ESPE Abstracts

Early identification of monogenic obesity, a rare condition, is quite challenging for pediatricians. Src-homology-2 (SH2) B adapter protein 1 (SH2B1) is an important component in the leptin-melanocortin pathway and it is found to play an important role in leptin and insulin signaling. In humans a rare deletion of a 220-kb region on chromosome 16p11.2 encompassing approximately 9 genes, including the SH2B1 gene, is associated with a highly penetrant form of isolated severe early-onset obesity, as well as obesity with developmental delay. We present the case of a young girl with an eterozigous mutation in SH2B1 gene (c.2039G>A; p.Arg680Gln) that could also be associated to obesity and insulin resistance according to clinical features. The same genetic studies are ongoing on the younger sister who presents the same clinical features. A twelve-year-old girl presented to our hospital with a progressive obesity that began during breastfeeding (weight: 64.7 kg, +1,59 SD; height: 148 cm, -0,54 SD; BMI: 29,5 kg/m2, +2,14 SD; waist circumference: 99 cm). The patient had been followed by a nutritionist since the age of four and although she followed calorie restriction and physical activity programs, she had a constant and progressive weight gain. The physical exam showed excess weight with central distribution, adipomastia and I stage of pubarche. We excluded the most frequent causes of secondary obesity: thyroid hormones were normal and Cushing disease was excluded. In the suspicion of genetic obesity, we searched for mutations in the LEP, LEPR, PCSK1, MC4R, SIM1, POMC, NCOA1, SH2B1 genes with NGS sequencing on the NovaSeq6000 platform (Illumina). A mutation of SH2B1 gene (c.2039G>A; p.Arg680Gln) in heterozygosity was found. During the last hospitalization, at 13 years and 6 months (weight: 66 kg, +1,25 SD; height: 151 cm, -1,11 SD; BMI: 28,9 kg/m2, +2,0 SD), she underwent an oral glucose tolerant test (OGTT) which highlighted severe hyperinsulinism (basal insulin level of 17,1 mU/l and insulin peak of 358 mU/l at 120’) and a glycemic level diagnostic for type 2 diabetes (glycaemia at 120 ' of 219 mg/dl). Based on these results, the patient started treatment with metformin at a dosage of 1000 mg three times a day. In our case, we are strongly oriented to identify the Arg680Gln mutation of SH2B1 as a cause of obesity and sequentially type 2 mellitus diabetes. The presence of the same mutation in the younger sister with the same clinical features could confirm our hypothesis.