Neurofibromatosis Type 2

Neurofibromatosis type 2 is a neurocutaneous disorder that can arise from mutations in the NF2 gene located in chromosome 22 and may be inherited in an autosomal dominant fashion or occur from de novo mutations. The main clinical features are bilateral vestibular schwannomas, intracranial/spinal meningioma, and intramedullary and extramedullary spinal tumors. Other features can include eye lesions such as cataracts, skin lesions, and peripheral neuropathy. Diagnosis is made clinically from history and examination and confirmed with MRI, molecular testing, and histopathology. Tumor surveillance and follow-up with screening of at-risk family members is recommended. Management includes surgical interventions, radiation therapy, and/or monoclonal antibody therapy with bevacizumab.

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Overview

Epidemiology

  • The incidence of neurofibromatosis type 2 (NF2) is 1 in 25,000.
  • Bilateral vestibular schwannomas are present in 90%–95% of affected individuals.
  • Meningiomas are present in 50% of affected individuals.
  • De novo mutations that occur in the absence of a positive family history are present in > 50% of affected individuals.
  • NF2 gene mutations are detected in > 93% of families, with multiple members affected with NF2.

Etiology

  • Caused by NF2 gene mutation located in chromosome 22
  • The abnormal gene:
    • May be passed down from 1 parent (autosomal dominant)
    • May occur via de novo mutations 
  • Risk of gene transmission from parent to offspring is 50%.

Pathogenesis

  • Mutations occur in NF2 gene, located on chromosome 22.
  • NF2 gene codes for merlin (schwannomin):
    • Cell-membrane–related protein 
    • Acts as a tumor suppressor 
    • Found on Schwann cells
  • Mutations lead to loss of merlin expression, allowing tumor eruption in the central and peripheral nervous systems.
  • 2-hit hypothesis:
    • Schwannomas and other tumors occur only after inactivation of both NF2 alleles:
      • Affected individuals are born with 1 abnormal allele.
      • Abnormalities of the 2nd allele are acquired.
    • Acquired loss of function in the entire NF2 gene or in chromosome 22 is most common.
    • Point mutations of the wild-type allele occur less commonly.

Clinical Presentation

The clinical presentation of NF2 may vary widely between individuals with de novo mutations and families carrying genetic mutations. Younger ages at onset are often associated with an atypical presentation with more severe symptoms.

Clinical manifestations of nf2

Clinical manifestations of NF2

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Age at onset

  • Childhood onset:
    • Visual/ocular manifestations
    • Pain
    • Weakness
    • Mononeuropathy
    • Cutaneous tumors
    • Seizures
  • Adult onset (most commonly at about age 20):
    • Hearing loss
    • Tinnitus

Neurologic lesions

  • Vestibular schwannomas (cranial nerve (CN) VIII):
    • Present in approximately 95% of NF2-affected individuals
    • Develop by 30 years of age
    • Typically bilateral
    • Typically benign
    • Symptoms:
      • Tinnitus
      • Hearing loss
      • Loss of balance/equilibrium
  • Schwannomas of other cranial nerves:
    • Present in 25%–50% of NF2-affected individuals
    • Not observed in CN I or CN II (absence of Schwann cells)
    • Cause compressive cranial nerve palsies
    • Most commonly observed in:
      • CN III (oculomotor)
      • CN V (trigeminal)
      • CN VII (facial)
  • Intracranial meningioma:
    • Present in 45%–60% of NF2-affected individuals
    • Often multiple
    • Develops in NF2 at a younger age than in sporadic cases
    • Symptoms depend on location and size:
      • Focal neurologic deficits
      • CSF flow obstruction
      • Seizures
  • Spinal meningioma:
    • Present in approximately 20% of NF2-affected individuals
    • Arise from extramedullary space
    • Symptoms depend on location and size:
      • Back pain
      • Nerve root pain/paresthesia
      • Muscle weakness/paralysis
      • CSF flow obstruction
  • Spinal ependymomas:
    • Present in 20%–50% of NF2-affected individuals
    • Typically arise from intramedullary space
    • Symptoms depend on location and size:
      • Back pain
      • Nerve root pain/paresthesia
      • Muscle weakness/paralysis
      • CSF flow obstruction
  • Peripheral neuropathy:
    • Present in > 65% of NF2-affected individuals
    • May present as a compression neuropathy (mononeuropathy)
    • May present as a mononeuropathy multiplex
    • May present as a systemic (nonfocal) sensorimotor neuropathy
    • Symptoms of mononeuropathy dependent on the affected nerve(s).
    • Symptoms of systemic polyneuropathy:
      • Neuropathic pain/paresthesias/sensory loss in a glove-and-stocking distribution
      • Loss of strength, coordination, dexterity in a glove-and-stocking distribution 

Eye lesions

  • Cataracts:
    • Present in 60%–80% of NF2-affected individuals
    • Present with visual loss, lens opacity
  • Epiretinal membranes:
    • Present in approximately 80% of NF2-affected individuals
    • White/gray membranes with distinct white edges
    • May be translucent or semitranslucent
    • Do not typically interfere with vision
  • Retinal hamartomas:
    • Present in 5%–20% of NF2-affected individuals
    • Affect the macula 
    • Present with visual loss

Skin lesions

  • May occur anywhere, no particular area of predilection 
  • Most commonly skin tumours are schwannomas, though neurofibromas or mixed histology may be observed.
  • Skin plaques:
    • Present in 40%–50% of NF2-affected individuals
    • Circumscribed, slightly raised, slightly hyperpigmented, scaly, rough lesions
    • Typically < 2 cm in diameter
  • Subcutaneous tumors:
    • Present in 40%–50% of NF2-affected individuals
    • Develop as swellings along peripheral nerves
    • May be palpated as fusiform or nodular swellings 
    • Tenderness to palpation may be noted.
  • Intradermal tumors:
    • Present in 60%–70% of NF2-affected individuals
    • Well-demarcated, superficial lesions with blue/purple coloration
    • Soft to palpation

Diagnosis

Clinical criteria for neurofibromatosis type 2 (revised Manchester criteria)

  • Any 1 of the following:
    • Bilateral vestibular schwannoma at < 70 years of age
    • Unilateral vestibular schwannoma at < 70 years and 1st-degree relative (not a sibling alone) with NF2
  • Any 2 of the following:
    • Meningioma, nonvestibular schwannoma, ependymoma, cataract; and 
    • 1st-degree relative with NF2 or unilateral vestibular schwannoma and negative LZTR1 testing (if ≥ 2 non-intradermal schwannomas)
  • Other criteria:
    • Multiple meningioma and:
      • Unilateral vestibular schwannoma or
      • Any 2 of the following: nonvestibular schwannoma, ependymoma, cataract
    • 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 

Clinical diagnosis

  • Detailed clinical and family history
  • Physical examination:
    • Auditory evaluation
    • Ophthalmic evaluation
    • Neurologic examination
    • Skin examination

Molecular testing

  • Indications:
    • 1st-degree relative with NF2 
    • Presence of multiple spinal tumors 
    • Presence of cutaneous schwannomas
    • Presence of vestibular schwannoma at < 30 years of age
    • Presence of meningioma or schwannoma (nonvestibular) at < 25 years of age
  • Begin with analysis of tumor DNA with sequencing for NF2 abnormalities, followed by analysis of blood lymphocytes for the same NF2 abnormality.
Vestibular schwannoma histopathology

Vestibular schwannoma histopathology

Image: “Vestibular schwannoma” by Pećina-Slaus N, Zeljko M, Pećina HI, Nikuseva Martić T, Bacić N, Tomas D, Hrasćan R. License: CC BY 2.5

Imaging

  • MRI with contrast is the method of choice.
  • Scans of the brain and entire spine are recommended to evaluate for intracranial/spinal tumors.

Management

Management of NF2 is multidisciplinary and often involves contributions from multiple specialists.

  • Consultations with the following specialties:
    • Oncology
    • Neurology
    • Neuroradiology
    • Ophthalmology
    • Dermatology
    • Audiology
    • Genetics/genetic counseling
    • Neurosurgery/skull-base surgery 
  • Tumor surveillance and follow-up:
    • Annual history and physical exam (audiology, ophthalmic evaluation, neurologic, and cutaneous examination)
    • Brain MRI every 12 months beginning at 10 years of age
    • Spinal MRI every 24–36 months beginning at 10 years of age
  • Vestibular schwannoma(s): 
    • Surgery:
      • Neurosurgery or skull-base surgery consultation
      • Surgery may be complex and high risk depending on size, location, and multifocality.
    • Bevacizumab: 
      • Monoclonal antibody against vascular endothelial growth factor
      • Induces tumor shrinkage and hearing improvement
    • Other targeted therapies:
      • Everolimus: chemotherapeutic kinase inhibitor that decreases tumor blood supply.
      • Lapatinib: chemotherapeutic tyrosine kinase inhibitor interrupts epidermal growth factor receptor (EGFR) pathways.
    • Hearing impairment: 
      • Cochlear implants
      • Brain stem implants 
  • Meningioma: 
    • Surgery: 
      • Rapidly growing tumors
      • Tumors threatening functional loss
    • Radiation therapy:
      • Tumors that are surgically inaccessible or for which only partial resection is possible
      • Concern for development of secondary neoplasms
    • Targeted therapy with lapatinib is being investigated.
  • Intramedullary spinal tumors: 
    • Usually grow very slowly, with no symptoms for a long period
    • MRI surveillance is usually adequate.
    • Bevacizumab is 1st-line therapy.
    • Surgery is recommended if symptoms require intervention.
  • Genetic evaluation:
    • Identification of specific NF2 gene mutation
    • Screening of at-risk family members

Differential Diagnosis

  • Sporadic vestibular schwannomas: also known as acoustic neuromas. In the general population, sporadic vestibular schwannomas are relatively common. In contrast to NF2, sporadic vestibular schwannomas are typically unilateral and present at > 30 years of age. Presentation is with hearing loss and equilibrium problems. These lesions are diagnosed on clinical suspicion and confirmed with neuroimaging. Conservative and surgical options are similar to those outlined for NF2. 
  • Schwannomatosis: rare sporadic or familial form of neurofibromatosis associated with mutations in the SMARCB1 and LZTR1 genes located on chromosome 22. Schwannomatosis is characterized by multiple noncutaneous peripheral and intracranial schwannomas in the absence of bilateral vestibular schwannomas. Diagnosis is made with clinical evaluation and confirmed with biopsy. Management is symptomatic, treating the chronic pain that occurs in roughly half of all patients with schwannomatosis. 
  • Neurofibromatosis type 1: autosomal dominant disorder caused by mutations in the NF1 gene located in chromosome 17q11.2. Clinical manifestations can overlap with NF2, but the key differences include that Lisch nodules are seen in few numbers in NF2, schwannomas rarely undergo malignant transformation to a neurofibrosarcoma, the “dumbbell” spinal root tumors that are seen in both NF2 and NF1 are schwannomas in NF2 and neurofibromas in NF1, and NF2 is not associated with the cognitive impairment seen in NF1. Management is based on the clinical features and may vary from surgical removal to chemotherapy/radiotherapy for tumors, occupational and physical therapy for motor impairments, and treatment with growth hormone and bracing in bone abnormalities. 
  • Tuberous sclerosis: autosomal dominant disorder with mainly neurocutaneous symptoms. Mutation in the TSC genes causes excessive tumor-like growths in the brain, eyes, heart, kidneys, and lungs. Cutaneous manifestations include hypopigmentation (i.e., ash-leaf spots, confetti lesions) or excessive growth (i.e., angiofibroma, shagreen patch). The diagnosis is made on clinical suspicion and confirmed by genetic testing. Management entails a multidisciplinary approach that targets monitoring and treatment of the various manifestations of the disorder.

References

  1. Evans, D.G. (2021). Neurofibromatosis type 2. UpToDate. Retrieved August 30, 2021, from https://www.uptodate.com/contents/neurofibromatosis-type-2
  2. Park, J.K. et al. (2020). Vestibular schwannoma (acoustic neuroma). UpToDate. Retrieved August 30, 2021, from https://www.uptodate.com/contents/vestibular-schwannoma-acoustic-neuroma
  3. Victorio, M.C. (2021). Neurofibromatosis. MSD Manual Professional Version. Retrieved August 28, 2021, from https://www.msdmanuals.com/professional/pediatrics/neurocutaneous-syndromes/neurofibromatosis
  4. Hsieh, D.T. (2018). Neurofibromatosis type 2. Medscape. Retrieved August 28, 2021, from https://emedicine.medscape.com/article/1178283
  5. Tiwari, R., Singh, A.K. (2021). Neurofibromatosis Type 2. StatPearls. https://www.ncbi.nlm.nih.gov/books/NBK470350/
  6. Asthagiri, A.R., et al. (2009). Neurofibromatosis type 2. Lancet 373:1974–1986. https://doi.org/10.1016/S0140-6736(09)60259-2

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