| Phenotype | NIH Rare Diseases: Congenital central hypoventilation syndrome (CCHS) is a disorder of the autonomic nervous system that affects breathing. It causes a person to hypoventilate (especially during sleep), resulting in a shortage of oxygen and a buildup of carbon dioxide in the blood. It have two forms of presentation, a classic form that usually begin shortly after birth in newborns, and a milder later-onset presentaition in toddlers, children and adults. Affected infants hypoventilate upon falling asleep and exhibit a bluish appearance of the skin or lips (cyanosis). Other features may include difficulty regulating heart rate and blood pressure; decreased perception of pain; low body temperature; sporadic profuse sweating; Hirschsprung disease; constipation; learning difficulties; eye abnormalities; and a characteristic facial appearance (having a short, wide, somewhat flattened face). They can also have tumors of neural crest origin, such as neuroblastoma, ganglioneuroblastoma, and ganglioneuroma. The later-onset form is milder, and some cases may present as infants and children who die suddenly and unexpectedly (“SIDS” and “sudden unexplained death of childhood [SUDC]”). CCHS is caused by a variation (mutation) in the PHOX2B gene and is inherited in an autosomal dominant manner. However, over 90% of cases are due to a new mutation in the affected person and are not inherited from a parent. Diagnosis is made with the clinical symptoms and the genetic test showing the variation in the PHOX2B gene. Treatment typically includes mechanical ventilation or use of a diaphragm pacemaker. People who have been diagnosed as newborns and adequately ventilated throughout childhood may reach the age of 20 to 30 years, and can live independently. In the later-onset form, people who were diagnosed when they were 20 years or older have now reached the age of 30 to 55 years.
OMIM: Idiopathic congenital central hypoventilation syndrome, also known as 'Ondine's curse' (Deonna et al., 1974), is a rare disorder characterized by abnormal control of respiration in the absence of neuromuscular, lung or cardiac disease, or an identifiable brainstem lesion. Patients breathe normally while awake, but hypoventilate with normal respiratory rates and shallow breathing during sleep; more severely affected patients hypoventilate both awake and asleep. These patients typically present in the first hours of life with cyanosis and increased carbon dioxide during sleep. A deficiency in autonomic control of respiration results in inadequate or negligible ventilatory and arousal responses to hypercapnia and hypoxemia (reviewed by Weese-Mayer et al., 1999). Congenital central hypoventilation syndrome has been associated with several disorders classified as neurocristopathies, that is, aberrant phenotypes arising from a defect of migration or differentiation of neural crest cells. These include neuroblastoma (Haddad et al., 1978), ganglioneuroma (Swaminathan et al., 1989), and most frequently Hirschsprung disease (HSCR) which appears in 16% of CCHS patients. The association of CCHS and HSCR is referred to as Haddad syndrome. Congenital central hypoventilation can be a feature of other developmental disorders, such as those caused by mutation in the MECP2 gene.
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