Endocrine Abstracts

JOINT1945

Background: Obesity is a multifactorial disease with increasing prevalence in childhood. Severe early-onset obesity, especially with hyperphagia and rapid weight gain, may indicate monogenic causes, such as MC4R-related.This form often leads to metabolic complications and resistance to conventional treatment. Early genetic diagnosis is essential for guiding management and identifying potential therapeutic targets.

Case report: We describe two male siblings, born at term and appropriate for gestational age to non-consanguineous parents, who developed severe early-onset obesity. The first sibling was evaluated at 1.4y due to hyperphagia, excessive weight gain, and accelerated growth from 6 months of age. He had no medication use or neuropsychomotor delay. At initial assessment, his weight and height-for-age, and BMI (z-scores) were 33 kg (+3), 88.5 cm (+3.1), and 42.3 (+9.5), respectively. He exhibited acanthosis nigricans on the neck, axillae, and groin, with normal genital examination. Laboratory evaluation revealed elevated triglycerides, reduced HDL, while insulin, calcium profile, and thyroid function were normal. A monogenic etiology was suspected, and a genetic panel with 16 genes related to monogenic obesity was carried out. The results revealed a compound heterozygous MC4R variant (c.896C>A; p.Pro299His/c.240C>A;p.Tyr80*). The younger sibling with similar symptoms around 1y. At 1.4y, his weight, height-for-age, and BMI (Zs) were 20.8 (+6.1), 83 (+0.8), and 30.2 (+7.5), respectively. Genetic testing confirmed the same variant. The father had mild obesity (BMI =32.8), and the mother was overweight (BMI =29). Both parents and their younger brother underwent MC4R gene sequencing and it was detected the variant c.240C>A in the father and the variant c.896C>A in the mother and in the younger sibling, all of them in heterozygous. Lifestyle modifications and caloric restriction were attempted, without success. After loss to follow-up, the patients currently have weight and BMI (z-scores) of 88.6 kg/56.25 (+11.1) and 45.9 kg/39.5 (+10.1) at 4.5y and 3.4y, respectively.

Conclusion: MC4R-related obesity is the most common monogenic obesity and can present in homozygous heterozygous, or compound heterozygous states, with phenotypes ranging from overweight to severe obesity. This variability highlights the need for early genetic investigation in rapidly progressing obesity, as identifying a monogenic cause aids prognosis, optimizes management, and supports family counseling.