Homozygous Leptin Receptor Mutation Due to Uniparental Disomy of Chromosome 1: Response to Bariatric Surgery

Context: Severe early-onset obesity with major hyperphagia associated with hypogonadotropic hypogonadism is recognized as the main clinical presentation of leptin (LEP) or LEP receptor (LEPR) gene complete deficiency. In a few reported cases, homozygous mutations have been found in patients from consanguineous families. Care of LEPR-deficient patients is complicated because they cannot benefit from LEP treatment. Furthermore, gastric surgery may not be recommended in such genetic hypothalamic obesity. Objective: We investigated in a morbidly obese patient the genetic origin of his obesity and evaluated the benefit of bariatric surgery in this case. Subject and Methods: The patient exhibited severe early-onset obesity with hyperphagia and delayed puberty in a nonobese family. He had clinical and hormonal follow-up from 3 to 26 years of age. Gastroplasty procedures were undertaken when he was 16 and 18 years old. LEPR genetic analysis of the patient and his relatives was performed. Results: A new homozygous LEPR sequence frameshift, predicted to generate a truncated protein from a premature stop codon in exon 14, was identified in the proband inherited from two paternal copies of chromosome 1 (isodisomy). Vertical ring gastroplasty was sufficient to induce and maintain a 40-kg weight loss into adulthood. Conclusion: We described the first case of a patient with chromosome 1 uniparental isodisomy revealed by molecular analysis of LEPR. In this case, gastroplasty may be partially effective for weight control as illustrated. (J Clin Endocrinol Metab 98: E397-E402, 2013)