The paired-like homeobox 2B gene (PHOX2B) is the disease-defining gene for congenital central hypoventilation syndrome (CCHS). Individuals with CCHS typically present in the newborn period with alveolar hypoventilation during sleep and often during wakefulness, altered respiratory control including reduced or absent ventilatory responses to hypercarbia and hypoxemia, and autonomic nervous system (ANS) dysregulation; however, a subset of individuals present well into adulthood. Thermoregulation is altered and perception of shortness of breath is absent, but voluntary breathing is retained. Structural and functional magnetic resonance imaging (MRI) and limited post-mortem studies in subjects with CCHS reveal abnormalities in both forebrain and brainstem. MRI changes appear in the hypothalamus (responsible for thermal drive to breathing), posterior thalamus and midbrain (mediating O2 and oscillatory motor patterns), caudal raphé and locus coeruleus (regulating serotonergic and noradrenergic systems), the lateral medulla, parabrachial pons, and cerebellum (coordinating chemoreceptor and somatic afferent activity with breathing), and insular and cingulate cortices (mediating shortness of breath perception). Structural and functional alterations in these sites may result from PHOX2B mutations or be secondary to hypoxia/perfusion alterations from suboptimal management/compliance. The study of CCHS, with collaboration between physician-scientists and basic scientists, offers a rare opportunity to investigate control of breathing within the complex physiological network of the ANS.
- Autonomic dysregulation
- Congenital central hypoventilation syndrome (CCHS)
- Control of breathing disorders
- PHOX2B gene
ASJC Scopus subject areas
- Pulmonary and Respiratory Medicine