Clinical characteristics: Congenital central hypoventilation syndrome (CCHS) represents the extreme manifestation of autonomic nervous system dysregulation (ANSD) with the hallmark of disordered respiratory control.

The age of initial recognition of CCHS ranges from neonatal onset (i.e., in the first 30 days of life) to (less commonly) later onset (from 1 month to adulthood).

1. Neonatal-onset CCHS is characterized by apparent hypoventilation with monotonous respiratory rates and shallow breathing either during sleep only or while awake as well as asleep; ANSD including decreased heart rate beat-to-beat variability and sinus pauses; altered temperature regulation; and altered pupillary response to light. Some children have altered development of neural crest-derived structures (i.e., Hirschsprung disease, altered esophageal motility/dysphagia, and severe constipation even in the absence of Hirschsprung disease) and/or tumors of neural crest origin (neuroblastoma, ganglioneuroma, and ganglioneuroblastoma). Neurocognitive delay is variable, and possibly influenced by cyanotic breath holding, prolonged sinus pauses, need for 24-hour/day artificial ventilation, and seizures.

2. Later-onset CCHS is characterized by alveolar hypoventilation during sleep and attenuated manifestations of ANSD.

Diagnosis/testing: The diagnosis of CCHS is established in a proband with suggestive findings and a heterozygous PHOX2B pathogenic variant identified on molecular genetic testing.

Management: Treatment of manifestations: Management by multidisciplinary specialists, including pediatric pulmonology, sleep medicine, cardiology, oncology, ophthalmology, gastroenterology, neurodevelopmental psychology, and neurology, is recommended. The treatment goals for CCHS are to secure the airway and to use chronic artificial ventilatory support at home to compensate for the hypoventilation and the altered/absent ventilatory responses to hypoxemia and hypercarbia. Prolonged transient asystoles that may present as syncope and/or staring spells and are of significant duration (≥3.0 seconds) may warrant placement of a cardiac pacemaker; abnormal pupillary reactivity may necessitate protective eye wear given the amount of light exposure in daily life from LED lights, and screen time in educational settings, computer-based work environments, and mobile devices. Other findings treated as per standard practice include Hirschsprung disease and other gastrointestinal motility issues; tumors of neural crest origin; and cognitive impairment/delay.

Surveillance: Assess every six months for the first three years, then annually thereafter: (1) in a pediatric respiratory physiology laboratory spontaneous breathing awake (in varied age-appropriate activities of daily living during the daytime and before sleep) and asleep, with recording of respiratory inductance plethysmography of the chest and abdomen, hemoglobin saturation with pulse waveform, end-tidal carbon dioxide level with visible waveform, electrocardiogram, blood pressure, cerebral regional blood flow/oxygenation, and appropriate sleep state staging measures; (2) hemoglobin/hematocrit and reticulocyte count for polycythemia; (3) 72-hour Holter recording for abrupt, prolonged asystoles; (4) echocardiogram changes consistent with right ventricular hypertrophy and cor pulmonale; (5) neurocognitive assessment/educational needs; and (6) comprehensive age-appropriate noninvasive autonomic testing.

Agents/circumstances to avoid: Swimming and breath-holding contests (risk of asphyxia, death); alcohol (respiratory depression), recreational drugs (varied effects including death), and prescription as well as non-prescription medications/sedatives/anesthetics that could induce respiratory depression.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of parents, sibs, and offspring of an individual with CCHS in order to identify as early as possible family members who would benefit from prompt initiation of treatment, surveillance, and awareness of agents/circumstances to avoid.

Genetic counseling: CCHS is typically inherited in an autosomal dominant manner (CCHS caused by biallelic reduced penetrance PHOX2B pathogenic variants has been reported in two families). The majority of affected individuals have the disorder as the result of a de novo pathogenic variant. Somatic/germline mosaicism is present in 5%-25% of asymptomatic parents. If a parent of the proband is known to be heterozygous for the PHOX2B pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Once the PHOX2B pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible (because of the high frequency of parental mosaicism in CCHS, a fetus should be considered at risk for CCHS even if the PHOX2B pathogenic variant detected in the proband was not identified in either parent).