Background

The most frequent monogenic causes of growth hormone insensitivity (GHI) include defects in genes encoding the GH receptor itself (GHR), the signal transducer and activator of transcription (STAT5B), the insulin like-growth factor type I (IGF1) and the acid-labile subunit (IGFALS). GHI is characterized by a continuum of mild to severe post-natal growth failure.

Objective

To characterize the molecular defect in a patient with short stature and partial GHI.

Patient and methods

The boy was born at term adequate for gestational age from non-consanguineous normal-stature parents. At 2.2 years, he presented proportionate short stature (height −2.77 SDS), wide forehead and normal mental development. Whole-exome analysis and functional characterization (site-directed mutagenesis, dual luciferase reporter assay, immunofluorescence and western immunoblot) were performed.

Results

Biochemical and endocrinological evaluation revealed partial GH insensitivity with normal stimulated GH peak (7.8 ng/mL), undetectable IGF1 and low IGFBP3 levels. Two heterozygous variants in the GH-signaling pathway were found: a novel heterozygous STAT5B variant (c.1896G>T, p.K632N) and a hypomorphic IGFALS variant (c.1642C>T, p.R548W). Functional in vitro characterization demonstrated that p.K632N-STAT5b is an inactivating variant that impairs STAT5b activity through abolished phosphorylation. Remarkably, the patient's immunological evaluation displayed only a mild hypogammaglobulinemia, while a major characteristic of STAT5b deficient patients is severe immunodeficiency.

Conclusions

We reported a novel pathogenic inactivating STAT5b variant, which may be associated with partial GH insensitivity and can present without severe immunological complications in heterozygous state. Our results contribute to expand the spectrum of phenotypes associated to GHI.

中文翻译：

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身材矮小且部分生长激素不敏感（GHI）的患者中的新型杂合子STAT5B变体

背景

生长激素不敏感性（GHI）的最常见单基因病因包括编码GH受体本身（GHR）的基因缺陷，信号转导和转录激活因子（STAT5B），I型胰岛素样生长因子（IGF1）和酸-不稳定亚基（IGFALS）。GHI的特征是连续的轻度至重度出生后生长衰竭。

目的

表征身材矮小和部分GHI的患者的分子缺陷。

患者和方法

该男孩出生于足月，足月来自非血缘正常身材父母。在2.2岁时，他的身材矮小（身高-2.77 SDS），额头宽大且智力发育正常。进行了全外显子组分析和功能表征（定点诱变，双重荧光素酶报告基因分析，免疫荧光和western免疫印迹）。

结果

生化和内分泌学评估显示部分GH不敏感，具有正常刺激的GH峰（7.8 ng / mL），未检测到的IGF1和低的IGFBP3水平。在GH信号通路中发现了两个杂合变异体：一种新型的杂合STAT5B变异体（c.1896G> T，p.K632N）和一个亚型IGFALS变异体（c.1642C> T，p.R548W）。功能性体外表征表明，p.K632N-STAT5b是一种灭活变体，可通过消除磷酸化来破坏STAT5b的活性。值得注意的是，患者的免疫学评估仅显示出轻度的低球蛋白球蛋白血症，而STAT5b缺陷患者的主要特征是严重的免疫缺陷。

结论

我们报道了一种新型的致病性STAT5b失活变体，它可能与部分GH不敏感有关，并且在杂合状态下可以出现而没有严重的免疫并发症。我们的结果有助于扩大与GHI相关的表型的范围。