Adult Thalamic Diffuse Midline Glioma, H3 K27-Altered, With KRAS Comutation and Potential Early Subependymal Dissemination

Diffuse midline glioma (DMG) is a highly aggressive central nervous system neoplasm that predominantly affects pediatric populations and is associated with a dismal prognosis. Adult DMGs remain relatively uncommon and continue to pose significant diagnostic and therapeutic challenges. We present the case of a 54-year-old adult patient with a left thalamic DMG, H3 K27-altered, World Health Organization (WHO) grade 4, harboring pathogenic H3F3A K27M, KRAS G12V, and PHF6 mutations. The patient presented with headaches, fatigue, imbalance, dizziness, and slowed dexterity. Imaging demonstrated a heterogeneously enhancing left thalamic lesion extending into the midbrain, with associated edema and third-ventricular compression. Stereotactic biopsy confirmed a DMG, H3 K27-altered. Given the surgically inaccessible location and the high risk of neurologic morbidity, the patient underwent definitive radiotherapy without concurrent temozolomide. Follow-up imaging showed an interval reduction in tumor size, consistent with treatment response; however, a new subependymal ventricular nodule raised concern for possible early dissemination. This case highlights the importance of molecular characterization in adult DMG and discusses the potential biological implications of a KRAS comutation in this rare entity. We also review the evolving literature on adult thalamic DMG, molecular alterations, therapeutic considerations, and emerging targeted therapies, including dordaviprone (ONC201).