Neurofibromatosis - Type 2

Contracting

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Etiology

• Disease characteristics
  • Genetic disorder that causes tumors to grow on various nerves
  • Also affects other tissues such as bones and skin
  • Two distinct types: NF-1 and NF-2
• Inheritance
  • Autosomal dominant
  • Affected individuals have 50% chance of passing on mutation to each of their children
  • Half of affected individuals have de novo mutations
  • If neither parent has NF2, recurrence risk is very low - only one case of germline mosaicism reported
  • Uniform age of onset within families
• Molecular genetics
  • Caused by mutation in the NF2 gene
  • Located at 22q12
  • Normal gene product is schwannomin or merlin
    • Homology to 4.1 family of cytoskeletal associated proteins
    • Has role in prevention of schwannoma formation
    • Tumor suppressor gene
• Incidence is 1 in 40,000 people

Clinical Features and Natural History

• Some variability in clinical manifestations
  • Variability within families is low
  • Suggests strong genotype-phenotype correlation
• Average age of onset of symptoms is 18-24
  • Some people don't develop signs until their 40's or 50's
  • Considered adult-onset so may be underdiagnosed in children
  • Nonsense and frame shift mutations more severe
• Bilateral vestibular schwannoma (acoustic neuroma)
  • Affect almost all patients with NF2
  • Tumor that arises from Schwann cells that support and protect nerves with insulation needed to conduct information on 8th cranial nerve
  • Initial symptoms include tinnitus (ringing in ears), hearing loss, and balance dysfunction
  • May result in hearing loss in one or both ears
• Spinal tumors (>66%)
  • Include schwannomas that may cause numbness in part of body
  • Intramedullary tumors such as astrocytoma and ependymoma (5-33%)
  • Most individuals with spinal cord tumors have more than one
• Meningiomas (50%)
  • Tumor that grows from cells that line the brain and spinal cord in protective sheets called meninges
  • May be intracranial or spinal
  • Cause different neurological symptoms depending on location
• Ocular involvement (33%)
  • Cataracts
    • Known as juvenile posterior sublenticular opacity
    • May impair vision if not removed
  • Optic gliomas
    • Tumors on vision nerve
    • May lead to blindness
• Other features
  • Other types of central nervous system tumors
  • Atypical café-au-lait spots
  • Cutaneous neurofibromas
• Somatic mosaicism
  • Suspected in individuals with unilateral vestibular schwannoma and multiple other tumors on one side
  • More difficult to diagnose
• Considerably shortened lifespan
  • Average age of death is 36 years
  • With improvements in diagnosis, monitoring, and surgery this is changing

Diagnosis/Testing Options

• Clinical diagnosis
  • Bilateral VIII nerve mass on CT or MRI (vestibular schwannomas)

OR

• • First degree relative with NF2 and either
    • Unilateral 8th nerve mass

OR

• • • Two of the following
      • Meningioma
      • Glioma
      • Schwannoma
      • Juvenile posterior subcapsular lenticular opacity
• Mutation analysis
  • Mutations identified in 65-80% of patients with clinical diagnosis
  • Testing provided by Athena Diagnostics/Mass Gen
  • Includes SSCP (single stranded conformational polymorphism)
  • May take up to 6 months for results
  • Costs about $2700
  • Considered appropriate to test unaffected at risk children and adults
• Linkage analysis
  • Appropriate if more than one affected family member
  • Doesn't work for 50% of patients with de novo mutations
  • High accuracy because markers are very closely linked
• Prenatal testing
  • Available for fetuses at 50% risk or greater
  • Can be performed if mutation identified in affected family member
  • Requires cells obtained from CVS or amniocentesis

Management

• Currently is no cure or treatment
• Early recognition allows for earlier intervention and improved outcome
• Begin screening in early teens
  • ABR and MRI exams for vestibular schwannomas
    • Surgery generally successfully preserves hearing is tumors small
    • Should begin learning sign language before hearing is lost
    • Hearing aids may help preserve hearing early on
  • Routine complete eye examinations
  • Routine neurological examinations
  • Intracranial, cranial nerve, and spinal tumors often slow growing

Differential Diagnosis

• NF1
  • Has Lisch nodules, axillary and inguinal freckling, and plexiform neurofibromas not seen in NF2
  • Patients with NF2 do not have mental retardation or learning problems
• Unilateral vestibular schwannoma
  • Accounts for 5-10% of intracranial tumors
  • Less than 5% are bilateral and associated with NF-2
• Schwannomatosis
  • Multiple schwannomas without vestibular schwannomas
  • Develop intracranial, spinal nerve root, or peripheral nerve tumors
• Multiple meningiomas
  • Without vestibular schwannomas
  • Typically occur in older adults

Psychosocial Issues

• Feelings of fear, anger, shock, denial over new diagnosis
• Difficulty adjusting to loss of hearing
• Burden of condition requiring extensive surveillance
• Anxiety about possibility of shortened life span
• Survivor guilt, transmitter guilt
• Support system to help cope with diagnosis

Support Resources

• National Neurofibromatosis Foundation

95 Pine Street, 16th Floor

New York, NY 10005

Phone: 800-323-7938

Web: www.nf.org

• Neurofibromatosis, Inc

8855 Annapolis Road, Suite 110

Lanham, MD 20706-2924

Phone: 410-461-5213

Web: www.nfinc.org

• The Acoustic Neuroma Association

PO Box 12402

Atlanta, GA 30355

Phone: 404-237-2704

Web: ANAUSA@aol.com

References

• GeneReviews. "Neurofibromatosis 2" (2002).
• "Neurofibromatosis Type 2: Information for Patients and Families." National Neurofibromatosis Foundation brochure.

Notes

The information in this outline was last updated in 2001.