ECEESPE2025 Poster Presentations Growth Axis and Syndromes (91 abstracts)
Aetiology of short stature in children originally diagnosed with idiopathic growth hormone deficiency: comprehensive genetic investigation of a single centre cohort
Lukas Plachy 1 , Shenali Amaratunga 1 , Petra Dusatkova 1 , Klara Maratova 1 , Lukas Kavciak 1 , Dana Zemkova 1 , Stanislava Kolouskova 1 , Barbora Obermannova 1 , Marta Snajderova 1 , Zdenek Sumnik 1 , Jan Lebl 1 & Stepanka Pruhova 1
1Department of Pediatrics of Second Faculty of Medicine Charles University in Prague and Motol University Hospital, Prague, Czech Republic
JOINT2419
Introduction: Diagnostics of growth hormone deficiency (GHD) is based on stimulation tests, IGF-1 and growth velocity. Children diagnosed with GHD are believed to have heterogeneous aetiology of short stature, frequently independent on GH secretion. Evidence supporting this hypothesis are lacking. The aim of the study was to elucidate genetic aetiology of children with diagnosed GHD.
Methods: Children treated for GHD in our centre with idiopathic GHD and therapy duration ≥5 years were enrolled to the study. Children were examined by various genetic methods including next-generation sequencing. Genetic variants were evaluated using ACMG guidelines. Clinical parameters were compared between children with genetically proven GHD and other groups of children based on their genetic aetiology.
Results: In total, 294 children were enrolled to the study. At GH treatment initiation, their median age was 5. 1 years (IQR 3. 5-6. 8 years), height -2. 9 (-3. 2 to -2. 6) SD, IGF1 -1. 7 (-2. 0 to -1. 3) SD, GHmax 5. 5 (4. 0-7. 3) mg/l, 32 had combined pituitary hormone deficiency. Of them, 269 (91%) consented with genetic testing. We elucidated genetic aetiology in 56/269 (21%) of them. Fourteen children (25%) had genetically confirmed GHD (genes OTX2 [4], GLI2, TBX3, PROP1, POU1F1, GHSR, GH1, CHD7, PROK2, PMM2, SALL4), 2 (4%) had impaired IGF proteins (genes IGFALS, HGMA2), 15 (27%) had primary growth plate disorders (genes NPR2 [3], FGFR3 [2], COL2A1 [2], COL9A2, MATN3, ACAN, EXT2, SOX9, LTBP3, TRPV4, ALPL), 14 (25%) impaired RAS signalling pathway (genes PTPN11 [8], SOS1 [3], NF1 [2], RAF1) and 11 (20%) complex genetic disorders (genes LMNA, KMTD2, SURF1, SOX10, MBTPS2, TSPAN7, FGFR2, GNAO1, CDC42, DiGeorge syndrome and Smith-Magenis syndrome). Prior to GH treatment, children with genetically confirmed GHD had lower GHmax (median 1. 8 mg/l vs. 4. 5 mg/l [growth plate disorder], 6. 6 mg/l [RASopathies] and 5. 4 mg/l [complex disorders]; P = 0. 05) and together with RASopathies less affected intrauterine growth (lower of the birth parameters [birth weight/length] -1. 2 SD [GHD] and -0. 8 SD [RASopathies] vs. -1. 8 SD [growth plate disorders] and -2. 0 SD [complex disorders]; P = 0. 009). After 5 years of therapy, GHD and growth plate disorders groups had better growth outcomes (-0. 7 SD [GHD] and -0. 8 SD [growth plate disorders] vs. -1. 8 SD [RASopathies] and -2. 0 SD [complex disorders] P = 0. 04).
Conclusions: Genetic aetiology of short stature in children diagnosed with GHD is heterogeneous. Lower stimulated GH concentration, near-normal size at birth, and better response to GH treatment might help to clinically differentiate those with genetically confirmed GHD.
Volume 110
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