Causes of Congenital Central Hypoventilation Syndrome
The underlying cause of CCHS is mutation in the PHOX2B gene, a key player in the prenatal development of the nervous system. The majority of individuals with CCHS (~90%) have mutations in exon 3 of the PHOX2B gene that normally has a repeat of 20 alanines. These mutations cause an increase in the number of these alanine repeats from the normal 20 alanines to a range of 24 to 33 alanines and are called poly-alanine repeat expansion mutations (PARMs). The remaining individuals with CCHS have different mutations in the PHOX2B gene not related to PARMs including missense, nonsense, frameshift, or stop codon mutations. These are non-poly-alanine repeat expansion mutations (NPARMs). Both PARMs and NPARMs lead to impaired function of the PHOX2B protein, and the variations in these mutations result in the broad range of symptoms and differing degrees of severity encountered among individuals with CCHS.

CCHS is a dominant mutation, meaning only one PHOX2B gene needs to contain a mutation to result in the phenotypic presentation of CCHS. Although most genetic diseases are inherited from parents, the majority of CCHS cases are spontaneous in nature. The rate of inheritance of CCHS from a parent who has CCHS is believed to be 50%. Mosaic parents have been identified within the CCHS population, but this is still extremely rare. Parents who wish to have additional children after having a child with CCHS are encouraged to seek genetic counseling. PHOX2B mutations are stable in transmission from one generation to the next, but penetrance and phenotype can still vary significantly.