Kratz C P, Holter S, Etzler J, Lauten M, Pollett A, Niemeyer C M, Gallinger S, Wimmer K
Division of Clinical Genetics, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University Innsbruck, Schoepfstr. 41, 6020 Innsbruck, Austria.
J Med Genet. 2009 Jun;46(6):418-20. doi: 10.1136/jmg.2008.064212. Epub 2009 Mar 16.
Biallelic germline mutations in the mismatch repair genes MLH1, MSH2, MSH6 or PMS2 cause a recessive childhood cancer syndrome characterised by early-onset malignancies and signs reminiscent of neurofibromatosis type 1 (NF1). Alluding to the underlying genetic defect, we refer to this syndrome as constitutional mismatch repair-deficiency (CMMR-D) syndrome. The tumour spectrum of CMMR-D syndrome includes haematological neoplasias, brain tumours and Lynch syndrome-associated tumours. Other tumours, such as neuroblastoma, Wilm tumour, ovarian neuroectodermal tumour or infantile myofibromatosis, have so far been found only in individual cases.
We analysed two consanguineous families that had members with suspected CMMR-D syndrome who developed rhabdomyosarcoma among other neoplasias. In the first family, we identified a pathogenic PMS2 mutation for which the affected patient was homozygous. In family 2, immunohistochemistry analysis showed isolated loss of PMS2 expression in all tumours in the affected patients, including rhabdomyosarcoma itself and the surrounding normal tissue. Together with the family history and microsatellite instability observed in one tumour this strongly suggests an underlying PMS2 alteration in family 2 also.
Together, these two new cases show that rhabdomyosarcoma and possibly other embryonic tumours, such as neuroblastoma and Wilm tumour, belong to the tumour spectrum of CMMR-D syndrome. Given the clinical overlap of CMMR-D syndrome with NF1, we suggest careful examination of the family history in patients with embryonic tumours and signs of NF1 as well as analysis of the tumours for loss of one of the mismatch repair genes and microsatellite instability. Subsequent mutation analysis will lead to a definitive diagnosis of the underlying disorder.
错配修复基因MLH1、MSH2、MSH6或PMS2的双等位基因种系突变会导致一种隐性儿童癌症综合征，其特征为早发性恶性肿瘤以及类似1型神经纤维瘤病（NF1）的体征。鉴于潜在的基因缺陷，我们将此综合征称为遗传性错配修复缺陷（CMMR-D）综合征。CMMR-D综合征的肿瘤谱包括血液系统肿瘤、脑肿瘤以及林奇综合征相关肿瘤。其他肿瘤，如神经母细胞瘤、肾母细胞瘤、卵巢神经外胚层肿瘤或婴儿肌纤维瘤病，目前仅在个别病例中发现。
我们分析了两个近亲家庭，其中有疑似CMMR-D综合征的成员，他们除了患有其他肿瘤外还患上了横纹肌肉瘤。在第一个家庭中，我们鉴定出一个致病的PMS2突变，患病患者为该突变的纯合子。在第二个家庭中，免疫组化分析显示，患病患者的所有肿瘤，包括横纹肌肉瘤本身及其周围正常组织，均出现PMS2表达单独缺失的情况。结合家族病史以及在一个肿瘤中观察到的微卫星不稳定性，这强烈提示第二个家庭也存在潜在的PMS2改变。
这两个新病例共同表明，横纹肌肉瘤以及可能的其他胚胎性肿瘤，如神经母细胞瘤和肾母细胞瘤，属于CMMR-D综合征的肿瘤谱。鉴于CMMR-D综合征与NF1在临床上存在重叠，我们建议对患有胚胎性肿瘤且有NF1体征的患者仔细检查家族病史，并分析肿瘤中错配修复基因之一的缺失情况以及微卫星不稳定性。随后的突变分析将有助于明确潜在疾病的诊断。
