Last updated:
8/27/2025
Years published: 2025
NORD gratefully acknowledges Marcelo Ramalho-Ortigao, DSc/PhD, Medical and Science Advisor, DIPG Advocacy Group, Marc Jr Foundation Board Member, for the preparation of this report.
Summary
Diffuse intrinsic pontine glioma (DIPG) is a fast-growing (aggressive) brain tumor that is hard to treat and primarily affects children between the ages of five and 10. DIPG grows within the part of the brain called the pons that controls major functions such as breathing, heart rate and motor control (dexterity). The pons, together with the medulla oblongata and the midbrain, form the brainstem. Anatomically, the brainstem is located at the base of the brain, slightly above the back of the neck, and connects the cerebellum and thalamus to the spinal cord.1,2
As suggested by its name, DIPG is characterized by a high potential to spread (diffuse) into surrounding brain tissue.2 Although DIPG tumors generally arise in the pons, they often spread into the surrounding tissues, particularly the cerebellum and thalamus as well as the spinal cord.3,4 About 80% of brainstem tumors in children are DIPG tumors.
Due to its location in the brain, surgical resection of the tumor is generally not an option for DIPG, and radiation therapy (RT) remains the standard of care.5 DIPG is still incurable and is the leading cause of pediatric brain tumor-related deaths. The prognosis for children diagnosed with DIPG remains poor, with a median survival time of nine to 10 months and a very low likelihood of surviving beyond two years.1-5
Introduction
While no definitive date exists for the first documented diagnosis, evidence suggests probable cases dating back nearly a century. DIPG gained recognition in the 1960s when astronaut Neil Armstrong’s daughter, Karen (“Muffy”) passed away from the disease.
Before 2016, tumors were classified mostly by where they appeared in the brain. In 2016, the World Health Organization (WHO) started to classify tumors not just by location but by genetic variants, so a new category was introduced called “diffuse midline glioma, H3 K27M-mutant”. This category replaced terms like “DIPG”, so a diffuse intrinsic pontine glioma with an H3 K27M mutation was called “diffuse midline glioma, H3 K27M-mutant.”
In 2021, the WHO updated the term to “diffuse midline glioma, H3 K27-altered”6 as it became clear that not all tumors with similar biology had the exact same K27M variant and that there were some tumors that had other variants that caused the same effect. The new term “K27-altered” is broader and more inclusive.
While DIPG is no longer a formal diagnostic category in WHO classifications, it is still used clinically or descriptively to refer to tumors in the pons that have classic imaging features. If the tumor has the H3 K27 variant, the formal diagnosis is “diffuse midline glioma, H3 K27-altered”. Diffuse midline glioma, H3 K27-altered also applies to other midline tumors with similar variants.
Development of DIPG likely involves specific cells in the brain and is linked to certain genetic markers known as drivers of tumorigenesis. Among the markers now identified to be directly or indirectly associated with DIPG, a change (variant) on in one of the histones H3 genes is recognized as one of the most important determinants of poor prognosis. This mutation leads to a change in the amino acid sequence of the histone protein at position 27 known as the H3K27M. H3K27M refers to the amino acid lysine (K) being replaced with a methionine (M) at position 27 in the secreted (produced) protein.3
Histones have critical roles within all cells. They help pack the DNA within the nucleus of cells and play a role in the mechanism by which proteins in the cell are synthesized by controlling which genes are turned on or off (gene expression). Thus, any change in the amino acid sequence of one of the histones H3 genes can have a severe effect on how the cell controls the expression of certain genes.
To date, other DIPG genetic markers have been identified, and many intracellular pathways have also been shown to be affected by or involved in the development of DIPG, which are providing new insights towards new therapeutic approaches. In August 2025, dordaviprone (Modeyso) was approved by the U.S. Food and Drug Administration (FDA) for treatment of diffuse midline gliomas that have the H3K27M variant.
DIPG most frequently develops and is diagnosed in children between the ages of three and 10 years but can occur in other age groups, including adults. Symptoms severely affect the child’s daily functioning and quality of life, especially at end-stage disease. DIPG symptoms range from cranial nerve palsy affecting facial expressions to issues with vision, particularly double vision (frequently observed at diagnosis) and progress to affect virtually all neuro-motor functions. Eventually DIPG symptoms will progress and affect speech abilities and the ability to swallow and eventually breathe unassisted. However, these symptoms do not necessarily occur in any particular order. Even when the person is severely debilitated, cognitive abilities remain.
Typical symptoms associated with DIPG include:
The evolution of severe symptoms varies widely among people with DIPG and in some people progression may occur rapidly. In some people, the disease may progress very quickly. Although the average survival time after diagnosis is approximately nine to 10 months, much shorter survival times of just a few weeks following diagnosis have been reported.7,8 Other affected people may live for several months more or in rare instances, a few years.
The reasons for this wide range in survival times are not yet fully understood. However, differences in tumor genetics and the specific clinical features at diagnosis may play a role. For example, research has shown that younger children (under 3 years old) and older people (over 10 years old) with DIPG who have a longer period between symptom onset and diagnosis, no cranial nerve involvement and receive systemic therapy early on are more likely to have longer survival.9
In addition, some people with brain tumors, including those with DIPG, may develop a condition known as leptomeningeal dissemination (LMD). This occurs when tumor cells spread to other parts of the central nervous system through the thin protective layers (meninges) surrounding the brain and spinal cord. LMD is often associated with a decline in symptoms, especially after radiation treatment.10 In many people, it appears following a temporary period of improvement, sometimes called the “honeymoon period”, when a child may seem to return to a more normal level of functioning.11
The development of DIPG seems to be closely linked to brain development. This theory is supported by the observation that these tumors are extremely rare in adults and occur most commonly in children between the ages of 5 and 10, a time when brain tissue is actively growing and maturing.12.13
Studies suggest that certain types of brain cells, such as neural stem cells, neural progenitor cells and early forms of glial cells (including astrocytes and oligodendrocytes) may be especially vulnerable during this early developmental stage.14-17 These cell types are generally not found in the midbrain, a region where DIPG tumors are virtually nonexistent, further supporting the idea that the location and timing of brain development may be important in tumor formation.18,19
Research has also identified high numbers of specific cells called “DIPG stem cells” in the ventral pons, a region of the brain where these tumors usually develop. These cells originate from precursor cells marked by genes such as OLIG2 (associated with oligodendrocytes development) and SOX2/Nestin (associated with neural development).14,20 The fact that DIPG tends to arise in midline brain structures during a narrow age window (typically between six and nine years old) has led researchers to describe them as “spatially and temporally restricted” tumors.21
Although the exact origin of DIPG is still unclear, several genetic markers that are strongly associated with these tumors have been identified, many of which are also linked to poor outcomes.21-23. In addition, development of DIPG is likely associated with a change (variant) in one of the genes that secretes (produces) a protein called histone H3.
Histones are proteins responsible for the packaging of DNA in the cell nucleus. Histones wrap DNA around themselves into structures called chromatin which are further condensed into chromosomes. Histones not only help the DNA fit inside the cell’s nucleus but also play a key role in controlling which genes are to be transcribed (used as a template for protein synthesis), influencing how the cell functions. There are different versions of the histone H3 protein, each secreted by a different gene. Among the histone H3 genes, H3F3A, HIST1H3B and HIST1H3C are responsible for the H3 proteins known as H3.3, H3.1 and H3.2, respectively.
One of the first genetic links found to be associated with DIPG is an amino acid change in the histone H3 protein at position 27.24,25 This change specifically replaces the amino acid lysine (K) with methionine (M). This is known as the H3K27M mutation and it has been traced back to one of the histone genes H3F3A, HIST1H3B and HIST1H3C. The most common of these are variants in H3F3A (histone H3.3) and HIST1H3B (histone H3.1).
Although the variants can occur in different histone H3 genes, they all seem to cause the same harmful effect in DIPG by altering chromatin accessibility and thus changing how genes are regulated.26,27 This variant is now recognized as a defining feature of DIPG and is thought to be one of the earliest steps in how the tumor develops.28 Such a seemingly small change in a histone gene can have a catastrophic effect by interfering with the cell’s ability to control gene activity. Specifically, the H3K27M variant interferes with gene expression which in turn can lead to tumorigenesis – this is usually referred to as a “driver of tumorigenesis”.23
The K27M variant in the H3F3A or HIST1H3B gene is found in about 80% of children with DIPG and about 60% of adults with DIPG.11,23,29 The K27M variant is particularly associated with a poor prognosis, especially in people with DIPG who are under 35 years of age.30
Other genetic markers associated with DIPG have been identified including variants in the tumor suppressor gene TP53, the activin receptor type-1 ACVR1 gene, involved in cell signaling, the PDGFRA gene involved in cell growth and survival and the chromatin remodeler ATRX gene, involved in organizing DNA structure.22,23 In some people, multiple copies of certain genes, like PDGFRA, may be present, which can also influence tumor behavior.31
In mouse models, researchers have induced tumor formation in neural cells by combining three specific genetic changes, the H3.3K27M variant, a loss-of-function T gene variant (that makes this gene unable to control cancer growth) and the continued (constitutive) activation of the Pdgfra gene.32 Variants in the tumor suppression gene Tp53 lead to a loss of function that is commonly found in cancer development.33 Pdgfra plays a critical role during embryonic development and high Pdgfra gene expression has been shown to be associated with neuroendocrine tumors.34 These results highlight how combinations of genetic alterations can drive DIPG development.
The H3.3K27M variant, in particular, appears to alter how genes are regulated, although the exact mechanisms in DIPG are still being studied.27 Overall, DIPG affects several cellular pathways involved in gene expression, cell growth, DNA repair and programmed cell death. These include the TERT pathway (involved in chromosome stability and cellular aging), the ARF pathway (associated with genome integrity and involved with cancer-inhibiting proteins), the AKT/PTEN pathway (regulates cell growth, survival, proliferation, and metabolism) and the TP53 pathway (genomic stability and cancer prevention through regulation of cell division, repairing DNA and eliminating damaged DNA).31
Lastly, it is yet to be determined what, if any, environmental factors are at play regarding these and other triggering mechanisms that are possibly associated with either the onset or the poor diagnosis of a DIPG diagnosis. However, research is ongoing to better understand what might trigger these tumors.
It is estimated that at least 250-to-300 new DIPG/ cases are diagnosed per year in the United States.2 The overall incidence is 0.35 per 100,000 population, with incidence rising when stratified by age groups. In young children, DIPG incidence is 0.38 per 100,000 in the 0-to-4-year-old age group and even higher in the 5-to-9-year-old group reaching an incidence of 0.51 per 100,000.35 Although DIPG primarily occurs in children between the ages of 3 and 10 years, DIPG can also occur in adolescents and young adults (19 to 30 years old)36,37 and in older adults.30,38,39
Previous studies have suggested that, in spite of DIPG occurring in all age groups, distribution in age groups appears to be bimodal, with one peak at 6–7 years on average19,40 and a second peak in adults aged 20–50 years (median age 34 years).41 DIPG is found to be equally prevalent in males and females.42
In addition, DIPG prevalence varies according to population background (Whites vs Hispanics vs African Americans). DIPG incidence has been reported to be higher in White (0.34 per 100,000) and Black (0.38 per 100,000) children and adolescents, as well as in non-Hispanics (0.37 per 100,000) compared to Hispanic (0.28 per 100,000) children and adolescents.35,43
The actual number of DIPG cases is difficult to estimate due to many issues. No mechanism currently exists for central pathology review of cases within the U.S. cancer registry system, and data reflect the prevailing criteria for the histopathology at the time of case registration.44 This means that reclassification of tumors based on any new more accurate criteria is not possible. In addition, there is significant variability in how pathologists classify gliomas, and this may result in a lower estimate of DIPG cases. Nevertheless, DIPG patient and tumor data collected by the DIPG Registry can assist clinicians and scientists during diagnosis and treatment selection, and provide a bridge for correlative data that may also be available from individual DIPG cases.
DIPG diagnosis is based on symptoms including cranial nerve deficits, motor problems and ataxia, in combination with one or more of the following:
Typical DIPG tumors are darker than normal brain tissue (hypointense) with indistinct margins or unclear edges when viewed using T1-weighted MRI, which is one method of looking at brain structure. In contrast, on under T2-weighted or fluid-attenuated inversion recovery (FLAIR) images, which highlight fluid and swelling in the brain, DIPG tumors appear brighter than surrounding tissue (hyperintense).45,46
Unlike some other brain tumors, such as pilocytic astrocytomas (a slower-growing tumor often seen in children) or other tumors of the central nervous system, DIPG usually does not show strong uptake of contrast dye (gadolinium) on MRI scans. This means the tumor often does not “light up” after contrast is given, which helps distinguish DIPG from other types of tumors.47 Due to its non- or less-invasive approach, MRI in general is the standard and safest method for diagnosing DIPG.
Conclusive DIPG diagnosis can typically be attained by combining the clinical symptoms observed with the radiologic and MRI scans without the need to remove a fragment of tumor for testing (biopsy). However, depending on the individual situation, a DIPG biopsy may be used to assess underlying details of the biology of the tumor. In spite of its inherent risks, stereotactic biopsies of DIPG are considered safe when performed by a properly trained neurosurgeon.48 Furthermore, genetic analyses of tissue biopsy of DIPG tumors through techniques like whole-genome sequencing and single-cell RNA profiling can be used to identify specific targets for therapy and provide a roadmap for individualized treatment potentially leading to better outcomes.49,50
DIPG is characterized by its rapid growth and spread within the pons (a part of the brainstem), making surgical removal impossible and conventional chemotherapy ineffective. Radiation (RT), either photon- or proton-based, remains the standard therapy for DIPG with dosage ranging between 54 to 60 Gray (Gy) typically spread out in 180–200 Centigray (cGy) fractions administered five days per week generally for six-to-eight weeks. However, when beneficial, the palliative nature of RT provides only temporary benefits and the tumor shrinkage observed following RT is reversed in a matter of weeks or months.5 Corticosteroids and/or anti-angiogenic drugs such as bevacizumab (Avastin) are often used to control the radiation-induced swelling (edema) that often follows RT.51,52
To date, various molecules or compounds have been used against DIPG, sometimes in combination with RT, but many failed to extend the life of children with DIPG.53 Effective delivery of drug compounds to the tumor cells is hampered by the low or complete lack of permeability of such drugs to the blood brain barrier. DIPG/DMG is still incurable and is the leading cause of pediatric brain tumor-related deaths.
In August 2025, dordaviprone (Modeyso) was approved by the U.S. Food and Drug Administration (FDA) as the first systemic therapy for diffuse midline glioma (DMG). Modeyso is an imipridone approved to treat adults and children one year of age or older who have a diffuse midline glioma with a H3K27M variant and progressive disease after RT therapy.
It is very important for DIPG patients to have access to and receive appropriate palliative care. As the DIPG symptoms progress, parents and other caregivers become completely responsible for providing all the support required, from personal hygiene and feeding, to taking care of any illness that may occur. DIPG patient care eventually will involve not only caretakers, family and physicians, but also a network of physical and speech therapists, support medicine and mental health care providers. Visit https://www.dipgregistry.org/patients-families/end-of-life-care/ for further details. However, no disease-specific guidelines pertaining to palliative and end-of-life care exist, even for DIPG.54
In addition to DIPG’s significant psychological impact, families deal with financial issues as the cost of available therapies for DIPG can be extremely high.55 Current DIPG average survival hovers between nine and 10 months. Pediatric cancer is the leading cause of childhood mortality in the U.S. with DIPG being the deadliest of all cancers.
Novel therapies for DIPG continue to emerge as new oncogenic targets are identified and efficient drug delivery approaches are developed and applied.53,56-58 In recent years, a few encouraging results have been observed. Oral treatment based on the new class of small molecules called imipridones, including ONC201 and ONC206, have shown benefits in people with DIPG, especially in people with a confirmed K27M variant.59-61
The use of chimeric antigen receptor (CAR) T-cell immunotherapy targeting cells markers such as GD2 and T7-H3 that are often overexpressed in tumor cells, have also shown encouraging results.62-64 Neverthelss, additional clinical trials focusing on combination therapy will likely provide the evidence that, for DIPG, a multitargeted approach with continued drug pressure is critical to prevent tumor cell resistance and regrowth of tumor. Genetic profiling of DIPG tumors may provide additional information about potential therapeutic targets.
Information on current clinical and natural history trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact: www.centerwatch.com
For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
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