Case Report: rapid progressive puberty in siblings with MC4R p. Arg165Gln: longitudinal follow-up and gonadotropin-releasing hormone agonist treatment

Background Pathogenic 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 report We 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/m 2 (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. Conclusion Longitudinal 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.