NFS-01. A case of H3K27 Diffuse Midline Glioma in a patient with Fanconi Anemia

Background Fanconi Anemia (FA) is known to predispose pediatric patients to childhood cancers, commonly leukemias, and rarely CNS tumors. FA is caused by mutations of several genes. Biallelic PALB2 mutations have recently been associated with predisposition to pediatric cancers, alongside the more commonly known biallelic BRCA2 mutations. Brain tumors in pediatric patients with FA are typically medulloblastomas, very rarely pediatric high-grade glioma (pHGG), with none identified in prior literature having diffuse midline glioma (DMG) characteristic H3K27M mutation. DMG is difficult to treat with few options for therapy and poor prognosis. EGFR mutations in DMG are associated with a bithalamic location and resistance to Onc201 therapy, but may have response to EGFR-targeting agents. Objective We report a novel case of H3K27M DMG in a patient with FA. Results A three-year-old female was noted to have microcephaly, mixed hearing loss, short stature, and café-au-lait macules. Whole exome sequencing was significant for mutations in the PALB2/FANCN gene, a paternal pathogenic variant and a maternal variant of unknown significance. She developed symptoms of tremor and right leg weakness, and on brain MRI was found to have a large bithalamic mass. Sterotactic biopsy was consistent with DMG, including diffusely positive H3K27M mutant protein and loss of H3K27me3. Tumor had EGFR missense mutation (likely activating) at p.A289V to 59.2% VAF, with overexpression of the EGFR transcript. Chromosomal breakage testing was within normal limits. Treatment included localized hypofractionated photon radiation to 4005 cGy, followed by EGFR-targeted therapy with cetuximab. She had continued radiographic improvement on therapy, though ultimately discontinued due to side effects in the absence of known curative therapy. Conclusion Annual abdominal ultrasound and brain MRI are currently recommended for patients with biallelic BRCA2 mutations, however screening in patients with biallelic PALB2 mutations may be warranted. EGFR may be an effective target for EGFR mutant DMGs.