Bernabeu Carmelo, Bayrak-Toydemir Pinar, McDonald Jamie, Letarte Michelle
Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas (CSIC) and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28040 Madrid, Spain.
ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT 84108, USA.
J Clin Med. 2020 Nov 5;9(11):3571. doi: 10.3390/jcm9113571.
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant genetic disorder that presents with telangiectases in skin and mucosae, and arteriovenous malformations (AVMs) in internal organs such as lungs, liver, and brain. Mutations in (endoglin), (ALK1), and (Smad4) genes account for over 95% of HHT. Localized telangiectases and AVMs are present in different organs, with frequencies which differ among affected individuals. By itself, HHT gene heterozygosity does not account for the focal nature and varying presentation of the vascular lesions leading to the hypothesis of a "second-hit" that triggers the lesions. Accumulating research has identified a variety of triggers that may synergize with HHT gene heterozygosity to generate the vascular lesions. Among the postulated second-hits are: mechanical trauma, light, inflammation, vascular injury, angiogenic stimuli, shear stress, modifier genes, and somatic mutations in the wildtype HHT gene allele. The aim of this review is to summarize these triggers, as well as the functional mechanisms involved.
遗传性出血性毛细血管扩张症（HHT）是一种常染色体显性遗传病，其特征为皮肤和黏膜出现毛细血管扩张，以及肺、肝、脑等内脏器官出现动静脉畸形（AVM）。内皮素（endoglin）、激活素受体样激酶1（ALK1）和Smad4基因的突变占HHT病例的95%以上。不同器官中存在局部毛细血管扩张和AVM，其出现频率在受影响个体之间有所不同。HHT基因杂合性本身并不能解释血管病变的局灶性本质和不同表现，因此提出了“二次打击”假说，即触发病变的因素。越来越多的研究已经确定了多种可能与HHT基因杂合性协同作用以产生血管病变的触发因素。推测的二次打击因素包括：机械创伤、光照、炎症、血管损伤、血管生成刺激、剪切应力、修饰基因以及野生型HHT基因等位基因的体细胞突变。本本综述的目的是总结这些触发因素以及相关的功能机制。
