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  • Updated 03.31.2023
  • Released 10.24.2021
  • Expires For CME 03.31.2026

High-grade midline glioma with histone mutation



Diffuse midline gliomas harboring the H3 K27M mutation potentially comprise a variety of subtypes of gliomas. One important subset was previously classified as brainstem gliomas or diffuse intrinsic pontine gliomas. The proposed cell of origin is a neural precursor-like cell in the ventral pons expressing nestin and OLIG-2 (36). The most common locations are the brainstem, thalamus, and spinal cord (34).

In the 2007 World Health Organization classification of central nervous system tumors, diffuse intrinsic pontine glioma was not defined as a separate entity. It was classified and graded according to the definition criteria of supratentorial diffuse gliomas (35). The 2016 WHO classification of CNS tumors identified H3 K27M-mutant diffuse midline glioma as a unique entity with distinct clinical behavior and molecular features. It is a diffuse (infiltrating) glioma with predominantly astrocytic differentiation and a K27M mutation in either the H3F3A or HIST1H3B/C genes (36). The 2021 WHO classification of CNS tumors further modified the classification of gliomas (37). Adult and pediatric gliomas were separately categorized. Pediatric diffuse gliomas were separated into prognostically and biologically distinct groups (pediatric high- and low-grade glioma). High-grade pediatric gliomas were further classified into biologically distinct groups, largely based on alteration in the histone genes (Table 1). Both the adult and pediatric categories harbored glial tumors with H3K27 alterations as well as other histone alterations, such as the H3 G34R mutant.

Table 1. 2021 WHO Classification Of Pediatric Diffuse High-Grade Glioma And Key Diagnostic Genes, Molecules, Pathways, or Combinations

Pediatric-type diffuse high-grade gliomas

Genes/Molecular Profiles Characteristically Altered

Diffuse midline glioma, H3 K27 altered

H3 K27, TP53, ACVR1, PDGFRA, EGFR, EZHIP overexpression

Diffuse hemispheric glioma, H3 G34-mutant

H3 G34, TP53, ATRX

Diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype

IDH-wildtype, H3-wildtype, PDGFRA, MYCN, EGFR (methylome)*

Infant-type hemispheric glioma


Abbreviations: WHO, World Health Organization; IDH, isocitrate dehydrogenase; ATRX, alpha thalassemia or mental retardation syndrome X-linked; EGFR, epidermal growth factor receptor; PDGFRA, platelet-derived growth factor receptor alpha; TP53, tumor protein p53; ACVR1, activin a receptor type 1; EZHIP, EZH inhibitory protein; ALK, anaplastic lymphoma kinase.

* methylome testing offers particular diagnostic guidance

From: (37)

Key points

• Pediatric diffuse gliomas are separated into prognostically and biologically distinct groups.

• High-grade pediatric gliomas were further classified into biologically distinct groups, largely based on alteration in the histone genes.

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