American Journal of Medical Genetics Part C (Semin. Med. Genet.

) 117C:42 48 (2003)

R E V I E W

Costello Syndrome: An Overview

RAOUL C.M. HENNEKAM*
Costello syndrome is characterized by prenatally increased growth, postnatal growth retardation, coarse face, loose skin resembling cutis laxa, nonprogressive cardiomyopathy, developmental delay, and a outgoing, friendly behavior. Patients can develop papillomata, especially around the mouth, and have a predisposition for malignancies (mainly abdominal and pelvic rhabdomyosarcoma in childhood). Costello syndrome is likely to be an autosomal dominant disorder. The pathogenesis is unclear, but there are many clues for a disturbed elastogenesis, possibly through a disturbed elastin-binding protein reuse by chondroitin sulfate-bearing proteoglycans accumulation. A review of the ndings in the 103 patients that have been described in sufcient detail is provided. 2003 Wiley-Liss, Inc. KEY WORDS: Costello syndrome; autosomal dominant inheritance; malignancy; cardiomyopathy; elastic bers; review

HISTORY
In 1971, J.M. Costello from Auckland, New Zealand reported at a meeting two unrelated children with mental retardation, high birth weight, neonatal feeding problems, curly hair, coarse facies, nasal papillomata, and loose integuments of the back of the hands [Costello, 1971]. The two children were reported in more detail in 1977 [Costello, 1977]. In the following years, several similar cases were presented at different meetings [Carey et al., 1981; Hall et al., 1990; Berberich et al., 1991] or published [Patton et al., 1987 (case 5)] without being recognized to have the same entity. The papers of Dr. Costello remained essentially unrecognized until 1991, when Der Kaloustian et al. [1991] reported an additional patient and named the condition

R.C.M. Hennekam received his M.D. degree, a specialty in Pediatrics, and a second specialty in Clinical Genetics at the State University of Utrecht. He wrote a Ph.D. thesis on the Rubinstein-Taybi syndrome. He is presently working as professor in Pediatrics and in Clinical Genetics in the Department of Pediatrics and the Institute for Human Genetics of the University of Amsterdam. His main scientic interests include mental disabilities, autism, connective tissue disorders, and (molecular) dysmorphology. *Correspondence to: Dr. Raoul C.M. Hennekam, Department of Pediatrics, Academic Medical Center, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands. E-mail: r.c.hennekam@amc.uva.nl DOI 10.1002/ajmg.c.10019

Costello syndrome (MIM 218040). Subsequently, the earlier described cases were recognized as cases with Costello syndrome [Johnson et al., 1992; Patton and Baraitser, 1993]. The entity named facio-cutaneous-skeletal syndrome and published in 1992 as a separate entity [Borochowitz et al., 1992] was also recognized to be the same entity [Borochowitz et al., 1993; Der Kaloustian, 1993; Martin and Jones, 1993; Philip and Mancini, 1993; Teebi, 1993]. Costello syndrome was diagnosed in many other patients, and received still more attention when the increased tendency to develop malignancies became clear. The original patients have been updated again in 1996 [Costello, 1996]. In total, 115 cases have been described. This review describes the ndings in 103 patients (the data on 12 cases were insufciently reported [Hinek et al., 2000; Gripp et al., 2002 (cases 4 and 5); Tandoi et al., 2001] or in a language unknown to this author [Fujikawa et al., 2001]), and discusses the possible etiology and pathogenesis of Costello syndrome. A summary of the clinical data is presented in Table I. Previous reviews are those of Philip and Sigaudy [1998] and Van Eeghen et al. [1999].

FACIAL CHARACTERISTICS
The major facial symptoms that allow recognition of Costello syndrome are an absolute or relative macrocephaly, with a

somewhat hirsute forehead, curly and often sparely implanted hair, thick eyebrows, epicanthal folds, strabismus, downward slanted palpebral ssures, low-set pinnae with often remarkably large ear lobes, and a depressed nasal bridge. The combination of macrocephaly with a bulbous nose, full cheeks, large mouth, thick lips, and large tongue gives the facies almost invariably a coarse impression (Fig. 1). Indeed, some patients have initially been suspected to have Hurler syndrome [Van Eeghen et al., 1999] and other mucopolysaccharidoses [Hinek et al., 2000]. Several other facial symptoms have been reported [Van Eeghen et al., 1999], the most frequent ones being large and persistent anterior fontanels, prominent scalp veins, hypertelorism, and capillary hemangioma over the glabella. Rare but possibly important malformations are chorioretinal dystrophy [DiRocco et al., 1993; Assadi et al., 1999], cataract at birth [Johnson et al., 1998] or at the age of 32 years [Suri and Garrett, 1998], choanal stenosis [Boente et al., 2001], and a congenital laryngeal web [Say et al., 1993]. Upon intraoral inspection, hypertrophy of the gingiva, a large tongue, and an apparently highly arched palate are often noted. Sometimes a bid uvula was found [Izumikawa et al., 1993; Mori et al., 1996]. The teeth may be buried in the gingiva, be widely spaced, and have expressed caries. There have been two

2003 Wiley-Liss, Inc.

REVIEW

AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.)

43

reports on difculties in intubation, even in the absence of abnormal airway features [Dearlove and Harper, 1997; Benni et al., 2002].

TABLE I. Main Characteristics in Costello Syndrome as Reported in Literature (n 73)* Symptom Number 35M/38F 39/67 54/61 67/70 56/58 24/32 6/15 66/66 47/53 33/36 58/69 70/72 28/48 40/47 49/60 24/44 55/61 55/66 49/55 49/53 50/65 41/55 64/66 32/45 13/20 15/25 17/19 43/49 33/46 18/30 30/39 54/62 29/33 30/33 35/44 20/24 53/65 70/71 56/56 23/34 39/51 26/35 29/60 58 89 96 97 Percentagea

MUSCULO-SKELETAL MANIFESTATIONS
The short neck accentuates the frequent increase of the anterior-posterior chest diameter. Inguinal hernias are common. Usually there is a generalized hypermobility of the joints, which is mostly expressed in the ngers. However, the elbows and sometimes other joints (the knees and wrists) can show a diminished extension. The carrying angle in the elbow may be increased. There are often position abnormalities in the feet, such as talipes and vertical talus, and one may notice a similar position anomaly in the ulnar deviation of the hands. Many authors report on the tightness of the Achilles tendons, which often have needed surgical correction. Other symptoms may be wide distal phalanges of the ngers, kyphoscoliosis, and pectus carinatum or excavatum. Radiographically large or late-closing anterior fontanels, osteoporotic long bones, and a delay in bone age have been found. Bone age may be advanced during puberty, however [Assadi et al., 1999; Gripp et al., 2000]. Unusual symptoms are spina bida occulta [Szalai et al., 1999; Van Eeghen et al., 1999; Gripp et al., 2000], wormian bones [Gripp et al., 2000], and elbow subluxation [Zampino et al., 1993].

SKIN MANIFESTATIONS
The most striking cutaneous sign in Costello syndrome is the redundant skin of especially the neck, hands, and feet. The skin is thickened, and soft and velvety in feel. As this is mostly expressed in the palms of the hands and plantar surfaces of the feet, this causes deep creases (Fig. 2). The skin over the digital pulps is also loose, like that of one whose hands have been in water overly long. Some authors have reported the presence of persistent fetal pads. With age, palmar and plantar hyperkeratoses are noted. The skin is darker (olive color)

Sex Pregnancy Polyhydramnios Birth weight >50th centile Growth and development Postnatal growth retardation Poor neonatal feeding Hypotonia Seizures Developmental delay Outgoing personality Hoarse voice Craniofacial characteristics Macrocephalyb Coarse face Thick eyebrows Downslanting palpebral ssures Epicanthal folds Strabismus Depressed nasal bridge Low-set ears Large, eshy ear lobes Full cheeks Short, bulbous nose Large mouth Thick lips Macroglossia Gingival hyperplasia Apparently highly arched palate Teeth anomalies Musculoskeletal characteristics Short neck Increased anterior-posterior thorax diameter Hernia Limited extension of elbow Hyperextensible ngers Broad distal phalanges Tight achilles tendons Abnormal foot position Delayed bone age Skin characteristics Curly, sparse hair Loose skin of hands and feet Deep palmar/plantar creases Hyperkeratosis Hyperpigmentation Dysplastic/thin/deep-set nails Papillomata

100

84 97

82 90 83 89 92 77 75 97

88

87

82 99 100 76 48

44

AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.)

REVIEW

TABLE I. (Continued ) Symptom Cardiovascular characteristics Congenital heart defects Dysrhythmia Hypertrophic cardiomyopathy Number 23/44 27/51 31/51 Percentage

53 61

Costello [1971]; Costello [1977]; Berberich et al. [1991]; Der Kaloustian et al. [1991]; Martin and Jones [1991]; Borochowitz et al. [1992]; Di Rocco et al. [1993]; Izumikawa et al. [1993]; Kondo et al. [1993]; Patton and Baraitser [1993]; Philip and Mancini [1993]; Say et al. [1993]; Teebi and Shaabani [1993]; Yoshida et al. [1993]; Zampino et al. [1993]; Costa et al. [1994]; Davies and Hughes [1994b]; Fryns et al. [1994]; Okamoto et al. [1994]; Vila Torres et al. [1994]; Wulfsberg et al. [1994]; Czeizel and Tmar [1995]; Torrelo et al. [1995]; Umans et al. [1995]; Costello [1996]; Fryns et al. [1996]; Fukao et al. [1996]; Mori et al. [1996]; Popa et al. [1996]; Johnson et al. [1998]; Kerr et al. [1998]; Pratesi et al. [1998]; Siwik et al. [1998]; Suri and Garrett [1998]; Tomita et al. [1998]; Yetkin et al. [1998]; Assadi et al. [1999]; Bisogno et al. [1999]; Feingold [1999]; Franceschini et al. [1999]; Szalai et al. [1999]; Van Eeghen et al. [1999]; Flores-Nava et al. [2000]; Gripp et al. [2000]; Hou and Tunnessen [2000]; Moroni et al. [2000]; Sigaudy et al. [2000]; Boente et al. [2001]; Gripp et al. [2002]; Kaji et al. [2002];Van Den Bosch et al. [2002]; Benni et al. [2002]; Lin et al. [2002]. a Percentage only provided if a symptom was at least described in 2/3rd of the cases. b Absolute (OFC > 98th centile) or relative to length (OFC > 50th centile at length <3rd centile).

than normal, usually again on the hands and feet but also elsewhere, as around the mouth. The presence of acanthosis nigricans has been reported, although it is often unclear how this was dened. Multiple pigmented nevi may be present [Martin and Jones, 1991; Say et al., 1993; Teebi and Shaabani, 1993; Davies and Hughes, 1994a; Torrelo et al., 1995]. The nails can be thin, deeply set, hyperconvex, and dysplastic. The second major skin symptom is the presence of papillomata. Only about half of the patients develop papillomata. They are usually not present in the newborn, but develop between the second and fteenth year. They can be found not only around the nose and mouth, but also over the joints (axilla, elbow, knee), abdomen, and perianally. The hoarse voice present in at least half of the patients is stated to be caused by papillomata on the vocal cords. Less frequent skin signs are hypertrichosis, either generalized or localized on the face, hyperhidrosis [Mori et al., 1996], multiple hemangiomata [Boente et al., 2001], hyperplastic nipples [Borochowitz et al., 1993; Tomita et al., 1998; Franceschini et al., 1999], supernumerary nipples [Borochowitz et al., 1993; Vila Torres et al., 1994], and mammary broadenosis [Costello, 1996]. Three patients had unusual fat depositions [Berberich et al., 1991; Fryns et al., 1994; Czeizel and Tmar, 1995]. A cranial dermoid cyst [DiRocco et al., 1993] and calcied epitheliomas [Martin and Jones, 1991] have also been reported.

INTERNAL ORGANS
Congenital heart defects are common in Costello syndrome, and have been the subject of a superb recent review [Lin et al., 2002]. Especially pulmonary valve stenosis or other right-sided stenoses, ventricular septal defects, and atrial septal defects can occur, but a bicuspid aortic valve, aortic stenosis, and mitral valve stenosis were also found. Thickening of the intraventricular septum and clear-cut hypertrophic cardiomyopathy, usually of the subaortic region or septum, but sometimes the subpulmonic

Figure 1. Drawing of face of patient with Costello syndrome. Note the relative macrocephaly, curly and sparely implanted hair, thick eyebrows, strabismus, downward slanted palpebral ssures, depressed nasal bridge, bulbous nose, large mouth with thick lips, and low-set pinnae with large lobes. The total face has a coarse impression.

REVIEW

AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.)

45

basal ganglia [Johnson et al., 1998], and hypodense white matter [Zampino et al., 1993; Johnson et al., 1998]. There are no long-term MRI follow-up studies. Although EEG abnormalities have been reported repeatedly, seizures are less common. In a single patient, reduction in amplitude in visual evoked potentials and brain stem evoked potentials was reported [Patton and Baraitser, 1993], but in others normal results were reported. IQs have ranged from below 25 to 85, but usually are between 25 and 50. Most patients have a pleasant, happy, outgoing nature, but some were reported to be apathic, nervous, without smile [Yoshida et al., 1993; Fukao et al., 1996; Popa et al., 1996], and to selfmutilate and have anxiety attacks [Van Eeghen et al., 1999]. Pubertal development has been reported to be somewhat delayed or complicated by primary [Van Eeghen et al., 1999] or secondary amenorrhea [Yetkin et al., 1998].

GROWTH
Almost all patients have been large for their ages, but from birth on, weight gain is severely problematic. Hypothyroidism, either subclinical or symptomatic, and possible ACTH deciency have been documented. In several patients, a partial growth hormone deciency or low response in stimulation tests is present, and a favorable growth to growth hormone suppletion has been reported [Assadi et al., 1999; Gripp et al., 2000; Legault and Cagnon, 2001]. Adult height has varied from 116 cm, 118 cm, 140 cm, 147 cm, 148 cm, to 161 cm.

Figure 2. Drawing of palms of hand in patient with Costello syndrome. Note the redundant, thickened skin with deep creases, and persistent fetal pads. The skin over palm and digits resembles that of one whose hands have been in water overly long.

region, have frequently been found. The cardiomyopathy may be present already at birth, or develop in the rst year of life or at a later age. Usually the cardiomyopathy is symptomless and nonprogressive, but in at least one patient the course was fatal [Tomita et al., 1998], and in two others it had a signicant impact on the patients life [Fukao et al., 1996]. Dysrhythmias such as atrial ectopic tachycardia, supraventricular tachycardia, and atrial brillation, as well as occasionally those of ventricular origin, have been reported, both in patients with and in patients without a cardiomyopathy. Dysrhythmias have even been detected during pregnancies [Fryns et al., 1996; Flores-Nava et al., 2000]. Other internal organs are only infrequently involved in Costello syndrome. One patient was found to have a nefrotic syndrome [Suri and Garrett,

1998], another urolithiasis [Assadi et al., 1999], hydronephosis in prematurely born twins [Van Den Bosch et al., 2002], and still another a tracheoesophageal stula [Popa et al., 1996]. Cryptorchidism is commonly found (10%).

NEUROLOGY AND DEVELOPMENT

Neuroradiological studies do often show aspecic symptoms, as enlarged ventricles or mild frontal atrophy. However, there have been reports of cerebellar atrophy [Zampino et al., 1993; Villa Torres et al., 1994; Mori et al., 1996], Chiari malformation [Say et al., 1993; Gripp et al., 2002], hydrocephaly needing shunting [Say et al., 1993; Zampino et al., 1993; Vila Torres et al., 1994; Pratesi et al., 1998], dysmyelinization of

NATURAL HISTORY
Polyhydramnios is noted in about 60%. In one case, increased nuchal thickness was noted at sonography at 16 weeks of gestation [Kerr et al., 1998]. Delivery is frequently by cesarean section. Poor suck is universally noted. In a single patient, pyloric hypertrophy occurred [Johnson et al., 1998]. Somatic problems thereafter (except for the increased risk for malignancies) are signicant but nonspecic, such as failure to thrive, upper airway infections, joint mobility

46

AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.)

REVIEW

problems, and strabismus. Sixteen patients have died: ten before 27 months of age, usually because of cardiac causes [Lin et al., 2002] but also because of an embryonal rhabdomyosarcoma [Bisogno et al., 1999] or rhabdomyolysis due to infection [Mori et al., 1996]; two around 4 years because of a rhabdomyosarcoma [Kerr et al., 1998; Gripp et al., 2002]; one at 5 and one at 22 years for unknown reasons [Lin et al., 2002]; one at 32 years because of a schwannoma [Suri and Garrett, 1998]; and one at 37 years because of a perforated duodenal ulcer [Van Eeghen et al., 1999; Hennekam, unpublished observations] (at autopsy she was found to also have extreme myxoid changes of the mitral valves).

GENETICS AND PATHOGENESIS

Although affected sibs were reported [Berberich et al., 1991; Zampino et al., 1993; Johnson et al., 1998] and one pair of monozygotic twins [Van Den Bosch et al., 2002], all other examples have been isolated. Consanguinity was found only in patients originating from populations where the consanguinity rate is high [Borochowitz et al., 1992; Franceschini et al., 1999]. In a careful analysis, Lurie [1994] concluded that Costello syndrome is caused by sporadic autosomal dominant mutations, the sib pairs representing gonadal mosaicism. Advanced paternal age has been demonstrated. A single chromosomal translocation [46,XX,t(1;22)(q25;q11)] associated with the condition has been reported [Czeizel and Tmar, 1995; Maroti et al., 2002]. Costello syndrome is probably an autosomal dominant inherited disorder of which almost all cases represent a spontaneous mutation, and of which at present the cause is unknown. The resemblance of Costello syndrome with cutis laxa and to a lesser extend Williams syndrome, the autopsy nding of ne, disrupted, and loosely constructed elastic bers in the skin, tongue, pharynx, larynx, and upper esophagus (but not in bronchi, alveoli, aorta, or coronary arteries) [Mori et al., 1996], and the loss of anastomosing points in elastic tissue [Vila Torres et al., 1994], are in favor of a disturbed elastogenesis. The major component of extracellular elastic bers is elastin, which is composed of cross-linked tropoelastin, and formed along a scaffold of microbrils composed of different glycoproteins. Tropoelastin is guided intracellularly by elastin-binding protein (EBP), an enzymatically inactive variant of betagalactosidase, which is also important in elastic ber assembly [Hinek and Rabinovitch, 1994]. Elastic ber formation may be disturbed by a low production of tropoelastin, inadequate intracellular trafcking or release from the cell surface through inadequate functioning of EBP, or disturbed extracellular assembly either of the tropoe-

MALIGNANCIES
Ganglioneuroblastoma (two times), bladder carcinoma (two times), acoustic neuroma (once), epitheliomata (once), neuroblastoma (once), and especially embryonal rhabdomyosarcoma (10 times) have been found [Gripp et al., 2002]. The rhabdomyosarcoma occurred mainly in the abdomen, pelvis, or urogenital area in infants and children between one-half to 6 years of age. The other tumors can occur in both children and adults. No abnormal reactions to therapy have been reported, and the prognosis was comparable to that of other children, without Costello syndrome, with a similar tumor; three children died because of the rhabdomyosarcoma. This prompted Gripp et al. [2002] to suggest a tumor screening protocol consisting of abdominal and pelvic ultrasound examinations every 36 months from birth until 810 years, urinary catecholamine excretion measurements every 6 12 months until 5 years, and annual screening for hematuria from 10 years on. In a commentary however, DeBaun [2002] called attention to several points of criticism for any screening program for Costello syndrome, and urged for careful monitoring of these programs to determine their clinical utility. The relatively small number of patients will probably necessitate this monitoring to be international.

lastin chains themselves or along the scaffold of microbrils. A production defect of tropoelastin can be found in Williams syndrome, a decient functioning of EBP is found in Hurler syndrome and other mucopolysaccharidoses, and an abnormal microbrillar scaffold (i.e., brillin type 1) is known in Marfan syndrome. In an excellent series of studies, Hinek et al. [2000] showed that cultured broblasts from Costello syndrome patients produce normal levels of tropoelastin and properly deposit the microbrillar scaffold, but do not assemble elastic bers by a deciency of EBP. The deciency of EBP was suggested to be secondary to an abnormal accumulation of chondroitin sulfate-bearing moieties, which leads to shedding of EBP from the cell surface instead of recycling and reuse [Hinek et al., 2000]. They also found an increased rate of proliferation of broblasts in Costello syndrome. Costello syndrome may thus be compared to the mucopolysaccharidoses. However, the fact that almost all mucopolysaccharidoses are autosomal recessively inherited and show progression in symptomatology, while Costello syndrome is autosomal dominantly inherited and not really progressive (including the essentially static cardiomyopathy) points against this, and points to the decient functioning of a structural protein. This protein seems to be inuenced by a maternal factor, taking into account the increased cell growth prenatally and decreased cell growth postnatally in patients. The lack of substantial changes in symptomatology after puberty makes a hormonal inuence less likely. The earlier nding that the absence of insoluble elastin may increase cell proliferation [Li et al., 1998] may be important in explaining the increased tumor rate in Costello syndrome.

REFERENCES
Assadi FK, Scott CI, McKay CP, Nicholson L, Cafone M, Hopp L, Fattori DA. 1999. Hypercalciuria and urolithiasis in a case of Costello syndrome. Pediatr Nephrol 13: 5759. Benni F, Leoni T, Iacobucci T, DAvolio S, de Francisci G. 2002. Anaesthesiological

REVIEW

AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.)

47

considerations in Costello syndrome. Paediatr Anaesth 12:374379. Berberich MS, Carey JC, Hall BH. 1991. Resolution of the perinatal and infantile failure to thrive in a new autosomal recessive syndrome with the phenotype of a storage disorder and furrowing of the palmar creases. Proc Greenwood Genet Cent 10:78. Bisogno G, Murgia A, Mammi I, Strafella MS, Carli M. 1999. Rhabdomyosarcoma in a patient with cardio-facio-cutaneous syndrome. J Pediatr Hematol Oncol 21:424 427. Boente MC, Carrero-Valenzuela RD, Frontini MV, Asial RA. 2001. Costello syndrome: report of a new case with choanal atresia and fatal outcome. Eur J Dermatol 11:453457. Borochowitz Z, Pavone L, Mazor G, Rizzo R, Dar H. 1992. New multiple congenital anomalies/mental retardation syndrome (MCA/MR) with facio-cutaneous-skeletal involvement. Am J Med Genet 43:678685. Borochowitz Z, Pavone L, Mazor G, Rizzo R, Dar H. 1993. Facio-cutaneous-skeletal syndrome: new nosological entity or Costello syndrome? Am J Med Genet 47:173. Carey JC, Smith DW, Graham JM, Thain WS, Haas JE, Hall BD. 1981. New syndrome of developmental/growth retardation, coarse facies, and unusual hands. Clin Res 29: 130A. Costa T, Eicheneld LF, Krafchik BR. 1994. Costello syndrome. Pediatr Dermatol 11: 277279. Costello JM. 1971. A new syndrome. NZ Med J 74:397. Costello JM. 1977. A new syndrome: mental subnormality and nasal papillomata. Aust Paediatr J 13:114118. Costello JM. 1996. Costello syndrome: update on the original cases and commentary. Am J Med Genet 62:199201. Czeizel AE, Tmar L. 1995. Hungarian case with Costello syndrome and translocation t(1;22). Am J Med Genet 57:501503. Davies SJ, Hughes HE. 1994a. Cutis laxa: a feature of Costello syndrome. J Med Genet 31:85. Davies SJ, Hughes HE. 1994b. Costello syndrome: natural history and differential diagnosis of cutis laxa. J Med Genet 31:486 489. Dearlove O, Harper N. 1997. Costello syndrome. Paediatr Anaesth 7:476477. DeBaun MR. 2002. Screening for cancer in children with Costello syndrome. Am J Med Genet 108:8890. Der Kaloustian VM. 1993. Not a new MCA/MR syndrome but probably Costello syndrome? Am J Med Genet 47:170171. Der Kaloustian VM, Moroz B, McIntosh N, Watters AK, Blaichman S. 1991. Costello syndrome. Am J Med Genet 41:6973. Di Rocco M, Gatti R, Gandullia P, Barabino A, Picco P, Borrone C. 1993. Report on two patients with Costello syndrome and sialuria. Am J Med Genet 47:11351140. Feingold M. 1999. Costello syndrome and rhabdomyomsarcoma. J Med Genet 36:582 583. Flores-Nava G, Canun-Serrano S, Moysen-Ramrez SG, Parraguirre-Martnez S, Escobedo-Chavez E. 2000. Sndrome de Costello asociado a neuroblastoma. Presentacion de un caso. Gac Med Mex 136:605609.

Franceschini P, Licata D, Di Cara G, Guala A, Bianchi M, Ingrosso G, Franceschini D. 1999. Bladder carcinoma in Costello syndrome: report on a patient born to consanguineous parents and review. Am J Med Genet 86:174179. Fryns JP, Vogels A, Haegeman J, Eggermont E, Van den Berghe H. 1994. Costello syndrome: a postnatal growth retardation syndrome with distinct phenotype. Genet Couns 5:337343. Fryns JP, Devlieger H, Gewillig M, Lukusa P, Devriendt K. 1996. Polyhydramnios and paroxysmal atrial tachycardia as rst clinical signs in Costello syndrome. Genet Couns 7: 237239. Fujikawa Y, Sugai K, Fukumizu M, Hanaoka S, Sasaki M, Kaga M. 2001. Three cases of Costello syndrome presenting with intractable epilepsy and profound psychomotor retardation/regression. No To Hattatsu 33: 430435. Fukao T, Sakai S, Shimozawa N, Kuwahara T, Kano M, Goto E, Nakashima Y, KatagiriKawade M, Ichihashi H, Masuno M, Orii T, Kondo M. 1996. Life-threatening cardiac involvement throughout life in a case of Costello syndrome. Clin Genet 50:244 247. Gripp KW, Scott CI, Nicholson L, Figueroa TE. 2000. Second case of bladder carcinoma in a patient with Costello syndrome. Am J Med Genet 90:256259. Gripp KW, Scott CI, Nicholson L, McDonaldMcGinn DM, Ozeran JD, Jones MC, Lin AE, Zackai EH. 2002. Five additional Costello syndrome patients with rhabdomyosarcoma: proposal for a tumor screening protocol. Am J Med Genet 108:8087. Hall BD, Berberich FR, Berberich MS. 1990. AMICABLE syndrome: a new unique disorder involving facial, cardiac, ectodermal, growth and intellectual abnormalities. Proc Greenwood Genet Cent 9:103. Hinek A, Rabinovitch M. 1994. 67-kD elastinbinding protein is a protective companion of extracellular insoluble elsatin and intracellular tropoelstin. J Cell Biol 126:563 574. Hinek A, Smith AC, Cutiongco EM, Callahan JW, Gripp KW, Weksberg R. 2000. Decreased elastin deposition and high proliferation of broblasts from Costello syndrome are related to functional deciency in the 67-kD elastin-binding protein. Am J Hum Genet 66:859872. Hou JW, Tunnessen WW. 2000. Picture of the month. Arch Pediatr Adolesc Med 154:631. Izumikawa Y, Naritomi K, Tohma T, Shiroma N, Hirayama K. 1993. The Costello syndrome: a boy with thick mitral valves and arrhythmias. Jpn J Hum Genet 38:329334. Johnson JP, Fries MH, Norton ME, Rosenblatt R, Feldman G, Yang S. 1992. Prenatal overgrowth with postnatal growth failure, dysmorphic facies, cutaneous features, and cardiomyopathy: overlap of AMICABLE, facio-cutaneous-skeletal (fcs) and Costello (cs) syndromes. Proc Greenwood Genet Cent 12:98. Johnson JP, Golabi M, Norton ME, Rosenblatt RM, Feldman GM, Yang SP, Hall BD, Fries MH, Carey JC. 1998. Costello syndrome. Phenotype, natural history, differential

diagnosis and possible cause. J Pediatr 133: 441448. Kaji M, Kurokawa K, Hasegawa T, Oguro K, Saito A, Fukuda T, Ito M, Sugie H. 2002. A case of Costello syndrome and glycogen storage disease type III. J Med Genet 39:E8. Kerr B, Eden OB, Dandamudi R, Shannon N, Quarrell O, Emmerson A, Ladusans E, Gerrard M, Donnai D. 1998. Costello syndrome: two cases with embryonal rhabdomyosarcoma. J Med Genet 35:1036 1039. Kondo I, Tamanaha K, Ashimine K. 1993. The Costello syndrome: report of a case and review of the literature. Jpn J Hum Genet 38: 433436. Legault L, Cagnon C. 2001. Growth hormone deciency in Costello syndrome: a possible explanation for the short stature. J Pediatr 138:151152. Li DY, Brooke B, Davis EC, Mecham RP, Sorensen LK, Boak BB, Eichwald E. 1998. Elastin is an essential determinant of arterial morphogenesis. Nature 393:276280. Lin AE, Grossfeld PD, Hamilton RM, Smoot L, Gripp KW, Proud V, Weksberg R, Wheeler P, Picker J, Irons M, Zackai E, Marino B, Scott CI, Nicholson L. 2002. Further delineation of cardiac abnormalities in Costello syndrome. Am J Med Genet 111: 115129. Lurie JW. 1994. Genetics of the Costello syndrome. Am J Med Genet 52:358359. Maroti Z, Kutsche K, Sutajova M, Gal A, Northwang HG, Czeizel AE, Timar L, Solyom E. 2002. Renement and delineation of the breakpoint regions of a chromosome 1;22 translocation in a patient with Costello syndrome. Am J Med Genet 109: 234237. Martin RA, Jones KL. 1991. Delineation of the Costello syndrome. Am J Med Genet 41: 346349. Martin RA, Jones KL. 1993. Facio-cutaneousskeletal syndrome is the Costello syndrome. Am J Med Genet 47:169. Mori M, Yamagata T, Mori Y, Nokubi M, Saito K, Fukushima Y, Momoi MY. 1996. Elastic ber degeneration in the Costello syndrome. Am J Med Genet 61:304309. Moroni I, Bedeschi F, Luksch R, Casanova M, DIncerti L, Uziel G, Selicorni A. 2000. Costello syndrome: a cancer predisposing syndrome? Clin Dysmorphol 9:265268. Okamoto N, Chiyo H, Imai K, Otani K, Futagi Y. 1994. A Japanese patient with the Costello syndrome. Hum Genet 93:605606. Patton MA, Baraitser M. 1993. Cutis laxa and the Costello syndrome. J Med Genet 30:622. Patton MA, Tolmie J, Ruthnum P, Bamforth S, Baraitser M, Pembrey M. 1987. Congenital cutis laxa with retardation of growth and development. J Med Genet 24:556561. Philip N, Mancini JC. 1993. Costello syndrome and facio-cutaneous-skeletal syndrome. Am J Med Genet 47:174175. Philip N, Sigaudy S. 1998. Costello syndrome. J Med Genet 35:238240. Popa M, Ioan DM, Fryns JP. 1996. Costello syndrome: report of an 8-month-old marasmic boy. Genet Couns 7:2730. Pratesi R, Santos M, Ferrari I. 1998. Costello syndrome in two Brazilian children. J Med Genet 35:5457.

48

AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.)

REVIEW

Say B, Gucsavas M, Morgan H, York C. 1993. The Costello syndrome. Am J Med Genet 47:163165. Sigaudy S, Vittu G, David A, Vigneron J, Lacombe D, Moncla A, Flori E, Philip N. 2000. Costello syndrome: report of six patients including one with an embryonal rhabdomyosarcoma. Eur J Pediatr 159:139 142. Siwik ES, Zakha KG, Wiesner GL. 1998. Cardiac disease in Costello syndrome. Pediatrics 101: 706708. Suri M, Garrett C. 1998. Costello syndrome with acoustic neuroma and cataract. Is the Costello locus linked to neurobromatosis type 2 on 22q? Clin Dysmorphol 7:149 151. Szalai S, Becker K, Torok E. 1999. Costello syndrome with decreased glucose tolerance. Eur J Dermatol 9:533536. Tandoi C, Botta A, Fini G, Sangiuolo F, Novelli G, Ricci R, Zampino G, Anichini C, Dallapicolla B. 2001. Exclusion of the elastin gene in the pathogenesis of the Costello syndrome. Am J Med Genet 98:286297.

Teebi AS. 1993. Costello or facio-cutaneousskeletal syndrome? Am J Med Genet 47:172. Teebi AS, Shaabani IS. 1993. Further delineation of the Costello syndrome. Am J Med Genet 47:166168. Tomita H, Fuse S, Ikeda K, Matsuda K, Chiba S. 1998. An infant with Costello syndrome complicated with fatal hypertrophic obstructive cardiomyopathy. Acta Paediatr Jpn 40:608611. Torrelo A, Lopez-Avila A, Mediero IG, Zambrano A. 1995. Costello syndrome. J Am Acad Dermatol 32:904907. Umans S, Decock P, Fryns JP. 1995. Costello syndrome: the natural history of a true postnatal growth retardation syndrome. Genet Couns 6:121125. Van Den Bosch T, Van Schoubroeck D, Fryns JP, Naulaers G, Inion AM, Devriendt K. 2002. Prenatal ndings in a monozygotic twin pregnancy with Costello syndrome. Prenat Diagn 22:415417. Van Eeghen AM, Van Gelderen I, Hennekam RCM. 1999. Costello syndrome: report and review. Am J Med Genet 82:187193.

Vila Torres J, Pineda Marfa M, Gonzalez Ensenat MA, Lloreta Trull J. 1994. Pathology of the elastic tissue of the skin in Costello syndrome. An image analysis study using mathematical morphology. Anal Quant Cytol Histol 16:421429. Wulfsberg EA, Lurie IW, Supovitz KR, Baffa JM, Scheel JN, Ringel RE, Brenner JI. 1994. Stereotypic posterior wall cardiomyopathy is a major feature of the Costello syndrome. Teratology 49:373374. Yetkin I, Ayvaz G, Arslan M, Yilmaz M, Cakir N. 1998. A case of Costello syndrome with endocrine features. Ann Genet 41: 157160. Yoshida R, Fukushima Y, Ohashi H, Asoh M, Fukuyama Y. 1993. Costello syndrome: are nasal papillomata essential? Jpn J Hum Genet 38:437444. Zampino G, Mastroiacovo P, Ricci R, Zollino M, Segni G, Martini-Neri ME, Neri G. 1993. Costello syndrome: further clinical delineation, natural history, genetic denition, and nosology. Am J Med Genet 47:176 183.