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Table of Contents
Year : 2021  |  Volume : 4  |  Issue : 4  |  Page : 68-84

Germline predisposition to glial neoplasms in children and young adults: A narrative review

Division of Hematology/Oncology, The Hospital for Sick Children (SickKids), Toronto, ON, Canada

Date of Submission04-Sep-2021
Date of Decision13-Sep-2021
Date of Acceptance17-Sep-2021
Date of Web Publication13-Jan-2022

Correspondence Address:
Dr. Uri Tabori
Division of Hematology/Oncology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, M5G 1X8
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/glioma.glioma_12_21

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Gliomas are the most common malignancies of the central nervous system (CNS). A significant proportion of both low- and high-grade gliomas in children, adolescents, and young adults have specific genetic events which can be traced to the germline. Despite integration of genomic findings in recent CNS tumor classifications, germline origins of these genetic events are seldom highlighted. These cancer predisposition syndromes can predispose the individual and family members to multiple cancers in different organs beyond the CNS and to other non-oncologic manifestations caused by the genetic dysfunction. Recent molecular discoveries and careful surveillance have resulted in improved survival and reduced morbidity for many of these conditions. Importantly, identifying a genetic predisposition can alter treatment of the existing malignancy, by mandating the use of a different protocol, targeted therapy, or other novel therapies. Hence, prompt diagnosis is sometimes crucial for these young patients. High index of suspicion and early referral to genetic testing and counseling are important and may be beneficial to these families. In this review, we discuss the clinical manifestations, genetics, tumor management, and surveillance in these patients. These provide insights into the complex mechanisms in glioma-genesis that can impact the treatment and survival for these patients and families in the future.

Keywords: Cancer predisposition, germline, glioma, pathogenic/likely pathogenic variants, review, surveillance

How to cite this article:
Das A, Hawkins C, Tabori U. Germline predisposition to glial neoplasms in children and young adults: A narrative review. Glioma 2021;4:68-84

How to cite this URL:
Das A, Hawkins C, Tabori U. Germline predisposition to glial neoplasms in children and young adults: A narrative review. Glioma [serial online] 2021 [cited 2023 Feb 6];4:68-84. Available from: http://www.jglioma.com/text.asp?2021/4/4/68/335757

  Introduction Top

Neoplasms of the central nervous system (CNS) are the second most common tumors in children, adolescents, and young adults (CAYA) and are the major cause of cancer-associated mortality in this age group.[1] Tumors of glial origin are the most common CNS tumors[1] and can be either acquired or inherited. Cancer results from unregulated cell growth driven by deleterious variations in the cell's genome or epigenome causing abnormal activation of oncogenes or inactivation of tumor-suppressor genes.[2] These inherited variants are more common in the young patients with CNS tumors including gliomas. Better understanding of cancer predisposition syndromes (CPSs) may affect the management and survival of the patients and their families.

The WHO Classification for CNS Tumors (Fifth edition, WHO-2021) has clearly demarcated the distinct biology of pediatric- and adult-type gliomas.[3] However, despite highlighting the integration of histological and molecular aberrations, it does not sufficiently elaborate on the germline versus somatic origins of many of these molecular alterations. This is of utmost significance, especially for young patients, as unlike older adults, up to 15%–21% of all childhood brain tumors,[4],[5] and up to 5%–10% of all gliomas[6],[7] are linked with CPS. Further, the increasing use of sequencing resulted in discovery of novel, putative pathogenic variants which can be traced back to the germline.

In this review, we divide the approach and diagnosis of CPS according to the pathological grade of the glioma (low-grade versus high-grade), as the initial and management plans may differ depending on this. We highlight the emerging considerations and clinical implications in well-known syndromes in CAYA diagnosed with CPS and glial and glioneuronal tumors and summarize some of the relevant discoveries in the field of glioma cancer genetics in the context of CPS.

  Database Search Strategy Top

Literature review was electronically performed using PubMed database. The following combinations of keywords were used to initially select the articles to be evaluated: Glioma and cancer predisposition; glioma and germline predisposition; glioma and genetic predisposition; familial and glioma. The authors then screened the reference list of all included studies to identify other potentially useful studies. After screening, manuscripts in the English language and full-text articles published between January 1991 and July 2021 were included in this nonsystematic, narrative review. As per current recommendations, we used the terms pathogenic and likely-pathogenic variants in lieu of the term “mutation” for germline defects due to negative connotations associated with this, restricting the term “mutations” for tumor-only (somatic) aberrations.

  Germline Predisposition in Patients with Low-Grade Glial and Glioneuronal Tumors Top

Low-grade glioma in neurofibromatosis type 1

Neurofibromatosis type 1 (NF1) is one of the most common (1:2600–1:3000) autosomal dominant multisystemic disorders, with well-characterized diagnostic criteria and associated anomalies [Table 1].[8]
Table 1: Summary of germline cancer predisposition syndromes in patients with glial neoplasms

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NF1 results from pathogenic variants in the NF1 gene located in chromosome 17q11. NF1 encodes the protein neurofibromin which inhibits the major oncogene RAS. Neurofibromin is a GTPase which catalyzes the hydrolysis of active guanosine triphosphate RAS to inactive guanosine diphosphate RAS.[30] Dysfunctional neurofibromin results in constitutive activation of downstream oncogenic pathways including mitogen-activated protein kinase (MAPK) and mammalian target of rapamycin (mTOR).

Penetrance in NF1 is complete. A child who inherits a pathogenic variant in NF1 will inevitably develop features of NF1, but it may be impossible to predict which features will evolve, even within the same kindred.[31] Hence, the clinical presentation can be extremely variable. Most pathogenic variants led to loss of function. In ~5%, NF1 is due to deletion of the entire gene.[31] Over 500 pathogenic and likely-pathogenic variants have been identified which are usually unique to families but inherited from an affected parent in only 50%.[32] When it appears de novo, siblings of the proband have a low risk of having inherited the disease; however, this can still happen due to germline mosaicism in one of the unaffected parents.

Tumor spectrum

Benign and malignant neoplasms seen in NF1 include neurofibromas, malignant nerve sheath tumors (transformed from neurofibromas), leukemia (particularly, juvenile myelomonocytic and chronic myelomonocytic leukemia), and solid tumors. However, the CNS is one of the most common locations for NF1-associated tumors. These include low-grade optic pathway/hypothalamic gliomas, gliomas arising in the brainstem, as well as low-grade glioma (LGG) and high-grade gliomas elsewhere along the neuraxis.[33]

Optic pathway gliomas in neurofibromatosis type 1

Optic pathway gliomas are the most common CNS tumors in NF1. These gliomas lack other (non-NF1) RAS/MAPK alterations like BRAF fusion or mutation that are otherwise seen in sporadic cases.[34] Although optic gliomas are WHO grade I tumors, morbidity may be significant. They may cause decreased vision, precocious puberty, and other endocrine abnormalities.

Natural history and genotype/phenotype associations

Optic gliomas usually in infancy and rarely develop after late childhood. They occur in ~13%–15% of individuals with NF1, with ~50% being symptomatic.[35] Prevalence is largely underestimated because routine screening with brain magnetic resonance imaging (MRI) is controversial. Patients with mutations at the 5' end of the gene[36] and from Caucasian descent[37] are at higher risk of developing gliomas, and adenylate cyclase-8 gene polymorphisms[38] may have a modulatory effect on glioma-genesis in patients with NF1.


NF1-related optic gliomas have similar neuroradiologic findings as non-NF1-associated optic gliomas, including solid-cystic appearance and variable enhancement.[39] The co-appearance of foci of abnormal signal intensity and bilateral involvement is highly suggestive of NF1 [Figure 1].
Figure 1: Typical magnetic resonance imaging findings in an NF1 patient. (A) Widened and convoluted bilateral optic nerves which are pathognomonic for NF1 (arrows). (B) T2-weighted images revealed bilateral high intensity subcortical lesions (arrows). Unpublished data. NF1: Neurofibromatosis 1, R: Right

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Lack of routine surgical biopsies has limited neuropathological studies of NF1 gliomas. However, NF1 gliomas are almost invariantly pilocytic astrocytoma or one of its variants (e.g., pilomyxoid) and are not distinguishable from those occurring sporadically based on histology. A recent study including integrated molecular and histologic analyses reported that up to 88% of low-grade gliomas (LGGs) in NF1 are classified as pilocytic astrocytoma by methylation, as compared to 56%–64% using histology alone.[40] Bi-allelic inactivation of NF1 was characteristic, and low mutation rates overall were observed, as expected. However, a small subset of optic gliomas (and 20% of LGGs elsewhere in NF1) harbored additional alterations, putatively co-(FGFR1) or exclusively (FGFR1, MYB:QK1) driving LGG in the backdrop of germline NF1. These variants were frequently detected in tumors not classifying as pilocytic astrocytoma on the methylation-based classifier.[40]

Tumor management

Routine screening using brain MRI is controversial for the diagnosis of clinically relevant optic gliomas in patients with NF1.[41],[42] Since only a subset of children with NF1 and optic gliomas will need any treatment, a conservative approach remains the standard. Watchful observation with ophthalmologic examinations every 6–12 months (including detailed assessment of visual fields using age-appropriate methods), imaging, and endocrine evaluation are recommended. Optical coherence tomography can help detect early retinal nerve fiber length thinning, and serial monitoring can detect early deterioration. However, practical applicability may be limited by need for sedation in small children.[43]

NF1-related optic gliomas have a better natural history and treatment response, with prolonged growth stability compared to sporadic tumors. Treatment is initiated only when one/both of serial tumor progression by MRI and/or symptom progression such as visual loss are observed. Patients with radiological involvement of the posterior optic tracts, age <2 years, and female gender are at increased risk of progression.[44]

As in sporadic optic gliomas, surgical resection is unfeasible in the majority of NF1-associated optic gliomas. Chemotherapy is the initial modality of treatment. Effective regimens include vincristine/carboplatin, vinblastine, vinorelbine, with or without bevacizumab, as the latter can potentially reverse visual loss. MEK-inhibition using trametinib or selumetinib are effective options at progression. Use as first-line agents or as combinations are being studied in ongoing clinical trials.[45],[46],[47] A summary of ongoing clinical trials for these patients is summarized in [Table 1].

Patients with NF1 are sensitive to ionizing radiation and are at high risk of radiation-induced cancers[48] as well as vascular insult, resulting in Moyamoya syndrome. Radiotherapy should be avoided at all cost for these patients.

Other white matter and brainstem lesions in neurofibromatosis type 1

Use of MRI has led to more frequent identification and delineation of signal abnormalities in asymptomatic NF1 patients. Presence of multiple, nonenhancing areas of high signal intensity, typically <5 mm without mass effect or edema, is well recognized on T2-weighted MRIs in children with NF1.[49] These lesions are often considered to be pathognomonic of NF1 in children,[49] although they are not currently considered to be one of the diagnostic criteria. It is thought that these lesions do not have potential for malignant transformation and hence can be observed. These brainstem hyperintensities are frequent and sometimes may be difficult to distinguish from LGGs.

Focal brainstem enlargements with or without abnormal signal change or mass effect are seen in ~10%–15% and usually present at a mean age of 7 years.[50],[51] In one study, 23 such brainstem lesions (~20%) were described among 125 NF1 patients and only six of these patients required treatment (surgery, irradiation, or chemotherapy).[51] Only one of the 17 untreated patients experienced radiographic and clinical deterioration.[51] Pathology data are limited by the small number of biopsied cases. In one retrospective series, pilocytic astrocytoma and diffuse LGG were both frequent.[52] As with optic gliomas, conservative management is favored for brainstem lesions because of their usually indolent behavior. Treatment is needed in those with documented progression on serial MRIs and neurological deterioration. A biopsy may be required before treatment initiation since these lesions may range from low-grade to high-grade ones.

Diagnosis of neurofibromatosis type 1

Genetic testing is not mandatory to establish a diagnosis of NF1 [Table 1]. However, genetic confirmation may be useful in certain situations like, offering prenatal diagnosis, in some patients with atypical features, and in younger patients with incomplete clinical features not sufficient to fulfill the diagnostic criteria. When indicated, testing should involve both mRNA and genomic DNA to detect not only pathogenic and likely-pathogenic variants in the coding region but also whole-gene deletions and splice site alterations.[31] Current strategies reach a detection rate of about 95%.[31] It is important to remember that mosaicism as a cause of segmental NF1 is relatively common.

Clinical implications for the diagnosis of neurofibromatosis type 1 in a patient with glioma

Patients diagnosed with NF1 and optic gliomas should avoid radiotherapy. Physicians should favor MRIs for diagnosis and monitoring rather than computed tomography scans to decrease radiation exposure. More studies are needed to improve our understanding about the malignant transformation of NF1-related gliomas. These findings may ultimately lead to the development of more targeted therapeutic agents for children with NF1.

Since NF1 is a systemic disease, surveillance by a dedicated team is recommended for all aspects of the syndrome in parallel to neuro-oncological surveillance/therapy [Table 1].[9] With age, patients are at risk of different cancers (premenopausal breast cancer: 2–4-fold risk, gastrointestinal stromal tumors, pheochromocytomas), bony complications (scoliosis, pseudarthrosis, bony dysplasia), vasculopathies, and neurocognitive/behavioral issues. Tumors and vasculopathies account for a reduction in life expectancy by ~15 years in patients with NF1.

  Low-Grade Glioma In Other Ras-Opathies Top

Other syndromes harboring germline alterations in the RAS-MAPK pathway have been reported to develop LGG. A recent review reported on patients with Noonan syndrome and gliomas harboring PTPN11 alterations.[53] Histologically, most were glial or glioneuronal tumors and were enriched for dysembryoplastic neuroepithelial tumors (40%). Response to mTOR inhibitor was reported in a single patient.[53]

  Subependymal Giant Cell Astrocytoma in Patients with the Tuberous Sclerosis Complex Top

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder with a prevalence of 1:6000. Like NF1, it is a multisystem disorder with established diagnostic criteria [Table 1].[13]


TSC can be caused by pathogenic variants in either of two different genes, TSC1 (chromosome 9q34) and TSC2 (chromosome 16p13).[54] These tumor-suppressor genes are inhibitors of mTOR, which is a key component of pro-proliferative and metabolic pathways and is involved in many cancers.[54] Penetrance is incomplete, which means that some individuals inherit a TSC1/TSC2 mutation but never develop any clinical feature of TSC. Even when the variant is not found in parents, there is a residual risk for siblings of a proband because of the risk of germline mosaicism (~2%).[54] There exist minor differences depending on whether the pathogenic/likely-pathogenic is in TSC1 versus TSC2.

Subependymal giant cell astrocytoma and tuberous sclerosis complex

The pathognomonic CNS neoplasm in TSC is subependymal giant cell astrocytoma (SEGA), a WHO grade I tumor classified as a “circumscribed astrocytic glioma” in WHO-2021,[3] which affects 5%–15% of patients, presenting in the first two decades of life.[55]


SEGAs can often be identified radiologically before they become symptomatic; they are usually well-circumscribed, sometimes calcified, and contrast-enhancing lesions [Figure 2].
Figure 2: SEGA in a patient with tuberous sclerosis. (A) SEGA (arrow) causing hydrocephalus. (B) Same tumor (arrow) after 3 months of therapy with oral sirolimus. (C) Pathology (hematoxylin and eosin) shows a low-grade tumor composed of cells with monomorphic round nuclei and abundant eosinophilic cytoplasm with low Ki67 (inset) and (D) focal GFAP positivity consistent with SEGA. Unpublished data. GFAP: Glial fibrillary acidic protein, R: Right, SEGA: Subependymal giant cell astrocytoma

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SEGAs are composed of fascicles and nests of epithelioid, gemistocyte-like cells with cytologic and immunophenotypic features intermediate between astrocytes and neurons. They are thought to arise from subependymal hamartomatous nodules (“candle gutterings”), which are disorganized collections of dysmorphic neurons and balloon cells with glioneuronal immunophenotype, such as cortical tubers.[56]

Tumor management

Due to their characteristic location near the foramen of Monro, SEGAs often cause increased intracranial pressure due to obstruction of CSF pathways.[57] Early diagnosis can improve chances of curative surgery. Such lesions can grow rapidly, especially in childhood, justifying serial follow-up MRIs during childhood and adolescence when the risk of SEGA is highest.

Surgical resection was the standard treatment until it was demonstrated that mTOR inhibitors are able to reduce tumor size in almost all patients [Figure 2].[58] Stopping therapy, however, results in regrowth in most cases. Currently, oral therapy with everolimus or sirolimus is used as initial therapy in many centers [Table 1]. mTOR inhibition has been reported to result in improvement in obstructive hydrocephalus from TSC-related SEGA,[57] delaying or obviating the need for surgical CSF diversion. Importantly, mTOR inhibition improves seizure control,[59] skin manifestations, and other lesions such as lymphoangiomatosis which can be life-threatening in patients with tuberous sclerosis. Therefore, although the improvement in surgical techniques[60] allows for individualized decisions between surgery and medical management, many patients remain on long-term therapy following discussions with the family.[14]

Diagnosis of tuberous sclerosis complex

Testing for TSC1 and TSC2 can be performed by sequencing and deletion/duplication analysis,[54] but it is not required to establishing the diagnosis [Table 1]. Genetic testing is helpful in atypical cases or to assess whether a seemingly unaffected first-degree relative is at risk of transmitting the disease to its offspring, since the pathogenic variant may be nonpenetrant in some individuals. Even in individuals with a clear clinical diagnosis of TSC, the detection rate when testing for TSC1 and TSC2 is 85%.[54]

Clinical implications for a diagnosis of tuberous sclerosis complex

As with NF1, TSC is a systemic condition requiring a multimodal approach. Given the range of organ systems affected, management requires coordination across several medical specialties over a patient's lifetime.[55] Surveillance protocols for all clinical aspects of TSC including tumors are available.[14] Periodic neuroimaging using MRI is recommended every 1–3 years up to 25 years of age.[61] The initial treatment of SEGAs and length of treatment remain controversial. Nevertheless, growing evidence of improvement in neuropsychiatric, seizure control, and other manifestations of TSC using mTOR inhibitors suggests that these agents remain an attractive option for medical management for these patients beyond SEGAs [Table 1].[59]

  Cerebellar Dysplastic Gangliocytoma in the Pten Hamartoma Syndrome Top

PTEN hamartoma tumor syndrome (PHTS) is an entity that includes four clinical syndromes inherited as autosomal dominant disorders with established clinical features, all associated with germline mutations in PTEN: Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, PTEN-related Proteus syndrome and PTEN-related Proteus-like syndrome [Table 1].[16] Prevalence estimate is 1:200,000.


PTEN is a major tumor suppressor of the PI3K-AKT-mTOR pathway, which is activated in many cancers including brain tumors. About 60%–90% of individuals carrying PTEN pathogenic variant inherit their pathogenic variant from a parent.[16]

Tumor spectrum

Malignancies develop mostly in adults and include benign and malignant tumors of breast (fibrocystic disease, carcinoma), thyroid (adenomas and epithelial, especially follicular carcinoma), endometrium (fibroids and carcinoma), skin (lipoma), kidney (renal cell carcinoma), and brain.[16]

  Cerebellar Dysplastic Gangliocytoma Or Lhermitte-Duclos Disease Top

This is a rare, focal cerebellar tumor composed of dysplastic ganglion cells. It is classified under glioneuronal and neuronal tumors in WHO-2021.[3] The lesion can be identified incidentally or cause mass effect in the posterior fossa and/or hydrocephalus. It is more common in adults, with incidence of up to 35%,[62],[63] and is regarded as one of the pathognomonic criteria for PHTS [Table 1]. In contrast, in children, there are only few cases of reported, occasionally with no identified PTEN germline pathogenic/likely-pathogenic variant.[62]


Imaging typically shows a nonenhancing gyri form pattern of enlargement of cerebellar folia, described as “tiger-striped” pattern on T2-weighted image in MRI [Figure 3]. This pathognomonic pattern can obviate the need for a diagnostic biopsy in asymptomatic patients.[64] Other abnormalities in brain MRI have also been noted in patients with PHTS.[65]
Figure 3: Cerebellar dysplastic gangliocytoma (Lhermitte-Duclos disease) (arrow) identified incidentally in magnetic resonance imaging in a child with PTEN Hamartoma Syndrome. Unpublished data. R: Right

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Surgical resection is the usual management, though some lesions can be conservatively observed.[66] A pediatric patient with unresectable tumor was treated with rapamycin with a good response.[67]

Diagnosis of PTEN hamartoma tumor syndrome

Diagnosis of a cerebellar dysplastic gangliocytoma should always prompt germline testing for pathogenic/likely-pathogenic variants in PTEN in all patients. Approximately 90% of patients with PHTS manifest with clinical symptoms before 20 years of age due to combination of macrocephaly and developmental delay/delay/another phenotypic feature. Probability for identification of a pathogenic variant can be calculated using the Cleveland clinic score (http://www.lerner.ccf.org/gmi/ccscore). Testing should include sequencing (including promoter region if possible) as well as deletion/duplication analyses.

Clinical implications for a diagnosis of PTEN hamartoma tumor syndrome

All carriers of germline PTEN pathogenic variant are considered to have increased risk of cancers and need to follow the cancer screening and surveillance strategies.[16],[17],[68]

  Low-Grade Gliomas with Increased Risk of Transformation in Cancer Predisposition Syndrome Commonly Associated with Malignant Gliomas Top

Some CPSs, such as Li-Fraumeni and DNA replication repair deficiency syndromes, are characterized by the high prevalence of high-grade gliomas. Although the majority of these patients will present with high-grade tumors, LGGs can be observed in these patients, especially when surveillance is employed. These will invariably transform to high-grade tumors, and early diagnosis and treatment may have an impact on outcome.[69] Detailed discussion of these syndromes is reserved to the next section.

  Germline Predisposition in Patients with High-Grade Glioma Top

Neurofibromatosis type 1

In patients with NF1, high-grade diffuse gliomas are reported throughout the CNS in both supra and infratentorial locations but rarely involve the optic tracts. High-grade tumors are frequent in adults (78%) in comparison to children. Malignant transformation from lower-grade gliomas is well recognized. These gliomas harbor a distinct biology, with higher mutation load than their lower-grade counterparts, and though they are commonly both IDH and histone-wild type, they are enriched for mutations in ATRX, TP53, and CDKN2A copy number losses.[70] Data suggest that anaplastic transformation can involve activation of the PI3K/AKT pathway and may not always be related to prior radiation therapy.[71] NF1-associated glioblastomas may have prolonged survival than their sporadic counterparts,[72] particularly in younger patients; however, cure is uncommon. Current management follows the same principles as in sporadic cases including radiation because of the absence of alterative effective treatment modalities.

Li-Fraumeni syndrome

Li-Fraumeni syndrome (LFS) is an autosomal dominant disorder, with a prevalence varying from 1:5000 to 20,000, and considered the prototype of CPS, with well-established diagnostic criteria [Table 1].


LFS is caused by germline pathogenic variants in the TP53 gene located on chromosome 17p13, a tumor-suppressor gene widely regarded as the “guardian of the genome”.[73] Most pathogenic/likely-pathogenic variants are inherited, but 7%–20% are de novo, with negative family history in most of those cases. Penetrance is high but not complete, and few genotype–phenotype correlations have already been established. The risk of cancer in LFS is up to 41% in childhood,[74] with >90% lifetime risk, though newer estimates are needed as more nonpenetrant cases are identified through nonspecific genetic testing. There are higher overall cancer risks in women, but more LFS males are affected with brain tumors.[75],[76]

Tumor spectrum

Individuals are at high risk of developing most types of adult cancers. In children, adrenocortical carcinoma, rhabdomyosarcoma, osteosarcoma, and leukemia are the most common non-CNS tumors. Brain tumors are the second most common LFS-associated childhood malignancy. Brain tumors associated with LFS are high-grade gliomas, choroid plexus carcinoma, and medulloblastoma.[77],[78]

High-grade gliomas in Li-Fraumeni syndrome

Malignant gliomas are the most frequent brain tumors in LFS and arise during late childhood and adult life, with 71% diagnosed in patients <25 years of age. In the setting of LFS, both de novo tumors as well as transformation from lower-grade tumors, even in the absence of radiation are reported.[79]


Histologically, these are usually diffuse astrocytic neoplasms. Though they can be IDH-mutant (dominated by non-p.R132H variants)[80] or wild-type, biology is considered distinct from sporadic HGG.[79] IDH-mutant diffuse astrocytoma is frequent in females, arises in the cerebral hemispheres in the 2nd–3rd decade, and usually has biallelic TP53 inactivation, ATRX mutations, and lack other chromosomal aberrations.[81] IDH-wild type tumors develop in males in the 1st and 2nd decades, arise anywhere in the neuroaxis, and in addition to uniform biallelic TP53 inactivation, are reported to harbor a host of aberrations including biallelic inactivation of NF1, point mutations in EGFR, and chromosomal copy number changes, including MYCN amplification and homozygous deletion of CDKN2A/B.[81]

Tumor management

While radiation may increase the risk of secondary tumors in LFS, in the absence of alterative effective therapies, currently, this remains the backbone for treatment for patients with diffuse gliomas. Specific therapies for TP53-associated tumors are being investigated and are greatly needed. In the setting of LFS, IDH-mutant gliomas have a longer median progression-free survival of 57 months, as compared to IDH-wild-type tumors where this was only 5 months.[81] Synchronous tumors may need to be excluded [Figure 4].
Figure 4: A patient with Li-Fraumeni syndrome presenting with synchronous adrenocortical carcinoma and glioblastoma (arrows) (A). (B) Whole body images to show the synchronous tumors (arrows) in the brain and adrenal cortex. (C) A dedicated magnetic resonance imaging of the brain showing the glioblastoma (arrow). Unpublished data. R: Right.

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Diagnosis of Li-Fraumeni syndrome

As LFS is a pure cancer syndrome, there are no other phenotypic characteristics associated with LFS that can prompt a diagnosis, except specific tumor types at a young age, and personal past or family history of cancers. Sequencing of TP53 detects about 95% of all pathogenic/likely-pathogenic variants, and deletion analysis can identify an additional 1% of pathogenic/likely-pathogenic variants in TP53.[77]

Clinical implications of a diagnosis of Li-Fraumeni syndrome

A diagnosis of LFS has implications for both the index patient and his/her family members. Surveillance and early diagnosis improve outcome [Table 1].[20],[21] Surveillance is also important for patients with the subset of high-grade gliomas demonstrated to have a relatively prolonged survival.[21]

DNA replication repair deficiency syndromes

The syndromes include constitutional mismatch repair deficiency syndrome (CMMRD), Lynch syndrome; and polymerase proofreading-associated polyposis (PPAP).[82]

DNA replication repair deficiency (RRD) syndromes include conditions arising from germline defects in the DNA mismatch repair (MMR: PMS2, MLH1, MSH2, MSH6, EPCAM) genes and polymerase-proofreading (PP: POLE, POLD1) genes.[25] Germline homozygous or biallelic loss of MMR function gives rise to CMMRD (exact prevalence unknown but increasingly recognized), while germline heterozygous loss results in Lynch syndrome (prevalence: 1:300). Each of these conditions has separate diagnostic criteria and clinical features[24],[83] [Table 1]. In older literature, these conditions have been included as brain tumor polyposis syndrome type 1 and as a subset of Turcot syndrome.[84] With increased recognition, RRD is being considered the most common of germline cancer predisposing syndromes causing malignant gliomas in humans.


Pathogenic variants in the MSH2, MSH6, PMS2, or MLH1 genes, or EPCAM, which leads to MSH2 silencing, are responsible for MMR deficiency.[25] In contrast to Lynch syndrome where pathogenic variants in MLH1 and MSH2 are frequent, in CMMRD biallelic PMS2 variants are most frequent, followed by MSH6. The MMR system is one of the major DNA repair pathways in humans. Its primary function is to repair specific types of DNA errors such as single base pair mismatches and insertion-deletion (indels) in microsatellites which commonly occur during DNA replication. This leads to accumulation of single nucleotide variants and insertion/deletions, particularly in microsatellites which are the hallmarks of a hypermutator phenotype.[85],[86] Penetrance of CMMRD is extremely high reaching >90% at age 20 years.[25]

Tumor spectrum

CMMRD is arguably the most aggressive and penetrant human cancer syndrome. As such, the individuals commonly present with leukemia and lymphomas and premalignant and malignant gastrointestinal lesions, but all cancer types were reported with this syndrome. Nevertheless, the most common malignancy and the most common cause of death are brain tumors.[25] Brain tumors associated with CMMRD are malignant gliomas and medulloblastoma/other embryonal tumors. Diagnosis of synchronous and metachronous tumors of different histology and molecular profiles is reported, and multiple lesions should not always be considered as metastatic disease.[87] Lynch and PPAP syndromes stem from similar mechanisms; however, since these are heterozygous germline mutations, penetrance is less strong and most individuals present later in age with gastrointestinal and genitourinary cancers which are the hallmark cancers for these syndromes. However, high-grade gliomas are increasingly recognized in adolescents and young adults with both Lynch and PPAP and may be more common than CMMRD as a cause of hypermutant gliomas in this age group.

  High-Grade Glioma in Germline Replication Repair Deficiency Top

Genotype/phenotype associations

Gliomas are seen in the first two decades in patients with CMMRD. In contrast, gliomas in Lynch syndrome are common among older adolescent and young adults. Importantly, tumors in patients with germline heterozygous Lynch syndrome can acquire a somatic hit in a second MMR gene, making the tumor biallelic MMR deficient with an identical clinical behavior. Further, MMR-deficient cancers in both CMMRD and Lynch patients can acquire further somatic hits in the DNA-polymerase proofreading genes (POLE, POLD1), leading to complete RRD, and an ultra-hypermutator phenotype (mutation burden >100 mutations/Mb).[85],[86] Likewise, tumors in germline PPAP can acquire secondary MMR deficiency resulting in similar tumor biology.[88]


Unique radiological features in patients with germline RRD, specifically CMMRD [Figure 5]A and [Figure 5]B, include multifocal tumors, which should not be construed as metastases,[87] subcortical hyperintensities, some of which may undergo neoplastic transformation, developmental venous anomalies, and cavernous hemangiomas.[89]
Figure 5: Unique features of high-grade gliomas in patients with CMMRD. (A) Bifocal glioblastoma: Two separate lesions (arrows) were diagnosed in an infant with CMMRD. Molecular and genetic analysis confirmed distinct biology, excluding the possibility of a metastatic disease. (B) MRI can reveal multiple developmental venous anomalies (arrow). (C) Pathology (hematoxylin & eosin) showing multi-nucleated giant cell (arrow) with inset showing positivity for GFAP and p53. (D) Glioblastoma with loss of PMS2 staining in cancer cells and normal tissue with retained staining for MLH1, MSH2 and MSH6, suggesting CMMRD. (E) A patient with glioblastoma and loss of PMS2 and MLH1 stains in tumor tissue and retained PMS2 and MLH1 staining of normal tissue suggesting Lynch syndrome. Stains for MSH2 and MSH6 were retained for both normal and tumor tissue. (F) High CD8+ T-cell infiltration and (G) PD-L1 expression in RRD gliomas make them amenable to immune checkpoint inhibition. Unpublished data. CMMRD: Constitutional mismatch repair deficiency syndrome, GFAP: Glial fibrillary acidic protein, MRI: Magnetic resonance imaging, PD-L1: Programmed death ligand 1, RRD: DNA replication repair deficiency

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Histologically, some RRD gliomas may have atypical morphology compatible with pleomorphic xanthro-astrocytoma. Giant cell morphology [Figure 5]C and increased immune infiltrates in the microenvironment [Figure 5]F and [Figure 5]G have been described.[90] Gliomas with an embryonal histology have also been reported.[91] RRD gliomas are characterized by extensive intra-tumoral heterogeneity and high tumor mutation burden secondary to the underlying error in DNA repair pathways.[86] High indel burden at microsatellite loci across the whole genome is common.[92] Surveillance can identify LGGs, which can transform to higher-grade tumors if left untreated.[69] Methylation-array analysis reveals that RRD gliomas cluster according to the specific drivers such as IDH and histone alterations.[93] Interestingly, RRD gliomas harboring IDH mutations are distinct from other IDH-mutant astrocytoma, as they cluster separately, show lower prevalence of copy number alterations, are driven by mutations in TP53, RB1, and PDGFRA, and have an aggressive clinical course.[94] The majority of RRD gliomas are both IDH and histone wild-type and cluster within the RTK-1 subgroup. It is important to test for RRD when an RTK-1 glioma is detected. The hypermutator phenotype in RRD gliomas results in RAS-MAP kinase pathway activation (oncogene addiction),[95] which can be used for therapy. In addition, TP53 mutation or loss of function is considered imperative for these gliomas.

Tumor management

RRD gliomas are resistant to temozolomide, historically contributing to the significantly inferior patient survival.[25] However, reports suggest that they retain sensitivity to CCNU (Lomustine).[96] Multiple reports have demonstrated encouraging responses to PD-1 immune checkpoint inhibition,[97] attributed to high mutation and microsatellite burden contributing to neoantigens and an immune response in the microenvironment [Figure 4]. Prompt diagnosis and management of immune flare contributing to pseudo-progression of these tumors are important. Oncogene addiction for RAS-MAP kinase pathway aberrations even in the backdrop of hypermutation offers an additional therapeutic vulnerability, as combinatorial therapy with MEK-inhibition has been reported to offer synergism to immune checkpoint inhibition therapy in RRD gliomas.[95] Anecdotal reports of successful treatment using adjuvant immune checkpoint inhibition following surgery avoiding radiation and chemotherapy have been published.[98]

Diagnosis of replication repair deficiency

Prevalence of RRD is enriched in certain situations, warranting detailed investigations to confirm this [Table 2]. Diagnosis can be made by immunohistochemistry (IHC) for the four MMR genes.[83] Screening of all high-grade glioma in CAYA using IHC may be an inexpensive yet robust screening tool. IHC revealing loss of the corresponding MMR protein in both normal and cancer cells is highly suggestive of a diagnosis of CMMRD, with >90% sensitivity and 100% specificity. Because normal (noncancerous) cells in the tissue specimen are usually positively stained in Lynch tumors and are negative in CMMRD, this simple tool can distinguish between the two syndromes [Figure 5]D and [Figure 5]E. IHC on normal tissue-like skin fibroblasts can diagnose germline deficiency in patients without tumors. Importantly, panel testing for microsatellite instability, which is useful for Lynch-related cancers, is not useful for CMMRD tumors. Newer tools investigating genome-wide microsatellite instability may be useful and can be performed on paraffin tissue and can detect both MMRD and polymerase-proofreading dysfunction.[92] Genetic testing for specific mutations in MMR and PP genes, functional assays on patient lymphocytes, extremely high tumor mutational burden, and unique COSMIC mutational signatures (6, 14, 15, 20, 26)[99] on tumor sequencing can point toward the diagnosis.
Table 2: Proposed indications for detailed evaluation of DNA replication repair deficiency in childhood, adolescent, and young adult with glial neoplasms

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Clinical implications of diagnosis of germline replication repair deficiency

Neuro-oncologists should be attentive to any young patients with high-grade glioma and café au lait spots, since malignant gliomas are relatively uncommon in individuals with NF1. It is paramount that these two conditions with overlapping phenotypic manifestations can be distinguished and properly diagnosed. The risk of a secondary malignancy from radiation or chemotherapy has not been extensively assessed in patients with germline RRD. Though no risk with radiotherapy has been identified, treatment with temozolomide, the most common chemotherapeutic agent used in gliomas, is ineffective and potentially harmful. Screening of at-risk family members and surveillance as per the published guidelines is strongly advocated in view of the significant impact on survival.[25],[100]

  Other Rare Cancer Predisposition Syndrome Linked to the Development of Glial Neoplasms Top

Germline pathogenic variants in the telomere shelterin complex gene POT1 on chromosome 7q31 can cause a familial form of oligodendroglioma.[101] Haplo-insufficiency leads to telomere lengthening with fragility and dysfunctional in telomeres. The POT1 CPS is characterized by increased risk of other cancers including cutaneous melanoma, leukemia, and cardiac angiosarcoma, with the age of onset of primary cancer varying between 15 and 80 years.[102] It is inherited in an autosomal dominant manner with unknown penetrance and prevalence. Surveillance has been recommended from 18 years of age,[102] but benefit is unknown.

Familial melanoma astrocytoma is a CPS caused by inactivating germline alteration of the CDKN2A tumor-suppressor gene on chromosome 9p21. These patients can develop melanomas and astrocytomas (majority are high-grade gliomas) and sometimes other nervous system neoplasms including peripheral nerve sheath tumors and meningiomas.[103],[104]

Ollier disease and Maffucci syndrome are two enchondromatosis syndromes characterized by the development of multiple benign cartilaginous tumors due to postzygotic acquisition of IDH mutations.[105] These patients can develop IDH-mutant gliomas. These are morphologically diffuse low-grade or anaplastic astrocytoma, seen at ~25 years of age, can present with multicenter disease involving the hemispheres or brainstem, harbor IDH and ATRX alterations, and lack 1p/19q co-deletion.[105]

Other rare genetic associations reported with glioma include BRCA1,[106] PALB2,[107] and SMARCB1;[108] however, all associations may not be pathogenic. Spinal ependymomas, which are considered glial neoplasms, have been described to arise due to germline MEN1 variants.[109] Further patients with neurofibromatosis type 2 develop spinal cord ependymomas. Importantly, it has been recently suggested that true high-grade gliomas do not develop in nonirradiated patients with neurofibromatosis type 2, and gliomas should be excluded from the diagnostic criteria for neurofibromatosis type 2.[110]

  Other Germline Links to the Development of Glial Neoplasms Top

Isolated familial gliomas, in the absence of a diagnosed CPS, are reported rarely but can be encountered in clinical practice. They seem to be like sporadic cases in terms of demographics and tumor characteristics. Most familial gliomas without an identified CPS appear to comprise cluster of two cases, suggesting low penetrance, and that the risk of developing additional gliomas is probably low, an information which may be important for both such patients and their families.[7]

In adults, ten independent inherited variants in eight chromosomal regions near the genes TERC, CDKN2B, TERT, EGFR, TP53, PHLDB1, RETL1, and CCDC26 have been associated with an increased risk for gliomas.[6] Although most of these variants increased the relative risk for primary adult gliomas by 20%–40%, a specific variant in chromosome 8 near CCDC26 (8q24; rs557505857) was found to confer a much higher, up to 6-fold relative risk, for developing IDH-mutant astrocytoma and oligodendroglial tumors. However, the prevalence was deemed as too low to confer any benefit of routine screening and surveillance for patients with this alteration.[6]

  An Approach to Cancer Predisposition in Glioma Top

Members of the neuro-oncology team managing young patients with brain tumors, particularly gliomas, need to be aware of the relatively high prevalence of germline pathogenic and likely-pathogenic variants in this patient population. Therefore, pathologists should screen most childhood malignant gliomas for RRD and TP53 by available tools, and high index of suspicion should be employed. Surgeons and medical oncologists should take detailed family history of cancers as this is particularly helpful in conditions such as LFS. A child with a brain tumor having consanguineous parents should raise a red flag. However, in communities with high prevalence of silent endogamy over centuries, a history of consanguinity may not be present. Clinical examination should focus on skin lesions, dysmorphism, and any other abnormality that can suggest a specific syndrome. In any case of suspicion, a referral to genetic counseling and testing is highly recommended. Characteristic features on the radiology may help point toward CPS [Figure 1] and [Figure 5]. Importantly, the absence of cues on clinical examination, radiology, and histology should not rule out a CPS in a patient. This is because the rate of de novo pathogenic and likely-pathogenic variants is high in specific CPS,[111] penetrance is not always complete,[54] especially in the context of younger parents, and some syndromes may have uninformative family history.[54] Molecular analysis of the cancer can point to a possible germline etiology that may need to be further evaluated (reverse genetics).


We acknowledge that, with the rapid advancement of our understanding of the molecular biology of gliomas and increased use of clinical and research cancer and germline sequencing, novel genotype–phenotype correlations will continue to be reported. However, not all associations reported may be causal. Some identified germline variants may be unrelated to the cancer being reported, while some may need more evidence of causality in future studies and hence have not been included in the current review.

  Conclusion Top

The diagnosis of a CPS in a patient with glioma has several practical implications. It is important to incorporate multidisciplinary management with the cancer genetics team upfront for patients with CPS, as the management of the specific cancers may need to be modified based on the underlying germline diagnosis. Early referral will also allow early cascade screening of family members and initiation of recommended surveillance for both the index patients and affected siblings [Table 1]. Importantly, sometimes, synchronous and metachronous tumors are diagnosed, which should not be erroneously treated as metastatic lesions [Figure 5]A. Finally, as these patients increasingly survive from their initial tumors, more information on future risk may become apparent, leading to modifications in surveillance recommendations. Therefore, while acknowledging the rapid pace of evolving knowledge for both “older” and “newer” syndromes, we believe that increased awareness and an early multidisciplinary approach remain the key for the optimal and synergistic management for individuals and families, especially in the current era of precision oncology. Finally, CPS provides links to understanding the complex process of gliomagenesis and an improved understanding of these syndromes may improve our understanding of the interplay of inherited and acquired alterations that give rise to glioma and contribute to their heterogeneity.

Financial support and sponsorship

This work was supported by a Stand Up to Cancer-Bristol-Meyers Squibb Catalyst Research Grant (No. SU2C-AACR-CT07-17), which is administered by the American Association for Cancer Research, the scientific partner of SU2C. This work is also supported by an Enabling Studies Program grant from BioCanRx-Canada's Immunotherapy Network (a Network Centre of Excellence), the Canadian Institutes for Health Research (CIHR) grant (No. PJT-156006), the CIHR Joint Canada-Israel Health Research Program, Meagan's Walk Foundation, LivWise Foundation, the Zane Cohen Center, BRAINchild Foundation, St. Baldrick's Foundation International Scholar Award (with generous support from the Team Campbell Foundation; No. 697257), the SickKids Research Training Center Clinician-Scientist Training Program (Fall 2019 award), and Guglietti We Love You Connie Foundation. None of the funding bodies play any role in the study other than to provide funding.

Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]

  [Table 1], [Table 2]


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