Diagnostic challenges of short stature and growth hormone insufficiency across different genetic etiologies.

Background: Recent advances in genetic research have significantly expanded our understanding of the molecular bases of growth hormone deficiency (GHD), and numerous genes have been identified as impacting final stature through isolated or combined abnormalities of growth hormone (GH), GH insensitivity, and insulin growth factor-1 (IGF-I) resistance. Objective: This review summarizes the current knowledge on the genetic causes of GHD in the context of pediatric short stature, emphasizing the role of next-generation sequencing technologies in real-life clinical practice and the potential impact of genetic diagnosis over therapeutic decisions regarding GH replacement therapy. Materials and methods: Articles from PubMed up to April 2025 dealing with GHD were retrieved and analyzed, focusing on genes influencing the GH pathway and stunted growth, with focused attention on relevant molecular and clinical studies. Results: Our analysis, besides cataloguing well-established and novel contributors to growth failure among genes associated with the GH–IGF1 axis, also emphasizes the crucial role of genetic testing and strategies that should be used to maximize the likelihood of identifying a specific genetic etiology, such as prioritizing genetic tests when a monogenic cause is strongly suspected or when there are peculiar clinical features that could be linked to specific genetic conditions. Conclusions: We have highlighted the most recent genetic etiologies of short stature related to GHD, providing an updated framework that is expected to be helpful in the diagnostic and therapeutic management of individuals with mutations related to the GH-IGF1 axis.