Abstract Context Growth hormone (GH) stimulation tests have limited reliability, and may lead to false-positive results. Objective Evaluate genetic causes of short stature in children clinically diagnosed with growth hormone deficiency (GHD) and assess genotype-phenotype correlations. Design, settings and patients A retrospective single-center study including 233 children with clinically diagnosed primary growth hormone deficiency (GHD) treated with GH for ≥5 years. Genetic testing was performed using a targeted next-generation sequencing panel of 398 growth-associated genes. Results A genetic cause was identified in 39/233 (17%) children. Only 13/39 (33%) findings confirmed GHD (genes CHD7, GH1, GHSR, GLI2, GNAO1, KMT2D, OTX2 3, POU1F1, PROP1, SALL4, TBX3). The remaining 26/39 (67%) revealed alternative etiologies of growth failure: RASopathies (13/39; genes NF1 2, PTPN11 7, RAF1, SOS1 2, SPRED1), growth plate disorders (8/39; genes ACAN, COL2A1, EXT2, FGFR3 2, NPR2 3), and miscellaneous conditions (5/39; genes CDC42, LMNA, HMGA2, PMM2, RAI1). Genetically confirmed GHD patients presented with lower peak GH (median 1.8 vs. 4.8 alternative genetic etiology and 5.9 ug/L no genetic etiology; p=0.017), more frequent combined pituitary hormones deficiency (46% vs. 4% and 12%; p=0.001) and MRI midbrain abnormalities (73% vs. 14% vs. 32%; P=0.003). Conversely, the alternative etiology group demonstrated the least robust 5-years GH therapy response (median height gain 1.4 vs. 2.3 GHD group and 1.8 No genetic etiology; p=0.001). Conclusions Population of children clinically diagnosed with GHD is genetically heterogeneous. A significant proportion harbors defects in RAS-MAPK signaling or growth plate disorders, highlighting the limitations of current methods of GHD diagnostics.
Plachý et al. (2026) studied this question.