In pursuit (and discovery) of a genetic basis for congenital central hypoventilation syndrome

Congenital central hypoventilation syndrome (CCHS) typically presents in the newborn period with a phenotype including alveolar hypoventilation, symptoms of autonomic nervous system dysregulation, and in a subset of cases Hirschsprung disease and later tumors of neural crest origin. Study of genes related to the autonomic dysregulation and the embryologic origin of the neural crest has led to identification of the genetic basis for CCHS, the mode of inheritance, and the presence of mosaicism in a subset of parents. Polyalanine expansion mutations in PHOX2B have been identified to be the disease-defining mutation in CCHS, with a small subset of patients having other mutations in PHOX2B. Further, the size of the polyalanine repeat mutation in PHOX2B is correlated with the severity of the phenotype in CCHS, and non-polyalanine repeat mutations appear to, in general, result in CCHS phenotypes at the severe end of the spectrum. These studies highlight the utility of PHOX2B genetic testing for confirmation of the CCHS diagnosis, for prenatal diagnosis, and for identification of previously undiagnosed adults with unexplained hypercarbia or control of breathing deficits. This diagnostic approach may be a consideration for other complex, seemingly undecipherable diseases that affect infants and children. The purpose of this article is to provide a comprehensive review of current research into the genetic basis for CCHS, an explanation for how these studies evolved, recent studies that begin to explain the mechanisms through which mutations in PHOX2B exert their effects, and clinical application of the genetic testing.