Letter to the Editor

Neuroblastoma in a Mother and Congenital CentralHypoventilation in Her Daughter: VariableExpression of the Same Genetic Disorder?

To the Editor:

Congenital central hypoventilation syndrome(CCHS, MIM 209880) [Online Mendelian Inheritancein Man, 1999] is a rare disorder thought to be caused byabnormal neural crest development, and characterizedby a decreased sensitivity of the respiratory centers tohypercarbia and hypoxia [Weese-Mayer et al., 1992,1999]. This results in hypoventilation during sleep.The inheritance pattern of CCHS remains uncertain[Weese-Mayer et al., 1992, 1999]. We report here forthe first time the observation of a girl with nonsyndro-mal CCHS whose mother had had a neuroblastomaduring infancy. This suggests that isolated CCHS andneuroblastoma might be the variable expression of apossibly autosomal dominant genetic defect.

The girl presented at term with unexplained respi-ratory failure associated with reduced body move-ments. During the first weeks the typical picture ofcentral hypoventilation developed, with hyposensitiv-ity of the central respiratory center to hypercapnia,evidenced by the absence of increase in ventilation af-ter hypercapnia induced by a rebreathing system. Thisresulted in apneic spells during sleep and hypoventila-tion when waking. This necessitated respiratory sup-port, continuously for 2 months, thereafter only duringsleep. Motor function of the limbs improved gradually.No other anomalies were present and no symptomssuggestive of Hirschsprung disease were present. Uri-nary catecholamines were elevated at 1 month [VMA20.1 mg/g creatinine (normal <7 mg/g creatinine), HVA21.1 mg/g creatinine (normal 3–16 mg/g creatinine)],but a scintigraphy with [123I]metaiodobenzylguani-dine (MIBG) did not show a neuroblastoma. Karyotypewas normal (46,XX). At 3 months, psychomotor devel-opment was normal. She was the first child of noncon-sanguineous parents. The mother had been treated bysurgery and radiotherapy for a neuroblastoma of the

right adrenal gland, diagnosed at 3 months. No patho-logical specimens of the tumor were available.

To our knowledge, the occurrence of neuroblastomain a mother and CCHS in her child has not been re-ported before. Although we cannot exclude a chanceassociation between these two disorders, the neuro-blastoma and CCHS probably represent the variableexpression of a single genetic developmental disorder.Both disorders share a common pathogenesis, relatedto abnormal development of neural crest–derived cells.CCHS is frequently associated with Hirschsprung dis-ease, and in several patients neuroblastoma or ganglio-neuroma have been observed [Weese-Mayer et al.,1992]. A probable role of the neural crest in CCHS isfurther supported by the finding of mutations in genesof the Ret-GDNF pathway and the endothelin pathway(known to be involved in Hirschsprung disease), insome patients with CCHS [Bolk et al., 1996; Amiel etal., 1998; Sakai et al., 1998]. Moreover, Ret-proto-oncogene knockout mice have a reduced respiratoryCO2 sensitivity [Burton et al., 1997]. Neuroblastomasconsist of neural crest cells and in vitro studies haveindicated a role for the Ret-GDNF pathway in the regu-lation of differentiation of neuroblastoma cells [Hishikiet al., 1998]. This suggests that the findings of CCHS ina child and neuroblastoma in her mother probably arenot a chance occurrence, but the expression of the samegenetic disorder.

The inheritance of CCHS is unclear at the presenttime. This hampers genetic counseling of parents of achild with CCHS [Weese-Mayer et al., 1999]. Mostcases of CCHS are sporadic, but the disorder has beenobserved in monozygotic female twins, in sibs of bothsexes, and in male-female half-sibs [Haddad et al.,1978; Khalifa et al., 1988; Hamilton and Bodurtha,1989; Marcus et al., 1991; Weese-Mayer et al., 1992;Kerbl et al., 1996]. Recently, mutations in the Ret andGDNF genes were detected in two patients with CCHSand in an unaffected parent, suggesting that the pres-ence of these mutations alone is not sufficient to causethe disease [Amiel et al., 1998]. This suggests morecomplex causation, and polygenic or multifactorial in-heritance has been proposed [Amiel et al., 1998; Weese-Mayer et al., 1993]. The present observation illustratesthe importance of the family history and suggests thatcounseling for recurrence of CCHS probably should in-

*Correspondence to: Dr. K. Devriendt, Center for Human Ge-netics, Herestreaat 49, B-3000 Leuven, Belgium.E-mail: koen.devriendt@med.kuleuven.ac.be

Received 3 August 1999; Accepted 26 October 1999

American Journal of Medical Genetics 90:430–431 (2000)

© 2000 Wiley-Liss, Inc.

clude the possibility of variable expressivity, manifest-ing as neuroblastoma.

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Koen Devriendt*Jean-Pierre FrynsCenter for Human GeneticsUniversity Hospital LeuvenLeuven, Belgium

Gunnar NaulaersHugo DevliegerDepartment of PediatricsUniversity Hospital LeuvenLeuven, Belgium

Philippe AllietPediatricianHasselt, Belgium

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