Journal of the Endocrine Society · 2026
Beyond GH stimulation tests: genetic heterogeneity and treatment response in children with diagnosed GH deficiency.
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Plachy Lukas, Dusatkova Petra, Kavciak Lukas, Amaratunga Shenali Anne, Slavenko Matvei, Drabova Jana, Maratova Klara, Neuman Vit, Obermannova Barbora, Kolouskova Stanislava, Snajderova Marta, Sumnik Zdenek, Lebl Jan, Pruhova Stepanka
Аннотация
CONTEXT: Growth hormone (GH) stimulation tests have limited reliability and may lead to false-positive results.
OBJECTIVE: This work aimed to evaluate genetic causes of short stature in children clinically diagnosed with GH deficiency (GHD) and assess genotype-phenotype correlations.
METHODS: 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.
RESULTS: 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).
CONCLUSION: 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.
OBJECTIVE: This work aimed to evaluate genetic causes of short stature in children clinically diagnosed with GH deficiency (GHD) and assess genotype-phenotype correlations.
METHODS: 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.
RESULTS: 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).
CONCLUSION: 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.