A novel mutation in the proopiomelanocortin (POMC) gene of a Hispanic child: metformin treatment shows a beneficial impact on the body mass index

Background Proopiomelanocortin (POMC) is a complex polypeptide that produces a variety of biologically active substances via cleavage in a tissue-specific manner [Challis BG, Millington GW. Proopiomelanocortin deficiency. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle, 1993–2018], yielding several products including adrenocorticotrophic (ACTH) and melanocyte stimulating hormones (MSH). These peptides have roles in the regulation of food intake, energy homeostasis, adrenal steroidogenesis, melanocyte stimulation and immune modulation. Rare mutations in the POMC gene can lead to ACTH deficiency and thus isolated hypocortisolism. The first cases of POMC mutation were documented by Krude et al. in 1998 [Krude H, Biebermann H, Luck W, Horn R, Brabant G, et al. Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet 1998;19:155–7]. Mutations in the POMC gene were linked with a clinical phenotype of adrenal insufficiency, red hair pigmentation, early onset and rapidly progressive obesity, early onset type 2 diabetes, hypothyroidism, hypogonadism and growth hormone deficiency. Case presentation We describe a prepubertal Hispanic boy with a novel homozygous POMC mutation with severe obesity, hypothyroidism, adrenal insufficiency and abnormal reddish hair pigmentation. The patient presented as a 2-year-old with exponential weight gain, abnormal thyroid labs and speech delay. Laboratory testing demonstrated central adrenal insufficiency and genetic testing confirmed a homozygous mutation (nucleotide change c.20_21ins25) in exon 3 of the POMC gene. Replacement therapy with thyroid hormone and hydrocortisone was coupled to a slight decrease in the rate of weight gain, although hyperphagia persisted. Parent-directed nutrition and activity education as well as attempts to restrict access to food resulted in a plateau of the body mass index (BMI). At 4 years of age, metformin treatment was initiated with the patient showing evolving signs of insulin resistance and failure of lifestyle/dietary intervention to adequately decrease the BMI. Over a 3-year metformin treatment span, the BMI decreased from 34.9 kg/m2 to 32.9 kg/m2. Conclusions We demonstrate a possible role for metformin in stemming progressive weight gain, thereby impacting the early onset obesity due to hyperphagia.