Congenital Central Hypoventilation Syndrome (CCHS) and PHOX2B Mutations

Congenital central hypoventilation syndrome (CCHS) is characterized by disordered respiratory control and autonomic nervous system (ANS) dysregulation. Disordered respiratory control, as demonstrated by absent/severely attenuated ventilatory, behavioral, and arousal responses to endogenous/exogenous hypoxemia/hypercarbia occurring at rest or in activities of daily living results in severe physiologic compromise. To clarify, PHOX2B encodes a highly conserved homeodomain transcription factor which plays a key role in early embryologic development of ANS reflex circuits in mice and has expression in both central autonomic neuron circuits and peripheral neural crest derivatives in the human embryo and in the rodent. A relationship between the PHOX2B genotype and need for continuous ventilatory dependence has been reported. Individuals with the 20/25 genotype have the mildest hypoventilation, typically requiring ventilatory support during sleep only. However, a few frameshift mutations located early in exon 3 of PHOX2B have been inherited and are variably penetrant, suggesting that frameshifts in this area may produce a milder functional deficit than other frameshift mutations.