Unraveling the relationship between head circumference and MC4R deficiency from infancy to adulthood: a case–control study

Abstract

Objective

The objective of this study was to investigate head circumference (HC) in patients with melanocortin 4 receptor (MC4R) deficiency, the most common cause of monogenetic obesity.

Methods

Patients with (likely) pathogenic MC4R variants were included. HC, height, and weight were measured, and BMI and standard deviation score (SDS) were calculated. HC SDS was compared to the Dutch reference population. Children were matched 1:1 to a control group with common obesity.

Results

Children with MC4R deficiency (n = 63, mean age, 10.32 years) had significantly larger HC (mean, +1.73 SDS) compared to the reference population (0 SDS; p < 0.001) and controls (+1.22 SDS; p = 0.009). In adults (n = 13), HC (median, + 0.86 SDS) did not differ from the reference population (0 SDS; p = 0.152). Macrocephaly (HC ≥ 2 SDS) was present in 43%, 25%, and 23% of pediatric patients with MC4R deficiency, controls, and adult patients, respectively. Children with MC4R deficiency were taller than controls (+1.00 SDS vs. +0.42 SDS; p = 0.016), with similar BMI (+3.99 SDS vs. +3.75 SDS; p = 0.157). HC SDS was associated with height SDS (R², 0.22; p < 0.001) and homeostatic model assessment of insulin resistance (correlation coefficient, 0.542; p < 0.05).

Conclusions

Macrocephaly is a common feature of patients with MC4R deficiency. We recommend measuring HC in patients suspected for genetic obesity, as it can be a clue for MC4R deficiency.