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

IF 4.4 Q2 ENDOCRINOLOGY & METABOLISM

Journal of the Endocrine Society Pub Date : 2026-05-07 eCollection Date: 2026-06-01 DOI:10.1210/jendso/bvag106

Lukas Plachy, Petra Dusatkova, Lukas Kavciak, Shenali Anne Amaratunga, Matvei Slavenko, Jana Drabova, Klara Maratova, Vit Neuman, Barbora Obermannova, Stanislava Kolouskova, Marta Snajderova, Zdenek Sumnik, Jan Lebl, Stepanka Pruhova

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Abstract

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.

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超越生长激素刺激试验：诊断为生长激素缺乏症儿童的遗传异质性和治疗反应。

背景：生长激素（GH）刺激试验的可靠性有限，可能导致假阳性结果。目的：本研究旨在评估临床诊断为生长激素缺乏症（GHD）儿童身材矮小的遗传原因，并评估基因型与表型的相关性。方法：对233例临床诊断为原发性GHD并接受生长激素治疗5年及以上的儿童进行回顾性单中心研究。使用398个生长相关基因的靶向下一代测序面板进行基因检测。结果：233名儿童中有39名（17%）被确定为遗传原因。39个结果中只有13个（33%）证实GHD（基因CHD7、GH1、GHSR、GLI2、GNAO1、KMT2D、OTX2[3]、POU1F1、PROP1、SALL4、TBX3）。其余26例（67%）显示了生长衰竭的其他病因：RASopathies(13/39；基因NF1 [2]， PTPN11 [7], RAF1, SOS1 [2], SPRED1)，生长板疾病（8/39；基因ACAN， COL2A1, EXT2, FGFR3 [2], NPR2[3]），和其他条件（5/39；基因CDC42， LMNA, HMGA2, PMM2, RAI1）。遗传学证实的GHD患者表现为GH峰值较低（中位数1.8 vs 4.8[替代遗传病因]和5.9 μg/L[无遗传病因]；P = 0.017），更频繁的联合垂体激素缺乏（46% vs 4% vs 12%; P = 0.001）和磁共振成像中脑异常（73% vs 14% vs 32%; P = 0.003）。相反，替代病因组表现出最不稳定的5年生长激素治疗反应（中位身高增加1.4比2.3 [GHD组]和1.8[无遗传病因]；P = .001）。结论：临床诊断为GHD的儿童群体具有遗传异质性。统计上有显著比例的RAS-MAPK信号缺陷或生长板紊乱，突出了当前GHD诊断方法的局限性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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