背景:线性骨生长是通过软骨细胞在生长板处的分裂来实现的,并且受内分泌和旁分泌因子如生长激素的调节。对软骨形成产生负面影响的突变可能是身材矮小的原因。一个这样的突变可以发生在ACAN基因中,导致身材矮小和骨龄提前。同样,生长激素受体(GHR)的突变可导致Laron综合征(LS),被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症(FHS),一种罕见的常染色体显性遗传,由于SRCAP基因突变,也可能导致身材矮小。
方法:我们报告了一例6岁女性,在上述三个基因中同时发生突变。这里报道的突变是在遗传研究中发现的,通常是良性的,导致意义不确定的变体。然而,我们患者的表型只能用这些基因致病突变的复合效应来解释。在患者的父亲和她的祖父身上也发现了一些相同的突变。两人也都身材矮小,虽然和我们的病人程度不同.虽然这些突变通常被报道为微不足道,当一起出现时,它们会在患者中引起严重的身材矮小和特定的表型。我们认为即使GHI光谱是通过常染色体隐性遗传模式遗传的,这些杂合突变的总和导致严重的身材矮小,尽管在我们的患者中看到了有限的GHI,父亲,还有爷爷,通过罕见的ACAN和SRCAP突变,根据我们的知识,以前在文献中没有报道过致病性突变。
结论:我们研究了这些变异对GHI体征和症状恶化或掩盖的可能协同作用,希望通过我们的罕见病例更好地了解这些基因及其功能。
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.
METHODS: 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.
CONCLUSIONS: 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.