Objective: To describe the clinical and biological phenotype of a child who is severely obese and is homozygous for a new melanocortin-4 receptor (MC4R) gene mutation leading to a truncated receptor.
Study design: Direct sequencing of the MC4R gene was performed in a child who was severely obese and his relatives. Phenotypic characterization included weight evolution, anthropometric parameters, and endocrine and metabolic complications. Growth curves were compared with those of children carrying leptin receptor (LEPR) homozygous mutation, MC4R heterozygous mutations, and MC4R wild type allele.
Results: We found a homozygous 2-base pair deletion (del 346-347AG) leading to a stop codon. This new mutation leads to a truncated MC4R after the second transmembrane domain in a 3-year-old boy with severe early-onset obesity. Segregation analysis of the mutation showed that the 2 parents and 2 adult relatives were heterozygous carriers for the mutation. Heterozygous carriers displayed an obese phenotype, but with a variable degree of severity. The homozygous carrier of the mutation was hyperphagic and showed a rapid increase in weight in the very first months of life. His weight evolution closely resembled that of patients who are LEPR deficient, but markedly differed with that of children carrying either heterozygous MC4R mutations or MC4R wild type allele. No other hormonal or metabolic anomaly was found in the child.
Conclusions: This phenotype of a boy carrying a new homozygous MC4R mutation confirms the critical role of MC4R in the early dynamic of weight gain and phenotypic differences with heterozygous carriers.