一个遗传性出血性毛细血管扩张症家系及其分子生物学研究

目的：探讨遗传性出血性毛细血管扩张症（HHT）家系的临床特征及分子生物学特点。方法：对先证者进行家系调查;对家系成员及30例健康志愿者的ALK-1及ENG基因外显子进行PCR扩增并对PCR产物进行序列分析;对序列分析发现突变者进行限制性酶切实验。结果：①本家系包括5代共62位家系成员,包括先证者在内共19位家系成员反复鼻衄;②序列分析显示反复鼻衄家系成员的ENG基因第2外显子存在G207A突变;③酶切分析显示存在ENG基因第2外显子G207A突变者不能被限制性内切酶GsuI切断,而无G207A突变者可被限制性内切酶GsuI切断。结论：本遗传性出血性毛细血管扩张症家系以反复鼻衄为主要表现,患者ENG基因第2外显子存在G207A突变,这种突变可能是遗传性出血性毛细血管扩张症导致的ENG基因多态性。     

由ALK1基因内含子突变引起的遗传性出血性毛细血管扩张症

目的 探讨遗传性出血性毛细血管扩张症发病的分子机制。方法（1）用聚合酶链式反应-单链构像多态性分析（PCR-SSCP）寻找异常突变的外显子及其相邻剪接位点。（2）通过DNA测序确定突变的类型。（3）使用逆转录-聚合酶链反应（RT-PCR）方法确定剪接方式。结果 用PCRSSCP方法发现扩增ALK1基因第4外显子及相邻的部分内含子片段有突变位点。对有突该片段,用DNA测序检测,发现第4外显子的给位剪接点相邻碱基A＞T（ⅣS4＋3a＞t）的突变,并用反向测序确认。用RT-PCR方法检测ALK1基因表达mRNA情况,电泳和测序发现第4外显子的丢失。结论 ALK1基因的ⅣS4＋3a＞1突变,导致ALK1基因表达异常,形成无功能截短蛋白,引起HHT2。     

一个遗传性出血性毛细血管扩张症家系的临床和基因诊断

目的：探讨一个遗传性出血性毛细血管扩张症(hereditary hemorrhagic telangiectasia,HHT)家系的临床特征 及基因诊断的可行性。方法：收集先证者及家系成员的病史资料并进行临床诊断。同时,对先证者进行致病基因突 变检测;鉴定出可能致病性变异后,对家系成员进行特定致病基因突变检测及基因诊断。结果：该家系中4代有5例 个体以鼻衄为突出临床表现。先证者临床诊断为HHT;2例在世家系成员为临床疑诊个体。ENG(endoglin)基因5'非编 码区c.1-127C>T突变见于先证者和2例临床疑诊个体,未见于其他家系成员;综合临床与基因突变分析2例临床疑诊个 体确诊为HHT。结论：HHT临床表现个体差异大,ENG基因c.1-127C>T突变是此HHT家系的可能致病性变异。临床 与基因诊断相结合可提高HHT的诊治水平。     

Ⅱ型遗传性出血性毛细血管扩张症ALK1基因突变鉴定及血浆凝血酶调节蛋白表达

目的 分析和确定遗传性出血性毛细血管扩张症(HHT)的临床表型。寻找鉴定HHT家系致病基因AIK1基因突变位点,建立HHT的基因诊断方法。方法 用鼻内镜直视并动态摄影观察先证者鼻腔黏膜扩张的毛细血管,并进行遗传史的家系调查;用聚合酶链反应(PCR)扩增先证者AIK1基因3、7、8号外显子,并进行PCR产物核苷酸测序。确定突变位点后,扩增2例正常人及HHT家系成员(4例)的对应基因区域并行核苷酸序列分析。用Western印迹技术对先证者及家系成员血浆中凝血酶调节蛋白(TM)进行检测,并对Western印迹结果进行灰度扫描,以半定量TM水平。结果 该家系5名成员中,除无血缘关系的先证者弟媳外,其余4例均有不同程度的鼻出血或其他部位出血史;先证者及其父亲分别有明显的鼻黏膜或手指皮肤的毛细血管扩张;基因筛查结果显示：先证者,先证者弟弟及其父亲均在ALK1基因8号外显子第1231位核苷酸存在C—T突变(CGG-IICB),而先证者弟媳和侄儿未检测到1231位核苷酸的C—T变异,正常人不存在该位点的核苷酸变异。Western印迹技术分析血浆TM表达显示分子量在56000处,2例正常对照,与3例HHT患者灰度扫描平均值分别为218．3和174．1;在28000处,2例正常对照,与3例HHT患者灰度扫描平均值分别为222．0和145．1,HHT患者血浆中TM蛋白含量明显低于正常人。结论 在中国的Ⅱ型HHT患者存在ALK1基因突变,突变位点位于8号外显子cC231T。HHT患者血浆中TM水平有降低趋势,其意义及机制尚待进一步确定。     

遗传性出血性毛细血管扩张症一家系ALK-1基因突变检测

目的:探讨一个遗传性出血性毛细血管扩张症家系的临床特点及遗传学病因。方法:对13名家系成员进行详细的临床检查、耳鼻咽喉科专科检查及实验室检查,用聚合酶链反应（PCR）扩增13名家系成员和2名健康对照者的ALK-1基因3,4,7,8号外显子。用 单链构象多态性（SSCP）进行ALK-1基因的突变分析。结果:13名家系成员中在3号外显子上PCR-SSCP呈明显异常带型者有4例,与正常对照者比较于大约700 bp处多出一条带,包括先证者及先证者的父亲、姑姑及叔辈姑姑。结论:该家系遗传性出血性毛细血管扩张症是由于ALK-1基因突变引起,突变位点位于3号外显子。     

遗传性出血性毛细血管扩张症所致消化道出血的研究进展

遗传性出血性毛细血管扩张症（HHT）所致消化道出血临床少见,在中老年人群中不明原因消化道出血更易被忽视,从而延误治疗。HHT发病机制主要与ENG、酰基辅酶A合成酶长链家族成员4 (ACVRL4)、激活素受体样激酶1 (ALK1)和母亲DPP同源物4 (Smad4)基因突变有关,消化道出血作为HHT的少见并发症,考虑与多种危险因素有关,消化道出血可发生于胃肠道任何部位,以中老年患者多见,常伴有家族遗传史和鼻出血病史。临床诊断主要依靠内镜检查,并需与其他毛细血管疾病相鉴别。目前国内外尚无统一的治疗标准,但随着内镜诊疗技术的发展,内镜联合药物治疗可取得满意的疗效。现就HHT所致消化道出血的临床研究进展进行综述,旨在提高临床医生对HHT所致消化道出血的认识,提高疾病诊断率,为治疗不明原因消化道出血提供依据。     

遗传性出血性毛细血管扩张症的研究进展

遗传性出血性毛细血管扩张症是一种常染色体显性遗传疾病,以出血和血管扩张为主要表现。其分子学发病机制为ENG和ALK1基因突变,临床症状主要表现为鼻出血、毛细血管扩张和内脏血管扩张。遗传性出血性毛细血管扩张症的诊断依据临床表现和阳性家族史,临床上治疗以对症治疗和预防为主。     

遗传性出血性毛细血管扩张症的药物治疗进展

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的血管病。典型的临床表现是存在血管畸形,最常见的临床表现是鼻出血、消化道出血、缺铁性贫血及特征性的皮肤黏膜毛细血管扩张。HHT的诊断主要依靠血管畸形的证据及基因检测。现阶段的治疗目标主要在于缓解症状。近年来关于HHT的药物治疗取得了一定进展,可考虑使用的药物包括抗血管生成药物、免疫调节剂、抗纤溶药物、激素、β受体阻滞剂等,为HHT患者的治疗提供了更多的选择。     

应加强对遗传性出血性毛细血管扩张症与血管生成和发育障碍的研究

新近的研究证明,遗传性出血性毛细血管扩张症(hereditary hemorrhagic telarIgiectasia,HHT)发病的分子机制涉及到转化生长因子β(TGF—β)信号转导系统的异常,其他的血管生长因子也不同程度参与了HHT的发病过程。由于HHT存在着病理性的血管发育障碍和原因性的基因突变(endoglin 基因和ALK1基因),     

Ⅱ型遗传性出血性毛细血管扩张症的发病机理研究进展

遗传性出血性毛细血管扩张征(hereditary hemorrhagictelangiectasia,HHT),又名Rendu-Osler-Weber综合征,是一种以血管发育异常为特征的常染色体显性遗传病。目前流行病学调查研究显示,该病发病率远比以前认为的要高,在法国约为1/2 351,丹麦的Funen约为1/3 500,美国佛蒙特约为1/6 500,北爱尔兰约为1/39 000。然而,国内尚未有大规模的资料统计。本病的发病与年龄相关,一般在40～45岁左右,无明     

Hereditary hemorrhagic telangiectasia. Genetics, pathogenesis, clinical manifestation and management

Hereditary hemorrhagic telangiectasia HHT, Morbus Osler or Osler-Weber-Rendu syndrome OMIM 187300, is an autosomal dominant disorder characterized by epistaxis, telangiectasia, multi-systemic vascular dysplasia and clinical presentation of wide variation. The pathogenesis involves dilated post-capillary venules or telangiectases in the mucus membrane of various organs as well as larger arteriovenous malformations. Genetic heterogeneity of HHT is confirmed; 2 disease loci, ACVRL1 and ENG genes, have been identified and characterized. The 2 major types of the disease, HHT1 and HHT2, are attributed to mutations in the ENG and ACVRL1 genes. ENG and ACVRL1 genes code for proteins, namely endoglin and activin-receptor-like kinase 1 ALK-1, which are members of the TGF-beta receptor family, are essential for maintaining vascular integrity. Another gene has been implicated in HHT; the HHT3 locus linked to chromosome 5. In the last 2 decades, the genetics, pathogenesis, clinical manifestations and management of HHT have been extensively researched. At this stage, it is deemed appropriate to review the wealth of information accumulated on the topic. Better understanding of the functions of endoglin, ALK-1, and other proteins involved in the pathogenesis of HHT should facilitate better management of patients with this disorder.     

Mutations in the ENG,ACVRL1, and SMAD4 genes and clinical manifestations of hereditary haemorrhagic telangiectasia: experience from the Center for Osler’s Disease,Uppsala University Hospital

Abstract

Aim: The aim of this retrospective single-centre study was to evaluate whether mutations in the ENG, ACVRL1, and SMAD4 genes were associated with different phenotypes in hereditary haemorrhagic telangiectasia (HHT).

Methods: The case records of 21 HHT patients with verified mutations in ENG, ACVRL1, or SMAD4 genes were reviewed. The numbers of HHT diagnostic criteria fulfilled for the three genotypes were compared, as was the prevalence of complications such as iron deficiency anaemia, gastrointestinal haemorrhage, stroke, and cerebral abscess.

Results: Our results indicate that mutations in the ENG (HHT1), ACVRL1 (HHT2), and SMAD4 genes result in different HHT phenotypes. Epistaxis debuts earlier and may be more severe in HHT1 than in HHT2. The prevalence of pulmonary arteriovenous malformations (AVM) is higher in HHT type 1, whereas hepatic AVMs are more common in HHT2. One patient with mutations in both ENG and ACVRL1 genes was identified, as were two SMAD4-mutated patients suffering from the overlapping juvenile polyposis-HHT syndrome. Nearly one in five patients in our HHT population has been diagnosed with stroke or cerebral abscess, indicating a high prevalence of cerebral complications.

Conclusion: Our results showing that ENG and ACVRL1 gene mutations result in different HHT phenotypes confirm the results from other HHT centres worldwide. Cerebral complications of HHT are common, underscoring the importance of regular screening for pulmonary AVMs and early intervention against such AVMs. We have identified an HHT patient with simultaneous mutations in the ENG and ACVRL1 genes. Surprisingly, this patient has had a mild course of the disease.     

Clinical phenotypes, ALK1 gene mutation and level of related plasma proteins in Chinese hereditary hemorrhagic telangiectasia

Background We determined the diagnosis of hereditary hemorrhagic telangiectasis (HHT) in a suspected HHT family, identified ALK1 gene mutation and established a gene diagnosis method of HHT. The level of related plasma proteins (transforming growth factor β and thrombomodulin ) were also analyzed,Methods Bleeding history and family history were collected; Dilatant nasal mucosal capillaries in proband were observed under nasal cavity endoscope; exons 3, 7, 8 of ALK1 gene in proband and her family members were amplified with polymerase chain reaction (PCR), and the PCR products were analyzed. Using enzyme-linked immunosorbent assay (ELISA), plasma TGF-β1 and TGF-β2.concentrations were measured. Plasma thrombomodulin (TM) level was detected by Westem blotting.Results Of all family members, four had epstaxis, two had evident telangiectases on skin or mucosa. Gene screening results showed that C to T substitution at position 1231 in exon 8 of ALK1gene (CGG→TGG) existed in proband,her affected brother and their father. The mutation did not exist in proband‘s sister-in-law and nephew. Plasma TGF-β1 concentrations in the affected HHT was 20538, 17194, 13131 pg/ml, while that of normal control and unaffected family members was 15950,20297, 12836 pg/ml, respectively. Plasma TGF-β2. in HHT patients was 14502, 9550, 10592 and that of normal controls 8579, 20297, 7680 pg/ml respectively. Level of plasma TM was in HHT subjects significantly lower than in normal subjects.Conclusions Chinese HHT individuals have mutant ALK1 gene, a C1231 T variation on exon 8 of ALK1 is responsible for HHT clinical phenotypes in this family. ALK1 gene analysis, together with special clinical phenotypes and family history, provides a reliable method in diagnosing HHT. In affected HHT subjects, plasma TGFβ levels were not obviously different from those of normal subject;while plasma TM concentration was significantly lower than that in normal subjects. The significance and mechanism remain to be elucidated.     

遗传性毛细血管扩张症1例报告及文献复习

目的提高对遗传性毛细血管扩张症（hereditary hemorrhagic telangiectasia,HHT）造成的大咯血患儿的诊治水平。方法总结1例以大量咯血为临床表现的HHT患儿的临床诊治经过并复习相关文献。结果通过数字减影血管造影（digital subtraction angiography,DSA）及病史诊断为HHT,DSA结果提示右侧支气管动脉中下部发育异常、支气管动脉一肺动脉瘘、左侧支气管动脉发育异常,行经导管栓塞（transcatheter embolotherapy,TCE）治疗,随访2年,无咯血表现。在国内外报道儿童咯血原因中,血管因素属少见原因。40％的HHT患者存在肺动静脉畸形（pulmonary arteriovenous malformation,PAVM）,70％的PAVM患者与HHT相关,2％—5％的PAVM患者为支气管动脉与肺动脉瘘。结论遗传性毛细血管扩张症为儿童大量咯血的少见原因。DSA可以明确病变部位。利用TCE治疗并应长期随访。     

Successful lobectomy in a patient of pulmonary arteriovenous malformation with hemoptysis

To the editor:Pulmonary arteriovenous malformation (PAVM) is abnormal communications between the pulmonary arteries and veins,and has been reported to be sporadic or to occur in association with hereditary hemorrhagic telangiectasia (HHT).1 The patients of PAVM may be asymptomatic,present with hypoxemia,paradoxical thromboembolism,or hemoptysis.Ference and coworkers 2 reported only 6 patients with hemoptysis in a review of 143 patients with PAVM.     

Hereditary haemorrhagic telangiectasia: a cause of preventable morbidity and mortality

Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant condition whose effects are mediated through deficient blood vessel formation and regeneration, with multisystem involvement. Patients are usually aware of resulting skin telangiectasia and epistaxis, but are also exposed to dangers posed by occult vascular malformations in other organs. About 15–35% of HHT patients have pulmonary AVMs (PAVMs), 10% have cerebral AVMs (CAVMs), 25–33% suffer significant GI blood loss from GI tract telangiectasia, and an unknown but high percentage have liver involvement. In total, 10% of affected individuals die prematurely or suffer major disability from HHT, largely because of bleeding from CAVMs and PAVMs, or paradoxical embolization through PAVMs. Screening for and early intervention to treat occult PAVMs and CAVMs can largely eliminate these risks, and should be undertaken in a specialist centre. The National HHT Center in The Mercy University Hospital in Cork is the referral centre for HHT screening in Ireland.     

遗传性全白甲家系的KLF7和CPO基因突变分析

目的:分析常染色体显性遗传全白甲病家系的候选基因KLF7和CPO的突变。方法:对KLF7和CPO基因的全部外显子区域及邻近内含子区域进行PCR扩增,其产物进行直接测序,根据测序结果分析KLF7和CPO的基因突变。结果:在KLF7和CPO基因外显子区域及邻近内含子区域内检测到5个变异位点,未检测到致病的基因突变。结论:KLF7和CPO基因编码区域的变异不是此家系全白甲的致病基因突变。