Objective: to describe the marked variability in clinical and biochemical patterns that are associated with a p.R209H GH1 missense variant in a large Argentinean pedigree, which makes the diagnosis of GHD elusive. Design: We describe a non-consanguineous pedigree composed by several individuals with short stature, including 2 pediatric patients with typical diagnosis of isolated growth hormone deficiency (IGHD) and 4 other siblings with severe short stature, low serum IGF-1 and IGFBP-3, but normal stimulated GH levels, suggesting growth hormone insensitivity (GHI) in the latter group. Results: Patients with classical IGHD phenotype carried a heterozygous variant in GH1: c.626G>A (p.R209H). Data from the extended pedigree suggested GH1 as the initial candidate gene, which showed the same pathogenic heterozygous GH1 variant in the four siblings with short stature and a biochemical pattern of GHI. Conclusions: We suggest considering GH1 sequencing in children with short stature associated to low IGF-1 and IGFBP-3 serum levels, even in the context of normal response to growth hormone provocative testing (GHPT).

目的：描述与大型阿根廷血统中p.R209H GH1错义变异相关的临床和生化模式的显着变异性，这使得 GHD 的诊断难以捉摸。设计：我们描述了由几个身材矮小个体组成的非血缘系谱，其中包括 2 名典型诊断为孤立性生长激素缺乏症 (IGHD) 的儿科患者和 4 名严重身材矮小、血清 IGF-1 和 IGFBP-3 低的其他兄弟姐妹，但正常刺激的 GH 水平，表明后一组的生长激素不敏感 (GHI)。结果：具有经典 IGHD 表型的患者在GH1 中携带杂合变异：c.626G>A（p.R209H）。来自扩展谱系的数据表明 GH1 作为初始候选基因，这在四个身材矮小和 GHI 生化模式的兄弟姐妹中显示相同的致病性杂合 GH1 变异。结论：我们建议考虑对与低 IGF-1 和 IGFBP-3 血清水平相关的身材矮小儿童进行GH1测序，即使在对生长激素激发试验 (GHPT) 的正常反应的情况下也是如此。