ESPE Abstracts

We present a 3-year-old boy with massive obesity and hyperphagia. His appetite symptoms were evident from age 3 months, and his parents report he has an insatiable appetite, and seeks food constantly. At presentation to our clinic, his BMI was 37.21 Kg/m² [+ 6.87 SDS]. Sleep apnoea is suspected, for which he is undergoing evaluation. Parents are second cousins. Both parents are moderately obese, but his siblings are normal weight for age. The mother did not have a history of gestational diabetes mellitus. Paternal and maternal grandmother have type 2 diabetes mellitus. In view of his early-onset obesity, monogenic obesity was suspected. His monogenic obesity panel revealed a previously unreported homozygous MC4R c.419T>C (p.Leu140Pro) variant of uncertain significance. It is known that he majority of disease-associated mutations in transmembrane protein-coding genes result in leucine to proline (as in our case) and glycine to arginine substitutions. Our patient’s variant is not found in the Gnomad or GME population databases and given his phenotype, we consider this to be the cause of his hyperphagia and obesity. Segregation analysis for the patient's two siblings is planned. Heterozygous loss-of-function mutations in MC4R are the most common genetic cause of monogenic obesity, occurring in approximately 2-5% of cases of severe, early-onset obesity, with an estimated population incidence of 1:500. In contrast, patients with homozygous MC4R mutations are extremely rare and their phenotype is characterised by intractable obesity with insatiable appetite, resistant to lifestyle modification or drug therapy. Even bariatric surgery is only transiently beneficial. However, we note the successful use of liraglutide in an adult with a homozygous MC4R mutation, and this may be worthy of consideration. [1] Liraglutide, an analogue of the enteric hormone, Glucagon-Like Peptide-1 (GLP1 is known to inhibit appetite, directly through effects on anorexigenic proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) neurons. However, this would be nullified in the case of MC4R homozygotes. However, inhibition of hypothalamic orexigenic agouti-related peptide (AgRP)/neuropeptide Y (NPY) neurons could be the mechanism in the reported case. [1] In summary, we present a 3-year-old boy with massive obesity secondary to a homozygous MC4R mutation and the challenging situation this presents. [1] Iepsen EW, Have CT, Veedfald S, et al. GLP-1 Receptor Agonist Treatment in Morbid Obesity and Type 2 Diabetes Due to Pathogenic Homozygous Melanocortin-4 Receptor Mutation: A Case Report. Cell Rep Med. 2020 Apr 21;1(1):100006. doi: 10.1016/j.xcrm.2020.100006.