Abstract
Background: Constitutional mismatch repair deficiency syndrome (CMMRD) represents a biallelic (homozygous or compound heterozygous) mutation in one of the mismatch repair genes (MLH1, MSH2, MSH6 or PMS2), resulting in a recessively inherited childhood cancer predisposition syndrome. A broad range of tumours in infants and children have been described in the CMMRD spectrum, most commonly brain tumours, intestinal tumours, and haematological malignancies. This contrasts with the monoallelic mismatch repair defects (MMR) of Lynch syndrome, in which there is an increased risk of development of malignancies in particular involving the gastrointestinal and genitourinary tract, with onset in adulthood. Phenotypic features of CMMRD overlap with neurofibromatosis, with café-au-lait macules a common finding in this cohort. Aims: To highlight an increasingly recognised childhood cancer predisposition syndrome, and the importance of identification of these cases given significant implications for family counselling. There is an increased cancer risk in siblings, as well as for the parents, who may not yet be aware of their own associated monoallelic MMR defect (Lynch syndrome). Methods: We present three cases of childhood primary brain tumours that were subsequently confirmed in the setting of CMMRD. The histological, immunohistochemical and genetic findings of these cases are discussed, with focus on diagnostic pathologic features that suggest an underlying CMMRD. Results and conclusions: Three high grade brain tumours described include two high grade gliomas (a glioblastoma multiforme and a high grade diffuse intrinsic pontine glioma, H3K27M negative), and a medulloblastoma. These examples all showed complete absence of PMS2 staining on immunohistochemistry in both tumour cells and normal ‘internal control’ tissues of the patient, correlating with biallelic loss of gene function. Review of the literature shows brain tumours as the most frequent presentation in children with CMMRD, with an increased risk of gastrointestinal tumours (including colonic carcinoma) and haematological malignancies also reported.
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