Molecular Tumor Board: H3K27M Diffuse Midline Glioma Diagnosed During Pregnancy by Cerebrospinal Fluid Next-Generation Sequencing

Abstract Background Diffuse midline glioma (DMG) with the H3K27M mutation is an aggressive WHO grade 4 central nervous system tumor characterized by diffuse infiltration of midline structures and a poor prognosis. Molecular characterization is essential for diagnosis and treatment planning; however, obtaining tissue can be infeasible, particularly in anatomically inaccessible locations or medically complex situations, like pregnancy. Patient Presentation A 34-year-old G2P1 woman at 19 weeks’ gestation presented with progressive right-sided numbness and weakness. Magnetic resonance imaging (MRI) demonstrated an infiltrative lesion in the left midbrain extending to the pons and thalamus with intralesional hemorrhage. Differential considerations included diffuse midline glioma and inflammatory demyelinating disease. Molecular Findings Because of the lesion location and concerns regarding stereotactic biopsy during pregnancy, cerebrospinal fluid (CSF) next-generation sequencing was pursued. CSF profiling identified an H3K27M mutation, establishing the diagnosis of DMG. Management and Outcome Following multidisciplinary discussion involving neuro-oncology, neurology, neurosurgery, radiation oncology, and maternal-fetal medicine, the patient underwent fractionated radiotherapy beginning at 22 weeks’ gestation using pregnancy-shielding techniques. Postpartum dordaviprone (ONC201) therapy was initiated and well tolerated. Follow-up imaging demonstrated radiographic improvement and neurological stabilization, with ongoing response at 12 months post diagnosis. Conclusions The case highlights the utility of CSF liquid biopsy in establishing a molecular diagnosis of diffuse midline glioma when tissue biopsy is contraindicated or deferred. The case also demonstrates how molecular profiling can guide precision oncology in medically complex situations like pregnancy.