A combined syndrome of juvenile polyposis and hereditary haemorrhagic telanglectasia associated with mutations in MADH4 (SMAD4)
A combined syndrome of juvenile polyposis and hereditary haemorrhagic telanglectasia associated with mutations in MADH4 (SMAD4)
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DOI：
10.1016/s0140-6736(04)15732-2
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发表时间：
2004-03-13
期刊：
影响因子：
168.9
通讯作者：
Marchuk, DA
中科院分区：
文献类型：
--
作者：
Gallione, CJ;Repetto, GM;Marchuk, DA
背景幼年性息肉病和遗传性出血性毛细血管扩张症是常染色体显性遗传病，具有明显且不重叠的临床特征。前者是一种遗传性胃肠道恶性肿瘤易感性，由MADH4(编码Smad4)或BMPR1A突变引起，后者是由ENG(Endoglin)或ACVRL1(ALK1)突变引起的血管畸形疾病。这四个基因都编码与转化生长因子-β信号通路有关的蛋白质。虽然有患者和家系合并这两种疾病表型的报道，但这种关联的遗传病因尚不清楚。方法采集7个分离这两种表型的无关家系的血样。对每个家系先证者的DNA进行ACVRL1、ENG和MADH4基因测序。在人群对照中检测突变与表型和有无家族性共隔离。结果没有患者有ENG或ACVRL1基因突变；所有患者都有MADH4突变。发现3例MADH4去新生突变。在其中一个案例中，突变被遗传给了一个同样受影响的孩子。MADH4的解释突变可导致包括幼年性息肉病和遗传性出血性毛细血管扩张症两种表型的综合征。由于患有这些疾病的患者通常是通过不同的医学专业确诊的，因此建议对出现任何一种表型的患者进行基因测试，以确定哪些人有这种综合征的风险。携带MADH4突变的幼年性息肉病患者应筛查与遗传性出血性毛细血管扩张症相关的血管病变，特别是内脏器官的隐匿性动静脉畸形，否则可能突然出现严重的医疗后果。
Background Juvenile polyposis and hereditary haemorrhagic telangiectasia are autosomal dominant disorders with distinct and non-overlapping clinical features. The former, an inherited gastrointestinal malignancy predisposition, is caused by mutations in MADH4 (encoding SMAD4) or BMPR1A, and the latter is a vascular malformation disorder caused by mutations in ENG (endoglin) or ACVRL1 (ALK1). All four genes encode proteins involved in the transforming-growth-factor-beta signalling pathway. Although there are reports of patients and families with phenotypes of both disorders combined, the genetic aetiology of this association is unknown.Methods Blood samples were collected from seven unrelated families segregating both phenotypes. DNA from the proband of each family was sequenced for the ACVRL1, ENG, and MADH4 genes. Mutations were examined for familial cosegregation with phenotype and presence or absence in population controls.Findings No patient had mutations in the ENG or ACVRL1 genes; all had MADH4 mutations. Three cases of de-novo MADH4 mutations were found. In one, the mutation was passed on to a similarly affected child. Each mutation cosegregated with the syndromic phenotype in other affected family members.Interpretation Mutations in MADH4 can cause a syndrome consisting of both juvenile polyposis and hereditary haemorrhagic telangiectasia phenotypes. Since patients with these disorders are generally ascertained through distinct medical specialties, genetic testing is recommended for patients presenting with either phenotype to identify those at risk of this syndrome. Patients with juvenile polyposis who have an MADH4 mutation should be screened for the vascular lesions associated with hereditary haemorrhagic telangiectasia, especially occult arteriovenous malformations in visceral organs that may otherwise present suddenly with serious medical consequences.