Abstract Brain tumors are the second most common malignancy in children, with high-grade gliomas (HGG) being the deadliest. Constitutional mismatch repair deficiency syndrome (CMMRD) is a rare cancer predisposition syndrome associated with increased risk of developing a variety of malignancies, including brain tumors. We report a case of a 9-year-old female with headaches, vomiting and photophobia. Imaging revealed a right temporoparietal tumor. Pathologic diagnosis of diffuse pediatric HGG, WHO grade 4 with NF1 somatic mutations and two pathologic variants in PMS2. The patient presented with a two-week history of intermittent headaches, emesis, photophobia, and auditory/visual hallucinations. Examination revealed café au lait macules and axillary freckling. Head CT showed a brain mass, and she was transferred to our institution where MRI brain confirmed a hemorrhagic lesion with surrounding vasogenic edema measuring 3.8 x 3.7 x 3.6 cm with cystic and solid components within the right temporoparietal lobe, with midline shift, and abnormal FLAIR in the left frontal region. Patient underwent a right temporoparietal craniotomy achieving a gross total resection. Pathology and methylation from the temporoparietal lesion was consistent with diffuse pediatric HGG, NOS, H3-wildtype, IDH-wildtype, WHO grade 4 and a left frontal biopsy was consistent with HGG. Genetic evaluation identified two pathogenic PMS2 variants and NF1 somatic mutations leading to CMMRD diagnosis. Patient completed radiotherapy and began Nivolumab, 3 mg/kg every 2 weeks and subsequently 6 mg/kg every 4 weeks. Upfront oral targeted therapy was started with trametinib due evidence of immune synergism in replication-repair-deficient HGG and NF1 mutations. The upfront combination of immunotherapy with targeted therapy to treat patients in this setting is a promising novel therapeutic intervention. Bringing trametinib upfront rather waiting for relapse/progression can truly be beneficial. This case highlights the importance of obtaining comprehensive tumor profiling to identify additional upfront therapeutic agents that improve patients’ overall survival.
Nieves et al. (Fri,) studied this question.