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Neurofibromatosis 2

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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.

The diagnosis of NF2 depends on the recognition of the signs and symptoms, coupled with a comprehensive examination and imaging studies of the brain and spine. Children of an affected individuals may often be diagnosed by a blood test before any symptoms are apparent. Rarely, individuals have some of the problems with NF2 without the development of bilateral vestibular schwannoma. Researchers are still trying to determine what causes these unusual cases and such persons may wish to contact a research center to learn more about such studies. Adults with a single schwannoma (including a single vestibular schwannoma ), meningioma or ependymoma who do not have an affected relative do not have NF2.

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.

Presently, the only treatments available for the tumors of NF2 are surgery and radiation therapy. Most persons with NF2 require at least one operation during their lifetime. Since the tumors of NF2 lie on nerves and/or near the brain and spinal cord, their surgical removal is not without risk. Surgery in these small and delicate areas may cause further injury to nerves--and further neurological problems. For these reasons the potential benefits and risks of every contemplated surgical procedure should be carefully considered and discussed with a health care providor familiar with the disease. When surgery is no longer an option for a particular person because of their medical problems or the size or location of a tumor, radiation therapy may be considered. As with surgery, radiation therapy has both risks and benefits which must be carefully considered. Recently, a device has been developed by the House Ear Institute in conjunction with the Cochlear Corporation that allows some individuals deafened by NF2 to perceive sound. This device (known as an auditory brainstem implant or ABI) is now undergoing investigational trials at a number of centers world wide.

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.

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. 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.

Although MRI scans can show very detailed structural information (what your body looks like), they cannot show functional information (how well your body is working). Audiometry and brainstem auditory response (BAER) testing show how well the hearing portion of the eighth cranial nerve is working. Information from audiometry and BAER augment the structural information from an MRI. Repeated testing will determine if the functional aspects of a tumor are changing and help a patient and physician to determine the best possible time for surgical intervention.

NF2 is a genetic disease that is passed from parent to child at the time of conception. About one half of persons with NF2 do not have a parent with the disorder and represent new genetic changes. All persons with NF2--those with affected parents and those without--have a 50-50 risk that each one of their children will be affected. Disorders such as NF2 which affect both sexes equally and are passed from an affected person to 50% of their children are termed autosomal dominant disorders.  Recently the exact piece of genetic material which causes NF2 was identified on chromosome 22. This identification has made it possible to find, by a blood test , if a relative of a person with NF2 also has NF2. Just like surgery, genetic testing has both risks and benefits and should be discussed thoroughly with your health care providor.

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.

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.

Selected References for health care professionals

Diagnosis and Natural History of NF2:

Martuza RL, Eldridge R: Neurofibromatosis 2 (bilateral acoustic neurofibromatosis). N Engl J Med 318:684, 1988.

Riccardi, VM: Neurofibromatosis: Phenotype, Natural History, and Pathogenesis, 2nd ed. Baltimore: Johns Hopkins University Press, 1992, p 224.

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.

Evans DG, Huson SM, Donnai D, Neary W, Blair V, Teare D, Newton V, Strachan T, Ramsden R, Harris R: A genetic study of type 2 neurofibromatosis in the United Kingdom. I. Prevalence, mutation rate, fitness and confirmation of maternal transmission effect on severity. J Med Genet 29: 841, 1992.

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.

NF2 in children

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

Spinal tumors

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

Nadol J, Chiong C, Ojemann R, McKenna M, Martuza R, Montgomery W, Levine R, Ronner S, Glynn R: Preservation of hearing and facial nerve function in resection of acoustic neuroma. Laryngoscope 102:1153, 1992.

Miyamoto R, Campbell R, Fritsch M, Lochmueller G: Preservation of hearing in neurofibromatosis 2. Otolaryngol Head Neck Surg 103:619, 1990.

Tatagiba M, Matthies C, Samii M: Facial nerve reconstruction in neurofibromatosis 2. Acta Neurochir (Wien) 126:72, 1994.

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

Brackmann D, Hitselberger W, Nelson R, Moore J, Waring M, Portillo F, Shannon R, Telischi F: Auditory brainstem implant: I. Issues in surgical implantation. Otolaryngol Head Neck Surg 108:624, 1993.

Staller S, Otto S, Menapace C: Clinical trials of the auditory brainstem implant. Audiology Today 7:9, 1995.

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.

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.

Mia MacColin, M.D.
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