- Central hypoventilation syndrome (CHS) is a rare disorder of respiratory control in which the brain fails to generate or maintain adequate automatic breathing, particularly during sleep.
- Unlike obstructive or neuromuscular causes of hypoventilation, CHS results from a failure of the central nervous system—most often the brainstem respiratory centers—to respond appropriately to rising levels of carbon dioxide (hypercapnia) and low oxygen (hypoxemia). This impaired ventilatory drive leads to inadequate breathing that can cause cyanosis, chronic hypoxemia, hypercapnia, and in severe cases, respiratory arrest during sleep.
- Because of its characteristic presentation, CHS is sometimes colloquially referred to as “Ondine’s curse”, a reference to the myth in which automatic breathing ceases during sleep.
- CHS is broadly divided into two forms: congenital and acquired.
- Congenital central hypoventilation syndrome (CCHS) is caused by mutations in the PHOX2B gene, a transcription factor crucial for autonomic nervous system development. It presents in newborns or infants with absent or severely blunted ventilatory responses during sleep, often requiring lifelong ventilatory support. CCHS is frequently associated with other autonomic and neural crest abnormalities, such as Hirschsprung disease, cardiac arrhythmias, abnormal pupillary responses, and neural crest-derived tumors (neuroblastoma, ganglioneuroma).
- Acquired central hypoventilation arises later in life as a result of brainstem injury or disease, including trauma, ischemic or hemorrhagic stroke, tumors, infections (encephalitis, poliomyelitis), demyelinating conditions, or neurodegeneration. Unlike congenital cases, acquired forms may have a variable prognosis depending on the extent of the underlying injury and potential for recovery.
- Clinically, CHS is characterized by hypoventilation that is most severe during non-REM sleep, when voluntary breathing control is minimal. Infants and children may present with cyanosis, apnea, or failure to thrive, while older patients often develop symptoms of chronic hypercapnia, such as morning headaches, daytime sleepiness, fatigue, and impaired concentration. In severe cases, hypoventilation can also occur during wakefulness. Unlike obstructive sleep apnea, CHS is not associated with snoring or airway obstruction; rather, it is defined by the absence of respiratory effort.
- Diagnosis requires a combination of polysomnography, arterial blood gas analysis, and neuroimaging. Polysomnography demonstrates reduced or absent ventilatory effort during sleep, while blood gases show persistent hypercapnia and hypoxemia. Genetic testing for PHOX2B mutations confirms congenital cases, while neuroimaging may reveal structural lesions in acquired forms. Because CHS can overlap with other autonomic disorders, comprehensive evaluation is essential.
- Management of CHS centers on ensuring adequate ventilation. Most patients require lifelong assisted ventilation during sleep, typically via positive-pressure mechanical ventilation delivered through a tracheostomy or non-invasive mask-based systems. In severe congenital cases, ventilatory support is also required during wakefulness. Diaphragmatic or phrenic nerve pacing is an alternative strategy in selected patients, allowing more physiologic breathing and greater independence. In congenital forms, multidisciplinary care is required to monitor for Hirschsprung disease, cardiac arrhythmias, and neural crest tumors, while in acquired forms, management includes treatment of the underlying cause whenever possible.
- In summary, central hypoventilation syndrome is a rare but life-threatening disorder of impaired automatic breathing due to dysfunction of brainstem respiratory control. It exists in congenital and acquired forms, with CCHS linked to PHOX2B mutations and acquired forms caused by brain injury or disease. Diagnosis is made through sleep studies, blood gases, and genetic or imaging evaluations, and management requires lifelong ventilatory support. Advances in supportive care have significantly improved survival, but patients remain at risk of hypoventilation-related complications and require continuous monitoring.
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