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