central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease

Central hypoventilation syndrome, congenital, 1 (often called CCHS) is a disorder of the autonomic nervous system in which the brain fails to control breathing normally, especially during sleep. Most affected babies show symptoms soon after birth and require lifelong assisted ventilation. Variants in the PHOX2B gene disrupt development of the neurons that regulate breathing and other automatic body functions. The condition is uncommon, with an estimated incidence of roughly 1 in 200 000 live births, and it affects both boys and girls. Severity and specific complications vary considerably from one individual to another.

The hallmark of CCHS is inadequate breathing that becomes most obvious during sleep. Newborns may have shallow breathing, bluish skin color, or pauses in respiration that prompt evaluation. As children grow, many continue to require ventilatory support both at night and, in more severe cases, during wakefulness. Because PHOX2B influences many autonomic pathways, additional features reflect broad nervous-system involvement. Cardiovascular signs can include low heart-rate variability and episodes of slow heart rate. Gastrointestinal problems are common; about one in six individuals also has Hirschsprung disease, a condition in which parts of the large intestine lack nerve cells, leading to severe constipation or aganglionic megacolon. Even those without Hirschsprung disease may experience chronic constipation or ineffective swallowing and esophageal motility. A smaller subset develops tumors derived from neural crest tissue, such as neuroblastoma or ganglioneuroblastoma, which may appear in childhood or adolescence. Not all individuals experience all features, and severity varies widely, underscoring the importance of personalized care and monitoring.

CCHS is most often caused by a heterozygous pathogenic variant in the PHOX2B gene. PHOX2B provides instructions for a transcription factor that guides development of neurons responsible for automatic control of breathing, heart rate, gut motility, and other involuntary functions. When one copy of the gene is altered, these neural networks do not mature normally, resulting in the characteristic breathing and autonomic problems. The condition follows an autosomal dominant inheritance pattern, meaning a person who carries a pathogenic PHOX2B variant has a 50 percent chance of passing it to each child. However, the range of symptoms in affected family members can differ markedly (variable expressivity). Families are encouraged to consult a genetic counselor to discuss testing of relatives and reproductive options.

Currently, management centers on supportive care tailored to each person’s needs. Most individuals require mechanical ventilation through a tracheostomy or a non-invasive interface, at least during sleep. Some older children and adults may use diaphragm pacing systems if deemed appropriate by their care team. Long-term management includes regular surveillance for potential complications. Ongoing monitoring of respiratory function, heart rhythm, gastrointestinal health, and screening for neural crest tumors helps identify problems early when intervention is most effective. Because multiple organ systems are involved, care is best coordinated through a multidisciplinary team that may include pulmonology, cardiology, gastroenterology, surgery, and genetics specialists. Genetic counseling should accompany medical care to address inheritance, family planning, and psychosocial support. Patients should discuss the full range of management options with their healthcare providers to determine what is most suitable for their situation.

With consistent ventilatory support and coordinated specialty care, many individuals with CCHS can grow, attend school, and participate in daily activities, although they remain dependent on assisted breathing. The risk of serious complications, including life-threatening respiratory events or tumor development, highlights the need for vigilant monitoring across the lifespan. Outcomes described in medical literature continue to evolve as standards of care improve. Severity and long-term health vary greatly between individuals, influenced by the extent of hypoventilation, presence of Hirschsprung disease, and development of tumors. Families often find it helpful to connect with expert centers and genetic counselors to stay informed about evolving recommendations and research opportunities.

Clinical trials are underway exploring new treatment approaches aimed at improving autonomic regulation or reducing reliance on mechanical ventilation. Individuals interested in participating can search ClinicalTrials.gov or consult their care team about eligibility.