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Congenital central hypoventilation syndrome: PHOX2B mutations and phenotype.

Abstract：

RATIONALE:Congenital central hypoventilation syndrome (CCHS), a unique disorder of respiratory control associated with Hirschsprung disease (HSCR) and tumors of neural crest origin, results from polyalanine repeat expansion mutations in the paired-like homeobox (PHOX)2B gene in more than 90% of cases, and alternative PHOX2B mutations in remaining cases. OBJECTIVES:To characterize CCHS-associated nonpolyalanine repeat mutations in PHOX2B, evaluate genotype-phenotype relationships, and compare clinical features of CCHS in cases with nonpolyalanine repeat mutations to those with polyalanine expansion mutations. METHODS:DNA from probands was analyzed by polymerase chain reaction for the common polyalanine repeat expansion. If no expansion was present, coding regions and intron-exon boundaries of PHOX2B were sequenced. When possible, parents and siblings were screened for the mutation found in the proband. RESULTS:Fourteen nonpolyalanine repeat mutations, including missense, nonsense, and frameshift mutations, and 170 polyalanine repeat mutations were identified in 184 CCHS probands. Both incomplete penetrance and parental mosaicism were observed within the family members of probands with nonpolyalanine repeat mutations. Increased prevalence of continuous ventilatory dependence, HSCR, and neural crest tumors was seen in the nonpolyalanine repeat group compared to those with polyalanine repeat mutations. CONCLUSIONS:These data suggest that nonpolyalanine repeat mutations produce more severe disruption of PHOX2B function. Patients carrying these mutations should be evaluated for HSCR and neural crest tumors. Because incomplete penetrance can occur in families of CCHS probands with PHOX2B mutations, genetic screening of appropriate family members is indicated to evaluate reproductive risk and because asymptomatic mutation carriers may be at risk for developing alveolar hypoventilation.

journal_name

Am J Respir Crit Care Med

journal_title

American journal of respiratory and critical care medicine

authors

Berry-Kravis EM,Zhou L,Rand CM,Weese-Mayer DE

doi

10.1164/rccm.200602-305OC

subject

Has Abstract

pub_date

2006-11-15 00:00:00

pages

1139-44

issue

eissn

1073-449X

issn

1535-4970

pii

200602-305OC

journal_volume

174

pub_type

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Congenital central hypoventilation syndrome: PHOX2B mutations and phenotype.