SAT-701 - A Novel SIM1 Sequence Variant Presenting with Prader-Willi Like Syndromic Obesity

Single-minded 1 (SIM1) is a basic helix–loop–helix transcription factor essential for hypothalamic development and regulation of appetite through the leptin–melanocortin–oxytocin pathway. Pathogenic SIM1 variants have been associated with severe early-onset hyperphagic obesity and neurodevelopmental delay, with phenotypic overlap with Prader–Willi syndrome. However, the clinical spectrum of SIM1-related disease and optimal management strategies remain incompletely defined.

A 20-year-old male with a history of primary hypothyroidism diagnosed in early childhood, developmental delay attributed to neonatal intracranial hemorrhage, and class III obesity presented for transition to adult endocrinology care. He reported lifelong hyperphagia without a family history of obesity. Physical examination revealed short stature (59 inches), pseudogynecomastia, normal secondary sexual characteristics, and absence of dysmorphic features. Laboratory evaluation demonstrated normal fasting blood glucose, hemoglobin A1c, lipid profile, and thyroid function. Genetic testing for monogenic obesity identified a heterozygous SIM1 missense mutation (c.1178T>G) not previously reported in the literature. The patient was initiated on glucagon-like peptide-1 receptor agonist therapy for weight management, as no targeted therapies for SIM1-related obesity are currently FDA approved.

This case expands the phenotypic spectrum of SIM1-related disease through the identification of a previously unreported sequence variant. Variants in SIM1 remain an underrecognized cause of syndromic obesity. Early recognition of SIM1-associated obesity is critical for accurate diagnosis, appropriate genetic counseling, and individualized management strategies. Continued characterization of SIM1 variants is needed to refine genotype–phenotype correlations and to advance the development and accessibility of targeted, mechanism-based therapies for rare genetic obesity syndromes.

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