Congenital central hypoventilation syndrome: a bedside-to-bench success story for advancing early diagnosis and treatment and improved survival and quality of life.
The "bedside-to-bench" Congenital Central Hypoventilation Syndrome (CCHS) research journey has led to increased phenotypic-genotypic knowledge regarding autonomic nervous system (ANS) regulation, and improved clinical outcomes. CCHS is a neurocristopathy characterized by hypoventilation and ANS dysregulation. Initially described in 1970, timely diagnosis and treatment remained problematic until the first large cohort report (1992), delineating clinical presentation and treatment options. A central role of ANS dysregulation (2001) emerged, precipitating evaluation of genes critical to ANS development, and subsequent 2003 identification of Paired-Like Homeobox 2B (PHOX2B) as the disease-defining gene for CCHS. This breakthrough engendered clinical genetic testing, making diagnosis exact and early tracheostomy/artificial ventilation feasible. PHOX2B genotype-CCHS phenotype relationships were elucidated, informing early recognition and timely treatment for phenotypic manifestations including Hirschsprung disease, prolonged sinus pauses, and neural crest tumors. Simultaneously, cellular models of CCHS-causing PHOX2B mutations were developed to delineate molecular mechanisms. In addition to new insights regarding genetics and neurobiology of autonomic control overall, new knowledge gained has enabled physicians to anticipate and delineate the full clinical CCHS phenotype and initiate timely effective management. In summary, from an initial guarantee of early mortality or severe neurologic morbidity in survivors, CCHS children can now be diagnosed early and managed effectively, achieving dramatically improved quality of life as adults.
Center for Autonomic Medicine in Pediatrics (CAMP), Ann & Robert H. Lurie Children's Hospital of Chicago and Stanley Manne Children's Research Institute, Chicago, Illinois.|Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
Debra E
DE
Weese-Mayer
Center for Autonomic Medicine in Pediatrics (CAMP), Ann & Robert H. Lurie Children's Hospital of Chicago and Stanley Manne Children's Research Institute, Chicago, Illinois.
Casey M
CM
Rand
Center for Autonomic Medicine in Pediatrics (CAMP), Ann & Robert H. Lurie Children's Hospital of Chicago and Stanley Manne Children's Research Institute, Chicago, Illinois.
Amy
A
Zhou
Center for Autonomic Medicine in Pediatrics (CAMP), Ann & Robert H. Lurie Children's Hospital of Chicago and Stanley Manne Children's Research Institute, Chicago, Illinois.|Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
Michael S
MS
Carroll
Pediatrics, F. Edward Hébert School of Medicine, Uniformed Services University, Bethesda, Maryland.|Pediatrics, George Washington University, Washington, D.C.
Carl E
CE
Hunt
D000818:Animals; D001921:Brain / Q000473:pathology; D056726:Genetic Association Studies; D005820:Genetic Testing; D005838:Genotype; D049673:History, 20th Century; D049674:History, 21st Century; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007040:Hypoventilation / Q000151:congenital* / Q000175:diagnosis / Q000628:therapy; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009154:Mutation; D015272:Pulmonary Medicine / Q000266:history*; D011788:Quality of Life; D012008:Recurrence; D020182:Sleep Apnea, Central / Q000175:diagnosis* / Q000628:therapy*; D014157:Transcription Factors / Q000235:genetics; D016896:Treatment Outcome
D018398:Homeodomain Proteins; C109220:NBPhox protein; D014157:Transcription Factors
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