SUN-681 SH2B1 Variants and Phenotypic Variability in Pediatric Obesity

Abstract Disclosure: G. Rivera Rodriguez: None. E.A. Delgado: None. A. Carrillo: None. A. Granados: None. C. Bustamante Escobar: None. Background: Obesity is a complex disease in which genetic susceptibility is increasingly recognized as a key contributor, particularly in severe early- onset cases. The SH2B1 gene encodes an adaptor protein involved in leptin and insulin signaling pathways, both crucial for energy homeostasis and appetite regulation. Deletion of SH2B1 results in severe leptin resistance, insulin resistance, hyperphagia, obesity, learning disabilities, and type 2 diabetes in humans. The aim of our study is to present a case series of 9 children with SH2B1 variants and highlight the phenotypic spectrum associated with these genomic alterations. While previous studies have identified biallelic SH2B1 mutations in individuals with obesity, the phenotypic spectrum associated with the presence of indeterminate variants, particularly in pediatric populations, remains poorly understood. Methods: This case series describes 9 children (age range 8.3 months-17.6 years) who were found to have a variant of unknown significance in the SH2B1 gene through genetic testing. Initial body mass index (BMI) on presentation, age of obesity onset, hyperphagia symptoms, learning disabilities, insulin resistance, presence of other genetic variants, and presence of other comorbidities associated with obesity were retrospectively reviewed and analyzed. Results: All children presented to the clinic with severe obesity with onset age range between 8 months and 9 years of age (average Z score 2.63 SD [2.2-3.48]). Five of the children had hyperphagia symptoms. None presented with learning disabilities. Six children had other genetic variants of uncertain interpretation which encompassed TTC8N, ADCY3, PCSK1, BBS12, BBS9, PLXNA1, WDPDP, IFT74 and PCNT. All children displayed comorbidities associated with obesity including four children with hypertriglyceridemia, two children with hypercholesterolemia, and two children with metabolic dysfunction-associated steatotic liver disease. Three children had insulin resistance. Conclusion: This case series highlights the phenotypic variability associated with SH2B1 variants in a pediatric population. While severe early-onset obesity and hyperphagia were common features, learning disabilities were not observed in our cohort. The presence of other genetic variants in many of these patients underscores the complex genetic landscape of obesity and suggests potential modifier genes may contribute to the phenotypic heterogeneity. Further research is needed to delineate the full spectrum of SH2B1- related phenotypes and to elucidate the complex interplay of genetic and environmental factors contributing to obesity development. Early identification of SH2B1 mutations is crucial for appropriate management and may facilitate the development of targeted therapies aimed at improving the metabolic health of these patients. Presentation: Sunday, July 13, 2025