title: Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation presenting in childhood.
abstract: OBJECTIVE
  The goal was to characterize the phenotype and potential candidate genes responsible for the syndrome of late-onset central hypoventilation with hypothalamic dysfunction.
  
  
  METHODS
  Individuals with late-onset central hypoventilation with hypothalamic dysfunction who were referred to Rush University Medical Center for clinical or genetic assessment in the past 3 years were identified, and medical charts were reviewed to determine shared characteristics of the affected subjects. Blood was collected for genetic testing of candidate genes (PHOX2B, TRKB, and BDNF) and for high-resolution conventional G-banding, subtelomeric fluorescent in situ hybridization, and comparative genomic hybridization analysis. A subset of these children were studied in the Pediatric Respiratory Physiology Laboratory at Rush University Medical Center.
  
  
  RESULTS
  Twenty-three children with what we are now naming rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation were identified. Comprehensive medical charts and blood for genetic testing were available for 15 children; respiratory physiology studies were performed at Rush University Medical Center on 9 children. The most characteristic manifestations were the presentation of rapid-onset obesity in the first 10 years of life (median age at onset: 3 years), followed by hypothalamic dysfunction and then onset of symptoms of autonomic dysregulation (median age at onset: 3.6 years) with later onset of alveolar hypoventilation (median age at onset: 6.2 years). Testing of candidate genes (PHOX2B, TRKB, and BDNF) revealed no mutations or rare variants. High-resolution chromosome analysis, comparative genomic hybridization, and subtelomeric fluorescent in situ hybridization results were negative for the 2 patients selected for those analyses.
  
  
  CONCLUSIONS
  We provide a comprehensive description of the clinical spectrum of rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation in terms of timing and scope of symptoms, study of candidate genes, and screening for chromosomal deletions and duplications. Negative PHOX2B sequencing results demonstrate that this entity is distinct from congenital central hypoventilation syndrome.
authors.affiliation: Department of Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Diego
authors.initials: D
authors.lastname: Ize-Ludlow
authors.forename: Juliette A
authors.initials: JA
authors.lastname: Gray
authors.forename: Mark A
authors.initials: MA
authors.lastname: Sperling
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Berry-Kravis
authors.forename: Jeff M
authors.initials: JM
authors.lastname: Milunsky
authors.forename: I Sadaf
authors.initials: IS
authors.lastname: Farooqi
authors.forename: Casey M
authors.initials: CM
authors.lastname: Rand
authors.forename: Debra E
authors.initials: DE
authors.lastname: Weese-Mayer
mesh_terms: D001342:Autonomic Nervous System Diseases / Q000175:diagnosis / Q000235:genetics*; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D003937:Diagnosis, Differential; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007027:Hypothalamic Diseases / Q000175:diagnosis / Q000235:genetics*; D007040:Hypoventilation / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics; D009765:Obesity / Q000235:genetics*; D020813:Receptor, trkB / Q000235:genetics; D020919:Sleep Disorders, Intrinsic / Q000175:diagnosis; D013577:Syndrome; D014157:Transcription Factors / Q000235:genetics
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D018398:Homeodomain Proteins; C109220:NBPhox protein; D009419:Nerve Tissue Proteins; D014157:Transcription Factors; D020813:Receptor, trkB