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Neurofibromatosis Type 2

  • Author: David T Hsieh, MD, FAAP; Chief Editor: Amy Kao, MD  more...
 
Updated: Oct 27, 2014
 

Practice Essentials

Central neurofibromatosis, or neurofibromatosis type 2 (NF2), is a genetic disorder marked by the predisposition to develop 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. (See the image below.)

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

Signs and symptoms

Clinical diagnosis of NF2 requires that an individual present with at least 1 of the following clinical scenarios[1] :

  • Bilateral vestibular schwannomas
  • A first degree relative with NF2 AND
    • Unilateral vestibular schwannoma OR
    • Any two of: meningioma, schwannoma, glioma, neurofibroma, posterior subcapsular lenticular opacities
  • Unilateral vestibular schwannoma AND
    • Any two of: meningioma, schwannoma, glioma, neurofibroma, posterior subcapsular lenticular opacities
  • Multiple meningiomas AND
    • Unilateral vestibular schwannoma OR
    • Any two of: schwannoma, glioma, neurofibroma, 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 by few external signs. Presenting symptoms include the following:

  • Hearing loss, ringing in the ears, and balance problems associated with vestibular nerve lesions
  • Visual deficits
  • Cranial nerve palsies

See Clinical Presentation for more detail.

Diagnosis

Diagnosis of NF2 involves the following:

  • Genetic testing
  • Imaging studies
  • Auditory, ophthalmic, and histologic examinations

Genetic testing

  • Once the clinical diagnosis has been established unequivocally in a given individual, direct molecular analysis can be offered
  • Detection rates for molecular-based testing approaches approaches 72% in simplex cases and 93% in familial cases [1]
  • If a mutation is found, other asymptomatic family members might benefit from presymptomatic testing
  • Molecular testing of tumor tissue may augment traditional molecular studies when analysis of DNA obtained from blood lymphocytes is nondiagnostic
  • For families in which no mutation can be identified in a known affected individual, linkage analysis or indirect genetic testing methods may be utilized
  • Presymptomatic testing of at-risk family members requires a vigorous informed consent process and might best be done during a genetic counseling session at a cancer, genetic, or neurofibromatosis center that specializes 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 direct gene mutation analysis when such a change has been identified or through linkage analysis
  • Prenatal testing may not be possible if the affected parent is the first affected person in the family and a mutation cannot be found
  • If a prospective parent has a known NF2 mutation, preimplantation genetic diagnosis may be possible if the couple 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 tumors
  • At-risk individuals may be monitored for CNS tumors beginning in their teens, with annual MRI scans of the head performed through their late 50s
  • MRI 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-risk individuals
  • MRI of the spine is indicated diagnostically when an individual presents with motor or sensory changes suggestive of a spinal cord lesion or lesions

Auditory Evaluation

  • Hearing evaluations, including brainstem auditory-evoked response (BAER) may demonstrate latency abnormalities before a mass is detectable on MRI
  • Auditory screening on an annual basis may be quite useful in asymptomatic or presymptomatic individuals
  • Once a vestibular schwannoma is identified, full audiometry testing, including acoustic reflex testing as well as BAER, is useful as a means of monitoring disease progression
  • The 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 NF2
  • Dilated eye examinations for lens opacities, retinal hamartomas, or epiretinal membranes may be quite useful even in a child at risk for NF2
  • Juvenile 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 a multidisciplinary clinic may provide the most comprehensive and cost-effective care over time. The following is an outline of reasonable guidelines in the care of the patient with NF2:

  • Annual neurologic examination looking for subtle deficits or changes in neurologic status that might suggest disease progression
  • Annual hearing screening with BAER, with referral to an audiologist for amplification, augmentation, or speech therapy recommendations
  • Annual 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 lesions
  • Rarely, radiation and/or chemotherapy may be recommended to treat disabling ependymomas
  • Palliative chemotherapy for surgically unresectable ependymomas may be attempted with lomustine, vincristine, and prednisone, or carboplatin and vincristine, following radiation therapy
  • Erlotinib 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 loss
  • A debulking procedure may result in preservation of hearing or, at the minimum, prolongation of auditory decompensation
  • Nonvestibular 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 be considered only when such lesions are causing serious, disabling symptoms
  • Resection of spinal cord tumors is often quite difficult, and the risks and benefits of surgery must be considered on an individual basis
  • Resection 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 loss secondary 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.

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Background

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

Subcutaneous and cutaneous lesions in a young man Subcutaneous and cutaneous lesions in a young man with 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 with significant 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 problems with balance
  • Meningiomas, gliomas, ependymomas, and other cerebral, cerebellar, or spinal cord lesions that may result in neurologic deficits, seizures, and/or hydrocephalus
  • Peripheral nerve schwannomas, mixed tumors, and, occasionally, neurofibromas
  • Peripheral neuropathies
  • Visually significant juvenile cataracts
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Etiology

NF2 is inherited as an autosomal dominant condition, although half of affected individuals have NF2 as a result of a new (de novo) gene mutation. The manifestations of NF2 result from mutations in (or, rarely, deletion of) the NF2 gene, located on the long arm of chromosome 22. Affected individuals need only 1 mutated or deleted NF2 gene to exhibit 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 these interactions may eventually lead to more effective targeted treatment strategies, since the benign nature of NF2 lesions 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 a truncated protein with loss of its usual function.

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Epidemiology

The estimated incidence of neurofibromatosis type 2 (NF2) is 1 in 37,000 per year, with about half of affected individuals 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 many years. The typical age of onset of symptoms is in the late teens to early 20s, but the age range covers the entire life span, to include congenital forms in infancy through the elderly.[10, 11, 12] Some evidence indicates that age of onset of clinical symptoms is lower in maternally transmitted NF2. While NF2 is quite variable in severity from person to person, family studies have shown some intrafamilial consistency in age of onset. Somatic mosaicism for the NF2 mutation in sporadic cases may also complicate the clinical picture, resulting in underdiagnosis or late diagnosis.

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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 similar within 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 that significant 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[13] ; however, this may be evolving with improved diagnosis, surgical techniques, surveillance, screening, and recognition of mild disease (due in part to increased physician awareness and availability of molecular diagnostic options).

Morbidity and mortality

Vestibular schwannomas are the most common and well-recognized feature of NF2 leading to significant morbidity. Symptoms of tinnitus, gradual hearing loss, and even vestibular dysfunction are frequently the initial signs of NF2. Although unilateral hearing loss is the most frequently presenting symptom, bilateral deafness would be expected to eventually occur in most affected individuals. Untreated vestibular schwannomas can extend locally and 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; they present 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.[14]

Nonvestibular schwannomas occur in more than half of patients and are often diagnosed in patients with an earlier age at diagnosis of NF2. Cranial nerves III and V are most commonly involved, but the rare occurrence of jugular foramen schwannomas potentially impacting the glossopharyngeal, vagus, and/or spinal accessory nerves may lead 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 slowly over time. This can complicate treatment decision making, since options include surgery, radiation therapy, and watchful waiting.[15]

Posterior subcapsular, or juvenile, cataracts can predate CNS symptomatology. These cataracts may progress over time, leading to decreased visual acuity. A fair percentage of affected individuals are found to have retinal hamartomas 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 tumors along the length of the peripheral nerve(s) of interest.

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Patient Education

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

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

Patients and their families may be referred to neurofibromatosis (NF)-specific regional and national support groups for continuous updates on advances in treatment, as well as for emotional support. Neurofibromatosis, Inc., for example, 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 their newsletter.

The NF2 Review, located in Los Angeles, CA, can be reached at 1-213-483-4431 and not only has an NF2-specific newsletter, but also has a particular research interest in NF2, with a team of specialists working on auditory brainstem 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.

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Contributor Information and Disclosures
Author

David T Hsieh, MD, FAAP Assistant Professor of Pediatrics, Assistant Professor of Neurology, Uniformed Services University of the Health Sciences, F Edward Hebert School of Medicine; Adjunct Assistant Professor of Pediatrics, Adjunct Assistant Professor of Neurology, University of Texas Health Science Center at San Antonio School of Medicine

David T Hsieh, MD, FAAP is a member of the following medical societies: American Academy of Neurology, American Academy of Pediatrics, American Epilepsy Society, Child Neurology Society

Disclosure: Nothing to disclose.

Coauthor(s)

Luis O Rohena, MD Chief, Medical Genetics, San Antonio Military Medical Center; Assistant Professor of Pediatrics, Uniformed Services University of the Health Sciences, F Edward Hebert School of Medicine; Assistant Professor of Pediatrics, University of Texas Health Science Center at San Antonio

Luis O Rohena, MD is a member of the following medical societies: American Academy of Pediatrics, American Chemical Society, American College of Medical Genetics and Genomics, American Society of Human Genetics

Disclosure: Nothing to disclose.

Chief Editor

Amy Kao, MD Attending Neurologist, Children's National Medical Center

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

Disclosure: Have stock from Cellectar Biosciences; have stock from Varian medical systems; have stock from Express Scripts.

Acknowledgements

The view(s) expressed herein are those of the author(s) and do not reflect the official policy or position of Brooke Army Medical Center, the U.S. Army Medical Department, the U.S. Army Office of the Surgeon General, the Department of the Army, the Department of the Air Force, Department of Defense or the U.S. Government.

David A Griesemer, MD Professor, Departments of Neuroscience and Pediatrics, Medical University of South Carolina

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

Disclosure: Nothing to disclose.

Beth 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.

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

Disclosure: Medscape Salary Employment

References
  1. Evans DG. Neurofibromatosis 2. Genet Med. 2009. 11:599-610. [Medline].

  2. Harris GJ, Plotkin SR, Maccollin M, et al. Three-dimensional volumetrics for tracking vestibular schwannoma growth in neurofibromatosis type II. Neurosurgery. 2008 Jun. 62(6):1314-9; discussion 1319-20. [Medline].

  3. Aboukais R, Baroncini M, Zairi F, Bonne NX, Schapira S, Vincent C, et al. Prognostic value and management of spinal tumors in neurofibromatosis type 2 patients. Acta Neurochir (Wien). 2013 May. 155(5):771-7. [Medline].

  4. Selch MT, Pedroso A, Lee SP, et al. Stereotactic radiotherapy for the treatment of acoustic neuromas. J Neurosurg. 2004 Nov. 101 Suppl 3:362-72. [Medline].

  5. Safavi-Abbasi S, Bambakidis NC, Zabramski JM, et al. Nonvestibular schwannomas: an evaluation of functional outcome after radiosurgical and microsurgical management. Acta Neurochir (Wien). 2010 Jan. 152(1):35-46. [Medline].

  6. Schwartz MS, Otto SR, Shannon RV, et al. Auditory brainstem implants. Neurotherapeutics. 2008 Jan. 5(1):128-36. [Medline].

  7. Matsuo M, Ohno K, Ohtsuka F. Characterization of early onset neurofibromatosis type 2. Brain Dev. 2013 Feb 13. [Medline].

  8. Beltrami S, Branchetti E, Sariyer IK, Otte J, Weaver M, Gordon J. Neurofibromatosis type 2 tumor suppressor protein, NF2, induces proteasome-mediated degradation of JC virus T-antigen in human glioblastoma. PLoS One. 2013. 8(1):e53447. [Medline]. [Full Text].

  9. Hanemann CO. Magic but treatable? Tumours due to loss of merlin. Brain. 2008 Mar. 131:606-15. [Medline].

  10. Goutagny S, Bah AB, Parfait B, Sterkers O, Kalamarides M. Neurofibromatosis type 2 in the elderly population: Clinical and molecular features. Am J Med Genet A. 2013 Apr. 161(4):667-70. [Medline].

  11. Ruggieri M, Gabriele AL, Polizzi A, et al. Natural history of neurofibromatosis type 2 with onset before the age of 1 year. Neurogenetics. 2013. 14:89-98. [Medline].

  12. Goutagny S, Bah AB, Parfait B, et al. Neurofibromatosis type 2 in the elderly population: Clinical and molecular features. Am J Med Genet Part A. 2013. 161A:667-70. [Medline].

  13. Evans DG, Huson SM, Donnai D, et al. A clinical study of type 2 neurofibromatosis. Q J Med. 1992. 304:603-18. [Medline].

  14. Aboukais R, Zairi F, Baroncini M, Bonne NX, Schapira S, Vincent C, et al. Intracranial meningiomas and neurofibromatosis type 2. Acta Neurochir (Wien). 2013 Apr 5. [Medline].

  15. Fisher LM, Doherty JK, Lev MH, et al. Distribution of nonvestibular cranial nerve schwannomas in neurofibromatosis 2. Otol Neurotol. 2007 Dec. 28(8):1083-90. [Medline].

  16. Lee HBH, Garrity JA, Cameron JD, Strianese D, Bonavolonta G, Patrinely JR. Primary optic nerve sheath meningioma in children. Surv Ophthalmol. 2008. 53:543-58.

  17. Sestini R, Provenzano A, Bacci C, et al. NF2 mutation screening by denaturing high-performance liquid chromatography and high-resolution melting analysis. Genet Test. 2008 Jun. 12(2):311-8. [Medline].

  18. Otto SR, Brackmann DE, Hitselberger W. Auditory brainstem implantation in 12- to 18-year-olds. Arch Otolaryngol Head Neck Surg. 2004 May. 130(5):656-9. [Medline].

  19. Kanowitz SJ, Shapiro WH, Golfinos JG, et al. Auditory brainstem implantation in patients with neurofibromatosis type 2. Laryngoscope. 2004 Dec. 114(12):2135-46. [Medline].

  20. Plotkin SR, Singh MA, O'Donnell CC, et al. Audiologic and radiographic response of NF2-related vestibular schwannoma to erlotinib therapy. Nat Clin Pract Oncol. 2008 Aug. 5(8):487-91. [Medline].

  21. Plotkin SR, Stemmer-Rachamimov AO, Barker FG 2nd, et al. Hearing improvement after bevacizumab in patients with neurofibromatosis type 2. N Engl J Med. 2009 Jul 23. 361(4):358-67. [Medline].

  22. Mukherjee J, Kamnasaran D, Balasubramaniam A, et al. Human schwannomas express activated platelet-derived growth factor receptors and c-kit and are growth inhibited by Gleevec (Imatinib Mesylate). Cancer Res. 2009 Jun 15. 69(12):5099-107. [Medline]. [Full Text].

  23. von Eckardstein KL, Beatty CW, Driscoll CL, Link MJ. Spontaneous regression of vestibular schwannomas after resection of contralateral tumor in neurofibromatosis Type 2. J Neurosurg. 2010 Jan. 112(1):158-62. [Medline]. [Full Text].

  24. Gerszten PC, Burton SA, Ozhasoglu C, McCue KJ, Quinn AE. Radiosurgery for benign intradural spinal tumors. Neurosurgery. 2008 Apr. 62(4):887-95; discussion 895-6. [Medline].

  25. Colletti V, Shannon R, Carner M, Veronese S, Colletti L. Outcomes in nontumor adults fitted with the auditory brainstem implant: 10 years' experience. Otol Neurotol. 2009 Aug. 30(5):614-8. [Medline].

 
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Subcutaneous and cutaneous lesions in a young man with neurofibromatosis type 2; note paucity of cafe-au-lait spots.
Right neck mass in a patient with neurofibromatosis type 2.
Facial asymmetry, OS proptosis, and exotropia, as well as several subcutaneous lesions on the forehead and face, in a 20-year-old man with neurofibromatosis type 2.
Posterior cervical scar from cord lesion resection, thoracic scoliosis, and subcutaneous masses in a young adult with neurofibromatosis type 2.
Meningioma to the left of midline in a patient with neurofibromatosis type 2.
Multiple meningiomas (on the left) on the surface of the brain in a patient with neurofibromatosis type 2.
Bilateral acoustic neuromas in a patient with neurofibromatosis type 2.
Bilateral acoustic neuromas and a left-sided meningioma in a patient with neurofibromatosis type 2.
Small ependymoma in a patient with neurofibromatosis type 2.
Multiple meningiomas in a patient with neurofibromatosis type 2.
 
 
 
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