Endocrine Abstracts

JOINT3315

Introduction and Purpose: Children with severe, early-onset obesity before the age of 5, accompanied by extreme episodes of hyperphagia, should be investigated for monogenic forms of obesity. The MC4R (melanocortin-4 receptor) pathway orchestrates the energy homeostasis, and deficiencies along the pathway may cause monogenic obesity. MC4R pathway deficiencies include mutations in the genes encoding leptin (Lep) and its receptor (LepR), pro-opiomelanocortin (POMC), MC4R, prohormone convertase subtilisin/kexin type 1 (PCSK1), nuclear receptor coactivator 1 (NCOA1), and SH2B Adaptor Protein 1 (SH2B1). The aim is to present three cases of children with early-onset obesity and to explore its genetic basis.

Patients and Methods: Three male patients were included aged 11^7/12, 8^10/12, and 9^3/12 years at their first visit to the Endocrinology Units. Detailed family and personal history was taken, along with comprehensive laboratory and imaging tests. Due to the early onset of obesity, resistance to dietary restrictions, and exercise, a suspicion of monogenic disease was raised. DNA analysis was performed using an obesity panel with next-generation sequencing (NGS) technology.

Results: All patients exhibited severe, early-onset obesity with hyperphagia and hepatic steatosis. From early infancy, they showed a strong interest in food intake, with a gradual increase in body mass index (BMI). Despite efforts to modify their lifestyle (changes in dietary habits, exercise, and psychological support), no improvement in BMI was observed. The first patient exhibited a potentially pathogenic variant, NM_005912:exon1:c.380C>T:p.S127L, in the MC4R, which was also confirmed in the father. It may disrupt MC4R function by altering its expression on the cell membrane and its biophysical properties. In the second child, the rs17782313 NC_000018.9:g.57851097T>C polymorphism in the MC4R gene was detected in heterozygous form. The polymorphism is significantly associated with hyperinsulinemia and severe obesity. Disruption of the transcriptional control of MC4R has been proposed as the potential functional mechanism for this variant. In the third child the variant of unknown significance NM_003743.5: c.3954C>T p. (Thr1318=) was detected in heterozygosity in the NCOA1 gene. In all children, the administration of metformin did not help control appetite or BMI. Following the genetic test results, treatment with setmelanotide will be initiated, which is approved for children with syndromic or monogenic obesity associated with the hypothalamic MC4R pathway.

Conclusions: The study demonstrates the importance of genetic investigation of children with the two hallmark symptoms of early-onset, severe obesity and hyperphagia, enabling timely selection of appropriate therapeutic approaches, prevent obesity consequences, and provide genetic counseling.