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
  • Severe progression (early diagnosis, multiple tumors, early death) in cases of truncations (frameshift or nonsense) of exons 2-13
  • Moderately severe progression with major deletions and splicing mutations in exons 1-6
  • Moderate progression in cases of exon 1 truncations, splice-variant mutations in exons 7-15, mosaicism in cases of exons 2-13 truncations evident in the blood
  • Mild progression (late diagnosis, often only vestibular schwannomas) in cases of missense mutations and mosaic mutations not detectable in the blood
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
    plus

  • Unilateral 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
    or

  • Multiple (≥ 2) meningiomas as well as unilateral VS or 2 gliomas/neurofibromas/non-vestibular schwannomas/cataracts

Differential Diagnoses

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