Context

ALS deficiency (ACLSD), caused by mutations in IGFALS, is characterized by a mild short stature, low concentrations of IGF-I and IGFBP-3, and a normal growth hormone (GH) stimulation test response. To our knowledge, no larger deletions have been reported.

Case description

A 17-year-old adolescent male was evaluated due to delayed puberty and short stature. He had a height of 154.4 cm (SDS -2.84), a weight of 53.3 kg (SDS -1.41), a BMI of 22.4 kg/m2 (SDS +0.31), a Tanner 2 pubertal stage with a testicular volume of 10 mL, and a bone age of 16 years (SDS -1.33). After biochemical evaluation, low IGF-I levels, undetectable IGFBP-3 levels, and a normal response to the GH stimulation test were observed, suggesting GH insensitivity. ACLSD was confirmed by ALS measurement (116 ng/mL, SDS -3.19) and genetic analysis of IGFALS. An apparently homozygous missense variant, p. Pro624Leu, was found in exon 2 of the proband; this mutation was observed on one allele of the proband's father but was absent in the mother and siblings. Deletion/duplication analysis by multiplex ligation-dependent probe amplification (MLPA) was consistent with a deletion encompassing a significant part of exon 2 on one allele in the proband and in his mother and siblings.

Conclusion

This is the first report of a large deletion in a patient with ACLSD. Deletion/duplication analysis should be considered in the genetic study of ACLSD, especially when homozygosity for a pathogenic variant cannot be confirmed by the study of the parents or when no variants are found but ALS concentrations are very low.

中文翻译：

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由外显子2缺失和编码ALS的基因中的新型错义变异导致的ALS缺乏症。

语境

由IGFALS突变引起的ALS缺乏症（ACLSD）的特征是身材矮小，IGF-1和IGFBP-3浓度低以及正常的生长激素（GH）刺激测试反应。据我们所知，没有更大的删除报道。

案例描述

由于青春期延迟和身材矮小，对一名17岁的青春期男性进行了评估。他身高154.4厘米（SDS -2.84），体重53.3千克（SDS -1.41），BMI为22.4 kg / m2（SDS +0.31），Tanner 2青春期，睾丸体积为10 mL，骨骼年龄为16岁（SDS -1.33）。生化评估后，观察到低的IGF-I水平，未检测到的IGFBP-3水平以及对GH刺激试验的正常反应，表明GH不敏感。通过ACLSD（116 ng / mL，SDS -3.19）和IGFALS的遗传分析证实了ACLSD。一个明显纯合的错义变体，p。Pro624Leu，在先证者的外显子2中发现；该突变在先证者父亲的一个等位基因上观察到，但在母亲和兄弟姐妹中却不存在。通过多重连接依赖探针扩增（MLPA）进行的缺失/重复分析与先证者及其母亲和兄弟姐妹的一个等位基因上包含显着部分外显子2的缺失一致。

结论

这是ACLSD患者大量缺失的首次报道。在ACLSD的基因研究中应考虑缺失/重复分析，特别是当通过父母的研究无法确定病原体变异的纯合性或未发现变异但ALS浓度很低时。