Congenital Central Hypoventilation Syndrome

Abstract

Rationale: Congenital central hypoventilation syndrome (CCHS), a unique disorder ofrespiratory control associated with Hirschsprung disease (HSCR) and tumors of neural crest origin, results from poly- alanine 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 reactionfor thecommonpolyalaninerepeatexpansion.Ifnoexpan- sion 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 mis- sense, nonsense, and frameshift mutations, and 170 polyalanine repeat mutations were identified in 184 CCHS probands. Both incomplete penetrance and parental mosaicism were observed within thefamily members ofprobands with nonpolyalaninerepeat mutations. Increased prevalence of continuous ventilatory depen- dence, HSCR, and neural crest tumors was seen in the nonpolyalan- ine repeat group compared to those with polyalanine repeat mutations. Conclusions: These data suggest that nonpolyalanine repeat muta- tions 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.