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A Novel Leptin Receptor LEPR Variant in a Toddler With Early-Onset Fatal Obesity
Kevin Perge1,2, Linda Pons3, Nastassja Protsenko4
1Hôpital Femme Mère Enfant, Service d'Endocrinologie Pédiatrique et Pédiatrie Générale, Hospices Civils de Lyon, Bron, France.
Insights
A novel genetic variant in the leptin receptor gene caused severe early-onset obesity and hyperphagia in an infant. This case highlights the critical role of leptin receptor signaling in early development and metabolic health.
Area of Science:
- Genetics
- Endocrinology
- Pediatrics
Background:
- Monogenic obesity presents as severe early-onset obesity with feeding and endocrine issues.
- Syndromic obesity often involves multiple developmental abnormalities.
Purpose of the Study:
- To report a unique case of severe early-onset obesity in an infant.
- To identify the genetic cause of the severe obesity and hyperphagia.
Main Methods:
- Clinical case presentation of an 11-month-old boy with severe obesity.
- Laboratory investigations including serum leptin levels.
- Next-generation sequencing of obesity-related genes.
Main Results:
- The patient exhibited severe early-onset obesity, hyperphagia, obstructive sleep apnea, dyslipidemia, hepatic steatosis, and insulin resistance.
- Elevated serum leptin levels were observed.
- A novel homozygous intronic variant (c.703+5G>A) in the leptin receptor gene (LEPR) was identified, predicted to cause protein truncation.
Conclusions:
- This case demonstrates a novel LEPR variant leading to severe monogenic obesity.
- The findings underscore the importance of LEPR in regulating early-life growth and metabolism.
- The severe phenotype and lack of specific therapies highlight the need for further research into targeted treatments.
Abstract:
Monogenic obesity generally results in severe early-onset obesity associated with abnormal feeding behavior and endocrine disorders. We report here an extremely severe case of early-onset obesity associated with hyperphagia in an 11-month-old boy without other signs of a syndromic obesity. He developed severe obstructive sleep apnea, dyslipidemia, hepatic steatosis with cytolysis, and acanthosis nigricans with insulin resistance in the first months of life. Laboratory investigations showed an elevated serum leptin level (80.03 ng/mL, normal range 2.45-6.55 ng/mL). Next-generation sequencing of obesity genes panel identified a novel homozygous intronic variant in leptin receptor gene (LEPR), c.703 + 5G>A, predicting affected splicing that resulted in a frameshift, premature stop, and truncation of the protein beyond the cytokine receptor homology domain 1. The child died at 27 months of age in the absence of available specific drug therapy.
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