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Published ahead of print on August 3, 2006, doi:10.1164/rccm.200602-305OC

Am. J. Respir. Crit. Care Med., Volume 174, Number 10, November 2006, 1139-1144

A more recent version of this article appeared on November 15, 2006
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Submitted on February 28, 2006
Accepted on August 3, 2006

Congenital Central Hypoventilation Syndrome: PHOX2B Mutations and Phenotype

Elizabeth M Berry-Kravis1*, Lili Zhou2, Casey M Rand2, and Debra E Weese-Mayer2

1 Department of Pediatrics, Rush University Medical Center, Chicago, IL, USA; Departments of Neurology and Biochemistry, Rush University Medical Center, Chicago, IL, USA, 2 Department of Pediatrics, Rush University Medical Center, Chicago, IL, USA

* To whom correspondence should be addressed. 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 PHOX2B gene in over 90% of cases, and alternative PHOX2B mutations in remaining cases. Objectives: To characterize CCHS-associated non- polyalanine repeat mutations in PHOX2B, evaluate genotype-phenotype relationships, and compare the clinical features of CCHS in cases with non-polyalanine repeat mutations and those with polyalanine repeat expansion mutations. Methods: DNA from probands was analyzed by PCR 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 non-polyalanine 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 non-polyalanine repeat mutations. Increased prevalence of continuous ventilatory dependence, HSCR, and neural crest tumors was seen in the non-polyalanine repeat group compared to those with polyalanine repeat mutations. Conclusions: These data suggest that non-polyalanine 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: Autonomic nervous system, polyalanine repeat, alveolar hypoventilation, Hirschsprung disease




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