Pediatric Pulmonology 44:521–535 (2009) State of the Art: Sleep Disordered Breathing in Children Congenital Central Hypoventilation Syndrome From Past to Future: Model for Translational and Transitional Autonomic Medicine Debra E. Weese-Mayer, 1 * Casey M. Rand, 1,2 Elizabeth M. Berry-Kravis, 2,3 Larry J. Jennings, 4 Darius A. Loghmanee, 1 Pallavi P. Patwari, 1 and Isabella Ceccherini 5 Summary. The modern story of CCHS began in 1970 with the first description by Mellins et al., came most visibly to the public eye with the ATS Statement in 1999, and continues with increasingly fast paced advances in genetics. Affected individuals have diffuse autonomic nervous system dysregulation (ANSD). The paired-like homeobox gene PHOX2B is the disease-defining gene for CCHS; a mutation in the PHOX2B gene is requisite to the diagnosis of CCHS. Approximately 90% of individuals with the CCHS phenotype will be heterozygous for a polyalanine repeat expansion mutation (PARM); the normal allele will have 20 alanines and the affected allele will have 24–33 alanines (genotypes 20/24–20/33). The remaining 10% of individuals with CCHS will have a non-PARM (NPARM), in the PHOX2B gene; these will be missense, nonsense, or frameshift. CCHS and PHOX2B are inherited in an autosomal dominant manner with a stable mutation. Approximately 8% of parents of a CCHS proband will be mosaic for the PHOX2B mutation. A growing number of cases of CCHS are identified after the newborn period, with presentation from infancy into adulthood. An improved understanding of the molecular basis of the PHOX2B mutations and of the PHOX2B genotype/CCHS phenotype relationship will allow physicians to anticipate the clinical phenotype for each affected individual. To best convey the remarkable history of CCHS, and to describe the value of recognizing CCHS as a model for translational and transitional autonomic medicine, we present this review article in the format of a chronological story, from 1970 to the presentday. Pediatr Pulmonol. 2009; 44:521–535. ß 2009 Wiley-Liss, Inc. Key words: congenital central hypoventilation syndrome; autonomic dysregulation; Hirschsprung disease; neuroblastoma. ‘‘Apparently rare cases are worth studying, not because they are rare, but because they provide an opportunity to unravel an important homeostatic mechanism of disease present in all of us but not so apparent except in those missing some important protective mechanism.’’ Robert B. Mellins, M.D. 2007 This article is one in a series of articles on Sleep Disordered Breathing in Children. This series will span upcoming issues of Pediatric Pulmonology. 1 Department of Pediatrics, Children’s Memorial Hospital, Northwestern University Feinberg School of Medicine, Chicago, Illinois. 2 Department of Pediatrics, Rush University Medical Center, Chicago, Illinois. 3 Departments of Neurological Sciences and Biochemistry, Rush University Medical Center, Chicago, Illinois. 4 Department of Pathology, Children’s Memorial Hospital, Northwestern University Feinberg School of Medicine, Chicago, Illinois. 5 Laboratory of Molecular Genetics, Instituto Giannina Gaslini, Genova, Italy. *Correspondence to: Dr. Debra E. Weese-Mayer, Professor of Pediatrics, Northwestern University Feinberg School of Medicine; Director, Center for Autonomic Medicine in Pediatrics, Children’s Memorial Hospital, 2300 Children’s Plaza, Chicago, IL 60614. E-mail: dweese-mayer@childrensmemorial.org Received 17 January 2009; Revised 2 March 2009; Accepted 4 March 2009. DOI 10.1002/ppul.21045 Published online 6 May 2009 in Wiley InterScience (www.interscience.wiley.com). Grant sponsor: Chicago Community Foundation PHOX2B Patent Fund. ß 2009 Wiley-Liss, Inc.