Definition
Neurofibromatosis type 2 is a relatively rare tumor predisposition syndrome characterized by progressive hearing loss that develops due to benign vestibular schwannomas on one or both sides, previously called acoustic neuromas. Other tumors, such as schwannomas, may also develop at the central and peripheral nerves, with meningiomas, gliomas, and neurofibromas occurring as well. In addition, premature reduction in visual acuity is indicative of a characteristic NF2 juvenile cataract.
Key Data
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Synonyms | NF2, central neurofibromatosis |
Gene | NF2 tumor suppressor gene |
Gene product | Merlin (moesin-ezrin-radixin-like protein) |
Function | Cytoskeletal protein, tumor suppression via contact-mediated (membrane) growth inhibition |
Heredity | Autosomal dominant (37%), de novo (63%, 1/3 of them mosaicism) |
Prevalence | 1:25.000-33.000 (1:150.000 in childhood) |
Genotype-phenotype correlation |
|
Penetrance | Nearly 100% during adulthood (by 30 years of age) |
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Diagnosis
Diagnostic Criteria (Manchester Diagnostic Criteria for NF2)
Bilateral vestibular schwannomas (VS) or a positive family history of NF2
plusUnilateral VS or 2 meningiomas/gliomas/neurofibromas/non-vestibular schwannomas/juvenile posterior subcapsular cataracts
Additional Criteria:
Unilateral VS plus ≥ 2 meningiomas/gliomas/neurofibromas/non-vestibular schwannomas/juvenile posterior subcapsular cataracts
orMultiple (≥ 2) meningiomas as well as unilateral VS or 2 gliomas/neurofibromas/non-vestibular schwannomas/cataracts
Differential Diagnoses
Sporadic VS
Ring chromosome 22 with mosaic loss of NF2 (NF2-typical tumors, learning disability, café au lait spots)
Clinical Presentation
Signs of progressive hearing loss and tinnitus in young adulthood and mild courses of the disease are common.
With onset during childhood (30%), meningiomas, non-cranial schwannomas, mononeuropathies, and ocular symptoms (retinal hamartomas, cataract) are often prominent.
Classical Findings
Benign nerve sheath tumors, primarily schwannomas
- Bilateral vestibular cranial nerve VIII (90-95%) – hearing loss, vertigo
- Multifocal: cranial (24-51%, except for cranial nerve I/II), spinal (63-90%), peripheral, intracutaneous
Meningiomas (45-77%, entire neural axis)
Low-grade ependymomas (5-33%, primarily intraspinal)
Astrocytomas
Skin: skin tumors (70, mainly schwannomas, rarely neurofibromas), presentation in three distinct forms:
- Plaque-like intracutaneous schwannomas (41-48%, slightly raised, hyperpigmented, hairier)
- Lower-lying subcutaneous nodular tumors (43-48% appearing like fusiform swelling)
- Intracutaneous neurofibromas (59-68%)
Café au lait spots
Eyes: Juvenile posterior subcapsular cataracts (60-81%), amblyopia, epiretinal membranes (12-40%), retinal hamartomas (6-22%), meningiomas of the optic nerve
Neuropathy (-66%), with spinal tumors especially causing pain, muscle weakness, and paresthesia
NF2 tumor associated risk up to 16 years of age (According to Evans et al., AACR 2016)
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Likelihood of tumor symptoms | Likelihood of detecting tumors by MRI | Risk in Adulthood | |
---|---|---|---|
Vestibular schwannomas | 25% | 70-80% | 100% |
Cranial schwannomas | <1% | 20% | 40% |
Meningiomas | 10% | 15-20% | 70% |
Ependymomas | 0,2-0,5% | 10% | 25% |
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Therapeutic Considerations
Microsurgery
Radiatio (please note: secondary malignancy risk in children)
Brainstem/cochlear implant
Bevacizumab (Avastin, VEGF inhibitor, NUB, off-label use) for progressive VS with imminent hearing loss
Surveillance Recommendations
Surveillance Recommendations
Examination Recommendations from AACR 2016 for Children with NF2
Annual medical history and clinical checkup, audiometry (tone and speech audiometry)
Annual high-resolution (1-3 mm layer thickness) cranial MRI as of age 10 (earlier for a high-risk genotype and when there are clinical symptoms) in the inner ear canal region, preferably on at least 2 orthogonal levels (2x in the year the diagnosis is made if there are abnormal findings in order to determine the growth rate)
If the MRI findings are unremarkable and there are no symptoms, an MRI screening every 2 years is sufficient.
Spinal MRI every 2-3 years as of age 10 (as soon as tumor growth is detected, with the first checkup recommended after 6 months to determine the tumor growth rate)
Consider performing a whole-body MRI
No general recommendation for routine screening with F-FDG-PET/CT or MRI
Pre-symptomatic testing as of 10-12 years of age