# Handbook of Genetic Counseling/Neurofibromatosis - Type 2

Neurofibromatosis - Type 2

## Contracting

* How have things been since your last visit?
* What questions or concerns would you like us to address today?

## 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.