Congenital Central Hypoventilation Syndrome (CCHS)

Congenital central hypoventilation syndrome (CCHS) is caused by a mutation in the PHOX2B gene, a gene involved in the embryologic development of the autonomic nervous system and control of breathing. Individuals with CCHS have markedly reduced to absent central and peripheral chemoreceptor responsiveness and, consequently, markedly reduced to absent physiologic and behavioral responses to hypercarbia and hypoxia. Individuals with CCHS are heterozygous for PHOX2B mutations, with the abnormal allele containing either a polyalanine repeat expansion mutation (PARM), a non-PARM (NPARM), or whole gene deletion. The PHOX2B PARM range is 20/24–20/33, reflecting the number of alanines on each allele (normal genotype is 20/20). PHOX2B NPARMS may be missense, nonsense, frameshift, or stop codon. Whole gene deletion might involve PHOX2B only or might additionally involve several neighboring genes. The type of mutation allows for anticipatory management relative to disease phenotype with the longer PARM expansions, especially 20/27 and longer, and NPARMS have more severe phenotypes. Patients with CCHS will demonstrate abnormal autonomic and respiratory features with variable gas exchange on polysomnography with spontaneous breathing during sleep, and in more severe cases awake and asleep. Hence, for the first several years of life, the standard of care is continuous mechanical ventilation for 24 h a day via tracheostomy until the child’s awake spontaneous breathing capability in varied levels of daily living is clearer. Additional comorbidities of CCHS include Hirschsprung disease, neural crest tumors, and prolonged cardiac sinus pauses. It is essential that patients are comprehensively evaluated every 6 months until age 3 and then annually thereafter to ensure the appropriate level of respiratory support is provided, with aim for optimal neurodevelopmental outcomes and quality of life.