MC4R Mutation in Early-onset Severe Childhood Obesity—Genotype–phenotype Correlation

Abstract

M elanocortin-4 receptor (MC4R; OMIM#155541) encodes a 332-amino acids protein possessing typical G-protein-coupled receptors' (GPCRs) structural design having three intact and functional domains, mutations which lead to the most recurrent type of monogenic obesity. Methods: We report here a case of a 5-year-old boy from Iraq who presented to the clinic for evaluation of progressive weight gain since he was 6 months of age. There were no symptoms of hypothalamic dysfunction except increase in appetite. His height was 120 cm (97th centile of the Centers for Disease Control and Prevention [CDC] growth chart, mid parental height was 50th centile), weight was 57 kg (>97th centile on CDC chart) and body mass index was 39.6 kg/m2 (>97th centile on CDC chart). A monogenic cause of obesity was strongly suspected in view of early onset severe childhood obesity. Results: Mutation screening of MC4R revealed a homozygous isoleucine by arginie at codon 69 (I69R) mutation in the patient, while his father was heterozygous for this mutation. Conclusion: We describe a monogenic form of obesity with characteristic presentation due to I69R MC4R mutation inherited as an autosomal recessive condition. The finding is different from previous reports which have documented this mutation to be inherited in a dominant manner. The findings of the present study reiterate the complex nature of obesity with possible involvement of modifier genes and/or genetic heterogeneity in its causation.