The Journal of Clinical Endocrinology and Metabolism Journal Article

Leptin and Leptin Receptor Deficiency

September 12, 2023
 

Özge Besci, Sevde Nur Fırat, Samim Özen, Semra Çetinkaya, Leyla Akın, Yılmaz Kör, Zafer Pekkolay, Şervan Özalkak, Elif Özsu, Şenay Savaş Erdeve, Şükran Poyrazoğlu, Merih Berberoğlu, Murat Aydın, Tülay Omma, Barış Akıncı, Korcan Demir, Elif Arioglu Oral
The Journal of Clinical Endocrinology & Metabolism, Volume 108, Issue 9, September 2023, Pages 2371–2388
https://doi.org/10.1210/clinem/dgad099

Abstract

Context

Homozygous leptin (LEP) and leptin receptor (LEPR) variants lead to childhood-onset obesity.

Objective

To present new cases with LEP and LEPR deficiency, report the long-term follow-up of previously described patients, and to define, based on all reported cases in literature, genotype-phenotype relationships.

Methods

Our cohort included 18 patients (LEP = 11, LEPR = 7), 8 of whom had been previously reported. A systematic literature review was conducted in July 2022. Forty-two of 47 studies on LEP/LEPR were selected.

Results

Of 10 new cases, 2 novel pathogenic variants were identified in LEP (c.16delC) and LEPR (c.40 + 5G > C). Eleven patients with LEP deficiency received metreleptin, 4 of whom had been treated for over 20 years. One patient developed loss of efficacy associated with neutralizing antibody development. Of 152 patients, including 134 cases from the literature review in addition to our cases, frameshift variants were the most common (48%) in LEP and missense variants (35%) in LEPR. Patients with LEP deficiency were diagnosed at a younger age [3 (9) vs 7 (13) years, P = .02] and had a higher median body mass index (BMI) SD score [3.1 (2) vs 2.8 (1) kg/m2, P = 0.02], which was more closely associated with frameshift variants (P = .02). Patients with LEP deficiency were more likely to have hyperinsulinemia (P = .02).

Conclusion

Frameshift variants were more common in patients with LEP deficiency whereas missense variants were more common in LEPR deficiency. Patients with LEP deficiency were identified at younger ages, had higher BMI SD scores, and had higher rates of hyperinsulinemia than patients with LEPR deficiency. Eleven patients benefitted from long-term metreleptin, with 1 losing efficacy due to neutralizing antibodies.

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