Endocrine Abstracts

JOINT3815

Background: The presence of monogenic mutations should be suspected in children with early onset non-syndromic obesity and hyperphagia. The SIM1 (Single-minded homolog 1) mutations are a well-known cause of monogenic obesity with an autosomal dominant inheritance. A variant of the SIM1 gene is associated with other obesity-related genetic mutations in a male patient with early-onset obesity.

Case Description: A 9-years-old boy, with a BMI of 30, 2 kg/m2 (2, 37 SDS), started to gain weight at 19 months of life, with progressive hyperphagia. He was born of full-term an uneventful pregnancy with an appropriate birth weight, to non-consanguineous parents. His mother presents severe obesity. He had no significant neonatal history. At the first evaluation, at the age of 3 years old, his height was 99 cm (+0, 69 SDS vs target height -1, 35 SDS), weight was 22 Kg (+3, 12 SDS) and BMI of 22, 3 Kg/m2 (+2, 23 SDS). Physical examination not revealed dysmorphic features. He presented a persistent polydipsia and water deprivation tests ruled out diabetes insipidus. Brain MRI was normal and additional endocrinological disease and hypothalamic disorders were excluded At the age of 6 years old, his height was 124, 7 cm (+0, 39 SDS), weight 42, 2 Kg (+2, 82 SDS) and BMI of 27, 4 Kg/m2 (+2, 27 SDS). Biochemical examinations documented an impaired fasting glucose (IFG) and impaired glucose tolerance (IGT), associated with mild hepatic steatosis at ultrasound. In addition, he presents behavior disorder with a delay in speech development. CGH array documented a de novo 546Kb microduplication in 16p11.2 (OMIM #614671). Next Generation Sequency (panel based on 80 genes), performed at the age of 9, revealed mainly a novel and frameshift variant, c.290dup p.(Asp98Argfs*29), detected in heterozygosity in the SIM1 gene, inherited from the father. NGS showed other heterozygosity variants classified as VOUS according to ACGM: c.437C>T p.(Ala146Val) in CREBBP gene; c.3041T>A p.(Val1014Glu) in PLXNA4 gene; c.915A>C p.(Leu305Phe) in SEMA3C gene.

Conclusion: SIM1 gene is implicated in the development of the paraventricular nucleus (PVN) that contains the melanocortin 4 receptor (MC4R), a key component of appetite regulation. CREBBP is implicated in mechanisms of neuroplasticity. SEMA3A, with its reactors also encoded by the PLXNA4 gene, is implicated in the development of hypothalamic neuronal circuits. Although the role of the SIM1 gene mutation is decisive, we suggest that the cumulative effects of the other identified variants could interact in determining a phenotype of severe obesity through abnormalities in the development and function of hypothalamic circuits.