PHOX2B Mutation–confirmed Congenital Central Hypoventilation Syndrome

Vanderbilt University, Нашвилл, Michigan, United States
American Journal of Respiratory and Critical Care Medicine (Impact Factor: 13). 11/2006; 174(8):923-7. DOI: 10.1164/rccm.200605-607CR
Source: PubMed


Congenital central hypoventilation syndrome (CCHS) typically presents in the newborn period. A case series of five adults is presented, each heterozygous for a documented polyalanine expansion mutation in the PHOX2B gene and evidence of nocturnal alveolar hypoventilation. All cases had symptoms in childhood, but survived to adulthood without ventilatory support. After identification of physiologic compromise, artificial ventilation was initiated. These adults have the mildest of the CCHS-related PHOX2B polyalanine expansion mutations, coding for only five extra alanines; three of the adults have affected offspring. Report of these cases should lead to a more rapid identification of CCHS presenting in adulthood.

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Available from: Debra E Weese-Mayer, Jun 08, 2015
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    • "The identification of PHOX2B as the disease-causing gene in CCHS (Amiel et al., 2003; Cummings et al., 2009; Matera et al., 2004; Sasaki et al., 2003) generated considerable interest in the role for this gene in CCHS as well as in prevalent conditions such as sleep apnea. PHOX2B mutations were recently found in adults with sleep-related hypoventilation and, in some instances, central apneas and severe hypoxemia, i.e., deficient blood oxygenation (Antic et al., 2006; Barratt et al., 2007; Diedrich et al., 2007; Doherty et al., 2007; Dubreuil et al., 2008; Gaultier et al., 2004; Hoppenbrouwers et al., 2005; Matera et al., 2004; Trochet et al., 2005). Thus, respiratory control disorders associated with PHOX2B mutations may be more prevalent than previously inferred from the very low incidence of CCHS in newborns. "

    Full-text · Dataset · Nov 2015
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    • "Some patients are at very high risk for postoperative hypoventilation even when given ‘normal’ doses of sedatives and opioids. Patients with congenital central hypoventilation syndrome [35] can be completely asymptomatic while awake, yet despite their normal daytime PaCO2, exhibit profound hypoventilation responses to sedation and opioids when asleep. Others at risk include patients with obesity hypoventilation syndrome [36], chest wall deformities, polio sequelae, advanced COPD [37], and severe hypothyroidism [38]. "
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    • "While these individuals are often diagnosed in infancy and childhood, they can remain undiagnosed even to adulthood . In these individuals, discovery of hypoventilation may, at times, require an environmental cofactor such as sedation, anesthesia , anticonvulsants, severe respiratory illness, treated obstructive sleep apnea (Antic et al., 2006; Weese-Mayer et al., 2005) or the homozygous condition (Trochet et al., 2008) to elicit overt clinical events like hypoventilation and/or respiratory arrest. Thus far, fewer than 50 LO-CCHS cases have been reported, but considering the subtlety of the clinical profile in those cases, the prevalence in the general population is likely to be significantly higher than suggested by these few cases. "
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    ABSTRACT: 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 O(2) 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.
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