Idiopathic Short Stature in the Genomic Era: Integrating Auxology, Endocrinology, and Emerging Genetic Insights

This is the authors' abstract. We don't add key points for this paper.

Idiopathic short stature (ISS) represents one of the most frequent yet enigmatic conditions in pediatric endocrinology. Traditionally defined by auxological parameters in the absence of identifiable causes, ISS has long served as a diagnosis of exclusion. However, with the advent of next-generation sequencing, our understanding of the etiological landscape has significantly evolved. Recent studies have revealed that many children previously labeled as idiopathic actually harbor monogenic variants in genes related to the growth hormone-insulin-like growth factor axis, extracellular matrix components, or growth plate signaling pathways. This review integrates auxological assessment with current knowledge on molecular diagnostics to propose a more accurate and individualized approach to short stature. We examine emerging genotype-phenotype correlations, criteria for selecting candidates for genetic testing, and implications for recombinant human growth hormone therapy. Additionally, we advocate for a shift in clinical mindset: from a descriptive to a biologically grounded framework. ISS should be regarded as a transitional label pending further endocrine and genetic clarification. Recognizing this paradigm shift will improve diagnostic accuracy, personalize treatment strategies, and ultimately enhance care for children with growth failure in the genomic era.