Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
Department of Pediatric Hematology, University Medical Centre, Utrecht, The Netherlands.
Clin Genet. 2018 Jan;93(1):134-137. doi: 10.1111/cge.13053. Epub 2017 Sep 15.
Constitutional mismatch repair deficiency (CMMRD) is a rare, recessively inherited childhood cancer predisposition syndrome caused by biallelic germline mutations in one of the mismatch repair genes. The CMMRD phenotype overlaps with that of neurofibromatosis type 1 (NF1), since many patients have multiple café-au-lait macules (CALM) and other NF1 signs, but no germline NF1 mutations. We report of a case of a healthy 6-year-old girl who fulfilled the diagnostic criteria of NF1 with >6 CALM and freckling. Since molecular genetic testing was unable to confirm the diagnosis of NF1 or Legius syndrome and the patient was a child of consanguineous parents, we suspected CMMRD and found a homozygous PMS2 mutation that impairs MMR function. Current guidelines advise testing for CMMRD only in cancer patients. However, this case illustrates that including CMMRD in the differential diagnosis in suspected sporadic NF1 without causative NF1 or SPRED1 mutations may facilitate identification of CMMRD prior to cancer development. We discuss the advantages and potential risks of this CMMRD testing scenario.
错配修复缺陷（CMMRD）是一种罕见的常染色体隐性遗传性儿童期癌症易感性综合征，由错配修复基因中的双等位基因突变引起。CMMRD 表型与神经纤维瘤病 1 型（NF1）重叠，因为许多患者有多个咖啡牛奶斑（CALM）和其他 NF1 特征，但无胚系 NF1 突变。我们报告了一例满足 NF1 诊断标准的 6 岁健康女孩，其具有>6 个 CALM 和雀斑。由于分子遗传学检测无法确认 NF1 或 Legius 综合征的诊断，且患者为近亲父母所生，我们怀疑为 CMMRD，并发现了一种纯合的 PMS2 突变，该突变会损害 MMR 功能。目前的指南建议仅在癌症患者中进行 CMMRD 检测。然而，该病例说明，在疑似散发型 NF1 中，若无致病性 NF1 或 SPRED1 突变，将 CMMRD 纳入鉴别诊断，可能有助于在癌症发生前识别 CMMRD。我们讨论了这种 CMMRD 检测方案的优势和潜在风险。
