Handbook of Genetic Counseling/Neurofibromatosis - Type 2

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
OR OR
 * Clinical diagnosis
 * Bilateral VIII nerve mass on CT or MRI (vestibular schwannomas)
 * First degree relative with NF2 and either
 * Unilateral 8th nerve mass
 * 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