ESPE Abstracts

Keywords: Non-syndromic obesity, single gene disorder, child.

Objective: This study aimed to evaluate the clinical characteristics, molecular genetic analysis results, and obesity-related comorbidities of patients with non-syndromic monogenic obesity

Materials and Methods: The results of a targeted next-generation sequence analysis panel (Clinical Exome Solution v2 - SOPHiA GENETICS) of 73 children and adolescents with non-syndromic obesity, followed up between 2003 and 2022 were analysed. Patients in whom variants were detected and who met at least two of the following criteria were included in the study; diagnosed with obesity at the age of <6 years, body mass index (BMI) SDS >2.5, presence of obesity in one of the parents, or a history of consanguinity between the parents. The pathogenicity of the variants was determined in accordance with the 2015 "American College of Medical Genetics and Genomics" criteria.

Results: Twenty of the patients had disease-associated variants, MC4R in 11patients, 5 in POMC, 2 in LEPR, 1 in LEP, and 1 in the CARTPT gene. The median age was 14.5 years (4.5-23.6), the age at presentation was 6.6 years (0-17.5), BMI SDS was 3.25 (1.8-10.1), and BMI according to the 95th percentile was 143.8% (101-311). Family history of obesity was found in 50%, and consanguineous marriage between parents was found in 45% of the patients. Hepatosteatosis (HS) was found in 8 (40%), hypertension (HT) in 3 (15%), and dyslipidemia in 3 (15%) patients. Patients with MC4R variants had hypothyroidism (primary, central, Hashimoto thyroiditis), tall stature, ectopic neurohypophysis, and psychiatric disorders. Adrenal insufficiency, central hypothyroidism, cholestasis, epilepsy, and psychiatric disorder were found in patients with POMC deficiency. Hypogonadotropic hypogonadism and subclinical hypothyroidism were found in patients with variants in LEPR. The patient with a variant in the LEP gene had a BMI of 34.4 kg/m2 and a BMI SDS of 4.67 at the age of 6. With metraleptin treatment, BMI decreased to 18.8 kg/m2, and BMI SDS decreased to 0.32 at 10.8 years old.

Conclusions: Elucidation of the causes of obesity due to single gene disorders is important for diagnosing and treating comorbidities such as central adrenal insufficiency, hypothyroidism, and hypogonadotropic hypogonadism. Early genetic evaluation allows for the identification of treatable obesity. Providing timely intervention and implementing personalized management protocols may result in more efficient positive outcomes.