Beyond GH stimulation tests: genetic heterogeneity and treatment response in children with diagnosed GH deficiency

Growth hormone (GH) stimulation tests have limited reliability and may lead to false-positive results.

This work aimed to evaluate genetic causes of short stature in children clinically diagnosed with GH deficiency (GHD) and assess genotype-phenotype correlations.

A retrospective single-center study was conducted including 233 children with clinically diagnosed primary GHD treated with GH for 5 years or more. Genetic testing was performed using a targeted next-generation sequencing panel of 398 growth-associated genes.

A genetic cause was identified in 39 of 233 (17%) children. Only 13 of 39 (33%) findings confirmed GHD (genes CHD7, GH1, GHSR, GLI2, GNAO1, KMT2D, OTX2 [3], POU1F1, PROP1, SALL4, TBX3). The remaining 26 of 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 μg/L [no genetic etiology]; P = .017), more frequent combined pituitary hormone deficiency (46% vs 4% and 12%; P = .001) and magnetic resonance imaging midbrain abnormalities (73% vs 14% vs 32%; P = .003). Conversely, the alternative etiology group demonstrated the least robust 5-year GH therapy response (median height gain 1.4 vs 2.3 [GHD group] and 1.8 [no genetic etiology]; P = .001).

The population of children clinically diagnosed with GHD is genetically heterogeneous. A statistically significant proportion harbors defects in RAS-MAPK signaling or growth plate disorders, highlighting the limitations of current methods of GHD diagnostics.