A Novel Leptin Receptor LEPR Variant in a Toddler With Early-Onset Fatal Obesity

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.