Adenylate cyclase 3 (ADCY3) is a transmembrane protein predominantly expressed in the primary cilia of neurons. It plays a vital role in converting ATP to cAMP, a secondary messenger that regulates various downstream signaling pathways such as carbohydrates and lipids metabolism. Homozygous loss-of-function variants in the ADCY3 gene lead to severe early-onset obesity and insulin resistance whereas gain-of-function variants protect against obesity. To describe a novel pathogenic ADCY3 variant implicated in early-onset obesity and functionally characterize this variant via in vitro and in silico validation, we identified a novel homozygous nonsense variant c.2520C>G, p.Thr840X in the ADCY3 gene using gene panel sequencing in a four-year-old girl. She was born to first-cousin consanguineous parents. The patient presented with severe obesity, and exhibited hepatomegaly and insulin resistance, with other biochemical and hormonal tests being normal. In vitro and in silico functional analyses showed downregulation and impaired activation of the ADCY3 protein. Our findings contribute to existing research that supports the role of ADCY3 in the genetic pathogenesis of early-onset obesity. In vitro and in silico functional characterization of the novel p.Thr840X variant showed impaired enzymatic activity leading to receptor loss of function, consistent with the patient’s phenotype. Genetic testing is essential in severe early-onset obesity and early diagnosis could benefit patients with personalized treatment strategies.

Monogenic forms of severe early-onset obesity often involve genetic disruptions in the hypothalamic leptin-melanocortin pathway. Pathogenic variants in the SIM1 gene, a key transcription factor required for the development of the paraventricular nucleus, are a known cause of Prader–Willi-like syndrome, characterized by hyperphagia, severe obesity, and developmental delay. We performed targeted next-generation sequencing of 52 obesity-associated genes on a cohort of pediatric patients with severe early-onset obesity. Identified variants were analyzed for population frequency and predicted pathogenicity using in silico tools. The structural impact of the novel missense variants was assessed using protein domain modeling with AlphaFold3. We identified five rare SIM1 variants in eleven patients. Four were heterozygous nonsynonymous variants: one frameshift in the bHLH domain (p.Ser18Ter), one frameshift in the Per-ARNT-Sim domain (p.His143Ter), and two missense variants, p.Pro30Ala and p.Ser663Leu. Structural modeling suggested that the missense variants are likely to disrupt critical protein–protein interactions. The fifth variant was a synonymous change, c.1173G>A, p.(Ser391Ser), which was detected in five unrelated patients. Bioinformatic analysis predicted that this variant could alter splicing. Structural modeling suggested that the missense variants interfere with SIM1 function. This study expands the mutational spectrum of SIM1-linked monogenic obesity, reporting novel likely pathogenic frameshift variants, a missense variant, and a recurrent synonymous variant with a potential splice-site effect. The majority of the variants are predicted to affect the SIM1 protein. Our findings strengthen the critical role of the SIM1 gene in hypothalamic development and energy homeostasis. The results underscore the importance of including the SIM1 gene in genetic testing panels for children with severe obesity and hyperphagia, enabling precise diagnosis and potential future personalized management. Functional in vitro or in vivo validation of these variants is required to confirm their pathogenicity.

Bardet-Biedl syndrome (BBS) and Alström syndrome (AS) are rare autosomal recessive ciliopathies characterized by severe multisystemic involvement, including metabolic, sensory, and developmental impairments. Both conditions result from primary cilia dysfunction, disrupting pathways such as leptin and insulin signaling, which leads to obesity and insulin resistance. While setmelanotide, a melanocortin-4 receptor agonist, may be an effective therapy for obesity in these conditions (especially BBS), its cost limits accessibility for many patients. We describe two pediatric cases (one with BBS and another with AS) demonstrating significant metabolic improvements with semaglutide, a glucagon-like peptide-1 receptor agonist. These observations suggest that some cases of BBS and AS may be treated with semaglutide.

Obesity is characterized by an excess accumulation of adipose tissue, independent of its distribution or function, and is associated with organ dysfunction and a broad range of metabolic and cardiac complications. Nutritional, environmental, behavioral, genetic, psychological, and metabolic factors contribute to obesity. It is associated with many secondary complications, including diabetes mellitus, hypertension, dyslipidemia, metabolic dysfunction-associated steatotic liver disease, reduced quality of life, and psychological illnesses. For practical purposes, childhood obesity can be classified into polygenic, monogenic, syndromic, and endocrine causes. Management should be patient-centered and multidisciplinary, integrating lifestyle/behavioral changes with adjunctive pharmacotherapy and bariatric surgery where appropriate. In monogenic or syndromic obesity, knowing the underlying genetic etiology allows precision-guided and more effective therapy. This review aims to provide a state-of-the-art review on the management of obesity in children.

Childhood obesity is a heterogeneous chronic disease shaped by genetic susceptibility, neuroendocrine signaling, energy homeostasis, adipose dysfunction, insulin resistance, and environmental exposure. Glucagon-like peptide-1 (GLP-1) receptor agonists have markedly improved treatment efficacy, but heterogeneous response, weight recurrence after withdrawal, residual organ risk, and limited long-term pediatric data expose the limitations of a single-pathway, weight-centered model. This narrative review integrates the molecular rationale and clinical evidence for precision pharmacotherapy beyond single GLP-1 receptor agonism. It examines glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 and GLP-1/glucagon co-agonism, triple agonism, amylin combinations, fibroblast growth factor 21 (FGF21) analogues, leptin replacement, and melanocortin-4 receptor (MC4R) agonism, separating established pediatric evidence from adult proof-of-concept and preclinical inference. Genotype-directed treatment for monogenic and syndromic obesity and lesion-directed treatment for acquired hypothalamic obesity provide the clearest examples of causal pathway correction. For common obesity, treatment selection should integrate developmental stage, hyperphagia, insulin resistance, ectopic fat, body composition, genetic context, treatment burden, and early response. Disease modification should be evaluated across growth, puberty, bone and lean tissue, beta cell and hepatic health, physical function, psychosocial well-being, safety, and durability. A dynamic cycle of phenotyping, mechanism-based treatment, multidomain monitoring, adaptation, and longitudinal re-phenotyping may improve the clinical relevance of pediatric obesity care.

Youth-onset type 2 diabetes (Y-T2D) is a heterogeneous cardiometabolic disease in which pubertal insulin resistance, limited β-cell reserve, obesity-related metabolic dysfunction, genetic susceptibility, early-life exposures, and barriers to care converge. This structured narrative review synthesizes evidence from pediatric randomized trials, longitudinal cohorts, clinical guidelines, and studies of metabolic bariatric surgery in adolescents identified through database searches updated to 15 October 2026. Pediatric evidence shows limited durability of metformin-based therapy in the selected TODAY population and continued β-cell deterioration in RISE, which included youth with impaired glucose tolerance and those with recently diagnosed type 2 diabetes. Contemporary trials demonstrate clinically important short-term glycemic efficacy for GLP-1 receptor agonists, SGLT2 inhibitors, and tirzepatide; among pediatric type 2 diabetes trials, only tirzepatide has produced a large concurrent reduction in BMI. However, differences in baseline HbA1c, background therapy, trial duration, estimands, and rescue-treatment rules preclude indirect efficacy rankings. Long-term effects on β-cell preservation, growth, puberty, bone and reproductive health, and cardiovascular or kidney outcomes remain unproven. Clinical priorities therefore include accurate classification, prompt treatment intensification, obesity-directed care, complication surveillance from diagnosis, and active mitigation of psychosocial and access barriers. This review provides an evidence-tiered interpretation of disease biology and a practical treatment-sequencing framework that distinguishes established pediatric findings from adult or experimental extrapolation.