LEPR variants and hyperphagia

Leptin is the body’s fuel-gauge signal, and the leptin receptor is the brain’s receiver. When the LEPR gene is broken, hunger can stay switched on from infancy. (medlineplus.gov) In leptin receptor deficiency, babies are usually born at normal weight, then become constantly hungry in the first months of life and gain weight rapidly. MedlinePlus says the condition also causes chronic excessive eating, called hyperphagia. (medlineplus.gov) The receptor sits on cells in the hypothalamus, a brain region that helps control hunger. Normally, fat cells release more leptin as they grow, and leptin binding tells the brain that energy stores are up and fullness has arrived. (medlineplus.gov) LEPR variants interrupt that message, so the body can make leptin but the brain does not respond to it. In a 2023 Pediatrics case report, an 11-month-old boy with a novel homozygous LEPR variant had hyperphagia, severe obesity, insulin resistance, sleep apnea, and a leptin level of 80.03 nanograms per milliliter, far above the listed normal range of 2.45 to 6.55. (aap.org) That pattern places LEPR deficiency inside a small group of single-gene obesities tied to the leptin-melanocortin pathway, the appetite-control circuit in the brain. A 2023 Journal of Clinical Endocrinology & Metabolism review said more than 60 genes have been linked to severe early-onset nonsyndromic monogenic obesity disorders. (academic.oup.com) The same review found 152 reported patients with leptin or leptin receptor deficiency across published cases and a multicenter cohort. Patients with leptin deficiency were diagnosed younger, while missense variants were more common in leptin receptor deficiency. (academic.oup.com) An earlier systematic review counted 88 published patients worldwide with leptin receptor deficiency as of 2020, including 21 in Europe. It found early-onset obesity in all patients, hyperphagia in 96%, and one or more pituitary hormone deficiencies in 34%. (pubmed.ncbi.nlm.nih.gov) Those hormone problems can extend beyond appetite. MedlinePlus says affected people can develop hypogonadotropic hypogonadism, with delayed puberty or no puberty and possible infertility. (medlineplus.gov) Diagnosis matters because this is one of the rare obesity syndromes with a targeted drug. The United States Food and Drug Administration label for setmelanotide says the drug is indicated for adults and children age 2 and older with obesity due to genetically confirmed proopiomelanocortin, proprotein convertase subtilisin-kexin type 1, or leptin receptor deficiency. (fda.gov) That does not mean every person with obesity has a leptin receptor disorder. The Food and Drug Administration label says setmelanotide is not indicated for general polygenic obesity or for LEPR variants classified as benign or likely benign. (fda.gov) The clinical lesson is narrow but important: when a child has relentless hunger and severe weight gain starting in infancy, doctors may need to think beyond willpower, diet, or parenting and look for a broken satiety signal in the leptin receptor pathway. (pubmed.ncbi.nlm.nih.gov)