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Genetics of congenital central hypoventilation syndrome: lessons from a seemingly orphan disease.

The initial response to a publication on a pediatric “orphan disease” is not necessarily enthusiasm, especially if the reader is an adult intensivist or pulmonologist. Although considered insignificant because of their rarity, orphan diseases can serve as models for other, more global phenomena. For example, idiopathic congenital central hypoventilation syndrome (CCHS), although first described in 1970 (1), was considered exclusively as a rare disorder of respiratory control, with nearly all publications in case report or small series format for the next 20-plus years. Although many early reports described symptoms compatible with autonomic nervous system (ANS) dysregulation, and reports on familial patterns appeared, it took another decade for the familial nature of CCHS and the associated ANS dysregulation to be identified. The American Thoracic Society increased the visibility of CCHS with the 1999 ATS statement entitled “Idiopathic Congenital Central Hypoventilation Syndrome: Diagnosis and Management” (2). The specific objectives were to (1) improve knowledge regarding CCHS to minimize delays in diagnosis; (2) state the components of a thorough diagnostic evaluation and for followup; (3) familiarize practitioners with diagnostic, treatment, and home health care options, and long-term outcomes; (4) emphasize the composite of ANS dysfunction beyond the narrow control of breathing deficit considered the hallmark of CCHS; and (5) provide evidence of a genetic component. Subsequent to the ATS statement we have documented an increase in the number of cases diagnosed, with earlier consideration of the disease. Nearly all subsequent publications have appeared in the genetics literature, leaving the readership of the American Journal of Respiratory and Critical Care Medicine potentially uninformed regarding the remarkable progress in determining the genetic basis of CCHS as well as the inheritance pattern. This Pulmonary Perspective has been prepared for three reasons: (1) to demonstrate the lesson that a seemingly straightforward orphan disease with disordered respiratory control is actually a more global phenomenon of ANS dysregulation; (2) to bring the remarkable genetic progress in CCHS, culminating with the identification of a defining gene, the paired-like homeobox gene (PHOX)2b, to the adult and pediatric pulmonologist/intensivist readership of the Journal; and (3) to demonstrate that this unique study population holds great promise for furthering our under-