Neurogenetic tumor syndromes: The current landscape of workup and treatment

Abstract

Experts and generalists from numerous clinical disciplines are likely to encounter and be involved in the care of patients with neurogenetic tumor syndromes. Considerations for genetic testing are discussed. Specific conditions including neurofibromatosis type 1, neurofibromatosis type 2-related schwannomatosis, von Hippel-Lindau disease, tuberous sclerosis, Lynch syndrome, Turcot syndrome, Li-Fraumeni syndrome, and others are reviewed. A variety of targeted therapies which have received regulatory approval for these disorders are described and promising future directions for therapeutics are highlighted.

Key Points.

• The evaluation and care of patients with neurogenetic tumor syndromes and their families crosses numerous clinical disciplines.

• Patient evaluations can begin with the phenotype and work to the gene (“forward genetics”) or begin with the gene and work back to the phenotype (“reverse genetics”).

• A number of targeted therapeutics have received regulatory approval and are now part of the armamentarium for the treatment of neurogenetic tumor syndromes.

Neurogenetic tumor syndromes constitute a large and heterogeneous number of complex disorders. Individually, each condition has a relatively low incidence, but in aggregate, these diseases affect a sizeable population (from 1/250 people to 1/25 000 people depending on the specific condition). The early onset and relatively indolent natural history of these syndromes suggest that prevalence is likely higher than incidence. The autosomal dominant inheritance pattern associated with most of these disorders means that for individuals with affected family members the risk of developing disease is substantial.

Exposure to these conditions during training and clinical practice is variable. As members of the neuro-oncology community are involved in the care of this patient population, a clear and contemporary understanding of these conditions is valuable for clinical practice. The Society for Neuro-Oncology 2024 Annual Meeting included a session organized by the Neurogenetics Tumor Syndrome Track chairs focused on this topic. This review highlights the resulting educational content.

The Patient Journey to Diagnosis-Indications for Genetic Testing for Suspected Neurogenetic Tumor Syndromes

Current Screening Recommendations for Neurogenetic Tumor Syndromes

Red flags—

While every patient with an oncologic diagnosis or a family member with an oncologic diagnosis does not require germline genetic testing for cancer predisposition conditions, there are a number of signs and symptoms a neuro-oncologist should be aware of that may indicate an underlying germline condition. These include, but are not limited to, aspects of the personal history such as young age at diagnosis, rare tumor type, tumor associated with a classic cancer predisposition condition, multiple primary tumors, other developmental and physical differences as well as a pathogenic variant detected in tumor tissue or abnormal tissue testing (eg, MSH6 absent immunohistochemistry in colon cancer). They can be expanded to elements of the family history including known cancer predisposition syndrome in another family member, multiple family members with tumors, pattern of cancers suggestive of a known syndrome, inclusion in specific ethnic groups, and consanguinity. Individual tumors such as adrenocortical carcinoma, anaplastic rhabdomyosarcoma, hemangioblastoma, choroid plexus carcinoma, and medulloblastoma warrant germline testing based on the frequent association of familial cancer predisposition syndromes in patients diagnosed with these rare tumors.

Genetic testing—

Several considerations must be made before genetic testing is performed as the results can have profound implications on the patient and their family members. Choosing a genetic test depends on whether the patient has a tumor associated with a known syndrome, if a pathogenic variant is known within the family, if the family history is suggestive of more than one hereditary condition, tissue availability, health insurance coverage, and applicable NCCN guidelines for testing. Germline testing is typically performed in non-tumor tissue (i.e., blood or saliva). However, tumor tissue testing may be needed in some situations, like suspected mosaicism. Genetic test results can impact clinical management and evaluation of prognosis. They can also inform the risk of tumor development in other family members. Genetic testing can also place individuals at risk of genetic discrimination. In the United States, the Genetic Information Nondiscrimination Act (GINA) provides some protection against discrimination with respect to health insurance and employment. Importantly, GINA does not apply to employers with fewer than 15 employees, military members, life insurance, long-term care insurance, and disability insurance.

Condition-Specific Considerations

Here, we review neuro-oncology specific considerations for cancer predisposition. While not comprehensive, an overview of some of most frequently encountered neuro-oncologic tumor predisposition conditions are highlighted in table format (Table 1). Patient evaluations can begin with the phenotype and work to the gene (“forward genetics”) or begin with the gene and work back to the phenotype (“reverse genetics”). Specific screening recommendations for patients with established diagnoses are highlighted as well (Table 2).

Table 1.

Neuro-oncologic Tumor Predisposition Syndromes

Syndrome	Inheritance, penetrance	Gene(s)	Genotype-phenotype correlations	Highly associated CNS and PNS tumors
Neurofibromatosis type 11,2	Autosomal dominant, 100%	NF1	NF1 gene deletion associated with more severe phenotype and ↑ risk of MPNST; unusually severe phenotype with missense variants in codons between 844–848; p.Arg1276 and p.Lys1423 missense variants associated with a higher-than-expected frequency of cardiovascular malformations (especially pulmonic stenosis), symptomatic spinal neurofibromas (p.Arg1276), and pNFs (p.Lys1423); p.Met992del is associated with lack of cNFs; p.Met1149 and p.Arg1809 missense variants associated with a mild phenotype	Optic pathway glioma, neurofibroma, MPNST
NF2-related schwannomatosis3–5	Autosomal dominant, 100%	NF2	Large deletions associated with a milder phenotype; nonsense and frameshift variants associated with severe disease; missense variants are usually associated with a mild phenotype; truncating variants associated with earlier onset and ↑ number of NF2-associated intracranial meningiomas, spinal tumors, and peripheral nerve tumors; variants in the 3’ half of NF2 (especially those in exons 14-16) associated with ↓ risk of meningioma	Schwannomas (particularly bilateral vestibular schwannomas), meningiomas, ependymomas
LZTR1- and SMARCB1-Related schwannomatosis5	Autosomal dominant, LZTR1: 40–50% and SMARCB1: < 100%	LZTR1, SMARCB1	LZTR1: no meningiomas SMARCB1: germline truncating variants, deletions of one or more exons, or deletion of the entire gene is found in 15%-60% of individuals with rhabdoid tumors	Schwannomas, meningiomas (SMARCB1 only)
Von Hippel-Lindau disease6–8	Autosomal dominant, 100%	VHL	Type 1: low risk for pheochromocytoma; truncating or missense variants affecting protein folding Type 2: high risk for pheochromocytoma; missense variants that do not disrupt HIF regulation - Type 2A: low risk for RCC -Type 2B: neuroendocrine tumors; high risk for RCC Type 2C: risk for pheochromocytomas only	Cerebellar hemangioblastoma
Tuberous Sclerosis complex9	Autosomal dominant, 100%	TSC1, TSC2	TSC2: more severe phenotype and more likely to be de novo, some TSC2 missense variants are associated with milder disease	Subpendymal giant cell astrocytomas, non-neoplastic CNS hamartomas
Lynch syndrome10,11	Autosomal dominant, < 100%	MLH1, MSH2, MSH6, PMS2, EPCAM	Pathogenic variants in mismatch repair genes are more commonly associated with glioblastoma MLH1: highest risk for colorectal cancer MSH2: greatest risk for extracolonic cancers MSH6 and PMS2: estimated to have ↓ disease penetrance and older ages at colorectal cancer diagnosis EPCAM: risk for extracolonic cancers is dependent on deletion size	glioblastoma IDH-wildtype
Familial adenomatous polyposis11	Autosomal dominant, 100%	APC	78% attenuated FAP due to pathogenic variants in one of three regions: the 5’ end of APC (codon 1-233), the alternative spliced region of exon 9 (codon 311-412), or 3’ of codon 1595; codons 697-1224 associated with 3x ↑ risk brain tumor and 13x ↑ risk medulloblastoma	Medulloblastoma
Li-Fraumeni syndrome12	Autosomal dominant, variable	TP53	Nonsense, frameshift, and missense pathogenic variants that cause complete loss of p53 function or a dominant-negative effect are associated with a more severe phenotype	choroid plexus carcinoma

Table 2.

Screening Recommendations for Neurogenetic Tumor Syndromes

Neurofibromatosis type 11,13–16
Organ system	Pathology	Recommendation
Brain	Optic glioma Low grade glioma High grade glioma	Annual ophthalmologic exam Symptom directed MRI brain
Peripheral nerves	Plexiform neurofibroma Malignant peripheral nerve sheath tumor	Symptom directed CT +/- PET +/- MRI Consider whole body MRI (clinical trial recommended)
Skin	Cutaneous neurofibroma	Annual whole body skin exam
Endocrine	Pheochromocytoma Growth/pubertal delay	Annual history and physical with blood pressure monitoring Annual head circumference and pubertal development assessment
Hematologic	Leukemia	Baseline CBC
Cardiovascular	Hypertension Peripheral vascular disease	Annual history and physical with blood pressure monitoring
Skeletal	Fracture risk	Annual Vitamin D levels
Schwannomatosis3,15
Organ system	Pathology	Recommendation
Brain	Schwannoma Meningioma Ependymoma	Symptom directed MRI brain Consider baseline MRI Brain at age 12 (when MRI can be performed without anesthesia) Annual neurologic exam including cranial nerves and audiogram
Peripheral nerves	Schwannoma	Annual pain assessment Consider baseline MRI Spine at age 12 (when MRI can be performed without anesthesia)
VHL Disease: Screening and surveillance: based on NIH, US VHL Family Alliance, Danish, and Dutch Guidelines6,7,17,18:
Screening/surveillance	Organ system	Initiation	Interval
Ophthalmoscopy	Retina	At birth	Annual
Vitals/Physical/Neurologic Exam	CNS/Adrenal	At birth	Annual
MRI Craniospinal Axis	CNS	8 - 11	Annual/Every 2 years
Audiogram	CNS (ELST)	5	Annual/Every2 years/PRN
Plasma/urine metanephrines	Adrenal gland	2 - 8	Annual
Ultrasound or MRI of Abdomen	Kidney/Pancreas/Adrenal	8 - 14	Annual/Every 2 years
Tuberous Sclerosis Complex: Screening at initial diagnosis19:
Organ system	Pathology	Recommendation
Brain	Subependymal nodules (SEN), Migration defects, Subependymal giant cell astrocytomas (SEGA)	MRI Brain every 1-3 years
	TSC-associated neuropsychiatric disorder (TAND)	TAND screen annually
	Seizures	EEG PRN
Kidney	Angiomyolipoma, Renal cysts	MRI abdomen every 1-3 years, BP and GFR check annually
Lung	Lymphangioleiomyomatosis (LAM)	Screen symptoms each visit, PFT, 6-min walk test every 2-3 years, HR CT (> 18 Females) every 5-10 years
Skin	Facial angiofibromas, fibrous cephalic changes…	Dertmatologic inspection annually
Teeth	Enamel defects, fibromas	Dental exam every 6 months
Heart	Rhabdomyomas, conduction defects	Echocardiography, EKG every 1-3 years
Eye	Retinal lesions, visual field defects	Detailed eye exam annually
Tuberous Sclerosis Complex: Surveillance19:
Organ system	Pathology	Recommendation
Brain	Subependymal nodules (SEN), Migration defects, Subependymal giant cell astrocytomas (SEGA)	MRI Brain every 1-3 years
	TSC-associated neuropsychiatric disorder (TAND)	TAND screen annually
	Seizures	EEG PRN
Kidney	Angiomyolipoma, Renal cysts	MRI abdomen every 1-3 years, BP and GFR check annually
Lung	Lymphangioleiomyomatosis (LAM)	Screen symptoms each visit, PFT, 6-min walk test every 2-3 years, HR CT (> 18 Females) every 5-10 years
Skin	Facial angiofibromas, fibrous cephalic changes…	Dertmatologic inspection annually
Teeth	Enamel defects, fibromas	Dental exam every 6 months
Heart	Rhabdomyomas, conduction defects	Echocardiography, EKG every 1-3 years
Eye	Retinal lesions, visual field defects	Detailed eye exam annually
Lynch Syndrome: Screening and Surveillance10,11,20:
Organ system	Pathology	Recommendation
Colon	Colorectal cancer	Colonoscopy (> 20 y) annually
Uterus	Endometrial cancer	Education annually, Transvaginal USG, Endometrial biopsy every 1-2 years
Ovaries	Ovarian cancer	Education annually
Upper GI Tract	Gastric and duodenal cancer	Upper GI endoscopy and biopsy (> 30 y) every 1-2 years
Distal small bowel	Small bowel cancer	Capsule endoscopy & small bowel enteroscopy if symptomatic
Urinary tract	Urinary tract cancers	Urinalysis (> 30 y) annually
Pancreas	Pancreatic cancer	Endoscopic USG or MRI/MRCP annually
Other	Glioblastoma	No formal recommendation. MRI Brain annually?
Turcot Syndrome: No established guidelines. Expert recommendations12:
Organ system	Pathology	Recommendation
Colon	Colorectal cancer	Colonoscopy annually
Brain	Medulloblastoma	Brain MRI annually
Other	Thyroid papillary carcinoma, Hepatoblastoma, Pancreatic cancer, Gastric and duodenal cancers	?

Neurofibromatosis type 1—

Neurofibromatosis type 1 (NF1), caused by mutations in the NF1 tumor suppressor gene, manifests with a diversity of phenotypes, and both clinical manifestations and genetic testing are useful to formally arrive at this diagnosis^1,2 NF1 is associated with increased cancer risk and shortened life expectancy,^13,21 with cancer serving as the primary driver for this shortened survival.²² The most common neoplasms in this population are neurofibromas (WHO grade 1), gliomas (grade 1–4), and malignant peripheral nerve sheath tumors (MPNSTs), and people with NF1 have lower disease-specific survival rates when diagnosed with the same malignancies when compared to members of the general population.²²

Due to increased incidence of specific malignancies,¹⁴ routine screening is advisable for patients with NF1. Specifically, the risk of optic pathway glioma (15–20%) supports annual ophthalmologic examination while the risk of leukemia (7× increase over baseline population) and pheochromocytoma (0.1–5.7%) warrant consideration of baseline complete blood count and blood pressure checks. The risk of MPNST (8–13%) warrants prompt workup of any new pain with progressive or symptomatic peripheral nerve lesions on imaging (CT, PET, or MRI).¹⁴ In the absence of symptoms or a malignant tumor diagnosis, the role of routine surveillance imaging in asymptomatic patients is unclear outside of a clinical trial setting.¹⁵ Currently, there is a clinical trial underway to determine whether surveillance and treatment initiation for asymptomatic but high-risk PN will be beneficial (NCT06188741).

The pathophysiology of neurofibromas begins with germline NF1 mutation followed by loss of the second NF1 allele.²³ As with other neuro-oncologic malignancies, additional mutations important for cell cycle control such as deletion of cyclin dependent kinase inhibitors (CDKN2A/B) are associated with malignant transformation, with subsequent recurrent alterations in the histone modulator polycomb repressive complex 2(PRC2) in MPNSTs.^24,25 Conventional histopathologic and immunohistochemical features have proven to be both prognostic and predictive of treatment response.²⁶

Numerous non-neoplastic manifestations of NF1, presumably due to neurofibromin haploinsufficiency, contribute to substantial morbidity for this patient population, requiring complex multidisciplinary care to best manage these issues. While many patients with NF1 have normal intelligence, 50–75% of patients exhibit some degree of learning disabilities which persist into adulthood. This may be further complicated by other neurologic symptoms including attention deficit hyperactivity disorder, seizures, and neuropathic pain. In addition to the neurologic manifestations, skeletal problems such as scoliosis and increased risk of fractures exist. In turn, annual serum vitamin D level could be considered. From a cardiovascular perspective, there is a greater risk of hypertension and peripheral vascular disease. For the pediatric population annual examinations including history, physical, head circumference, and pubertal develop should be assessed to provide anticipatory guidance regarding potential clinical manifestations and when possible, guide early interventions.¹⁶

NF2-related schwannomatosis (NF2-SWN)—

NF2-SWN is the contemporary term used for what was formerly described as neurofibromatosis type 2. The incidence of NF2-SWN is ~1:50 000 births.²⁷ Classic clinical manifestations include bilateral schwannomas, family history, and other CNS tumors such as meningiomas and ependymomas. Formal criteria can aid in the clinical diagnosis and are essential for guiding inclusion criteria for clinical studies.³ Screening recommendations support MRI of the brain and spine at age 12, MRI brain every 1–3 years, and genetic testing to rule out alternate SWN syndromes caused by LZTR1 and SMARCB1 mutations. Additional considerations are guided by clinical symptoms and include whole body MRI, total body skin exam, annual neurologic exam, annual auditory exam given risk of vestibular schwannomas, and annual pain assessment given risk of symptomatic schwannomas along the neuroaxis.

Non-NF2-SWN—

Non-NF2-SWN is a group of disorders presenting with multiple schwannomas without germline NF2 mutations. The most common causative mutations are LZTR1 and SMARCB1, and emerging data suggests these may have distinct clinical courses, underscoring the importance of genetic testing.⁴ In turn, the most contemporary nomenclature categorizes these syndromes as LZTR1- and SMARCB1- related schwannomatosis.⁵ Unlike NF2-SWN, pain, and not hearing loss, is the most common presenting symptom of non-NF2-SWN. This is in large part due to the less frequent involvement of cranial nerve 8, and the more common observation of schwannomas involving spinal nerve roots or peripheral nerves. Unlike NF2-SWN, non-NF2-SWN may lack a negative impact on survival. Clinical screening is analogous to what is recommended for NF2-SWN.

Von Hippel-Lindau disease (VHL)—

VHL is a disorder driven by germline mutations of the VHL gene. The germline loss of a single VHL allele is inconsequential to most cells of the human body. However, with a “second hit,”²⁸ few cells lose the critical second (“normal”) VHL allele, leading to absence of functional VHL protein in these cells.^29,30 The VHL protein is a critical E3 ubiquitin ligase that leads to degradation of constitutively transcribed HIF1α and HIF2α (hypoxia inducible factor) proteins. Loss of VHL protein activity leads to increased cellular HIF activity, and a cellular perception of a hypoxic state (pseudo-hypoxia). Since the HIF proteins are potent transcription factors, this results in a cellular upregulation of tumorigenic mechanisms, angiogenesis, and metabolism. VHL disease is associated with brain/spine hemangioblastomas, retinal angiomas, and endolymphatic sac tumors in the CNS. Visceral tumors include clear cell renal cell cancer (RCC), pheochromocytomas, pancreatic neuroendocrine tumors (pNET), and epididymal/broad ligament cystadenomas. Formal guidelines for CNS screening in patients with known VHL recommend annual neurological examination and MRI of the neuraxis every two years.^6,7 This is based on population-based studies which have helped clarify the age of initial tumor diagnosis and the rate of tumor development.^17,18

CNS hemangioblastomas are the most common manifestation of VHL. The most frequent locations for these tumors are in the cerebellum, followed by the spine (most often on the dorsal surface) and the brainstem. They can also be observed in the roots of the cauda equina, and very rarely are found in the supratentorial brain parenchyma.^6,8 Unlike with sporadic CNS hemangioblastomas, most patients with VHL will develop multiple tumors at a rate of 0.4 tumors/year.³¹ CNS hemangioblastomas create space-occupying pathologies via solid tumor growth, peri-tumoral cysts, or by creating edema in the surrounding brain. The tumors and cysts often demonstrate stop-start saltatory growth patterns or periods of quiescence making tumor growth predictions inaccurate. Therefore, clinical management of VHL patients remains complicated, and understanding the results of clinical studies challenging (especially studies lacking long term follow-up). In visceral VHL related tumors including RCC and pNETs, size cutoffs for intervention have been established since the risk of metastatic disease increases with tumor size. However, interventions for CNS hemangioblastomas are best guided by clinical symptoms rather than size cutoffs. When imaging, as opposed to clinical symptomatology, has been used to guide surgical intervention, the likelihood of unnecessary surgical interventions increases.^32,33 For unresectable lesions or residual disease following resection, radiotherapeutic approaches such as stereotactic radiosurgery is an alternative option to provide local control.

More recently, the mechanistic understanding of the disease has led to an advent of systemic therapy for its treatment. Specifically, the HIF-2α inhibitor, belzutifan, has demonstrated efficacy for the treatment of RCC, pNET, and CNS hemangioblastomas.^34,35 Its use has demonstrated a decrease in the need for surgical intervention for CNS hemangioblastomas.³⁶

Tuberous sclerosis complex (TSC)—

TSC is a disorder due to germline mutations of either TSC1 or TSC2, genes which encode negative regulators of the mammalian target of rapamycin (mTOR) pathway.³⁷ The mTOR pathway serves as an energy sensor which when appropriate signaling is present leads to cell proliferation and differentiation.

As with the other disorders discussed, TSC manifests with CNS and non-CNS findings. In the CNS, low-grade (WHO grade 1) subpendymal giant cell astrocytomas (SEGAs) may develop in the ventricular linings causing cerebrospinal fluid flow obstruction and hydrocephalus. These are observed in 6–16% of patients with TSC. More commonly, non-neoplastic CNS hamartomas (“tubers” or subependymal nodules) are found in up to 80% of TSC patients. Independent of these radiographically evident structural abnormalities patients may experience seizures, intellectual disability, and autism spectrum disorder.⁹ Non-CNS manifestations are myriad and include cardiac (cardiac rhabdomyoma, most frequently observed in the pediatric population), renal (angiomyolipoma, renal cysts), pulmonary (lymphangioleiomyomatosis [LAM], most frequently observed in women), and dermatologic (hypopigmentation, angiofibromas, ungal fibromas, and shagreen patches). While the incidence of cardiac rhabdomyomas rapidly drops from ~90% of TSC patients at birth to ~20% by 5 years of age, most other manifestations increase over time. Pulmonary LAM are often the latest manifestation to develop, with > 80% of female TSC patients developing this by 40 years of age. Suggested surveillance for patients with known TSC includes MRI brain, MRI abdomen, EKG, and echocardiogram every 1–3 years. Annual dermatologic and ophthalmologic exams and twice annual dental exams are suggested. For women, pulmonary evaluation for LAM is also recommended.

Lynch syndrome—

Lynch syndrome is caused by a germline mutation in one of a number of DNA mismatch repair genes, specifically MutL homolog 1 (MLH1), MutS homolog 2 (MSH2), MSH6, postmeiotic segregation increased 2 (PMS2), or the deletion of the epithelial cellular adhesion molecule (EPCAM).¹⁹ Lynch syndrome is associated with a notably increased risk of non-CNS malignancies such as colon cancer and endometrial cancer. It is also associated with an increased risk of glioblastoma IDH-wildtype. Screening involves annual colonoscopy beginning at 20 years of age, upper endoscopy every 1–2 years, and transvaginal ultrasound every 1–2 years. As the risk of glioblastoma IDH wild-type is still relatively low with this syndrome, there are no widely agreed upon recommendations for CNS screening.¹⁰

Turcot syndrome—

Turcot syndrome is comprised of two distinct types. Type 1 is analogous to Lynch syndrome, and has previously been termed hereditary nonpolyposis colorectal cancer (HNPCC) syndrome when manifesting with colorectal cancer. Type 2 is also known as familial adenomatous polyposis coli (APC) syndrome. Germline mutations of APC, a gene which encodes a tumor suppressor that interacts with β-catenin by shuttling it between the nucleus and the cytoplasm and plays a role in cell cycle regulation,³⁸ leads to Turcot syndrome with an autosomal dominant inheritance pattern. Mutation of MutY homolog (MUTYH), which encodes a DNA repair enzyme, leads to the development of an autosomal recessive variant of Turcot syndrome.³⁹

Type 1 Turcot syndrome, as stated in the Lynch syndrome section is associated with glioblastoma IDH wild-type as well as colorectal cancer. Type 2 Turcot syndrome is also associated with colorectal cancer but has an increased risk of medulloblastoma instead. While not extensively studied, presumably the risk is greatest for the Wnt subtype of medulloblastoma due to the aberrancy of the β-catenin/Wnt pathway in this syndrome. Screening recommendation favor annual colonoscopy and MRI brain.¹¹

Li-Fraumeni syndrome—

Li-Fraumeni syndrome is due to germline mutation of TP53 or specific CHEK2 polymorphisms, leading to impairment of DNA repair, growth arrest, and apoptosis. Unsurprisingly, this is associated with a wide range of cancers including leukemias, bone and soft tissue sarcomas, lung cancer, breast cancer, and adrenocortical tumors. It is also associated with CNS tumors at a young age, particularly infiltrating gliomas.^20,27 The role of routine surveillance has played an essential role in improved survival for this patient population, allowing disease to be detected early and treated in a curative fashion.¹² Recommended screening includes annual brain MRI as well as whole body MRI and blood work.

Recent Advances in Targeted Therapies for Neurogenetic Tumor Syndromes

Inherited cancer syndromes with well-understood driver mutations are optimal candidates for targeted therapies. While additional genetic and/or epigenetic alterations create complexity within the tumors, there is often a single primary pathway which is central to tumorigenesis, survival, and proliferation. The first of the neurogenetic tumor syndromes to benefit from a targeted therapy was TSC. The mTOR inhibitor everolimus demonstrated radiographic responses in TSC patients with SEGAs. Over one-third of patients experienced > 50% volumetric decrease in tumor size in the pivotal phase 3 trial.⁴⁰ The radiographic control appears sustained with a prolonged course of treatment. A notable decrease in seizure frequency has also been observed with this therapeutic approach.⁴¹ The approach has been well tolerated.

For patients with VHL the use of the HIF2α inhibitor belzutifan has demonstrated benefit with radiographic responses seen in RCC, pNET, and CNS hemangioblastomas.^34–36 Radiographic improvement occurred relatively quickly in many patients, while in others it continued to evolve over months. In the CNS hemangioblastomas both solid and cystic components of tumor decreased in size.³⁶ As would be expected based on HIF2α’s role in induction of erythropoietin, a high incidence of anemia is observed with this agent.^34–36

As noted earlier, Lynch syndrome is due to germline mutations to a number of genes which play key roles in DNA repair. When these mutations are present in all cells of a tumor, there is potential for the tumors to accumulate a large number of mutations (hypermutated phenotype), in turn expressing a larger number of abnormal epitopes on the cell surface, and a greater potential for those epitopes to be immunogenic. This differs from tumors with somatic (not germline) mutations where only certain subclones may harbor the DNA repair deficits and in turn only a subpopulation of tumor cells may be highly immunogenic. PD1 checkpoint blockade has been demonstrated effective in the treatment of a wide array of tumors with germline DNA repair deficits.⁴² The PD1 antibody pembrolizumab has histology-agnostic regulatory approval for use in patients with tumors in the setting of Lynch syndrome.

NF1 mutation leads to activation of Ras and its downstream effectors. In particular, Ras mediated RAF/MEK/ERK signaling has been extensively explored as potential therapeutic targets in NF1. The MEK1/MEK2 inhibitor selumetinib has demonstrated clear benefit in the treatment of plexiform neurofibroma in patients with NF1. Radiographic responses were observed with 71% of patients exhibiting a ≥ 20% decrease in tumor volume, and these radiographic responses were accompanied by clinically meaningful benefits in a phase 1 trial.⁴³ A subsequent non-randomized phase 2 trial of children with inoperable plexiform neurofibromas confirmed findings first noted in the phase 1 trial.⁴⁴ Over two-third of patients exhibited a ≥ 20% decrease in tumor volume. Improvements in pain and functionality were also observed. Data from the phase IIII randomized trial comparing selumetenib to placebo in pediatric and adult patients with NF1-PN is pending. Additionally, recently published data shows from ReNeu, a Phase2b trial of the MEKi mirdametinb in adults and children with symptomatic NF1-PN demonstrated a median target PN volumetric best response of −41% in adults and −42% in children. Both cohorts reported significant and clinically meaningful improvement in patient- or parent proxy-reported outcome measures including worst tumor pain severity, pain interference, and health-related quality of life that began early and were maintained during treatment.⁴⁵ Finally, ongoing efforts are underway to understand mediators of MEK inhibitor response to design combination or second line therapies for patients who do not respond to or cannot tolerate MEK inhibitors.⁴⁶

For patients with NF2-related schwannomatosis, LZRT1 or SMARCB1 schwannomatosis, there are currently no systemic treatments with regulatory approval. However, this is an active area of both preclinical and clinical research. Potential therapeutic approaches undergoing investigation within the context of clinical trials include blockade of FAK/FAK2/FER by brigatinib,⁴⁷ blockade of the polypeptide nerve growth factor with the monoclonal antibody tanezumab, blockade of IL-6 with the monoclonal antibody siltuximab, and blockade of calcitonin gene-related peptide with the monoclonal antibody erenumab. All of these approaches are centered on reduction of pain, a key symptom related to these disorders, and not reduction of tumor volume.

Conclusions

The field of neurogenetic tumor syndromes is complex, multifaceted, and constantly evolving. With a wide array of relatively uncommon diseases which fall within this bucket, it is helpful to have an understanding of common themes summarized above. In this field, knowledge gained studying one specific disease may help inform understanding of other neurogenetic and non-genetic neurologic neoplastic processes. In addition, these understandings can help optimize clinical care for the patients and their families. When this care is not consistently available locally, mechanisms for a near real-time exchange of knowledge such as rare-CNS tumor board, can help facilitate high-quality care over long distances.⁴⁸ Conferences such as the Society for Neuro-Oncology Annual Meeting and its Neurogenetic Tumor Syndromes track serve as another important means for disseminating knowledge.

Funding

R.V.L. is supported by National Institute of Health, National Cancer Institute [P50CA221747].

Conflict of interest statement. R.V.L. has received research support (drug only) from BMS; served on speaker’s bureau for Merck, Novocure, and Servier; received honoraria for consulting for Cardinal Health, Merck, Novocure, Servier, and Telix; and honoraria for editing for EBSCO, Elsevier, and Medlink Neurology.

Author Contributions

R.V.L. and A.C.H. conceptualized the manuscript. R.V.L. wrote the initial draft. R.V.L., A.C., P.C., H.N.V., J.B., and A.C.H. revised the draft.