ESPE Abstracts

Background: Biallelic loss of function (LoF) mutations in the leptin receptor gene (LEPR) cause a striking phenotype of early-onset severe obesity and hyperphagia. Additionally, hypogonadotropic hypogonadism, growth hormone deficiency, and/or hypothyroidism are often present. Currently, 19 European patients (all aged <30 years) are described in literature. As clinical trials investigating MC4R-agonist treatment are performed throughout Europe, identification of these patients is vital. The aim of this study was to estimate the number of LepR deficient patients in Europe.

Methods: We performed a systematic literature search and developed a list of LoF variants in LEPR from literature and our in-house genetic data. Subsequently, we extracted the allele frequencies from the Genome Aggregation Database (data of ~64.000 European individuals without severe paediatric disease). Through a comprehensive epidemiologic analysis, we estimated the number of individuals with homozygous or compound heterozygous known and predicted pathogenic variants in LEPR in Europe analogous to Ayers et al. (JCEM 2018:2601-12) and a conservative estimation using only known pathogenic mutations previously identified in patients.

Results: Literature research revealed that there are 75 cases published, with 42 distinct LEPR mutations. We add two new cases: a boy diagnosed at age 1 year with BMI 24.6 kg/m² (+4.4SD), hyperphagia, growth hormone deficiency and central hypothyroidism; and a girl with early-onset obesity and hyperphagia, diagnosed at age 11 years with a BMI of 28.5kg/m² (+3.1SD). Our conservative prevalence estimation (n=7 pathogenic variants from known patients) results in a predicted 278 (95% CI 179-378) patients with LepR deficiency in Europe, suggesting that at utmost 8% of European patients are described in literature. By using the less conservative method (n=94 variants with known or predicted pathogenicity), the number of estimated European patients is 8926 (95% CI 8039-9814).

Conclusion: We find a large gap between the estimated number of patients with LepR deficiency in Europe and those described in literature. This discrepancy suggests that the typical clinical phenotype of LepR deficiency (extreme weight gain in first years of life and often clinical signs of hypopituitarism) is not sufficiently recognized. A possible cause is lack of access to LEPR genetic testing, which only recently became accessible. Moreover, the phenotype might not be overtly present or might resolve over time. The young age of known patients suggests that high mortality could also play a role. With promising clinical trial results of MC4R-agonist treatment in LepR deficient patients, the importance of diagnosing LepR deficiency is paramount.