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Neurofibromatosis 2

Synonyms: Bilateral Acoustic Neurofibromatosis, Central Neurofibromatosis, NF2, Neurofibromatosis Type II
, MD, FRCP
Director, Neurofibromatosis Clinic
Central Manchester Foundation NHS Trust Regional Genetic Service
St Mary's Hospital
Manchester, United Kingdom

Initial Posting: ; Last Update: August 18, 2011.

Summary

Disease characteristics. Neurofibromatosis 2 (NF2) is characterized by bilateral vestibular schwannomas with associated symptoms of tinnitus, hearing loss, and balance dysfunction. The average age of onset is 18 to 24 years. Almost all affected individuals develop bilateral vestibular schwannomas by age 30 years. Affected individuals may also develop schwannomas of other cranial and peripheral nerves, meningiomas, ependymomas, and, very rarely, astrocytomas. Posterior subcapsular lens opacities that rarely progress to a visually significant cataract are the most common ocular findings and may be the first sign of NF2. Mononeuropathy that occurs in childhood is an increasingly recognized finding; it frequently presents as a persistent facial palsy, a squint (third nerve palsy), or hand/foot drop.

Diagnosis/testing. Diagnosis of NF2 is based on clinical criteria. NF2 is the only gene in which mutation is known to cause neurofibromatosis 2. Molecular genetic testing of NF2 that includes a combination of sequence analysis or mutation scanning and duplication/deletion testing detects a mutation in most affected individuals who have a positive family history and are not the first individual in the family known to have the disorder.

Management. Treatment of manifestations: Treatment of vestibular schwannoma is primarily surgical; stereotactic radiosurgery, most commonly with the gamma knife, may be an alternative to surgery. Individuals with vestibular tumors need to be aware of insidious problems with balance and underwater disorientation, which can result in drowning. Treatment for hearing loss includes referral to an audiologist, lip-reading and sign language instruction, and possibly hearing aids and/or cochlear or brain stem implants.

Surveillance: For affected or at-risk individuals: annual MRI beginning at approximately age ten to 12 years and continuing until at least the fourth decade of life; hearing evaluation, including BAER testing.

Agents/circumstances to avoid: Radiation therapy of NF2-associated tumors, especially in childhood, may induce, accelerate, or transform tumors.

Evaluation of relatives at risk: Early identification of relatives who have inherited the family-specific NF2 mutation allows for appropriate surveillance, resulting in earlier detection and treatment of disease manifestations.

Genetic counseling. NF2 is inherited in an autosomal dominant manner. Approximately 50% of individuals with NF2 have an affected parent, and 50% have NF2 as the result of a de novo mutation. However, 25% to 30% of simplex cases (i.e., single occurrence in a family) are mosaic for an NF2 mutation. If the proband has other affected family members, each child of the proband has a 50% chance of inheriting the mutation. Prenatal testing for pregnancies at increased risk is possible if the family-specific disease-causing mutation is known or linkage has been established in the family.

Diagnosis

Clinical Diagnosis

Modifications 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 schwannomas
  • A first-degree relative with NF2 AND
    • Unilateral vestibular schwannoma OR
    • Any 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 AND
    • Unilateral vestibular schwannoma OR
    • Any two of: schwannoma, glioma, neurofibroma, cataract *

* Any two of = two individual tumors or cataract

Testing

Chromosome 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 Testing

Gene. NF2 is the only gene in which mutations are known to cause neurofibromatosis 2.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Neurofibromatosis 2

Gene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1, 2
NF2Sequence analysis / mutation scanning 3Sequence variants 4See footnotes 5 and 6
Deletion / duplication testing 7Partial- and whole-gene deletions 8See footnote 9
Linkage analysis 10NANA

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. 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 results

Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).

Testing Strategy

To confirm/establish the diagnosis in a proband. One of two sample types is used:

Molecular 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.

Clinical Description

Natural History

The 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 NF2

Symptom% of Affected Individuals
Unilateral 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 polyneuropathy

Vestibular 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 Correlations

Intrafamilial 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)
Figure 1

Figure

Figure 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].

Penetrance

Penetrance is close to 100%. Virtually all individuals who have a pathogenic germline mutation develop the disease in an average lifetime.

Age at onset can vary with mutation type; see Genotype-Phenotype Correlations.

Anticipation

Although some reports suggested anticipation in NF2, these were likely to be instances of milder disease associated with mosaicism for an NF2 mutation in the first generation and more severe disease associated with an NF2 germline (i.e., constitutional) mutation in the second and subsequent generations.

Nomenclature

The term "neurofibromatosis" is a misnomer because the primary tumor types in NF2 are schwannoma and meningioma. Vestibular schwannoma (previously termed acoustic neuroma) was initially considered part of von Recklinghausen neurofibromatosis type 1, leading to multiple instances in which individuals with NF2 were included in series of individuals with NF1.

Since 1987, the great majority of reports have correctly distinguished between NF1 and NF2, with NF2 described as "bilateral acoustic" or "central" neurofibromatosis.

Prevalence

Initially the incidence of NF2 was reported as 1:33,000-40,000 individuals and the disease prevalence somewhat lower at 1:200,000.

Based on a 2010 study, the original 1:33,000 estimate of incidence has been confirmed, whereas the estimated prevalence (1:60,000) is higher than originally thought [Evans et al 2010].

Note: An update in 2005 erroneously suggested that the incidence may be as high as 1:25,000 [Evans et al 2005b].

NF2 has no ethnic or racial predilections.

Differential Diagnosis

Neurofibromatosis 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 Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with neurofibromatosis 2 (NF2), the following evaluations are recommended:

  • Head MRI
  • Hearing evaluation, including BAER
  • Ophthalmologic evaluation
  • Cutaneous examination
  • Genetics consultation

Note: 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].

Treatment of Manifestations

Vestibular 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 Complications

Treatment 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].

Surveillance

For 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 Avoid

Radiotherapy should be avoided in children with NF2 [Evans et al 2006].

Evaluation of Relatives at Risk

Consideration 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 Management

Although 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 Investigation

The 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Neurofibromatosis 2 (NF2) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Approximately 50% of individuals with NF2 have an affected parent, and 50% have NF2 as the result of a de novo mutation. However, 25% to 33% of individuals who are simplex cases (i.e., individuals with no family history of NF2) are mosaic for an NF2 mutation [Kluwe et al 2003, Moyhuddin et al 2003, Evans et al 2007b].
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include a clinical history and, if any suspicion of NF2 exists, an MRI scan. The possibility that a parent has NF2 can be excluded if his/her offspring is shown to be mosaic, but absence of a mutation detected in the child does not eliminate the possibility of mosaicism in the parent. Because the age of onset of symptoms is consistent within families, it is usually not necessary to offer surveillance to asymptomatic parents.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the parents.
  • If a parent of the proband is affected, the risk to the sibs is 50%.
  • If neither parent of an individual with NF2 is symptomatic, the risk to the sibs of the affected individual is low because the age of onset of symptoms is relatively uniform within families. However, a single case of germline mosaicism in a clinically normal parent has been reported. In addition, somatic mosaicism (which may include germline mosaicism) is found in 25%-33% of individuals with NF2 who are simplex cases.

Offspring of a proband. Each child of an individual with NF2 has up to a 50% chance of inheriting the mutation:

  • If the proband has other affected family members, each child of the proband has a 50% chance of inheriting the mutation.
  • If the proband is the only affected individual in the family, two possibilities exist:
    • The proband may have somatic mosaicism for the disease-causing mutation. Offspring of an individual who is mosaic may have less than a 50% risk of inheriting the disease-causing mutation.
    • The proband may have a de novo germline mutation (i.e., present in the egg or sperm at the time of conception). Each offspring of an individual with a de novo germline mutation has a 50% chance of inheriting the mutation.
  • Persons with somatic mosaicism and bilateral vestibular tumors have less than a 50% chance of having an affected child [Evans et al 1998b]. If the mutation is detected in DNA from multiple tumors, but not in DNA from leukocytes, the risk to offspring is probably less than 5%.

Other family members of a proband. The risk to other family members depends on the genetic status of the proband's parents. If a parent is affected, his or her family members may be at risk, depending on the family structure.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

Considerations in families with an apparent de novo mutation. When the parents of a proband with an autosomal dominant condition are unaffected, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Testing of at-risk asymptomatic family members. Consideration of molecular genetic testing of at-risk family members during childhood is appropriate for surveillance (see Surveillance). Molecular genetic testing used in early identification of at-risk family members may be either mutation analysis or linkage analysis. Mutation analysis can be used for testing of at-risk relatives only if a disease-causing mutation has been identified in an affected family member. Linkage analysis is the preferred method of testing in families with more than one affected family member if the family-specific mutation has not been identified.

Because early detection of at-risk individuals affects medical management, testing of at-risk asymptomatic individuals younger than age 18 years is beneficial. Parents often want to know the genetic status of their children prior to initiating screening in order to avoid unnecessary procedures for a child who has not inherited the altered gene. Special consideration should be given to education of the children and their parents prior to genetic testing. A plan should be established for the manner in which results are to be given to the parents and children.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutation has been identified or linkage has been established in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Children's Tumor Foundation: Ending Neurofibromatosis Through Research
    95 Pine Street
    16th Floor
    New York NY 10005
    Phone: 800-323-7938 (toll-free); 212-344-6633
    Fax: 212-747-0004
    Email: info@ctf.org
  • National Library of Medicine Genetics Home Reference
  • NCBI Genes and Disease
  • Neurofibromatosis Network
    213 South Wheaton Avenue
    Wheaton IL 60187
    Phone: 800-942-6825
    Fax: 630-510-8508
    Email: admin@nfnetwork.org
  • NF2 Review
    c/o the House of Ear Institute
    2100 West Third Street
    Second Floor
    Los Angeles CA 90057
    Phone: 213-483-4431
    Fax: 213-413-0950
    Email: mrspetitohead@hotmail.com
  • NF2 Sharing Network
    10074 Cabachon Court
    Ellicott City MD 21042
    Phone: 410-461-5213
  • Acoustic Neuroma Association (ANA)
    600 Peachtree Parkway
    Suite 108
    Cumming GA 30041-6899
    Phone: 877-200-8211 (toll free); 770-205-8211
    Fax: 877-202-0239 (toll free); 770-205-0239
    Email: info@anausa.org
  • Children's Tumor Foundation: Ending Neurofibromatosis Through Research
    95 Pine Street
    16th Floor
    New York NY 10005
    Phone: 800-323-7938 (toll-free); 212-344-6633
    Fax: 212-747-0004
    Email: info@ctf.org
  • Medline Plus

Molecular Genetics

Information 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 Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
NF222q12​.2MerlinNF2 homepage - Mendelian genesNF2

Data 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)

101000NEUROFIBROMATOSIS, TYPE II; NF2
607379NEUROFIBROMIN 2; NF2

Normal 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.

References

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Suggested Reading

  1. Hanemann CO, Evans DG. News on the genetics, epidemiology, medical care and translational research of Schwannomas. J Neurol. 2006;253:1533–41. [PubMed: 17219030]
  2. Houshmandi SS, Gutmann DH. All in the family: using inherited cancer syndromes to understand de-regulated cell signaling in brain tumors. J Cell Biochem. 2007;102:811–9. [PubMed: 17721931]
  3. MacCollin M, Gusella J. Neurofibromatosis 2. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill; Chap 40. Available online. Accessed 9-21-12.

Chapter Notes

Author History

D Gareth Evans, MD, FRCP (2004-present)
Mia MacCollin, MD; Harvard Medical School (1998-2004)

Revision History

  • 18 August 2011 (me) Comprehensive update posted live
  • 19 May 2009 (me) Comprehensive update posted live
  • 6 June 2006 (me) Comprehensive update posted to live Web site
  • 6 April 2004 (me) Comprehensive update posted to live Web site
  • 29 October 2001 (me) Comprehensive update posted to live Web site
  • 14 October 1998 (pb) Review posted to live Web site
  • 5 August 1998 (mm) Original submission
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