Guideline on severe pediatric obesity with MC4R variant and puberty managementTwo siblings with severe obesity and early puberty found to have genetic changes affecting their growth and health over fourteen years

BackgroundPathogenic variants in melanocortin-4 receptor (MC4R) are the most common cause of nonsyndromic monogenic obesity. However, links between MC4R-related obesity and pubertal tempo, and the long-term endocrine–metabolic trajectory in East Asian children, remain insufficiently characterized. Objective: To describe the longitudinal endocrine and metabolic features and treatment response of two siblings carrying a pathogenic MC4R variant who developed rapidly progressive puberty with central activation.Case reportWe report two Chinese siblings with severe early-onset obesity and accelerated pubertal tempo. Trio-based whole-exome sequencing with segregation analysis identified a heterozygous MC4R variant (NM_005912.3: p.Arg165Gln). The proband,a girl, initially presented with premature thelarche, followed by rapid progression with advanced bone age and increased growth velocity. A GnRH stimulation test demonstrated a pubertal luteinizing hormone response (peak LH 6.61 mIU/mL). GnRH agonist (GnRHa) therapy stabilized pubertal progression until discontinuation, after which spontaneous puberty resumed and menarche occurred at 13 years 6 months. At 11 years 8 months, metabolic evaluation revealed impaired glucose tolerance with hyperinsulinemia/insulin resistance and hypertriglyceridemia.Short-term metformin therapy, together with intensified lifestyle intervention, was followed by sustained weight reduction and durable glycemic normalization. At the most recent follow-up (14 years 5 months), height was 162 cm (SDS + 0.49), weight was 55 kg (SDS + 0.77), BMI was 20.96 kg/m2 (SDS + 0.66), and fasting blood glucose remained within the normal range. The younger brother showed concordant severe obesity with rapid pubertal progression, pubertal basal gonadotropins, and a strongly positive GnRH stimulation test (peak LH 50.82 mIU/mL; peak LH/FSH ratio 1.30). Although GnRHa was initiated relatively late, at 10 years 3 months, treatment was undertaken not only because of rapid pubertal progression, persistent bone-age advancement, and concern for compromised height potential, but also because of marked psychosocial distress and strong parental preference for active intervention. Biochemical suppression was achieved at 10 years 6 months (peak LH 0.88 mIU/mL), with stable clinical staging thereafter.ConclusionLongitudinal follow-up of siblings carrying the pathogenic MC4R p. Arg165Gln variant highlights two clinical priorities in severe pediatric obesity, timely recognition and individualized management of rapidly progressive centrally activated puberty, and sustained guideline-informed surveillance and treatment of cardiometabolic comorbidities through long-term lifestyle intervention.