ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT, USA.
Department of Pathology, University of Utah, Salt Lake City, UT, USA.
Genet Med. 2019 Sep;21(9):2007-2014. doi: 10.1038/s41436-019-0443-z. Epub 2019 Feb 14.
EPHB4 variants were recently reported to cause capillary malformation-arteriovenous malformation 2 (CM-AVM2). CM-AVM2 mimics RASA1-related CM-AVM1 and hereditary hemorrhagic telangiectasia (HHT), as clinical features include capillary malformations (CMs), telangiectasia, and arteriovenous malformations (AVMs). Epistaxis, another clinical feature that overlaps with HHT, was reported in several cases. Based on the clinical overlap of CM-AVM2 and HHT, we hypothesized that patients considered clinically suspicious for HHT with no variant detected in an HHT gene (ENG, ACVRL1, or SMAD4) may have an EPHB4 variant.
Exome sequencing or a next-generation sequencing panel including EPHB4 was performed on individuals with previously negative molecular genetic testing for the HHT genes and/or RASA1.
An EPHB4 variant was identified in ten unrelated cases. Seven cases had a pathogenic EPHB4 variant, including one with mosaicism. Three cases had an EPHB4 variant of uncertain significance. The majority had epistaxis (6/10 cases) and telangiectasia (8/10 cases), as well as CMs. Two of ten cases had a central nervous system AVM.
Our results emphasize the importance of considering CM-AVM2 as part of the clinical differential for HHT and other vascular malformation syndromes. Yet, these cases highlight significant differences in the cutaneous presentations of CM-AVM2 versus HHT.
最近有报道称 EphB4 变异可导致毛细血管畸形-动静脉畸形 2 型（CM-AVM2）。CM-AVM2 类似于 RASA1 相关的 CM-AVM1 和遗传性出血性毛细血管扩张症（HHT），因为其临床特征包括毛细血管畸形（CMs）、毛细血管扩张和动静脉畸形（AVMs）。有报道称，在几个病例中还存在与 HHT 重叠的鼻出血这一临床表现。基于 CM-AVM2 和 HHT 的临床重叠，我们假设在未检测到 HHT 基因（ENG、ACVRL1 或 SMAD4）中变异的情况下，被认为具有 HHT 临床可疑性的患者可能存在 EphB4 变异。
对先前分子遗传学检测 HHT 基因（ENG、ACVRL1 或 SMAD4）和/或 RASA1 均为阴性的个体进行外显子组测序或包含 EphB4 的下一代测序 panel。
在十个无关联的病例中鉴定出 EphB4 变异。七个病例存在致病性 EphB4 变异，包括一个存在嵌合体。三个病例存在 EphB4 意义不明的变异。大多数患者有鼻出血（6/10 例）和毛细血管扩张（8/10 例），以及 CMs。十个病例中有两个存在中枢神经系统 AVM。
我们的结果强调了将 CM-AVM2 视为 HHT 和其他血管畸形综合征临床鉴别诊断的一部分的重要性。然而，这些病例突出了 CM-AVM2 与 HHT 在皮肤表现方面的显著差异。
