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.