Neurofibromatosis Type 2 (NF2)

Neurofibromatosis Type 2 (NF2)

National Organization for Rare Disorders, Inc.

Important

It is possible that the main title of the report Neurofibromatosis Type 2 (NF2) is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.

Synonyms

  • Bilateral Acoustic Neurofibromatosis
  • Central Form, Neurofibromatosis
  • Vestibular Schwannoma Neurofibromatosis
  • NF2

Disorder Subdivisions

  • None

General Discussion

Neurofibromatosis type 2 (NF2) is a rare genetic disorder that is primarily characterized by benign (noncancerous) tumors of the nerves that transmit sound impulses from the inner ears to the brain (bilateral acoustic neuromas vestibular schwannomas). Associated symptoms and findings may become evident during childhood, adolescence, or early adulthood. Depending on the exact location and size of the acoustic neuromas/vestibular schwannomas, such findings may include disturbances of balance and walking (gait); dizziness; headache; facial weakness, numbness, or pain; ringing in the ears (tinnitus); and/or progressive hearing loss.



In some individuals with NF2, additional abnormalities may also be present. These may include loss of transparency of the lenses of the eyes (juvenile posterior subcapsular opacities), progressive visual impairment, or an increased risk of developing certain tumors of the brain and spinal cord (central nervous system).



NF2 results from changes (mutations) of a gene on the long arm (q) of chromosome 22 (22q12.2). The NF2 gene regulates the production of a protein that functions as a tumor suppressor. In some individuals with NF2, the disorder is caused by new (sporadic) mutations of the gene that occur for unknown reasons. In other affected individuals, NF2 is inherited as an autosomal dominant trait.



The term "neurofibromatosis" is sometimes also used to describe a second, distinct form of NF known as neurofibromatosis type I (NF1). More common than NF2, NF1 is primarily characterized by the development of multiple noncancerous (benign) tumors of nerves and skin (neurofibromas) and areas of abnormally decreased or increased coloration (hypo- or hyperpigmentation) of the skin, such as pale tan or light brown discolorations (cafe-au-lait spots) on the skin of the trunk or other regions. In contrast, in individuals with NF2, benign fibrous tumors of the skin (cutaneous neurofibromas) and areas of abnormal pigmentation are considered relatively rare. As with NF2, NF1 may be inherited as an autosomal dominant trait or appear to occur randomly due to new (sporadic) genetic changes.

Symptoms

The characteristic symptoms of neurofibromatosis type 2 usually develop around the time of puberty or during early adulthood. These may include balance problems, buzzing or ringing in the ears (tinnitus), and/or gradual hearing loss. These symptoms usually result from the presence of benign tumors on both auditory nerves (acoustic neuromas vestibular schwannomas). Other tumors of the central nervous system may also develop including neurofibromas, meningiomas, gliomas, and schwannomas. Benign tumors may also occur on the spinal cord. (For more information on tinnitus, choose "tinnitus" as your search term in the Rare Disease Database.)



Individuals with neurofibromatosis type 2 may also develop cloudiness on the lenses of the eyes (posterior capsular cataracts) at a younger age than would otherwise be expected. Symptoms of cataracts may include impaired vision, and in some cases the progressive loss of vision. (For more information on this disorder, choose "cataracts" as your search term in the Rare Disease Database.)



People with neurofibromatosis type 2 generally have fewer brown spots (cafe-au-lait) on the skin than those who have neurofibromatosis type 1. Affected individuals may also experience spasms of the facial muscles; generalized muscle weakness, numbness, pain, and/or partial paralysis; difficulty swallowing; and/or impaired speech. Other neurological problems may also develop including headaches and/or seizures.

Causes

In some individuals with NF2, the disorder is inherited as an autosomal dominant trait. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother. In dominant disorders, a single copy of the disease gene (received from either the mother or father) will be expressed "dominating" the other normal gene and resulting in the appearance of the disease. The risk of transmitting the disorder from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.



In other individuals with NF2, there is no family history of the disease. In such cases, NF2 is caused by new (sporadic) genetic changes (mutations) that appear to occur randomly for unknown reasons.



NF2 results from mutations of a gene located on the long arm of chromosome 22 (22q12.2). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as "p" and a long arm identified by the letter "q". Chromosomes are further subdivided into bands that are numbered.



The NF2 gene regulates (encodes for) the production of a protein known as merlin/schwannomin that plays a role in suppressing the development of certain tumors (tumor suppressor). According to investigators, merlin/schwannomin is related to a class of proteins (ezrin-radixin-moesin proteins) that serve to link the internal, supportive system within a cell (cytoskeleton) to proteins in cell membranes. Several different mutations of the NF2 gene have been identified in individuals with the disorder (e.g., deletions, nonsense and frameshift mutations). Investigators suggest that different mutations of the gene may contribute to the wide variability of symptoms and findings in affected individuals.

Affected Populations

NF2 is a rare disorder that affects males and females in equal numbers. All races and ethnic groups are affected by this disorder. The estimated incidence of neurofibromatosis type 2 is 1 in 40,000 people. The symptoms of this disease typically become obvious during puberty or early adulthood.

Standard Therapies

The diagnosis of NF2 is confirmed by a thorough clinical evaluation and specialized testing (i.e., CT scan, magnetic resonance imaging (MRI), pneumoencephalogram, or arteriogram).



The treatment of acoustic neuromas associated with NF2 is the surgical removal of the tumors, when possible. The surgical procedure that is performed is based upon the size and precise location of the tumors. Radiation therapy may be considered for some individuals with this disorder, especially those who are not candidates for surgery. Other treatment is symptomatic and supportive.



Genetic counseling will be of benefit for people with NF2 and their families.

Investigational Therapies

On July 27, 2009 - PTC Therapeutics, Inc. (PTC) announced the initiation of a Phase 2 clinical trial of PTC299 in adult patients with NF2. PTC299 is a novel, orally administered investigational new drug that is designed to selectively block tumor-related vascular endothelial growth factor (VEGF). With its novel mechanism of action, PTC299 has the potential to meet significant unmet medical need in NF2 and other conditions resulting from the over-expression of VEGF.



For additional information contact:

Diane Goetz

PTC Therapeutics, Inc.

(908) 912-9256

patientinfo@ptcbio.com



The Ohio State University Department of Otolaryngology-Head and Neck Surgery is currently (2009) conducting a study to determine the frequency of birth defects and miscarriages in patients with NF2 and to investigate the frequency of color blindness in NF2 patients. Individuals over 18 with NF2 are eligible to participate.



To enroll in the study and to receive a study packet contact:



Beth Miles-Markley

Research Assistant to Dr. Bradley Welling

(614)366-9244

Beth.Miles-Markley@osumc.edu



Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.



For more information about clinical trials being conducted at the National Institutes of Health (NIH) Clinical Center in Bethesda, MD, contact the NIH Patient Recruiting Office:



Tollfree: (800) 411-1222

TTY: (866) 411- 1010

Email: prpl@cc.nih.gov



For information about clinical trials sponsored by private sources, contact:

www.centerwatch.com



Information about current clinical trials is also available from Neurofibromatosis, Inc. at http://www.nfinc.org



The Children's Tumor Foundation launched an NF Registry in 2012. The purpose of this registry is to find people who may be eligible for clinical trials or other research studies being conducted in the field of NF, and to determine the commonality of specific NF characteristics. Please go to www.nfregistry.org for more information.

References

TEXTBOOKS

Fauci AS, et al., eds. Harrison's Principles of Internal Medicine. 14th ed. New York, NY: McGraw-Hill Companies, Inc.; 1998:2404.



Adams RD, et al., eds. Principles of Neurology. 6th ed. New York, NY: McGraw-Hill Companies, Inc.; 1997:1016.



Jones KL. Smith's Recognizable Patterns of Human Malformation. 5th ed. Philadelphia, PA: W.B. Saunders Company; 1997:508-509.



Behrman RE, et al., eds. Nelson Textbook of Pediatrics. 15th ed. Philadelphia, PA: W.B. Saunders Company; 1996:1705-1707.



Wyngaarden JB, et al., eds. Cecil Textbook of Medicine. 19th ed. Philadelphia, PA: W.B. Saunders Company; 1992:2144.



Buyse ML. Birth Defects Encyclopedia. Dover, MA: Blackwell Scientific Publications, Inc.; 1990:1233-1234.



JOURNAL ARTICLES

Alegre M, et al. Auditory brain stem potentials evoked by electrical stimulation of cochlear nuclei during central auditive implant setting. Rev Neurol. 1999;29:198-200.



Legoix P, et al. Characterisation of 16 polymorphic markers in the NF2 gene: application to hemizygosity detection. Hum Mutat. 1999;13:290-293.



Temple RH, et al. Auditory rehabilitation in neurofibromatosis type 2: a case for cochlear implantation. J Laryngol Otol. 1999;113:161-163.



Waring MD, et al. Activating separate ascending auditory pathways produces different human thalamic/cortical responses. Hear Res. 1999;130:219-229.



Laszig R, et al. Central electrical stimulation of the auditory pathway in neurofibromatosis type 2. Ear Nose Throat J. 1999;78:110-1, 115-117.



Evans DGR, et al. Genotype/phenotype correlations in type 2 neurofibromatosis (NF2): evidence for more severe disease associated with truncating mutations. J Med Genet. 1998;35:450-455.



Kluwe L, et al. Mosaicism in sporadic neurofibromatosis 2 patients. Hum Molec Genet. 1998;7:2051-2055.



Vautrin R, et al. Oto-neuro-surgical approach and accessibility to the cochlear nuclei. Significance in auditory brain stem implant. Rev Laryngol Otol Rhinol (Bord). 1998;119:171-176.



Otto SR, et al. The multichannel auditory brain stem implant: performance in twenty patients. Otolaryngol Head Neck Surg. 1998;118:291-303.



Gutmann D, et al. The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. JAMA. 1997;278:51-57.



Kluwe L, et al. A missense mutation in the NF2 gene results in moderate and mild clinical phenotypes of neurofibromatosis type 2. Hum Genet. 1996;97:224-227.



Trofatter JA, et al. A novel moesin-, ezrin-, radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor. Cell. 1993;72:791-800.



Rouleau GA, et al. Alteration in a new gene encoding a putative membrane-organizing protein causes neuro-fibromatosis type 2. Nature. 1993;363:515-521.



Bouzas EA, et al. Lens opacities in neurofibromatosis 2: further significant correlations. Brit J Ophthal. 1993;77:354-357.



Evans DGR, et al. A clinical study of type 2 neurofibromatosis. Quart J Med. 1992;84:603-618.



Mayfrank L, et al. Neurofibromatosis 2: a clinically and genetically heterogeneous disease? Report on 10 sporadic cases. Clin Genet. 1990;38:362-370.



Martuza RL, et al. Neurofibromatosis 2 (bilateral acoustic neurofibromatosis). New Engl J Med. 1988;318:684-688.



FROM THE INTERNET

Online Mendelian Inheritance in Man, OMIM (TM). John Hopkins University, Baltimore, MD. MIM Number 101000; 6/3/99. Available at: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?101000.

Resources

Children's Tumor Foundation

95 Pine Street

16th Floor

New York, NY 10005-4002

Tel: (212)344-6633

Fax: (212)747-0004

Tel: (800)323-7938

TDD: (212)344-6633

Email: info@ctf.org

Internet: http://www.ctf.org/



Neurofibromatosis, Inc.

213 S. Wheaton Ave.

Wheaton, IL 60187

USA

Tel: (630)510-1115

Fax: (630)510-8508

Tel: (800)942-6825

Email: admin@nfnetwork.org

Internet: http://www.nfnetwork.org



Better Hearing Institute

1444 I Street NW

Suite 700

Washington, DC 20005

United States

Tel: (202)449-1100

Fax: (703)684-6048

Tel: (800)327-9355

Email: mail@betterhearing.org

Internet: http://www.betterhearing.org



National Association of the Deaf

8630 Fenton Street

Suite 820

Silver Springs, MD 20910

USA

Tel: (301)587-1788

Fax: (301)587-1791

TDD: (301)587-1789

Email: NADinfo@nad.org

Internet: http://www.nad.org



Cedars-Sinai Medical Genetics Institute

8700 Beverly Blvd

PACT Suite 400

Los Angeles, CA 90048

USA

Tel: (310)423-9914

Fax: (310)423-2080

Tel: (800)233-2771

Internet: http://www.cedars-sinai.edu/Patients/Programs-and-Services/Medical-Genetics-Institute/



Children's National Medical Center

Genetics Department

Attn: Kenneth Rosenbaum MD

111 Michigan Ave. NW

Suite 1950

Washington, DC 20010

Tel: (202)476-2327

Tel: (888)884-2327

Email: tbear@cnmc.org

Internet: http://www.childrensnational.org/



NIH/National Institute of Neurological Disorders and Stroke

P.O. Box 5801

Bethesda, MD 20824

Tel: (301)496-5751

Fax: (301)402-2186

Tel: (800)352-9424

TDD: (301)468-5981

Internet: http://www.ninds.nih.gov/



Massachusetts General Hospital Neurofibromatosis Clinic

15 Parkman St. 8th Floor, Room 835

Boston, MA 02114

USA

Tel: (617)724-7856

Fax: (617)724-8769

Email: SPlotkin@partners.org

Internet: http://neurosurgery.mgh.harvard.edu/NFclinic/



NF-2 Sharing Network

10074 Cabachon Court

Ellicott City, MD 21241

Tel: (410)461-2245

Fax: (410)461-2245

TDD: (410)461-5213



NIH/National Institute on Deafness and Other Communication Disorders

31 Center Drive, MSC 2320

Communication Avenue

Bethesda, MD 20892-3456

Tel: (301)402-0900

Fax: (301)907-8830

Tel: (800)241-1044

TDD: (800)241-1105

Email: nidcdinfo@nidcd.nih.gov

Internet: http://www.nidcd.nih.gov



Comer Children's Hospital - University of Chicago (Neurofibromatosis Clinic)

Pediatric Neurology

5721 S. Maryland Avenue, MC3055

Chicago, IL 60637

USA

Tel: (773)834-8064

Fax: (773)702-4786

Email: cmacmill@peds.bsd.uchicago.edu

Internet: http://www.uchicagokidshospital.org/specialties/neurology/patient-guides/neurofibromatosis/



Acoustic Neuroma Association of Canada

PO Box 193

Buckthorn, Ontario, KOL 1JO

Canada

Tel: 8005612622

Email: info@anac.ca

Internet: http://www.anac.ca



BC Neurofibromatosis Foundation

Box 5339

Victoria, BC, V8R 6S4

Canada

Tel: 800385BCNF (2263)

Email: info@bcnf.bc.ca

Internet: http://www.bcnf.bc.ca



Rare Cancer Alliance

1649 North Pacana Way

Green Valley, AZ 85614

USA

Internet: http://www.rare-cancer.org



Genetic and Rare Diseases (GARD) Information Center

PO Box 8126

Gaithersburg, MD 20898-8126

Tel: (301)251-4925

Fax: (301)251-4911

Tel: (888)205-2311

TDD: (888)205-3223

Internet: http://rarediseases.info.nih.gov/GARD/



Madisons Foundation

PO Box 241956

Los Angeles, CA 90024

Tel: (310)264-0826

Fax: (310)264-4766

Email: getinfo@madisonsfoundation.org

Internet: http://www.madisonsfoundation.org



Let Them Hear Foundation

1900 University Avenue, Suite 101

East Palo Alto, CA 94303

Tel: (650)462-3174

Fax: (650)462-3144

Email: info@letthemhear.org

Internet: http://www.letthemhear.org



Alberta Neurofibromatosis Association

636 Hunterfield Place NW

Calgary

Alberta, T2K 4L6

Canada

Tel: 4032754894

Tel: 8669392263

Email: pam@albertanf.org or cathy@albertanf.org

Internet: http://www.albertanf.org



American Academy of Audiology

11730 Plaza America Drive, Suite 300

Reston, VA 20190

Tel: (703)790-8466

Fax: (703)790-8631

Tel: (800)222-2336

Email: infoaud@audiology.org

Internet: http://www.audiology.org



Cancer.Net

American Society of Clinical Oncology

2318 Mill Road Suite 800

Alexandria, VA 22314

Tel: (571)483-1780

Fax: (571)366-9537

Tel: (888)651-3038

Email: contactus@cancer.net

Internet: http://www.cancer.net/



Hearing Loss Association of America

7910 Woodmont Avenue

Suite 1200

Bethesda, MD 20814

Tel: (301)657-2248

Fax: (301)913-9413

Email: info@hearingloss.org

Internet: http://www.hearingloss.org



For a Complete Report

This is an abstract of a report from the National Organization for Rare Disorders, Inc.® (NORD). Cigna members can access the complete report by logging into myCigna.com. For non-Cigna members, a copy of the complete report can be obtained for a small fee by visiting the NORD website. The complete report contains additional information including symptoms, causes, affected population, related disorders, standard and investigational treatments (if available), and references from medical literature. For a full-text version of this topic, see http://www.rarediseases.org/search/rdblist.html.

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