Monogenic and syndromic obesity in children: Clinical recognition, genetics, and precision management

ABSTRACT Obesity is increasingly being recognized as a heterogeneous condition with strong genetic underpinnings. Monogenic obesity, caused by single‐gene mutations, primarily affects the leptin–melanocortin pathway, which regulates hunger and satiety. Mutations in genes, such as LEP , LEPR , POMC , PCSK1 , and MC4R , lead to hyperphagia, early onset severe obesity, and metabolic dysregulation. LEP and LEPR mutations impair leptin signaling, resulting in defective appetite suppression, whereas POMC and PCSK1 deficiencies disrupt prohormone processing. MC4R mutations, the most common cause of monogenic obesity, impair satiety signaling and are linked to rapid weight gain. Syndromic obesity, including the Bardet‐Biedl and Alström syndromes, involves ciliary dysfunction, leading to developmental abnormalities alongside obesity. Other genes such as SH2B1 , SIM1 , and BDNF play crucial roles in hypothalamic development and energy regulation. Advances in genomic sequencing have improved the recognition of genetic etiologies; however, many patients remain undiagnosed due to limited testing availability and a lack of clinician awareness. Precision therapies, including set‐melanotide for specific melanocortin pathway defects, demonstrate the promise of targeted treatments. However, management must extend beyond pharmacology; lifestyle interventions, psychosocial support, and family‐centered care remain essential, especially when intellectual disability or behavioral challenges complicate adherence. Ethical considerations surrounding access and equity are critical, as high‐cost therapies and the limited availability of genetic testing risk widening disparities between health systems. Polygenic risk scores and multi‐omics approaches may expand precision medicine beyond rare genetic syndromes to common obesity, highlighting the importance of integrating genetics, psychosocial care, and policy advocacy in the management of pediatric obesity.