ESPE Abstracts

Background: Melanocortin4-receptor (MC4R) deficiency is the most common cause of monogenetic obesity. Other forms of genetic obesity, like 16p11.2 deletion syndrome, are associated with increased head circumference (HC). Little is known about HC in patients with MC4R deficiency.

Methods: This study included patients with homozygous or heterozygous, pathogenic or likely pathogenic ACMG class 4 or 5 MC4R variants. Pediatric patients were matched 1:1 to an age and sex matched control group with multifactorial obesity. HC, height, weight and body-mass index (BMI) were measured. Measurements were expressed by age and sex corrected standard deviation scores (SDS). HC SDS of the patients was compared to the reference population (Dutch National Growth charts) and pediatric patients were also compared to the control group, using one-sample t-tests, unpaired t-tests, one-sample Wilcoxon Signed Rank Test and linear regression analysis.

Results: Pediatric patients with MC4R deficiency (n = 64, mean age 10.31 years) had a significantly larger mean HC of 1.73 SDS (1.13 SD) compared to the reference population (p-value <0.001) and control group (HC 1.21 SDS, 95% CI -0.89 to -0.14, p-value 0.007). In adults (n = 11) HC (median +0.86 SDS, min –2.27 max 3.42 SDS) was not significantly different to the reference population (p-value 0.109). In children, 42% of the patients were classified as macrocephalic (HC ≥2 SDS), compared to 25% of the controls (p-value 0.040) and 27% in adult patients. Children with MC4R deficiency had a significantly larger mean height compared to controls (1.00 SDS and 0.42 SDS respectively, p-value 0.014), but similar mean BMI (3.98 SDS and 3.76 SDS respectively, p-value 0.184). Pediatric patients with homozygous (n = 3) variants tended to have a larger HC compared to heterozygous (n = 63) variants (2.84 SDS and 1.66 SDS respectively, 95% CI -2.51 to 0.14, p-value 0.079). An association was found between HC SDS and height SDS (R2 0.22, p-value <0.001), but not between HC SDS and BMI SDS (R2 0.03, p-value 0.22).

Conclusion: Pediatric patients with MC4R deficiency present with a larger HC compared to the reference population and obese controls. This difference was not found in adults. HC measurement is essential in the diagnostic work-up of children suspected for genetic obesity, since it can be a clue for MC4R deficiency.