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Some frequently asked questions Some unanswered questions Selected references for health care providors

ABOUT NF2

Neurofibromatosis 2 (previously called bilateral acoustic neurofibromatosis or central neurofibromatosis and abbreviated as NF2, NFII or BAN) affects about 1 in 40,000 people without regard to sex or race. Patients with NF2 develop tumors throughout the body and must cope with a variety of neurological problems. The following sections outline what is currently known about this disorder. We hope that if you or your family is dealing with NF2, you will use this introduction to asked more informed questions of your own healthcare providor.

Figure 1. Bilateral Vestibular Schwannomas. These MRI scans show the typical appearance of bilateral vestibular schwannomas. In part A, a 14 year old boy has tiny tumors (arrows) on his eighth cranial nerves. The tumors lie within the bones of the skull and do not touch the base of the brain. Tumors of this size are often asymptomatic; sometimes a person will notice only that they have difficulty using a telephone in one ear. In part B, the 50 year old uncle of the teenager in part A has huge tumors at the junction of the pons and the lobes of the cerebellum. These tumors are pressing on the base of the brain, and could only be removed with damage to the eighth cranial nerve with resulting deafness. The goal of current NF2 management is to detect tumors while they are the size seen in part A and amenable to treatment.

Almost all individuals with NF2 develop tumors on both nerves to the ears (also called the eighth cranial nerve). The eight cranial nerve has two portions: the acoustic (hearing) nerve which carries information about sound to the brain and the vestibular nerve which carries balance information the brain. The early symptoms of NF2 are usually symptoms of dysfunction of these nerves: hearing loss, ringing in the ears (called tinnitus) and problems with balance.

Although tumors on the eighth cranial nerve are most common, most persons with NF2 develop tumors on other nerves also. These tumors are called schwannomas because they arise from the Schwann cells. Schwann cells support and protect nerve cells and provide nerves with the insulation they need to conduct information. The symptoms of a schwannoma will depend on its location. Those that arise on cranial nerves (like the eight cranial nerve tumors) affect the head and neck unless they grow large enough to push on the base of the brain (called the brainstem) and affect the body also. Those which grow on nerves as they exit the spinal cord may cause numbness of a part of the body; some tumors may grow large enough to press on the spinal cord and cause weakness and numbness in the legs.

Figure 2. Spinal Schwannoma. A dumbbell shaped tumor is outlined as it begins on a spinal root and extends both out of and into the spinal canal (C).

Those that grow in the bundles of nerves gathered in the armpits and groin area may cause weakness in one arm or leg. Schwannomas may even grow in tiny nerves in the skin where one can see them.

These peripheral schwannomas rarely cause neurological symptoms, but they may rub on clothing or be cosmetically disfiguring.

In addition to schwannomas, persons with NF2 frequently develop other sorts of tumors which grow on the coverings of the brain and spinal cord. The most frequent such tumor is called a meningioma; more rarely ependymomas or astrocytomas develop.

These tumors may cause many different kinds of neurological symptoms depending on their location. As with schwannomas, a physician may detect signs of a tumor on a detailed neurological examination before a patient can detect symptoms in every day life, making an annual neurological examination important for every NF2 patient. Finally, some persons with NF2 develop a special sort of cataract, known as a juvenile posterior sublenticular opacity, or have other problems with the eyes. Since all individuals with NF2 are at risk for losing hearing, it is very important to have a detailed eye examination by a specialist familiar with NF2 to prevent loss of sight also.

The time course of NF2 varies from individual to individual. Most individuals with NF2 get their first neurological symptoms during late teenage years or in their early 20’s. Skin tumors and cataracts may be apparent on examination even earlier in a child with NF2. A few people develop deafness and neurological symptoms in childhood and some do not have problems until their 40’s or 50’s. Unfortunately, studies have shown that a person will often have symptoms for many years before the true nature of the problem is realized. Since the tumors of NF2 grow slowly, it is likely that they are present in an individual form many years before they cause symptoms.

Figure 3. Skin tumors in a patient with NF2. Photo courtesy of Dr. Dilys Parry of the National Institutes of Health. Although people with NF1 often get large numbers of skin tumors, people with NF2 usually have less then 10.

Once someone has been found to have NF2, a number of tests may be helpful to define its nature and progression. Magnetic resonance imaging (MRI) scans are used to visualize the anatomy of the body. They are most commonly taken of the brain, but may also be used to "see" the spine or nerves in the arms and legs.

Figure 4. Multiple meningiomas (arrows) in a patient with NF2. Older patients with NF2 may develop tumors throughout the brain. These tumors are very slow growing, and their resection should be carefully considered. If a tumor is not causing severe symptoms, removing it may cause more damage then merely watching it carefully.

To undergo an MRI scan a patient is asked to lie very still on a small bed which slides into a donut-shaped machine. Magnets are activated around the patient and produce a banging sound. At some point, the patient may be injected with a dye that enhances the appearance of some parts of the brain. No X-irradiation is used. Repeated MRI scans over time will define if a tumor is static or growing. This is important information since a large static tumor may cause fewer problems than a small but growing tumor.

Many individuals and families with NF2 have found it helpful to seek the advice of a multi-disaplanary NF clinic.  Peer support groups may provide practical advice and support to augment professional providers’ skills . Finally, several other web sties and resources may provide helpful information.

Figure 5. Spinal cord tumor. Patients with NF2 often develop tumors within their spinal cord (ependymomas and astrocytomas) especially in the neck region (labeled with a * in this figure). In patients without NF2, such tumors are always removed immediately, but if a patient has NF2 it may be more prudent to watch such tumors closely and only intervene when neurological symptoms develop.

Selected References for health care professionals

Diagnosis and Natural History of NF2:

Neurofibromatosis: Phenotype, Natural History, and Pathogenesis edited by J. M. Friedman, M.D., Ph.D., David H. Gutmann, M.D.-Ph.D., Mia MacCollin, M.D., and Vincent M. Riccardi, M.D., third edition, John Hopkins University Press.

Mulvihill JJ, Parry DM, Sherman JL, Pikus A, Kaiser-Kupfer MI, Eldridge R: NIH conference. Neurofibromatosis 1 (Recklinghausen disease) and neurofibromatosis 2 (bilateral acoustic neurofibromatosis). An update. Ann Intern Med 113:39, 1990.

Parry DM, Eldridge R, Kaiser-Kupfer MI,Bouzas E, Pikus A, Patronas N: Neurofibromatosis 2 (NF2): Clinical characteristics of 63 affected individuals and clinical evidence for heterogeneity. Am J Med Genet 52: 450, 1994.

Evans DGR, Huson SM, Donnai D, Neary W, Blair V, Newton V, Harris R: A clinical study of type 2 neurofibromatosis. Quart J. Medicine, New Series 84, 304:603, 1992.

Gutmann DH, Aylsworth A, Carey JC, Korf B, Marks J, Pyeritz RE, Rubenstein A, Viskochil D. The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. JAMA. 1997 Jul 2; 278(1): 51-7.

NF2 in children Nunes F, MacCollin M. Neurofibromatosis 2 in the pediatric population.
J Child Neurol. 2003 Oct; 18(10): 718-24.

Mautner VF, Tatagiba M, Guthoff R, Samii M, Pulst SM: Neurofibromatosis 2 in the pediatric age group. Neurosurg 33:92, 1993.

Spinal tumors

Patronas NJ, Courcoutsakis N, Bromley CM, Katzman GL, MacCollin M, Parry DM.
Intramedullary and spinal canal tumors in patients with neurofibromatosis 2: MR imaging findings and correlation with genotype. Radiology. 2001 Feb; 218(2): 434-42.

Mautner VF, Tatagiba M, Lindenau M, Funsterer C, Pulst SM, Kluwe L, Zanella F: Spinal tumors in patients with neurofibromatosis type 2: MR imaging study of frequency, multiplicity, and variety. AJR 165:951, 1995.

Opthalmologic consequences of NF2

Kaiser-Kupfer M, Freidlin V, Datiles M, Edwards P, Sherman J, Parry D, McCain L, Eldridge R: The assocation of posterior capsular lens opacities with bilateral acoustic neuromas in patients with neurofibromatosis type 2. Arch Ophthalmol 107:541, 1989.

Bouzas E, Parry D, Eldridge R, Kaiser-Kupfer M: Visual impairment in patients with neurofibromatosis 2. Neurology 43:622, 1993.

Ragge N, Baser M, Klein J, Nechiporuk A, Sainz J, Pulst SM, Riccardi V: Ocular abnormalities in neurofibromatosis 2. Am J Ophthal 120:634, 1995.

Management issues

Weber DC, Chan AW, Bussiere MR, Harsh GR 4th, Ancukiewicz M, Barker FG 2nd, Thornton AT, Martuza RL, Nadol JB Jr, Chapman PH, Loeffler JS. Proton beam radiosurgery for vestibular schwannoma: tumor control and cranial nerve toxicity.
Neurosurgery. 2003 Sep; 53(3): 577-86; discussion 586-8.

Barker FG 2nd, Carter BS, Ojemann RG, Jyung RW, Poe DS, McKenna MJ. Surgical excision of acoustic neuroma: patient outcome and provider caseload.
Laryngoscope. 2003 Aug; 113(8): 1332-43.

Briggs R, Brackmann D, Baser M, Hitselberger W: Comprehensive management of bilateral acoustic neuromas. Arch Oto Head Neck Surg 120:1307, 1994.

Otto SR, Brackmann DE, Hitselberger WE, Shannon RV, Kuchta J. Multichannel auditory brainstem implant: update on performance in 61 patients. J Neurosurg. 2002 Jun; 96(6): 1063-71.

Alternative phenotyes

Bourn D, Carter SA, Evans DGR, Goodship J, Coakham H, Strachan T: A mutation in the neurofibromatosis type 2 tumor-suppressor gene, giving rise to widely different clinical phenotypes in two unrelated individuals. Am J Hum Genet 55:69, 1994.

MacCollin M, Woodfin W, Kronn D, Short MP: Schwannomatosis: A clinical and pathologic study. Neurology 46:1072, 1996.

Pulst SM, Rouleau G, Marineau C, Fain P, Sieb J: Familial meningioma is not allelic to neurofibromatosis 2. Neurology 43:2096, 1993.

Blakley P, Louis DN, Short MP, MacCollin M. A clinical study of patients with multiple isolated neurofibromas. J Med Genet. 2001 Jul; 38(7): 485-8.

Pathology

Louis D, Ramesh V, Gusella J: Neuropathology and molecular genetics of neurofibromatosis 2 and related tumors. Brain Pathology 5: 163, 1995.

Molecular biology

Trofatter J, MacCollin M, Rutter J, Murrell J, Duyao M, Parry D, Eldridge R, Kley N, Menon A, Pulaski K, Haase V, Ambrose C, Munroe D, Bove C, Haines J, Martuza R, MacDonald M, Seizinger B, Short MP, Buckler A, Gusella J: A novel Moesin-, Ezrin-, Radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor. Cell 72:791, 1993.

Rouleau G, Merel P, Lutchman M, Sanson M, Zucman J, Marineau C, Hoang-Xuan K, Demczuk S, Desmaze C, Plougastel B, Pulst S, Lenoir G, Bijisma E, Fashold R, Dumanski J, de Jong P, Parry D, Eldridge R, Aurias A, Delattre O, Thomas G: Alteration in a new gene encoding a putative membrane-organizing protein causes neuro-fibromatosis type 2. Nature 363:515, 1993.

MacCollin M, Ramesh V, Jacoby L, Louis D, Rubio MP, Pulaski K, Trofatter J, Short MP, Bove C, Eldridge R, Parry D, Gusella J: Mutational analysis of patients with neurofibromatosis 2. Am J Hum Genet 55: 314, 1994.

Heinrich B, Hartmann C, Stemmer-Rachamimov AO, Louis DN, MacCollin M. Multiple meningiomas: Investigating the molecular basis of sporadic and familial forms.
Int J Cancer. 2003 Feb 10; 103(4): 483-8.

MacCollin M, Willett C, Heinrich B, Jacoby LB, Acierno JS Jr, Perry A, Louis DN. Familial schwannomatosis: exclusion of the NF2 locus as the germline event.
Neurology. 2003 Jun 24; 60(12): 1968-74.

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