两名复合杂合子瘦素受体缺乏症患者的诊断和治疗奥德赛。

IF 2.4 Q1 PEDIATRICS Molecular and cellular pediatrics Pub Date : 2020-11-03 DOI:10.1186/s40348-020-00107-3
Stefanie Zorn, Julia von Schnurbein, Katja Kohlsdorf, Christian Denzer, Martin Wabitsch
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摘要

背景:瘦素-黑色素皮质素信号通路中的罕见基因变异会严重影响食欲调节,导致幼儿期极度肥胖:我们的病例报告描述了一个女孩和一个非亲缘关系男孩的诊断和治疗过程,他们的父母都是德国人,非近亲结婚,患有严重的早发性肥胖症、明显的多食和永久性觅食行为。出生后第一年体重增长过快,医生对其进行了广泛的诊断,但没有找到病因。此外,为控制体重而采取的各种强化、跨学科和行为疗法均未奏效。在接受减肥手术之前,18 岁女孩和 14 岁男孩的体重指数分别为 67.7 kg/m2 和 55.2 kg/m2。然而,即使是手术结果也不尽如人意。随后启动的基因分析(包括瘦素受体基因测序)发现,复合杂合变体是导致这两名患者早发严重肥胖症的原因(c.2598-3_2607delTAGAATGAAAAAG 和 c.2227T>C;c.1874G>A 和 c.2051A>C)。这两名患者都参加了 RM-493-015 临床研究,并接受了黑色素皮质素受体激动剂 Setmelanotide 的治疗。目前,他们仍在 RM-493-022 扩展试验中接受塞美拉诺肽治疗:我们的病例报告说明,对于早发重度肥胖症患儿,迫切需要尽早进行基因诊断,以避免令人沮丧且可能造成损害的治疗。因此,在进行减肥手术前应先进行遗传学检查。未来,将有多种药物疗法可用于治疗某些形式的单基因肥胖症。
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Diagnostic and therapeutic odyssey of two patients with compound heterozygous leptin receptor deficiency.

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/m2 and 55.2 kg/m2, 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.

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