Abstract
Background A 13-year-old girl presented with rectal bleeding and was found to have two colonic carcinomas (stage Dukes' C) and multiple colonic polyps. At the age of 7 years she had widespread hyperpigmented and hypopigmented skin lesions, and had developed medulloblastoma, which was treated with chemotherapy and craniospinal irradiation. At the age of 10 years she had developed acute myelocytic leukemia, M5. She was treated with chemotherapy including sibling bone marrow transplant with busulfan/cyclophosphamide conditioning. A three-generation family history identified no relatives with colonic carcinomas or polyposis.
Investigations Immunohistochemical analysis was performed on a sample of colonic adenoma. Staining for MLH1 and MSH2 was normal but was absent for MSH6. Direct sequencing of MSH6 was performed in the proband and both parents.
Diagnosis Constitutional biallelic mutations in the mismatch repair gene MSH6 were identified in the proband. Both parents are carriers of one mutation. This is the first individual with biallelic MSH6 mutations reported with either medulloblastoma or acute myelocytic leukemia.
Management Cascade genetic testing and colonoscopic screening for colorectal carcinoma has been offered to relatives carrying one mutation. The proband underwent panproctocolectomy and received adjuvant capecitabine. Identification of constitutional biallelic mismatch repair gene mutations allows the avoidance of chemotherapeutic agents likely to be ineffective and mutagenic in the context of the underlying mismatch repair deficiency. It is important to consider this diagnosis in children presenting with malignancy and abnormal skin pigmentation, even in the absence of a strong family history of tumors.
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Acknowledgements
Informed consent for the research and publication of this case report including photographs was obtained from the patient and her parents. We thank Mike Stratton and Andy Futreal for their comments on the manuscript. This work is part of the Factors Associated with Childhood Tumours (FACT) study, which is a Children's Cancer and Leukaemia Group (CCLG) study. The study has been approved by the London Multicentre Research Ethics Committee (MREC05/MRE02/17). The work was supported by the Institute of Cancer Research (UK). RH Scott is supported by a grant which forms part of the Michael and Betty Kadoorie Cancer Genetics Research Programme.
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Scott, R., Mansour, S., Pritchard-Jones, K. et al. Medulloblastoma, acute myelocytic leukemia and colonic carcinomas in a child with biallelic MSH6 mutations. Nat Rev Clin Oncol 4, 130–134 (2007). https://doi.org/10.1038/ncponc0719
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DOI: https://doi.org/10.1038/ncponc0719
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