Close
New

Medscape is available in 5 Language Editions – Choose your Edition here.

 

Neurofibromatosis Type 2 Workup

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

Approach Considerations

Now that the gene for neurofibromatosis type 2 (NF2) has been identified, analysis for disease-causing mutations can be offered in some clinical settings. Detection rates for molecular-based testing approaches 72% in simplex cases; therefore, such testing has some inherent limitations when trying to confirm a diagnosis of NF2. However, for a patient with suspected NF2 who is still young, has a negative family history, and may eventually develop additional criteria, the identification of a specific mutation may be very helpful.

In light of the high rate of somatic mosaicism in sporadic cases of NF2 (perhaps as many as 25%), molecular testing of tumor tissue may augment traditional molecular studies when analysis of deoxyribonucleic acid (DNA) obtained from blood lymphocytes is nondiagnostic.

Imaging studies and auditory, ophthalmic, and histologic examinations are also important in the diagnosis and management of NF2.

Next

Genetic Studies

Attempts to increase the detection rate of NF2 mutations have met with some success by using a variety of technologies. Denaturing high-performance liquid chromatography has shown promise in identifying more point mutations in affected individuals, and, when used in conjunction with multiplex ligation-dependent probe amplification, may uncover NF2 gene rearrangements. The addition of a third technique, high-resolution melting analysis, rounds out the new molecular armamentarium, which enables exons to be more efficiently scanned, thereby further improving the detection rate by uncovering additional point mutations.[17]

For families with asymptomatic, at-risk members, the application of molecular testing is viewed from a slightly different perspective. Once the clinical diagnosis has been established unequivocally in a given individual, he or she could be offered direct molecular analysis to see if a mutation can be identified. If a mutation were found, then other asymptomatic family members might benefit from presymptomatic testing to see who would and who would not develop neurofibromatosis type 2 (NF2). Screening and surveillance recommendations would then be based on the results of this testing and, if a sibling or child of an affected person were found not to carry the mutation, he or she would need not be concerned about developing NF2 in the future.

For families in which no mutation can be identified in a known affected individual, linkage analysis or indirect genetic testing methods may be utilized. However, this requires cooperation on the part of the family, as well as DNA samples from multiple affected and unaffected individuals. Even utilizing the best technology available, diagnostic uncertainty may remain, depending on the geographical relationship between the genetic markers and the disease-causing gene. On the other hand, with advances that have taken place in genetic mapping and the likelihood of finding informative markers close to or within the gene itself, linkage analysis remains an excellent choice for determining risk from a molecular standpoint.

For a parent who 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. For an affected parent with a known mutation, preimplantation genetic diagnosis may be possible if the couple is willing to undergo in vitro fertilization with transfer of unaffected embryos.

One note of caution must be made in light of advances in molecular genetic technology. 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. This is of even greater concern when considering testing of minors, in whom the potential harm must be weighed against medical benefit.

Since aggressive medical surveillance can still be implemented in the absence of a definitive diagnosis and no preventive or curative measures are currently available, the decision to undergo presymptomatic testing for this adult-onset disease is a personal one that must be made after a frank and complete discussion with health professionals.

Previous
Next

Imaging Studies

Radiography

Plain films of the spine may be helpful in evaluating scoliosis but are of limited value in looking for spinal cord tumors that may occur in NF2.

Magnetic resonance imaging

Magnetic resonance imaging (MRI) remains the mainstay for diagnosis and screening of CNS, cranial nerve, and spinal cord tumors (see the images below). 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. Clear molecular diagnosis may help to modify risks for family members and prevent unnecessary testing for asymptomatic individuals who are found not to carry a gene mutation.

Meningioma to the left of midline in a patient wit Meningioma to the left of midline in a patient with neurofibromatosis type 2.
Multiple meningiomas (on the left) on the surface 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 neur Bilateral acoustic neuromas in a patient with neurofibromatosis type 2.
Bilateral acoustic neuromas and a left-sided menin Bilateral acoustic neuromas and a left-sided meningioma in a patient with neurofibromatosis type 2.
Small ependymoma in a patient with neurofibromatos Small ependymoma in a patient with neurofibromatosis type 2.
Multiple meningiomas in a patient with neurofibrom Multiple meningiomas in a patient with neurofibromatosis type 2.

MRI using 3-dimensional (3D) volumetrics is now the preferred method for following vestibular schwannoma growth over time.[2]

MRI of the spine is indicated diagnostically when an individual presents with motor or sensory changes suggestive of a spinal cord lesion or lesions. The key point here is early detection, which may result in prompt action and provide a better outcome. However, routine MRI imaging of the spinal cord probably is not indicated for asymptomatic affected or at-risk individuals.

Previous
Next

Auditory Evaluation

Hearing evaluations, including brainstem auditory-evoked response (BAER), are important in the identification of early hearing loss and may demonstrate latency abnormalities before a mass is detectable on MRI. In light of this, 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. Clinical experience clearly indicates that the size of the vestibular tumor often does not correlate with the degree of hearing loss.

Previous
Next

Ophthalmic Examination

Dilated eye examinations are an important part of the care of affected individuals because they are at a risk for developing visually significant cataracts or retinal lesions. As a diagnostic test, an eye examination for lens opacities, retinal hamartomas, or epiretinal membranes may be quite useful even in a child at risk for neurofibromatosis type 2 (NF2). In fact, juvenile cataracts, as the name implies, frequently occur in children and may be seen long before there is any evidence of vestibular schwannomas.

For children and adults with NF2, annual eye examinations are recommended, since unrecognized visual impairment can further interfere with activities of daily living, especially in an individual with concomitant hearing loss.

Previous
Next

Histologic Findings

Unlike the tumors associated with neurofibromatosis type 1 (NF1), those found in NF2 are usually made up of 1 of 3 cell types—Schwann cells, glial cells, or meningeal cells. Although the tumors in NF2 can be locally invasive and cause significant morbidity as a result of their growth properties, they rarely, if ever, undergo malignant transformation. This is somewhat different than in NF1, in which plexiform neurofibromas occasionally develop into neurosarcomas.

However, vestibular schwannomas and meningiomas in NF2 tend to be more aggressive than they are in cases of sporadic tumors (ie, those not related to NF2), with a tendency for more extensive local invasion and with histologic evidence of increased mitoses.

Previous
 
 
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].

 
Previous
Next
 
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.
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2016 by WebMD LLC. This website also contains material copyrighted by 3rd parties.