Disorder (gene) | Gene | Clinical features |
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. Obesity and hyperphagia respond to replacement with exogenous 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. Responds to treatment with setmelanotide, a melanocortin 4 receptor agonist*, but not to exogenous leptin[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. Obesity and hyperphagia respond to treatment with exogenous 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]. Responds to treatment with 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]. Responds to treatment with 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]. |
Melanocortin 2 receptor accessory protein 2 | MRAP2 | Severe nonsyndromic early-onset obesity (probably very rare)[10]. |
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. |
POMC: pro-opiomelanocortin; PCSK1: proprotein convertase subtilisin/kexin type 1; PTH: parathyroid hormone; GNAS: encodes the G-alphas (stimulatory G-protein alpha subunit) protein; TSH: thyroid-stimulating hormone; fT4: free thyroxine.
* 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.Do you want to add Medilib to your home screen?