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Orphanet Journal of Rare Diseases
Published in: Orphanet Journal of Rare Diseases 1/2018

Open Access 01-12-2018 | Research

ROHHAD and Prader-Willi syndrome (PWS): clinical and genetic comparison

Authors: Sarah F. Barclay, Casey M. Rand, Lisa Nguyen, Richard J. A. Wilson, Rachel Wevrick, William T. Gibson, N. Torben Bech-Hansen, Debra E. Weese-Mayer

Published in: Orphanet Journal of Rare Diseases | Issue 1/2018

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Abstract

Background

Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) is a very rare and potentially fatal pediatric disorder, the cause of which is presently unknown. ROHHAD is often compared to Prader-Willi syndrome (PWS) because both share childhood obesity as one of their most prominent and recognizable signs, and because other symptoms such as hypoventilation and autonomic dysfunction are seen in both. These phenotypic similarities suggest they might be etiologically related conditions. We performed an in-depth clinical comparison of the phenotypes of ROHHAD and PWS and used NGS and Sanger sequencing to analyze the coding regions of genes in the PWS region among seven ROHHAD probands.

Results

Detailed clinical comparison of ROHHAD and PWS patients revealed many important differences between the phenotypes. In particular, we highlight the fact that the areas of apparent overlap (childhood-onset obesity, hypoventilation, autonomic dysfunction) actually differ in fundamental ways, including different forms and severity of hypoventilation, different rates of obesity onset, and different manifestations of autonomic dysfunction. We did not detect any disease-causing mutations within PWS candidate genes in ROHHAD probands.

Conclusions

ROHHAD and PWS are clinically distinct conditions, and do not share a genetic etiology. Our detailed clinical comparison and genetic analyses should assist physicians in timely distinction between the two disorders in obese children. Of particular importance, ROHHAD patients will have had a normal and healthy first year of life; something that is never seen in infants with PWS.
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Literature
1.
Ize-Ludlow D, Gray JA, Sperling MA, Berry-Kravis EM, Milunsky JM, Farooqi IS, Rand CM, Weese-Mayer DE. Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation presenting in childhood. Pediatrics. 2007;120(1):e179–88.CrossRefPubMed
2.
Fishman LS, Samson JH, Sperling DR. Primary alveolar hypoventilation syndrome (Ondine’s curse). Am J Dis Child. 1965;110:155–61.CrossRefPubMed
3.
Katz ES, McGrath S, Marcus CL. Late-onset central hypoventilation with hypothalamic dysfunction: a distinct clinical syndrome. Pediatr Pulmonol. 2000;29(1):62–8.CrossRefPubMed
4.
Bougneres P, Pantalone L, Linglart A, Rothenbuhler A, Le Stunff C. Endocrine manifestations of the rapid-onset obesity with hypoventilation, hypothalamic, autonomic dysregulation, and neural tumor syndrome in childhood. J Clin Endocrinol Metab. 2008;93(10):3971–80.CrossRefPubMed
5.
De Pontual L, Trochet D, Caillat-Zucman S, Abou Shenab OA, Bougneres P, Crow Y, Cunningham S, Esteva B, Heberle LC, Leger J, et al. Delineation of late onset hypoventilation associated with hypothalamic dysfunction syndrome. Pediatr Res. 2008;64(6):689–94.CrossRefPubMed
6.
Onal H, Ersen A. A case of late-onset central hypoventilation syndrome with hypothalamic dysfunction: through a new phenotype. Turk J Pediatr. 2010;52(2):198–202.PubMed
7.
Patwari PP, Wolfe LF. Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation: review and update. Curr Opin Pediatr. 2014;26(4):487–92.CrossRefPubMed
8.
Weese-Mayer DE, Rand CM, Ize-Ludlow D. Commentary: rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD): remember your ABCs (airway, breathing, circulation). J Can Acad Child Adolesc Psychiatry. 2013;22(3):238–9.PubMedPubMedCentral
9.
Cassidy SB, Schwartz S, Miller JL, Driscoll DJ. Prader-Willi syndrome. Genet Med. 2012;14(1):10–26.CrossRefPubMed
10.
11.
McCandless SE, Committee on G. Clinical report-health supervision for children with Prader-Willi syndrome. Pediatrics. 2011;127(1):195–204.CrossRefPubMed
12.
Holm VA, Cassidy SB, Butler MG, Hanchett JM, Greenswag LR, Whitman BY, Greenberg F. Prader-Willi syndrome: consensus diagnostic criteria. Pediatrics. 1993;91(2):398–402.PubMed
13.
Schaaf CP, Gonzalez-Garay ML, Xia F, Potocki L, Gripp KW, Zhang B, Peters BA, McElwain MA, Drmanac R, Beaudet AL, et al. Truncating mutations of MAGEL2 cause Prader-Willi phenotypes and autism. Nat Genet. 2013;45(11):1405–8.CrossRefPubMedPubMedCentral
14.
Fountain MD, Aten E, Cho MT, Juusola J, Walkiewicz MA, Ray JW, Xia F, Yang Y, Graham BH, Bacino CA, et al. The phenotypic spectrum of Schaaf-Yang syndrome: 18 new affected individuals from 14 families. Genet Med. 2017;19(1):45–52.CrossRefPubMed
15.
Barclay SF, Rand CM, Borch LA, Nguyen L, Gray PA, Gibson WT, Wilson RJ, Gordon PM, Aung Z, Berry-Kravis EM, et al. Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD): exome sequencing of trios, monozygotic twins and tumours. Orphanet J Rare Dis. 2015;10:103.CrossRefPubMedPubMedCentral
16.
Van der Auwera GA, Carneiro MO, Hartl C, Poplin R, Del Angel G, Levy-Moonshine A, Jordan T, Shakir K, Roazen D, Thibault J, et al. From FastQ data to high confidence variant calls: the Genome Analysis Toolkit best practices pipeline. Curr Protoc Bioinformatics. 2013;43:11–33. 11 10PubMed
17.
Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 2010;38(16):e164.CrossRefPubMedPubMedCentral
18.
Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, O'Donnell-Luria AH, Ware JS, Hill AJ, Cummings BB, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536(7616):285–91.CrossRefPubMedPubMedCentral
19.
Whittington J, Holland A, Webb T, Butler J, Clarke D, Boer H. Relationship between clinical and genetic diagnosis of Prader-Willi syndrome. J Med Genet. 2002;39(12):926–32.CrossRefPubMedPubMedCentral
20.
Reppucci D, Hamilton J, Yeh EA, Katz S, Al-Saleh S, Narang I. ROHHAD syndrome and evolution of sleep disordered breathing. Orphanet J Rare Dis. 2016;11(1):106.CrossRefPubMedPubMedCentral
21.
North KN, Ouvrier RA, McLean CA, Hopkins IJ. Idiopathic hypothalamic dysfunction with dilated unresponsive pupils: report of two cases. J Child Neurol. 1994;9(3):320–5.CrossRefPubMed
22.
Ouvrier R, Nunn K, Sprague T, McLean C, Arbuckle S, Hopkins I, North K. Idiopathic hypothalamic dysfunction: a paraneoplastic syndrome? Lancet. 1995;346(8985):1298.
23.
Sanklecha M, Sundaresan S, Udani V. ROHHAD syndrome: the girl who forgets to breathe. Indian Pediatr. 2016;53(4):343–4.CrossRefPubMed
24.
Ibanez-Mico S, Marcos Oltra AM, de Murcia LS, Ruiz Pruneda R, Martinez Ferrandez C, Domingo Jimenez R. Rapid-onset obesity with hypothalamic dysregulation, hypoventilation, and autonomic dysregulation (ROHHAD syndrome): a case report and literature review. Neurologia. 2017;32(9):616–22.
25.
Aljabban L, Kassab L, Bakoura NA, Alsalka MF, Maksoud I. Rapid-onset obesity, hypoventilation, hypothalamic dysfunction, autonomic dysregulation and neuroendocrine tumor syndrome with a homogenous enlargement of the pituitary gland: a case report. J Med Case Rep. 2016;10(1):328.CrossRefPubMedPubMedCentral
26.
Carroll MS, Patwari PP, Kenny AS, Brogadir CD, Stewart TM, Weese-Mayer DE. Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD): response to ventilatory challenges. Pediatr Pulmonol. 2015;50(12):1336–45.CrossRefPubMed
27.
Nixon GM, Brouillette RT. Sleep and breathing in Prader-Willi syndrome. Pediatr Pulmonol. 2002;34(3):209–17.CrossRefPubMed
28.
Livingston FR, Arens R, Bailey SL, Keens TG, Ward SL. Hypercapnic arousal responses in Prader-Willi syndrome. Chest. 1995;108(6):1627–31.CrossRefPubMed
29.
Schluter B, Buschatz D, Trowitzsch E, Aksu F, Andler W. Respiratory control in children with Prader-Willi syndrome. Eur J Pediatr. 1997;156(1):65–8.CrossRefPubMed
30.
Manni R, Politini L, Nobili L, Ferrillo F, Livieri C, Veneselli E, Biancheri R, Martinetti M, Tartara A. Hypersomnia in the Prader Willi syndrome: clinical-electrophysiological features and underlying factors. Clin Neurophysiol. 2001;112(5):800–5.CrossRefPubMed
31.
Arens R, Gozal D, Burrell BC, Bailey SL, Bautista DB, Keens TG, Ward SL. Arousal and cardiorespiratory responses to hypoxia in Prader-Willi syndrome. Am J Respir Crit Care Med. 1996;153(1):283–7.CrossRefPubMed
32.
Gozal D, Arens R, Omlin KJ, Ward SL, Keens TG. Absent peripheral chemosensitivity in Prader-Willi syndrome. J Appl Physiol (1985). 1994;77(5):2231–6.CrossRef
33.
Schrander-Stumpel CT, Curfs LM, Sastrowijoto P, Cassidy SB, Schrander JJ, Fryns JP. Prader-Willi syndrome: causes of death in an international series of 27 cases. Am J Med Genet A. 2004;124A(4):333–8.CrossRefPubMed
34.
35.
Erensoy H, Ceylan ME, Evrensel A. Psychiatric symptoms in rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation syndrome and its treatment: a case report. Chin Med J. 2016;129(2):242–3.CrossRefPubMedPubMedCentral
36.
Sethi K, Lee YH, Daugherty LE, Hinkle A, Johnson MD, Katzman PJ, Sullivan JS. ROHHADNET syndrome presenting as major behavioral changes in a 5-year-old obese girl. Pediatrics. 2014;134(2):e586–9.CrossRefPubMed
37.
Grudnikoff E, Foley C, Poole C, Theodosiadis E. Nocturnal anxiety in a youth with rapid-onset obesity, hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD). J Can Acad Child Adolesc Psychiatry. 2013;22(3):235–7.PubMedPubMedCentral
38.
Kot K, Moszczynska E, Lecka-Ambroziak A, Migdal M, Szalecki M. ROHHAD in a 9-year-old boy - clinical case. Endokrynol Pol. 2016;67(2):226–31.CrossRefPubMed
39.
Fan Z, Greenwood R, Fisher A, Pendyal S, Powell CM. Characteristics and frequency of seizure disorder in 56 patients with Prader-Willi syndrome. Am J Med Genet A. 2009;149A(7):1581–4.CrossRefPubMed
Metadata
Title
ROHHAD and Prader-Willi syndrome (PWS): clinical and genetic comparison
Authors
Sarah F. Barclay
Casey M. Rand
Lisa Nguyen
Richard J. A. Wilson
Rachel Wevrick
William T. Gibson
N. Torben Bech-Hansen
Debra E. Weese-Mayer
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Orphanet Journal of Rare Diseases / Issue 1/2018
Electronic ISSN: 1750-1172
DOI
https://doi.org/10.1186/s13023-018-0860-0

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