Endocrine Abstracts

JOINT3892

SH2B Adaptor Protein 1 (SH2B1) is an important component in the leptin-melanocortin pathway. Microdeletions in chromosome 16p11. 2, encompassing the SH2B1 gene, as well as pathogenic SH2B1 variants, are found to be associated with severe, early-onset obesity, hyperphagia, developmental delay, and insulin resistance. One year of treatment with setmelanotide (IMCIVREE™, Rhythm Pharmaceuticals), a melanocortin-4 (MC4) receptor agonist, was associated with clinically meaningful reductions in weight-related parameters in patients with heterozygous SH2B1 variants or 16p11. 2 deletion in a previous study. We present the effect of setmelanotide treatment over 4 years in an adolescent patient with severe, early-onset obesity due to a heterozygous 16p11. 2 deletion, encompassing the SH2B1 gene. The patient (female, 12 years old) presented with hyperphagia and severe obesity due to 16p11. 2 microdeletion (BMI Z score 2. 51). She had a mild developmental delay, concentration and learning deficits and displayed aggressive behavior. At the age of 9 years, treatment with metformin was initiated due to prediabetes, which progressed to T2DM at the age of 12 years. Further screening for comorbidities revealed arterial hypertension, microalbuminuria, obstructive sleep apnea syndrome, dyslipidemia, and steatotic liver disease. Treatment with setmelanotide, in the context of participation in the trial (NCT03013543, NCT03651765), was started at the age of 12 ^7/12 years. During setmelanotide treatment, BMI Z score change was -0. 19 and -0. 26 at months 3 and 12 compared to baseline, respectively. During this period, HbA1c levels decreased to normal and hunger was well controlled. After month 12, BMI levels increased gradually (max. BMI Z score change: 0. 5 at month 39 from baseline), which may be attributed in part to lack of physical activity and motivation. Likewise, HbA1c levels increased up to 7. 0% and glp-1 analogues (at first liraglutide, then semaglutide) were added. Combined treatment resulted in stabilization of BMI and improvement of glycemic control. When setmelanotide administration was stopped after 4 years according to study protocol, the patient experienced sudden excessive weight gain and pronounced hyperphagia. Reintroduction of setmelanotide resulted in weight loss and good hunger control. Central body weight regulation in young patients with monogenic obesity remains challenging. Combined administration of setmelanotide and semaglutide resulted in BMI, hunger and glucose control in an adolescent patient with severe obesity and type 2 diabetes mellitus, due to a 16p11. 2 microdeletion, encompassing the SH2B1 gene. An individualized therapeutic approach, including different pharmacological regiments in combination with lifestyle intervention and psychological support, should be considered in patients with monogenic obesity.