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Selected genetic disorders in which obesity is an isolated or predominant feature

Selected genetic disorders in which obesity is an isolated or predominant feature
Disorder (gene) Gene Clinical features Specific treatment
Leptin deficiency
(various mutations interfering with synthesis or secretion of leptin)		 LEP Severe early-onset obesity, hypometabolic rate, hyperphagia, pubertal delay, impaired glucose tolerance, hypothalamic hypogonadism, frequent infections. Leptin levels are very low or undetectable. Recombinant leptin[1]
Leptin receptor deficiency LEPR Severe early-onset obesity, hypometabolic rate, hyperphagia, pubertal delay, hypothalamic hypogonadism. Leptin levels are high but are proportional to the degree of obesity, so they are not a useful marker for this defect. Setmelanotide*; (recombinant leptin is not effective[2,3])
Leptin dysfunction
(biologically inactive leptin)		 LEP (LEP p.D100Y) Severe early-onset obesity, hyperphagia. Leptin level are high (consistent with degree of obesity) but biologically inactive. Recombinant leptin[4]
Pro-opiomelanocortin deficiency POMC Adrenal insufficiency (typically presenting in the neonatal period), severe early-onset obesity, hyperphagia, with pale skin and red hair in White individuals[5,6]. Setmelanotide*
Proprotein convertase 1/3 deficiency PCSK1, also known as prohormone convertase 1 Early-onset obesity, diarrhea, abnormal glucose homeostasis, hypogonadotropic hypogonadism, hypocortisolism, elevated plasma proinsulin and POMC[7]. Setmelanotide*
Melanocortin 4 receptor haploinsufficiency MC4R Early-onset moderate to severe obesity, early-onset hyperphagia, increased bone density, accelerated linear growth, severe hyperinsulinemia, mild central hypothyroidism[8,9]. Setmelanotide has no established efficacy and is not approved for this group of patients
Melanocortin 2 receptor accessory protein 2 MRAP2 Severe nonsyndromic early-onset obesity (probably very rare)[10]. None established
GNAS mutations GNAS complex locus Severe early-onset obesity with or without developmental delay, short stature, brachydactyly, subcutaneous ossifications, pseudohypoparathyroidism (hypocalcemia, PTH resistance) and thyrotropin resistance (elevated TSH with normal or low fT4)[11] (eg, Albright's hereditary osteodystrophy). Obesity is likely mediated by disrupted MC4R signaling. None established

fT4: free thyroxine; GNAS: encodes the G-alphas (stimulatory G-protein alpha subunit) protein; PCSK1: proprotein convertase subtilisin/kexin type 1; POMC: pro-opiomelanocortin; PTH: parathyroid hormone; TSH: thyroid-stimulating hormone.

* Setmelanotide, a melanocortin 4 receptor agonist, is available for the treatment of obesity due to mutations in the POMC, PCSK1, or LEPR (leptin receptor) genes, and for patients with Bardet-Biedl syndrome[12]. Refer to UpToDate content on genetic contributions to obesity.
References:
  1. Farooqi IS, Matarese G, Lord GM et al. Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic function of human congenital leptin deficiency. J Clin Invest 2002; 110:1093.
  2. Clement K, Vaisse C, Lahlou N et al. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 1998; 392:398.
  3. Farooqi IS, Wangensteen T, Collins S et al. Clinical and molecular spectrum of congenital deficiency of the leptin receptor. New Engl J Med 2007; 356:237.
  4. Wabitsch M, Funcke JB, Lennerz B et al. Biologically inactive leptin and early-onset extreme obesity. New Engl J Med 2015; 372:48.
  5. Krude H, Biebermann H, Luck W et al. Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet 1998; 19:155.
  6. Anisimova AS, Rubtsov PM, Akulich KA, et al. Late diagnosis of POMC deficiency and in vitro evidence of residual translation from allele with c.-11C>A mutation. J Clin Endocrinol Metab 2017; 102:359.
  7. Jackson RS, Creemers JW, Ohaqi S et al. Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nat Genet 1997; 16:303.
  8. Farooqi IS, Keogh JM, Yeo GS et al. Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. New Engl J Med 2003; 348:1085.
  9. Farooqi IS. The severely obese patient – a genetic workup. Nat Clin Pract Endocrinol Metab 2006; 2:172.
  10. Asai M, Ramachandrappa S, Joachim M, et al. Loss of function of the melanocortin 2 receptor accessory protein 2 is associated with mammalian obesity. Science 2013; 341:275.
  11. Mendes de Oliveira E, Keogh JM, Talbot F, et al. Obesity-Associated GNAS Mutations and the Melanocortin Pathway. N Engl J Med 2021; 385:1581.
  12. Imcivree. US FDA approved product information: Rhythm Pharmaceuticals; June 2022. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/213793s001lbl.pdf (Accessed on June 17, 2022).
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