ESPE Abstracts (2022) 95 P1-474


1Division of Pediatric Endocrinology, Dokuz Eylül University, Faculty of Medicine, İzmir, Turkey; 2Division of Endocrinology and Metabolism, University of Health Sciences Ankara Training and Research Hospital, Ankara, Turkey; 3Division of Pediatric Endocrinology, Ege University, Faculty of Medicine, İzmir, Turkey; 4Division of Pediatric Endocrinology, Health Sciences University, Dr Sami Ulus Obstetrics and Gynecology, Children's Health and Disease, Health Implementation and Research Center, Ankara, Turkey; 5Division of Pediatric Endocrinology, Faculty of Medicine, Ondokuz Mayıs University, Samsun, Turkey; 6Division of Pediatric Endocrinology, Ministry of Health, Adana Public Hospitals Association, Adana City Hospital, Adana, Turkey; 7Division of Endocrinology and Metabolism, Dicle University Faculty of Medicine, Diyarbakır, Turkey; 8Division Pediatric Endocrinology, Diyarbakir Gazi Yaşargil Training and Research Hospital, Diyarbakır, Turkey; 9Department of Pediatric Endocrinology, Ankara University Faculty of Medicine, Ankara, Turkey; 10Department of Pediatric Endocrinology, Istanbul University Istanbul Faculty of Medicine, İstanbul, Turkey; 11Division of Endocrinology and Metabolism, Department of Internal Medicine, Dokuz Eylul University, İzmir, Turkey; 12Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA

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.

Volume 95

60th Annual ESPE (ESPE 2022)

Rome, Italy
15 Sep 2022 - 17 Sep 2022

European Society for Paediatric Endocrinology 

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