Genetics of idiopathic short stature: Insights into growth regulation

Idiopathic short stature (ISS) is characterized by a height more than two standard deviations below the corresponding mean height of a given age, sex, and population group without evidence of systemic, endocrine, nutritional, or chromosomal abnormalities, and normal stimulated growth hormone levels. While growth is influenced by genetic, nutritional, hormonal, and environmental factors, ISS remains a diagnosis of exclusion after ruling out systemic, endocrine, or chromosomal disorders. Although multiple genes have been linked to be associated with linear growth, they account only for a small proportion of cases of short stature. Advances in genetic testing, including whole-exome sequencing and copy number variant analysis, have improved diagnostic precision, yet the yield remains low. Mutations in genes SHOX, ACAN , natriuretic peptide receptor-B, and insulin-like growth factor 1 receptor along with epigenetic factors have been implicated in ISS. Identifying pathogenic variants aids in personalized management, early detection of comorbidities, and genetic counseling. This review compiles current insights into genetic basis of ISS, emphasizing the need for further research to unravel its complex etiology and improve management strategies for affected individuals.