Overlapping Spectra of SMAD4 Mutations in Juvenile Polyposis (JP) and JP-HHT Syndrome
Overlapping Spectra of SMAD4 Mutations in Juvenile Polyposis (JP) and JP-HHT Syndrome
复制标题
DOI：
10.1002/ajmg.a.33206
复制
发表时间：
2010-02-01
影响因子：
2
通讯作者：
Marchuk, Douglas A.
中科院分区：
文献类型：
--
作者：
Gallione, Carol;Aylsworth, Arthur S.;Marchuk, Douglas A.
幼年性息肉病 (JP) 和遗传性出血性毛细血管扩张症 (HHT) 是临床上不同的疾病，由 SMAD4 和 BMPR1A（JP）以及内皮糖蛋白和 ALK1（HHT）突变引起。最近，描述了一种 JP-HHT 联合综合征，该综合征也是由 SMAD4 突变引起的。尽管JP和JP-HHT都是由SMAD4突变引起的，但注意到可能的基因型：表型相关性，因为JP-HHT患者中的所有SMAD4突变都聚集在蛋白质的COOH末端MH2结构域中。如果有效，这种相关性将为表型差异提供分子解释，并提供症状前诊断测试，以区分有重叠但不同临床特征的疾病风险的患者。在这项研究中，我们收集了 19 名新的 JP-HHT 患者，从中我们鉴定出了 15 个额外的 SMAD4 突变。我们还回顾了有关具有 HHT 症状且已确诊 SMAD4 突变的 JP 患者的其他文献报道。我们的综合结果表明，尽管 JP-HHT 患者的 SMAD4 突变确实表现出聚集在 MH2 结构域的趋势，但该基因其他部分的突变也会导致联合综合征。因此，SMAD4 的任何突变都可能导致 JP-HHT。因此，任何具有 SMAD4 突变的 JP 患者均面临 HHT 内脏表现的风险，而任何具有 SMAD4 突变的 HHT 患者均面临早发性胃肠癌的风险。总之，任何 SMAD4 突变检测呈阳性的患者都必须被视为有 JP-HHT 联合综合征的风险，并进行相应的监测。 (C) 2010 Wiley-Liss, Inc.
Juvenile polyposis (JP) and hereditary hemorrhagic telangiectasia (HHT) are clinically distinct diseases caused by mutations in SMAD4 and BMPR1A (for JP) and endoglin and ALK1 (for HHT). Recently, a combined syndrome of JP-HHT was described that is also caused by mutations in SMAD4. Although both JP and JP-HHT are caused by SMAD4 mutations, a possible genotype:phenotype correlation was noted as all of the SMAD4 mutations in the JP-HHT patients were clustered in the COOH-terminal MH2 domain of the protein. If valid, this correlation would provide a molecular explanation for the phenotypic differences, as well as a pre-symptomatic diagnostic test to distinguish patients at risk for the overlapping but different clinical features of the disorders. In this study, we collected 19 new JP-HHT patients from which we identified 15 additional SMAD4 mutations. We also reviewed the literature for other reports of JP patients with HHT symptoms with confirmed SMAD4 mutations. Our combined results show that although the SMAD4 mutations in JP-HHT patients do show a tendency to cluster in the MH2 domain, mutations in other parts of the gene also cause the combined syndrome. Thus, any mutation in SMAD4 can cause JP-HHT. Any JP patient with a SMAD4 mutation is, therefore, at risk for the visceral manifestations of HHT and any HHT patient with SMAD4 mutation is at risk for early onset gastrointestinal cancer. In conclusion, a patient who tests positive for any SMAD4 mutation must be considered at risk for the combined syndrome of JP-HHT and monitored accordingly. (C) 2010 Wiley-Liss, Inc.