NORD gratefully acknowledges Kristina Bundra, Pharm. D, NORD Editorial Intern, Madeline Zupan, NORD Editorial Intern from the University of Notre Dame, and D Gareth Evans, MD, FRCP, Director, Neurofibromatosis Clinic, Central Manchester Foundation NHS Trust Regional Genetic Service, St Mary's Hospital, Manchester, UK, for assistance in the preparation of this report.
Neurofibromatosis 2 (NF2) is a rare genetic disorder that is primarily characterized by noncancerous (benign) tumors of the nerves that transmit balance and sound impulses from the inner ears to the brain (bilateral acoustic neuromas/vestibular schwannomas). Symptoms may become apparent during childhood, adolescence, early adulthood or later in adult life. Depending on the exact location and size of the acoustic neuromas/vestibular schwannomas, or other schwannomas such findings may include problems with balance and walking (gait); dizziness; headache; facial weakness, numbness, or pain; but more typically ringing in the ears (tinnitus); and/or progressive hearing loss.
In some individuals with NF2, additional abnormalities may be present. These may include clouding of the lenses of the eyes (juvenile posterior subcapsular opacities), progressive visual impairment, or an increased risk of developing certain tumors of the lining of the brain (meningiomas) 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 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 also used to describe a second, distinct form of NF known as neurofibromatosis 1 (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 (café-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 multiple areas of abnormal color (pigmentation) are considered relatively uncommon. 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 NF2 usually develop around the time of puberty or during early adulthood. These symptoms may include problems with balance, 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). Almost all affected individuals develop bilateral vestibular schwannomas by age 30 years. Other tumors of the central nervous system may also develop, and can include neurofibromas, meningiomas, low grade gliomas (mainly benign ependymomas of the spinal cord), and schwannomas.. The size, location, and number of tumors may vary in different people affected. (For more information on tinnitus, choose “tinnitus” as your search term in the Rare Disease Database.)
Individuals with NF2 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 NF2 generally have fewer brown spots (café-au-lait) on the skin than those who have NF1. 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. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.
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 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 equally affected by this disorder. The estimated incidence of NF2 is 1 in 33,000 people worldwide. The symptoms of this disease typically become apparent during puberty or early adulthood. The average age of onset is 18 to 24 years.
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 are very rarely used nowadays). Molecular genetic testing for mutations in the NF2 gene is available for most affected individuals who have a positive family history.
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. The VEGF inhibitor bevacizumab may also be considered to treat rapidly growing schwannomas but is very expensive.
Other treatment is symptomatic and supportive.
Regular monitoring may be required for affected or at-risk individuals. An annual magnetic resonance imaging (MRI) may be necessary beginning at approximately age 10 to 12 years and continuing until at least the fourth decade of life in addition to regular hearing evaluations. Earlier diagnosis and better treatment lend itself to improved survival in those affected.
Genetic counseling can be beneficial for people with NF2 and their families.
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:
For information about clinical trials conducted in Europe, contact:
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
RareConnect offers a safe patient-hosted online community for patients and caregivers affected by this rare disease. For more information, visit www.rareconnect.org.
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