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Glioblastoma in Congenital Mismatch Repair Deficiency (CMMRD) Syndrome

  • Background:
    • CMMRD is a distinct childhood cancer predisposition syndrome that results from biallelic germline mutations in 1 of the 4 MMR genes: MLH1, MSH2, MSH6, or PMS2.
    • DNA mismatch repair (MMR) deficiency is a well-characterized form of genetic instability in cancer, characterized by a failure to repair DNA replication–associated errors.
    • A defective MMR system leads to the persistence of mismatched mutations across the genome, particularly in regions of repetitive DNA (microsatellites), leading to microsatellite instability (MSI). MSI causes the production of truncated protein products, resulting in the development of life-threatening malignancies including gastrointestinal, brain, and hematologic malignancies.
  • Clinical Presentation:
    • CMMRD should be suspected in a case of childhood malignancy with a first- or second-degree relative having colorectal, endometrial, ureteric, bladder, or stomach carcinomas.
    • Important premalignancies/malignancies associated in this condition include high-grade gliomas (III or IV), supratentorial PNETs, non-Hodgkin lymphoma, leukemias, and bowel adenomas.
    • Other non-neoplastic findings include corpus callosum agenesis, café-au-lait macules, hypopigmented patches, cavernomas of the brain, capillary hemangiomas of skin, and lupus erythromatosus.
  • Key Diagnostic Features:
    • Glioblastoma can have an acute presentation with headache, seizure, and loss of consciousness when associated with a large bleed.
    • Imaging features include an ill-defined expansile lesion with mass effect that appears hypodense on CT. Associated hyperdensity due to intralesional bleed can occur.
    • MRI shows an ill-defined, T2-hyperintense, T1-hypointense lesion with heterogeneous postcontrast enhancement. There is expansion of the affected areas with mass effect. Diffusion restriction can be seen in highly cellular areas. SWI may show macro- or microbleeds characteristic of glioblastoma. Perfusion imaging shows elevated rCBV as compared with normal adjacent white matter. MRS shows elevated choline with decreased NAA.
  • Differential Diagnoses:
    • Important differentials to be considered in this case include hemorrhagic diathesis leading to intracranial hemorrhage, leukemic deposits with hemorrhage, and hemorrhagic metastases from a second unknown primary. However, the ill-defined expansile lesion with heterogeneous enhancement and bleed should prompt the diagnosis of glioblastoma.
  • Treatment:
    • Surgery for complete resection or debulking with chemotherapy and radiotherapy
    • Immunotherapy with checkpoint inhibitors is being considered a promising approach.
May 12, 2022

A 4-year-old child born of second-degree consanguineous parentage presents to the emergency department in status epilepticus; history of T-cell acute lymphoblastic leukemia diagnosed 8 months back; father had colon cancer and paternal grandmother had cervical cancer; clinical examination shows multiple hyperpigmented macules on the trunk.

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