Neuro Fibroma

4/3/2014 Neurofibromatosis Type 2

http://emedicine.medscape.com/article/1178283-overview#showall 1/7

Neurofibromatosis Type 2

Author: Beth A Pletcher, MD; Chief Editor: Amy Kao, MD more...

Updated: May 14, 2013

Practice Essentials

Central neurofibromatosis, or neurofibromatosis type 2 (NF2), is a genetic disorder marked by the predisposition todevelop a variety of tumors of the central and peripheral nervous systems. In contrast to neurofibromatosis type 1(NF1), NF2 produces a paucity of cutaneous manifestations.

Essential update: Facial nerve dysfunction in patients with neurofibromatosis type 2

In a historical analysis of a national database of patients undergoing resection for acoustic neuromas between1998 and 2006, patients with NF2 had a 220% increased risk for facial nerve dysfunction after surgery. Facialnerve dysfunction was associated with increased inpatient days (5 days vs 4 days), hospital costs ($53,679 vs$46,992 in 2006 US dollars), and nonroutine discharge (17% vs 9%). In addition to NF2 status, nonwhite race and

Medicaid pay status (vs all other insurance) were significant predictors of facial nerve dysfunction.[1]

Signs and symptoms

Clinical diagnosis of NF2 requires that an individual present with at least 1 of the 3 following disease indications:

Bilateral eighth nerve masses visualized on MRI scan, using thin cuts, with and without gadolinium and onaxial and coronal viewsFirst-degree relative with documented NF2 for an individual with a unilateral eighth nerve mass, imaged asalready describedFirst-degree relative with documented NF2 for an individual with at least 2 of the following findings:meningioma, glioma, schwannoma, juvenile cataract

However, because approximately half of cases result from new mutations, family history is often negative.

Unlike NF1, which frequently is associated with a number of cutaneous diagnostic clues, NF2 is accompanied byfew external signs. Presenting symptoms include the following:

Hearing loss, ringing in the ears, and balance problems associated with vestibular nerve lesionsVisual deficitsCranial nerve palsies

See Clinical Presentation for more detail.

Diagnosis

Diagnosis of NF2 involves the following:

Genetic testingImaging studiesAuditory, ophthalmic, and histologic examinations

Genetic testing

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Once the clinical diagnosis has been established unequivocally in a given individual, direct molecularanalysis can be offeredDetection rates for molecular-based testing approaches 65%If a mutation is found, other asymptomatic family members might benefit from presymptomatic testingMolecular testing of tumor tissue may augment traditional molecular studies when analysis of DNAobtained from blood lymphocytes is nondiagnosticFor families in which no mutation can be identified in a known affected individual, linkage analysis orindirect genetic testing methods may be utilizedPresymptomatic testing of at-risk family members requires a vigorous informed consent process and mightbest be done during a genetic counseling session at a cancer, genetic, or neurofibromatosis center thatspecializes in such matters

Prenatal testing for NF2 is as follows:

When a parent has NF2, prenatal testing can be done on amniocytes or chorionic villi, either through directgene mutation analysis when such a change has been identified or through linkage analysisPrenatal testing may not be possible if the affected parent is the first affected person in the family and amutation cannot be foundIf a prospective parent has a known NF2 mutation, preimplantation genetic diagnosis may be possible if thecouple is willing to undergo in vitro fertilization with transfer of unaffected embryos

Magnetic resonance imaging

MRI remains the mainstay for diagnosis and screening of CNS, cranial nerve, and spinal cord tumorsAt-risk individuals may be monitored for CNS tumors beginning in their teens, with annual MRI scans of thehead performed through their late 50sMRI using 3-dimensional (3D) volumetrics is now the preferred method for following vestibular schwannoma

growth over time[2]

Routine MRI imaging of the spinal cord probably is not indicated for asymptomatic affected or at-riskindividualsMRI of the spine is indicated diagnostically when an individual presents with motor or sensory changessuggestive of a spinal cord lesion or lesions

Auditory Evaluation

Hearing evaluations, including brainstem auditory-evoked response (BAER) may demonstrate latencyabnormalities before a mass is detectable on MRIAuditory screening on an annual basis may be quite useful in asymptomatic or presymptomatic individualsOnce a vestibular schwannoma is identified, full audiometry testing, including acoustic reflex testing as wellas BAER, is useful as a means of monitoring disease progressionThe size of the vestibular tumor often does not correlate with the degree of hearing loss

Ophthalmic Examination

Annual eye examinations are recommended for children and adults with NF2Dilated eye examinations for lens opacities, retinal hamartomas, or epiretinal membranes may be quiteuseful even in a child at risk for NF2Juvenile cataracts may be seen long before a child shows any evidence of vestibular schwannomas

See Workup for more detail.

Management

Medical care for patients with NF2 consists of routine examinations focusing on early detection of some of the

potential complications related to CNS or spinal cord lesions.[3] Management by a team of specialists through amultidisciplinary clinic may provide the most comprehensive and cost-effective care over time. The following is anoutline of reasonable guidelines in the care of the patient with NF2:

Annual neurologic examination looking for subtle deficits or changes in neurologic status that mightsuggest disease progressionAnnual hearing screening with BAER, with referral to an audiologist for amplification, augmentation, orspeech therapy recommendationsAnnual MRI to monitor existing lesions or look for presymptomatic lesions



Annual ophthalmologic evaluations to monitor visual acuity

Treatment of symptomatic tumors is as follows:

Surgical resection represents the most common approach to clinically significant lesionsRarely, radiation and/or chemotherapy may be recommended to treat disabling ependymomasPalliative chemotherapy for surgically unresectable ependymomas may be attempted with lomustine,vincristine, and prednisone, or carboplatin and vincristine, following radiation therapyErlotinib has shown promise in the treatment of unresectable, progressive vestibular schwannomas

Tumor resection and radiotherapy

For small vestibular schwannomas, surgical resection and stereotactic radiosurgery may preserve hearing

and facial nerve function in selected patients[4]

Larger tumors may require surgical resection despite irreversible hearing lossA debulking procedure may result in preservation of hearing or, at the minimum, prolongation of auditorydecompensationNonvestibular cranial nerve schwannomas may be treated effectively with a combination of microsurgery

and radiosurgery[5]

Unlike vestibular lesions, intracranial meningiomas may be quite slow growing; surgical resection should beconsidered only when such lesions are causing serious, disabling symptomsResection of spinal cord tumors is often quite difficult, and the risks and benefits of surgery must beconsidered on an individual basisResection of cutaneous or subcutaneous growths can be accomplished by any competent surgeon

Auditory Brainstem Implants

Auditory brainstem implants (ABIs) have been used successfully in some patients with hearing losssecondary to vestibular schwannomas

ABIs often improve the patient's ability to appreciate environmental sounds and facilitate communication[6]

ABIs in patients with NF2 do not enable high levels of speech recognition

See Treatment and Medication for more detail.

Image library

Bilateral acoustic neuromas in a patient w ith neurofibromatosis type 2.

Background

Central neurofibromatosis, or neurofibromatosis type 2 (NF2), is a multisystem genetic disorder associated withbilateral vestibular schwannomas, spinal cord schwannomas, meningiomas, gliomas, and juvenile cataracts, witha paucity of cutaneous features (which are seen more consistently in neurofibromatosis type 1 [NF1]). (See theimage below.)



Subcutaneous and cutaneous lesions in a young man w ith neurofibromatosis type 2; note paucity of cafe-au-lait spots.

Although quite variable in its age of onset and severity of symptoms in affected individuals, NF2 is associated withsignificant morbidity and decreased life span. Furthermore, diagnosis in childhood is often difficult because of the

absence of central nervous system (CNS) involvement at a young age.[7] (See Prognosis, Clinical, and Workup.)

Complications of NF2 may include the following (See Clinical, Workup, and Treatment):

Unilateral or, frequently, bilateral vestibular schwannomas leading to tinnitus, hearing loss, and/or problemswith balanceMeningiomas, gliomas, ependymomas, and other cerebral, cerebellar, or spinal cord lesions that mayresult in neurologic deficits, seizures, and/or hydrocephalusPeripheral nerve schwannomas, mixed tumors, and, occasionally, neurofibromasPeripheral neuropathiesVisually significant juvenile cataracts

Etiology

NF2 is inherited as an autosomal dominant condition, although half of affected individuals have NF2 as a result of anew (de novo) gene mutation. The manifestations of NF2 result from mutations in (or, rarely, deletion of) the NF2gene, located on the long arm of chromosome 22. Affected individuals need only 1 mutated or deleted NF2 gene toexhibit signs of the condition.

The NF2 gene product known as merlin serves as a tumor suppressor; decreased function or production of this

protein results in a predisposition to develop a variety of tumors of the central and peripheral nervous systems.[8]

Increasing evidence indicates that merlin is involved in a number of cellular pathways and works in concert with

other proteins to promote cellular adhesion and responses via the growth factor receptor.[9] Understanding theseinteractions may eventually lead to more effective targeted treatment strategies, since the benign nature of NF2lesions makes tumors frequently less responsive to chemotherapy or radiation therapy.

Numerous mutations in the NF2 gene have been identified, most of which are predicted to result in production of atruncated protein with loss of its usual function.

Epidemiology

The estimated incidence of neurofibromatosis type 2 (NF2) is 1 in 37,000 per year, with about half of affectedindividuals representing first cases in the family as a result of new, dominant mutations.

Although the genetic change causing NF2 is present at conception, the clinical manifestations occur over manyyears. The typical age of onset of symptoms is in the late teens to early 20s, but the age range covers the entire

life span.[10] Some evidence indicates that age of onset of clinical symptoms is lower in maternally transmittedNF2. While NF2 is quite variable in severity from person to person, family studies have shown some intrafamilialconsistency in age of onset. Somatic mosaicism for the NF2 mutation in sporadic cases may also complicate theclinical picture, resulting in underdiagnosis or late diagnosis.

Prognosis

The prognosis of neurofibromatosis type 2 (NF2) depends on a number of factors, including age of symptom onset,degree of hearing deficit, and number and location of various tumors. Although age of onset is relatively similarwithin families, the age range can vary from 2-70 years. While the tumors themselves are relatively indolent and do



not undergo malignant transformation, studies performed in the late 1980s and early 1990s showed clearly thatsignificant rates of mortality and morbidity are associated with the diagnosis of NF2.

One such study suggested that the survival from the time of actual diagnosis averages 15 years; however, thismay be changing for the better with improved diagnosis, surgical techniques, surveillance, screening, andrecognition of mild disease (due in part to increased physician awareness and availability of molecular diagnosticoptions).

Morbidity and mortality

Vestibular schwannomas are the most common and well-recognized feature of NF2 leading to significantmorbidity. Symptoms of tinnitus, gradual hearing loss, and even vestibular dysfunction are frequently the initialsigns of NF2. Although unilateral hearing loss is the number 1 presenting symptom, bilateral deafness would beexpected to eventually occur in most affected individuals. Untreated vestibular schwannomas can extend locallyand may result in brainstem compression, hydrocephalus, and, occasionally, facial nerve palsy.

Dumbbell-shaped spinal cord schwannomas are quite common in NF2 and result in significant morbidity; theypresent a great therapeutic challenge. Spinal cord ependymomas, astrocytomas, and meningiomas also occur,but less frequently. Intracranial meningiomas, on the other hand, are a frequent finding; they may be

asymptomatic, or they may cause a variety of symptoms and CNS deficits.[11]

Nonvestibular schwannomas occur in more than half of patients and are often diagnosed in patients with an earlierage at diagnosis of NF2. Cranial nerves III and V are most commonly involved, but the rare occurrence of jugularforamen schwannomas potentially impacting the glossopharyngeal, vagus, and/or spinal accessory nerves maylead to dysphagia, esophageal dysmotility, hoarseness, or aspiration.

On the other hand, nonvestibular schwannomas in patients with NF2 tend to be more indolent and to grow slowlyover time. This can complicate treatment decision making, since options include surgery, radiation therapy, and

watchful waiting.[12]

Posterior subcapsular, or juvenile, cataracts can predate CNS symptomatology. These cataracts may progressover time, leading to decreased visual acuity. A fair percentage of affected individuals are found to have retinalhamartomas or epiretinal membranes that may or may not be visually significant.

Sensory motor polyneuropathy is seen in some individuals with NF2 who may or may not have identifiable tumorsalong the length of the peripheral nerve(s) of interest.

Patient Education

Patients and at-risk family members should be made aware of specific symptoms, such as tinnitus, hearingdeficits, focal weakness, sensory changes, or balance problems, that might suggest tumor growth and shouldprompt immediate medical attention.

Patients with vestibular schwannomas should be cautioned about diving and underwater activities, because ofincreased risks for disorientation and potential for drowning.

Patients and their families may be referred to neurofibromatosis (NF)-specific regional and national support groupsfor continuous updates on advances in treatment, as well as for emotional support. Neurofibromatosis, Inc., forexample, can be reached at the toll-free number 1-800-942-6825.

The Children's Tumor Foundation has a toll-free number (1-800-323-7938) for information and to sign up for theirnewsletter.

The NF2 Review, located in Los Angeles, CA, can be reached at 1-213-483-4431 and not only has an NF2-specificnewsletter, but also has a particular research interest in NF2, with a team of specialists working on auditorybrainstem implants (ABIs) and the newest surgical approaches to vestibular schwannomas.

Online resources include the NIH Web site and an NF2 person-to-person support group known as the NF2 crew.

Contributor Information and DisclosuresAuthorBeth A Pletcher, MD Associate Professor, Co-Director of The Neurofibromatosis Center of New Jersey,



Department of Pediatrics, University of Medicine and Dentistry of New Jersey

Beth A Pletcher, MD is a member of the following medical societies: American Academy of Pediatrics,American College of Medical Genetics, American Medical Association, and American Society of Human

Genetics

Disclosure: Nothing to disclose.

Chief EditorAmy Kao, MD Attending Neurologist, Children's National Medical Center

Amy Kao, MD is a member of the following medical societies: American Academy of Neurology, AmericanAcademy of Pediatrics, American Epilepsy Society, and Child Neurology Society


Additional ContributorsDavid A Griesemer, MD Professor, Departments of Neuroscience and Pediatrics, Medical University of SouthCarolina

David A Griesemer, MD is a member of the following medical societies: American Academy for Cerebral Palsyand Developmental Medicine, American Academy of Neurology, American Epilepsy Society, Child NeurologySociety, and Society for Neuroscience


Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical CenterCollege of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

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Medscape Reference 2011 WebMD, LLC

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