ESPE Abstracts

It is estimated that single-gene mutations are responsible for 3-10% of childhood obesity cases. The most common of these is a mutation in the MC4R gene, occurring in about 1-6% of children and 1% of adults with early-onset severe obesity. We report on of 7-year-old male twins with severe obesity (86% and 75% excess body mass relative to height), starting from the second year of life, along with hyperphagia. The boys were born from a twin pregnancy, PIII, CC, at 37 weeks of gestation, (twin I (TI) birth weight 2780g/ length 53cm/ head circumference 34cm, twin II (TII) 31690g/ length 55cm/ head circumference 34cm) and scored 10 points on the Apgar scale. Physical examination revealed the same dysmorphic features in both: large ears, thick earlobes, wide earlobe base, and bitemporal narrowing. Biochemical tests showed high levels of liver enzymes (TI AST 60,8 U/L; TII 55,9U/l (N: 15-50); ALT T1 80U/L, TII 71U/L (N: 10-25); GGT T1 38U/L, TII 27 U/l (N: 10-18); uric acid TI 354,96umol/l; TII 361,48umol/l (N: 120-295), and low morning cortisol level (TI 35,7ng/ml TII 66,7 ng/ml (N: 50-170)). NGS (NGS-007FP) testing identified the presence of the c.922G>A (p.Glu308Lys) variant, rs 375095163 in the homozygous state in the MC4R gene, classified as a variant of uncertain clinical significance but leaning towards pathogenicity. Further family-wide diagnostics (parents and five siblings) identified the same homozygous variant in the boys' father, who also had obesity (BMI 31.1 kg/m²) with subtle dysmorphic features similar to the described twins. The same c.922G>A (p.Glu308Lys) variant, rs 375095163 in the heterozygous state was present in the remaining family members, but obesity was present in only one of them (11-year-old brother).

Conclusion: The c.922G>A (p.Glu308Lys) variant, rs 375095163 in the MC4R gene identified in family members may have pathogenic significance. However, penetrance may be incomplete, and the variation in clinical symptoms highlights the influence of environmental factors and other potential genetic modulators.