Sleep-Related Hypoventilation Syndromes; Congenital Alveolar Hypoventilation Syndrome

Madeleine M. Grigg-Damberger, MD

Associate Medical Director
Clinical Neurophysiology Laboratory
Director, Pediatric Sleep Medicine Services at the University Hospital Sleep Disorders Center
Medical Director, Inpatient Neurology Services
University of New Mexico
Albuquerque, New Mexico

Central congenital hypoventilation syndrome (CCHS) is a rare, complex disorder of autonomic nervous system dysregulation caused by a genetic mutation of the PHOX2B gene.1, 2 CCHS usually manifests in newborns who present with cyanosis, oxygen desaturation, and hypercarbia after falling asleep. Autonomic dysregulation prevents a normally-expected increase in respiratory rate, ventilatory effort, or awakening in response to hypoxic or hypercarbic conditions during sleep.3 If undetected or misdiagnosed, patients will present again at a later age with signs of right heart failure and pulmonary hypertension.4 Often misdiagnosed as congenital heart disease, diagnostic criteria for CCHS includes hypoventilation during sleep in the absence of primary neuromuscular, lung, cardiac or metabolic disease, or an identifiable brainstem lesion.4, 5 Today, 99% of patients can be diagnosed through genetic testing as it is now believed that virtually all individuals with CCHS have mutations in the PHOX2B gene.6 Its role as a transcriptional regulator of gene expression localized to neural tissue remains an important area of clinical research. No known cure for CCHS exists and the disorder appears to be life-long. Management of these patients usually involves mechanical-assisted ventilation during sleep, with others requiring it during wakefulness.4 Adverse effects associated with CCHS include cognitive impairment, tumors of neural crest origin, and swallowing difficulties.1, 7-10 Discovery of the relationship between a CCHS and PHOX2B mutations is a major breakthrough that will certainly facilitate a greater understanding of the disease, a more accurate diagnosis and prognosis.

References

Berry-Kravis EM, Zhou L, Rand CM, Weese-Mayer DE. Congenital central hypoventilation syndrome: PHOX2B mutations and phenotype. Am J Respir Crit Care Med. Nov 15 2006;174(10):1139-1144.
Weese-Mayer DE, Berry-Kravis EM. Genetics of congenital central hypoventilation syndrome: lessons from a seemingly orphan disease. Am J Respir Crit Care Med. Jul 1 2004;170(1):16-21.
Lesser DJ, Ward SL, Kun SS, Keens TG. Congenital hypoventilation syndromes. Semin Respir Crit Care Med. Jun 2009;30(3):339-347.
Chen ML, Keens TG. Congenital central hypoventilation syndrome: not just another rare disorder. Pediatr Respir Rev. Sep 2004;5(3):182-189.
Weese-Mayer DE, Silvestri JM, Menzies LJ, Morrow-Kenny AS, Hunt CE, Hauptman SA. Congenital central hypoventilation syndrome: diagnosis, management, and long-term outcome in thirty-two children. J Pediatr. Mar 1992;120(3):381-387.
Weese-Mayer DE, Marazita ML, Berry-Kravis EM. Congenital central hypoventilation syndrome. Gene Reviews. Vol: National Institues of Health; 2008.
Faure C, Viarme F, Cargill G, Navarro J, Gaultier C, Trang H. Abnormal esophageal motility in children with congenital central hypoventilation syndrome. Gastroenterology. May 2002;122(5):1258-1263.
Raabe EH, Laudenslager M, Winter C, et al. Prevalence and functional consequence of PHOX2B mutations in neuroblastoma. Oncogene. Jan 17 2008;27(4):469-476.
Ruof H, Hammer J, Tillmann B, Ghelfi D, Weber P. Neuropsychological, behavioral, and adaptive functioning of Swiss children with congenital central hypoventilation syndrome. J Child Neurol. Nov 2008;23(11):1254-1259.
Zelko FA, Nelson MN, Leurgans SE, Berry-Kravis EM, Weese-Mayer DE. Congenital central hypoventilation syndrome: neurocognitive functioning in school age children. Pediatr Pulmonol. Jan;45(1):92-98.

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