Neurofibromatosis type 2 (NF2) is a hereditary syndrome characterized by non-malignant nervous system tumors involving the nerve sheath and meninges. Associated conditions include ocular impairments, cutaneous lesions, and neuropathies. It is a related but distinct disorder from neurofibromatosis type 1 (NF1).
NF2 is caused by mutations of the NF2 gene on chromosome 22q12.2 encoding the protein merlin (also known as schwannomin), a cytoskeletal protein that regulates cell growth and proliferation; thus, the absence of merlin may predispose to tumor formation.1
Epidemiology including risk factors and primary prevention
Incidence is 1 in 25,000 live births, with onset of symptoms in the late teens to early 20s. NF2 is an autosomal dominant condition, with a positive family history. However, 50% of the cases may be due to de novo mutations.1,2 There is phenotypic variability because of sporadic mutations, even within families. Given the high rate of transmission from an affected parent, genetic testing and counseling is paramount. Prenatal testing via amniocentesis or chorionic villus sampling is also available. Risk factors for more severe presentation include frame shift and nonsense mutations identified on genetic testing, and younger age at diagnosis.1
The hallmark of NF2 is bilateral vestibular schwannomas, occurring in up to 95% of patients. Paraspinal schwannomas involve the dorsal nerve root and have a classic “dumb bell” radiographic appearance.
Over half of patients also have at least one intracranial meningioma in their lifetime; spinal meningiomas are less common. NF2-associated meningiomas tend to be higher grade and may grow more rapidly. Gliomas (i.e. ependymomas and astrocytomas) may be seen on imaging, but tend to be less symptomatic.1
There is risk for malignant transformation of tumors; however, the rate of radiation-associated malignant transformation is higher.
Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)
The course of disease in NF2 is variable but progressive. All tumors in this disorder have a high rate of recurrence, and the morbidity associated with multiple tumors across the neuraxis and need for multiple surgical resections is high. Hearing loss is inevitable for patients given the recurrence of vestibular schwannomas and the morbidity of treatments.
Vestibular schwannomas are typically slow-growing, but cause vestibular impairment, vertigo, hearing loss, and tinnitus. Hearing loss occurs from cochlear nerve compression, ischemia, local invasion by the surrounding tumor, or as a sequela of radiation and surgical treatments. Meningiomas result in headaches, seizures, and weakness. Visual impairment from ocular conditions is common, as are early impairments in mobility. In contrast to NF1, osseous lesions are not typically seen.
Specific secondary or associated conditions and complications
Facial nerve mononeuropathy is common given its close proximity to vestibular schwannomas and due to risk of perioperative injury. Sensorimotor, axonal peripheral polyneuropathy is seen in up to 5% of patients.
Ocular manifestations include cataracts, optic meningiomas, and retinal hamartomas. Plaque-like cutaneous lesions are common but have low rate of tumor occurrence.
Essentials of Assessment
Those affected present with hearing loss and vestibular dysfunction from vestibular schwannomas. There is cognitive impairment with intelligence quotient (IQ) in low-average range. Pain and gait abnormalities occur due to polyneuropathy. Paraplegia or tetraplegia, with neurogenic bowel and bladder, occurs due to meningiomas, ependymomas, and both central and peripheral neurofibromas.
Patients suspected of having NF2 should undergo:
- Thorough skin evaluation for cutaneous or subcutaneous neurofibromas.
- Ophthalmoscopic or slit-lamp examination for ocular abnormalities.
- Complete neurologic examination including cranial nerve, reflexes, sensory testing, assessments of coordination and balance.
- Musculoskeletal evaluation to assess for atrophy, changes in tone, strength testing, joint range of motion and alignment, and gait.
Diagnosis of NF2 is made by revised Manchester criteria, with any of the following:3
- Bilateral vestibular schwannomas, diagnosed before age 70
- Unilateral vestibular schwannoma and first-degree relative with NF2
- Any two of: meningioma, gliomas, schwannoma, neurofibroma, cerebral calcification, ependymoma, cataract; and
- first-degree relative with NF2 or
- unilateral vestibular schwannoma and negative LZTR1 testing
- Multiple meningiomas and
- Any two of the following: unilateral vestibular schwannoma, nonvestibular schwannoma, neurofibroma, ependymoma, cataract, glioma, cerebral calcification
- Constitutional or mosaic pathogenic NF2 gene mutation from the blood or by the identification of an identical mutation from 2 separate tumors in the same individual
Useful clinical functional assessments include:
- Functional Independence Measure (FIM), Activity Measure for Post-Acute Care (AM-PAC), Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function form
- Mobility: Timed Up and Go (TUG), Six Minute Walk test (6MWT), Short Physical Performance Battery (SPPB) which includes a balance test, gait speed and sit-to-stands.
- Vestibular function: Berg Balance Scale (BSS), Dynamic Gait Index (DGI)
- Cognition: Mini Mental Status Exam (MMSE), neuropsychological testing
Quality of life: Short Form-36 (SF-36), Patient Health Questionaire-9 (PHQ-9)
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.
Contrast-enhanced magnetic resonance imaging (MRI) of the brain or spinal cord is often required to appropriately characterize tumors prior to 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 needs 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,4 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.6
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.
Social role and social support system
Family and peer support is critical for those with NF2, who will inevitably suffer prolonged hospital courses and functional declines. The Neurofibromatosis Network and Children’s Tumor Foundation offer online content, as well as local, state, and regional resources for counseling and support.
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. Thus, 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.
Patients will require annual hearing evaluation, which may include brainstem auditory evoked responses to detect for clinical signs of schwannoma recurrence before additional symptoms develop. Preoperative audiologic testing can guide operative planning to reduce morbidity and help preserve hearing. Annual ophthalmologic and cutaneous evaluations are required to monitor for disease progression. Craniospinal MRI, beginning at age 10-12 years, should be repeated every 2 years for those under 20 years old, and every 3-5 years thereafter. If tumors are detected, imaging should be performed annually.1
At different disease stages
Functional deficits are commonplace for patients with NF2 but hearing loss and vestibular impairment have the most dramatic impact on quality of life. Hearing rehabilitation includes compensatory strategies like lip reading and environmental localization, and optimization of hearing aids. Typical hearing aids that amplify sound, including contralateral routing of signals (CROS) systems, are best for mild-to-moderate sensorineural hearing loss. Auditory brainstem implants (ABI) are used in bilateral and more severe hearing loss. Cochlear implants (CI) have been successful for cases of severe, unilateral hearing loss, but require the affected cochlear nerve to be relatively preserved, which is less common in NF2 and limiting its applicability.
The course of vestibular impairment mimics hearing loss. After vestibular schwannoma resection, facial weakness, dysgeusia, hearing loss, vestibular dysfunction, and headaches are common. vestibular rehabilitation is recommended to aid in postoperative mobility and reduce fall risk after vestibular schwannoma surgery.
Intellectual disability, though not an intrinsic part of the disease, is under recognized in those with a history of intracranial intervention. Weakness, paresis, and spasticity also follow intracranial involvement. Damage to the cranial nerves and brain stem is not only disabling but can be life-threatening.
Neurogenic bowel and bladder due to intracranial or spinal tumor involvement predispose to infections, constipation, and impair community integration.
Impairments after spinal tumor resection include spinal cord injury, neurogenic bowel and bladder, neuropathic and spinal pain syndromes.
Post-radiation sequelae include myelopathy, plexopathy, lymphedema, encephalopathy, and pain syndromes. Progression of chemotherapy-induced peripheral neuropathy adds to weakness, atrophy, impaired manual dexterity, balance impairment, and pain.
Disuse osteoporosis, due to poor mobility, portends a high fracture risk. Fall risk is heightened by vestibular, sensory, and proprioceptive deficits. Many patients will require wheelchairs for mobility by early adulthood.
Coordination of care
Appropriate multi-disciplinary care may include audiology, neurology, neurosurgery, orthopedic surgery, otolaryngology, ophthalmology, endocrinology, radiation oncology, and physiatry. Patients with NF2 frequently require inpatient rehabilitation after surgical interventions and all disciplines of outpatient therapies. Needs for durable medical equipment fluctuate. Multi-disciplinary clinics can enhance coordination by temporally and spatially uniting providers.
Patient & family education
Genetic counseling is crucial in familial cases of NF2. Given the phenotypic variance within families, education from physicians and therapists is vital to address new impairments that were not previously identified, or to provide prognostic information and enhance delivery of care upon hospital discharge.
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 enjoyed activities 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 coordination of care with other physicians, providing access to appropriate skilled therapies and screening tests, monitoring for and treating sequelae including hearing/vestibular impairment, pain, bowel and bladder impairments, and procuring needed adaptive equipment.
Cutting Edge/ Emerging and Unique Concepts and Practice
Targeted therapy agents have been on the horizon for NF2; however, chemotherapy with a vascular endothelial growth factor inhibitor, bevacizumab, has shown response in hearing improvement and tumor reduction.2,5 Stereotactic radiosurgery, radiation therapy, or microsurgery are 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
The appropriate timing of surgical interventions, and efficacy of radiation therapies and chemotherapeutic agents continues to be studied. The incidence of functional impairment following tumor development and treatment is not well characterized. Furthermore, impact of rehabilitation efforts on functional outcomes, prognosis, and quality of life still need exploration.
- Ardern-Holmes S, Fisher G, North K. Neurofibromatosis type 2. J Child Neurol. 2017;32(1):9-22.
- Kresak JL, Walsh M. Neurofibromatosis: A Review of NF1, NF2, and Schwannomatosis. J Pediatr Genet. 2016;5(2):98-104.
- Smith, M.J.; Bowers, N.L.; Bulman, M.; Gokhale, C.; Wallace, A.J.; King, A.T.; Lloyd, S.K.; Rutherford, S.A.; Hammerbeck-Ward, C.L.; Freeman, S.R.; et al. Revisiting Neurofibromatosis Type 2 Diagnostic Criteria to Exclude LZTR1-Related Schwannomatosis. Neurology 2017;88(1):87–92
- Selvanathan SK, Shenton A, Ferner R, et al. Further genotype–phenotype correlations in neurofibromatosis 2. Clin Genet. 2010;77(2):163-70.
- Sverak P, Adams ME, Haines SJ, et al. Bevacizumab for Hearing Preservation in Neurofibromatosis Type 2: Emphasis on Patient-Reported Outcomes and Toxicities: Otolaryngolo Head Neck Surg 2018;260:526.
- 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.
- 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
- 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.
- 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.
- 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.
- 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.
- 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.
- 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
Nikola Dragojlovic, DO
Nothing to Disclose
An Ngo-Huang, DO
Nothing to Disclose