J Pediatr Genet 2021; 10(03): 194-204
DOI: 10.1055/s-0041-1731035
Review Article

Evaluation and Management of Early Onset Genetic Obesity in Childhood

Sonali Malhotra
1   Department of Pediatric Endocrinology, Massachusetts General Hospital for Children, Harvard Medical School, Boston, Massachusetts, United States
,
Ramya Sivasubramanian
2   Division of Pediatric Nephrology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States
,
3   Department of Medicine; Department of Pediatrics; Department of Surgery; Division of Endocrinology, Diabetes & Metabolism, Vanderbilt University School of Medicine, Nashville, Tennessee, United States
› Author Affiliations
Funding None.

Abstract

One in five children and adolescents in the United States are diagnosed with obesity and nearly 6% of them are being classified under the severe obesity category. With over 7% of severe obesity being attributed to genetic disorders, in this review we aim to focus on monogenic and syndromic obesity: its etiology, wide spectrum of clinical presentation, criticalness of early identification, and limited management options. Advanced genetic testing methods including microarray and whole genome sequencing are imperative to identify the spectrum of mutations and develop targeted treatment strategies including personalized multidisciplinary care, use of investigational drugs, and explore surgical options in this unique subset of severe pediatric obesity.

Note

S.M. serves as a consultant to Rhythm Pharmaceuticals. R.S. has nothing to disclose. G.S. serves as a consultant to NovoNordisk and Rhythm Pharmaceuticals.




Publication History

Received: 18 February 2021

Accepted: 16 April 2021

Article published online:
03 July 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 
  • References

  • 1 Ogden CL, Carroll MD, Lawman HG. et al. Trends in obesity prevalence among children and adolescents in the United States, 1988-1994 through 2013-2014. JAMA 2016; 315 (21) 2292-2299
  • 2 Thaker VV. Genetic and epigenetic causes of obesity. Adolesc Med State Art Rev 2017; 28 (02) 379-405
  • 3 Farooqi IS, O'Rahilly S. Mutations in ligands and receptors of the leptin-melanocortin pathway that lead to obesity. Nat Clin Pract Endocrinol Metab 2008; 4 (10) 569-577
  • 4 Huvenne H, Dubern B, Clément K, Poitou C. Rare genetic forms of obesity: clinical approach and current treatments in 2016. Obes Facts 2016; 9 (03) 158-173
  • 5 Farooqi S. Insights from the genetics of severe childhood obesity. Horm Res 2007; 68 (Suppl. 05) 5-7
  • 6 Kleinendorst L, Abawi O, van der Kamp HJ. et al. Leptin receptor deficiency: a systematic literature review and prevalence estimation based on population genetics. Eur J Endocrinol 2020; 182 (01) 47-56
  • 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 (01) 13-22
  • 8 Hinney A, Volckmar AL, Knoll N. Melanocortin-4 receptor in energy homeostasis and obesity pathogenesis. Prog Mol Biol Transl Sci 2013; 114: 147-191
  • 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 (12) 1085-1095
  • 10 Hainerová IA, Lebl J. Treatment options for children with monogenic forms of obesity. World Rev Nutr Diet 2013; 106: 105-112
  • 11 Kühnen 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 (03) 502-509
  • 12 Foucan L, Larifla L, Durand E. et al. High prevalence of rare monogenic forms of obesity in obese guadeloupean afro-caribbean children. J Clin Endocrinol Metab 2018; 103 (02) 539-545
  • 13 Bohonowych J, Miller J, McCandless SE, Strong TV. The global Prader-Willi syndrome registry: development, launch, and early demographics. Genes (Basel) 2019; 10 (09) 10
  • 14 Dayton K, Miller J. Finding treatable genetic obesity: strategies for success. Curr Opin Pediatr 2018; 30 (04) 526-531
  • 15 Yu YH, Vasselli JR, Zhang Y, Mechanick JI, Korner J, Peterli R. Metabolic vs. hedonic obesity: a conceptual distinction and its clinical implications. Obes Rev 2015; 16 (03) 234-247
  • 16 Andermann ML, Lowell BB. Toward a wiring diagram understanding of appetite control. Neuron 2017; 95 (04) 757-778
  • 17 Roh E, Kim MS. Brain regulation of energy metabolism. Endocrinol Metab (Seoul) 2016; 31 (04) 519-524
  • 18 Srivastava G, Apovian CM. Current pharmacotherapy for obesity. Nat Rev Endocrinol 2018; 14 (01) 12-24
  • 19 Kuczmarski RJ, Ogden CL, Grummer-Strawn LM. et al. CDC growth charts: United States. Adv Data 2000; (314) 1-27
  • 20 Cuda SE, Censani M. Pediatric obesity algorithm: a practical approach to obesity diagnosis and management. Front Pediatr 2019; 6: 431
  • 21 Krebs NF, Himes JH, Jacobson D, Nicklas TA, Guilday P, Styne D. Assessment of child and adolescent overweight and obesity. Pediatrics 2007; 120 (Suppl. 04) S193-S228
  • 22 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 (03) 709-757
  • 23 Gulati AK, Kaplan DW, Daniels SR. Clinical tracking of severely obese children: a new growth chart. Pediatrics 2012; 130 (06) 1136-1140
  • 24 Heymsfield SB, Avena NM, Baier L. et al. Hyperphagia: current concepts and future directions proceedings of the 2nd international conference on hyperphagia. Obesity (Silver Spring) 2014; 22 (Suppl. 01) S1-S17
  • 25 Dykens EM, Maxwell MA, Pantino E, Kossler R, Roof E. Assessment of hyperphagia in Prader-Willi syndrome. Obesity (Silver Spring) 2007; 15 (07) 1816-1826
  • 26 Lowe MR, Butryn ML, Didie ER. et al. The Power of food scale. A new measure of the psychological influence of the food environment. Appetite 2009; 53 (01) 114-118
  • 27 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 (03) 237-247
  • 28 Miller JL. Approach to the child with Prader-Willi syndrome. J Clin Endocrinol Metab 2012; 97 (11) 3837-3844
  • 29 Alsaif M, Elliot SA, MacKenzie ML, Prado CM, Field CJ, Haqq AM. Energy metabolism profile in individuals with Prader-Willi syndrome and implications for clinical management: a systematic review. Adv Nutr 2017; 8 (06) 905-915
  • 30 Butler MG. Management of obesity in Prader-Willi syndrome. Nat Clin Pract Endocrinol Metab 2006; 2 (11) 592-593
  • 31 Deal CL, Tony M, Höybye C, Allen DB, Tauber M, Christiansen JS. 2011 Growth Hormone in Prader-Willi Syndrome Clinical Care Guidelines Workshop Participants. GrowthHormone Research Society workshop summary: consensus guidelines for recombinant human growth hormone therapy in Prader-Willi syndrome. J Clin Endocrinol Metab 2013; 98 (06) E1072-E1087
  • 32 Carrel AL, Myers SE, Whitman BY, Eickhoff J, Allen DB. Long-term growth hormone therapy changes the natural history of body composition and motor function in children with prader-willi syndrome. J Clin Endocrinol Metab 2010; 95 (03) 1131-1136
  • 33 Koves IH, Roth C. Genetic and syndromic causes of obesity and its management. Indian J Pediatr 2018; 85 (06) 478-485
  • 34 Forsythe E, Beales PL. Bardet-Biedl syndrome. Eur J Hum Genet 2013; 21 (01) 8-13
  • 35 Mazaheri MM, Rae-Seebach RD, Preston HE. et al. The impact of Prader-Willi syndrome on the family's quality of life and caregiving, and the unaffected siblings' psychosocial adjustment. J Intellect Disabil Res 2013; 57 (09) 861-873
  • 36 Meienberg J, Bruggmann R, Oexle K, Matyas G. Clinical sequencing: is WGS the better WES?. Hum Genet 2016; 135 (03) 359-362
  • 37 LaDuca H, Farwell KD, Vuong H. et al. Exome sequencing covers >98% of mutations identified on targeted next generation sequencing panels. PLoS One 2017; 12 (02) e0170843
  • 38 Bamshad MJ, Ng SB, Bigham AW. et al. Exome sequencing as a tool for Mendelian disease gene discovery. Nat Rev Genet 2011; 12 (11) 745-755
  • 39 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 (02) 241-246
  • 40 De Rosa MC, Chesi A, McCormack S. et al. Characterization of rare variants in MC4R in African American and Latino children with severe early-onset obesity. J Clin Endocrinol Metab 2019; 104 (07) 2961-2970
  • 41 Ng SB, Turner EH, Robertson PD. et al. Targeted capture and massively parallel sequencing of 12 human exomes. Nature 2009; 461 (7261): 272-276
  • 42 Girirajan S, Brkanac Z, Coe BP. et al. Relative burden of large CNVs on a range of neurodevelopmental phenotypes. PLoS Genet 2011; 7 (11) e1002334
  • 43 Lappalainen T, Scott AJ, Brandt M, Hall IM. Genomic analysis in the age of human genome sequencing. Cell 2019; 177 (01) 70-84
  • 44 Federici G, Soddu S. Variants of uncertain significance in the era of high-throughput genome sequencing: a lesson from breast and ovary cancers. J Exp Clin Cancer Res 2020; 39 (01) 46
  • 45 Dykens EM, Miller J, Angulo M. et al. Intranasal carbetocin reduces hyperphagia in individuals with Prader-Willi syndrome. JCI Insight 2018; 3 (12) 3
  • 46 Grolla E, Andrighetto G, Parmigiani P. et al. Specific treatment of Prader-Willi syndrome through cyclical rehabilitation programmes. Disabil Rehabil 2011; 33 (19-20): 1837-1847
  • 47 Paz-Filho G, Mastronardi CA, Licinio J. Leptin treatment: facts and expectations. Metabolism 2015; 64 (01) 146-156
  • 48 Wabitsch M, Funcke JB, Lennerz B. et al. Biologically inactive leptin and early-onset extreme obesity. N Engl J Med 2015; 372 (01) 48-54
  • 49 Gonçalves JPL, Palmer D, Meldal M. MC4R agonists: structural overview on antiobesity therapeutics. Trends Pharmacol Sci 2018; 39 (04) 402-423
  • 50 Kühnen P, Clément K, Wiegand S. et al. Proopiomelanocortin deficiency treated with a melanocortin-4 receptor agonist. N Engl J Med 2016; 375 (03) 240-246
  • 51 Clément K, Biebermann H, Farooqi IS. et al. MC4R agonism promotes durable weight loss in patients with leptin receptor deficiency. Nat Med 2018; 24 (05) 551-555
  • 52 Clément K, van den Akker E, Argente J. et al; Setmelanotide POMC and LEPR Phase 3 Trial Investigators. Efficacy and safety of setmelanotide, an MC4R agonist, in individuals with severe obesity due to LEPR or POMC deficiency: single-arm, open-label, multicentre, phase 3 trials. Lancet Diabetes Endocrinol 2020; 8 (12) 960-970
  • 53 Hainerová IA, Zamrazilová H, Sedláčková D, Hainer V. Hypogonadotropic hypogonadism in a homozygous MC4R mutation carrier and the effect of sibutramine treatment on body weight and obesity-related health risks. Obes Facts 2011; 4 (04) 324-328
  • 54 James WP, Caterson ID, Coutinho W. et al; SCOUT Investigators. Effect of sibutramine on cardiovascular outcomes in overweight and obese subjects. N Engl J Med 2010; 363 (10) 905-917
  • 55 Lu K, Chen Q, Li M. et al. Programmed cell death factor 4 (PDCD4), a novel therapy target for metabolic diseases besides cancer. Free Radic Biol Med 2020; 159: 150-163
  • 56 Khera R, Murad MH, Chandar AK. et al. Association of pharmacological treatments for obesity with weight loss and adverse events: a systematic review and meta-analysis. JAMA 2016; 315 (22) 2424-2434
  • 57 Senda M, Ogawa S, Nako K, Okamura M, Sakamoto T, Ito S. The glucagon-like peptide-1 analog liraglutide suppresses ghrelin and controls diabetes in a patient with Prader-Willi syndrome. Endocr J 2012; 59 (10) 889-894
  • 58 Kim YM, Lee YJ, Kim SY, Cheon CK, Lim HH. Successful rapid weight reduction and the use of liraglutide for morbid obesity in adolescent Prader-Willi syndrome. Ann Pediatr Endocrinol Metab 2020; 25 (01) 52-56
  • 59 Sze L, Purtell L, Jenkins A. et al. Effects of a single dose of exenatide on appetite, gut hormones, and glucose homeostasis in adults with Prader-Willi syndrome. J Clin Endocrinol Metab 2011; 96 (08) E1314-E1319
  • 60 Salehi P, Hsu I, Azen CG, Mittelman SD, Geffner ME, Jeandron D. Effects of exenatide on weight and appetite in overweight adolescents and young adults with Prader-Willi syndrome. Pediatr Obes 2017; 12 (03) 221-228
  • 61 Lomenick JP, Buchowski MS, Shoemaker AH. A 52-week pilot study of the effects of exenatide on body weight in patients with hypothalamic obesity. Obesity (Silver Spring) 2016; 24 (06) 1222-1225
  • 62 Ando T, Haraguchi A, Matsunaga T. et al. Liraglutide as a potentially useful agent for regulating appetite in diabetic patients with hypothalamic hyperphagia and obesity. Intern Med 2014; 53 (16) 1791-1795
  • 63 Zoicas F, Droste M, Mayr B, Buchfelder M, Schöfl C. GLP-1 analogues as a new treatment option for hypothalamic obesity in adults: report of nine cases. Eur J Endocrinol 2013; 168 (05) 699-706
  • 64 Hamilton JK, Conwell LS, Syme C, Ahmet A, Jeffery A, Daneman D. Hypothalamic obesity following craniopharyngioma surgery: results of a pilot trial of combined diazoxide and metformin therapy. Int J Pediatr Endocrinol 2011; 2011: 417949
  • 65 Brauner R, Serreau R, Souberbielle JC. et al. Diazoxide in children with obesity after hypothalamic-pituitary lesions: a randomized, placebo-controlled trial. J Clin Endocrinol Metab 2016; 101 (12) 4825-4833
  • 66 Jafferany M, Patel A. Skin-picking disorder: a guide to diagnosis and management. CNS Drugs 2019; 33 (04) 337-346
  • 67 Zhao L. The gut microbiota and obesity: from correlation to causality. Nat Rev Microbiol 2013; 11 (09) 639-647
  • 68 Stefater MA, Wilson-Pérez HE, Chambers AP, Sandoval DA, Seeley RJ. All bariatric surgeries are not created equal: insights from mechanistic comparisons. Endocr Rev 2012; 33 (04) 595-622
  • 69 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 (03) 15
  • 70 Aslan IR, Ranadive SA, Ersoy BA, Rogers SJ, Lustig RH, Vaisse C. Bariatric surgery in a patient with complete MC4R deficiency. Int J Obes 2011; 35 (03) 457-461
  • 71 Hatoum IJ, Stylopoulos N, Vanhoose AM. et al. Melanocortin-4 receptor signaling is required for weight loss after gastric bypass surgery. J Clin Endocrinol Metab 2012; 97 (06) E1023-E1031
  • 72 Valette M, Poitou C, Le Beyec J, Bouillot JL, Clement K, Czernichow S. Melanocortin-4 receptor mutations and polymorphisms do not affect weight loss after bariatric surgery. PLoS One 2012; 7 (11) e48221
  • 73 Tripodi M, Casertano A, Peluso M. et al. Prader-Willi syndrome: role of bariatric surgery in two adolescents with obesity. Obes Surg 2020; 30 (11) 4602-4604
  • 74 Martinelli V, Chiappedi M, Pellegrino E. et al. Laparoscopic sleeve gastrectomy in an adolescent with Prader-Willi syndrome: psychosocial implications. Nutrition 2019; 61: 67-69
  • 75 Liu SY, Wong SK, Lam CC, Ng EK. Bariatric surgery for Prader-Willi syndrome was ineffective in producing sustainable weight loss: long term results for up to 10 years. Pediatr Obes 2020; 15 (01) e12575
  • 76 Daskalakis M, Till H, Kiess W, Weiner RA. Roux-en-Y gastric bypass in an adolescent patient with Bardet-Biedl syndrome, a monogenic obesity disorder. Obes Surg 2010; 20 (01) 121-125
  • 77 Ogino S, Nishihara R, VanderWeele TJ. et al. Review article: the role of molecular pathological epidemiology in the study of neoplastic and non-neoplastic diseases in the era of precision medicine. Epidemiology 2016; 27 (04) 602-611
  • 78 Ogino S, Nowak JA, Hamada T, Milner Jr DA, Nishihara R. Insights into pathogenic interactions among environment, host, and tumor at the crossroads of molecular pathology and epidemiology. Annu Rev Pathol 2019; 14: 83-103
  • 79 Eneli I, Xu J, Webster M. et al. Tracing the effect of the melanocortin-4 receptor pathway in obesity: study design and methodology of the TEMPO registry. Appl Clin Genet 2019; 12: 87-93
  • 80 Hulbert AJ, Else PL. Basal metabolic rate: history, composition, regulation, and usefulness. Physiol Biochem Zool 2004; 77 (06) 869-876
  • 81 Nelms M, Sucher KP, Lacey K, Roth SL. Nutrition Therapy and Pathophysiology. 2nd ed.. Belmont, CA: Wadsworth, Cengage Learning; 2011