ESPE Abstracts

Background: Melanocortin 4 receptor (MC4R) deficiency is the commonest monogenic form of non-syndromic obesity. MC4R is a seven transmembrane G-protein coupled receptor implicated in central regulation of body weight. The loss-of-function mutations in MC4R gene will contribute to early-onset obesity associated with hyperinsulinemia, hyperphagia and “binge eating”. We aim to determine the prevalence of MC4R variants in a Pediatrics Portuguese cohort with obesity. We present our preliminary results and the clinical description of the identified cases.

Material and Methods: Patients with obesity onset before 10 years and BMI > 95th centile observed at Pediatrics Hospital of Coimbra, without intellectual disability were screened for MC4R variants by Sanger sequencing after PCR amplification. Molecular and clinical characterization was performed in cases with identified MC4R variants.

Results: A total of 134 patients (mean age was 11 years, 62 boys) were included in the study. It was identified one already described (1/134, 0.75 %) pathogenic heterozygous MC4R variant inherited from the mother: c.631_634del (p.Leu211Metfs*6). Additionally, we identified four (4/134, 2.98%) patients with heterozygous variants at MC4R classified as unknown significance (VUS) according to ACMG/AMP classification but with in silico predictions reporting them as deleterious. All of them were inherited from one progenitor.

Conclusions: Our results point out that MC4R deficiency is underdiagnosed in the Portuguese population. The absence of distinctive phenotypic features reinforce the need of screening large cohorts with broad inclusion criteria. This diagnosis will contribute to the follow-up of identified cases, an early diagnosis in other family members and the prospective of using the specific therapies that are under development, partial agonists of the MC4R. We will describe the case reports with discussion of reported variants.