Diffuse Midline Glioma: Symptoms, Types, Causes and Treatment

Diffuse midline glioma (DMG) is a devastating and aggressive brain tumor that predominantly affects children but can also occur in adults. Advances in molecular biology have transformed our understanding of DMG, especially since the discovery of hallmark mutations in histone H3. This article provides a comprehensive, evidence-based overview of DMG, covering its symptoms, types, causes, and current treatment strategies.

Symptoms of Diffuse Midline Glioma

Diffuse midline gliomas are notorious for their subtle and diverse symptoms, which often depend on the tumor’s precise location in the central nervous system. Early recognition is crucial, but symptoms can be non-specific, making diagnosis challenging. Both pediatric and adult patients may present differently, and in some cases, symptoms can be surprisingly absent or misleading.

Symptom	Typical Patient	Location	Source(s)
Headache	Both	Brainstem, Thalamus	1 2 4
Motor/Sensory Deficits	Both	Brainstem, Spinal Cord	1 2 4 8
Ataxia	Both	Cerebellum, Brainstem	1 4
Cranial Nerve Deficit	Both	Brainstem	1 4 8
Confusion	Adults	Various	1 8
Intracranial Hypertension	Children	Spinal Cord (rare)	2

Table 1: Key Symptoms

Understanding Symptom Presentation

DMG symptoms arise as the tumor infiltrates midline structures of the central nervous system, including the brainstem, thalamus, cerebellum, and spinal cord. The symptoms manifest based on the affected region:

• Brainstem Involvement: This is most common in children, especially as diffuse intrinsic pontine glioma (DIPG). Symptoms often include progressive weakness, facial palsy, double vision, problems with swallowing, and ataxia. Cranial nerve deficits may appear early due to the dense concentration of cranial nerve nuclei in the brainstem 1 4 8.

• Thalamic and Pineal Tumors: Presentations can include sensory deficits, confusion, and, less commonly, seizures. Headaches and changes in consciousness may occur if the tumor affects cerebrospinal fluid (CSF) flow, leading to hydrocephalus 1 4 8.

• Spinal Cord DMG: Motor or sensory changes in the limbs, gait disturbances, and sometimes bowel or bladder dysfunction may be seen. However, as highlighted in a pediatric case, there are rare instances where a spinal cord DMG first presents with only symptoms of increased intracranial pressure, such as headache and vomiting, without any spinal symptoms 2.

• Cerebellar Involvement: Ataxia, uncoordinated movements, and balance difficulties are typical when the cerebellum is involved 1 4.

Symptom Variability and Diagnosis

The spectrum of DMG symptoms can make early diagnosis difficult. Especially in children, symptoms may be subtle or progress rapidly. Some patients—particularly with spinal cord DMG—may initially lack localizing neurological findings, as in cases presenting only with signs of raised intracranial pressure due to tumor dissemination 2. In adults, presentations may be more varied and sometimes less dramatic, with confusion and mild deficits noted 1 8. Imaging, primarily MRI, is critical for identifying the tumor when symptoms suggest central nervous system involvement.

Types of Diffuse Midline Glioma

Diffuse midline gliomas are not a single disease but a spectrum, classified by their location, genetic mutations, and, increasingly, molecular characteristics. Understanding these types is essential for prognosis and therapeutic decisions.

Type/Variant	Key Feature	Typical Age Group	Source(s)
DIPG (Pontine DMG)	Brainstem origin	Children	3 5 7
Thalamic DMG	Thalamus location	Both	1 5 8
Spinal Cord DMG	Spinal cord origin	Both	2 4 5 8
H3 K27M-mutant DMG	H3 K27M mutation	Mostly children	3 4 5 6 8
H3 Wild-type DMG	Absence of H3 mutation, may overexpress EZHIP	Both	1 7

Table 2: Main Types and Variants

Anatomical Classification

DMGs can arise in any midline structure of the CNS:

• Diffuse Intrinsic Pontine Glioma (DIPG): This subtype is the most recognized, typically arising in the pons. DIPGs are almost exclusively found in children and are universally fatal 3 5 7.

• Thalamic DMG: Tumors originating in the thalamus can occur in both children and adults and tend to behave aggressively, mirroring the prognosis seen in pontine DMG 1 5 8.

• Spinal Cord DMG: These are rare but can occur at any age. They pose unique diagnostic and management challenges, especially when presenting atypically 2 4 5 8.

• Other Midline Sites: DMGs have also been described in the pineal region, cerebellum, corpus callosum, and even the lateral ventricles 1 4 5 8.

Molecular and Genetic Subtypes

H3 K27M-Mutant DMG

The 2016 WHO classification recognized “Diffuse midline glioma, H3 K27M-mutant” as a distinct entity 3 6 9. This mutation in the histone H3 gene (H3F3A or HIST1H3B/C) is a hallmark in most pediatric DMGs and also appears in some adults. Tumors with this mutation are assigned WHO grade IV due to their universally aggressive nature, regardless of histological appearance or location 3 4 5 6 8 9.

H3 Wild-type DMG

A minority of DMGs do not carry the H3 K27M mutation but may have other molecular alterations—such as overexpression of the EZHIP protein—that lead to similar epigenetic dysregulation 1 7. These cases highlight the expanding spectrum of DMG biology.

Subclassification by Histone Variant

Recent studies show that DMGs carrying mutations in H3.1 versus H3.3 variant histones may have unique transcriptional and epigenetic signatures, suggesting further biological diversity within H3 K27M-mutant tumors 5.

Causes of Diffuse Midline Glioma

While the precise causes of DMG remain under investigation, significant progress has been made in understanding the molecular events that drive these tumors. The discovery of recurrent mutations and epigenetic dysregulation has reshaped both diagnosis and research.

Cause/Factor	Description	Impact	Source(s)
H3 K27M Mutation	Mutation in histone H3 genes	Drives tumor, poor prognosis	3 4 5 6 9
TP53 Mutation	Tumor suppressor gene mutation	Common co-driver	1 8
Epigenetic Changes	Chromatin modification, PRC2 inhibition	Central in pathogenesis	5 7 9
Other Genetic Alterations	PDGFRA, PIK3CA, PTEN, etc.	Variable roles	1 8

Table 3: Principal Causes and Drivers

Histone H3 K27M Mutation: The Central Driver

The defining feature of most DMGs is a lysine-to-methionine (K27M) mutation in the histone H3 gene (either H3F3A or HIST1H3B/C). This single amino acid change disrupts the normal methylation of histone tails, leading to widespread epigenetic dysregulation 3 4 5 6 9. The result is a globally altered chromatin landscape that drives uncontrolled tumor cell growth and survival.

Epigenetic Dysregulation and PRC2 Inhibition

The H3 K27M mutation inhibits the Polycomb Repressive Complex 2 (PRC2), leading to reduced methylation (H3K27me3) and failure to silence genes that should be turned off during normal brain development. This “epigenetic chaos” is now considered central to DMG biology 5 7 9.

Other Genetic Events

• TP53 Mutations: Frequently observed in both pediatric and adult DMGs, these mutations disable a key tumor suppressor pathway 1 8.

• Additional Mutations: Other genes commonly mutated include PDGFRA, PIK3CA, PTEN, ATRX, and NF1 1 8. These mutations may cooperate with H3 K27M or occur in H3-wildtype DMG.

• EZHIP Overexpression: In some H3-wildtype tumors, overexpression of EZHIP mimics the effects of H3 K27M by similarly inhibiting PRC2 7.

Age and Genetic Heterogeneity

While DMGs are most common in children, adults can also develop these tumors. Interestingly, adult DMGs less frequently harbor the H3 K27M mutation and may have distinct genetic profiles 1 8. This suggests that while the core driver may be similar, the pathogenesis of DMG can vary by age and molecular subtype.

Treatment of Diffuse Midline Glioma

Treating DMG remains one of the greatest challenges in neuro-oncology. The tumor’s infiltrative nature, critical location, and unique molecular features render traditional therapies largely ineffective. Nevertheless, advances in our molecular understanding and experimental therapeutics offer hope on the horizon.

Treatment	Approach/Agent	Effectiveness	Source(s)
Radiotherapy	Focal radiation	Temporary benefit	3 8
Surgical Resection	Biopsy only, not curative	Diagnostic, not therapeutic	3 8
Chemotherapy	Temozolomide, others	Limited impact	3 12
HDAC Inhibitors	Panobinostat, quisinostat, romidepsin	Promising in trials	12 13
CAR T-Cell Therapy	GD2-targeted CAR T-cells	Early success, ongoing trials	10 11
Combination Therapy	HDACi + Marizomib	Synergistic in models	12

Table 4: Major Treatment Approaches

Standard Therapies: Radiotherapy and Surgery

• Radiotherapy: The mainstay of current DMG treatment is focal radiation, which can temporarily improve symptoms and modestly prolong survival. However, the benefit is usually short-lived, and the disease inevitably progresses 3 8.

• Surgical Resection: Due to the tumor’s location within critical brain structures, complete surgical removal is impossible. Biopsy may be performed to confirm diagnosis and enable molecular testing but is not therapeutic 3 8.

• Chemotherapy: Standard chemotherapy agents, such as temozolomide, have not demonstrated significant efficacy in DMG 3 12.

Emerging Molecular and Immunotherapies

Epigenetic Therapies: HDAC Inhibitors

Given the central role of epigenetic dysregulation in DMG, histone deacetylase inhibitors (HDACi) such as panobinostat have shown preclinical promise. Combination regimens with other agents, like the proteasome inhibitor marizomib, can induce a “metabolic catastrophe” in tumor cells, offering a potential new therapeutic strategy 12. New HDACi agents, including quisinostat and romidepsin, have also demonstrated efficacy in laboratory models and are under investigation 13.

Immunotherapy: CAR T-Cell Approaches

A groundbreaking approach involves engineering the patient’s own T-cells to express chimeric antigen receptors (CARs) targeting the GD2 molecule, which is highly expressed on DMG cells. Early-phase clinical trials report radiographic and clinical improvement in some children, with manageable toxicity when neurocritical care precautions are in place 10 11. While still experimental, CAR T-cell therapy is one of the most promising avenues for DMG treatment.

Other Experimental Strategies

High-throughput drug screens continue to identify novel agents and combinations with potential anti-DMG activity. With growing understanding of the tumor’s vulnerabilities, future clinical trials are likely to be more rationally designed and tailored to each tumor’s molecular profile 12 13.

The Future: Personalized and Combination Therapy

The future of DMG therapy will almost certainly involve:

• Personalized medicine based on the tumor’s genetic and epigenetic profile
• Rational drug combinations targeting key vulnerabilities
• Integration of novel immunotherapeutic approaches
• Careful clinical trial design to maximize benefit and minimize risk

Conclusion

Diffuse midline glioma remains one of the most challenging pediatric and young adult brain tumors, but our understanding of its biology and treatment options is rapidly evolving.

Key takeaways:

• Symptoms: Highly variable, depending on tumor location; can include headache, cranial nerve deficits, motor/sensory changes, and signs of increased intracranial pressure 1 2 4 8.
• Types: Classified by anatomic location (brainstem, thalamus, spinal cord, etc.) and molecular features (notably H3 K27M mutation) 1 3 4 5 7 8.
• Causes: Driven by mutations in histone H3 (K27M), leading to profound epigenetic dysregulation; other genetic alterations often present 3 4 5 6 7 9.
• Treatment: Standard therapies offer limited benefit; emerging options include HDAC inhibitors, combination regimens, and CAR T-cell immunotherapy, all under active investigation 10 11 12 13.

Ongoing research and clinical trials give hope that future therapies will transform outcomes for patients and families affected by this devastating disease.