Congenital central hypoventilation syndrome.

Congenital central hypoventilation syndrome (CCHS) is characterized by hypoventilation during sleep and impaired ventilatory responses to hypercapnia and hypoxemia. Most cases are sporadic and caused by de novo PHOX2B gene mutations, which are usually polyalanine repeat expansions. Physiological and neuroanatomical studies of genetically engineered mice and analyses of cellular responses to mutated Phox2b have shed light on the pathophysiological mechanisms of CCHS. Findings in Phox2b(27Ala/+) knock-in mice consisted of unstable breathing with apneas, absence of the ventilatory response to hypercapnia, death within a few hours after birth, and absence of the retrotrapezoid nucleus (RTN). Conditional mouse mutants in which Phox2b(27Ala) was targeted to the RTN also lacked the ventilatory response to hypercapnia at birth but survived to adulthood and developed a partial hypercapnia response. The therapeutic effects of desogestrel are being evaluated in clinical trials, and recent analyses of cellular responses to polyAla Phox2b aggregates have suggested new pharmacological approaches designed to counteract the toxic effects of mutated Phox2b.