DiagnosisClinical DiagnosisModifications to NIH consensus diagnostic criteria for neurofibromatosis 2 (NF2) have been suggested to enable earlier diagnosis of a founder (i.e., the individual in the first generation of a family known to be affected). These clinical diagnostic criteria for NF2 have been found to improve sensitivity substantially without affecting specificity [Baser et al 2002]. According to the modified criteria, NF2 is diagnosed in individuals with one of the following:Bilateral vestibular schwannomasA first-degree relative with NF2 ANDUnilateral vestibular schwannoma ORAny two of: meningioma, schwannoma, glioma, neurofibroma, posterior subcapsular lenticular opacities *Unilateral vestibular schwannoma AND any two of: meningioma, schwannoma, glioma, neurofibroma, posterior subcapsular lenticular opacities *Multiple meningiomas ANDUnilateral vestibular schwannoma ORAny two of: schwannoma, glioma, neurofibroma, cataract ** Any two of = two individual tumors or cataractTestingChromosome analysis. A variety of chromosome abnormalities can be associated with NF2; however, gross chromosomal changes detectable on normal cytogenetic analysis are fairly uncommon.Cytogenetically visible deletions encompassing NF2 may cause intellectual disability and can cause congenital abnormalities [Barbi et al 2002]. Ring chromosome 22 can also cause multiple meningiomas and vestibular schwannomas fulfilling NF2 diagnostic criteria [Tsilchorozidou et al 2004]. The NF2 locus itself is usually present within the ring, but the ring itself is frequently lost as a result of instability.Apparently balanced chromosomal translocations that disrupt NF2 have also been described as causing NF2 [Tsilchorozidou et al 2004]. Fluorescence in situ hybridization (FISH) analysis. Smaller deletions that remove multiple exons of NF2 or the whole gene can also be identified by FISH analysis [Tsilchorozidou et al 2004].Molecular Genetic TestingGene. NF2 is the only gene in which mutations are known to cause neurofibromatosis 2.Clinical testingTable 1. Summary of Molecular Genetic Testing Used in Neurofibromatosis 2View in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method ^{1, 2Test AvailabilityNF2Sequence analysis / mutation scanning 3Sequence variants 4See footnotes 5 and 6Clinical Deletion / duplication testing 7Partial- and whole-gene deletions 8See footnote 9Linkage analysis 10NANA1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Mutation detection rates are lower in simplex cases and in the person in the first generation of a family to have NF2 because they are more likely to have somatic mosaicism (see Interpretation of test results).3. The detection rate of disease-causing mutations using mutation scanning is comparable to that of sequence analysis in up to two thirds of cases.4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.5. When mutation scanning is combined with deletion/duplication analysis of single exons, the mutation detection rate approaches 72% in simplex cases and exceeds 92% for familial cases [Wallace et al 2004, Kluwe et al 2005, Evans et al 2007b, Evans 2009]. 6. Other studies have reported lower mutation detection rates, which may reflect the inclusion of some more mildly affected individuals with somatic mosaicism. Approximately 25% to 33% of mutations are not detected as a result of somatic mosaicism [Kluwe et al 2003, Moyhuddin et al 2003]. Mutations with mosaicism levels greater than 10% can be detected in lymphocyte DNA [Evans et al 2007b]. Identification of the remainder of mosaic mutations usually requires testing of tumor material [Evans et al 2007b] (see Interpretation of test results).7. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.8. Most large deletions and, less commonly, duplications of single exons or multiple exons can be detected by MLPA [Kluwe et al 2005, Evans et al 2007b].9. At least 10% to 15% of NF2 constitutional aberrations are deletions ranging in size from 10 to 600 kb [Zucman-Rossi et al 1998, Wallace et al 2004, Kluwe et al 2005]. However, in inherited cases they make up approximately 20%, boosting sensitivity of the combination of sequence analysis and deletion/duplication testing to 93% (101/108) [Evans 2009].10. Linkage analysis can be considered in families in whom no disease-causing mutation is identified and at least two family members of different generations are affected. Linkage studies are based on an accurate clinical diagnosis of NF2 in the affected family members and accurate understanding of genetic relationships in the family. Linkage analysis depends on the availability and willingness of family members to be tested. The markers used for linkage analysis of NF2 are highly informative and very tightly linked to NF2; thus, they can be used in more than 95% of families with NF2 with greater than 99% accuracy. Linkage testing is not usually available to families with a single affected individual, a situation that often occurs when an individual has a de novo gene mutation and no affected offspring; however, modified linkage analysis using both constitutional and tumor DNA can exclude NF2 in those offspring of a simplex case who have not inherited the allele lost in the tumor [Kluwe et al 2005, Evans et al 2007b].Interpretation of test resultsFor issues to consider in interpretation of sequence analysis results, click here.Research has shown that as many as 25% to 33% of individuals with NF2 caused by a de novo mutation have somatic mosaicism for the mutation [Kluwe et al 2003, Moyhuddin et al 2003, Evans et al 2007b]. Recognition of individuals who have somatic mosaicism for an NF2 disease-causing mutation can be difficult because these individuals:May not have bilateral vestibular schwannomas [Evans et al 2008];May have normal molecular genetic testing of NF2 in unaffected tissue, such as lymphocytes; thus, molecular genetic testing of tumor tissue may be necessary to establish the presence of somatic mosaicism [Mohyuddin et al 2002, Evans et al 2007b].A parent can be excluded as having NF2 if his/her offspring is shown to have somatic mosaicism for an NF2 mutation. Absence of an NF2 mutation in an offspring does not eliminate the possibility of somatic mosaicism for an NF2 mutation in the offspring or parent. Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing StrategyTo confirm/establish the diagnosis in a proband. One of two sample types is used:Leukocyte DNA from an individual who has an affected parentTumor DNA from an individual who reperesents a simplex caseMolecular genetic testing to detect a germline mutation is performed in the following order:1.Testing for large deletions using a technique such as MLPA 2.Sequence analysis of exons 1-15 (Mutations in exons 16-17 have never been described.)When tumor DNA is tested, mutations in both NF2 alleles must be identified:This may mean testing for loss (or inactivation) of one NF2 allele by assessing for loss of heterozygosity (LOH).Once both NF2 mutant alleles are identified in the tumor, leukocyte DNA can be tested to determine which of the mutations is constitutional and which is somatic (i.e., present in the tumor only).Predictive testing At-risk relatives whose genetic status is unknown can be tested for presence of the NF2 mutation (either constitutional or somatic mosaic) identified in an affected relative (e.g., the proband).In the rare instance in which an NF2 mutation cannot be identified, linkage analysis can be used in families with at least two affected family members of different generations or tumor DNA can be used to clarify the genetic status of offspring of a simplex case.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family. Genetically Related (Allelic) DisordersNo other phenotypes are known to be associated with mutations in NF2.}

Natural HistoryThe average age of onset of findings in individuals with neurofibromatosis 2 (NF2) is 18 to 24 years (onset range: birth to 70 years). Almost all affected individuals develop bilateral vestibular schwannomas by age 30 years. In addition to vestibular schwannoma, individuals with NF2 develop schwannomas of other cranial and peripheral nerves, meningiomas, ependymomas, and, very rarely, astrocytomas.Variable expressivity of NF2 among individuals results in varying size, location, and number of tumors. Although these tumors are not malignant, their anatomical location and multiplicity lead to great morbidity and early mortality. The average age of death is 36 years. Actuarial survival from the time of establishing the correct diagnosis is 15 years. Survival is improving with earlier diagnosis and better treatment in specialty centers [Baser et al 2002, Evans et al 2005a].Because NF2 is considered an adult-onset disease, it may be under-recognized in children, in whom skin tumors and ocular findings may be the first manifestations [Evans et al 1999, Ruggieri et al 2005]. The presenting symptoms of 120 individuals with NF2 studied by Evans et al [1992] in Great Britain are listed in Table 2. (This study did not include skin tumors or cataracts as a first symptom.)Table 2. Presenting Symptoms of 120 Individuals with NF2View in own windowSymptom% of Affected IndividualsUnilateral hearing loss35%Focal weakness ^{112%Tinnitus10%Bilateral hearing loss9%Balance dysfunction8%Seizure8%Focal sensory loss6%Blindness1%No symptom, but detected on screening because a parent was affected11%Adapted from Evans et al [1992]1. Can result from spinal tumors, mononeuropathy, or polyneuropathyVestibular schwannoma. Initial symptoms include tinnitus, hearing loss, and balance dysfunction. Onset of disability is usually insidious, although occasionally hearing loss may occur suddenly, presumably as a result of vascular compromise by the tumor. Affected individuals often report difficulty in using the telephone in one ear or unsteadiness when walking at night or on uneven ground.With time, vestibular tumors extend medially into the cerebellar pontine angle and, if left untreated, cause compression of the brain stem and hydrocephalus. Significant facial palsy is rare even in large tumors.Schwannomas may also develop on other cranial and peripheral nerves, with sensory nerves more frequently affected than motor nerves.Spinal tumors. At least two thirds of individuals with NF2 develop spinal tumors, which are often the most devastating and difficult to manage [Dow et al 2005]. The most common spinal tumors are schwannomas, which usually originate within the intravertebral canal on the dorsal root and extend both medially and laterally, taking the shape of a "dumbbell." Intramedullary tumors of the spinal cord, such as astrocytoma and ependymoma, occur in 5% to 33% of individuals with NF2. Most persons with spinal cord involvement have multiple tumors. Although multiple tumors are often present on imaging studies, they remain asymptomatic in many individuals.Meningioma. Approximately half of individuals with NF2 have meningiomas in cross-sectional studies [Goutagny & Kalamarides 2010]; however, lifetime risk may approach 80% [Smith et al 2011]. Most are intracranial; however, spinal meningiomas occur. NF2 meningiomas tend to occur less frequently in the skull base than supratentorially and are usually of the fibroblastic variety [Evans et al 2000, Kros et al 2001]. Meningiomas in the orbit may compress the optic nerve and result in visual loss. Those at the skull base may cause cranial neuropathy, brain stem compression, and hydrocephalus. Meningioma may be the presenting feature of NF2, particularly in childhood [Evans et al 1999, Perry et al 2001]. See Genotype-Phenotype Correlations.Ocular involvement. One third of individuals with NF2 have decreased visual acuity in one or both eyes. Posterior subcapsular lens opacity rarely progressing to a visually significant cataract is the most common ocular finding. Lens opacities may appear prior to the onset of symptoms from vestibular schwannoma and can be seen in children. Cataracts can be present at birth and in these children amblyopia is common in the formative years [Feucht et al 2008].Retinal hamartoma and epiretinal membrane are seen in up to one third of individuals. Rarely, other ocular manifestations may occur: persistent hyperplastic primary vitreous (PHPV) has been reported in a father and son [Nguyen et al 2005]. In adulthood particular problems with the cornea can occur, especially after surgery that results in the loss of facial, trigeminal, and intermedius nerve function.Intracranial and intraorbital tumors may result in decreased visual acuity and diplopia.Mono-/polyneuropathy. A recognized feature of NF2 is a mononeuropathy occurring particularly in childhood [Evans et al 1999] and frequently presenting as a facial palsy that usually only partially recovers, a squint (third nerve palsy), or a foot or hand drop. The foot drop may mimic polio.A progressive polyneuropathy of adulthood not directly related to tumor masses is also recognized [Sperfeld et al 2002].Further evidence for the mononeuropathy of childhood and the polyneuropathy of adulthood has come from sural nerve biopsies [Hagel et al 2002].Other. Renal vascular disease similar to that occurring in neurofibromatosis type 1 (NF1) has been reported once [Cordeiro et al 2006].Somatic mosaicism for disease-causing mutations in NF2. Mosaicism has been suspected in individuals with unilateral vestibular schwannoma and multiple other, often ipsilateral, tumors [Moyhuddin et al 2003, Evans et al 2008]. This has now been confirmed for most cases in which DNA from multiple tumors has been analyzed [Moyhuddin et al 2003, Wallace et al 2004, Aghi et al 2006, Evans et al 2008].Histopathology. The tumors of NF2 are derived from Schwann cells, meningeal cells, and glial cells. They are uniformly benign. Approximately 40% of NF2 vestibular tumors have a lobular pattern that is uncommon in tumors from individuals who have no known family history of NF2. NF2-associated vestibular schwannomas tend to be more invasive and to have a higher degree of dividing cells than non-NF2 tumors. NF2-associated meningiomas have a higher degree of dividing cells than non-NF2 meningiomas. NF2 meningiomas are usually of the fibroblastic variety. No histologic differences have been observed between glial tumors in individuals with NF2 and individuals who do not have NF2.}

Genotype-Phenotype CorrelationsIntrafamilial variability is much lower than interfamilial variability, suggesting a strong effect of the underlying genotype on the resulting phenotype.Unlike neurofibromatosis type 1 (NF1), large deletions of NF2 have been associated with a mild phenotype [Baser et al 2004]. At least 10% to 15% of NF2 constitutional aberrations are deletions ranging in size from 10 to 600 kb [Zucman-Rossi et al 1998, Wallace et al 2004, Kluwe et al 2005]; even if quite large, these deletions are not associated with intellectual disability.The type of NF2 constitutional mutation is an important determinant of the number of NF2-associated intracranial meningiomas, spinal tumors, and peripheral nerve tumors [Baser et al 2004]: Nonsense and frame-shifting mutations have been associated with severe disease regardless of their position within the gene [Baser et al 2004].Splice site mutations have been associated with both mild and severe disease [Kluwe et al 1998, Baser et al 2005] and may be milder if occurring in the 3' half of the gene [Baser et al 2005].Missense mutations are usually mild, often causing the mildest form of NF2 [Evans et al 1998a, Baser et al 2002].Truncating mutations are associated with earlier onset and greater number of NF2-associated intracranial meningiomas, spinal tumors, and peripheral nerve tumors. In general, truncating mutations (frameshift and nonsense) are associated with greater disease-related mortality than missense and splice site mutations or deletions [Baser et al 2002, Baser et al 2005]. Truncating mutations are also associated with increased prevalence of spinal tumors [Patronas et al 2001, Dow et al 2005]. Although most of these mutations would be predicted to result in nonsense-mediated decay and, thus, no protein product, the apparent dominant negative affect of these mutations requires further investigation.Mutations in the 3’ half of NF2 (especially those in exons 14-16) are associated with lower risk of meningioma than mutations in the 5’ half of the gene [Smith et al 2011]. (See Figure 1)FigureFigure 1. The position of mutations in NF2 affects the likelihood of developing a meningioma.

A. The Kaplan-Meier plot shows the risk of meningioma within each functional domain. Gene regions are divided into exons 1-3, 4-6, 7-9, 10-13, (more...)Somatic mosaicism (even when detected in lymphocyte DNA) for typical truncating mutations that would normally cause severe NF2 may result in a milder phenotype [Evans et al 1998a, Evans et al 2007b].

Differential DiagnosisNeurofibromatosis type 1. Although the two disorders are clinically distinct and caused by mutations in different genes at different chromosomal loci, diagnostic confusion continues to exist between neurofibromatosis type 1 (NF1) and neurofibromatosis 2 (NF2); thus, it is worth noting several features that distinguish them:Individuals with NF2 do not have the cognitive problems (intellectual disability and learning disability) seen in some individuals with NF1, nor do they have significant numbers of Lisch nodules (i.e., iris hamartomas).In individuals with NF2, schwannomas rarely, if ever, undergo malignant transformation to neurofibrosarcoma.Individuals with NF2, contrary to a common misconception, do not have significant numbers of café au lait macules, although they are probably more numerous than in the general population.The dumbbell configuration of the spinal root tumors, which are schwannomas in NF2 and neurofibromas in NF1, may occasionally cause initial diagnostic confusion between the two disorders.Schwannomatosis is defined as multiple schwannomas without the vestibular schwannomas that are diagnostic of NF2 [MacCollin et al 2005]. Previous terminology for this condition has included multiple neurilemomas, multiple schwannomas, and neurilemomatosis [MacCollin et al 2005].Individuals with schwannomatosis may develop intracranial, spinal nerve root, or peripheral nerve tumors; malignant transformation may rarely occur. One third of individuals with schwannomatosis have anatomically localized tumors suggestive of segmental disease [MacCollin et al 2005].Familial cases appear to be inherited in an autosomal dominant manner, with highly variable expressivity and incomplete penetrance. Schwannomatosis is clinically and genetically distinct from NF1 and NF2, although some individuals with multiple schwannomas eventually fulfill NF2 diagnostic criteria and some simplex cases of schwannomatosis are mosaic for an NF2 mutation [Moyhuddin et al 2003]. The locus for schwannomatosis had been mapped to an area close to, but excluding, NF2 [MacCollin et al 2003]. A mutation in SMARCB1 (INI1) was identified in a family with schwannomatosis [Hulsebos et al 2007]. Subsequent analysis has shown that SMARCB1 mutations cause 30%-60% of familial schwannomatosis, but only a small percentage of simplex disease (i.e., a single occurrence in a family) [Boyd et al 2008, Hadfield et al 2008, Sestini et al 2008].Unilateral vestibular schwannoma is a common tumor in the general population, accounting for 5% to 10% of all intracranial tumors and the vast majority of cerebellar pontine angle tumors.Approximately 5% of vestibular schwannomas are bilateral [Evans et al 2005b] and thus associated with NF2; 95% are unilateral occurrences in individuals who have no underlying genetic predisposition to such tumors. The risk that a unilateral tumor is the first manifestation of NF2 is closely related to the age of the affected individual.Individuals younger than age 30 years, with a symptomatic unilateral vestibular schwannoma, are at high risk of developing a contralateral tumor and NF2 and should be monitored closely. Indeed, approximately 6% of individuals with an apparently isolated vestibular schwannoma are mosaic for an NF2 mutation [Mohyuddin et al 2002, Evans et al 2007a].Individuals older than age 30 years who have a unilateral vestibular schwannoma are at very low risk of developing NF2 [Evans et al 2007a].The offspring of individuals with unilateral vestibular schwannoma and no known family history of schwannomas do not have an increased incidence of either NF2 or unilateral vestibular schwannoma. Somatic involvement of NF2 in isolated vestibular schwannomas is almost universal [Mohyuddin et al 2002, Szijan et al 2003]; however, it is possible that mutations in other genes on chromosome 22 predispose to schwannoma development [Mantripragada et al 2003]. Meningioma. Multiple meningiomas typically occur in older adults; thus, the finding of a single meningioma in an individual younger than age 25 years should prompt evaluation for an underlying genetic condition [Evans et al 2005c]. Meningiomas may predate the development of vestibular schwannomas, and any childhood meningioma should be considered as a possible early sign of NF2 [Evans et al 1999, Perry et al 2001, Evans et al 2005c]. Individuals with multiple meningiomas may occasionally be mosaic for an NF2 mutation without the presence of vestibular schwannoma; in general, however, adults with multiple meningiomas and no vestibular schwannoma are at low risk for NF2 [Evans et al 2005c].Rare instances of multiple meningiomas without vestibular schwannoma segregating as an autosomal dominant disorder have been reported [Maxwell et al 1998, Goutagny & Kalamarides 2010]. Recently a mutation in SMARCB1 that causes a proportion of schwannomatosis was reported in one family [Christiaans et al 2011], but the great majority of individuals with multiple meningioma do not harbor a SMARCB1 mutation [Hadfield et al 2010]. Linkage analysis of one affected family has implicated a locus distinct from the NF2 locus. A gene other than NF2 is implicated in more than 60% of all meningiomas that occur in individuals with no known family history of meningiomas [Lomas et al 2005].Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with neurofibromatosis 2 (NF2), the following evaluations are recommended:Head MRIHearing evaluation, including BAEROphthalmologic evaluationCutaneous examinationGenetics consultationNote: Evaluation and treatment of individuals with neurofibromatosis 2 (NF2) are best undertaken in an NF2 center experienced in managing the multiple complications of the disease [Baser et al 2002, Evans et al 2005a]. For NF specialists see www.ctf.org. For the four specialist centers designated in England see www.specialisedservices.nhs.uk.Treatment of ManifestationsVestibular schwannoma. Untreated tumors may be slow growing and not require active intervention in the short term [Masuda et al 2004, Slattery et al 2004]. Therapy remains primarily surgical. Small vestibular tumors (<1.5 mm) that are completely intercanalicular can often be completely resected, with preservation of both hearing and facial nerve function. Larger tumors are probably best managed expectantly, with debulking or decompression carried out only when brain stem compression, deterioration of hearing, and/or facial nerve dysfunction occur [Evans et al 2005a]. However, balancing between early surgery and preservation of facial function and later surgery when a patient is still hearing is difficult [Evans et al 2005a].Stereotactic radiosurgery, most commonly with the gamma knife, has been offered as an alternative to surgery in select individuals with vestibular schwannoma. However, the outcomes from radiation treatment in individuals with NF2 are not as good as for individuals with sporadic unilateral vestibular schwannoma, with only approximately 60% long-term tumor control [Rowe et al 2003].Malignant transformation is a possible, though probably not common, sequela [Baser et al 2000]; however, it should be noted that tumor development following radiation may take 15 years [Evans et al 2006]. This may involve development of a malignancy within the treated lesion or a new malignancy (e.g., glioblastoma) in the radiation field [Balasubramaniam et al 2007].Management of individuals with vestibular tumors should include counseling for insidious problems with balance and underwater disorientation, which can result in drowning.Other tumors. Other intracranial, cranial nerve, or spinal nerve tumors are very slow growing, and surgical intervention for a tumor producing little impairment may cause disability years before it would occur naturally.Although ependymoma in individuals without NF2 is optimally treated with complete resection, and occasionally with radiotherapy and chemotherapy, it is unclear whether ependymoma in individuals with NF2 warrants aggressive management.Radiation therapy of NF2-associated tumors should be carefully considered because radiation exposure may induce, accelerate, or transform tumors in an individual (especially a child) with an inactive tumor suppressor gene [Baser et al 2000, Evans et al 2006].Hearing. Hearing preservation and augmentation are important in the management of individuals with NF2. All affected individuals and their families should be referred to an audiologist to receive training in optimization of hearing and speech production. Lip-reading skills may be enhanced by instruction. Sign language may often be more effectively acquired before the individual loses hearing.Hearing aids may be helpful early in the course of the disease [Evans et al 2005a]. Auditory rehabilitation with a cochlear or brain stem implant should be discussed with those who have lost hearing [Evans et al 2005a]. Rarely, individuals who have had vascular insult to the cochlea, but otherwise are without nerve damage, may benefit from a cochlear implant.Ocular involvement. Early recognition and management of visual impairment from other manifestations of NF2 are extremely important. Prevention of Secondary ComplicationsTreatment concentrates on prevention of secondary complications. Prevention of substantial handicap from the disease can be achieved by appropriate expert treatment of tumors:A cervical spinal scan should be performed before cranial surgery to prevent complications from manipulation under anesthesia [Evans et al 2005a].Spinal tumors may make epidural analgesia difficult; therefore, lumbosacral imaging should be performed before regional analgesia is given [Sakai et al 2005, Spiegel et al 2005].SurveillanceFor at-risk individuals (1) in whom the known disease-causing mutation in the family has been identified or (2) whose genetic status cannot be clarified by molecular genetic testing:MRI is usually begun between ages ten and 12 years but can be delayed in families in which the onset is known to be later [Evans et al 2005a]. MRI should be continued on an annual basis until at least the fourth decade of life. It is not clear if earlier surveillance (i.e., cranial MRI before age 10 years) is beneficial, and it is not known at what age monitoring can be safely stopped. Although some individuals with NF2 do not have symptoms until they are in their fifties, it is likely that "silent" tumors would be detected on an MRI performed at a younger age.Hearing evaluation, including BAER testing, may be useful in detecting changes in auditory nerve function before changes can be visualized by MRI.Routine complete eye examinations should be part of the care of all individuals with NF2. Agents/Circumstances to AvoidRadiotherapy should be avoided in children with NF2 [Evans et al 2006].Evaluation of Relatives at RiskConsideration of molecular genetic testing of at-risk family members (see Genetic Counseling) during childhood is appropriate for surveillance:Early identification of relatives who have inherited the family-specific NF2 mutation allows for appropriate screening using MRI for neuroimaging and brain stem auditory evoked response (BAER) testing for audiologic evaluation, thus resulting in earlier detection of disease manifestations and improved final outcomes [Evans et al 2005a].Early identification of those who have not inherited the family-specific NF2 mutation eliminates the need for costly screening with MRI and BAER testing.See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy ManagementAlthough no convincing evidence exists that schwannomas increase in size during pregnancy, hormonal effects on meningiomas are possible; therefore, assessment of the potential risk of increased intracranial pressure is important for women considering pregnancy.Therapies Under InvestigationThe search for an effective medical treatment for NF2-related tumors continues. One of the first groups of agents suggested were PAK1-blocking drugs [Hirokawa et al 2004]. Targeting the ERK1, AKT, integrin/focal adhesion kinase/Src/Ras signaling cascades, PDGFRbeta, phosphatidylinositol 3-kinase/protein kinase C/Src/c-Raf pathway, VEG-F, and other pathways [Hanemann 2008, Evans et al 2009, Blair et al 2011], drugs such as avastin, elotinib [Plotkin et al 2008], lapatinib, and sorafenib [Ammoun et al 2008] may well be effective treatments for NF2. These agents could be tried on the Nf2 mouse model; the first human clinical trials in North America and the UK are also commencing. The most promising results have come from short- to medium-term treatment with avastin [Plotkin et al 2009], which seems to have efficacy against rapidly growing schwannomas and possibly ependymomas, although not meningiomas. Further development of treatment trials is underway [Evans et al 2009].Recently drug trials have identified bevacizumab as a potential treatment [Plotkin et al 2009]. Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Neurofibromatosis 2: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDNF222q12​.2MerlinNF2 homepage - Mendelian genesNF2Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Neurofibromatosis 2 (View All in OMIM) View in own window 101000NEUROFIBROMATOSIS, TYPE II; NF2 607379NEUROFIBROMIN 2; NF2Normal allelic variants. NF2 spans 110 kb and comprises 16 constitutive exons and one alternatively spliced exon. NF2 is widely expressed, producing mRNAs in three different lengths of approximately 7, 4.4, and 2.6 kb. No frequent normal allelic variants, even in codon wobble positions, have been reported in NF2.Pathologic allelic variants. At least 200 different mutations in NF2, the majority of which are point mutations, have been described [Legoix et al 2000, Baser 2006].A wide variety of mutations have been identified in all NF2 exons, except for the alternatively spliced exons 16 and 17. Ninety percent of point mutations are predicted to truncate the protein by introduction of a premature stop codon, a frameshift with premature termination, or a splicing alteration, supporting the view that loss of the protein's normal function is necessary for the development of tumors. C to T transitions in CGA codons causing nonsense mutations are an especially frequent occurrence. Fewer than 10% of detected mutations involve in-frame deletions and missense mutations, which may indicate that alteration of particular functional domains can abolish the NF2 tumor suppressor activity [Baser et al 2006].Normal gene product. The NF2 protein product has been named "merlin" (for moezin-ezrin-radixin-like protein) because of the high homology to the 4.1 family of cytoskeletal associated proteins. Alternatively, the name schwannomin has been proposed in recognition of its role in preventing schwannoma formation. All 4.1 family members have a homologous domain of approximately 270 amino acids at the N terminus. In the NF2 protein and its close relatives, this domain is followed by a long alpha helical segment and a charged C terminal domain. Protein 4.1, the best studied member of the family, plays a critical role in maintaining membrane stability and cell shape in the erythrocyte by connecting integral membrane proteins, glycophorin, and the anion channel to the spectrin-actin lattice of the cytoskeleton. Protein 4.1 is the only other family member in which disease-causing mutations are known (hereditary elliptocytosis). Two major alternative forms of the NF2 protein product exist. Isoform 1 is a protein of 595 amino acids produced from exons 1 through 15 and exon 17. Presence of the alternatively spliced exon 16 alters the C terminus of the protein, replacing 16 amino acids with 11 novel residues in isoform 2. Additional alternative splices predicting other minor species have also been described.Although the complete function of the NF2 protein remains elusive, recent studies suggest that “merlin” may coordinate the processes of growth-factor receptor signaling and cell adhesion. Varying use of this organizing activity by different types of cells could provide an explanation for the unique spectrum of tumors associated with NF2 deficiency in mammals [McClatchey & Giovannini 2005].Abnormal gene product. Abnormal NF2 protein is caused by either a somatic or constitutional mutation. Attempts to identify truncated protein product have been unsuccessful in the main, although the non-truncated product from missense mutations may have partial function. It is thought that nonsense-mediated decay may account for the lack of identifiable product from most mutational types; however, this does not explain why phenotypes are more severe for this type of mutation than for whole-gene deletions.