Author(s): Mia Robb Stahler, DO, Alyssa Low, Rajashree Srinivasan, MD, MBBS
Originally published: August 1, 2017 Last updated: May 23, 2024
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Disease/Disorder

Definition

Neurofibromatosis type 2 (NF2) is a hereditary condition characterized by benign, non-malignant tumors primarily affecting the nervous system, specifically the nerve sheath and meninges. Unlike its more common counterpart, neurofibromatosis type 1 (NF1), NF2 features distinct clinical manifestations such as ocular impairments, cutaneous lesions, and various neuropathies. Recently, experts have started to use the term “NF2-related schwannomatosis” to better represent its overlap with schwannomatosis (SWN). This term encompasses a spectrum of related conditions further classified based on specific genetic variants, including SMARCB1-related and LZTR1-related schwannomatosis, illustrating the complex genetic landscape of this disorder.1 

Etiology 

NF2 results from mutations in the NF2 gene on chromosome 22q12.2, encoding merlin, a tumor suppressor protein. This dysfunction can lead to tumor formation through disrupted cell growth regulation pathways such as PI3K/AKT, Raf/MEK/ERK, and mTOR.2,3 

Epidemiology including risk factors and primary prevention 

The incidence of NF2 is approximately 1 in 25,000 live births, typically manifesting symptoms from late teens to early 20s. The disorder follows an autosomal dominant inheritance pattern, although about 50% of cases arise from spontaneous mutations (de novo mutations). The clinical presentation of NF2 can vary significantly even within the same family, due to the nature of the mutations and their effects on gene expression. Genetic counseling and prenatal testing, such as amniocentesis or chorionic villus sampling, are highly recommended due to the significant inheritability and variability of the disorder.3,5 

Patho-anatomy/physiology

Central to NF2 is the development of bilateral vestibular schwannomas, occurring in up to 95% of individuals with the condition. These tumors, while benign, can cause significant complications as they grow, such as hearing loss and balance issues. NF2 patients often develop other types of tumors like meningiomas and ependymomas, which can vary in location and severity. The risk of malignant transformation exists but is less common compared to other neoplastic disorders.3 

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time) 

NF2 is a progressive disorder characterized by the growth and recurrence of tumors throughout the nervous system, leading to increasing disability over time. The most frequent initial symptom is hearing loss, which can progress rapidly due to the tumors affecting auditory nerves. Over time, patients may experience a range of symptoms including severe headaches, seizures, and muscle weakness due to the involvement of other cranial nerves and spinal cord.6,7 

Specific secondary or associated conditions and complications 

Patients with NF2 are prone to several complications due to the tumors’ locations and growth. Facial nerve mononeuropathy is commonly observed due to the proximity of facial nerves to vestibular schwannomas. Sensorimotor axonal peripheral polyneuropathy affects up to 5% of patients, manifesting in muscle weakness and sensory deficits. Ocular complications include cataracts, optic meningiomas, and retinal hamartomas, which can significantly affect vision.3

Essentials of Assessment

History

Individuals affected by this condition often experience hearing loss and vestibular dysfunction due to vestibular schwannomas. They may also show cognitive impairment, with IQ typically in the low-average range. Polyneuropathy can lead to pain and gait abnormalities. Furthermore, meningiomas, ependymomas, and neurofibromas, both central and peripheral, can result in paraplegia or tetraplegia accompanied by neurogenic bowel and bladder issues. 

Physical examination 

Patients suspected of having NF2 should undergo comprehensive assessments, including skin evaluation for neurofibromas, ophthalmoscopic exams for ocular issues, full neurological exams to check cranial nerves, reflexes, and coordination, and musculoskeletal evaluations to detect changes in muscle tone and strength. Diagnosis now emphasizes comprehensive molecular genetic testing due to the phenotypic overlap of NF2 and SWN, moving beyond the primarily clinical-based Manchester criteria.1 

A diagnosis of NF2-related schwannomatosis is confirmed if an individual has bilateral vestibular schwannomas or an identical NF2 pathogenic variant in at least two anatomically distinct tumors like schwannoma, meningioma, or ependymoma. If the variant allele fraction (VAF) in unaffected tissues is under 50%, the condition is classified as mosaic. Diagnosis may also be based on criteria combinations: either two major, or one major and two minor, with major criteria including unilateral vestibular schwannomas, having a first-degree relative with NF2-related schwannomatosis, or two or more meningiomas, and minor criteria such as multiple distinct schwannomas, ependymomas, or juvenile ocular abnormalities. 

Functional assessment 

Useful clinical functional assessments include

  • Functional Independence Measure, Activity Measure for Post-Acute Care, Patient-Reported Outcomes Measurement Information System, Physical Function Form
  • Mobility: Timed Up and Go, Six Minute Walk test, Short Physical Performance Battery which includes a balance test, gait speed and sit-to-stands
  • Vestibular function: Berg Balance Scale, Dynamic Gait Index
  • Cognition: Mini Mental Status Exam, neuropsychological testing
  • Quality of life: Short Form-36, Patient Health Questionaire-9  

Laboratory studies 

Genetic testing identifies abnormalities of the NF2 gene on chromosome 22, altering expression of the tumor suppressor merlin. Frame shift and missense mutations are most common in familial cases. Hypothalamic-pituitary-adrenal axis disorders are possible in those with optic chiasm gliomas. Otherwise, there are no known lab abnormalities specific to NF2.  

Imaging 

Contrast-enhanced MRI of the brain or spinal cord is often required to appropriately characterize tumors before resection. Additional neuroimaging may be necessary if other focal neurologic signs or symptoms are observed. 

Supplemental assessment tools 

Audiologic testing is common to assess hearing and identify those in need of hearing aids. Vestibular testing is used to identify and treat balance impairments and vertigo associated with vestibular schwannomas. 

Early predictions of outcomes 

In a study of 268 NF2 patients by Selvanathan et al,8 those with frame shift and nonsense mutations on genetic testing were diagnosed at younger age and with higher tumor burden. Younger age at diagnosis is a poor prognostic risk factor, as tumor burden is higher in affected children than adults. Asymptomatic patients have improved survival with longer time to surgical intervention compared to those with symptoms.9 

Environmental 

The functional assessment includes knowledge of living situation, housing, access to transportation, and interests. Home or vehicle modifications may be required. A home safety evaluation can help limit falls and improve safety. Individualized school or occupational accommodations help improve community reintegration. 

Professional issues

Quality of life is often impacted by a range of symptoms including hearing loss, difficulty with communicating or expressing emotions due to facial weakness, and self-consciousness. Social support and support from a multidisciplinary care team are vital. 

Pain Management Approach

Available or current treatment guidelines

Unfortunately, there is no cure for NF2. Treatment guidelines focus on early detection of tumors and appropriate treatment including surgical resection, chemotherapy, radiation therapy, and multidisciplinary rehabilitation. Treatment’s primary goal is preserving neurological function and quality of life. 

Patients need an annual hearing assessment, potentially including brainstem auditory evoked responses, to check for early signs of schwannoma recurrence before other symptoms appear. Preoperative audiologic tests can inform surgical strategies to minimize complications and aid in preserving hearing. Regular yearly examinations by an ophthalmologist and dermatologist are necessary to track disease progression. Starting between the ages of 10 and 12, craniospinal MRI should be conducted every two years for individuals under 20, and every three to five years afterward. If tumors are identified, imaging should be carried out annually.3 

At different disease stages 

Functional deficits are common in NF2, with hearing loss and vestibular issues significantly affecting quality of life. Hearing rehabilitation techniques such as lip reading, environmental localization, and using hearing aids are essential. For mild-to-moderate hearing loss, typical hearing aids work well, while auditory brainstem implants and cochlear implants address more severe cases, although the latter depends on the preservation of the cochlear nerve, which is rare in NF2. 

Vestibular impairments often mirror hearing loss symptoms and can lead to facial weakness, taste disturbances, and headaches following vestibular schwannoma surgery. Vestibular rehabilitation helps improve mobility and reduce fall risks post-surgery. 

Intellectual disability is not inherent to NF2 but tends to be overlooked in patients with prior intracranial surgeries. Post-surgical effects can include weakness, paralysis, and muscle stiffness, with damage to cranial nerves and the brainstem posing severe, potentially fatal risks. Dysphagia from schwannomas affecting lower cranial nerves is a notable risk factor for mortality.5 

Neurogenic bowel and bladder, often resulting from intracranial or spinal tumors, increase the risk of infections and constipation, affecting social integration. Spinal tumor removal can lead to spinal cord injuries, pain, and further bladder issues. Radiation can cause conditions like myelopathy and encephalopathy, while chemotherapy may lead to peripheral neuropathy, causing muscle weakness and balance problems. Lack of mobility can cause osteoporosis and increase fracture risk. Sensory deficits often necessitate the use of wheelchairs for mobility in early adulthood. 

Coordination of care 

Effective management of NF2 requires a coordinated approach among various healthcare professionals including neurologists, surgeons, audiologists, and genetic counselors. Regular follow-ups and a comprehensive care plan are essential for managing the multifaceted aspects of the disorder. 

Family and Peer Support and Education  

Family and peer support, facilitated by resources from the Neurofibromatosis Network and Children’s Tumor Foundation, is essential for those with NF2 facing prolonged hospital stays and functional declines. Additionally, genetic counseling and targeted education from healthcare professionals are crucial to manage the significant phenotypic variance within families and improve post-discharge care outcomes. 

Measurement of treatment outcomes 

Serial monitoring of functional status, including mobility, self-care, and performance of activities of daily living is key to optimizing quality of life. In addition, community integration and participation in activities enjoyed outside the home should be discussed during follow-up visits.  

Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills 

NF2 patients with recurrent or multiple new tumors have complicated medical courses, requiring multiple surgeries for decompression and resection, radiation and/or chemotherapy, and may benefit from multiple inpatient rehabilitation stays to address their progressive functional deficits. 

The physiatrist has a prominent role in coordinating care with other physicians, providing access to appropriately skilled therapies and screening tests, monitoring for and treating sequelae including hearing/vestibular impairment, pain, bowel, and bladder impairments, and procuring necessary adaptive equipment. 

Cutting Edge/Emerging and Unique Concepts and Practice

Targeted therapy agents have been on the horizon for NF2 – ongoing preclinical studies and clinical trials for targeted therapies include pharmaceuticals aimed at intervening with cell surface receptors (e.g. epidermal growth factor receptors, platelet-derived growth factors), angiogenesis, and intracellular signaling pathways (e.g. RAF/MEK/ERK, ALK/MET, ALK, mTOR, P21-associated kinases, PI3K/AKT, Heat shock protein 90, COX, NF-kB).10  In particular, treatment with a vascular endothelial growth factor inhibitor, bevacizumab, has been shown to maintain stable hearing, as well as facilitate tumor reduction and hearing improvement, although use may be limited by potential adverse events.4,11 Stereotactic radiosurgery, radiation therapy, or microsurgery are also treatment options for vestibular schwannoma. Microsurgery for smaller vestibular schwannomas can preserve hearing compared to radiosurgery, but with higher risk of recurrence. Advances in cochlear and auditory brainstem implantation have provided new treatment options for hearing loss.

Genetic testing in patients with NF2 continues to advance and reveal new implications for tumorigenesis and prognosis. In the future, this data may be used to individualize surgical and medical treatments, and better plan for future health care and equipment needs. 

Gaps in the Evidence-Based Knowledge

Significant knowledge gaps remain in managing Neurofibromatosis type 2 (NF2), especially concerning the best timing for surgical interventions and the efficacy of radiation and chemotherapy. The impact of tumor development and treatment on functional impairments is poorly understood, and the influence of rehabilitation on functional outcomes, prognosis, and quality of life requires further exploration. 

In drug development, challenges include a shortage of in vitro models that accurately replicate NF2 tumor pathophysiology. The primary model used, the HEI-193 cell line, derived from a patient with aggressive bilateral vestibular schwannomas, does not represent the typical NF2 tumor behavior. This highlights the need for new cell lines from primary tumors or through induced pluripotent stem cells, and for improved transgenic and xenograft models that better mimic the disease.12 

Moreover, the clinical application of gene therapy in NF2 is complicated by the blood-labyrinth barrier, analogous to the blood-brain barrier, which isolates the inner ear from systemic circulation and grants it a semi-immune-privileged status. Current drug delivery methods like intratympanic or transtympanic injections achieve low and variable drug concentrations in the inner ear. Potential alternatives being explored include delivery through the round or oval windows. Looking forward, a focused effort to develop a systematic and quantitative framework to optimize drug delivery systems for sustained intracochlear or intrathecal delivery of gene therapies could significantly enhance treatment efficacy for NF2.13

An additional gap in NF2 research involves understanding the disease’s immune dysregulation. Early studies indicate that NF2 patients exhibit an immunosuppressed state, with elevated cytokine levels and an abundance of immunosuppressive myeloid cells that inhibit anti-tumor responses. This emerging knowledge suggests that targeting these immune cells could lead to novel therapeutic strategies for NF2.14

References

  1. Plotkin SR, Messiaen L, Legius E, Pancza P, Avery RA, Blakeley JO, Babovic-Vuksanovic D, Ferner R, Fisher MJ, Friedman JM, Giovannini M, Gutmann DH, Hanemann CO, Kalamarides M, Kehrer-Sawatzki H, Korf BR, Mautner VF, MacCollin M, Papi L, Rauen KA, Riccardi V, Schorry E, Smith MJ, Stemmer-Rachamimov A, Stevenson DA, Ullrich NJ, Viskochil D, Wimmer K, Yohay K; International Consensus Group on Neurofibromatosis Diagnostic Criteria (I-NF-DC); Huson SM, Wolkenstein P, Evans DG. Updated diagnostic criteria and nomenclature for neurofibromatosis type 2 and schwannomatosis: An international consensus recommendation. Genet Med. 2022 Sep;24(9):1967-1977. 
  2. Tamura R. Current Understanding of Neurofibromatosis Type 1, 2, and Schwannomatosis. Int J Mol Sci. 2021 May 29;22(11):5850.  
  3. Ardern-Holmes S, Fisher G, North K. Neurofibromatosis type 2. J Child Neurol. 2017;32(1):9-22. 
  4. Lu VM, Ravindran K, Graffeo CS, Perry A, Van Gompel JJ, Daniels DJ, Link MJ. Efficacy and safety of bevacizumab for vestibular schwannoma in neurofibromatosis type 2: a systematic review and meta-analysis of treatment outcomes. J Neurooncol. 2019 Sep;144(2):239-248. 
  5. Aboukais, R., Zairi, F., Bonne, N. X., Baroncini, M., Schapira, S., Vincent, C., & Lejeune, J. P. (2015). Causes of mortality in neurofibromatosis type 2. British Journal of Neurosurgery, 29(1), 37–40. 
  6. Jiramongkolchai P, Schwartz MS, Friedman RA. Management of Neurofibromatosis Type 2-Associated Vestibular Schwannomas. Otolaryngol Clin North Am. 2023 Jun;56(3):533-541. 
  7. Boone N-X, Aboukais R, Baroncini M, et al. Pediatric neurofibromatosis type 2: clinical and molecular presentation, management of vestibular schwannomas, and hearing rehabilitation. Child’s Nervous System 2016;32(12):2403-2413. 
  8. Selvanathan SK, Shenton A, Ferner R, et al. Further genotype–phenotype correlations in neurofibromatosis 2. Clin Genet. 2010;77(2):163-70. 
  9. Forde C, King AT, Rutherford SA, et al. Disease course of Neurofibromatosis Type 2; a 30-year follow-up study of 353 patients seen at a single institution. Neuro Oncol. 2020 Dec 18:noaa284. 
  10. Cumpston EC, Rhodes SD, Yates CW. Advances in Targeted Therapy for Neurofibromatosis Type 2 (NF2)-Associated Vestibular Schwannomas. Curr Oncol Rep. 2023 May;25(5):531-537. 
  11. Plotkin SR, Allen J, Dhall G, Campian JL, Clapp DW, Fisher MJ, Jain RK, Tonsgard J, Ullrich NJ, Thomas C, Edwards LJ, Korf B, Packer R, Karajannis MA, Blakeley JO. Multicenter, prospective, phase II study of maintenance bevacizumab for children and adults with NF2-related schwannomatosis and progressive vestibular schwannoma. Neuro Oncol. 2023 Aug 3;25(8):1498-1506. 
  12. Hung G, Li X, Faudoa R, Xeu Z, Kluwe L, Rhim JS, Slattery W, Lim D. Establishment and characterization of a schwannoma cell line from a patient with neurofibromatosis 2. Int J Oncol. 2002 Mar;20(3):475-82. 
  13. Ren Y, Chari DA, Vasilijic S, Welling DB, Stankovic KM. New developments in neurofibromatosis type 2 and vestibular schwannoma. Neurooncol Adv. 2020 Nov 16;3(1):vdaa153. 
  14. Wang Y, Li P, Wang B, Wang S, Liu P. Identification of myeloid-derived suppressor cells that have an immunosuppressive function in NF2 patients. J Cancer Res Clin Oncol. 2019 Feb;145(2):523-533. 
  15. Blakeley JO, Ye X, Duda DG, et al. Efficacy and biomarker study of bevacizumab for hearing loss resulting from neurofibromatosis type 2-associated vestibular schwannomas. J Clin Oncol. 2016;34(14):1669-75. 
  16. Deep NL, Patel EJ, Shapiro WH, Waltzman SB, Jethanamest D, McMenomey SO, Roland JT Jr, Friedmann DR. Cochlear Implant Outcomes in Neurofibromatosis Type 2: Implications for Management. Otol Neurotol. 2021 Apr 1;42(4):540-548. 
  17. Mahboubi H, Slattery WH 3rd, Mehta GU, Lekovic GP. Options and strategies for hearing restoration in pediatric neurofibromatosis type 2. Childs Nerv Syst. 2020 Oct;36(10):2481-2487. 
  18. Ngo A. Neurofibromatosis Type 1 and Type 2. In: Shin KY and Buschbacher R, eds. Cancer Rehabilitation (Rehabilitation Medicine Quick Reference Series). New York (NY): Demos Medical Publishing; 2013. Chapter 14. 
  19. Patel CM, Ferner R, Grunfeld EA. A qualitative study of the impact of living with neurofibromatosis type 2. Psychol Health Med. 2011;16(1):19-28. 
  20. Van Gompel JJ, Agazzi S, Carlson ML, et al. Congress of Neurological Surgeons Systematic Review and Evidence-Based Guidelines on Emerging Therapies for the Treatment of Patients With Vestibular Schwannomas. Neurosurgery. 2018 Feb 1;82(2):E52-E54. 

Original Version of the Topic

An Ngo-Huang, DO and Nikola Dragojlovic, DO. Neurofibromatosis 2. 8/1/2017

Previous Revision(s) of the Topic

Nikola Dragojlovic, DO, An Ngo-Huang, DO. Neurofibromatosis 2. 6/29/2021

Author Disclosures

Mia Robb Stahler, DO
Nothing to Disclose

Alyssa Low
Nothing to Disclose

Rajashree Srinivasan, MD, MBBS
Nothing to Disclose