Expanding the reproductive spectrum of congenital leptin deficiency: Spontaneous pregnancies and long-term metreleptin therapy in two siblings with a candidate novel LEP variant
Obesity Research and Clinical Practice, 2026 (SCI-Expanded, Scopus)
- Yayın Türü: Makale / Tam Makale
- Basım Tarihi: 2026
- Doi Numarası: 10.1016/j.orcp.2026.10.002
- Dergi Adı: Obesity Research and Clinical Practice
- Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, CINAHL, EMBASE, MEDLINE
- Anahtar Kelimeler: Congenital leptin deficiency, LEP variant, Metreleptin, Monogenic obesity, Reproductive spectrum
- Dokuz Eylül Üniversitesi Adresli: Evet
Özet
Purpose: Congenital leptin deficiency (CLD) is an ultra-rare monogenic obesity syndrome classically associated with hypogonadotropic hypogonadism and delayed pubertal development. We report a previously unreported LEP variant in two sisters, expanding the recognized reproductive spectrum of CLD. Case presentation: Two Turkish sisters presented with severe early-onset obesity, hyperphagia, and severely suppressed/undetectable serum leptin (<0.10 and 0.38 ng/mL). Genetic analysis identified a homozygous likely pathogenic nonsense variant in the LEP gene (c.33 G>A; p.Trp11Ter; NM_000230.3). Remarkably, both siblings achieved spontaneous pregnancies despite untreated CLD in early adulthood, though Case 1 exhibited delayed menarche (age 21), indicating underlying reproductive axis dysfunction. The index case (BMI 61.0 kg/m²) conceived three children (including twins), with her second pregnancy following a 36 kg weight loss induced by metreleptin. Her sister (BMI 41.4 kg/m²) had two spontaneous pregnancies prior to diagnosis. Under metreleptin therapy, both patients demonstrated substantial long-term metabolic improvement: the index case’s weight decreased from 139 kg to 87 kg (BMI 61.0–38.2 kg/m²) over 3 years of follow-up, and her sister’s weight decreased from 102 kg to 65 kg over 3.5 years of continuous treatment. Conclusion: The identified LEP variant expands the genotypic and reproductive spectrum of monogenic obesity. While spontaneous conception occurred in both siblings, variable penetrance or subclinical reproductive dysfunction remains evident. Early diagnosis and metreleptin therapy remain essential for long-term metabolic recovery, glycemic control, and overall quality of life.