The Indian Journal of Pediatrics

, Volume 85, Issue 6, pp 478–485 | Cite as

Genetic and Syndromic Causes of Obesity and its Management

  • Ildiko H. Koves
  • Christian Roth
Review Article


The aim of this article is to provide an in depth review of the rare genetic and syndromic forms of childhood obesity. The authors demonstrate the complexity and inter-relationships of the leptin-melanocortin signaling pathway and its central nervous system and systemic effects. Authors highlight the clinical distinctive features of genetic/syndromic causes for childhood obesity, in particular, relative shorter height to their genetic potential, developmental challenges and in some instances, ophthalmological and retina changes. They outline specific genetic testing and treatment options available for these conditions.


Monogenic obesity Syndromic obesity Clinical assessment Leptin-melanocortin signaling pathway 



IHK drafted the manuscript and developed it ready for submission. IHK is the corresponding author. CR provided oversight of manuscript editing and developed the included figure and Table 1. Senior author. Dr. Catherine Pihoker, Professor of Pediatrics / University of Washington, Division of Endocrinology and Diabetes, Seattle Children’s Hospital will act as guarantor for this paper.

Compliance with Ethical Standards

Conflict of Interest


Source of Funding



  1. 1.
    Farooqi S. Insights from the genetics of severe childhood obesity. Horm Res. 2007;68:5–7. ed. 2007;356:237–47.Google Scholar
  2. 2.
    Farooqi IS, Wangensteen T, Collins S, et al. Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor. N Engl J Med. 2007;356:237–47.Google Scholar
  3. 3.
    Wabitsch M, Funcke JB, Lennerz B, et al. Biologically inactive leptin and early-onset extreme obesity. N Engl J Med. 2015;372:48–54.CrossRefPubMedGoogle Scholar
  4. 4.
    Wabitsch M, Funcke JB, von Schnurbein J, et al. Severe early-onset obesity due to bioinactive leptin caused by a p.N103k mutation in the leptin gene. J Clin Endocrinol Metab. 2015;100:3227–30.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Abaci A, Catli G, Bayram E, et al. A case of rapid-onset obesity with hypothalamic dysfunction, hypoventilation, autonomic dysregulation, and neural crest tumor: Rohhadnet syndrome. Endocr Pract. 2013;19:e12–6.CrossRefPubMedGoogle Scholar
  6. 6.
    Jacobson P, Ukkola O, Rankinen T, et al. Melanocortin 4 receptor sequence variations are seldom a cause of human obesity: the swedish obese subjects, the heritage family study, and a memphis cohort. J Clin Endocrinol Metab. 2002;87:4442–6.CrossRefPubMedGoogle Scholar
  7. 7.
    Vollbach H, Brandt S, Lahr G, et al. Prevalence and phenotypic characterization of MC4R variants in a large pediatric cohort. Int J Obes. 2017;41:13–22.CrossRefGoogle Scholar
  8. 8.
    Hinney A, Volckmar AL, Knoll N. Melanocortin-4 receptor in energy homeostasis and obesity pathogenesis. Prog Mol Biol Transl Sci. 2013;114:147–91.CrossRefPubMedGoogle Scholar
  9. 9.
    Farooqi IS, Keogh JM, Yeo GS, Lank EJ, Cheetham T, O'Rahilly S. Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med. 2003;348:1085–95.CrossRefPubMedGoogle Scholar
  10. 10.
    Paolini B, Maltese PE, Del Ciondolo I, et al. Prevalence of mutations in LEP, LEPR, and MC4R genes in individuals with severe obesity. Genet Mol Res. 2016;15(3).
  11. 11.
    Hainerova IA, Lebl J. Treatment options for children with monogenic forms of obesity. World Rev Nutr Diet. 2013;106:105–12.PubMedGoogle Scholar
  12. 12.
    Wardlaw SL. Hypothalamic proopiomelanocortin processing and the regulation of energy balance. Eur J Pharmacol. 2011;660:213–9.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Krude H, Biebermann H, Luck W, Horn R, Brabant G, Gruters A. Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by pomc mutations in humans. Nat Genet. 1998;19:155–7.CrossRefPubMedGoogle Scholar
  14. 14.
    Kuehnen P, Mischke M, Wiegand S, et al. An alu element-associated hypermethylation variant of the pomc gene is associated with childhood obesity. PLoS Genet. 2012;8:e1002543.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Kuhnen P, Handke D, Waterland RA, et al. Interindividual variation in DNA methylation at a putative pomc metastable epiallele is associated with obesity. Cell Metab. 2016;24:502–9.CrossRefPubMedGoogle Scholar
  16. 16.
    Kuhnen P, Clement K, Wiegand S, et al. Proopiomelanocortin deficiency treated with a melanocortin-4 receptor agonist. N Engl J Med. 2016;375:240–6.CrossRefPubMedGoogle Scholar
  17. 17.
    Loffler D, Behrendt S, Creemers JW, et al. Functional and clinical relevance of novel and known pcsk1 variants for childhood obesity and glucose metabolism. Mol Metab. 2017;6:295–305.CrossRefPubMedGoogle Scholar
  18. 18.
    Jackson RS, Creemers JW, Ohagi S, et al. Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nat Genet. 1997;16:303–6.CrossRefPubMedGoogle Scholar
  19. 19.
    Khan MJ, Gerasimidis K, Edwards CA, Shaikh MG. Mechanisms of obesity in Prader-Willi syndrome. Pediatr Obes. 2016;
  20. 20.
    Holm VA, Cassidy SB, Butler MG, et al. Prader-Willi syndrome: consensus diagnostic criteria. Pediatrics. 1993;91:398–402.Google Scholar
  21. 21.
    Driscoll DJ, Miller JL, Schwartz S, Cassidy SB. Prader-Willi syndrome. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean, LJH, Bird TD, Ledbetter N, Mefford HC, Smith RJH, Stephens K, editors. GeneReviews® [Internet]. Seattle: University of Washington, Seattle; 1993-2017.Google Scholar
  22. 22.
    Ize-Ludlow D, Gray JA, Sperling MA, et al. Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation presenting in childhood. Pediatrics. 2007;120:e179–88.CrossRefPubMedGoogle Scholar
  23. 23.
    Chew HB, Ngu LH, Keng WT. Rapid-onset obesity with hypothalamic dysfunction, hypoventilation and autonomic dysregulation (rohhad): a case with additional features and review of the literature. BMJ Case Rep. 2011;2011.Google Scholar
  24. 24.
    Chandrakantan A, Poulton TJ. Anesthetic considerations for rapid-onset obesity, hypoventilation, hypothalamic dysfunction, and autonomic dysfunction (rohhad) syndrome in children. Paediatr Anaesth. 2013;23:28–32.CrossRefPubMedGoogle Scholar
  25. 25.
    Sumanasena SP, de Silva S, Perera I, Sudeen A, Wasala R. Rapid onset obesity, hypoventilation, hypothalamic, autonomic and thermal dysregulation, and neural tumour (rohhadnet) syndrome presenting with cushing syndrome. Ceylon Med J. 2012;57:47–8.CrossRefPubMedGoogle Scholar
  26. 26.
    Barclay SF, Rand CM, Borch LA, 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.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Barclay SF, Rand CM, Gray PA, et al. Absence of mutations in hcrt, hcrtr1 and hcrtr2 in patients with rohhad. Respir Physiol Neurobiol. 2016;221:59–63.CrossRefPubMedGoogle Scholar
  28. 28.
    Alvarez-Satta M, Castro-Sanchez S, Valverde D. Alstrom syndrome: current perspectives. Appl Clin Genet. 2015;8:171–9.PubMedPubMedCentralGoogle Scholar
  29. 29.
    Nikopoulos K, Butt GU, Farinelli P, et al. A large multiexonic genomic deletion within the ALMS1 gene causes Alstrom syndrome in a consanguineous Pakistani family. Clin Genet. 2015;
  30. 30.
    Das Bhowmik A, Gupta N, Dalal A, Kabra M. Whole exome sequencing identifies a homozygous nonsense variation in ALMS1 gene in a patient with syndromic obesity. Obes Res Clin Pract. 2017;11:241–6.CrossRefPubMedGoogle Scholar
  31. 31.
    Forsythe E, Beales PL. Bardet-biedl syndrome. Eur J Hum Genet. 2013;21:8–13.CrossRefPubMedGoogle Scholar
  32. 32.
    Seo S, Guo DF, Bugge K, Morgan DA, Rahmouni K, Sheffield VC. Requirement of Bardet-Biedl syndrome proteins for leptin receptor signaling. Hum Mol Genet. 2009;18:1323–31.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Gruters-Kieslich A, Reyes M, Sharma A, et al. Early-onset obesity: unrecognized first evidence for GNAS mutations and methylation changes. J Clin Endocrinol Metab. 2017;102:2670–7.Google Scholar
  34. 34.
    Mason K, Page L, Balikcioglu PG. Screening for hormonal, monogenic, and syndromic disorders in obese infants and children. Pediatr Ann. 2014;43:e218–24.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Ali O, Cerjak D, Kent JW Jr, et al. Methylation of SOCS3 is inversely associated with metabolic syndrome in an epigenome-wide association study of obesity. Epigenetics. 2016;11:699–707.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Farooqi IS, Jebb SA, Langmack G, et al. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med. 1999;341:879–84.CrossRefPubMedGoogle Scholar
  37. 37.
    Styne DM, Arslanian SA, Connor EL, et al. Pediatric obesity-assessment, treatment, and prevention: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2017;102:709–57.CrossRefPubMedGoogle Scholar
  38. 38.
    Yanovski JA, Krakoff J, Salaita CG, et al. Effects of metformin on body weight and body composition in obese insulin-resistant children: a randomized clinical trial. Diabetes. 2011;60:477–85.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Kendall D, Vail A, Amin R, et al. Metformin in obese children and adolescents: the moca trial. J Clin Endocrinol Metab. 2013;98:322–9.CrossRefPubMedGoogle Scholar
  40. 40.
    Maahs D, de Serna DG, Kolotkin RL, et al. Randomized, double-blind, placebo-controlled trial of orlistat for weight loss in adolescents. Endocr Pract. 2006;12:18–28.CrossRefPubMedGoogle Scholar
  41. 41.
    Chanoine JP, Hampl S, Jensen C, Boldrin M, Hauptman J. Effect of orlistat on weight and body composition in obese adolescents: a randomized controlled trial. JAMA. 2005;293:2873–83.CrossRefPubMedGoogle Scholar

Copyright information

© Dr. K C Chaudhuri Foundation 2017

Authors and Affiliations

  1. 1.Division of Endocrinology and Diabetes, Department of PediatricsSeattle Children’s Hospital, University of WashingtonSeattleUSA
  2. 2.Center for Integrative Brain Research, Seattle Children’s Research InstituteSeattleUSA

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