ESPE2022 Poster Category 1 Fat, Metabolism and Obesity (73 abstracts)
Introduction: Homozygous leptin (LEP) and leptin receptor (LEPR) mutations lead to childhood-onset obesity due to deficient leptin signaling. The specific aims of this work are to explore genotype/phenotype correlations in a national multicenter cohort of 18 subjects with leptin (LEP) and leptin receptor (LEPR) deficiency, report on the long-term clinical follow-up of these rare cases, and systematically review all patients with pathogenic LEP/LEPR variants that have been reported so far.
Methods: Our cohort includes 11 patients with LEP and 7 patients with LEPR from 12 independent families. Of these patients, 8 have been previously reported. A systematic literature review in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) was conducted in December 2021. 42/47 studies on LEP/LEPR were selected. Data are presented as the median (interquartile range).
Results: Childhood-onset obesity was caused by LEP mutations in 11 (current age:5-57 years, F/M:3/8) and LEPR mutations in 7 cases (current age:1.4-22, F/M:2/5). Two novel mutations were identified: one frameshift in LEP (c.16delC, p.Leu6CysfsTer65) and one splice site in LEPR (c.40+5G>C). The median follow-up was 5 (6) years. Eleven patients with LEP deficiency received metreleptin, four of whom had been receiving treatment for more than two decades. Among them, one patient developed loss of efficacy associated with neutralizing antibody development. Among 151 patients which includes 133 cases from the literature review in addition to our cases, frameshift mutations were the most common (48%) in 54 patients with LEP deficiency, whereas missense mutations (35%) were more common among 97 patients with LEPR variants. LEP deficient patients were diagnosed at a younger age (3 (9) vs. 7 (13) years, P=0.02), and had a higher median BMI SD score (3.1 (2) vs. 2.8 (1) kg/m2, P=0.02), which was more closely associated with frameshift mutations (P=0.02). Both groups had similar incidences of hypogonadism, recurrent infections, hyperlipidemia, growth failure, and hypothyroidism. On the other hand, LEP deficient patients were more likely to have hyperinsulinemia (P=0.02).
Conclusion: Our analysis revealed that frameshift mutations were more common in LEP whereas missense mutations were more common in LEPR genes. LEP deficient patients were identified at younger ages, had higher BMI SD scores, and had higher rates of hyperinsulinemia than LEPR deficient patients. In our experience, 11 patients took metreleptin treatment for long term with persistent benefit, with one patient developing loss of efficacy due to neutralizing antibody.
15 Sep 2022 - 17 Sep 2022