- Congenital central hypoventilation syndrome (CCHS) is a rare, life-long disorder of the autonomic nervous system characterized by impaired control of breathing, most prominently during sleep.
- Unlike healthy individuals, who maintain rhythmic breathing automatically, patients with CCHS lack an adequate ventilatory response to hypercapnia (elevated carbon dioxide) and hypoxemia (low oxygen). This results in insufficient or absent respiratory drive, particularly during non-REM sleep when voluntary control of breathing is minimal. Because of this hallmark feature, CCHS is often referred to as “Ondine’s curse”, after the myth of Ondine, in which voluntary functions are lost during sleep.
- The underlying cause of CCHS is most often heterozygous mutations in the PHOX2B gene, a transcription factor critical for the development of the autonomic nervous system and neural crest-derived structures. Over 90% of cases are due to polyalanine repeat expansion mutations (PARMs), while the remainder involve non-polyalanine repeat mutations (NPARMs), which are usually associated with more severe or atypical phenotypes. These mutations impair the maturation and function of brainstem autonomic circuits responsible for ventilatory regulation. Inheritance follows an autosomal dominant pattern with variable penetrance, though many cases arise de novo.
- Clinically, CCHS typically presents in newborns or infants who develop life-threatening hypoventilation during sleep, often discovered shortly after birth when cyanosis or apnea is observed. Some individuals also experience hypoventilation during wakefulness, especially in more severe cases. Beyond respiratory dysfunction, CCHS is recognized as a multisystem disorder of autonomic dysregulation. Associated features may include Hirschsprung disease (aganglionic megacolon), neural crest tumors such as neuroblastoma, abnormal heart rate variability, reduced perception of pain, altered temperature regulation, and impaired pupillary light reflexes. The combination of CCHS with Hirschsprung disease and neural crest tumors is referred to as Haddad syndrome, reflecting the broad spectrum of neural crest involvement.
- Diagnosis of CCHS is based on clinical findings, exclusion of other causes of hypoventilation, and confirmatory genetic testing for PHOX2B mutations. Polysomnography typically demonstrates profound hypoventilation and absence of ventilatory responses to hypercapnia during sleep. Blood gas analysis shows persistent hypercapnia and hypoxemia without evidence of primary lung or neuromuscular disease. Because of the genetic basis, family screening and genetic counseling are important components of care.
- Management of CCHS focuses on lifelong ventilatory support, as there is no curative therapy. Most infants require assisted ventilation during sleep, delivered via positive-pressure ventilation (either through tracheostomy or non-invasive mask-based systems). In severe cases, ventilation is required both during sleep and wakefulness. Some patients may be candidates for diaphragmatic/phrenic nerve pacing, which allows more physiologic breathing patterns and greater independence from mechanical ventilation. Multidisciplinary care is essential, addressing cardiac monitoring (to detect arrhythmias), gastrointestinal management (for Hirschsprung disease), and surveillance for neural crest tumors. With advances in ventilatory support and monitoring, many patients now survive into adulthood, though they require continuous vigilance against hypoventilation-related complications.
- In summary, congenital central hypoventilation syndrome is a rare genetic disorder of autonomic and respiratory control caused by PHOX2B mutations. It manifests as life-long hypoventilation, especially during sleep, and may be associated with broader autonomic dysfunction including Hirschsprung disease and neural crest tumors. Diagnosis relies on clinical recognition and genetic confirmation, and management requires lifelong ventilatory support and multidisciplinary care. While prognosis has improved with modern interventions, CCHS remains a serious condition demanding constant medical attention to ensure safe respiration and overall quality of life.
