Medulloblastoma, acute myelocytic leukemia and colonic carcinomas in a child with biallelic MSH6 mutations

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.

Homozygous PMS2 germline mutations in two families with early-onset haematological malignancy, brain tumours, HNPCC-associated tumours, and signs of neurofibromatosis type 1

“…32 Recently, the terms 'CoLoN' (for Colon tumours and/or leukaemia/lymphoma and/or neurofibromatosis features), 34 and 'mismatch repair deficiency syndrome (MMR-D)' have been suggested. 28 Hereby, we provide evidence for CCS in six children from two consanguineous families carrying homozygous PMS2 germline mutations. Five of them were affected by earlyonset malignancies from the tumour spectrum reported so far in biallelic MMR germline mutation carriers, and presented with multiple CALS.…”

Constitutional mismatch repair-deficiency syndrome

“…[12][13][14][15] However, signs reminiscent of neurofibromatosis type 1 (NF1), in particular café-aulait macules (CALMs), are much more common and were observed in the majority of the reported cases (63/92). There are only 2 patients explicitly reported to lack CALMs or other signs of NF1.…”

“…Péron et al 2 have shown in 3 CMMR-D patients that 15,19,20 . It remains to be seen whether defective IgA and IgG production is a common feature of CMMR-D. Fortunately, severe bacterial infections have not been reported to occur at high frequencies in persons with CMMR-D.…”

Genetic Instability in Paediatric and Adult Brain Tumours

“…Mismatch repair deficiencies have been associated with paediatric brain tumours in a hereditary context. Case reports have described MMR germline mutations combined with NF1-like clinical features in children presenting medulloblastoma or high-grade glioma, described as a "mismatch repair-deficiency (MMR-D) syndrome" (summary in Table 5) (Agostini et al, 2005;De Rosa et al, 2000;Giunti et al, 2009;Hegde et al, 2005;Kruger et al, 2008;Menko et al, 2004;Ostergaard et al, 2005;Poley et al, 2007;Roy et al, 2009;Scott et al, 2007;Toledano et al, 2009;Viana-Pereira et al, submitted;Wagner et al, 2003;Wang et al, 1999). Also in our study there was a MSI-H paediatric high-grade glioma with clinical characteristics of NF1 (multiple café-au-lait spots).…”