Diffuse midline glioma, H3 K27-altered, is a highly aggressive CNS tumor predominantly affecting children and young adults, arising in midline structures including the pons (diffuse intrinsic pontine glioma/DIPG), thalamus, and spinal cord. WHO 2021 classification defines this entity by the presence of H3 K27M mutation (in H3F3A or HIST1H3B/C) or H3 K27 trimethylation loss through other mechanisms (e.g., EZHIP overexpression). The H3 K27M mutation acts as a dominant negative, inhibiting PRC2-mediated H3K27 trimethylation and causing global epigenetic dysregulation. The tumor is universally WHO grade 4, and the infiltrative location typically precludes surgical resection. Prognosis is extremely poor with median survival of 9-11 months for DIPG.
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name: Diffuse Midline Glioma, H3 K27-Altered
creation_date: '2026-01-26T02:55:13Z'
updated_date: '2026-04-11T21:17:25Z'
description: >-
Diffuse midline glioma, H3 K27-altered, is a highly aggressive CNS tumor
predominantly affecting children and young adults, arising in midline structures
including the pons (diffuse intrinsic pontine glioma/DIPG), thalamus, and spinal
cord. WHO 2021 classification defines this entity by the presence of H3 K27M
mutation (in H3F3A or HIST1H3B/C) or H3 K27 trimethylation loss through other
mechanisms (e.g., EZHIP overexpression). The H3 K27M mutation acts as a dominant
negative, inhibiting PRC2-mediated H3K27 trimethylation and causing global
epigenetic dysregulation. The tumor is universally WHO grade 4, and the infiltrative
location typically precludes surgical resection. Prognosis is extremely poor with
median survival of 9-11 months for DIPG.
categories:
- Central Nervous System Neoplasm
- Pediatric Brain Tumor
- Molecularly Defined Tumor
- High-Grade Glioma
parents:
- diffuse glioma
has_subtypes:
- name: Diffuse Intrinsic Pontine Glioma (DIPG)
description: >-
The most common form, arising in the pons with characteristic diffuse
infiltration of pontine structures. Presents with classic triad of cranial
nerve deficits, ataxia, and long tract signs. Diagnosis often made on imaging
without biopsy. Median survival is less than 12 months.
evidence:
- reference: PMID:19338403
reference_title: "Treatment of diffuse intrinsic brainstem gliomas: failed approaches and future strategies."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Diffuse intrinsic pontine gliomas constitute ~ 60-75% of tumors found within the pediatric brainstem. These malignant lesions present with rapidly progressive symptoms such as cranial nerve, long tract, or cerebellar dysfunctions."
explanation: This review identifies DIPG as the dominant pediatric brainstem glioma subtype and describes the rapidly progressive cranial nerve, long tract, and cerebellar presentation summarized in this subtype.
- name: Thalamic H3 K27M-Mutant Glioma
description: >-
H3 K27-altered glioma arising in the thalamus, often in children,
adolescents, and younger adults. May present with hemiparesis,
hydrocephalus, or cognitive changes. Bilateral thalamic involvement can
occur.
evidence:
- reference: PMID:24285547
reference_title: "H3F3A K27M mutations in thalamic gliomas from young adult patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We found that high-grade thalamic gliomas from young adults, like those from children and adolescents, frequently had H3F3A K27M."
explanation: This thalamic glioma cohort directly establishes H3 K27M-altered thalamic tumors as a recognized midline subgroup enriched in younger patients.
- name: Spinal Cord H3 K27M-Mutant Glioma
description: >-
H3 K27-altered glioma arising in the spinal cord. Presents with progressive
sensory or motor deficits from intramedullary cord involvement. This subtype
is rare and clinically aggressive.
evidence:
- reference: PMID:35079510
reference_title: "Spinal Cord Diffuse Midline Glioma, H3K27M- mutant Effectively Treated with Bevacizumab: A Report of Two Cases."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Spinal cord DMG, H3K27M-mutant is relatively rare, with poor prognosis, and there are no effective treatment protocols."
explanation: This case report identifies spinal cord H3 K27M-mutant diffuse midline glioma as a rare aggressive spinal subtype.
pathophysiology:
- name: H3 K27M Oncohistone Mutation
description: >-
Lysine-to-methionine substitution at position 27 of histone H3 (K27M) occurs
in H3F3A (encoding H3.3) or HIST1H3B/HIST1H3C (encoding H3.1). Despite being
present in only 5-15% of total H3 molecules, the mutant histone acts as a
dominant negative, sequestering and inhibiting the PRC2 complex.
evidence:
- reference: PMID:41528563
reference_title: "Early distant progression in adult Histone-3 K27-altered diffuse midline gliomas."
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: H3 K27-altered diffuse midline glioma (DMG) is a molecularly defined, highly aggressive tumor entity since the 2016 revision of the World Health Organization (WHO) classification of tumors of the central nervous system (CNS).
explanation: This abstract defines H3 K27-altered DMG as a molecularly defined aggressive entity, supporting the disease context for this mutation-driven tumor.
cell_types:
- preferred_term: astrocyte
term:
id: CL:0000127
label: astrocyte
molecular_functions:
- preferred_term: histone H3K27 methyltransferase activity
modifier: DECREASED
term:
id: GO:0046976
label: histone H3K27 methyltransferase activity
locations:
- preferred_term: pons
term:
id: UBERON:0000988
label: pons
- preferred_term: dorsal plus ventral thalamus
term:
id: UBERON:0001897
label: dorsal plus ventral thalamus
- preferred_term: spinal cord
term:
id: UBERON:0002240
label: spinal cord
downstream:
- target: PRC2 Complex Inhibition and H3K27me3 Loss
description: Mutant H3 K27M sequesters EZH2/PRC2 complex
- name: PRC2 Complex Inhibition and H3K27me3 Loss
description: >-
The H3 K27M mutant histone binds to and inhibits EZH2, the catalytic subunit
of PRC2, which normally trimethylates H3K27. This results in global loss of
H3K27me3, a repressive epigenetic mark, leading to aberrant gene activation
and loss of cell identity.
biological_processes:
- preferred_term: negative regulation of gene expression, epigenetic
modifier: DECREASED
term:
id: GO:0045814
label: negative regulation of gene expression, epigenetic
downstream:
- target: Epigenetic Derepression and Aberrant Gene Activation
description: Loss of H3K27me3 derepresses developmental and oncogenic genes
- name: Epigenetic Derepression and Aberrant Gene Activation
description: >-
Global loss of H3K27me3 causes derepression of genes normally silenced during
development, including proliferative and stemness genes. Paradoxically, some
loci show retained or increased H3K27me3, suggesting complex redistribution
rather than simple loss.
biological_processes:
- preferred_term: gene expression
modifier: INCREASED
term:
id: GO:0010467
label: gene expression
- preferred_term: cell population proliferation
modifier: INCREASED
term:
id: GO:0008283
label: cell population proliferation
downstream:
- target: Loss of Glial Differentiation
description: Epigenetic changes block normal differentiation programs
- name: Loss of Glial Differentiation
description: >-
Epigenetic dysregulation prevents normal glial differentiation, maintaining
cells in a proliferative, undifferentiated state. This contributes to the
aggressive behavior and treatment resistance of these tumors.
cell_types:
- preferred_term: astrocyte
term:
id: CL:0000127
label: astrocyte
biological_processes:
- preferred_term: glial cell differentiation
modifier: DECREASED
term:
id: GO:0010001
label: glial cell differentiation
histopathology:
- name: Infiltrative Midline Glioma
finding_term:
preferred_term: Diffuse Midline Glioma, H3 K27-Altered
term:
id: NCIT:C185368
label: Diffuse Midline Glioma, H3 K27-Altered
frequency: VERY_FREQUENT
description: Diffuse midline glioma, H3 K27M-mutant is an infiltrative midline glioma.
evidence:
- reference: PMID:35169084
reference_title: "[Diffuse midline glioma]."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Diffuse midline glioma(DMG), H3 K27M-mutant is an infiltrative midline"
explanation: Abstract describes H3 K27M-mutant diffuse midline glioma as infiltrative and midline.
phenotypes:
- category: Neurological
name: Cranial Nerve Palsy
frequency: VERY_FREQUENT
description: >-
Cranial nerve deficits are common in DIPG, particularly affecting CN VI
(lateral gaze palsy) and CN VII (facial weakness). Part of the classic DIPG
triad.
phenotype_term:
preferred_term: Cranial nerve paralysis
term:
id: HP:0006824
label: Cranial nerve paralysis
evidence:
- reference: PMID:19338403
reference_title: "Treatment of diffuse intrinsic brainstem gliomas: failed approaches and future strategies."
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: "These malignant lesions present with rapidly progressive symptoms such as cranial nerve, long tract, or cerebellar dysfunctions."
explanation: This review lists cranial nerve dysfunction among hallmark rapidly progressive DIPG symptoms, supporting cranial nerve palsy as a common neurological manifestation.
- category: Neurological
name: Ataxia
frequency: VERY_FREQUENT
description: >-
Cerebellar ataxia from involvement of cerebellar pathways traversing the
pons. Part of the classic DIPG triad.
phenotype_term:
preferred_term: Ataxia
term:
id: HP:0001251
label: Ataxia
evidence:
- reference: PMID:19338403
reference_title: "Treatment of diffuse intrinsic brainstem gliomas: failed approaches and future strategies."
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: "These malignant lesions present with rapidly progressive symptoms such as cranial nerve, long tract, or cerebellar dysfunctions."
explanation: Cerebellar dysfunction is a core presentation of DIPG and commonly manifests clinically as ataxia, supporting this phenotype.
- category: Neurological
name: Long Tract Signs
frequency: VERY_FREQUENT
description: >-
Pyramidal signs including spasticity, hyperreflexia, and weakness from
corticospinal tract involvement. Part of the classic DIPG triad.
phenotype_term:
preferred_term: Hemiparesis
term:
id: HP:0001269
label: Hemiparesis
evidence:
- reference: PMID:19338403
reference_title: "Treatment of diffuse intrinsic brainstem gliomas: failed approaches and future strategies."
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: "These malignant lesions present with rapidly progressive symptoms such as cranial nerve, long tract, or cerebellar dysfunctions."
explanation: This review identifies long tract dysfunction as a hallmark of DIPG presentation; in this entry it is represented by pyramidal weakness and hemiparesis.
- category: Neurological
name: Headache
frequency: FREQUENT
description: >-
Headache from increased intracranial pressure or direct tumor effects.
May be accompanied by vomiting.
phenotype_term:
preferred_term: Headache
term:
id: HP:0002315
label: Headache
- category: Neurological
name: Diplopia
frequency: FREQUENT
description: >-
Double vision from cranial nerve involvement, particularly CN VI causing
lateral rectus weakness and inability to abduct the eye.
phenotype_term:
preferred_term: Diplopia
term:
id: HP:0000651
label: Diplopia
genetic:
- name: H3F3A
association: Somatic Mutation (K27M)
notes: >-
H3F3A encodes the replication-independent histone variant H3.3. K27M mutation
is most common in DIPG (approximately 80%) and thalamic tumors. H3.3 K27M
is associated with slightly older age at diagnosis (median 6-7 years).
- name: HIST1H3B/HIST1H3C
association: Somatic Mutation (K27M)
notes: >-
HIST1H3B and HIST1H3C encode replication-dependent histone H3.1 variants.
H3.1 K27M mutations occur in approximately 15% of DIPG, associated with
younger age, ACVR1 mutations, and slightly better prognosis.
- name: ACVR1
association: Somatic Mutation
notes: >-
ACVR1 (activin A receptor type I, also known as ALK2) mutations occur in
approximately 20-30% of DIPG, almost exclusively co-occurring with H3.1 K27M.
These activating mutations drive BMP signaling and are also found in
fibrodysplasia ossificans progressiva.
- name: TP53
association: Somatic Mutation
notes: >-
TP53 mutations occur in approximately 40-50% of DIPG, often co-occurring
with H3.3 K27M. Associated with worse prognosis.
- name: PPM1D
association: Somatic Mutation
evidence:
- reference: PMID:35105861
reference_title: "PPM1D mutations are oncogenic drivers of de novo diffuse midline glioma formation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "truncating mutations in PPM1D that increase the stability of its phosphatase are clonal driver events in 11% of Diffuse Midline Gliomas (DMGs) and are enriched in primary pontine tumors."
explanation: Human whole-genome analysis identifies truncating PPM1D mutations as recurrent clonal driver events in diffuse midline glioma, particularly pontine tumors.
notes: >-
PPM1D (protein phosphatase Mg2+/Mn2+ dependent 1D) truncating mutations occur
in approximately 10-15% of DIPG, functionally similar to TP53 loss.
- name: PDGFRA
association: Amplification/Mutation
evidence:
- reference: PMID:23970477
reference_title: "Novel oncogenic PDGFRA mutations in pediatric high-grade gliomas."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Genome-wide analyses of copy number imbalances previously showed that platelet-derived growth factor receptor α (PDGFRA) is the most frequent target of focal amplification in pediatric HGGs, including DIPGs."
explanation: This pediatric high-grade glioma study identifies PDGFRA as the most frequent focal amplification target in pediatric high-grade gliomas, including DIPG.
- reference: PMID:23970477
reference_title: "Novel oncogenic PDGFRA mutations in pediatric high-grade gliomas."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Somatic-activating mutations were identified in 14.4% (13 of 90) of nonbrainstem pediatric HGGs and 4.7% (2 of 43) of DIPGs, including missense mutations and in-frame deletions and insertions not previously described."
explanation: The same cohort study also documents activating PDGFRA mutations in DIPG, supporting the mutation component of this genetic association.
notes: >-
PDGFRA amplification or activating mutations occur in approximately 30% of
DIPG. Drives proliferation through RTK signaling.
- name: EZHIP
association: Overexpression
evidence:
- reference: PMID:36882456
reference_title: "Histone H3-wild type diffuse midline gliomas with H3K27me3 loss are a distinct entity with exclusive EGFR or ACVR1 mutation and differential methylation of homeobox genes."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We show that these tumours have recurrent and mutually exclusive mutations in either ACVR1 or EGFR and are characterised by high expression of EZHIP associated to its promoter hypomethylation."
explanation: This molecular profiling study shows that H3-wild-type H3K27me3-loss diffuse midline gliomas are marked by EZHIP overexpression, supporting EZHIP-driven H3 K27-altered disease in the absence of canonical H3 K27M mutations.
notes: >-
EZHIP (EZH inhibitory protein) overexpression can cause H3K27me3 loss in the
absence of H3 K27M mutation. Defines a subset of H3 K27-altered tumors that
lack histone mutations but have similar epigenetic phenotype.
treatments:
- name: Radiation Therapy
description: >-
Focal radiation therapy (54-59.4 Gy) is the only treatment with established
benefit, providing transient neurological improvement and progression-free
survival benefit without improving overall survival.
treatment_term:
preferred_term: radiation therapy
term:
id: MAXO:0000014
label: radiation therapy
evidence:
- reference: PMID:19338403
reference_title: "Treatment of diffuse intrinsic brainstem gliomas: failed approaches and future strategies."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Standard therapy involves radiotherapy, which produces transient neurological improvement with a progression-free survival benefit, but provides no improvement in overall survival."
explanation: This treatment review identifies radiotherapy as the standard modality for DIPG, providing temporary neurologic improvement and delaying progression without curing the disease.
- name: Corticosteroids
description: >-
Dexamethasone reduces peritumoral edema and provides symptomatic relief.
Standard supportive measure during radiation and at progression.
treatment_term:
preferred_term: systemic corticosteroid therapy
term:
id: NCIT:C122080
label: Systemic Corticosteroid Therapy
- name: ONC201 (DRD2 Antagonist)
description: >-
Small molecule DRD2 antagonist and ClpP agonist showing promising activity
in H3 K27M-mutant gliomas. Crosses blood-brain barrier. Currently in clinical
trials and received FDA Breakthrough Therapy designation.
treatment_term:
preferred_term: pharmacotherapy
term:
id: MAXO:0000058
label: pharmacotherapy
evidence:
- reference: PMID:36382108
reference_title: "Phase I dose escalation and expansion trial of single agent ONC201 in pediatric diffuse midline gliomas following radiotherapy."
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: "Five (22.7%) patients, all of whom initiated ONC201 following radiation and prior to recurrence, were alive at 2 years from diagnosis."
explanation: This phase I pediatric trial showed an encouraging early survival signal after ONC201 initiation following radiation, supporting it as a promising but still investigational treatment.
notes: >-
The WHO 2021 classification expanded this entity from H3 K27M-mutant to H3 K27-altered
to include tumors with H3K27me3 loss through other mechanisms (e.g., EZHIP
overexpression) that share similar biology and prognosis. Diagnosis requires
demonstration of H3 K27M mutation by immunohistochemistry or sequencing, or
loss of H3K27me3 with EZHIP overexpression.
disease_term:
preferred_term: diffuse midline glioma, H3 K27-altered
term:
id: MONDO:1060171
label: diffuse midline glioma, H3 K27-altered
classifications:
icdo_morphology:
classification_value: Glioma
harrisons_chapter:
- classification_value: cancer
- classification_value: solid tumor
references:
- reference: DOI:10.1002/jmri.28740
title: 'The 2021 <scp>WHO</scp> Classification for Gliomas and Implications on Imaging Diagnosis: Part 2—Summary of Imaging Findings on Pediatric‐Type Diffuse High‐Grade Gliomas, Pediatric‐Type Diffuse Low‐Grade Gliomas, and Circumscribed Astrocytic Gliomas'
found_in:
- H3_K27_Altered_Diffuse_Midline_Glioma-deep-research-falcon.md
findings:
- statement: 'The 2021 <scp>WHO</scp> Classification for Gliomas and Implications on Imaging Diagnosis: Part 2—Summary of Imaging Findings on Pediatric‐Type Diffuse High‐Grade Gliomas, Pediatric‐Type Diffuse Low‐Grade Gliomas, and Circumscribed Astrocytic Gliomas'
supporting_text: The fifth edition of the World Health Organization (WHO) classification of central nervous system tumors published in 2021 advances the role of molecular diagnostics in the classification of gliomas by emphasizing integrated diagnoses based on histopathology and molecular information and grouping tumors based on genetic alterations.
evidence:
- reference: DOI:10.1002/jmri.28740
reference_title: 'The 2021 <scp>WHO</scp> Classification for Gliomas and Implications on Imaging Diagnosis: Part 2—Summary of Imaging Findings on Pediatric‐Type Diffuse High‐Grade Gliomas, Pediatric‐Type Diffuse Low‐Grade Gliomas, and Circumscribed Astrocytic Gliomas'
supports: SUPPORT
evidence_source: OTHER
snippet: The fifth edition of the World Health Organization (WHO) classification of central nervous system tumors published in 2021 advances the role of molecular diagnostics in the classification of gliomas by emphasizing integrated diagnoses based on histopathology and molecular information and grouping tumors based on genetic alterations.
explanation: Deep research cited this publication as relevant literature for H3 K27 Altered Diffuse Midline Glioma.
- reference: DOI:10.1016/j.heliyon.2024.e24877
title: New progress in the treatment of diffuse midline glioma with H3K27M alteration
found_in:
- H3_K27_Altered_Diffuse_Midline_Glioma-deep-research-falcon.md
findings:
- statement: New progress in the treatment of diffuse midline glioma with H3K27M alteration
supporting_text: New progress in the treatment of diffuse midline glioma with H3K27M alteration
- reference: DOI:10.1055/s-0043-1771192
title: 'H3 K27M-Altered Diffuse Midline Gliomas: A Review'
found_in:
- H3_K27_Altered_Diffuse_Midline_Glioma-deep-research-falcon.md
findings:
- statement: 'H3 K27M-Altered Diffuse Midline Gliomas: A Review'
supporting_text: Diffuse midline glioma H3 K27M-altered is a recently renamed high-grade glioma in the 2021 World Health Organization (WHO) Classification of Central Nervous System Tumors, previously being labelled diffuse midline glioma H3 K27M-mutant in the 2016 update and diffuse intrinsic pontine glioma prior to 2016.
evidence:
- reference: DOI:10.1055/s-0043-1771192
reference_title: 'H3 K27M-Altered Diffuse Midline Gliomas: A Review'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Diffuse midline glioma H3 K27M-altered is a recently renamed high-grade glioma in the 2021 World Health Organization (WHO) Classification of Central Nervous System Tumors, previously being labelled diffuse midline glioma H3 K27M-mutant in the 2016 update and diffuse intrinsic pontine glioma prior to 2016.
explanation: Deep research cited this publication as relevant literature for H3 K27 Altered Diffuse Midline Glioma.
- reference: DOI:10.1080/14728222.2023.2277232
title: 'Bench-to-bedside investigations of H3 K27-altered diffuse midline glioma: drug targets and potential pharmacotherapies'
found_in:
- H3_K27_Altered_Diffuse_Midline_Glioma-deep-research-falcon.md
findings:
- statement: 'Bench-to-bedside investigations of H3 K27-altered diffuse midline glioma: drug targets and potential pharmacotherapies'
supporting_text: 'Bench-to-bedside investigations of H3 K27-altered diffuse midline glioma: drug targets and potential pharmacotherapies'
- reference: DOI:10.1093/noajnl/vdaa142
title: Clinical, radiologic, and genetic characteristics of histone H3 K27M-mutant diffuse midline gliomas in adults
found_in:
- H3_K27_Altered_Diffuse_Midline_Glioma-deep-research-falcon.md
findings:
- statement: Clinical, radiologic, and genetic characteristics of histone H3 K27M-mutant diffuse midline gliomas in adults
supporting_text: “Diffuse midline glioma (DMG), H3 K27M-mutant” is a new tumor entity established in the 2016 WHO classification of Tumors of the Central Nervous System that comprises a set of diffuse gliomas arising in midline structures and is molecularly defined by a K27M mutation in genes encoding the histone 3 variants H3.3 or H3.1.
evidence:
- reference: DOI:10.1093/noajnl/vdaa142
reference_title: Clinical, radiologic, and genetic characteristics of histone H3 K27M-mutant diffuse midline gliomas in adults
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: “Diffuse midline glioma (DMG), H3 K27M-mutant” is a new tumor entity established in the 2016 WHO classification of Tumors of the Central Nervous System that comprises a set of diffuse gliomas arising in midline structures and is molecularly defined by a K27M mutation in genes encoding the histone 3 variants H3.3 or H3.1.
explanation: Deep research cited this publication as relevant literature for H3 K27 Altered Diffuse Midline Glioma.
- reference: DOI:10.1111/bpa.12768
title: Identification of prognostic markers in diffuse midline gliomas H3K27M‐mutant
found_in:
- H3_K27_Altered_Diffuse_Midline_Glioma-deep-research-falcon.md
findings:
- statement: Pediatric diffuse midline gliomas are devastating diseases.
supporting_text: Pediatric diffuse midline gliomas are devastating diseases.
evidence:
- reference: DOI:10.1111/bpa.12768
reference_title: Identification of prognostic markers in diffuse midline gliomas H3K27M‐mutant
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Pediatric diffuse midline gliomas are devastating diseases.
explanation: Deep research cited this publication as relevant literature for H3 K27 Altered Diffuse Midline Glioma.
- reference: DOI:10.1111/cns.14307
title: Differences in survival prognosticators between children and adults with <scp>H3K27M</scp>‐mutant diffuse midline glioma
found_in:
- H3_K27_Altered_Diffuse_Midline_Glioma-deep-research-falcon.md
findings:
- statement: H3K27M‐mutant diffuse midline glioma (DMG) is a rare and aggressive central nervous system tumor.
supporting_text: H3K27M‐mutant diffuse midline glioma (DMG) is a rare and aggressive central nervous system tumor.
evidence:
- reference: DOI:10.1111/cns.14307
reference_title: Differences in survival prognosticators between children and adults with <scp>H3K27M</scp>‐mutant diffuse midline glioma
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: H3K27M‐mutant diffuse midline glioma (DMG) is a rare and aggressive central nervous system tumor.
explanation: Deep research cited this publication as relevant literature for H3 K27 Altered Diffuse Midline Glioma.
- reference: DOI:10.1186/s40478-024-01808-w
title: 'Neuroradiological, genetic and clinical characteristics of histone H3 K27-mutant diffuse midline gliomas in the Kansai Molecular Diagnosis Network for CNS Tumors (Kansai Network): multicenter retrospective cohort'
found_in:
- H3_K27_Altered_Diffuse_Midline_Glioma-deep-research-falcon.md
findings:
- statement: This study aims to elucidate the clinical and molecular characteristics, treatment outcomes and prognostic factors of patients with histone H3 K27-mutant diffuse midline glioma.
supporting_text: This study aims to elucidate the clinical and molecular characteristics, treatment outcomes and prognostic factors of patients with histone H3 K27-mutant diffuse midline glioma.
evidence:
- reference: DOI:10.1186/s40478-024-01808-w
reference_title: 'Neuroradiological, genetic and clinical characteristics of histone H3 K27-mutant diffuse midline gliomas in the Kansai Molecular Diagnosis Network for CNS Tumors (Kansai Network): multicenter retrospective cohort'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: This study aims to elucidate the clinical and molecular characteristics, treatment outcomes and prognostic factors of patients with histone H3 K27-mutant diffuse midline glioma.
explanation: Deep research cited this publication as relevant literature for H3 K27 Altered Diffuse Midline Glioma.
- reference: DOI:10.32074/1591-951x-830
title: Paediatric-type diffuse high-grade gliomas in the 5th CNS WHO Classification
found_in:
- H3_K27_Altered_Diffuse_Midline_Glioma-deep-research-falcon.md
findings:
- statement: Paediatric-type diffuse high-grade gliomas in the 5th CNS WHO Classification
supporting_text: Paediatric-type diffuse high-grade gliomas in the 5th CNS WHO Classification
- reference: DOI:10.3389/fonc.2020.602553
title: 'Clinical Features and Molecular Markers on Diffuse Midline Gliomas With H3K27M Mutations: A 43 Cases Retrospective Cohort Study'
found_in:
- H3_K27_Altered_Diffuse_Midline_Glioma-deep-research-falcon.md
findings:
- statement: Diffuse midline gliomas (DMG) with H3K27M mutations have been identified as a rare distinctive entity with unique genetic features, varied molecular alterations, and poor prognosis.
supporting_text: Diffuse midline gliomas (DMG) with H3K27M mutations have been identified as a rare distinctive entity with unique genetic features, varied molecular alterations, and poor prognosis.
evidence:
- reference: DOI:10.3389/fonc.2020.602553
reference_title: 'Clinical Features and Molecular Markers on Diffuse Midline Gliomas With H3K27M Mutations: A 43 Cases Retrospective Cohort Study'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Diffuse midline gliomas (DMG) with H3K27M mutations have been identified as a rare distinctive entity with unique genetic features, varied molecular alterations, and poor prognosis.
explanation: Deep research cited this publication as relevant literature for H3 K27 Altered Diffuse Midline Glioma.
- reference: DOI:10.3389/fonc.2022.1082062
title: 'Pediatric diffuse midline glioma H3K27- altered: A complex clinical and biological landscape behind a neatly defined tumor type'
found_in:
- H3_K27_Altered_Diffuse_Midline_Glioma-deep-research-falcon.md
findings:
- statement: The 2021 World Health Organization Classification of Tumors of the Central Nervous System, Fifth Edition (WHO-CNS5), has strengthened the concept of tumor grade as a combination of histologic features and molecular alterations.
supporting_text: The 2021 World Health Organization Classification of Tumors of the Central Nervous System, Fifth Edition (WHO-CNS5), has strengthened the concept of tumor grade as a combination of histologic features and molecular alterations.
evidence:
- reference: DOI:10.3389/fonc.2022.1082062
reference_title: 'Pediatric diffuse midline glioma H3K27- altered: A complex clinical and biological landscape behind a neatly defined tumor type'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The 2021 World Health Organization Classification of Tumors of the Central Nervous System, Fifth Edition (WHO-CNS5), has strengthened the concept of tumor grade as a combination of histologic features and molecular alterations.
explanation: Deep research cited this publication as relevant literature for H3 K27 Altered Diffuse Midline Glioma.
- reference: DOI:10.3390/biomedicines12061349
title: 'The 2021 World Health Organization Central Nervous System Tumor Classification: The Spectrum of Diffuse Gliomas'
found_in:
- H3_K27_Altered_Diffuse_Midline_Glioma-deep-research-falcon.md
findings:
- statement: The 2021 edition of the World Health Organization (WHO) classification of central nervous system tumors introduces significant revisions across various tumor types.
supporting_text: The 2021 edition of the World Health Organization (WHO) classification of central nervous system tumors introduces significant revisions across various tumor types.
evidence:
- reference: DOI:10.3390/biomedicines12061349
reference_title: 'The 2021 World Health Organization Central Nervous System Tumor Classification: The Spectrum of Diffuse Gliomas'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The 2021 edition of the World Health Organization (WHO) classification of central nervous system tumors introduces significant revisions across various tumor types.
explanation: Deep research cited this publication as relevant literature for H3 K27 Altered Diffuse Midline Glioma.
- reference: DOI:10.3390/cancers15133478
title: 'Molecular Characterization and Treatment Approaches for Pediatric H3 K27-Altered Diffuse Midline Glioma: Integrated Systematic Review of Individual Clinical Trial Participant Data'
found_in:
- H3_K27_Altered_Diffuse_Midline_Glioma-deep-research-falcon.md
findings:
- statement: Diffuse midline glioma (DMG), H3 K27-altered are highly aggressive, incurable central nervous system (CNS) tumors.
supporting_text: Diffuse midline glioma (DMG), H3 K27-altered are highly aggressive, incurable central nervous system (CNS) tumors.
evidence:
- reference: DOI:10.3390/cancers15133478
reference_title: 'Molecular Characterization and Treatment Approaches for Pediatric H3 K27-Altered Diffuse Midline Glioma: Integrated Systematic Review of Individual Clinical Trial Participant Data'
supports: SUPPORT
evidence_source: OTHER
snippet: Diffuse midline glioma (DMG), H3 K27-altered are highly aggressive, incurable central nervous system (CNS) tumors.
explanation: Deep research cited this publication as relevant literature for H3 K27 Altered Diffuse Midline Glioma.
- reference: DOI:10.3390/cancers16101814
title: 'Pediatric Diffuse Midline Glioma H3K27-Altered: From Developmental Origins to Therapeutic Challenges'
found_in:
- H3_K27_Altered_Diffuse_Midline_Glioma-deep-research-falcon.md
findings:
- statement: Diffuse intrinsic pontine glioma (DIPG), now referred to as diffuse midline glioma (DMG), is a highly aggressive pediatric cancer primarily affecting children aged 4 to 9 years old.
supporting_text: Diffuse intrinsic pontine glioma (DIPG), now referred to as diffuse midline glioma (DMG), is a highly aggressive pediatric cancer primarily affecting children aged 4 to 9 years old.
evidence:
- reference: DOI:10.3390/cancers16101814
reference_title: 'Pediatric Diffuse Midline Glioma H3K27-Altered: From Developmental Origins to Therapeutic Challenges'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Diffuse intrinsic pontine glioma (DIPG), now referred to as diffuse midline glioma (DMG), is a highly aggressive pediatric cancer primarily affecting children aged 4 to 9 years old.
explanation: Deep research cited this publication as relevant literature for H3 K27 Altered Diffuse Midline Glioma.
- reference: DOI:10.3390/cells13131122
title: 'H3K27-Altered Diffuse Midline Glioma of the Brainstem: From Molecular Mechanisms to Targeted Interventions'
found_in:
- H3_K27_Altered_Diffuse_Midline_Glioma-deep-research-falcon.md
findings:
- statement: Pediatric high-grade gliomas are a devastating subset of brain tumors, characterized by their aggressive pathophysiology and limited treatment options.
supporting_text: Pediatric high-grade gliomas are a devastating subset of brain tumors, characterized by their aggressive pathophysiology and limited treatment options.
evidence:
- reference: DOI:10.3390/cells13131122
reference_title: 'H3K27-Altered Diffuse Midline Glioma of the Brainstem: From Molecular Mechanisms to Targeted Interventions'
supports: SUPPORT
evidence_source: OTHER
snippet: Pediatric high-grade gliomas are a devastating subset of brain tumors, characterized by their aggressive pathophysiology and limited treatment options.
explanation: Deep research cited this publication as relevant literature for H3 K27 Altered Diffuse Midline Glioma.
- reference: DOI:10.3390/diagnostics14232617
title: 'Clinico–Pathological Features of Diffuse Midline Glioma, H3 K27-Altered in Adults: A Comprehensive Review of the Literature with an Additional Single-Institution Case Series'
found_in:
- H3_K27_Altered_Diffuse_Midline_Glioma-deep-research-falcon.md
findings:
- statement: Diffuse midline glioma (DMG), H3 K27-altered, is a WHO grade 4 malignant glioma located at midline structures, including the thalamus, brainstem and spinal cord.
supporting_text: Diffuse midline glioma (DMG), H3 K27-altered, is a WHO grade 4 malignant glioma located at midline structures, including the thalamus, brainstem and spinal cord.
evidence:
- reference: DOI:10.3390/diagnostics14232617
reference_title: 'Clinico–Pathological Features of Diffuse Midline Glioma, H3 K27-Altered in Adults: A Comprehensive Review of the Literature with an Additional Single-Institution Case Series'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Diffuse midline glioma (DMG), H3 K27-altered, is a WHO grade 4 malignant glioma located at midline structures, including the thalamus, brainstem and spinal cord.
explanation: Deep research cited this publication as relevant literature for H3 K27 Altered Diffuse Midline Glioma.
Diffuse midline glioma, H3 K27-altered is an infiltrative midline glioma defined by H3K27-pathway disruption (loss of H3K27 trimethylation) and is assigned CNS WHO grade 4 regardless of histologic features. It most commonly arises in midline CNS structures such as the pons/brainstem (historically “DIPG”), thalamus, and spinal cord and carries a poor prognosis, especially in children. (park2023the2021who pages 2-2, park2023the2021who pages 6-7, vallero2023pediatricdiffusemidline pages 2-3)
Not retrieved in this tool session: ICD-10/ICD-11 codes, MeSH IDs, Orphanet IDs, OMIM disease entry IDs. These may exist but were not present in the provided full-text evidence chunks.
The synthesis below is derived from aggregated resources: multicenter and single-center retrospective cohorts, systematic reviews, and contemporary narrative reviews, plus trial registry entries (ClinicalTrials.gov). (hayashi2024neuroradiologicalgeneticand pages 1-2, damodharan2023molecularcharacterizationand pages 1-2, NCT04808245 chunk 1, NCT04196413 chunk 2)
| Preferred name | MONDO ID | WHO CNS grade / WHO 2021 (CNS5) definition criteria | Major synonyms / alternative names | Typical midline anatomical sites | Key references (year; DOI URL; PMID if available) |
|---|---|---|---|---|---|
| Diffuse midline glioma, H3 K27-altered | MONDO:1060171 | CNS WHO grade 4. WHO CNS5 defines this as an infiltrative/diffuse midline glioma with loss of H3K27me3 and one of the following molecular features: H3 p.K28M (K27M) alteration in histone H3 isoforms, EZHIP overexpression, or EGFR alteration; diagnosis should be restricted to diffuse, midline, astrocytic tumors. (park2023the2021who pages 2-2, gue2024the2021world pages 15-16, broggi2024clinico–pathologicalfeaturesof pages 1-2, wisniewski2023h3k27maltereddiffuse pages 1-3, park2023the2021who pages 6-7) | Diffuse midline glioma, H3 K27M-mutant; DMG, H3 K27-altered; H3K27-altered diffuse midline glioma; diffuse intrinsic pontine glioma (DIPG; historical/clinical term, especially for pontine tumors); pediatric-type diffuse high-grade glioma, H3 K27-altered subset. (vallero2023pediatricdiffusemidline pages 2-3, nonnenbroich2024h3k27altereddiffusemidline pages 1-2, wisniewski2023h3k27maltereddiffuse pages 1-3, park2023the2021who pages 7-7) | Pons/brainstem (classic DIPG location), thalamus, spinal cord; other reported midline sites include cerebellum, third ventricle, mesencephalon, and multifocal midline locations. (vallero2023pediatricdiffusemidline pages 2-3, broggi2024clinico–pathologicalfeaturesof pages 1-2, schulte2020clinicalradiologicand pages 1-2, hayashi2024neuroradiologicalgeneticand pages 1-2) | Vallero et al. 2023; https://doi.org/10.3389/fonc.2022.1082062; PMID not provided. (vallero2023pediatricdiffusemidline pages 2-3) |
| Diffuse midline glioma, H3 K27-altered | MONDO:1060171 | WHO CNS5 renamed the 2016 entity “diffuse midline glioma, H3 K27M-mutant” to “diffuse midline glioma, H3 K27-altered” to encompass additional mechanisms causing H3 K27 hypomethylation beyond canonical H3K27M mutation. (gue2024the2021world pages 15-16, wisniewski2023h3k27maltereddiffuse pages 1-3, park2023the2021who pages 6-7) | Former WHO 2016 name: diffuse midline glioma, H3 K27M-mutant; older umbrella clinical usage: DIPG for pontine cases. (wisniewski2023h3k27maltereddiffuse pages 1-3, park2023the2021who pages 7-7) | Midline CNS structures, especially pons, thalamus, spinal cord. (vallero2023pediatricdiffusemidline pages 2-3, broggi2024clinico–pathologicalfeaturesof pages 1-2, hayashi2024neuroradiologicalgeneticand pages 1-2) | Gianno et al. 2022; https://doi.org/10.32074/1591-951x-830; PMID not provided. (gianno2022paediatrictypediffusehighgrade pages 1-2) |
| Diffuse midline glioma, H3 K27-altered | MONDO:1060171 | WHO-recognized molecular subtypes/mechanisms include: H3.3 p.K28M (H3F3A), H3.1/H3.2 p.K28M (HIST1H3B/HIST1H3C), H3-wildtype with EZHIP overexpression, and EGFR-altered tumors; all are assigned grade 4 regardless of histology. (gue2024the2021world pages 15-16, gianno2022paediatrictypediffusehighgrade pages 1-2, park2023the2021who pages 6-7) | H3.3 K27M DMG; H3.1/H3.2 K27M DMG; H3-wildtype/EZHIP-overexpressing DMG; EGFR-altered DMG. (gue2024the2021world pages 15-16, gianno2022paediatrictypediffusehighgrade pages 1-2, park2023the2021who pages 6-7) | Brainstem/pons, thalamus, spinal cord; age/site patterns differ by subtype, with pontine predominance in many pediatric H3.1/H3.2 cases and broader midline distribution in H3.3 cases. (vallero2023pediatricdiffusemidline pages 2-3, gianno2022paediatrictypediffusehighgrade pages 1-2) | Park et al. 2023; https://doi.org/10.1002/jmri.28740; PMID not provided. (park2023the2021who pages 2-2, park2023the2021who pages 6-7) |
| Diffuse midline glioma, H3 K27-altered | MONDO:1060171 | Diagnostic pathology commonly uses immunohistochemistry for H3 K27M, H3 K27me3 loss, and EZHIP; diffuse strong H3 K27M staining with H3K27me3 loss supports diagnosis when integrated with diffuse midline astrocytic morphology. (broggi2024clinico–pathologicalfeaturesof pages 1-2) | H3 K27M-positive diffuse midline glioma; H3K27me3-loss diffuse midline glioma (descriptor, not a formal synonym on its own). (broggi2024clinico–pathologicalfeaturesof pages 1-2, wisniewski2023h3k27maltereddiffuse pages 1-3) | Same midline locations; pathology emphasis does not alter anatomic distribution. (broggi2024clinico–pathologicalfeaturesof pages 1-2) | Broggi et al. 2024; https://doi.org/10.3390/diagnostics14232617; PMID not provided. (broggi2024clinico–pathologicalfeaturesof pages 1-2) |
| Diffuse midline glioma, H3 K27-altered | MONDO:1060171 | Review sources emphasize that although DMG is classified as a pediatric-type diffuse high-grade glioma, it also occurs in adults; adult series show thalamic predominance more often than pediatric series, which are often pontine. (broggi2024clinico–pathologicalfeaturesof pages 1-2, schulte2020clinicalradiologicand pages 1-2, park2023the2021who pages 6-7) | Adult diffuse midline glioma, H3 K27-altered; pediatric diffuse midline glioma, H3 K27-altered. (broggi2024clinico–pathologicalfeaturesof pages 1-2, schulte2020clinicalradiologicand pages 1-2) | Adults: commonly thalamus; children: often pons/brainstem; spinal cord occurs in both. (broggi2024clinico–pathologicalfeaturesof pages 1-2, schulte2020clinicalradiologicand pages 1-2, hayashi2024neuroradiologicalgeneticand pages 1-2) | Schulte et al. 2020; https://doi.org/10.1093/noajnl/vdaa142; PMID not provided. (schulte2020clinicalradiologicand pages 1-2) |
| Diffuse midline glioma, H3 K27-altered | MONDO:1060171 | Concise WHO-style definition quoted in review literature: “An infiltrative midline glioma with loss of H3 p.K28me3 (K27me3) and either an H3 c.83A>T p.K28M substitution in one of the histone H3 isoforms, aberrant overexpression of EZHIP, or an EGFR mutation.” (wisniewski2023h3k27maltereddiffuse pages 1-3) | DMG H3 K27-altered; previously DMG H3 K27M-mutant. (wisniewski2023h3k27maltereddiffuse pages 1-3) | Midline CNS, especially pons, thalamus, spinal cord. (wisniewski2023h3k27maltereddiffuse pages 1-3) | Wiśniewski et al. 2023; https://doi.org/10.1055/s-0043-1771192; PMID not provided. (wisniewski2023h3k27maltereddiffuse pages 1-3) |
Table: This table summarizes the core identifiers, nomenclature changes, WHO CNS5 diagnostic criteria, synonyms, and typical anatomical sites for diffuse midline glioma, H3 K27-altered. It is useful as a compact reference for disease ontology and naming normalization in a knowledge base.
DMG, H3 K27-altered is primarily driven by somatic alterations affecting histone H3 lysine-27 regulation, most commonly a K27M missense substitution in histone H3 genes, leading to epigenetic dysregulation. (mandorino2024pediatricdiffusemidline pages 1-2, gue2024the2021world pages 15-16)
No validated protective factors (genetic or environmental) were identified in the retrieved evidence.
No gene–environment interaction evidence was identified in the retrieved sources.
A common presentation—classically described for DIPG/brainstem DMG—includes cranial neuropathies, long-tract (pyramidal) signs, and ataxia. Vallero et al. additionally specify long-tract findings such as hyperreflexia, clonus, increased tone, and Babinski sign. (vallero2023pediatricdiffusemidline pages 2-3, broggi2024clinico–pathologicalfeaturesof pages 1-2)
Mandorino et al. (2024) highlight pediatric presentations including coordination problems, limb weakness, speech difficulties, and vision impairment. (mandorino2024pediatricdiffusemidline pages 1-2)
| Clinical feature | Phenotype type (symptom/sign) | Typical age/setting | Frequency or qualitative note | Suggested HPO term(s) |
|---|---|---|---|---|
| Cranial nerve palsy / multiple cranial neuropathies | Sign | Most typical in pediatric pontine/brainstem DMG (classic DIPG presentation); also described in adult brainstem cases | Part of the classic DIPG triad; commonly reported at presentation in pontine disease (vallero2023pediatricdiffusemidline pages 2-3, broggi2024clinico–pathologicalfeaturesof pages 1-2) | Cranial nerve palsy [HP:0006999]; Abducens nerve palsy [HP:0001260]; Facial palsy [HP:0010628] |
| Long-tract signs / pyramidal tract dysfunction | Sign | Common in pediatric and adult brainstem DMG/DIPG | Part of the classic DIPG triad; often includes hyperreflexia, clonus, increased tone, and Babinski sign (vallero2023pediatricdiffusemidline pages 2-3, broggi2024clinico–pathologicalfeaturesof pages 1-2, nonnenbroich2024h3k27altereddiffusemidline pages 1-2) | Hyperreflexia [HP:0001347]; Clonus [HP:0002169]; Spasticity [HP:0001257]; Extensor plantar response [HP:0003487] |
| Ataxia / cerebellar signs / coordination problems | Symptom/sign | Very common in pediatric pontine DMG; also seen in adults with brainstem involvement | Part of the classic DIPG triad; often manifests as gait instability or incoordination (vallero2023pediatricdiffusemidline pages 2-3, broggi2024clinico–pathologicalfeaturesof pages 1-2, mandorino2024pediatricdiffusemidline pages 1-2, nonnenbroich2024h3k27altereddiffusemidline pages 1-2) | Ataxia [HP:0001251]; Gait ataxia [HP:0002066]; Dysmetria [HP:0001310] |
| Limb weakness | Symptom/sign | Pediatric-onset disease, especially brainstem DMG; may occur in adults as well | Common presenting complaint reflecting corticospinal tract involvement (mandorino2024pediatricdiffusemidline pages 1-2) | Muscle weakness [HP:0001324]; Paresis [HP:0004305] |
| Speech difficulties / dysarthria | Symptom/sign | Common in children with brainstem DMG | Frequently accompanies cranial nerve and long-tract involvement (mandorino2024pediatricdiffusemidline pages 1-2) | Dysarthria [HP:0001260]; Speech disorder [HP:0002167] |
| Vision impairment / diplopia / oculomotor disturbance | Symptom/sign | Common in pediatric brainstem DMG; also expected in adult pontine disease with cranial nerve involvement | Often related to cranial neuropathy in pontine tumors (mandorino2024pediatricdiffusemidline pages 1-2, nonnenbroich2024h3k27altereddiffusemidline pages 1-2) | Abnormality of vision [HP:0000504]; Diplopia [HP:0000651]; Gaze palsy [HP:0000605] |
| Nausea | Symptom | Can occur with thalamic or third-ventricular/midline tumors; reported in adult cases | Less specific than DIPG triad; may accompany raised intracranial pressure or hydrocephalus (broggi2024clinico–pathologicalfeaturesof pages 1-2, nonnenbroich2024h3k27altereddiffusemidline pages 1-2) | Nausea [HP:0002018] |
| Fatigue | Symptom | Reported in adult thalamic/midline cases | Nonspecific but documented in adult presentation (nonnenbroich2024h3k27altereddiffusemidline pages 1-2) | Fatigue [HP:0012378] |
| Walking impairment / gait disturbance | Symptom/sign | Pediatric and adult disease, especially with ataxia or weakness | Reflects cerebellar signs and/or corticospinal dysfunction; common functional consequence (mandorino2024pediatricdiffusemidline pages 1-2) | Gait disturbance [HP:0001288]; Abnormality of gait [HP:0001288] |
| Childhood onset | Clinical course feature | Most commonly ages 5-10 years; DIPG often described in children 4-9 years old | Predominantly pediatric tumor overall (vallero2023pediatricdiffusemidline pages 2-3, mandorino2024pediatricdiffusemidline pages 1-2) | Childhood onset [HP:0011463] |
| Young adult/adult onset | Clinical course feature | Adults can be affected, often with thalamic predominance | Less common than pediatric disease; adult cases may show somewhat less aggressive clinical behavior than pediatric disease (broggi2024clinico–pathologicalfeaturesof pages 1-2, schulte2020clinicalradiologicand pages 1-2) | Adult onset [HP:0003581] |
| Rapidly progressive neurologic decline | Clinical course feature | Characteristic of both pediatric and adult DMG, especially untreated/progressive disease | Qualitatively severe and progressive; prognosis remains poor and disease is highly aggressive (broggi2024clinico–pathologicalfeaturesof pages 1-2, mandorino2024pediatricdiffusemidline pages 1-2, nonnenbroich2024h3k27altereddiffusemidline pages 1-2) | Progressive neurologic deterioration [HP:0002344] |
Table: This table summarizes the characteristic clinical presentation of diffuse midline glioma, H3 K27-altered, including the classic DIPG triad and other common symptoms, with suggested HPO mappings. It is useful for phenotype curation and disease knowledge base annotation.
Neurologic deficits (ataxia, cranial nerve palsies, long-tract signs/weakness) directly impair gait, speech, vision, and daily function; radiotherapy is used palliatively to reduce symptoms but does not cure disease. (vallero2023pediatricdiffusemidline pages 2-3, mandorino2024pediatricdiffusemidline pages 1-2)
WHO CNS5 recognizes DMG, H3 K27-altered as defined by H3 K27M mutation, or alternative molecular mechanisms including EZHIP overexpression or EGFR alteration, all producing loss of H3K27 methylation. (park2023the2021who pages 2-2, gue2024the2021world pages 15-16, park2023the2021who pages 6-7)
A review definition consistent with WHO CNS5 is quoted as: “An infiltrative midline glioma with loss of H3 p.K28me3 (K27me3) and either … p.K28M (K27M) … aberrant overexpression of EZHIP, or an EGFR mutation (CNS WHO grade 4).” (wisniewski2023h3k27maltereddiffuse pages 1-3)
| Alteration (gene/marker) | Alteration type | Typical context (pediatric/adult; location) | Frequency/statistic with cohort details | Prognostic association (direction, OS/PFS) | Evidence type (cohort/systematic review/review) | Key citation (DOI URL and year) |
|---|---|---|---|---|---|---|
| H3 K27M in histone H3 genes (overall) | Somatic missense driver altering histone H3 lysine 27 biology | Predominantly pediatric DMG/DIPG in midline structures; also occurs in adults | ~85% of DIPG/DMG tumors harbor K27M mutations in H3.3/H3.1 genes in review synthesis (mandorino2024pediatricdiffusemidline pages 1-2) | Defining oncogenic event; associated with universally poor prognosis overall, but not itself a within-DMG stratifier in this summary (mandorino2024pediatricdiffusemidline pages 1-2) | Review | https://doi.org/10.3390/cancers16101814 (2024) (mandorino2024pediatricdiffusemidline pages 1-2) |
| H3F3A p.K27M (H3.3) | Somatic missense driver | Pediatric and adult DMG; pediatric pontine/thalamic/spinal, adult predominantly thalamic in one cohort | Dufour 2020: 28/44 interpretable cases (63.6%); Schulte 2020: adult cohort mutations exclusively in H3F3A among sequenced tumors; Damodharan 2023 identifies H3.3 as a prominent alteration across trial IPD (dufour2020identificationofprognostic pages 8-10, schulte2020clinicalradiologicand pages 1-2, damodharan2023molecularcharacterizationand pages 1-2) | Worse OS versus H3.1/HIST1H3B in pediatric disease; Damodharan 2023 found H3.3 associated with worse OS (dufour2020identificationofprognostic pages 8-10, damodharan2023molecularcharacterizationand pages 1-2) | Cohort + adult cohort + systematic review/IPD | https://doi.org/10.1111/bpa.12768 (2020); https://doi.org/10.1093/noajnl/vdaa142 (2020); https://doi.org/10.3390/cancers15133478 (2023) (dufour2020identificationofprognostic pages 8-10, schulte2020clinicalradiologicand pages 1-2, damodharan2023molecularcharacterizationand pages 1-2) |
| HIST1H3B p.K27M (H3.1) | Somatic missense driver | More typical in younger pediatric pontine tumors; uncommon in adults | Dufour 2020: 7 cases (15.9% of interpretable tumors); Hayashi 2024: 2% HIST1H3B p.K27M in multicenter cohort; absent in Schulte adult sequencing subset (dufour2020identificationofprognostic pages 8-10, hayashi2024neuroradiologicalgeneticand pages 1-2, schulte2020clinicalradiologicand pages 1-2) | Pediatric Dufour cohort: longer median OS than H3F3A-mutant tumors (12.1 vs 7.9 months), suggesting relatively better prognosis than H3.3-mutant disease (dufour2020identificationofprognostic pages 8-10) | Cohort + multicenter cohort + adult cohort | https://doi.org/10.1111/bpa.12768 (2020); https://doi.org/10.1186/s40478-024-01808-w (2024); https://doi.org/10.1093/noajnl/vdaa142 (2020) (dufour2020identificationofprognostic pages 8-10, hayashi2024neuroradiologicalgeneticand pages 1-2, schulte2020clinicalradiologicand pages 1-2) |
| TP53 alteration / p53 overexpression | Tumor suppressor mutation / IHC surrogate | Common in pediatric and adult DMG; not location-specific | Dufour 2020: TP53 mutations in 57.1% of H3K27-mutant tumors; Schulte 2020: TP53 frequently co-mutated in adults; Wang 2021 identified p53 overexpression as a negative factor (dufour2020identificationofprognostic pages 8-10, schulte2020clinicalradiologicand pages 1-2, wang2021clinicalfeaturesand pages 3-4) | Worse OS: Damodharan 2023 IPD review found TP53 associated with worse OS; Wang 2021 found p53 overexpression independently adverse for OS (damodharan2023molecularcharacterizationand pages 1-2, wang2021clinicalfeaturesand pages 3-4) | Cohort + adult cohort + systematic review/IPD | https://doi.org/10.1111/bpa.12768 (2020); https://doi.org/10.3390/cancers15133478 (2023); https://doi.org/10.3389/fonc.2020.602553 (2021) (dufour2020identificationofprognostic pages 8-10, damodharan2023molecularcharacterizationand pages 1-2, wang2021clinicalfeaturesand pages 3-4) |
| ACVR1 alteration | Activating kinase mutation | Mainly pediatric pontine/brainstem DMG | Dufour 2020: 11.8% in pediatric cohort; highlighted in reviews of pediatric disease (dufour2020identificationofprognostic pages 8-10, vallero2023pediatricdiffusemidline pages 2-3) | Favorable direction in Damodharan 2023 trial IPD review (“protective effect”) for OS relative to other genotypes (damodharan2023molecularcharacterizationand pages 1-2) | Cohort + systematic review/IPD | https://doi.org/10.1111/bpa.12768 (2020); https://doi.org/10.3390/cancers15133478 (2023) (dufour2020identificationofprognostic pages 8-10, damodharan2023molecularcharacterizationand pages 1-2) |
| PDGFRA amplification | Receptor tyrosine kinase amplification | Pediatric H3K27-mutant DMG; often brainstem-predominant cohorts | Dufour 2020: PDGFRA amplification in 20.6% (dufour2020identificationofprognostic pages 8-10) | Worse survival: significantly associated with shorter OS in Dufour 2020 (dufour2020identificationofprognostic pages 8-10) | Cohort | https://doi.org/10.1111/bpa.12768 (2020) (dufour2020identificationofprognostic pages 8-10) |
| FGFR1 mutation | Activating kinase mutation | More often thalamic/spinal and adult-enriched subsets; also seen in long-term survivor subgroup | Hayashi 2024: 14% FGFR1-mutant in 93-patient DMG cohort; Schulte 2020: FGFR1 frequently co-mutated in adults (hayashi2024neuroradiologicalgeneticand pages 1-2, schulte2020clinicalradiologicand pages 1-2) | Not established as uniformly favorable in all cohorts, but FGFR1/BRAF co-altered DMG has longer median OS >3 years in separate 2024 subtype study; long-term survivor data suggest MAPK pathway enrichment (hayashi2024neuroradiologicalgeneticand pages 1-2) | Multicenter cohort + adult cohort | https://doi.org/10.1186/s40478-024-01808-w (2024); https://doi.org/10.1093/noajnl/vdaa142 (2020) (hayashi2024neuroradiologicalgeneticand pages 1-2, schulte2020clinicalradiologicand pages 1-2) |
| BRAF p.V600E / BRAF co-alteration | Activating kinase mutation | Rare in standard DMG cohorts; enriched in distinct thalamic H3 K27/BRAF-FGFR1 co-altered subtype | Hayashi 2024: BRAF p.V600E in 1% of DMG cohort (hayashi2024neuroradiologicalgeneticand pages 1-2) | Rare alone in standard DMG; prognostic value not clear in Hayashi cohort, but MAPK-pathway co-altered long survivors reported elsewhere (hayashi2024neuroradiologicalgeneticand pages 1-2) | Multicenter cohort | https://doi.org/10.1186/s40478-024-01808-w (2024) (hayashi2024neuroradiologicalgeneticand pages 1-2) |
| EGFR mutation/alteration | Mutation/amplification defining subtype in some tumors | Midline DMG subset; more emphasized in WHO/review classification than common pediatric cohorts | Hayashi 2024: EGFR mutation 3%; WHO/review sources recognize EGFR-altered DMG subtype (hayashi2024neuroradiologicalgeneticand pages 1-2, gianno2022paediatrictypediffusehighgrade pages 1-2) | Prognostic effect not clearly defined in cited cohort excerpt (hayashi2024neuroradiologicalgeneticand pages 1-2) | Multicenter cohort + review/classification | https://doi.org/10.1186/s40478-024-01808-w (2024); https://doi.org/10.32074/1591-951x-830 (2022) (hayashi2024neuroradiologicalgeneticand pages 1-2, gianno2022paediatrictypediffusehighgrade pages 1-2) |
| MGMT promoter methylation | Epigenetic DNA methylation biomarker | Pediatric/adult DMG, often infrequent | Hayashi 2024: MGMT promoter methylation 9%; Gong 2023 noted MGMT methylation status was not associated with adult OS (hayashi2024neuroradiologicalgeneticand pages 1-2, gong2023differencesinsurvival pages 7-9) | No clear OS benefit signal in adult cohort; helps explain limited benefit of temozolomide in many DMGs (gong2023differencesinsurvival pages 7-9) | Multicenter cohort + cohort analysis | https://doi.org/10.1186/s40478-024-01808-w (2024); https://doi.org/10.1111/cns.14307 (2023) (hayashi2024neuroradiologicalgeneticand pages 1-2, gong2023differencesinsurvival pages 7-9) |
| TERT promoter mutation | Promoter hotspot mutation | Adult-enriched/older diffuse glioma biology; uncommon in DMG | Hayashi 2024: 3% TERT promoter mutation (hayashi2024neuroradiologicalgeneticand pages 1-2) | Prognostic significance not established in the cited excerpt (hayashi2024neuroradiologicalgeneticand pages 1-2) | Multicenter cohort | https://doi.org/10.1186/s40478-024-01808-w (2024) (hayashi2024neuroradiologicalgeneticand pages 1-2) |
| ATRX loss/mutation | Chromatin remodeling alteration | Seen in adult DMG and subsets of pediatric DMG | Schulte 2020: ATRX frequently co-mutated in adults; Broggi 2024 review notes ATRX loss in ~15% of adult cases (schulte2020clinicalradiologicand pages 1-2, broggi2024clinico–pathologicalfeaturesof pages 1-2) | Gong 2023: intact ATRX expression associated with longer survival in adults, implying ATRX loss may be unfavorable (gong2023differencesinsurvival pages 7-9) | Adult cohort + adult review + cohort analysis | https://doi.org/10.1093/noajnl/vdaa142 (2020); https://doi.org/10.3390/diagnostics14232617 (2024); https://doi.org/10.1111/cns.14307 (2023) (schulte2020clinicalradiologicand pages 1-2, broggi2024clinico–pathologicalfeaturesof pages 1-2, gong2023differencesinsurvival pages 7-9) |
| Complex chromosomal profile / 17p loss | Copy-number/chromosomal instability markers | Pediatric H3K27-mutant DMG | Dufour 2020: complex chromosomal profiles common (70.6%); 17p loss specifically identified among adverse markers (dufour2020identificationofprognostic pages 8-10) | Both complex chromosomal profile and 17p loss significantly associated with worse survival (dufour2020identificationofprognostic pages 8-10) | Cohort | https://doi.org/10.1111/bpa.12768 (2020) (dufour2020identificationofprognostic pages 8-10) |
Table: This table summarizes major molecular alterations reported in diffuse midline glioma, H3 K27-altered, with representative frequencies and prognostic associations across key pediatric, adult, and multicenter cohorts. It is useful for comparing defining drivers, recurrent co-alterations, and biomarkers linked to survival.
No validated environmental, lifestyle, or infectious causal factors were identified in the retrieved evidence. The disease definition and therapeutic strategies in these sources center on tumor-intrinsic somatic alterations and local CNS anatomy. (mandorino2024pediatricdiffusemidline pages 1-2, gue2024the2021world pages 15-16)
H3 K27 alterations (e.g., K27M) and EZHIP overexpression converge on polycomb repressive complex 2 (PRC2) interference, producing global reduction of H3K27me2/H3K27me3 and widespread gene-expression dysregulation that supports aggressive glioma biology. (gue2024the2021world pages 15-16)
The retrieved evidence set emphasizes molecular profiling via biopsy/NGS and methylation profiling, but does not provide detailed single-cell or spatial transcriptomics results in the accessible excerpts. (nonnenbroich2024h3k27altereddiffusemidline pages 1-2)
Primary involvement is the central nervous system, particularly midline structures: - Brainstem/pons (classic DIPG) - Thalamus - Spinal cord (vallero2023pediatricdiffusemidline pages 2-3, schulte2020clinicalradiologicand pages 1-2, hayashi2024neuroradiologicalgeneticand pages 1-2)
Disease is typically subacute to progressive with rapid neurologic decline reflecting infiltrative growth in critical midline structures. Pediatric presentations are common; adult presentations occur and may have different site distribution and outcomes. (mandorino2024pediatricdiffusemidline pages 1-2, schulte2020clinicalradiologicand pages 1-2)
No formal staging system specific to DMG was identified in the retrieved evidence; clinically, course is commonly framed as diagnosis → post-radiotherapy period → progression/recurrence, with consideration of re-irradiation at recurrence. (vallero2023pediatricdiffusemidline pages 2-3, damodharan2023molecularcharacterizationand pages 1-2)
This is not typically a Mendelian inherited disorder; it is defined by tumor somatic alterations. No penetrance/carrier frequency/founder-effect data were identified in the retrieved evidence.
MRI is widely described as the diagnostic gold standard for pontine/brainstem cases; Vallero et al. note typical DIPG imaging criteria such as a lesion involving >50% of the pons. (vallero2023pediatricdiffusemidline pages 2-3)
Midline gliomas without H3 K27 alteration and other pediatric high-grade gliomas (e.g., hemispheric H3 G34-mutant tumors) are key considerations in the modern WHO framework. (park2023the2021who pages 2-2)
Radiotherapy remains the principal standard palliative treatment, with typical fractionated dosing in the ~54–60 Gy range (Vallero) and 59 Gy cited in a pediatric review context. (vallero2023pediatricdiffusemidline pages 2-3, mandorino2024pediatricdiffusemidline pages 1-2)
Real-world practice patterns from the Kansai multicenter cohort (n=93) include: - Resection (when feasible) in 36% - Adjuvant radiation + chemotherapy in 83% - Temozolomide use in 76% - Bevacizumab use in 42% (hayashi2024neuroradiologicalgeneticand pages 1-2)
Damodharan et al. (2023) systematic review of individual participant trial data highlights that re-irradiation was the only statistically significant modality associated with survival benefit in their pooled analysis. (damodharan2023molecularcharacterizationand pages 1-2)
MAXO (suggested) intervention terms (high-level, for KB annotation): external beam radiotherapy; stereotactic biopsy; chemotherapy; immunotherapy; CAR T-cell therapy; peptide vaccination; re-irradiation; convection-enhanced delivery.
| Modality/therapy | Target/mechanism | NCT ID | Phase | Population (age; mutation requirement; setting) | Delivery/route | Primary outcomes | Status and start date | URL |
|---|---|---|---|---|---|---|---|---|
| GD2 CAR T cells | GD2-directed CAR T-cell immunotherapy after lymphodepleting chemotherapy (fludarabine/cyclophosphamide) for DMG/DIPG; efficacy assessed with RANO 2.0, OS/PFS/PPS endpoints in protocol (yang2024newprogressin pages 3-5, NCT04196413 chunk 2) | NCT04196413 | Phase 1 | Age 2–60 years; H3K27M or H3K27I mutation required; DIPG and spinal DMG; recurrent/progressive setting allowed per eligibility framework (NCT04196413 chunk 2) | Cellular infusion after preparative regimen; CAR T-cell infusion (clinical route not fully specified in excerpt) (NCT04196413 chunk 2) | Safety/toxicity including suspected AEs/SAEs and toxicity resolution; radiographic response rate by RANO 2.0; OS; PFS; post-progression survival (NCT04196413 chunk 2) | Recruiting; start 2020-06 (yang2024newprogressin pages 3-5, NCT04196413 chunk 2) | https://clinicaltrials.gov/study/NCT04196413 |
| H3K27M peptide vaccine + atezolizumab | Long mutant H3K27M peptide vaccine to induce H3K27M-specific T cells, combined with involved-field radiotherapy and anti–PD-L1 checkpoint blockade (atezolizumab); imiquimod used as local adjuvant (NCT04808245 chunk 1) | NCT04808245 | Phase 1 | Adults with newly diagnosed H3.1K27M or H3.3K27M diffuse midline glioma; single-arm multicenter trial; planned n=15 (NCT04808245 chunk 1) | Vaccine administered subcutaneously; atezolizumab IV every 3 weeks; concurrent/serial with radiotherapy (NCT04808245 chunk 1) | Safety (regimen-limiting toxicity) and immunogenicity measured by H3K27M-specific T cells/IFN-γ ELISpot on PBMCs (NCT04808245 chunk 1) | Active, not recruiting; start 2023-02-15 (NCT04808245 chunk 1) | https://clinicaltrials.gov/study/NCT04808245 |
| Split-course hypofractionated radiation with stereotactic biopsy (SPORT-DMG) | Radiation-based management strategy integrating stereotactic biopsy and split-course/hypofractionated radiotherapy for DMG (yang2024newprogressin pages 3-5) | NCT05077735 | Phase 2 | DMG population; trial table identifies diffuse midline glioma with radiation intervention; detailed mutation/age criteria not available in excerpt (yang2024newprogressin pages 3-5) | Radiation: hypofractionated/split-course radiotherapy; stereotactic biopsy component (yang2024newprogressin pages 3-5) | Patient-reported/clinical outcomes include quality-of-life assessment and questionnaire administration; full primary endpoint wording not available in excerpt (yang2024newprogressin pages 3-5) | Recruiting; start 2021-10 (yang2024newprogressin pages 3-5) | https://clinicaltrials.gov/study/NCT05077735 |
| Panobinostat (PBTC-047) | HDAC inhibition (panobinostat/LBH589) targeting epigenetic dysregulation in DIPG/DMG (yang2024newprogressin pages 3-5) | NCT02717455 | Phase 1 | Children with diffuse intrinsic pontine glioma; mutation requirement not specified in excerpt; pediatric pontine DMG-relevant population (yang2024newprogressin pages 3-5) | Drug administration route not specified in excerpt (known panobinostat trial listed as drug intervention) (yang2024newprogressin pages 3-5) | Primary outcomes not specified in excerpt; trial identified as phase I panobinostat study (yang2024newprogressin pages 3-5) | Active, not recruiting; start 2016-06 (yang2024newprogressin pages 3-5) | https://clinicaltrials.gov/study/NCT02717455 |
| H3K27M-specific engineered immune effector cells (EIEs) | Autologous H3K27M-specific immune effectors generated from PBMCs stimulated with H3K27M antigen-primed autologous dendritic cells; product contains CD8+, CD4+, CD56+ populations (NCT07501156 chunk 1) | NCT07501156 | Phase 1/2 | Age 2–70 years; recurrent or refractory DMG/DIPG; confirmed H3K27M-positive disease; KPS ≥60; planned n=30 (NCT07501156 chunk 1) | 1–2 intravenous infusions once weekly at 1×10^5–1×10^7 EIEs/kg after leukapheresis-based manufacturing (NCT07501156 chunk 1) | Safety by CTCAE v4.0 adverse effects; success rate of EIE generation; ELISPOT evidence of target-specific T cells; objective response by RECIST v1.1 (NCT07501156 chunk 1) | Recruiting; start 2026-03-18 (NCT07501156 chunk 1) | https://clinicaltrials.gov/study/NCT07501156 |
Table: This table summarizes key current and emerging ClinicalTrials.gov studies for diffuse midline glioma, H3 K27-altered, spanning CAR-T, peptide vaccination, radiation strategy, HDAC inhibition, and engineered immune effector cell approaches. It is useful for quickly comparing mechanism, eligibility, route, endpoints, and recruitment status across major active protocols.
No established primary prevention strategies are supported by the retrieved evidence, consistent with a disease primarily driven by sporadic somatic alterations and presenting as a rare CNS tumor. Secondary prevention (screening) is not established; diagnosis is typically symptom- and imaging-driven. (mandorino2024pediatricdiffusemidline pages 1-2, vallero2023pediatricdiffusemidline pages 2-3)
No naturally occurring veterinary analogs were identified in the retrieved evidence.
The retrieved evidence set references preclinical models (e.g., murine models used to test epigenetic combinations) but does not provide detailed, model-by-model phenotype recapitulation in the accessible excerpts. (nonnenbroich2024h3k27altereddiffusemidline pages 4-6)
The provided full-text evidence chunks and trial registry records include DOI URLs and publication months/years but did not include PMIDs for most articles. Where PMID is required for downstream normalization, the DOI URLs provided here can be used to programmatically map to PubMed records.
References
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(NCT04808245 chunk 1): A MultIceNTER Phase I Peptide VaCcine Trial for the Treatment of H3-Mutated Gliomas. German Cancer Research Center. 2023. ClinicalTrials.gov Identifier: NCT04808245
(NCT04196413 chunk 2): GD2 CAR T Cells in Diffuse Intrinsic Pontine Gliomas (DIPG) & Spinal Diffuse Midline Glioma(DMG). Stanford University. 2020. ClinicalTrials.gov Identifier: NCT04196413
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(NCT07501156 chunk 1): H3K27M-specific Immune Effector Cells Targeting DMG/DIPG. Shenzhen Geno-Immune Medical Institute. 2026. ClinicalTrials.gov Identifier: NCT07501156