NF2-associated Schwannomatosis – Definition
NF2-associated schwannomatosis, or central neurofibromatosis, is a genetic – or hereditary – disease that typically appears during young adulthood and is associated with the development of benign tumors of the central nervous system. What is characteristic in patients with NF2-associated schwannomatosis is the development of benign tumors of the 8th cranial nerve, typically on both sides, referred to as bilateral vestibular schwannomas and previously called acoustic neuromas as well. Since the 8th cranial nerve is responsible for hearing and equilibrium, these tumors lead to increasing hearing loss and sometimes to impaired balance or an unsteady gait. Other benign tumors, brain tumors, and spinal tumors may occur as well. A decline in visual acuity, triggered by a special form of juvenile cataract, is also characteristic. NF2-associated schwannomatosis is classified as a tumor disposition disease.
Synonyms:
NF2, central neurofibromatosis
Gene:
NF2 tumour suppressor gene
Gene products:
Merlin (Moesin-Ezrin-Radixin-Like Protein)
Function:
Cytoskeletal protein, tumour suppression through (membrane) contact-mediated growth inhibition
Pattern of inheritance:
autosomal dominant (37%), de novo (63%, of which 1/3 mosaic)
Prevalence:
1:25.000-33.000 (in childhood 1:150.000)
Genotype-phenotype correlation:
Severe course (early diagnosis, multiple tumours, early death) with truncating mutations (frameshift or nonsense) in exons 2-13
Moderate-severe course with larger deletions and splice mutations in exons 1-6
Moderate course with truncating mutations in exon 1, splicing mutations in exons 7-15, mosaic for blood-detectable truncating mutations in exons 2-13
Mild course (late diagnosis, often only vestibular schwannomas) with missense mutations and mosaic mutations not detectable in the blood
Penetrance:
Almost 100% in adulthood (up to 30 years)
NF2-associated Schwannomatosis – Diagnosis
Diagnostic criteria (Manchester diagnostic criteria)
- Bilateral vestibular schwannomas (VS) or positive family history of NF2-associated schwannomatosis
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 plus unilateral VS or 2 gliomas/neurofibromas/non-vestibular schwannomas/cataracts
Differential Diagnoses
- Schwannomatosis (especially LZTR1)
- Neurofibromatosis type 1
- Sporadic VS
- Ring chromosome 22 with mosaic loss of NF2 (NF2-associated schwannomatosis-typical tumours, learning disability, CALF)
Clinical Presentation
Progressive hearing loss and tinnitus in young adulthood are typical, with a mild course.
In childhood (30%), meningiomas, non-cranial schwannomas, mononeuropathies and ocular manifestations (retinal hamartomas, cataracts) are common.
Classic findings
- Benign nerve sheath tumours, mainly schwannomas
- Bilateral vestibular VIII. HN (90-95%) – hearing loss, balance problems
- Multifocal: cranial (24-51%, except I./II. HN), spinal (63-90%), peripheral, intracutaneous Meningiomas (45-77%, entire neuroaxis)
- Low-grade ependymomas (5-33%, mainly intraspinal)
- Astrocytomas
- Skin: Skin tumours (70%, predominantly schwannomas, rarely neurofibromas) present in three different forms:
- Plaque-like intracutaneous schwannomas (41-48%, slightly raised, hyperpigmented, increased hairiness)
- Deeper subcutaneous nodular tumours (43-48%, presenting as a fusiform swelling)
- Intracutaneous neurofibromas (59-68%)
- CALF
- Eye: Juvenile posterior subcapsular cataracts (60-81%). amblyopia, epiretinal membranes (12-40%), retinal hamartomas (6-22%), meningiomas of the optic nerve
- Neuropathies (-66%), especially spinal tumours, cause pain, muscle weakness and paresthesias
Tumour risk in NF2-associated schwannomatosis up to the age of 16 (according to Evans et al., AACR 2016)
| Tumour symptom Probability |
Tumour probability in 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% |
Special Features of Treatment
- Microsurgery
- Radiotherapy (caution: risk of secondary malignancy in children)
- Brainstem/cochlear implant
- Bevacizumab (Avastin, VEGF inhibitor, NUB, off-label use) for progressive VS with impending hearing loss
Diagnosis of NF2-associated Schwannomatosis- What's Next?
Once diagnosed, it is recommended that a cancer predisposition specialist manage the patient. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. Some additional information, including links to support groups, is also included at the end of this page.
Diagnosis of NF2-associated Schwannomatosis - What's Next?
Once diagnosed, it is recommended that a cancer predisposition specialist manage the patient. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. Some additional information, including links to support groups, is also included at the end of this page.
Recommendations for Early Detection in Your Patients
According to the latest AACR guidelines, the following screening tests are recommended for patients with NF2-associated schwannomatosis:
Baseline: at 10 years of age or at diagnosis (whichever is later)
- Contrast-enhanced MRI of the head including dedicated high-resolution images of the internal auditory canal (3 Tesla, 1-3 mm slices)
- MRI of the spine
- Full-body MRI (cannot replace other MRI scans)
- Hearing screening
- Eye examination
- Dermatological examination for Schwannomatous plaques
Periodic examinations for asymptomatic patients or patients with stable findings
- Physical examination, including neurological examination with recording of any pain, annually from diagnosis
- Audiometry with pure tone thresholds and word recognition annually from diagnosis
- Contrast-enhanced MRI of the head, including dedicated high-resolution imaging of the internal auditory canal (3 Tesla, 1-3 mm slices), annually from 10 years of age
- Consider earlier screening for high-risk genotypes or after first tumour diagnosis before 10 years of age
- Consider head MRI every 6 months for the first year after tumour diagnosis
- MRI of the spine every 3 years from the age of 10
Regular examinations for symptomatic patients
- Specific MRI of painful or symptomatic region
