Genetic obesity in children: overview of possible diagnoses with a focus on SH2B1 deletion

Abstract

Introduction: Genetic obesity is rare, and quite challenging for pediatricians in terms of early identification. SH2B1 is an important component in the leptin-melanocortin pathway and is found to play an important role in leptin and insulin signaling, and therefore in the pathogenesis of obesity and diabetes. Microdeletions in chromosome 16p11.2, encompassing the SH2B1 gene, are known to be associated with obesity, insulin resistance, hyperphagia and developmental delay. Aim of our study is to report on a case series of young individuals with 16p11.2 microdeletions, including the SH2B1 gene, and provide detailed information on BMI development and obesity-associated comorbidities. In this way, we want to raise awareness of this syndromic form of obesity as a differential diagnosis of genetic obesity. Methods: We describe the phenotype of 7 children (3 male; age range: 2.8 – 18.0 years) with 16p11.2 microdeletions, encompassing the SH2B1 gene, and present their BMI-trajectories from birth onwards. Screening for obesity-associated comorbidities was performed at time of genetic diagnosis. Results: All children presented with severe, early-onset obesity already at the age of 5 years combined with variable developmental delay. 5 patients presented with elevated fasting insulin levels, 1 patient developed diabetes mellitus type 2, 4 patients had dyslipidaemia and 4 developed non-alcoholic fatty liver disease. Discussion/Conclusion: Chromosomal microdeletions in 16p11.2, including the SH2B1 gene, in children are associated with severe, early-onset obesity and comorbidities associated with insulin resistance. Early genetic testing in suspicious patients and early screening for comorbidities is recommended.