Mutations of uncertain significance in heterozygous variants as a possible cause of severe short stature: a case report.

IF 2.4 Q1 PEDIATRICS
Nami Mohammadian Khonsari, Sahar Mohammad Poor Nami, Benyamin Hakak-Zargar, Tessa Voth
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引用次数: 2

Abstract

Background: Linear bone growth is achieved by the division of chondrocytes at the growth plate and is regulated by endocrine and paracrine factors such as growth hormone. Mutations that negatively affect chondrogenesis can be a contributor to short stature. One such mutation can occur in the ACAN gene, causing short stature and advanced bone age. Similarly, mutations in growth hormone receptors (GHR) can lead to Laron syndrome (LS), one of the several disorders that are collectively called growth hormone insensitivity syndrome (GHI). Another example is Floating-Harbor syndrome (FHS), a rare autosomal dominant due to mutations in the SRCAP gene that can also result in short stature.

Case presentation: We report the case of a 6-year-old female with concomitant mutations in the three genes mentioned above. The mutations reported here were found on genetic studies and are usually benign, causing a variant of undetermined significance. However, our patient's phenotype could only be explained by the compounded effects of pathogenic mutations of these genes. Some of the same mutations were also found in the patient's father and her paternal grandfather. Both also presented with short stature, though not to the same degree as our patient. While these mutations are often reported to be insignificant, they gave rise to severe short stature and a specific phenotype in the patient when presented together. We think that even though the GHI spectrum is inherited through an autosomal recessive pattern, the sum of these heterozygous mutations resulted in severe short stature despite the limited GHI seen in our patient, the father, and the grandfather, through a rare ACAN and SRCAP mutation that, to our knowledge, has not been previously reported as a pathogenic mutation in the literature.

Conclusion: We investigated the possible synergistic effects of these variations on exacerbation or masking of the signs and symptoms of GHI with the hope of providing a better understanding of these genes and their function through our rare case.

杂合变异体中不确定意义的突变可能导致严重身材矮小:一份病例报告。
背景:线状骨生长是通过生长板软骨细胞的分裂来实现的,受生长激素等内分泌和旁分泌因素的调节。对软骨形成有负面影响的突变可能会导致身材矮小。一种这样的突变可能发生在ACAN基因上,导致身材矮小和骨质老化。同样,生长激素受体(GHR)的突变可导致Laron综合征(LS),这是统称为生长激素不敏感综合征(GHI)的几种疾病之一。另一个例子是浮港综合征(FHS),这是一种罕见的常染色体显性遗传病,由SRCAP基因突变引起,也会导致身材矮小。病例介绍:我们报告的情况下,6岁的女性伴随突变的三个基因上述。这里报道的突变是在基因研究中发现的,通常是良性的,引起一种意义不明的变异。然而,我们的患者的表型只能通过这些基因的致病性突变的复合作用来解释。在患者的父亲和祖父身上也发现了一些相同的突变。两人都表现出身材矮小,但程度不同于我们的病人。虽然这些突变通常被报道为无关紧要,但当它们一起出现时,会导致患者严重的身材矮小和特定的表型。我们认为,尽管GHI谱系是通过常染色体隐性模式遗传的,但这些杂合突变的总和导致了严重的身材矮小,尽管我们的患者,父亲和祖父通过罕见的ACAN和SRCAP突变看到了有限的GHI,据我们所知,以前在文献中没有报道过作为致病突变。结论:我们调查了这些变异对GHI症状和体征的加重或掩盖可能的协同作用,希望通过我们的罕见病例更好地了解这些基因及其功能。
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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CiteScore
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