Background Rare genetic variations in the leptin-melanocortin signalling pathway can severely impair appetite regulation and cause extreme obesity in early childhood. Case presentation Our case reports describe the diagnostic and therapeutic procedures in a girl as well as in a non-related boy of non-consanguineous, German parents with severe early-onset obesity, pronounced hyperphagia, and permanent food-seeking behaviour. Excessive weight gain within the first year of life initiated extensive diagnostics without finding a causal diagnosis. Furthermore, a wide range of intensive, interdisciplinary, and behavioural therapies for weight control were unsuccessful. Prior to bariatric surgery, the 18-year-old girl and the 14-year-old boy reached a BMI of 67.7 kg/m 2 and 55.2 kg/m 2 , respectively. However, even surgical outcomes were unsatisfactory. A subsequently initiated genetic analysis including sequencing of the leptin receptor gene revealed compound heterozygous variants as a cause of the severe early-onset obesity in both patients (c.2598-3_2607delTAGAATGAAAAAG and c.2227 T>C; c.1874G>A and c.2051A>C). Both patients were enrolled in the clinical study RM-493-015 and treated with melanocortin receptor agonist setmelanotide. Currently, they are still on setmelanotide treatment in the extension trial RM-493-022. Conclusion Our case report illustrates the urgent necessity of early genetic diagnostics in children with severe early-onset obesity to avoid frustrating and potentially damaging therapies. Thus, genetic examination should precede bariatric surgery. In the future, several pharmacological therapies will be available for some forms of monogenetic obesity.

中文翻译：

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两例复合杂合瘦素受体缺乏症患者的诊治历程

背景瘦素-黑皮质素信号通路中的罕见遗传变异会严重损害食欲调节并导致儿童早期极度肥胖。案例介绍 我们的案例报告描述了一个女孩和一个非血缘德国父母的非血缘男孩的诊断和治疗程序，这些男孩患有严重的早发性肥胖症、明显的食欲亢进和永久性的觅食行为。出生后第一年体重增加过多导致了广泛的诊断，但没有找到因果诊断。此外，用于体重控制的各种强化、跨学科和行为疗法均未成功。在减肥手术之前，18 岁女孩和 14 岁男孩的 BMI 分别达到 67.7 kg/m 2 和 55.2 kg/m 2 。然而，即使是手术结果也不尽如人意。随后启动的包括瘦素受体基因测序在内的遗传分析显示，复合杂合变异是导致两名患者严重早发性肥胖的原因（c.2598-3_2607delTAGAATGAAAAAG 和 c.2227 T>C；c.1874G>A 和 c .2051A>C)。两名患者都参加了临床研究 RM-493-015，并接受了黑皮质素受体激动剂 setmelanotide 的治疗。目前，他们仍在扩展试验 RM-493-022 中接受 setmelanotide 治疗。结论我们的病例报告说明了对严重早发性肥胖儿童进行早期基因诊断的迫切必要性，以避免令人沮丧和潜在的破坏性治疗。因此，基因检查应在减肥手术之前进行。将来，将有几种药物疗法可用于某些形式的单基因肥胖症。