Division of Pediatrics, Department of Health Sciences, Università del Piemonte Orientale, Via Solaroli 17, 28100, Novara, Italy.
Laboratory of Human Genetics, Department of Health Sciences, Università del Piemonte Orientale, Via Solaroli 17, 28100, Novara, Italy.
BMC Med Genomics. 2019 Jan 9;12(1):5. doi: 10.1186/s12920-018-0445-8.
Mutations of SHOX represent the most frequent monogenic cause of short stature and related syndromes. The genetic alterations include point mutations and deletions/duplications spanning both SHOX and its regulatory regions, although microrearrangements are confined to either the downstream or upstream enhancers in many patients. Mutations in the heterozygous state have been identified in up to 60-80% of Leri-Weill Dyschondrosteosis (LWD; MIM #127300) and approximately 4-5% of Idiopathic Short Stature (ISS; MIM#300582) patients. Homozygous or compound heterozygous mutations as well as biallelic deletions of SHOX and/or the enhancer regions result in a more severe phenotype, which is known as Langer Mesomelic Dysplasia (LMD; MIM #249700).
A 17 year old girl, presented with severe short stature, growth hormone deficiency (GHD), precocious puberty, dorsal scoliosis, dysmorphisms and urogenital malformations. She was born with agenesis of the right tibia and fibula, as well as with a supernumerary digit on the left foot. Array comparative genomic hybridization (aCGH) analysis detected the presence of two distinct duplications on Xp22.1 flanking the SHOX coding sequence and involving its regulatory regions. An additional duplication of 1.6-2.5 Mb on 15q25.2 that included 13 genes was also identified. The girl was adopted and the parent's DNA was not available to establish the origin of the chromosome imbalances.
The complex phenotype observed in our patient is probably the result of the co-occurrence of rearrangements on chromosomes Xp22.1 and 15q25.2. The duplicated region on 15q25.2 region is likely to contain dosage-sensitive genes responsible for some of the clinical features observed in this patient, whereas the extreme short stature and the skeletal anomalies are likely attributable to the comorbidity of GHD and copy number variants in the SHOX region.
SHOX 基因突变是导致身材矮小和相关综合征的最常见的单基因病因。遗传改变包括点突变和跨越 SHOX 及其调控区的缺失/重复，尽管在许多患者中，微重排仅限于下游或上游增强子。在 Leri-Weill 软骨发育不全症（LWD；MIM#127300）高达 60-80%的患者中和特发性身材矮小（ISS；MIM#300582）约 4-5%的患者中发现杂合状态的突变。SHOX 和/或增强子区域的纯合或复合杂合突变以及双等位基因缺失导致更严重的表型，称为 Langer 中胚层发育不良（LMD；MIM#249700）。
一名 17 岁女孩，因严重身材矮小、生长激素缺乏症（GHD）、性早熟、脊柱侧凸、畸形和泌尿生殖系统畸形就诊。她出生时右胫骨和腓骨发育不全，左足有多余的脚趾。Xp22.1 侧翼 SHOX 编码序列并涉及其调控区的两个不同的 Xp22.1 侧翼的重复，通过比较基因组杂交分析（aCGH）检测到。还鉴定出 15q25.2 上 1.6-2.5Mb 的额外重复，其中包括 13 个基因。该女孩被收养，父母的 DNA 无法确定染色体失衡的来源。
我们患者观察到的复杂表型可能是 Xp22.1 和 15q25.2 染色体重排同时发生的结果。15q25.2 区域上的重复区域可能包含对该患者观察到的一些临床特征有剂量敏感作用的基因，而极端身材矮小和骨骼异常可能归因于 GHD 和 SHOX 区域的拷贝数变异的共病。
