Diagnostic Approach to Genetic Obesity in Children: From Pathophysiology to Precision Medicine

Childhood obesity is a major global health concern with a strong heritable component. While most cases are polygenic and environmentally driven, a subset of children present with rare genetic forms of obesity, including syndromic and monogenic disorders. Over the past three decades, advances in gene discovery—from candidate gene studies to genome-wide association studies (GWAS) and next-generation sequencing (NGS)—have significantly improved our understanding of the biological pathways regulating appetite and energy balance, particularly the leptin–melanocortin pathway. Early identification of genetic obesity is clinically relevant, as it allows tailored management, targeted pharmacological interventions, genetic counselling, and reduction of psychosocial stigma. However, distinguishing rare genetic obesity from common polygenic obesity remains challenging in clinical practice. This review summarizes the current knowledge on the genetic architecture of pediatric obesity, highlights red flags suggestive of monogenic and syndromic forms, discusses available diagnostic algorithms and genetic testing strategies, and explores the transition from gene discovery to precision medicine. The integration of genetic, epigenetic, and environmental data will be crucial to refine risk prediction and therapeutic strategies in the pediatric population.