Idiopathic short stature in the genomic era: a focused narrative review of genotype-phenotype correlation, selective neuroimaging, IGF-1 biology, and growth hormone responsiveness.

Abstract

Idiopathic short stature (ISS) is a provisional clinical label rather than a final diagnosis. This narrative review (2000-2026) synthesizes how genomic findings intersect with neuroimaging, IGF-1 biology, and GH responsiveness. Diagnostic yield varies by modality: candidate-gene (4.7%), chromosomal microarray (16.3%), multigene panels (21.6%), and exome sequencing (33.3% overall; 15.1% isolated). These estimates decrease if variants of uncertain significance (VUS) are excluded. Recurrent genes include ACAN, NPR2, SHOX, IHH, FGFR3, IGF1R, and PAPPA2. Study comparisons are limited by heterogeneous definitions and neuroimaging selection bias. While major structural hypothalamic-pituitary lesions are uncommon in ISS, pituitary size overlaps significantly with both controls and GH deficiency. GH response is genotype-dependent; SHOX deficiency typically shows robust gains, while ACAN variants yield more modest, sustained responses. ISS should be managed as a heterogeneous working phenotype. A clinically effective approach integrates careful phenotyping, selective MRI, explicit separation of pathogenic findings from VUS, and genotype-informed counseling regarding prognosis and treatment response.