Background Diffuse midline glioma, H3K27‐altered, is defined by global loss of H3K27me3 resulting from disruption of the polycomb repressive complex 2 (PRC2). Although this epigenetic state is classically driven by H3K27M oncohistone mutations, a histone H3–mutant–negative subset with H3K27me3 loss has been recognized, mediated by alternative mechanisms such as EZHIP overexpression or receptor tyrosine kinase (RTK) activation. Case Presentation We report the case of a 13‐year‐old boy who presented with progressive brainstem‐related neurological symptoms. Neuroimaging revealed an infiltrative midline lesion involving the brainstem and cerebellum with obstructive hydrocephalus. Histopathological examination showed a diffusely infiltrating high‐grade glioma. Immunohistochemistry demonstrated retained ATRX expression, IDH1 wild‐type status, absence of H3K27M, and diffuse loss of H3K27me3 with preserved internal controls. Molecular analysis confirmed wild‐type H3F3A and HIST1H3 genes, identified a pathogenic TP53 frameshift mutation, and revealed high‐level amplification of the IGF1R locus. These findings supported a diagnosis of diffuse midline glioma, H3K27‐altered (histone H3–mutant–negative with global H3K27me3 loss), driven by an alternative mechanism of PRC2 inactivation. Conclusion This case expands the spectrum of diffuse midline gliomas with global H3K27me3 loss by implicating IGF1R amplification as a potential upstream driver of PRC2 dysfunction. Our findings support the concept that oncogenic RTK activation may converge on epigenetic deregulation in pediatric diffuse midline glioma and suggest that IGF1R amplification may represent a diagnostically and therapeutically relevant alteration within the H3K27‐altered glioma spectrum.
López et al. (Thu,) studied this question.