Published online July 2, 2007
PEDIATRICS Vol. 120 No. 1 July 2007, pp. e179-e188 (doi:10.1542/peds.2006-3324)
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ARTICLE

Rapid-Onset Obesity With Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation Presenting in Childhood

Diego Ize-Ludlow, MDa, Juliette A. Gray, BScb, Mark A. Sperling, MDa, Elizabeth M. Berry-Kravis, MD, PhDc,d,e, Jeff M. Milunsky, MDf,g,,h, I. Sadaf Farooqi, MD, PhDb, Casey M. Rand, BSc and Debra E. Weese-Mayer, MDc

a Department of Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania
b University Department of Clinical Biochemistry, Addenbrooke's Hospital, Cambridge, England
c Departments of Pediatrics
d Neurology
e Biochemistry, Rush Children's Hospital, Rush University Medical Center, Chicago, Illinois
f Center for Human Genetics
g Departments of Pediatrics
h Genetics and Genomics, Boston University School of Medicine, Boston, Massachusetts

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.

Key Words: rapid-onset obesity • hypothalamic dysfunction • alveolar hypoventilation • autonomic nervous system dysregulation • PHOX2B gene • NTRK2 gene • BDNF gene

Abbreviations: PHOX2B—paired-like homeobox 2B • ROHHAD—rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation • RUMC—Rush University Medical Center • FISH—fluorescent in situ hybridization • CGH—comparative genomic hybridization • LO-CHS—late-onset central hypoventilation syndrome • HD—hypothalamic dysfunction • CCHS—congenital central hypoventilation syndrome • BDNF—brain-derived neurotrophic factor • TRKB—tyrosine kinase receptor b • NTRK2—neurotrophic tyrosine kinase, receptor, type 2

Accepted Jan 26, 2007.




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