Abstract
BACKGROUND: Single-minded homolog 1 (SIM1) gene mutations with autosomal dominant inheritance have been related to hyperphagia and early-onset severe obesity. SIM1 is implicated in the development of hypothalamic nuclei, which play a crucial role in energy homeostasis. The development of melanocortin neural circuits in the hypothalamus is promoted by other factors such as Semaphorine 3 (SEMA3) and its receptors, such as PLXNA1-4 and NRP1-2. Loss-of-function across multiple SEMA3/NRP/PLXNA genes can collectively contribute to obesity onset. CASE DESCRIPTION: A 3-year-old male was referred for the first time to Outpatient pediatric endocrinology due to early-onset and progressive severe obesity and hyperphagia. He presented neurobehavior disorders and partial diabetes insipidus. At age 6, the child was diagnosed with obesity-related complications, including hyperinsulinemia, impaired glucose tolerance, hypercholesterolemia, hepatic steatosis, and hypovitaminosis. The NGS analysis revealed four variants related to obesity: SIM1, SEMA3C, PLXNA4, and CREBBP gene mutations. CONCLUSIONS: The case presents the association of SIM-1 gene mutation with other obesity-related variants. The interactive and cumulative effects of the identified variants could coexist in the determination of severe obesity through abnormalities in the development and function of hypothalamic melanocortin circuits related to energy homeostasis. Although the pathogenic mutation of the SIM1 gene plays the main role, the complex clinical picture may be related to the possible cumulative effect of the other genetic mutations.