Obesity due to congenital leptin resistance

Obesity due to congenital leptin resistance is an extremely rare genetic disorder characterized by severe, early-onset obesity caused by mutations in the leptin receptor gene (LEPR). Also known as leptin receptor deficiency or LEPR deficiency, this condition renders the body unable to respond appropriately to leptin, a hormone produced by fat cells that plays a critical role in regulating appetite, energy balance, and body weight. Although leptin levels in the blood are typically elevated, the defective receptors in the hypothalamus cannot transduce the satiety signal, leading to constant, insatiable hunger (hyperphagia) and rapid weight gain beginning in infancy. The condition primarily affects the endocrine and metabolic systems. Key clinical features include severe obesity from the first months of life, intense hyperphagia, and hypogonadotropic hypogonadism, which can lead to delayed or absent puberty. Some patients may also exhibit alterations in immune function, including recurrent infections, due to leptin's role in immune regulation. Growth hormone secretion may also be impaired. Body composition is markedly abnormal, with excessive fat mass accumulation. Unlike congenital leptin deficiency (where recombinant leptin therapy is effective), leptin resistance due to receptor defects does not respond to exogenous leptin administration, since the underlying problem is the inability of receptors to respond to the hormone. Management has historically been limited to dietary interventions and behavioral strategies, which are often insufficient given the severity of hyperphagia. More recently, setmelanotide, a melanocortin 4 receptor (MC4R) agonist that acts downstream of the leptin receptor in the leptin-melanocortin signaling pathway, has been approved for the treatment of obesity in patients with confirmed biallelic LEPR deficiency, representing a significant therapeutic advance for this condition.

Inheritance

Autosomal recessive

Passed on when both parents carry the same gene change; often skips generations

Age of Onset

Infantile

Begins in infancy, roughly 1 month to 2 years old

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