ESPE Abstracts

Introduction: Many genes have now been identified in which rare, high penetrant variants cause obesity, accounting for ~10% of children with severe obesity.

Aim: To describe clinical characteristics, genetics, and associated comorbidities in pediatirc endogenous obesity due to rare genetic obesity syndromes.

Methods: After excluding patients with obesity due to endocrine disturbances patients with BMI>2.5 SDS, early-onset obesity (<5 years) and/or any of dysmorphic features/behavioral problems/hyperphagia/family history underwent cytogenetic analysis, obesity panel screening, or next-generation WES.

Results: Of the 40 cases, 19 (40%) had a genetic etiology. Eleven (27%) had syndromic obesity; (Prader-Willi syndrome n = 10; Bardet-Biedl syndrome [BBS] n = 1). Fourteen (79%) were male and 17 (89.5%) were prepubertal. The follow-up was 4.1 (0.33-14) years and onset of obesity was 4.9 (1-10) years. Ten (52.6%) had early-onset obesity. Diagnosis age was 7.1 (0.33-14) years. BMI SDS was 2.7 (-3.1 to +7.4) and height SDS was -0.06 (-2.7 to +2.9). Sixteen (84.2%) presented with obesity, two (10.5%) with hypotonia and one (5.3%) with polyuria/polydipsia. The causes of monogenic obesity are shown in Table 1. Nine patients had monogenic obesity (Table 1) with four novel variants (Patients 6, 7, 8 and 9). 6/7 variants of unknown significance (VUS) appear to explain the phenotype, except for Patient 3. Accompanying comorbidities included: hepatosteatosis (n = 4; 21%); dyslipidemia (n = 6; 31.6%); and impaired glucose tolerance (n = 6; 31.6%). Fifteen (78.9%) had mental retardation. Type 2 diabetes developed in one patient with PWS, and in Patient 2 (P2) and P4 (Table 1). P4 had central adrenal insufficiency and central hypothroidism. P9 had polydactyly, retinitis pigmentosa, and grade 1 hydronephrosis.

Discussion: There was a marked male predominance. Four novel variants in obesity-related genes were identified. In patients whose obesity begins >5years, if there are dysmorphic findings and multisystem findings, genetic etiology should be investigated. A genetic diagnosis may be beneficial for the child and their family and suggest patients suitable for a trial of new anti-obesity therapies.

Key Words: Monogenic obesity, syndromic obesity, obesity