Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
Eur J Hum Genet. 2013 Jan;21(1):55-61. doi: 10.1038/ejhg.2012.117. Epub 2012 Jun 13.
Constitutional mismatch repair deficiency (CMMR-D) syndrome is a rare inherited childhood cancer predisposition caused by biallelic germline mutations in one of the four mismatch repair (MMR)-genes, MLH1, MSH2, MSH6 or PMS2. Owing to a wide tumor spectrum, the lack of specific clinical features and the overlap with other cancer predisposing syndromes, diagnosis of CMMR-D is often delayed in pediatric cancer patients. Here, we report of three new CMMR-D patients all of whom developed more than one malignancy. The common finding in these three patients is agenesis of the corpus callosum (ACC). Gray matter heterotopia is present in two patients. One of the 57 previously reported CMMR-D patients with brain tumors (therefore all likely had cerebral imaging) also had ACC. With the present report the prevalence of cerebral malformations is at least 4/60 (6.6%). This number is well above the population birth prevalence of 0.09-0.36 live births with these cerebral malformations, suggesting that ACC and heterotopia are features of CMMR-D. Therefore, the presence of cerebral malformations in pediatric cancer patients should alert to the possible diagnosis of CMMR-D. ACC and gray matter heterotopia are the first congenital malformations described to occur at higher frequency in CMMR-D patients than in the general population. Further systematic evaluations of CMMR-D patients are needed to identify possible other malformations associated with this syndrome.
错配修复缺陷（CMMR-D）综合征是一种罕见的遗传性儿童期癌症易感性疾病，由四个错配修复（MMR）基因之一的种系双等位基因突变引起，这四个基因分别是 MLH1、MSH2、MSH6 和 PMS2。由于肿瘤谱广泛、缺乏特异性临床特征以及与其他癌症易感性综合征重叠，儿科癌症患者的 CMMR-D 诊断常常被延误。在这里，我们报告了 3 例新的 CMMR-D 患者，他们都患有多种恶性肿瘤。这 3 例患者的共同发现是胼胝体发育不全（ACC）。2 例患者存在灰质异位症。在之前报道的 57 例 CMMR-D 伴脑瘤患者中（因此所有患者可能都进行了脑部成像），也有 1 例患者存在 ACC。根据本报告，脑畸形的患病率至少为 60 例中的 4 例（6.6%）。这一数字明显高于这些脑畸形在人群中的出生患病率 0.09-0.36%，提示 ACC 和灰质异位症是 CMMR-D 的特征。因此，儿科癌症患者存在脑畸形时应警惕可能的 CMMR-D 诊断。ACC 和灰质异位症是首次描述的在 CMMR-D 患者中比在普通人群中更频繁发生的先天性畸形。需要进一步对 CMMR-D 患者进行系统评估，以确定与该综合征相关的其他可能的畸形。
