Short stature with elevated IGF-1: Diagnostic pitfalls and growth hormone therapy outcomes across etiologies

Background: Short stature in children is typically linked to low insulin-like growth factor 1 (IGF-1), reflecting growth hormone (GH) deficiency or nutritional deprivation. However, a distinct and diagnostically challenging subgroup presents with short stature despite normal or elevated IGF-1 concentrations. This paradox indicates possible underlying resistance to IGF-1 action or dysregulation of the GH-IGF axis. Etiologies include genetic mutations (e.g., IGF1R, STAT5b), syndromic conditions (e.g., Noonan syndrome), endocrine disorders (e.g., hyperthyroidism, insulin resistance), and exogenous GH administration. The growth response to GH therapy in this population varies widely and remains insufficiently characterized in the literature. Objectives: This review aimed to (1) analyze the diverse causes of short stature with elevated IGF-1 levels, (2) assess growth outcomes after GH therapy across distinct etiological categories, and (3) propose diagnostic and therapeutic strategies to individualize care. Methods: A systematic literature review was conducted using PubMed, Scopus, and Web of Science for studies published between 2000 and 2025. Inclusion criteria encompassed pediatric patients with short stature (height SDS < –2), normal to high IGF-1, and reported GH therapy outcomes. Studies were grouped by etiology into seven categories: IGF-1 resistance, GH resistance, syndromic causes, exogenous GH use, endocrine dysregulation, obesity/metabolic factors, and rare genetic syndromes. Data on growth velocity, IGF-1 dynamics, and final height outcomes were extracted. Study quality and therapeutic impact were evaluated using validated scales. Results: GH therapy outcomes were highly variable. Children with IGF1R haploinsufficiency or partial receptor defects showed modest height gains. In contrast, those with GH resistance (e.g., STAT5b mutations) had poor responses, requiring alternate strategies. Syndromic conditions like Noonan syndrome exhibited attenuated GH sensitivity due to downstream pathway disruptions. Exogenous GH use often elevated IGF-1 without proportional linear growth, necessitating dose adjustment. Obese children and those with endocrine dysregulation showed paradoxical IGF-1 elevations but poor growth outcomes unless the underlying metabolic imbalance was corrected. Conclusions: Short stature with elevated IGF-1 is a heterogeneous condition that cannot be managed by uniform GH therapy. Diagnostic precision—integrating clinical, biochemical, and genetic findings—is essential for predicting response and guiding individualized therapy. A precision medicine framework should guide future interventions, including consideration of IGF-1 analogs and metabolic optimization strategies to improve growth outcomes in resistant cases.