Congenital Central Hypoventilation Syndrome (CCHS) is a disorder characterized by respiratory and autonomic regulation dysfunction that leads to disordered breathing, especially during sleep. Onset is typically in the newborn period; however, a late onset form has been reported (LO-CCHS) with symptoms first appearing in later childhood or adulthood (Weese-Mayer et al., 2004). Hypoventilation at night is characteristic of both CCHS and LO-CCHS. Patients may or may not exhibit hypoventilation while awake. In both cases, a thorough workup is indicated to exclude primary neuromuscular, lung, cardiac, or a brain stem lesion that could account for these symptoms. In some cases, other abnormalities of the autonomic nervous system are observed such as Hirschsprung disease, decreased pain perception, low body temperature, and episodes of profuse sweating. Increased risk for tumors of the neural crest origin and cardiac arrhythmia have also been reported with CCHS (Kamihara et al., 2017; Bishara et al., 2018).

CCHS is caused by pathogenic/likely pathogenic (P/LP) variants in the PHOX2B gene (Bishara et al., 2018). It is inherited in an autosomal dominant manner, but most cases are de novo. The associated complications of CCHS vary by PHOX2B variant type. Expansion variants of a specific polyalanine repeat within this gene account for the majority of PHOX2B P/LP variants and are almost exclusively associated with isolated CCHS. Frameshift variants that cause a more severe effect on the gene are observed in patients with additional autonomic phenotypes (Di Lascio et al., 2018). Duplications in this gene have been reported in patients with milder respiratory phenotypes (Byers et al., 2018). More recent data suggest additional genetic factors that may be associated with CCHS (Trang et al., 2020). 

Diagnosis of CCHS is first suspected based on the clinical symptoms of alveolar hypoventilation, and confirmed by the presence of a disease-causing P/LP variant in PHOX2B. Diagnosis and management guidelines for CCHS have been outlined by the American Thoracic Society, which indicate that PHOX2B P/LP variant analysis is required to confirm the diagnosis of CCHS as well as to anticipate the severity of the condition (Weese-Mayer et al., 2010). Mechanical ventilation or a diaphragm pacemaker may be necessary to support normal breathing patterns at night. Among the surveillance recommendations are yearly echocardiogram due to risk for right ventricular hypertrophy and possible yearly ECG/24 hour holter monitoring for arrhythmia, depending on the variant type. The reduced life expectancy is related to less than adequate ventilation, and more recent cases with successfully treated ventilation suggest the potential for a normal lifespan in individuals with CCHS. 

Genetic testing for asymptomatic parents is important once a child has been diagnosed. Approximately 25% of asymptomatic parents of an affected individual have germline mosaicism with or without somatic mosaicism, and thus have an increased recurrence risk for future children (Weese-Mayer et al., 2004). In addition, some asymptomatic adults may still be at risk for respiratory compromise with certain triggers. Prompt diagnosis, treatment, and identification of at-risk family members could potentially avoid life-threatening complications and neurocognitive compromise (Weese-Mayer et al., 2010; Bishara et al., 2018).