Supplementary Material for: Diverse Obesity Trajectories in a Family including Identical Twins with a Pathogenic MC4R Variant

Introduction: Pathogenic heterozygous melanocortin-4 receptor (MC4R) variants are the most common cause of monogenic obesity, affecting central satiety and appetite regulatory areas of the brain. Case Presentations: We report a pedigree with a pathogenic MC4R variant (c.380C>T, p.Ser127Leu). In the proband with obesity (BMI 35 kg/m2) and severe insulin resistance, use of combination semaglutide and naltrexone-bupropion was successful in reducing insulin requirements and weight. His adult monozygotic twin daughters both had childhood-onset obesity, however weight trajectories differed. Twin 1 had a peak BMI of 29.1 kg/m2, which decreased to 19.7 kg/m2 with intensive exercise and diet control without weight-lowering medication. Twin 2 had a sedentary lifestyle and epilepsy and had a peak BMI of 30.1 kg/m2; she responded well to naltrexone-bupropion and BMI decreased to 26 kg/m2. Conclusion: The manifestation of obesity, even in cases of monogenic obesity, can vary significantly due to the influence of environmental and lifestyle factors.

引言：致病性杂合型黑皮质素4受体（melanocortin-4 receptor, MC4R）变异是单基因肥胖最常见的病因，可影响大脑中枢饱腹感与食欲调节区域。
病例报告：本研究报道一个携带致病性MC4R变异（c.380C>T，p.Ser127Leu）的家系。先证者为肥胖患者，体质量指数（Body Mass Index, BMI）为35 kg/m²，且合并严重胰岛素抵抗；联合使用司美格鲁肽与纳曲酮-安非他酮治疗后，成功减少了胰岛素用量并减轻了体质量。其成年同卵双生女儿均为儿童起病型肥胖，但二者的体重变化轨迹存在显著差异：双胎1的BMI峰值达29.1 kg/m²，在未使用减重药物的情况下，通过强化运动与饮食控制，其BMI降至19.7 kg/m²；双胎2存在久坐生活方式且合并癫痫，BMI峰值为30.1 kg/m²，经纳曲酮-安非他酮治疗后反应良好，BMI降至26 kg/m²。
结论：即便为单基因肥胖，受环境与生活方式因素的影响，其肥胖表型也可存在显著差异。