PDF(Pubmed)
Abstract：
The Ehlers-Danlos Syndromes (EDS), a group of hereditary connective tissue disorders, were classified into 13 subtypes in the 2017 International Classification. Recently, a new subtype of EDS called classical-like EDS type 2 (clEDS2), which is caused by biallelic variants in the adipocyte enhancer binding protein 1 (AEBP1) gene, was identified. We describe the 11th patient (9th family) with clEDS2, who was complicated by a critical vascular event (superior mesenteric artery aneurysm and rupture). A next-generation sequencing panel-based analysis revealed compound heterozygous variants in AEBP1: NM_001129.5:c.[2296G>T]; [2383dup], p.[(Glu766*)]; [(Glu795Glyfs*3)]. Light microscopic analyses showed increased interfibrillar spaces in the reticular dermis, a disorganized arrangement of collagen fibers, and decreased collagen content. An electron microscopic analysis showed the presence of collagen fibrils with irregular contours (flower-like appearance) and small collagen fibrils. A biochemical analysis showed reduced secretion of type I and type III procollagen. Clinical and molecular features of the current patient and all previously reported patients were reviewed comprehensively. Manifestations noted in most cases (>80%) included skin features (hyperextensibility, atrophic scars, easy bruising, excessive skin/skin folding, delayed wound healing, translucency, piezogenic papules), skeletal features (generalized joint hypermobility, dislocations/subluxations, pes planus), dental abnormalities, and neuromuscular abnormalities. Critical complications, each occurring in a single case, included superior mesenteric artery multiple aneurysm and rupture, aortic root dilation requiring surgery, and bowel rupture. Most AEBP1 variants were predicted or experimentally confirmed to lead to nonsense-mediated mRNA decay, whereas one variant resulted in a protein that was retained intracellularly and not secreted. Clinical, molecular, pathological, and biochemical features of the current patient, as well as a review of all previously reported patients, suggest the importance of the aortic carboxypeptidase-like protein encoded by AEBP1 in collagen fibrillogenesis.
摘要：
Ehlers-Danlos综合征（EDS），一组遗传性结缔组织疾病，在2017年国际分类中分为13种亚型。最近,一种新的EDS亚型，称为经典EDS类型2（clEDS2），这是由脂肪细胞增强子结合蛋白1（AEBP1）基因的双等位基因变体引起的，已确定。我们描述了患有clEDS2的第11例患者（第9个家庭），该患者并发了严重的血管事件（肠系膜上动脉瘤和破裂）。基于下一代测序组的分析揭示了AEBP1:NM_001129.5:c中的复合杂合变体。[2296G>T]；[2383dup]，p.[(Glu766*)]；[(Glu795Glyfs*3)]。光学显微镜分析显示网状真皮纤维间隙增加，胶原纤维的无序排列，胶原蛋白含量降低。电子显微镜分析显示存在具有不规则轮廓（花状外观）的胶原纤维和小的胶原纤维。生化分析表明I型和III型前胶原的分泌减少。全面回顾了当前患者和所有先前报告的患者的临床和分子特征。在大多数情况下（>80％）注意到的表现包括皮肤特征（过度扩张，萎缩性疤痕,容易擦伤,过度的皮肤/皮肤折叠，伤口愈合延迟，半透明,压电性丘疹)，骨骼特征(广义关节过度活动，脱位/半脱位,pesplanus)，牙齿异常,和神经肌肉异常。严重的并发症,每个都发生在一个案例中，包括肠系膜上动脉多发性动脉瘤和破裂，主动脉根部扩张需要手术,肠破裂.大多数AEBP1变体被预测或实验证实会导致无义介导的mRNA衰变，而一个变体导致一种蛋白质保留在细胞内且不分泌。临床,分子，病态,以及当前患者的生化特征，以及对以前报告的所有患者的回顾，提示AEBP1编码的主动脉羧肽酶样蛋白在胶原纤维形成中的重要性。
