Abstract
Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD) is a rare and complex pediatric disorder. Despite increased identification and advancing knowledge of the disease course, the variable onset and timing of phenotypic features in ROHHAD often result in delayed or missed diagnosis, potentially leading to fatal central hypoventilation, cardiorespiratory arrest, and impaired neurocognitive development. The 5-hydroxytryptamine receptor 1A (HTR1A), orthopedia (OTP), and pituitary adenylate cyclase activating polypeptide (PACAP) genes were targeted in the etiology of ROHHAD based on their roles in the embryologic development of the hypothalamus and autonomic nervous system. We hypothesized that variations of HTR1A, OTP, and/or PACAP would be associated with ROHHAD. All coding regions and intron-exon boundaries of the HTR1A, OTP, and PACAP genes, in addition to the promoter region of the HTR1A gene, were analyzed by standard sequencing in 25 ROHHAD cases and 25 matched controls. Thirteen variations, including six protein-changing mutations, were identified. None of these variations were significantly correlated with ROHHAD. This report provides evidence that variation of the HTR1A, OTP, and PACAP genes are not responsible for ROHHAD. These results represent a further step in the investigation of the genetic determinants of ROHHAD.
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Abbreviations
- ANS:
-
autonomic nervous system
- CCHS:
-
Congenital Central Hypoventilation Syndrome
- CMH:
-
Children's Memorial Hospital
- HTR 1A :
-
5-hydroxytryptamine (serotonin) receptor 1A
- LO-CCHS:
-
later onset-Congenital Central Hypoventilation Syndrome
- OTP:
-
orthopedia
- PACAP:
-
pituitary adenylate cyclase activating polypeptide
- ROHHAD:
-
rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation
- RUMC:
-
Rush University Medical Center
References
Fishman LS, Samson JH, Sperling DR 1965 Primary alveolar hypoventilation syndrome (Ondine's Curse). Am J Dis Child 110: 155–161
Katz ES, McGrath S, Marcus CL 2000 Late-onset central hypoventilation with hypothalamic dysfunction: a distinct clinical syndrome. Pediatr Pulmonol 29: 62–68
Amiel J, Laudier B, Attie-Bitach T, Trang H, de Pontual L, Gener B, Trochet D, Etchevers H, Ray P, Simonneau M, Vekemans M, Munnich A, Gaultier C, Lyonnet S 2003 Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome. Nat Genet 33: 459–461
Berry-Kravis EM, Zhou L, Rand CM, Weese-Mayer DE 2006 Congenital central hypoventilation syndrome: PHOX2B mutations and phenotype. Am J Respir Crit Care Med 174: 1139–1144
Weese-Mayer DE, Berry-Kravis EM, Zhou L, Maher BS, Silvestri JM, Curran ME, Marazita ML 2003 Idiopathic congenital central hypoventilation syndrome: analysis of genes pertinent to early autonomic nervous system embryologic development and identification of mutations in PHOX2B. Am J Med Genet A 123A: 267–278
Sasaki A, Kanai M, Kijima K, Akaba K, Hashimoto M, Hasegawa H, Otaki S, Koizumi T, Kusuda S, Ogawa Y, Tuchiya K, Yamamoto W, Nakamura T, Hayasaka K 2003 Molecular analysis of congenital central hypoventilation syndrome. Hum Genet 114: 22–26
Trochet D, Bourdeaut F, Janoueix-Lerosey I, Deville A, de Pontual L, Schleiermacher G, Coze C, Philip N, Frebourg T, Munnich A, Lyonnet S, Delattre O, Amiel J 2004 Germline mutations of the paired-like homeobox 2B (PHOX2B) gene in neuroblastoma. Am J Hum Genet 74: 761–764
Ize-Ludlow D, Gray JA, Sperling MA, Berry-Kravis EM, Milunsky JM, Farooqi IS, Rand CM, Weese-Mayer DE 2007 Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation presenting in childhood. Pediatrics 120: e179–e188
De Pontual L, Trochet D, Caillat-Zucman S, Abou Shenab OA, Bougneres P, Crow Y, Cunningham S, Esteva B, Heberle LC, Leger J, Pinto G, Polak M, Shafik MH, Straus C, Trang H, Munnich A, Lyonnet S, Desguerre I, Amiel J 2008 Delineation of late onset hypoventilation associated with hypothalamic dysfunction syndrome. Pediatr Res 64: 689–694
Bougnéres P, Pantalone L, Linglart A, Rothenbühler A, Le Stunff C 2008 Endocrine manifestations of the rapid-onset obesity with hypoventilation, hypothalamic, autonomic dysregulation and neural tumor syndrome in childhood. J Clin Endocrinol Metab 93: 3971–3980
Onal H, Ersen A 2010 A case of late-onset central hypoventilation syndrome with hypothalamic dysfunction: through a new phenotype. Turk J Pediatr 52: 198–202
Paz-Priel I, Cooke DW, Chen AR 2011 Cyclophosphamide for rapid-onset obesity, hypothalamic dysfunction, hypoventilation, and autonomic dysregulation syndrome. J Pediatr 158: 337–339
Yadav VK, Oury F, Suda N, Liu ZW, Gao XB, Confavreux C, Klemenhagen KC, Tanaka KF, Gingrich JA, Guo XE, Tecott LH, Mann JJ, Hen R, Horvath TL, Karsenty G 2009 A serotonin-dependent mechanism explains the leptin regulation of bone mass, appetite, and energy expenditure. Cell 138: 976–989
Thor KB, Blitz-Siebert A, Helke CJ 1992 Autoradiographic localization of 5HT1 binding sites in autonomic areas of the rat dorsomedial medulla oblongata. Synapse 10: 217–227
Thor KB, Blitz-Siebert A, Helke CJ 1992 Autoradiographic localization of 5HT1 binding sites in the medulla oblongata of the rat. Synapse 10: 185–205
Bardet SM, Martinez-de-la-Torre M, Northcutt RG, Rubenstein JL, Puelles L 2008 Conserved pattern of OTP-positive cells in the paraventricular nucleus and other hypothalamic sites of tetrapods. Brain Res Bull 75: 231–235
Das M, Vihlen CS, Legradi G 2007 Hypothalamic and brainstem sources of pituitary adenylate cyclase-activating polypeptide nerve fibers innervating the hypothalamic paraventricular nucleus in the rat. J Comp Neurol 500: 761–776
Farnham MM, Li Q, Goodchild AK, Pilowsky PM 2008 PACAP is expressed in sympathoexcitatory bulbospinal C1 neurons of the brain stem and increases sympathetic nerve activity in vivo. Am J Physiol Regul Integr Comp Physiol 294: R1304–R1311
Légrádi G, Shioda S, Arimura A 1994 Pituitary adenylate cyclase-activating polypeptide-like immunoreactivity in autonomic regulatory areas of the rat medulla oblongata. Neurosci Lett 176: 193–196
Sundler F, Ekblad E, Hannibal J, Moller K, Zhang YZ, Mulder H, Elsas T, Grunditz T, Danielsen N, Fahrenkrug J, Uddman R 1996 Pituitary adenylate cyclase-activating peptide in sensory and autonomic ganglia: localization and regulation. Ann N Y Acad Sci 805: 410–426
Gray SL, Cummings KJ, Jirik FR, Sherwood NM 2001 Targeted disruption of the pituitary adenylate cyclase-activating polypeptide gene results in early postnatal death associated with dysfunction of lipid and carbohydrate metabolism. Mol Endocrinol 15: 1739–1747
Adams BA, Gray SL, Isaac ER, Bianco AC, Vidal-Puig AJ, Sherwood NM 2008 Feeding and metabolism in mice lacking pituitary adenylate cyclase-activating polypeptide. Endocrinology 149: 1571–1580
Cummings KJ, Willie C, Wilson RJ 2008 Pituitary adenylate cyclase-activating polypeptide maintains neonatal breathing but not metabolism during mild reductions in ambient temperature. Am J Physiol Regul Integr Comp Physiol 294: R956–R965
Cummings KJ, Pendlebury JD, Sherwood NM, Wilson RJ 2004 Sudden neonatal death in PACAP-deficient mice is associated with reduced respiratory chemoresponse and susceptibility to apnoea. J Physiol 555: 15–26
Ouvrier R, Nunn K, Sprague T, McLean C, Arbuckle S, Hopkins I, North K 1995 Idiopathic hypothalamic dysfunction: a paraneoplastic syndrome?. Lancet 346: 1298
Sirvent N, Berard E, Chastagner P, Feillet F, Wagner K, Sommelet D 2003 Hypothalamic dysfunction associated with neuroblastoma: evidence for a new paraneoplastic syndrome?. Med Pediatr Oncol 40: 326–328
Didelot A, Honnorat J 2009 Update on paraneoplastic neurological syndromes. Curr Opin Oncol 21: 566–572
Nath U, Grant R 1997 Neurological paraneoplastic syndromes. J Clin Pathol 50: 975–980
Overeem S, Black JL 3rd, Lammers GJ 2008 Narcolepsy: immunological aspects. Sleep Med Rev 12: 95–107
Patwari PP, Rand CM, Berry-Kravis EM, Jennings LJ, Yu M, Weese-Mayer DE : Rapid onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD): Report on identical twins discordant for ROHHAD phenotype. Pediatrics, in press
Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, Ballestar ML, Heine-Suner D, Cigudosa JC, Urioste M, Benitez J, Boix-Chornet M, Sanchez-Aguilera A, Ling C, Carlsson E, Poulsen P, Vaag A, Stephan Z, Spector TD, Wu YZ, Plass C, Esteller M 2005 Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci USA 102: 10604–10609
Hirasawa R, Feil R 2010 Genomic imprinting and human disease. Essays Biochem 48: 187–200
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Supported by the ROHHAD Fight Inc., Scott R. Conlon ROHHAD Research Fund, the Chicago Community Trust Foundation, the Alberta Innervates Health Solution, Canadian Institute of Health Research, and Calgary SIDS.
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Rand, C., Patwari, P., Rodikova, E. et al. Rapid-Onset Obesity With Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation: Analysis of Hypothalamic and Autonomic Candidate Genes. Pediatr Res 70, 375–378 (2011). https://doi.org/10.1203/PDR.0b013e318229474d
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DOI: https://doi.org/10.1203/PDR.0b013e318229474d
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