Department of Pediatrics of Second Faculty of Medicine Charles University in Prague and Motol University Hospital, Prague, Czechia.
Front Endocrinol (Lausanne). 2023 Jan 13;13:1102968. doi: 10.3389/fendo.2022.1102968. eCollection 2022.
The growth hormone deficiency (GHD) diagnosis is controversial especially due to low specificity of growth hormone (GH) stimulation tests. It is therefore believed that children diagnosed with GHD form a heterogeneous group with growth disorder frequently independent on GH function. No study evaluating the complex etiology of growth failure in children with diagnosed GHD has been performed thus far.
To discover genetic etiology of short stature in children with diagnosed GHD from families with short stature.
Fifty-two children diagnosed with primary GHD and vertically transmitted short stature (height SDS in the child and his/her shorter parent <-2 SD) were included to our study. The GHD diagnosis was based on growth data suggestive of GHD, absence of substantial disproportionality (sitting height to total height ratio <-2 SD or >+2 SD), IGF-1 levels <0 for age and sex specific SD and peak GH concentration <10 ug/L in two stimulation tests. All children were examined using next-generation sequencing methods, and the genetic variants were subsequently evaluated by American College of Medical Genetics standards and guidelines.
The age of children at enrollment into the study was 11 years (median, IQR 9-14 years), their height prior to GH treatment was -3.0 SD (-3.6 to -2.8 SD), IGF-1 concentration -1.4 SD (-2.0 to -1.1 SD), and maximal stimulated GH 6.3 ug/L (4.8-7.6 ug/L). No child had multiple pituitary hormone deficiency or a midbrain region pathology. Causative variant in a gene that affects growth was discovered in 15/52 (29%) children. Of them, only 2 (13%) had a genetic variant affecting GH secretion or function ( and ). Interestingly, in 10 (67%) children we discovered a primary growth plate disorder (, , , , , , , , [2x]), in one (7%) a genetic variant impairing IGF-1 action () and in two (12%) a variant in miscellaneous genes (, ).
In children with vertically transmitted short stature, genetic results frequently did not correspond with the clinical diagnosis of GH deficiency. These results underline the doubtful reliability of methods standardly used to diagnose GH deficiency.
生长激素缺乏症（GHD）的诊断存在争议，尤其是由于生长激素（GH）刺激试验的特异性低。因此，人们认为被诊断为 GHD 的儿童形成了一个异质群体，其生长障碍通常与 GH 功能无关。迄今为止，尚未有研究评估患有诊断为 GHD 的儿童生长障碍的复杂病因。
从患有身材矮小的家族中发现患有 GHD 的儿童身材矮小的遗传病因。
我们纳入了 52 名被诊断为原发性 GHD 和垂直传播性身材矮小（儿童身高 SDS 和其较矮的父母 <-2 SDS）的儿童进行研究。GHD 的诊断基于提示 GHD 的生长数据、不存在实质性不成比例（坐高与身高之比 <-2 SDS 或 >+2 SD）、IGF-1 水平低于年龄和性别特异性 SDS 且在两项刺激试验中 GH 浓度峰值 <10 ug/L。所有儿童均采用下一代测序方法进行检查，随后根据美国医学遗传学学院标准和指南对遗传变异进行评估。
研究开始时儿童的年龄为 11 岁（中位数，IQR 9-14 岁），治疗前的身高为 -3.0 SDS（-3.6 至-2.8 SDS），IGF-1 浓度 -1.4 SDS（-2.0 至-1.1 SDS），最大刺激 GH 为 6.3 ug/L（4.8-7.6 ug/L）。没有儿童存在多种垂体激素缺乏或中脑区域病变。在 52 名儿童中的 15 名（29%）发现了影响生长的基因中的致病变异。其中，只有 2 名（13%）的基因变异影响 GH 分泌或功能（和）。有趣的是，在 10 名（67%）儿童中，我们发现了原发性生长板疾病（、、、、、、、、[2x]），在 1 名（7%）儿童中发现了影响 IGF-1 作用的基因变异（），在 2 名（12%）儿童中发现了杂类基因的变异（、）。
在垂直传播性身材矮小的儿童中，遗传结果通常与 GH 缺乏症的临床诊断不一致。这些结果强调了标准用于诊断 GH 缺乏症的方法的可靠性值得怀疑。
