caused by CAG expansion in the HD gene
- Normally a late-onset condition, characterised by progressive neurologic deterioration
- Caused in part by a gain-of-function mutation
- Also affected by amplification
- Juvenile HD: presents before age 20
o 10% of patients
o Clinical features: myoclonus, seizures, behavioural problems, parkinsonism

Hypophosphatasia
early loss of deciduous teth, late fontanelle closure, bowlegs, normal Vit D studies ?
( ALP, +/- Ca, normal/ PO4 -only disorder to cause both Ca/ PO
4
)
Hypophosphatasia

Incontinentia Pigmenti

Jervell and Lange-Nielsen Syndrome

Joubert Syndrome and Related Disorders

Juvenile Polyposis Syndrome

Kallmann Syndrome

abnormal development of the olfactory lobe
XLR
mutation of the KAL gene likely important in neuronal migration

Clinical
anosmia
hypogonadotropic hypogonadism
(neurons that secrete GnRH migrate from olfactory placode to hypothalamus)
cleft palate
congenital deafness
colour blindness
renal agenesis

Investigations
FSH/ LH
delayed bone age

Treatment
hormonal therapy for puberty

Kartageners Syndrome
When syndrome is characteized by situs inversus, sinusitis, bronchiectasis ?

Kasserback Merick syndrome,

Rapidly growing haemangioma resulting in a consumptive coagulopathy.
aetiology unknown

Klippel-Feil
short stature
fused cervical vertebrae short neck with low hair line
limited mvmt of head (most common finding)
Type I massive fusion cervical spine
Type II fusion of 1 or 2 vertebrae
Type III additional thoracic and lumbar spine abnormalities
other features: hearing loss (conductive +/- sensorineural)
30% cardiac defect (mostly VSD)
30% renal malformation
torticollis
spinal complications (spinal canal stenosis, craniocervical junction instability)
scoliosis (60%)
omovertebral bone - tethers scapula to the spine - ossifies with age further limits ROM
synkinesia mirror movement of an upper extremity with the opposite hand (improves with age)









Klippel-Trenauney-Weber


Background
angiogenesis resulting in extensive port wine stains with underlying venous and/or lymphatic malformations of the extremity
mutation in the gene for an angiogenic factor (expressed in blood vessels)

Triad of
cutaneous vascular malformation (port wine)
o generally localised
o associated with underlying soft tissue swelling and bony hypertrophy

bony and soft tissue hemihypertrophy
o lower limb in 95%
o upper limb in 5%
o both limbs in 15%
o majority are unilateral

venous varicosities

Langer-Gideon Syndrome


tricho-rhino-phalangeal syndrome type 2
multiple exostoses
bulbous nose
micrognathia
peculiar face
ID

Genetics
TRPS type II
o sporadic
o deletion in region of 8q - the larger the deletion the higher risk of ID

TRPS type I
o AD
o similar features = bulbous nose, long philtre, sparse hair, cone-shaped epiphyses, mild growth retardation
o difference = lack of multiple exostoses & redundant skin

Features
face: bulbous nose, large protruding ears, recessed mandible
hair: sparse wispy hair
skin: loose redundant skin as an infant
bone: multiple exostoses on long bones as well as ribs, pelvic bones, scapulae - can lead to impairment of growth
scoliosis
brittle nails/ syndactyly
intellectual impairment in all - moderate to severe in 70%
recurrent infections - some develop CLD
dentition
cardiac defects





Langerhans histiocytosis

Classification of the Childhood Histiocytoses
CLASS DISEASE CELLULAR CHARACTERISTICS OF LESIONS TREATMENT
I Langerhans'cell histiocytosis Langerhans'cells (CD1a-positive) with Birbeck
granules
Local therapy for isolated lesions;
chemotherapy for disseminated disease
II Familial erythrophagocytic
lymphohistiocytosis
[*]

Morphologically normal reactive macrophages with
prominent erythrophagocytosis
Chemotherapy;allogeneic bone marrow
transplantation
Infection-associated
hemophagocytic syndrome
[]


III Malignant histiocytosis Neoplastic proliferation of cells with characteristics of
monocytes/macrophages or their precursors
Antineoplastic chemotherapy, including
anthracyclines
Acute monocytic leukemia

Overview
- Normal Langerhans cell is an APC of the skin
- Hallmark of LCH is the presence of a clonal proliferation of cells of the monocyte lineage containing the characteristic electron
microscopic findings of a Langerhans' cell. This is the Birbeck granule, a tennis racketshaped bilamellar granule that, when seen in
the cytoplasm of lesional cells in LCH, is diagnostic of the disease.
- The Birbeck granule expresses a newly characterized antigen, langerin (CD207), which is involved in antigen presentation to T
lymphocytes.


Laurence-Moon Syndrome
rare AR
genetic defect metabolic error failure of embryologic development
progressive CNS
eye
endocrine manifestations
= deteriorating handicapping condition

Clinical
present in childhood
intellectual disability
ataxia progressive loss of ambulation spastic quadriplegia by early adulthood
visual impairment - retinitis pigmentosa progressive optic atrophy & blindness
medullary cystic disease of the kidney
endocrinopathy - obesity
hypogonadotrophic hypogonadism
LEOPARD Syndrome

Lentiginous skin lesions (melanotic lesion unrelated to sun-exposure)
o often face, neck, upper trunk
o also soles, palms and sclerae
ECG abnormality - PR interval, LAD
Ocular hypertelorism
Pulmonary stenosis
Abnormal genitalia
o hypospadius/ cryptorchidism
Retarded growth
o after birth (most normal birth weight)
Deafness sensorineural


Barry is a 10 year old boy who presents to cardiology clinic with newly diagnosed pulmonary stenosis. You notice on his ECG there is a
prolonged PR interval with left axis deviation. His only past history is hypospadius repair at the age of 2yo.

Li-Fraumeni Syndrome

Loeys-Dietz Syndrome

Lowe Syndrome
hypotonia, cataracts, renal tubular dysfunction ?
Lowe syndrome (oculocerebrorenal)
















Madeline Albright
Skin lesions
o Dont cross the midline
o Hyperpigmented lesions
o Endocrine eg precocious puberty

Mafucci
hemangioma, cartilage abnromalities ?

Mafucci


McCune Albright Syndrome
fibrous dysplasia, precocious puberty, cafe-au-lait spots ?



Malignant Hyperthermia Susceptibility

Marfan Syndrome



Genetics and Pathophys
Autosomal dominant
Mutation in gene coding for extracellular matrix (ECM) protein Fibrillin-1 connective tissue issues
o ?deranged elastic fiber deposition and elastic fiber fragmentation
o ?cytokine regulatory role for Fibrillin-1
o ?TGF-beta signalling
30% cases are sporadic (with minimal recurrence rate for future pregnancies)
Paternal age effect (link to older fathers)
Near-complete penetrance but variable expression
1:5000 1:10 000

Features

Skeletal
Long bone overgrowth
o arm span > 1.05 height
o UL:LL
o arachnodactyly
Chest deformity* (d/t rib overgrowth)
o pectus carinatum/ excavatum
Scoliosis
Protrusio acetabuli
o Inward bulging of the acetabulum into the pelvic cavity
Pes planus (flat feet)
Craniofacial
o Dolichocephaly (long narrow skull)
o Enophthalmos (Recession of the eyeball into the socket)
o Retrognathia, macrognathia
o Malar flattening
o Downward slanting of palpebral fissures
Ligamentous laxity
o Exception - elbow extension
o Wrist sign*
Full overlap of the distal phalanges of the thumb and 5
th
finger when wrapped around the contralateral wrist
o Thumb sign*
Distal phalynx of the thumb fully extends beyond the ulnar border of the hand when folded across the palm

CVS
AV valves
o Thickened AV valves +/- prolapse +/- regurgitation
o (MV insufficicency leading cause of Marfan death in infancy)
Aortic root dilatation*
o aneurysm, dissection
o (most life threatening Marfan complications)
o Eventually get aortic valve insufficiency from aortic annulus dilation
Other vasculopathy
o Coronary artery dilation/ dissection
o Cerebral artery dilation/ dissection
Dilated cardiomyopathy (beyond that just d/t valve issues)
Arhythmias
o Ventricular dysrhythmias
o SVTs d/t MV dysfunction
o Prolonged QT
Eyes
Ectopia Lentis*
o Dislocation of the ocular lens
o 60-70% of Marfans
o Differentials
Homocysteinuria, familial ectopia lentis
Myopia, flat cornea, hypoplastic iris
risk retinal detachment, cataracts glaucoma
Others
Lungs
o restrictive lung disease d/t scoliois, pectus
o distal air space widening bullae/blebs spontaneous pneumothorax
Skin
o stria atrophicae (in 2/3) (but minimal other skin findings vs other connective tissue disorders)
o Inguinal hernia
Dural ectasia
o Widening of the dural root sleeves or dural sac lumbar back pain


Table 693-1 -- Diagnostic Criteria for Marfan Syndrome (MFS)
In the absence of a family history of MFS, a diagnosis can be reached in 1 of 4 scenarios:
1 Aortic diameter at Sinuses of Valsalva Z-score 2 AND Ectopia Lentis = MFS*
2 Aortic diameter at Sinuses of Valsalva Z-score 2 AND FBN1 mutation = MFS
3 Aortic diameter at Sinuses of Valsalva Z-score 2 AND Systemic Score 7 = MFS*
4 Ectopia Lentis AND FBN1 mutation known to associate with aortic aneurysm = MFS

In the absence of a family history of MFS, alternative diagnoses to MFS include:

1 Ectopia Lentis Systemic Score AND FBN1 mutation not known to associate with aortic aneurysm or no FBN1 mutation = Ectopia
Lentis syndrome

2 Aortic diameter at Sinuses of Valsalva Z-score <2 AND Systemic Score 5 (with at least one skeletal feature) without Ectopia Lentis
= MASS phenotype

3 Mitral Valve Prolapse AND Aortic diameter at Sinuses of Valsalva Z-score <2 AND Systemic Score <5 without Ectopia Lentis = Mitral
Valve Prolapse syndrome

In the presence of a family history of MFS, a diagnosis can be reached in 1 of 3 scenarios:
1 Ectopia Lentis AND Family History of MFS = MFS
2 Systemic Score 7 AND Family History of MFS = MFS*
3 Aortic diameter at Sinuses of Valsalva Z-score 2 if older than 20 yr or 3 if younger than 20 yr AND Family History of MFS = MFS*

SCORING OF SYSTEMIC FEATURES (IN POINTS)
[]

Wrist AND thumb sign = 3 (wrist OR thumb sign = 1)
Pectus carinatum deformity = 2 (pectus excavatum or chest asymmetry = 1)
Hindfoot deformity = 2 (plain pes planus = 1)
Pneumothorax = 2
Dural ectasia = 2
Protrusio acetabuli = 2
Reduced US/LS AND increased arm/height AND no severe scoliosis = 1
Scoliosis or thoracolumbar kyphosis = 1
Reduced elbow extension = 1
Facial features (3/5) = 1 (dolichocephaly, enophthalmos, downslanting palpebral fissures, malar hypoplasia, retrognathia)
Skin striae = 1
Myopia >3 diopters = 1
Mitral valve prolapse (all types) = 1

CRITERIA FOR CAUSAL FBN1 MUTATION
Mutation previously shown to segregate in a Marfan family

Any one of the following de novo mutations (with proven paternity and absence of disease in parents):
Nonsense mutation
In-frame and out-of-frame deletion/insertion
Splice site mutations affecting canonical splice sequence or shown to alter splicing on mRNA/cDNA level
Missense mutation affecting/creating cysteine residues

Missense mutation affecting conserved residues of the EGF consensus sequence [(D/N)X(D/N)(E/Q)Xm(D/N)Xn(Y/F),
with m and n representing variable number of residues; D, aspartic acid; N, asparagine; E, glutamic acid; Q, glutamine; Y,
tyrosine; F, phenylalanine]

Other missense mutations: segregation in family, if possible, + absence in 400 ethnically matched control chromosomes;
if no family history, absence in 400 ethnically matched control chromosomes

Linkage of haplotype for n6 meioses to the FBN1 locus


Differentials
Homocysteinuria
o Similar
Mitral Valve Prolapse
Ectopia Lentis
Tall stature, long bone overgrowth
o Different
Intravascular thrombosis
Mental retardation
MASS phenotype
o Mitral valve prolapse
o Aortic dilatation
o Skin findings
Striae
o Skeletal findings
Rib cage deformity
Long limbs
Ehlers Danlos IV
o Mitral Valve Prolapse
o Medium to large vessel dilation and rupture (but not aorta)
o Joint hypermobility
o Different
Translucent skin
Easy bruising
Hernias
Rupture of hollow organs
Atrophic scars
Familial Ectopia Lentis
Loeys Dietz syndrome
o artery dilation and dissection
o thoracic cage deformities, joint laxity
o no ectopia lentis, no long bone overgrowth
o hyperteloric

Investigations
Exclude homocysteinuria
o Urinary cyanide nitroprusside test
o Plasma amino acids
FBN1 mutation
o Positive > 95% Marfans
o Not specific for Marfans occurs in other connective tissue disorders as well

Management
aortic dilatation risk
o moderate physical activity to improve neuromuscular tone (but avoid strenuous activity)
o Aortic root surgery
Diameter >50mm, or growth >5-10/year
o haemodynamic stress to aorta
beta blockers
or ACE i/ ca channel blockers
o Ang II blockers
Role in haemodynamic stress
Also role in TGF beta signaling?

OTHER CONNECTIVE TISSUE DISORDERS



Milroy Disease

Mobius Syndrome
Congenital - genetics unknown
Congenital facial paresis (CN IV and VII hypoplasia) usually bilateral but asymmetrical with weakness of eye abduction. Tends to spare
the lower face. Can also involve IX, X, XII cranial nerves)
Associated with absent hands, feet, toes, extra fingers, pectoral muscle weakness, palatal weakness, micrognathia.
Problems swallowing and feeding
http://www.moebiussyndrome.com/videos/MoebiusEduc1.mpg


hypoxic insult to structures supplied by developing subclavian artery
hypoplasia of the brainstem nuclei esp CN 6 & 7
unilateral or bilateral mask like facies + cross-eyed
sporadic - 2 genetic loci have been mapped (13q, 3q)
associations
o Poland anomaly - absence of the pectoralis major muscle and limb abnormalities
o in utero exposure to misoprostol (synthetic prostaglandin E1 analogue)
gastric antisecretory agent that is used to protect against NSAID induced gastric ulcers
used to improve fat absorption in children with CF

Clinical features
typically
o CN7 - facial diplegia and absence of facial expression (giving a false impression of mental
retardation)
o CN 6 (75%) bilateral lateral gaze palsy
o CN12 (25%) tongue atrophy & weakness
o CN 9, 10 - dysphagia may be present if CN9 is involved

other variably present manifestations include
o intellectual disability (15%)
o limbs - peripheral neuropathy, arthrogryposis, limb deficiencies, flexion finger contractures
o hypogonadotropic hypogonadism
o Klippel-Feil anomaly
o ocular ptosis

Investigations
no diagnostic laboratory tools
consider MRI bilateral calcifications of CN 6 nuclei, brainstem hypoplastic
consider EMG

Treatment
strabismus
indications for strabismus surgery include:
strabismus in the primary position of gaze (straight ahead)
abnormal head posture
significant upshoot or downshoot of the eye in adduction
in addition, those patients with involvement of the facial nerve require observation for and treatment
of corneal exposure.
speech therapy
physical therapy

Muenke Syndrome

Multiple Endocrine Neoplasia Type 1

Multiple Endocrine Neoplasia Type 2

Myotonic Dystrophy

Nephrogenic Diabetes Insipidus

Neurofibromatosis 1

Neurofibromatosis
Autosomal dominant

Tumours to grow on nerves & result in other abnormalities such as skin changes and bone deformities

Clinical Manifestations and Diagnosis

NF-1
Incidence: 1/3000

Diagnosed when any 2 of the following 7 features are present:
1. 6 or more caf-au-lait macules over 5 mm in diameter in prepubertal individuals & >15mm in postpubertal
2. axillary or inguinal freckling consisting of multiple hyperpigmented areas 2-3mm in diameter
a. usu appears bw 3-5yo
b. >80% by 6 yrs
3. 2 or more iris Lisch nodules
= hamartomas located within the iris
4. 2 or more neurofibromas or 1 plexiform neurofibroma
a. typically involve the skin but they may be situated along peripheral nerves & blood vessels &
within viscera including the GI tract
b. typically appear during adoescence or pregnancy, suggesting a hormonal influence
c. usu small, rubbery lesions with a sligh purplish discoloration of the overlying skin
d. plexiform neurofibromas
i. usu evident at birth
ii. result from diffuse thickening of nerve trunks that are frequently located in the orbital or temporal region of the
face
iii. skin may be hyperpigmented to a greater degree than a caf au lait spot
iv. may produce overgrowth of an extremity ^ a deformity of the corresponding bone
5. distinctive osseous lesion such as sphenoid dysplasa (may cause pulsating exophthalmos) or cortical thinning of long bones (e.g.
tibia) with or without pseudoarthritis
6. Optic gliomas (15%)
a. Mostly low grade astrocytomas
b. Therefore recommended all children aged 10yrs or younger with NF1 must undergo annual ophthalmologic
examinations
c. When they progress, visual symptoms are produced because tumors enlarge & put
pressure on the optic nerves & chiasm impaired visual acuity & visual fields
d. Extension into hypothalamus can lead to endocrine deficiencies or FTT
e. MRI: diffuse thickening, localized enlargement or a distinct focal mass originating from the
optic nerve or chiasm
7. A first degree relative with NF1 whose diagnosis was based on the aforementioned criteria
Neurologic complications
Abnormal hyperintense T2 weighted signals in the optic tracts, brainstem, globus pallidus,
thalamus, internal capsule and cerebellum = unidentified bright objects
o Tend to disappear with age, most disappeared by 30yo
o Unclear what they represent pathologically
o ?related to learning disabilities, attention deficit disorders, behavioural and psychosocial problems & abnormalities of
speech
LEARNING DISABILITY
o 30%
Seizures
o 8%
cerebral aneurysms
cerebral vessel stenosis moya moya disease
o TIA, hemiparesis & cognitive defects
precocious pubery may be evidenct in the presence or absence of lesions of the optic chiasm & hypothalamus
Malignant neoplasma (#%)
o Neurofibroma occasionally differentitates into a malignant peripheral nerve sheath tumour (MPNST)
o Pheochromocytoma, rhabdomyosarcoma, leukemia and Wilms tumour
Scoliosis (10%)
Hypertension
o Resulting from renal vascular stenosis or a phaeochromocytoma

Optic gliomas in 15%
MRI: diffuse thickening, localized enlargement or a distinct focal mass originating from the optic nerve or chiasm

Neurofibromatosis 2

Bilateral or unilateral vestibular schwannoma
Meningioma
Schwannoma
Glioma
Neurofibroma
posterior subcapsular lenticular opacities


Incidence: 1/25 000

Diagnosed when 1 of the following 4 features is present:
1. Bilateral vestibular schwannomas
2. Parent, sibling or child with NF-2 and either unilateral vestibular schwannoma or any 2 of the following: meningioma, schwannoma,
glioma, neurofibroma, posterior subcapsular lenticular opacities
3. Unilateral vestibular schwannoma and any 2 of the following: meningioma, schwannoma, flioma, neurofibroma or posterior
subcapsular lenticular opacities
4. Multiple meningiomas (2 or more) & unilateral vestibular schwannoma or any 2 of the following: schwannoma, glioma, neurofibroma,
or cataract

Symptoms of tinnitus, hearing loss, facial weakness, headache or unsteadiness may appear during childhood

Signs of cerebellopontine anglemass are more commonly present in the 2
nd
or 3
rd
decades of life

Caf au lait spots and skin neurofibromas are much less common

Posterior subcapsular lens opacities are identified in about 50%

NF2 gene is on 22q1.11

Management:

Multidiciplinary follow up

Yearly ophthalmologic examination
Neurological assessment
Blood pressure monitoring
Scoliosis
Neuropsychologic and educational testing
NIH consensus & developmental conference: advised against routine imaging studies of the brain & optic tracts because treatment in
asymptomative NF1 children rarely required
All symptomatic cases (visual disturbance, proptosis or icreased intracranial pressure) must be studied without delay

Table 589-1 -- FREQUENCY OF LESIONS ASSOCIATED WITH NEUROFIBROMATOSIS TYPE 2
FREQUENCY OF ASSOCIATION WITH NF2
NEUROLOGIC LESIONS
Bilateral vestibular schwannomas 90-95%
Other cranial nerve schwannomas 24-51%
Intracranial meningiomas 45-58%
Spinal tumors 63-90%
Extramedullary 55-90%
Intramedullary 18-53%
Peripheral neuropathy Up to 66%
OPHTHALMOLOGIC LESIONS
Cataracts 60-81%
Epiretinal membranes 12-40%
Retinal hamartomas 6-22%
CUTANEOUS LESIONS
Skin tumors 59-68%
Skin plaques 41-48%
Subcutaneous tumors 43-48%
Intradermal tumors Rare
From Asthagiri AR, Parry DM, Butman JA, et al: Neurofibromatosis type 2, Lancet 373:19741984, 2009, Table 1.)

Neuronal Ceroid-Lipofuscinoses

Nevoid Basal Cell Carcinoma Syndrome

Niemann-Pick Disease Type C

Noonan Syndrome


similar to Turner but normal karyotype
main differences are:
o characteristic face
o mental retardation more common
o cardiac lesions are right sided
o puberty is not as delayed
o haematological disease
o normal karyotype
o =

Genetics
1:2000 births
AD with variable expression sporadic
Chr 12q22 (NOONan = 12
th
chromosome)

Clinically
Similar to Turner (short stature, webbed neck, broad chest with pectus abnormalities and wide-spaced nipples, cubitus valgus, posterior hairline,
hand and feet dorsal oedema) but:
characteristic face:
o hypertelorism
o epicanthus
o micrognathia
o ear abnormalities
moderate mental retardation occurs in 25% (Turner tends to be normal)
right sided heart lesions rather then coarctation
o PS most common (thick and dysplastic valves) a/w LAD
o HOCM/ cardiomyopathy
o ASD
hepatosplenomegaly (25%)
cryptorchidism
haematological disease
o factor XI and XII
o ALL
o CML
skin
o lentigines - crossover with NF-1 (?involvement of chr 17q)

NB. crossover with LEOPARD syndrome
Lentigenes
ECG abnormalities - PR interval, LAD
Ocular hypertelorism
PS
Abnormal genitalia
Retardation of growth
Deafness

Treatment
hGH
o similar outcome to Turner
puberty
o usually delayed about 2 years consider sex steroids

webbing of neck, pulmonic stenosis, cryptorchidism, pectus excavatum


- 1:1000 2500 births
- 20% of cases are familial with AD inheritance
- M = F
- 50% due to missense mutations in PTPN11 on 12q24.1
- Presentation
o Short stature, webbed neck, pectus carinatum or excavatum, cubitus valgus
o R sided congenital heart disease
o Characteristic facies: hypertelorism, epicanthus, downslanting palpebral fissures, ptosis, micrognathia, ear abnormalities
o Clinodactyly, hernias, vertebral anomalies less frequent
o Mean IQ 86
o Sensorineural hearing loss is common
o Cardiac defect
Often pulmonary valve stenosis, hypertrophic cardiomyopathy or ASD
o Hepatosplenomegaly, haematologic disease
o Cryptorchidism, small testes, impaired spermatogenesis
o Delayed puberty

Oculocutaneous Albinism Type 1

Oculocutaneous Albinism Type 2

Oculocutaneous Albinism Type 4

Osler-Weber-Rendu



Weber-Osler-Rendu: nosebleeds, telangiectasias and AV fistulae

Osteogenesis Imperfecta

Caused by structural or quantitative defects in Type I collagen.

AD, Incidence in infancy is 1 in 20,000

Clincal:
Triad of fragile bones, blue sclera, early deafness.
OI Type I:
o Mild
o Found in large pedigrees.
o Easy bruising, joint laxity, mild short stature
o Fractures decrease after puberty
OI Type II
o Perinatal Lethal
o SGA
o Extreme fragility of the skeleton
o Large skull, enlarged anterior and posterior fontanelles
OI Type III
o Progressive deforming
o Relative macrocephaly
o Triangular facies
o Fracture with minor trauma and heal with deformity
o Growth failure
OI Type IV
o Hyperplastic callus

Diagnosis:
Confirmed by collagen biochemical studies using fibroblast culture.
Genetic testing for the mutations

Complications
Recurrent pneumonias
Cardiac failure
CNS:
o Basilar invagination (esp Types III and IV)
o Brainstem compression
o Hydrocephalus
o Syringohydromyelia

Treatment
Physiotherapy and orthopaedic involvement
Bisphosphonates improve mobility and decrease symptoms in many patients
Calcium, Calcitonin, Fluoride do NOT improve OI

Osteopetrosis

Osteopetrosis dense thick bones, secondary pancytopenia and cranial nerve compression ?

Pallister-Hall Syndrome

Pallister-Killian Syndrome

This disorder is characterized by coarse facies, pigmentary skin anomalies, localized alopecia,
diaphragmatic hernias, cardiovascular anomalies, supernumerary nipples, and profound mental
retardation. The syndrome is due to mosaicism for isochromosome 12p. The presence of the
isochromosome 12p in cells gives four copies of 12p in the affected cells. The isochromosome
12p is preferentially cultured from fibroblasts and is seldom present in lymphocytes. The abnormalities
seen in affected individuals probably reflect the presence of abnormal cells during early
embryogenesis.


Pendred Syndrome/DFNB4

Peutz-Jeghers Syndrome

PHACES Syndrome


large segmental facial haemangioma a/w a number of underlying congenital malformations
(most commonly structural or cerebrovascular anomalies of the brain)
spectrum of disease (few infants manifest all signs)
structural anomalies suggests an insult that occurs to the developing fetus between 3-12 weeks of
gestation

P Posterior fossa
malformation (>50%)
Dandy-Walker malformations most common
o absent/hypoplastic cerebellar vermis + markedly dilated
4
th
ventricle (referred to as a posterior fossa cyst)
o can cause hydrocephalus + head circumference
others
o agenesis of corpus callosum, cerebellar atrophy,
arachnoid cysts
H Haemangiomas large facial haemangioma
involves several facial dermatomes
may be mistaken for port-wine stain of Sturge Weber syndrome
difference is that a port-wine stain is a vascular malformation
that does NOT proliferate/regress in infancy
A Arterial anomalies cerebrovascular anomalies
o can cause progressive arterial occlusion, stroke & other
neurologic complications
C Cardiac anomalies coarctation of the aorta
PAPVR
tricuspid & aortic atresia
PDA
VSD
E Eye abnormalities
(33%)
optic nerve atrophy
exophthalmos
colobomas
strabismus
congenital cataracts
congential glaucoma (rare)
S Sternal cleft or
supraumbilical raphe
sternal cleft
o from sternal pit (without underlying bony deformity)
o to separation of sternal bars
supraumbilical raphe
o resembles a well-healed scar
o extending several centimetres above the umbilicus
Pierre-Robin Sequence

o sporadic syndrome with micrognathia and high or
cleft palate

clinical
o micrognathia with mandibular hypoplasia
o cleft palate (U > V shape)
o abnormal anchoring of the tongue so that there is
pseudomacroglossia (the tongue is actually
normal size)
pseudoglossoptosis (tongue flops back in
pharynx)
+/- airway obstruction

management
o persistent airway obstruction 2 to tongue can be
managed with nasopharyngeal airway
o 30% of kids require tracheostomy
o usually able to feed but sometimes require gavage
(for swallowing difficulties)

outcome
o often the mandible will regain normal growth at age 4 - 6 years
o normal IQ
o normal life span

associations
o Stickler Syndrome
in 30%
AD
early arthritis and ocular abnormalities

Pierre Robin Sequence is the combination of micrognathia, cleft palate and glossoptosis. It can be associated with a syndrome, but in 20% of
cases is isolated. There are multiple possible causes, therefore it does not by itself constitute a syndrome (which can only have one cause).



Main features
- Incidence of 1:8500
- Main issues are airway obstruction and feeding difficulty
- Larynx is under the base of the tongue, making laryngoscopy or intubation difficult
- If its isolated Pierre Robin sequence, the mandible may reach normal size within a couple of years
- If associated with a known syndrome e.g. Treacher Collins or Stickler syndrome, mandibular hypoplasia will persist throughout life
unless surgical intervention is performed
- The associated cleft is U-shaped, unlike V shaped clefts in primary defects
o Thought to be due to the posteriorly displaced tongue preventing the palatal shelves from closing

Polands Syndrome

1/30,000 live births
>
cause unknown ? blood flow via subclavian artery (similar to Klippel-Feil, Moebius)

Clinical
unilateral aplasia/hypoplasia of the sternocostal portion of pectoralis major
hand abnormality syndactyly, brachydactyly, oligodactyly
+/- associated rib defects
associations Moebius syndrome (agenesis of BS nuclei usually unilateral/bilateral CN7 involvement)
dextrocardia (in L sided Poland)

Management
repair is undertaken for children with severe chest wall abnormalities, including rib aplasia

Prader-Willi Syndrome

Prader-Willi syndrome
o paternal copy of chr15q11 is missing
o can occur in 2 ways:
70 % have a microdeletion on chr 15 (long arm = q)
deletion is of the paternally derived chromosone
detectable by FISH using specific probes
30% have maternal disomy (ie 2 maternal copies and no paternal
copies)
maternal copy is imprinted ("turned off")
specific DNA testing is needed to detect in this case

Most common syndromic form of obesity
= absent expression of paternally active genes on long arm chr 15
- deletion
- maternal disomy

Features:
- hyperphagia
- early onset obesity
- hypogonadism
- devel delay
- facial features
- infants: hypotonia, feeding difficulties

1: 16000 25000

Genetics:
- genomic imprinting
- 15q11.2-13 loss paternal copy
-
- majority sporadic
- 70% are 15q11.2-13 del
- 28% maternal uniparental disomy
- <1% mutation in imprinting center
- our and psychosis
- recurrence risk:
o 50% if imprinting control mutation
o 25% if parental translocation
- testing with methylation analysis

Clinical features:
- prenatal
o reduced fetal activity
- infancy:
o neonatal hypotonia
o feeding problems
o poor suck
o FTT
o Weak cry
o Genital hypoplasia
o Depigmentation skin or eyes
- Early childhood:
o Lack acquire major motor milestones
o
o Short stature from GH deficiency
- Late childhood/adolescence:
o pubic/axillary hair early
o Delayed secondary sexual characteristics
o Delayed menarche up to 30 years
o Sleep apnoea, cor pulmonale, diabetes, atherosclerosis
o
- Behavioural problems:
o Learning difficulties
o Tantrums, stubborn, OCD
o Similar to autism
o Skin picking
o Rectal gouging
o
o Mild-mod cognitive impairment
o Food seeking behaviour:
Eating garbage
Stealing food
Bingeing
Levels of GI peptides elevated, e.g. ghrelin

Diagnosis:
- clinical
- genetic
o karyotype and methylation studies
o FISH
o microsatellite probes for maternal uniparental disomy

Comorbidities:
- hypothalamic/pituitary dysfunction
o short stature
o central obesity
o hypogonadism
o osteoporosis
- growth hormone deficiency
o measure IGF-1 and IGFBP3
- hypogonadism:
o low LH and high FSH
o most patients are sterild
o 2/3 boys cryptorchidism
o may need HCG or sex steroid treatment
- Osteoporosis:
o DEXA bone density
o May need sex hormone or growth hormone
o Check vit D, Ca, thyroid
- Thyroid: hypo
- Obeseity related problems:
o Type 2 DM: need OGTT
o Sleep apnoea
70% SDB
snoring, pauses, daytime, sleep
tonsil/adenoids
CPAP
o Dyslipidemia
o Cholelithiasis
o GORD
o NAFLD
o HTN
- Other risks:
o Gastric distension/rupture from overeating!!!!
o Scoliosis
o Hip dysplasias

Treaetment:
- growth hormone
o beneficieal for linear growth
o also good for bone density
o indicated to all PWS with growth failure,
o CONTRAINDICATION:
Severe obesity
Resp compromise
Severe OSA~ therefore need PSG
- Feeding/obesity treatment:
o Neonates:
Assist feeding
Oromotor evaluation,
thickened hi calorie feeds
OT/PT/ST
o Obesity prevention in older children
Strict food blockage with locks
Coordinate with family, friends, school
Watch carefully for stealing/hoharding food
Structured home environment

Primary Ciliary Dyskinesia

Primary Congenital Glaucoma

Proteus Syndrome

hamartomatous disorder = elephant man
gene locus yet to be identified

Clinical
skin lesions vascular malformations, lipomas, hyperpigmentation, various nevi
partial gigantism overgrowth (pathognomonic) of limb, digit, cranium, vertebrae, external auditory meatus, spleen, thymus
unusual body habitus
cerebriform thickening of soles of feet results in challenging orthopaedic complications
facies dolichocephaly, long face, down-slanting palpebrae, ptosis, depressed nasal bridge, anteverted nares, open mouth
position at rest



Red-Green Color Vision Defects

Retinitis Pigmentosa Overview

Rett syndrome

Frequency: ~1/15 000 1/22 000 (predominantly girls)

Disorder of early brain development marked by a period of developmental regression and deeleration of brain growth after a relatively normal
neonatal course

Caused by mutations in MeCP2 (transcription factor that binds to methylated CpG islands & silences transcription)

Features:
Development may proceed normally until 1 yr of age, when regression of language and motor milestones & acquired microcephaly
became apparent
Ataxic gait or fine tremor of hand movements
Peculiar sighing resprations with intermittent periods of apnea that may be associated with cyanosis
HALLMARK: repetitive hand wringing movements & loss of purposeful and spontaneous use of the hands (may appear at 2-3 yr)
Autistic behaviour
Generalised tonic-clonic convulsions (majority)
o Usually well controlled with anticonvulsants
Feeding disorders and poor weight gain
Cardiac arrhythmias may result in sudden unexpected death
After initial period of neurologic regression, the disease process appears to plateau, with persistence of the autistic behaviour

Generally girls survive into adulthood

Postmortem studies
Significantly reduced brain weight (60-80% of normal)
Decreased no. of synapses
Decreased dendritic lenth & branching
Phenotype may be related to failure to suppress expression of genes that are normally silent in the early phases of postnatal development

Romano-Ward Syndrome

Rothmund-Thomson Syndrome

Rubinstein-Taybi Syndrome



intellectual disability
growth retardation
short broad thumbs
typical facial features
hairy

Genetics
sporadic chr 16

Clinical
short stature (90%)
o postnatal onset growth short stature
o mostly due to delayed bony maturation

dysmorphic - common features (evolved with time)
o beaked or straight nose
o high arch palate
o downward slanting palpebral fissures
o broad nasal bridge

neuro
o developmental delay (in 99%)
o IQ < 50 (75%)
o seizures (30%)
o self stimulating behaviours
o microcephaly (95%)

eyes strabismus/ refractive error/ ptosis
heavy eyebrows/ long lashes

skeletal broad, short thumbs and/or great toes (100%)
scoliosis

skin hairy (75%)
capillary haemangioma (60%)

other less common
o laryngomalacia
o CHD

Outcome
normal life span
slow development
recurrent ear and URTI infections

Russel Silver Syndrome




General points
one of the syndromic causes of short stature usually LBW
occurs sporadically - may be 2 to UDP of chromosome 7

Clinical features
IUGR with postnatal growth retardation
triangular facies - frontal bossing, small jaw
with blue sclera
clinodactyly - shortened & incurved 5
th
fingers
body asymmetry - hemihypertrophy
sparse subcutaneous tissues
caf au lait spots
sweating
IQ usually normal

Associations
cardiac abnormalities (congenital heart diseases)
malignancy (Wilms tumour, craniopharyngioma, testicular seminoma and hepatocellular carcinoma)

SCN9A-Related Inherited Erythromelalgia

Seckel Syndrome


rare autosomal recessive disorder

Clinical
stature
o IUGR, resulting in LBW & short stature

intellectual impairment

dysmorphism
o microcephaly
o beak-like nose protrusion
o large eyes
o narrow face
o malformed ears
o micrognathia

skeletal
o clinodactyly - permanent fixation of the fifth fingers in a bent position
o hip dysplasia
o radial dislocation

Septo-Optic Dysplasia



aka de Moisiers syndrome

hypoplastic optic nerves and optic chiasm
absent (complete or partial) septum pellucidum
o squared of appearance of frontal horns of lateral ventricles
o associations
hypopituitarism
other CNS malformations

Genetics
usually sporadic
unknown cause
risk with young maternal age and nulliparity

Clinical
vision problems
o nystagmus
o impaired visual acuity
hypopituitarism
o function due to hypothalamic dysfunction
o isolated GH deficiency usually
o multiple pituitary hormone deficiency possible also (central DI possible)
o associated midline defect small penis
CNS problems

Shprintzen-Goldberg Syndrome

Shwachman-Diamond Syndrome

Smith-Magenis Syndrome



Genetics
17p micro-deletion
sporadic
AD passed on
o if parents normal risk recurrence 1%
o if NOT normal risk recurrence 50%

Clinical
dysmorphic
o broad square face
o prominent forehead
o 1 eyebrow
o deep set eyes
o broad nasal bridge
o marked facial hypoplasia
o small jaw
o fleshy everted upper lip with a tented appearance (characteristic)

CNS
o majority mild to moderate intellectual disability
o hypotonia, FTT

behaviour
o sleep disturbance
o ADHD
o self injury
o naughty kids

stereotypic behaviour (2 most common)
o upper body squeezing
self hugging
hand linking
o page flipping

Diagnosis
chromosome FISH


Sotos Syndrome

= cerebral gigantism
large size (a rare cause of tall stature)
large hands and feet
unknown genetics

Clinical
growth
o large baby
o length increases rapidly so that all kids > 97th centile by 1yo
o normal adult height

appearance
o large head w frontal bossing
o large jaw & high arched palate
o hypertelorism
o large hands and feet

CNS
o cognitive IQ low
o poor co-ordination difficulty riding bikes and playing sport
o significant behavioural problems

tumourgenesis
o esp hepatic carcinoma & Wilms tumour

Investigation
GH normal
CT head = may show ventricular dilatation
abnormal EEG

Stickler Syndrome


Stickler and Marshall syndromes are related disorders of connective tissue with overlapping characteristics.
Stickler is also known as hereditary arthro-ophthalmopathy

Genetics
Autosomal dominant
mutations of the gene for the alpha-1 chain of type II collagen (COL2A1) located on chromosome 12
type II collagen is a major component of cartilage, vitreous, and nucleus pulposus
mutation encoding for the alpha-1 chain of type XI collagen have also been found

Stickler features
orofacial dysmorphism
o flat midface
o depressed nasal bridge
o short nose with anteverted nares
o micrognathia
o midline cleft palate can occur (ranges in severity from a cleft in the soft palate to the Robin sequence)

ophthalmologic abnormalities
o abnormal architecture of the vitreous gel (pathognomonic)
o high myopia (usually)
o retinal detachment (frequently)

arthritis
o joint hypermobility (present in infancy and decreases with age)
o osteoarthritis (in the 3
rd
or 4
th
decade)

sensorineural deafness (some)

mitral valve prolapse may occur

Marshal features
similar to Stickler syndrome
o similar craniofacial features
o similar ocular abnormalities (eg, cataracts, myopia)
o similar sensorineural hearing loss
o similar spondyloepiphyseal abnormalities

anhidrotic ectodermal dysplasia may occur

Tay Sachs


Teratogens


1. Fetal alcohol syndrome
2. Fetal warfarin syndrome
nasal hypoplasia with grroves on either side of septum and stippled epiphyses ?

3. Fetal phenytoin syndrome
4. Other AEDs
5. Other teratogens!

Thanatophoric Dysplasia

Thrombocytopenia Absent Radius Syndrome

Tourette Disorder Overview

Treacher Collins Syndrome

Tuberous Sclerosis Complex
Dermatologic manifestations of TS - Uptodate
- Hypopigmented macules, (ash leaf spots), epileptic in shape
- Angiofibromas (previously called adenoma sebaceum) typically involve the macular regions of the face
-
- Shagreen patches
- A distinctive brown fibrous plaque on the forehead, which may be the first and most readily recognized
feature of TSC to be appreciated on physical examination of affected neonates and infants


Skin (Wikipedia skin features TS)
Some form of dermatological sign will be present in 96% of individuals with TSC. Most cause no problems but are
helpful in diagnosis. Some cases may cause disfigurement, necessitating treatment. The most common skin
abnormalities include:
Facial angiofibromas ("adenoma sebaceum"): A rash of reddish spots or bumps, which appear on the nose
and cheeks in a butterfly distribution. They consist of blood vessels and fibrous tissue. This socially
embarrassing rash starts to appear during childhood and can be removed using dermabrasion or laser
treatment.
Periungual fibromas: Also known as Koenen's tumors, these are small fleshy tumors that grow around and
under the toenails or fingernails and may need to be surgically removed if they enlarge or cause bleeding.
These are very rare in childhood but common by middle age. They are generally more common on toes than
on ngers, develop at 1529 years and are more common in women than in men. They can be induced by nail-
bed trauma.
Hypomelanic macules ("ash leaf spots"): White or lighter patches of skin that may appear anywhere on the
body and are caused by a lack of melanin. These are usually the only visible sign of TSC at birth. In fair-
skinned individuals a Wood's lamp (ultraviolet light) may be required to see them.
Forehead plaques: Raised, discolored areas on the forehead.
Shagreen patches: Areas of thick leathery skin that are dimpled like an orange peel,pigmented and usually
found on the lower back or nape of the neck. They can also be scattered across the trunk or thighs. The
frequency of these lesions rises with age.
Other skin features are not unique to individuals with TSC, including molluscum fibrosum or skin tags, which
typically occur across the back of the neck and shoulders, caf au lait spots or flat brown marks, and poliosis, a
tuft or patch of white hair on the scalp or eyelids.


Van Der Woude
cleft lip and palate, lip pits, missing 2nd premolars, autosomal dominant ?



VATER/VACTERL

VACTERL

V - verterbral anomalies
A anal atresia
C cardiovascular anomalies
TE tracheoeosophageal fistula
R renal and/or radial anomalies
L limb defects

Vertebral defects: 80%
hypoplastic vertebrae
hemivertebra
Anal atresis (55%)

Cardiac (75%)
VSD
ASD
Tetralogy of fallot
Less common
o Truncus arteriosus
o Transposition of the great arteries
Tracheo-oesophageal fistula (70%)
Up to 50% of infants with TOF are nonsyndromic without other abnormalities, and the rest have assoc anomalies, most oftern VATER
or VACTERL
Renal defects (50%)
Up to 35% patients with VACTERL association have a single umbilical artery (often associated with kidney or urologic problems)
Radial-ulnar synostosis



Von Hippel-Lindau Disease

Waardenburg Syndrome Type I

Heterochromia Iridum Refers to a difference in colouration of the iris; usually as a result of relative excess or lack of melanin
Waardenburg Syndrome Autosomal dominant inherited pigmentary disorder; abnormal distribution of melanocytes during embryogenesis
results in patchy areas of depigmentation
Other distinctive features include pigmentary abnormalities of the iris (heterochromia irides) and a broad nasal root, secondary to displacement
of the inner canthi of the eyes
Congenital deafness occurs in 1 in 5 patients


Williams Syndrome
Williams syndrome:

- Due to a contiguous microdeletion 7q11.23
- Characterised by short stature, CHD (supravalvular aortic stenosis), coarse elfin-like facies with prominent lips, hypercalcaemia or
hypercalciuria of infancy, developmental delay, neonatal irritability evolving into an overly friendly personality
- May require calcium restriction in childhood to prevent nephrocalcinosis
- Diagnosed by FISH analysis of the critical region
- The elastin gene (ELN) has been implicated in the aetiology of some symptoms, but is not known to be expressed in the brain

- Genetic inheritance deletion within elastin gene on chromosome 7q11.23
- Incidence is 1:20000
- Males: Females = 1:1
- Clinical features:
Dysmorphic facies elfin-like:
o Flat nose with anteverted nostrils
o Long philtrum and prominent lips
o Prominent blue eyes with stellate iris
o Medial eyebrow flare
o Short palpebral fissures and epicanthal folds
Supraclavicular aortic stenosis and less commonly pulmonary artery stenosis
Renal artery stenosis
Mental retardation and cocktail party personality (happy and talkative)
Idiopathic hypercalcaemia
Low birthweight and decreased growth
Hypoplastic nails and hallux valgus
- Diagnosis:
FISH is used for diagnosis of microdeletions and duplications
Karyotype will not pick up small deletions such as in Williams Syndrome



Wilms Tumor Overview

Associated with 11pm microdeletion, also known as WAGR syndrome
Haploinsufficiency of PAX6 and Wilms Tumour 1 genes


Wilson Disease

Wolf-Hirschhorn Syndrome
4p deletion
Greek helmet; prominent forehead and small face
A wolf goes for a pee in the wood

X-Linked Adrenoleukodystrophy

X-Linked Agammaglobulinemia


Locations of mutant proteins (X) in B cells identified in primary immunodeficiency
diseases. 2m, 2 microglobulin; BLNK, B-cell linker adaptor protein; Btk, Bruton
tyrosine kinase; HLA, human leukocyte antigen; Ig, immunoglobulin; RFX, RFXAP and
CIITA transcription factors; SLAM, signaling lymphocyte activation molecule; TAP1 and
TAP2, transporters of processed antigen.


X-Linked agammaglobulinemia

= profound defect in B-lymphocyte development resulting in severe hypogammaglobulinemia, an absence of circulating B cells, small to absent
tonsils & no palpable LN

Genetics and pathogenesis
Abnormal gene encodes for B cell protein tyrosine kinase (Btk)
o Maps to q22 on the long arm of the X chromosome
Appears to be necessary for pre B cell expansion and maturation into surface Ig expressing B cells
Also found in cells of the myeloid series
o Therefore boys w XLA often have neutropenia at height of acute infection
Carrier are detected by mutation analysis
Prenatal diagnosis of affected male fetuses is possible if the mutation is known in the family

Some pre-B cells found in BM, but the percentage of peripheral blood B lymphocytes is <1%

% T cells increased, ratios of T-cell subsets are normal. T cell function is intact

Thymus is normal

6 autosomal recessive defects have also been shown to result in agammaglobulinemia with an absence of circulating B cells,
including mutations of genes encoding:

o the heavy chain gene
o the Ig & Ig signalling molecles
o B cell linker adaptor protein (BLNK)
o The surrogate light chain
o Leucine-rich repeat-containing 8 (LRRC8)



X-Linked Severe Combined Immunodeficiency

Xeroderma Pigmentosum
Multigenic, multiallelic autosomal recessive impaired ability to repair UV induced DNA damage
Frequency ~ 1:250,000.
Homozygotes have severe sun sensitivity that leads to degeneration of regions of the skin and eyes, leading to various forms of
cutaneous malignancy.
o SCC, BCC, melanomas beginning in early childhood. 50% lifetime risk of nonmelanoma skin cancer, median age at first Dx
is 8 years, ratio of SCC: BCC = 1:2
o Ocular abnormalities: keratitis, opacification of cornea, iritis with synechia [adhesions bw iris and lens or cornea], melanoma
of choroid
8 mutations identified, 7 involved in nucleotide excision repair of carcinogen adducts after UV irradiation
~25% have neurologic abnormalities of varying severity caused by primary neuronal degeneration
Neurologic features may be mild or severe and can include progressive cognitive impairment, ataxia, choreoathetosis, sensorineural
hearing loss, spasticity, seizures, and peripheral neuropathy with diminished or absent deep tendon reflexes
Acquired microcephaly also may be seen.

Y Chromosome Infertility