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Congenital Central Hypoventilation Syndrome

PHOX2B Mutations and Phenotype

Departments of Neurology, Biochemistry, and Pediatrics, Rush University Medical Center, Chicago, Illinois

Correspondence and requests for reprints should be addressed to Elizabeth Berry-Kravis, M.D., Ph.D., 1725 West Harrison Street, Suite 718, Chicago, IL 60612. E-mail: elizabeth_m_berry-kravis{at}rush.edu

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.

Key Words: alveolar hypoventilation • autonomic nervous system • Hirschsprung disease • polyalanine repeat

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Congenital central hypoventilation syndrome, a disease characterized by autonomic nervous system dysregulation, Hirschsprung disease, and tumors of neural crest origin, results from PHOX2B polyalanine repeat expansion mutations in over 90% of cases and alternatively, nonpolyalanine repeat expansion mutations in remaining cases. What This Study Adds to the Field This study characterizes a group of congenital central hypoventilation syndrome–associated nonpolyalanine repeat mutations in PHOX2B and concludes that these mutations are mostly de novo, although some can be inherited from a parent, predominantly affect the 3' end of PHOX2B, and are generally associated with a more severe phenotype with regard to hypoventilation, Hirschsprung disease, and incidence of neuroblastoma than are the more common polyalanine repeat mutations.

 

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