Department of Genetics, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands.
Eur J Cancer. 2011 May;47(7):965-82. doi: 10.1016/j.ejca.2011.01.013. Epub 2011 Mar 4.
Bi-allelic germline mutations of one of the DNA mismatch repair genes, so far predominantly found in PMS2, cause constitutional MMR-deficiency syndrome. This rare disorder is characterised by paediatric intestinal cancer and other malignancies. We report the clinical, immunohistochemical and genetic characterisation of four families with bi-allelic germline PMS2 mutations. We present an overview of the published gastrointestinal manifestations of CMMR-D syndrome and propose recommendations for gastro-intestinal screening.
The first proband developed a cerebral angiosarcoma at age 2 and two colorectal adenomas at age 7. Genetic testing identified a complete PMS2 gene deletion and a frameshift c.736_741delinsTGTGTGTGAAG (p.Pro246CysfsX3) mutation. In the second family, both the proband and her brother had multiple intestinal adenomas, initially wrongly diagnosed as familial adenomatous polyposis. A splice site c.2174+1G>A, and a missense c.137G>T (p.Ser46Ile) mutation in PMS2 were identified. The third patient was diagnosed with multiple colorectal adenomas at age 11; he developed a high-grade dysplastic colorectal adenocarcinoma at age 21. Two intragenic PMS2 deletions were found. The fourth proband developed a cerebral anaplastic ganglioma at age 9 and a high-grade colerectal dysplastic adenoma at age 10 and carries a homozygous c.2174+1G>A mutation. Tumours of all patients showed microsatellite instability and/or loss of PMS2 expression.
Our findings show the association between bi-allelic germline PMS2 mutations and severe childhood-onset gastrointestinal manifestations, and support the notion that patients with early-onset gastrointestinal adenomas and cancer should be investigated for CMMR-D syndrome. We recommend yearly follow-up with colonoscopy from age 6 and simultaneous video-capsule small bowel enteroscopy from age 8.
迄今为止，已在 PMS2 中发现了 DNA 错配修复基因的双等位基因突变，导致了结构型 MMR 缺陷综合征。这种罕见的疾病以小儿肠癌和其他恶性肿瘤为特征。我们报告了四例双等位基因突变的 PMS2 胚系突变的临床、免疫组织化学和遗传学特征。我们总结了已发表的 CMMR-D 综合征胃肠道表现，并提出了胃肠道筛查建议。
首例先证者在 2 岁时发生脑血管肉瘤，在 7 岁时发生 2 个结直肠腺瘤。基因检测发现 PMS2 基因完全缺失和框移突变 c.736_741delinsTGTGTGTGAAG(p.Pro246CysfsX3)。在第二个家庭中，先证者及其弟弟都有多发性肠腺瘤，最初误诊为家族性腺瘤性息肉病。发现 PMS2 存在剪接位点 c.2174+1G>A 和错义突变 c.137G>T(p.Ser46Ile)。第三个患者在 11 岁时被诊断为多发性结直肠腺瘤，在 21 岁时发展为高级别异型性结直肠腺瘤腺癌。发现了两个 PMS2 基因内缺失。第四个先证者在 9 岁时发生脑间变性神经节胶质瘤，在 10 岁时发生高级别结直肠异型性腺瘤，携带纯合 c.2174+1G>A 突变。所有患者的肿瘤均显示微卫星不稳定性和/或 PMS2 表达缺失。
我们的研究结果表明，双等位基因突变 PMS2 与儿童期起病的严重胃肠道表现有关，并支持这样的观点，即早发胃肠道腺瘤和癌症的患者应进行 CMMR-D 综合征的检查。我们建议从 6 岁开始每年进行结肠镜检查，同时从 8 岁开始进行视频胶囊小肠内镜检查。
