Genetic factors are key determinants in the pathophysiology of obesity, regulating energy homeostasis. Monogenic non-syndromic obesity accounts for 2–3% of obesity in both children and adults and is most often attributable to mutations in genes encoding components of the leptin–melanocortin pathway. Genetic testing is indicated in children with severe obesity before age 5, hyperphagia, a family history of obesity, and neurodevelopmental delay or organ dysfunction. Mutations associated with monogenic obesity follow autosomal recessive (LEP, LEPR, POMC, and PCSK1) or autosomal dominant (MC4R, SH2B1, SIM1, GNAS) modes of inheritance. Other gene mutations in heterozygous states (MRAP2, MC3R, SRC1, KSR2) are associated with obesity and may exhibit autosomal dominant inheritance; however, the clinical phenotype depends on the degree of genetic penetrance and interactions with other genetic and/or environmental factors. No approved targeted pharmacotherapies are currently available for autosomal dominant monogenic obesity, and the frequent detection of variants of uncertain significance often hinders timely diagnostic confirmation. The review provides a comprehensive appraisal of autosomal dominant forms of monogenic non-syndromic obesity, analyzing genetic and molecular features, clinical presentations, and therapeutic strategies.

Youth-onset type 2 diabetes (T2D) is a growing public health challenge. This narrative review aims to provide a comprehensive overview of epidemiology, pathophysiology, diagnosis, complications, and therapeutic strategies in children and adolescents with T2D, highlighting the most recent evidence and the distinctive features that differentiate youth-onset from adult-onset disease. Over recent decades, its incidence has increased worldwide, closely linked to rising rates of childhood obesity, sedentary behavior, and socioeconomic disparities. The disease typically emerges around puberty, a period marked by physiological insulin resistance, and is influenced by a complex interplay of genetic, environmental, and developmental factors. Diagnosis can be delayed or missed due to overlapping features with type 1 diabetes and limitations in current screening tools. The clinical course is often aggressive, with early onset of microvascular and macrovascular complications. Management is particularly challenging due to the limited number of pharmacologic agents approved for pediatric use and the psychological and behavioral complexities of adolescence. While metformin remains the first-line treatment, newer therapies such as GLP-1 receptor agonists and SGLT2 inhibitors show promise in improving metabolic outcomes. In conclusion, early diagnosis, multidisciplinary management, and equitable access to effective therapies are essential to improve long-term outcomes in this vulnerable population.

Background: Genetic causes of growth failure should be suspected in patients born small for gestational age (SGA) who fail to show postnatal catch-up growth, present with severe short stature (SS), and exhibit a poor or absent response to growth hormone (rhGH) therapy. Mutations in the insulin-like growth factor 1 receptor (IGF1R) gene are associated with impaired growth, intrauterine growth restriction (IUGR), low birth weight and/or length, and postnatal SS. Case Description: A 9-year-old boy, born SGA for birth length, was evaluated for severe SS. Common causes of SS were excluded. At 9 years and 7 months of age, his height was 112.6 cm (−3.99 SDS), weight 18 kg (−3.79 SDS), and BMI 14.2 kg/m² (−1.8 SDS); pubertal development was Tanner stage 1. The target height was 158 cm (−2.62 SDS). Bone age was delayed by approximately one year compared with chronological age. Serum IGF-1 levels were within the upper-normal range for age. GH therapy (0.035 mg/kg/day) was initiated due to the lack of catch-up growth in an SGA subject. After three years of treatment, the height gain was only 0.5 SDS. IGF-1 levels showed a transient treatment-related increase, followed by persistent normalization during ongoing therapy. Next-generation sequencing (NGS) analysis identified novel heterozygous paternal nonsense variant in the IGF1R gene: c.3498C>G (p.Tyr1166Ter). At 12 years of age, impaired fasting glucose and reduced glucose tolerance were detected; consequently, it was decided to discontinue rhGH therapy, also in light of the IGF1R mutation and the lack of height recovery. Conclusions: This case underlines the critical role of genetic testing in the evaluation of patients born SGA. The coexistence of SGA status and an IGF1R gene mutation may provide a clear explanation for both the poor response to rhGH therapy and the increased risk of alterations in glucose metabolism. An extensive narrative review of the literature on growth outcomes and glucose metabolism abnormalities during GH treatment in SGA patients carrying IGF1R variants was also performed.