ESPE Abstracts

Introduction: The leptin-melanocortin pathway plays a key-role in weight control. Pathogenic variants in the five major genes (LEP, LEPR, POMC, PCSK1, MC4R) are associated with early severe obesity. However, the specific associated phenotype with presence of mono-allelic variants and especially BMI trajectories are not well known.

Objective: In order to identify specific profiles, we compared BMI trajectories during the first 6 years of life in subjects carrying pathogenic mono-allelic variant in one of the five major genes of the leptin-melanocortin pathway with those of subjects either carrying bi-allelic variant or no identified variant.

Methods: We retrospectively collected anthropometric data (weight, height, BMI) from 64 subjects carrying a pathogenic mono-allelic or bi-allelic variant in at least one of the 5 major genes of the pathway (LEP (n=3), LEPR (n=22), POMC (n=9), PCSK1 (n=8), and MC4R (n=22)) and from 24 subjects in whom no variant in the same genes were identified. BMI and BMI Z-score at each age between 0 and 6 years were compared between the groups (mono-allelic (HET) or bi-allelic (HOM) or no variant (NM)).

Results: The evolution of weight of HET patients (n=30) whatever the gene (LEP, LEPR, POMC, PCSK1, MC4R) were not significantly different before the age of 6 years. Similarly, the BMI trajectory of patients with a pathogenic mono-allelic MC4R variant was comparable to patients with one mono-allelic variant in one of the four other genes (age 3 years: BMI Zscore MC4R (n=12) 4.9 SD vs other genes (n=18) 3.7 SD (NS); age 5 years: BMI Zscore MC4R (n=10) 6.6 SD vs other genes (n=18) 6.6 SD (NS)). Between 1 and 5 years, HOM patients (n=14) had significantly higher BMI compared to HET patients with a difference of at least 2.5 SD at each age (P<0.01) and earlier obesity (P<0.01). The evolution of BMI before 6 years of age was not significantly different between patients carrying mono-allelic variant and patients without identified variant (age 3 years: BMI ZScore HET (n=29) 4,3 SD vs NM (n=16) 3.6 SD (NS) ; age 5 years: BMI Zscore HET (n=27) 5,2 vs NM (n=13) 6.3 (NS)).

Conclusion: Patients carrying bi-allelic variant develop more severe obesity in the early childhood than patients carrying mono-allelic variant or no variant. The lack of specific BMI profile in patients with a mono-alllelic variant in one of the 5 major of the leptin-melanocortin pathway requires systematic genetic exploration if the BMI is > 25 kg/m2 at 2 years.