Homozygous germ-line mutation of the PMS2 mismatch repair gene: a unique case report of constitutional mismatch repair deficiency (CMMRD).
Homozygous germ-line mutation of the PMS2 mismatch repair gene: a unique case report of constitutional mismatch repair deficiency (CMMRD).
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DOI：
10.1186/s12881-017-0391-x
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发表时间：
2017-04-05
影响因子：
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通讯作者：
Evans DG
中科院分区：
文献类型：
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作者：
Ramchander NC;Ryan NA;Crosbie EJ;Evans DG
体质错配修复缺陷综合征是由影响关键DNA错配修复基因MLH1、MSH2、MSH6或PMS2突变的双等位基因遗传引起的。具有双等位基因突变的个体从出生起就有功能失调的错配修复系统；因此，体质错配修复缺陷综合征的特点是早期发病的恶性肿瘤。在过去的20年里，文献报道的病例不到150例。这是首次报道创始人PMS2突变- NM_000535.5:c。该家族外显子11中的1500del （p.v all501trpfster94）及其相关癌症。先证者今年30岁，现在还活着。她是巴基斯坦裔，是血缘关系的产物。她最初于24岁时因结肠直肠息肉引起的直肠无痛性出血而就诊于临床遗传学。临床检查发现两个卡萨-au-lait病变，扁平苔藓和皮样囊肿。她的妹妹在童年时被诊断出患有侵袭性脑瘤，随后患上了结肠直肠癌。在随访中，先证者发生37例结直肠腺瘤性息肉，同时性卵巢和子宫内膜腺癌，最终发生异时性胃腺癌。外周血淋巴细胞DNA测序显示PMS2突变NM_000535.5:c具有双等位基因遗传。外显子11中的1500del （p.Val501TrpfsTer94）。卵巢肿瘤组织表现出低微卫星不稳定性。到目前为止，她已经做了全腹部子宫切除术，双侧输卵管卵巢切除术和全胃切除术。阿司匹林和仅雌激素的激素替代疗法分别提供一些化学预防和管理绝经后症状。一个18个月的结肠镜检查计划导致了三个高度发育不良的结肠管状腺瘤性息肉的切除。先证者的家族谱系显示，有多个亲属患有癌症，其中包括一个可能是“真正的”特考特综合征的病例。如果患者早发性癌症，有强烈的癌症家族史，皮肤特征类似于i型神经纤维瘤病，则应考虑体质错配修复缺陷综合征。肿瘤和正常组织的免疫组织化学分析对于识别错配修复缺陷患者是敏感和特异性的，并应指导淋巴细胞组织的DNA测序以建立诊断。微卫星不稳定状态在识别可能患有体质错配修复缺陷综合征的患者方面似乎没有什么价值。
Constitutional mismatch repair deficiency syndrome results from bi-allelic inheritance of mutations affecting the key DNA mismatch repair genes: MLH1, MSH2, MSH6 or PMS2. Individuals with bi-allelic mutations have a dysfunctional mismatch repair system from birth; as a result, constitutional mismatch repair deficiency syndrome is characterised by early onset malignancies. Fewer than 150 cases have been reported in the literature over the past 20 years. This is the first report of the founder PMS2 mutation - NM_000535.5:c.1500del (p.Val501TrpfsTer94) in exon 11 and its associated cancers in this family. The proband is 30 years old and is alive today. She is of Pakistani ethnic origin and a product of consanguinity. She initially presented aged 24 with painless bleeding per-rectum from colorectal polyps and was referred to clinical genetics. Clinical examination revealed two café-au-lait lesions, lichen planus, and a dermoid cyst. Her sister had been diagnosed in childhood with an aggressive brain tumour followed by colorectal cancer. During follow up, the proband developed 37 colorectal adenomatous polyps, synchronous ovarian and endometrial adenocarcinomas, and ultimately a metachronous gastric adenocarcinoma. DNA sequencing of peripheral lymphocytes revealed a bi-allelic inheritance of the PMS2 mutation NM_000535.5:c.1500del (p.Val501TrpfsTer94) in exon 11. Ovarian tumour tissue demonstrated low microsatellite instability. To date, she has had a total abdominal hysterectomy, bilateral salpingo-oophorectomy, and a total gastrectomy. Aspirin and oestrogen-only hormone replacement therapy provide some chemoprophylaxis and manage postmenopausal symptoms, respectively. An 18-monthly colonoscopy surveillance programme has led to the excision of three high-grade dysplastic colorectal tubular adenomatous polyps. The proband’s family pedigree displays multiple relatives with cancers including a likely case of ‘true’ Turcot syndrome. Constitutional mismatch repair deficiency syndrome should be considered in patients who present with early onset cancer, a strong family history of cancer, and cutaneous features resembling neurofibromatosis type I. Immunohistochemistry analysis of tumour and normal tissue is sensitive and specific for identifying patients with mismatch repair deficiency and should direct DNA sequencing of lymphocytic tissue to establish a diagnosis. Microsatellite instability status appears to be of little value in identifying patients who may have constitutional mismatch repair deficiency syndrome.