Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium.
Matrix Biol. 2018 Oct;71-72:380-395. doi: 10.1016/j.matbio.2018.04.013. Epub 2018 Apr 27.
The Ehlers-Danlos Syndromes comprise a heterogeneous group of rare monogenic conditions that are characterized by joint hypermobility, skin and vascular fragility and generalized connective tissue friability. The latest classification recognizes 13 clinical subtypes, with mutations identified in 19 different genes. Besides defects in fibrillar collagens (collagen types I, III and V), their modifying enzymes (ADAMTS-2, lysylhydroxylase 1 (LH1)), and molecules involved in collagen folding (FKBP22), defects have recently been identified in other constituents of the extracellular matrix (e.g. Tenascin-X, collagen type XII), enzymes involved in glycosaminoglycan biosynthesis (β4GalT7 and β3GalT6), dermatan 4-O-sulfotransferase-1 (D4ST1), dermatan sulfate epimerase (DSE)), (putative) transcription factors (ZNF469, PRDM5), components of the complement pathway (C1r, C1s) and an intracellular Zinc transporter (ZIP13). Easy bruising is, to a variable degree, present in all subtypes of EDS. A variable bleeding tendency, manifesting e.g. as gum bleeding, menometrorraghia, postnatal or peri-operative hemorrhage is observed in many EDS-patients of varying EDS subtypes. Life-threatening arterial aneurysms, dissections and ruptures of medium-sized and large arteries are a hallmark of the vascular subtype of EDS, caused by a molecular defect in collagen type III, an important constituent of blood vessel walls and hollow organs. They may however also occur in other EDS subtypes, especially in classical EDS, caused by defects in type V collagen or, rarely, type I collagen, and in kyphoscoliotic EDS, caused by defects in LH1 or FKBP22. These manifestations of vascular fragility and bleeding are usually attributed to fragility of the blood vessel walls and the perivascular connective tissues, but the molecular pathomechanisms underlying these complications are poorly studied. This review summarizes current knowledge on manifestations of vascular fragility in the different EDS subtypes.
埃勒斯-当洛斯综合征是一组罕见的单基因遗传性疾病，其特征为关节过度活动、皮肤和血管脆弱以及广泛的结缔组织脆弱。最新的分类识别出 13 种临床亚型，在 19 种不同的基因中发现了突变。除了纤维胶原（I 型、III 型和 V 型胶原）及其修饰酶（ADAMTS-2、赖氨酰羟化酶 1（LH1））以及参与胶原折叠的分子（FKBP22）缺陷外，最近还在细胞外基质的其他成分（例如，Tenascin-X、XII 型胶原）、参与糖胺聚糖生物合成的酶（β4GalT7 和 β3GalT6）、硫酸皮肤素 4-O-硫酸转移酶-1（D4ST1）、硫酸皮肤素差向异构酶（DSE）、（假定）转录因子（ZNF469、PRDM5）、补体途径的成分（C1r、C1s）和细胞内锌转运体（ZIP13）中发现了缺陷。容易瘀伤在所有 EDS 亚型中都存在不同程度的表现。许多 EDS 患者表现出不同程度的出血倾向，例如牙龈出血、月经过多、产后或围手术期出血，这在不同 EDS 亚型的患者中都有观察到。危及生命的动脉动脉瘤、中到大动脉的夹层和破裂是 EDS 血管亚型的特征，这是由于血管壁和中空器官的重要组成部分 III 型胶原的分子缺陷引起的。然而，它们也可能发生在其他 EDS 亚型中，尤其是在经典 EDS 中，由 V 型胶原或罕见的 I 型胶原的缺陷引起，以及在脊柱侧凸型 EDS 中，由 LH1 或 FKBP22 的缺陷引起。这些血管脆弱和出血的表现通常归因于血管壁和血管周围结缔组织的脆弱性，但这些并发症的分子发病机制研究甚少。本文综述了不同 EDS 亚型中血管脆弱性表现的最新知识。
