Rare genetic forms of obesity in childhood and adolescence, a comprehensive review of their molecular mechanisms and diagnostic approach

Abstract

Obesity represents a major health problem in the pediatric population with an increasing prevalence worldwide, associated with cardiovascular and metabolic disorders, and due to both genetic and environmental factors. Rare forms of obesity are mostly monogenic, and less frequently due to polygenic influence. Polygenic form of obesity is usually the common obesity with single gene variations exerting smaller impact on weight and is commonly non-syndromic.Non-syndromic monogenic obesity is associated with variants in single genes typically related to the hypothalamic leptin-melanocortin signalling pathway, which plays a key role in hunger and satiety regulation, thus body weight control. Patients with these genetic defects usually present with hyperphagia and early-onset severe obesity. Significant progress in genetic diagnostic testing has recently made for early identification of patients with genetic obesity, which guarantees prompt intervention in terms of therapeutic management of the disease. What is Known: • Obesity represents a major health problem among children and adolescents, with an increasing prevalence worldwide, associated with cardiovascular disease and metabolic abnormalities, and it can be due to both genetic and environmental factors. • Non-syndromic monogenic obesity is linked to modifications in single genes usually involved in the hypothalamic leptin-melanocortin signalling pathway, which plays a key role in hunger and satiety regulation. What is New: • The increasing understanding of rare forms of monogenic obesity has provided significant insights into the genetic causes of pediatric obesity, and our current knowledge of the various genes associated with childhood obesity is rapidly expanding. • A useful diagnostic algorithm for early identification of genetic obesity has been proposed, which can ensure a prompt intervention in terms of therapeutic management of the disease and an early prevention of the development of associated metabolic conditions.

Keywords: Childhood obesity; Hyperphagia; Leptin-melanocortin pathway; Monogenic obesity.