Congenital central hypoventilation syndrome (CCHS) is a disorder of ventilatory control and autonomic dysregulation that can be caused by mutations in the paired-like homeobox 2B (PHOX2B) gene.
PHOX2B plays a key function in the development of neural crest derivatives, and heterozygous mutations cause a complex dysautonomia associating HSCR, Congenital Central Hypoventilation Syndrome (CCHS) and neuroblastoma (NB) in various combinations.
Clinical testing for PHOX2B mutations is widely used for patients with any symptoms suggestive of hypoventilation (with/without anatomic/physiologic autonomic dysregulation), though not necessarily with the congenital central hypoventilation syndrome (CCHS) phenotype.
Study of genes related to autonomic dysregulation and the embryologic origin of the neural crest led to the discovery of PHOX2B as the disease-defining gene for CCHS.
Our results confirm that PHOX2B affects the development of the autonomic nervous system, possibly causing absence of normal maturation of carotid body and visceral sensory ganglia and leading to autonomic dysfunction in adult-onset CCHS.