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Congenital Central Hypoventilation Syndrome.

Source

GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.
2004 Jan 28 [updated 2014 Jan 30].

Excerpt

DISEASE CHARACTERISTICS:

Congenital central hypoventilation syndrome (CCHS) is a rare disorder of respiratory and autonomic regulation. It is typically characterized by a classic presentation in newborns and, rarely, a milder later-onset (LO-CCHS) presentation in toddlers, children, and adults. Classic CCHS presents in newborns as: Apparent hypoventilation with monotonous respiratory rates and shallow breathing either during sleep only or while awake as well as asleep; Autonomic nervous system dysregulation (ANSD); and In some individuals, altered development of neural crest-derived structures (i.e., Hirschsprung disease) and/or tumors of neural crest origin (neuroblastoma, ganglioneuroma, and ganglioneuroblastoma). Individuals with CCHS who have been diagnosed as newborns and ventilated conservatively and consistently throughout childhood have now reached the age of 20 to 30 years; they are highly functional and live independently. LO-CCHS manifests as nocturnal alveolar hypoventilation and mild ANSD. Individuals with LO-CCHS who were not identified until age 20 years or older have now reached the age of 30 to 55 years.

DIAGNOSIS/TESTING:

Diagnosis of CCHS is established based on: Clinical findings of alveolar hypoventilation and ANSD in the absence of primary pulmonary, cardiac, or neuromuscular disease, or a causative brain stem lesion that can account for the entire phenotype; and Identification of a disease-causing mutation in PHOX2B. PHOX2B is the only gene in which mutations are known to cause CCHS.

MANAGEMENT:

Treatment of manifestations: Tracheostomy and home ventilator for individuals requiring ventilatory support 24 hours per day and for infants/children/adults requiring ventilatory support during sleep only. Diaphragm pacing by phrenic nerve stimulation can be considered in ambulatory children requiring mechanical ventilation 24 hours a day and potentially in older children and adults requiring nocturnal ventilation only, though tracheostomy removal for nocturnal diaphragm pacing is not assured. Mask ventilation or negative-pressure ventilation is a consideration in cooperative older children requiring ventilatory support during sleep; however, during intercurrent illnesses more aggressive ventilatory support such as intubation with continuous mechanical ventilation in an intensive care setting may be needed. A cardiac pacemaker may be required for prolonged sinus pauses. Hirschsprung disease is treated in the usual manner. Neuroblastomas are removed surgically; those beyond Stage 1 are treated with chemotherapy. Treatment of other tumors of neural crest origin is based on location and type, though surgical removal is typically recommended. Prevention of secondary complications: Mask ventilation in the infant and young child is strongly discouraged because it is not adequately stable as a life-sustaining support, with risk for repeated hypoxemia and neurocognitive compromise. Surveillance: For all individuals with CCHS: at least yearly (every 6 months until age 3 years) comprehensive, multiple-day in-hospital physiologic evaluation to optimize ventilatory support awake and asleep and in varied levels of activity and concentration simulating activities of daily living; yearly 72-hour Holter recording to identify any prolonged sinus pauses; yearly echocardiogram to identify right ventricular hypertrophy or cor pulmonale; yearly hemoglobin, hematocrit, and reticulocyte counts to identify polycythemia; and yearly neurocognitive testing to evaluate the success of artificial ventilation. For children with specific PHOX2B mutations placing them at higher risk: evaluate for Hirschsprung disease and tumors of neural crest origin. Agents/circumstances to avoid: Swimming (asphyxia; death); breathholding contests (asphyxia; death); alcohol (respiratory depression), recreational drugs (varied effects including death), and prescribed as well as non-prescribed medications/sedatives/anesthetics that could induce respiratory depression. Evaluation of relatives at risk: Both parents of children with a known PHOX2B mutation should be tested for the family-specific mutation to determine their risk for later-onset CCHS or mosaicism.

GENETIC COUNSELING:

CCHS is inherited in an autosomal dominant manner. Most individuals with CCHS are heterozygous for a de novo PHOX2B mutation; some have an affected parent and up to 25% have an asymptomatic parent who has mosaicism for a PHOX2B mutation. Each child of an individual with CCHS has a 50% chance of inheriting the PHOX2B mutation; the risk to the offspring of an individual with mosaicism is 50% or lower. Prenatal testing for pregnancies at increased risk is possible if the causative mutation has been identified in an affected family member. Some families choose to pursue prenatal testing in order to make informed decisions about the pregnancy and, if the pregnancy is continued, allow for a smooth transition to extrauterine life for the affected infant.

Copyright © 1993-2014, University of Washington, Seattle. All rights reserved.

PMID:
20301600
[PubMed]
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