Matthew L. Bush, MD
D. Bradley Welling, MD, PhD
DESCRIPTION 
- Neurofibromatosis type 2 (NF2) is a highly penetrant autosomal dominant genetic disorder with variable expressivity that is characterized by the development of multiple nervous system tumors. The presence of bilateral vestibular schwannomas is diagnostic of NF2; however, NF2 patients may also develop other cranial nerve schwannomas, spinal schwannomas, meningiomas, and ependymomas. The Manchester criteria diagnoses NF2 in individuals with:
- Bilateral vestibular schwannomas
- A first-degree relative with NF2 AND either a unilateral vestibular schwannoma OR any two of: meningioma, schwannoma, glioma, neurofibroma, posterior subcapsular lenticular opacities
- Unilateral vestibular schwannoma AND any two of: Meningioma, schwannoma, glioma, neurofibroma, posterior subcapsular lenticular opacities
- Multiple meningiomas AND unilateral vestibular schwannoma OR any two of: Schwannoma, glioma, neurofibroma, cataract
- Cutaneous manifestation of NF2 occurs in many patients; however, skin lesions are sparse and much less common when compared to NF1. Tumors include cutaneous schwannomas, neuromas, and/or café au lait spots. These lesions may cause persistent neuropathic pain, but less so than the schwannomas associated with schwannomatosis, a distinctly different entity.
EPIDEMIOLOGY
Incidence
The incidence of NF2 is 1 in 25,000 live births, and the disease prevalence is 1 per 60,000. NF2 typically has an early onset, which is typically between 18 and 24 years; however, subtle disease presentation in children may delay diagnosis. Nearly all individuals develop bilateral vestibular schwannomas by the age of 30 years. Genetic mosaicism accounts for 20–30% of NF2 patients without a family history of the disease and one half of patients with NF2 represent acquisition of a new mutation.
Genetics
Genetic testing is available and may be helpful in pre-symptomatic care of patients within families with NF2.
ETIOLOGY
NF2 is due to a germ-line mutation within a tumor suppressor gene, known as neurofibromatosis type 2 (NF2), located on chromosome 22q12. This gene encodes a cytoskeletal protein known as merlin or schwannomin and modulates cellular proliferation, adhesion, and motility. Phenotype may vary greatly within families of NF2; however, disease severity appears to be related to the type and location of NF2 mutation present. A more severe form of the disease has been associated with frameshift or nonsense mutations. Merlin interacts with multiple transcellular receptors and intracellular signaling pathways such as PI3K/Akt, Raf/MEK/ERK, ErbB, and PDGFR and mTOR pathways, which represent potential targets for drug development for NF2 patients.
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HISTORY
- Vestibular schwannomas may be asymptomatic when small; however, the majority of patients experience unilateral auditory and vestibular dysfunction. Tinnitus, sensorineural hearing loss, and chronic disequilibrium are common.
- Meningiomas may present with recurrent headaches and/or seizures. Spinal lesions may lead to chronic pain, focal weakness, and sensory loss. The ocular presentation of posterior subcapsular lens opacities, meningiomas, and retinal hamartomas may result in progressive vision decline and permanent loss.
PHYSICAL EXAM
- Expansion of the tumor within the cerebellopontine angle, or the presence of synchronous cranial nerve schwannomas or meningiomas, may lead to brainstem compression and cranial nerve dysfunction with resultant diplopia, facial hypesthesia, facial paralysis, dysphagia, hoarseness, hydrocephalus, and, potentially, death.
- Mono- and polyneuropathy may also occur in a minority of patients leading to severe muscle wasting. 10% of patients may also experience epilepsy unrelated to tumor burden.
DIAGNOSTIC TESTS AND INTERPRETATION
Audiogram
Speech discrimination scores which are unusually poor when compared to pure tone thresholds may be an early sign of a vestibular schwannoma.
Imaging
Initial Approach
MRI of the brain with and without contrast and with thin cuts through the internal auditory canal is the gold standard in evaluation of patients with unilateral auditory and vestibular dysfunction in order to identify enhancing vestibular schwannomas, cranial nerve schwannomas, and meningiomas. A comprehensive spinal MRI with contrast is also useful to evaluate for spinal tumors. Monitoring tumor growth with three-dimensional volumetric analysis may be more sensitive in monitoring small changes of tumor growth over time.
Pathological Findings
Histological features consistent with schwannoma or meningioma
DIFFERENTIAL DIAGNOSIS
Non-NF2-related schwannomas or meningiomas affecting the cranial nerves and/or skull base
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ADDITIONAL TREATMENT
General Measures
The management of NF2 patients is complex due to chronic nature of the disease and the presence of high tumor burden in many patients. These patients are best managed in centers that specialize in the care of NF2 patients and provide multi-disciplinary comprehensive care.
Additional Therapies
- Serial imaging: Tumor burden can be monitored with serial MRI over time. NF2-associated vestibular schwannomas exhibit an average growth rate of 1.3 mm/year. Patients that opt for observation should have their first follow-up MRI at 6 months and yearly thereafter. Any change in symptoms should result in repeat imaging.
- Radiation: Stereotactic radiation therapy can be used to treat a variety of NF2-associated intracranial tumors in patients that refuse surgery or are unable to safely undergo surgery. Vestibular schwannomas are treated with doses between 12 and 13 Gray (Gy) to 50% isodose line at the periphery of the tumor. Extracranial disease can be treated with stereotactic radiotherapy or external beam radiation. NF2-associated vestibular schwannoma treated with stereotactic radiation has shown tumor control rates of 71–85% with approximately 50% retaining functional hearing at 5 years following treatment. Radiation-associated complication rates are higher in NF2 patients than in those with sporadic tumors. Concern has been raised over the potential of inducing secondary malignancies from radiation in patients with inherent genetic mutations.
- Chemotherapy: Although no FDA-approved NF2 chemotherapeutic agents exist, patients with severe disease have been treated with chemotherapeutic agents. Inhibitors directed at the ErbB receptor family, AKT/PI3 kinase signaling pathway, and VEGF have shown evidence of inhibition of NF2 vestibular schwannoma growth. Some agents have shown initial improvement in hearing and tumor size reduction in early trials.
SURGERY/OTHER PROCEDURES
Microsurgery: In order to preserve neurologic and hearing function in NF2 patients, early intervention is indicated. Vestibular schwannoma progression will eventually result in deafness and potentially brainstem compression. The surgical approach is chosen based on the size and location of the tumor, as well as the presence of functional hearing. The suboccipital and middle fossa approaches have hearing preservation rates of 50%. NF2 patients may also undergo auditory brainstem implantation (ABI) at the time of suboccipital or translabyrinthine tumor resection to rehabilitate the loss of hearing. In the event that the cochlear nerve is preserved during tumor resection, cochlear implantation can be performed and offers improved auditory function over ABIs. Bony decompression of the internal auditory canal may also afford an extension of functional hearing in patients that are experiencing disease progression. Surgical management of other NF2-associated tumors is based on the symptoms, as well as the anatomic location. Cranial base and spinal lesions are treated surgically in the situation of progressive neurologic decline.
IN-PATIENT CONSIDERATIONS
Admission Criteria
Typically admitted for surgical resection of NF2 schwannomas or meningiomas
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PATIENT MONITORING
- NF2 patients should undergo annual comprehensive neurologic examinations, MRI of the brain with and without contrast, and audiograms. Development of new symptoms should be followed with repeat imaging. Spinal MRI is indicated at the time of development of symptoms. Children with NF2 should undergo frequent surveillance and rehabilitation of sensory deficits. Pre-symptomatic NF2 children should undergo MRI of the brain every 2 years through adolescence. Along with regular ophthalmologic and audiologic exams, individuals with visual and/or hearing loss should receive prompt rehabilitative services.
- Genetic testing should be offered for first-degree relatives of NF2 patients, and genetic counseling should be offered to NF2 patients.
PATIENT EDUCATION
Support groups such as the Acoustic Neuromas Association (www.anausa.org) and the Children's Tumor Foundation (www.ctf.org) provide many educational and social resources for patients and families affected by NF2.
PROGNOSIS
The prognosis of NF2 patients is poor as they face a life of progressive neurologic decline; however, the rate of decline is variable. Progressive cranial base tumor growth can lead to lower cranial nerve dysfunction, which may lead to chronic aspiration, gastrostomy tube dependence, and recurrent pneumonia, and is often the root cause of death. Patients diagnosed from 1970 to 1990 were found to have a 15-year life expectancy from the time of diagnosis. Improved diagnosis and early intervention have improved current life expectancies.
COMPLICATIONS
Loss of hearing, facial nerve paralysis, vestibular dysfunction, and impaired function of other cranial nerves due to tumor compression and/or surgery.
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