遗传性出血性毛细血管扩张症：一家系研究与文献复习

目的 调查一例遗传性出血性毛细血管扩张症（HHT）患者及其家系，并复习相关文献。方法 调查先证者及其家系，抽取家系4例HHT患者及4名无HHT对照者外周血提取DNA，对活化素受体类激酶1（activin Areceptor type Ⅱ-ike1，ACVRLI）基因常见突变位点外显子3、7、8进行聚合酶链反应（PCR）和直接DNA测序，确定突变位点。结果 （1）家族5代45中人10人有HHT，其祖母死于“心脏病”，父死于“脑溢血”；（2）先证者为73岁女性，因反复自发性鼻衄60年，头昏、胸闷23年，加重2周收住院，临床主要诊断为HHT、高血压病3级（极高危）、腔隙性脑梗塞、高血压性心脏病、心功能Ⅱ级、高醛固酮血症、动脉硬化症、非胰岛素依赖性糖尿病，她的内脏损害包括胃毛细血管扩张症并出血和肾血管扩张并小动静脉瘘；（3）4例HHT患者存在ACVRLI基因第3外显子145鸟嘌呤碱基缺失（delG145），引起框移突变，并导致第53密码子为UAG终止密码子（frameshifi＋Stop：×53），4例对照者未见此突变；（4）文献报道63．4％的HHT患者急诊原因是鼻衄和胃肠道出血，但也可有脑、肺、心、肝等病变。结论 （1）ACVRLI基因delG145突变是这个家系致病的遗传学基础，此突变方式系国内首次报道；（2）HHT是一种慢性病，经常鼻衄会影响患者的生活质量，而血管畸形就有可能突然引起危机生命的情况，因此我们应该关注HHT患者，抓住主要矛盾，即要避免病情恶化，又要兼顾并发症和／或伴随症的处理，同时还要注意家系的调查。

Hereditary Hemorrhmgic Telamgiectasia (HHT):investigation of one pedigree and review of the literature

Objective To investigate one HHT case as well as their at-risk familial relatives and review the relevant Literature. Methods Four patients with HHT and four collators without HHT in the pedigree were investigated. Genomic DNA was extracted from their peripheral blood. The exons 3, 7 and 8 of the activin receptor-ike kinase 1 （ALK1）gene were amplified by polymerase chain reaction（PCR）,and the PCR products were sequenced. Results （ 1 ） 10 subjects in 45 people of 5 generations had HHT. All of them had recurrent spontaneous epistaxis and telangiectases on the fingertips, nasal and oral mucosa. Her grandmother died of heart disease. Her father died of cerebral hemorrhage ; （ 2 ） The proband was a 73-year-old woman. She was in hospital because of suffering from nosebleeds for 60 years, dizziness and chest distress for 23years, and aggravation for 2 weeks. Clinical main diagnosis was HHT, grade 3-hypertensive disease （ very high added risk）, lacunar infarction, and hypertensive heart disease, aortosclerosis, and hyperaldosteronemia and non-insulin-dependent diabetes mellitus. Her visceral lesions included gastrointestinal telangiectases with hemorrhage and renal hemangiectasia with arteriovenous malformations ; （ 3 ） ALK1 gene analysis confirmed that one frameshift ＋ stop mutation caused by deletion of G145 in the exon 3 existed in four patients, and negatively in four collators; （4）Most commonly, the patients with HHT sought urgent medical attention for nosebleeds and gastrointestinal bleeding （63.4%）, but there were also disorders of the brain, lung, heart and liver in the literature. Conclusion （ 1 ） HHT in the pedigree resuhed from the frameshift ＋ stop mutation caused by deletion of G145 in the ALK-1 gene, which has not been identified previously in china; （2）The clinical picture of HHT is frequently that of a chronic disease, with daily nosebleeds affecting the quality of life of patients, but patients may harbor vascular malformations that can suddenly give rise to l