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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.
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.
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.
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.
Symptoms of the following disorders can be similar to those of neurofibromatosis type 2. Comparisons may be useful for a differential diagnosis:
Neurofibromatosis type 1 (NF1) is a rare inherited disorder of the nervous system and is characterized by the development of tumors on the covering of nerves. The symptoms of this disorder include brown spots (cafe- au-lait) and freckles on the skin, especially under the arms and in the groin area. Small, grayish, benign tumors may develop on the iris of the eyes (lisch nodules). Multiple benign tumors develop on the covering of the nerves. These tumors can grow on any nerve and may appear at any time, including childhood, adolescence, or adulthood. Orthopedic problems may develop including curvature of the spine (scoliosis) and bone loss on weight- bearing long bones (pseudoarthrosis). (For more information on this disorder, choose "neurofibromatosis type 1" as your search term in the Rare Disease Database.)
The following disorders may be associated with neurofibromatosis type 2 as secondary characteristics. They are not necessary for a differential diagnosis:
Tinnitus describes the experience of hearing sound that does not exist in the environment. The sounds associated with tinnitus have been described as clicking, buzzing, whistling, ringing, and/or roaring. They may always be continuous or they may come and go. Eventually hearing loss may occur. Many ear disorders can be associated with tinnitus including various infections of the ear, obstructions, tumors, drug side effects, and other disorders such as neurofibromatosis type 2. (For more information on this disorder, choose "tinnitus" as your search term in the Rare Disease Database.)
Cataracts are abnormalities in the lens of the eye that cause a loss of transparency (opacity). They can occur in one or both eyes and are quite common in elderly people. Congenital cataracts affect babies or young children and are considered a rare birth defect. The symptoms of cataracts include cloudy vision, and nearsightedness (myopia). In many cases, cataracts may result in blindness if left untreated. Cataracts may have a variety of causes. Some are inherited whereas others are due to injury, aging, or other diseases such as neurofibromatosis. (For more information on this disorder, choose "cataracts" as your search term in the Rare Disease Database.)
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.
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:
PTC Therapeutics, Inc.
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:
Research Assistant to Dr. Bradley Welling
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
For information about clinical trials sponsored by private sources, contact:
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.
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5721 S. Maryland Avenue, MC3055
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Home page: http://www.uchicagokidshospital.org/specialties/neurology/patient-guides/neurofibromatosis/
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7910 Woodmont Avenue
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15 Parkman St. 8th Floor, Room 835
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213 S. Wheaton Ave.
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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.
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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.
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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.
Report last updated: 2013/02/05 00:00:00 GMT+0