Central Hypoventilation Syndromes and Autonomic Dysfunction

Central hypoventilation syndromes encompass a group of rare disorders in which the automatic control of breathing is impaired, most notably during sleep. At their core lies a failure of central chemoreception, often linked to genetic mutations that disrupt the development and function of brainstem neurons responsible for sensing carbon dioxide levels. The most prominent example, Congenital Central Hypoventilation Syndrome (CCHS), arises from mutations in the PHOX2B gene and manifests as life-threatening hypoventilation, autonomic dysregulation and a spectrum of cardiovascular and metabolic disturbances. A related condition, ROHHAD (rapid-onset obesity with hypoventilation, hypothalamic dysfunction and autonomic dysregulation), presents later in childhood and combines respiratory failure with hypothalamic and endocrine abnormalities. Across these syndromes, patients contend with unstable blood pressure, heart-rate variability, thermoregulatory defects and gastrointestinal dysmotility, reflecting widespread autonomic nervous system involvement. Lifelong ventilatory support, early recognition of dysautonomia and targeted interventions to stabilise breathing and autonomic function are central to improving patient outcomes.

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Central Hypoventilation Syndromes and Autonomic Dysfunction publication trend

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Technical terms

Congenital Central Hypoventilation Syndrome (CCHS): A genetic disorder characterised by impaired automatic control of breathing, especially during sleep, often due to PHOX2B mutations.

PHOX2B: A transcription factor essential for the development of autonomic and central chemoreceptor neurons; pathogenic variants underlie CCHS.

Retrotrapezoid nucleus (RTN): A cluster of brainstem neurons that detect elevated carbon dioxide and drive respiratory effort.

ROHHAD: A syndrome marked by rapid-onset childhood obesity, central hypoventilation, hypothalamic dysfunction and widespread autonomic dysregulation.

Chemoreflex: The automatic adjustment of breathing in response to changes in blood carbon dioxide or oxygen levels.

Hypercapnia: A physiological state characterised by elevated arterial carbon dioxide tension, which normally stimulates increased ventilation.

References

1. Knockdown of PHOX2B in the retrotrapezoid nucleus reduces the central CO2 chemoreflex in rats. eLife (2024).
2. Anti-ZSCAN1 Autoantibodies Are a Feasible Diagnostic Marker for ROHHAD Syndrome Not Associated with a Tumor. International Journal of Molecular Sciences (2024).
3. Serotonin and the ventilatory effects of etonogestrel, a gonane progestin, in a murine model of congenital central hypoventilation syndrome. Frontiers in Endocrinology (2023).