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Last updated: 02/10/2023
Years published: 1985, 1986, 1987, 1988, 1989, 1990, 1991, 1992, 1993, 1994, 1995, 1996, 1998, 2000, 2001, 2003, 2015, 2018, 2023
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, Manchester Universities Foundation NHS Trust Regional Genetic Service, St Maryโs Hospital, Manchester, UK, for assistance in the preparation of this report.
NF2-related schwannomatosis (NF2; previously known as neurofibromatosis 2) 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 or ependymomas) and spinal cord (central nervous system).
NF2 results from changes (mutations or variants) in the NF2 gene. The NF2 gene regulates the production of a protein that functions as a tumor suppressor. In more than half of individuals with NF2, the disorder is caused by spontaneous (new) variants in the gene. In other affected individuals, NF2 is inherited in an autosomal dominant pattern.
Introduction
The term โneurofibromatosisโ is also used to describe the second, distinct, and much more common form of NF known as neurofibromatosis 1 (NF1). NF1 is primarily characterized by the development of multiple 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 (cafรฉ-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 in an autosomal dominant pattern or occur randomly due to new gene variant. NF2 is now classified along with other forms of schwannoma predisposition such as SMARCB and LZTR1-related schwannomatosis.
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 vestibular nerves pressing on the adjacent 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 hybrid tumors, meningiomas, low grade ependymomas of the spinal cord), and non-vestibular schwannomas on the other cranial nerves, spinal nerves or peripheral nerves. The size, location, and number of tumors may vary in different people affected. (For more information on tinnitus, choose โtinnitusโ 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, although surgery is not usually required.
People with NF2 generally have fewer brown spots (cafรฉ-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.
NF2 is caused by a variant in the NF2 gene. 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 types of variants of the NF2 gene have been identified in individuals with the disorder (e.g., large deletions, nonsense, splice site, missense and frameshift variants). Investigators suggest that different variants in the gene may contribute to the wide variability of symptoms and findings in affected individuals.
In some individuals with NF2, the disorder is inherited in an autosomal dominant pattern. 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 a new gene variant.
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 variants in the NF2 gene is available for most affected individuals who have a positive family history.
The treatment of vestibular (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.
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 is recommended for people with NF2 and their family members.
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: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
The Childrenโs 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 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.
REVIEW ARTICLES
Plotkin SR, Messiaen L, Legius E, Pancza P, Avery RA, Blakeley JO, Babovic-Vuksanovic D, Ferner R, Fisher MJ, Friedman JM, Giovannini M, Gutmann DH, Hanemann CO, Kalamarides M, Kehrer-Sawatzki H, Korf BR, Mautner VF, MacCollin M, Papi L, Rauen KA, Riccardi V, Schorry E, Smith MJ, Stemmer-Rachamimov A, Stevenson DA, Ullrich NJ, Viskochil D, Wimmer K, Yohay K; International Consensus Group on Neurofibromatosis Diagnostic Criteria (I-NF-DC), Huson SM, Wolkenstein P, Evans DG. Updated diagnostic criteria and nomenclature for neurofibromatosis type 2 and schwannomatosis: An international consensus recommendation. Genet Med. 2022 Sep;24(9):1967-1977. doi: 10.1016/j.gim.2022.05.007
Slattery, WH. Neurofibromatosis type 2. Otolaryngol Clin North Am. 2015 Jun; 48(3): 443-460.
Choi JW, Lee JY, Phi JH, et al. Clinical course of vestibular schwannoma in pediatric neurofibromatosis type 2. J Neurosur Pediatr. 2014 Jun; 13(6): 650-7.
Cosetti MK, Golfinos JG, Roland JT. Quality of life (QoL) assessment in patients with neurofibromatosis type 2 (NF2). Otolaryngol Head Neck Surg. 2015 Mar 16.
Vranceanu AM, Merker VL, Park E, et al. Quality of life among adult patients with neurofibromatosis 1, neurofibromatosis 2 and schwannomatosis: a systematic review of the literature. J Neurooncol. 2013 Sep; 114(3): 257-62.
Merker VL, Bredella MA, Cai W, et al. Relationship between whole-body tumor burden, clinical phenotype, and quality of life in patients with neurofibromatosis. Am J Med Genet A. 2014 Jun; 164A(6): 1431-7.
Kontorinis G, Nichani J, Freeman Sr, et al. Progress of hearing loss in neurofibromatosis type 2: implications for future management. Eur Arch Otorhinolaryngol.2014 Oct. 8.
Hilton DA, Hanemann CO. Schwannomas and their pathogenesis. Brain Pathol. 2014 Apr; 24(3): 205-20.
Schulz A, Zoch A, Morrison H. A neuronal function of the tumor suppressor protein merlin.ActaNeuropatholCommun. 2014 Jul 12; 2:82.
Lloyd SK, Evans DG. Neurofibromatosis type 2 (NF2): diagnosis and management. HandbClin Neurol. 2013; 115: 957-67.
Aboukais R, Bonne NX, Baroncini M, et al. Management of multiple tumors in neurofibromatosis type 2 patients. Neurochirugie. 2015 Jun 9.
Maniakas A, Saliba I. Neurofibromatosis type 2 vestibular schwannoma treatment: a review of the literature, trends, and outcomes. OtolNeurotol. 2014 Jun: 35(5): 889-94.
Szudek J, Briggs R, Leung R. Surgery for neurofibromatosis 2. CurrinOpinOtolaryngol head Neck Surg. 2012 Oct; 20(5): 347-52.
Lin Al, Gutmann DH.Advances in the treatment of neurofibromatosis-associated tumours. Nat Rev ClinOncol. 2014 Nov; 10(11): 616-24.
PlotkinSr, Bredella MA, Cai W, et al. Quantitative assessment of whole-body tumor burden in adult patients with neurofibromatosis.PLoS One. 2012; 7(4).
Hochart A, Gaillard V, Baroncini M, et al. Bevacizumab vestibular schwannomas growth rate in children and teenagers with neurofibromatosis type 2. J Neurooncol. 2015 May 29.
Monteiro TA, Goffi-Gomez MV, Tsuji RK, et al. Neurofibromatosis 2: hearing restoration options. Braz J Otorhinolaryngol. 2012 Oct; 78(5): 128-34.
Wolters PL, Martin S, Merker VL, et al. Patient-reported outcomes in neurofibromatosis and schwannomatosis clinical trials. Neurology. 2013 Nov 19; 81:S6-14.
INTERNET
Evans DG. Neurofibromatosis 2. 1998 Oct 14 [Updated 2018 Mar 15]. In: Adam MP, Everman DB, Mirzaa GM, et al., editors. GeneReviewsยฎ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1201/ Accessed Dec 8, 2022.
Neurofibromatosis type 2. Genetics Home Reference (GHR). Updated July 27, 2022.Available at: https://ghr.nlm.nih.gov/condition/neurofibromatosis-type-2. Accessed Dec 8, 2022.
Online Mendelian Inheritance in Man, OMIM (TM). John Hopkins University, Baltimore, MD. MIM Number 101000; Updated04.11.2021. Available at: https://omim.org/entry/101000. Accessed Dec 8, 2022.
Evans G. Neurofibromatosis type 2. Orphanet. Available at: https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=637.0. Last update: June 2009. Accessed Dec 8, 2022.
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