NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

Neurofibromatosis 2

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

Initial Posting: ; Last Update: March 15, 2018.

Summary

Clinical 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. Because NF2 is considered an adult-onset disease, it may be underrecognized in children, in whom skin tumors and ocular findings (retinal hamartoma, thickened optic nerves, cortical wedge cataracts, third cranial nerve palsy) may be the first manifestations. Mononeuropathy that occurs in childhood is an increasingly recognized finding; it frequently presents as a persistent facial palsy or hand/foot drop.

Diagnosis/testing.

The diagnosis of NF2 is established in a proband with clinical findings that meet the consensus diagnostic criteria and/or by identification of a heterozygous pathogenic variant in NF2 on molecular genetic testing.

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; annual complete eye examination.

Agents/circumstances to avoid: Radiation therapy of NF2-associated tumors, especially in childhood, when malignancy risks are likely to be substantially larger.

Evaluation of relatives at risk: Early identification of relatives who have inherited the family-specific NF2 pathogenic variant 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 pathogenic variant. However, 25% to 30% of simplex cases (i.e., single occurrence in a family) are mosaic for an NF2 pathogenic variant. If the proband has other affected family members, each child of the proband has a 50% chance of inheriting the pathogenic variant. Once the NF2 pathogenic variant has been identified in the family, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

Diagnosis

Suggestive Findings

Neurofibromatosis type 2 (NF2) should be suspected in individuals with the following findings:

In children (two or more of these findings)

  • A schwannoma at any location including intradermal
  • Skin plaques present at birth or in early childhood (often plexiform schwannoma on histology)
  • A meningioma, particularly non-meningothelial (non-arachnoidal) cell in origin
  • A cortical wedge cataract
  • A retinal hamartoma
  • A mononeuropathy, particularly causing a facial nerve palsy, foot or wrist drop, or third nerve palsy

In adults

  • Bilateral vestibular schwannomas
  • Unilateral vestibular schwannoma accompanied by ANY TWO of the following: meningioma, schwannoma, glioma, neurofibroma, cataract in the form of subcapsular lenticular opacities or cortical wedge cataract
  • Multiple meningiomas accompanied by EITHER of the following:
    • Unilateral vestibular schwannoma
    • ANY TWO of the following: schwannoma, glioma, neurofibroma, cataract in the form of subcapsular lenticular opacities or cortical wedge cataract

For individuals of all ages with any of these clinical findings, having a first-degree relative with NF2 increases the likelihood of the disorder being present.

Establishing the Diagnosis

The diagnosis of NF2 is established in a proband with clinical findings that meet the consensus diagnostic criteria and/or by identification of a heterozygous pathogenic variant in NF2 on molecular genetic testing (see Table 1).

Clinical Findings

By the modified NIH consensus diagnostic criteria [Baser et al 2002], 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 the following: meningioma, schwannoma, glioma, neurofibroma, cataract in the form of posterior subcapsular lenticular opacities or cortical wedge cataract
  • Unilateral vestibular schwannoma AND ANY TWO of the following: meningioma, schwannoma, glioma, neurofibroma, cataract in the form of posterior subcapsular lenticular opacities or cortical wedge cataract
  • Multiple meningiomas AND
    • Unilateral vestibular schwannoma OR
    • ANY TWO of the following: schwannoma, glioma, neurofibroma, cataract in the form of posterior subcapsular lenticular opacities or cortical wedge cataract

Note: Those with suspicious findings should have molecular genetic testing.

Molecular Genetic Testing

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (chromosomal microarray analysis, exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of NF2 is broad, individuals with the distinctive findings described in Suggestive Findings and adults who meet the consensus diagnostic criteria described in Establishing the Diagnosis are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of NF2 has not been considered (especially in children) or those who do not fulfill the consensus diagnostic criteria are more likely to be diagnosed using genomic testing (see Option 2).

Option 1

When the phenotypic and laboratory findings suggest the diagnosis of NF2, molecular genetic testing approaches can include single-gene testing, chromosomal microarray analysis (CMA), or use of a multigene panel.

  • Single-gene testing. Sequence analysis of NF2 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected.
    Perform sequence analysis first. If no pathogenic variant is found perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
  • Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including NF2) that cannot be detected by sequence analysis.
  • A multigene panel that includes NF2 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2

When the diagnosis of NF2 is not considered because an individual has atypical phenotypic features (features in a child may not immediately suggest NF2) or does not meet the clinical consensus diagnostic criteria as an adult, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is the most commonly used genomic testing method; genome sequencing is also possible.

Exome array (when clinically available) may be considered if exome sequencing is non-diagnostic, to evaluate for a large deletion/duplication type of variant in NF2.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Neurofibromatosis Type 2 (NF2)

Gene 1Test MethodProportion of Probands with a Pathogenic Variant 2 Detectable by This Method
NF2Sequence analysis 375% 4
Gene-targeted deletion/duplication analysis 5, 6 or CMA 720% 8
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.
5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes may not be detected by these methods.

7.

Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including NF2) that cannot be detected by sequence analysis. The ability to determine the size of the deletion/duplication depends on the type of microarray used and the density of probes in the 22q12.2 region. CMA designs in current clinical use target the 22q12.2 region.

8.

Testing for somatic mosaicism. Somatic mosaicism is frequent in NF2. As many as 25% to 33% of individuals with a de novo pathogenic NF2 variant have somatic mosaicism for the variant [Kluwe et al 2003, Mohyuddin et al 2003, Evans et al 2007b, Evans et al 2013].

Such individuals 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].

When tumor DNA is tested, pathogenic variants 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.
  • Once both variant NF2 alleles are identified in the tumor, leukocyte DNA can be tested to determine which of the pathogenic variants is constitutional and which is somatic (i.e., present in the tumor only).

Clinical Characteristics

Clinical Description

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 anatomic 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, Hexter et al 2015].

Because NF2 is considered an adult-onset disease, it may be underrecognized in children, in whom skin tumors and ocular findings may be the first manifestations [Evans et al 1999, Ruggieri et al 2005, Ruggieri et al 2016].

The presenting symptoms of 120 individuals with NF2 studied by Evans et al [1992] in Great Britain are listed in Table 2. Although individuals in this study were mostly adults, some children were included. The study did not include as a first symptom skin tumors or cataracts, either of which may be the earliest finding in children.

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

Presenting Features of NF2 in Childhood

Skin findings include intradermal plaque-like tumors that often have excess hair and skin pigmentation.

Ocular findings include [Evans et al 2005a, Feucht et al 2008, Ruggieri et al 2016]:

  • Retinal hamartoma
  • Thickened optic nerves
  • Cortical wedge cataracts that may be congenital and associated with amblyopia
  • Third cranial nerve palsy

Other

Details of Typical Clinical Findings in NF2

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.

Children and young adults with an apparently isolated vestibular or other cranial nerve schwannoma should be considered at risk for de novo and often mosaic NF2 [Pathmanaban et al 2017].

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, although 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.

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.

Retinal hamartoma and epiretinal membrane are seen in up to one third of individuals. Rarely, other ocular manifestations may occur: persistent hyperplastic primary vitreous has been reported in a father and son [Nguyen et al 2005]. In adulthood, particular problems with the cornea can occur especially after surgery, resulting 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 (3rd 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], but may be coincidental as it has not been reported again.

Somatic mosaicism for pathogenic variants in NF2. Mosaicism has been suspected in individuals with unilateral vestibular schwannoma and multiple other, often ipsilateral, tumors [Mohyuddin et al 2003, Evans et al 2008]. This has now been confirmed for most cases in which DNA from multiple tumors has been analyzed [Mohyuddin 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 without a diagnosis 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]; even if quite large, these deletions are not associated with intellectual disability.

The type of NF2 germline pathogenic variant 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 variants have been associated with severe disease regardless of their position within the gene [Baser et al 2004].
  • Splice site variants 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 variants are usually associated with a mild phenotype, often causing the mildest form of NF2 [Evans et al 1998a, Baser et al 2002].
  • Truncating variants are associated with earlier onset and greater number of NF2-associated intracranial meningiomas, spinal tumors, and peripheral nerve tumors. In general, truncating variants (frameshift and nonsense) are associated with greater disease-related mortality than missense and splice site variants or deletions [Baser et al 2002, Baser et al 2005]. Truncating variants are also associated with increased prevalence of spinal tumors [Patronas et al 2001, Dow et al 2005]. Although most of these pathogenic variants would be predicted to result in nonsense-mediated decay, and thus no protein product, the apparent dominant-negative effect of these variants requires further investigation.
  • Pathogenic variants in the 3' half of NF2 (especially those in exons 14-16) are associated with lower risk of meningioma than pathogenic variants in the 5' half of the gene [Smith et al 2011] (see Figure 1).
Figure 1. . The position of pathogenic variants in NF2 affects the likelihood of developing a meningioma.

Figure 1.

The position of pathogenic variants 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, and 14-15.

Somatic mosaicism (even when detected in lymphocyte DNA) for typical pathogenic truncating variants that would normally cause severe NF2 may result in a milder phenotype [Evans et al 1998a, Evans et al 2007b, Evans et al 2013].

Penetrance

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

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

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

The estimated prevalence of NF2 is 1:60,000 [Evans et al 2010], with a birth incidence of 1:33,000.

NF2 has no ethnic or racial predilections.

Differential Diagnosis

Table 3.

Disorders to Consider in the Differential Diagnosis of NF2

DisorderGene(s)MOIClinical Features of This Disorder
Overlapping w/NF2Distinguishing from NF2
Neurofibromatosis type 1NF1ADDumbbell configuration of spinal tumors
  • Intellectual/learning disability
  • Lisch nodules
  • Café au lait macules
Schwannomatosis 1
(OMIM 162091)
SMARCB1ADMultiple schwannomasNo vestibular schwannomas
Schwannomatosis 2
(OMIM 615670)
LZTR1 1ADUnilateral vestibular schwanomma & other schwannomasNo intradermal schwannoma plaques, cataract, or ependymoma
Unilateral vestibular schwannoma 2N/AN/AVestibular schwannoma
  • Schwannoma on one side only
  • No underlying predisposition to vestibular schwannomas
Meningioma 3Typically N/A; rarely SMARCB1 4Rarely ADMultiple meningiomasNo vestibular schwannomas

N/A = not applicable

1.

Smith et al [2017] found that for individuals with a unilateral vestibular schwannoma and additional non-intradermal schwannomas, a constitutional LZTR1 pathogenic variant is a significant possibility.

2.

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, while individuals older than age 30 years who have a unilateral vestibular schwannoma are at very low risk of developing NF2 [Evans et al 2007a].

3.

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 2005b].

4.

A pathogenic variant in SMARCB1 was found to be responsible for schwannomatosis in several members of one family [Christiaans et al 2011]; however, the great majority of individuals with multiple meningiomas do not harbor a SMARCB1 pathogenic variant [Hadfield et al 2010].

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with neurofibromatosis 2 (NF2), the following are recommended if they have not already been completed:

  • Head MRI
  • Hearing evaluation, including brain stem auditory evoked response (BAER)
  • Ophthalmologic evaluation
  • Cutaneous examination
  • Consultation with a clinical geneticist and/or genetic counselor

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 an affected individual 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, Chung et al 2018].

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, Halliday et al 2018].

More recently, treatment with the VEGF antibody bevacizumab has shown promise in the treatment of rapidly growing vestibular schwannomas, with some individuals regaining hearing [Plotkin et al 2009, Morris et al 2016, Halliday et al 2018]. Response to treatment occurs in about 60%-70% of individuals; treatment can be sustained over years but with some concerns over renal toxicity [Slusarz et al 2014, Morris et al 2016, Halliday et al 2018].

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. However, bevacizumab has shown some clinical benefit in some individuals [Farschtschi et al 2016, Morris et al 2017].

Use of radiation therapy for 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. Implants can also be used in stable tumors where hearing has been lost but there is evidence of cochlear nerve function [North et al 2016]

Ocular involvement. Early recognition and management of visual impairment from other manifestations of NF2 are extremely important. Most NF2-associated cataracts do not require removal, but particular attention should be paid to cataracts in infancy that may affect vision by causing amblyopia. These may require removal and patching of the unaffected eye.

Cutaneous involvement. While removal of cutaneous schwannomas is not required, it may be indicated if the shawannomas are causing disfigurement or pain. Removal may also help diagnostically.

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 pathogenic variant 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.
  • Complete eye examinations should be part of the care of all individuals with NF2 and ideally should be conducted annually.

Agents/Circumstances to Avoid

Radiotherapy for NF2 should be avoided in childhood, when malignancy risks are likely to be substantially larger [Evans et al 2006].

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic older and younger sibs of a proband and other at-risk relatives in order to identify as early as possible those who would benefit from prompt initiation of appropriate screening (see Surveillance), thus resulting in earlier detection of disease manifestations and improved final outcomes [Evans et al 2005a].

Note: Tumor testing can identify both mutational hits in the majority of cases of isolated NF2 and allow exclusion testing in sibs and other at-risk relatives.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Although there is no convincing evidence 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

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for 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 diagnosed with NF2 have an affected parent. While there is a strong genotype-phenotype correlation, significant variability within families and even between identical twins can be seen.
  • Approximately 50% of individuals diagnosed with NF2 have the disorder as the result of a de novo NF2 pathogenic variant.
    25% to 33% of individuals who are simplex cases (i.e., individuals with no family history of NF2) are mosaic for an NF2 pathogenic variant [Kluwe et al 2003, Mohyuddin et al 2003, Evans et al 2007b, Evans et al 2013].
  • Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant.
  • If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent. The incidence of pure germline mosaicism in NF2 is extremely low as thus far all parents having more than one affected child have had a detectable pathogenic variant in NF2 in blood DNA and have been clinically affected [Evans et al 2013]. There is one historical case of two affected children born to apparently unaffected parents before NF2 testing was available [Parry et al 1996].
  • The family history of some individuals diagnosed with NF2 may appear to be negative because of failure to recognize the disorder in family members or early death of the parent before the onset of symptoms. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband.
  • The possibility that a parent has NF2 can be excluded if his/her offspring is shown to be mosaic, but absence of a pathogenic variant 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.
  • If the parent is the individual in whom the pathogenic variant first occurred, s/he may have somatic mosaicism for the variant and may be mildly/minimally affected.

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 the parents have been tested for the NF2 pathogenic variant identified in the proband and:
    • One parent of the proband has the NF2 pathogenic variant, the risk to the sibs of inheriting the variant is 50%. The age of onset of symptoms within a family is relatively consistent.
    • The NF2 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism. A single case of germline mosaicism in a clinically normal parent has been reported [Parry et al 1994].
  • If the parents have not been tested for the NF2 pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. The sibs of a proband with clinically unaffected parents are still at increased risk for NF2 because of the possibility of parental germline mosaicism.

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

Other family members. 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.

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.

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).

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 pathogenic variant. 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.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, 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.

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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the NF2 pathogenic variant has been identified in the family, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

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
    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
  • My46 Trait Profile
  • 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

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
NF222q12​.2MerlinNF2 databaseNF2NF2

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) 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

Gene structure. The longest and predominant NF2 transcript NM_000268.3 comprises 16 exons. NF2 is widely expressed, producing mRNA transcripts in three different lengths of approximately 7, 4.4, and 2.6 kb. Two predominant and a number of minor transcript variants are produced by alternative splicing that encodes different protein isoforms. See Table A, Gene for a detailed summary of gene, transcript, and protein information.

Pathogenic variants. At least 400 NF2 pathogenic variants have been described, with missense, nonsense, and splicing variants and small deletions being the most common (Table A, HGMD and Locus-Specific Databases).

A wide variety of pathogenic variants have been identified in all NF2 exons, except for the alternatively spliced exons.

  • 90% of single-nucleotide variants 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 pathogenic nonsense variants are an especially frequent occurrence.
  • Fewer than 10% of detected pathogenic variants are in-frame deletions and missense variants, 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 α-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 pathogenic variants are known (hereditary elliptocytosis).

Two major alternative forms of the NF2 protein product exist, isoforms 1 and 2. Additional alternative splices predicting other minor species have also been described. See Table A, Gene for a detailed summary of gene, transcript, and protein isoforms.

Although the complete function of the NF2 protein remains elusive, 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]. More recently a critical role in the Hippo pathway mediated through suppression of Yap and Taz has been shown [Reginensi et al 2016].

Abnormal gene product. Abnormal NF2 protein is caused by either a somatic or a constitutional pathogenic variant.

Attempts to identify truncated protein product have been unsuccessful in the main, although the non-truncated product from pathogenic missense variants may have partial function. It is thought that nonsense-mediated decay may account for the lack of identifiable product from most variant types; however, this does not explain why phenotypes are more severe for this type of variant than for whole-gene deletions.

Cancer and benign tumors. Sporadic tumors (including schwannomas at any site, similarly for meningiomas) occurring as single tumors in the absence of any other findings of NF2 frequently harbor somatic variants in NF2 that are not present in the germline. In these circumstances predisposition to these tumors is not heritable [Mohyuddin et al 2002, Pathmanaban et al 2017].

References

Literature Cited

  • Aghi M, Kluwe L, Webster MT, Jacoby LB, Barker FG 2nd, Ojemann RG, Mautner VF, MacCollin M. Unilateral vestibular schwannoma with other neurofibromatosis type 2-related tumors: clinical and molecular study of a unique phenotype. J Neurosurg. 2006;104:201–7. [PubMed: 16509493]
  • Balasubramaniam A, Shannon P, Hodaie M, Laperriere N, Michaels H, Guha A. Glioblastoma multiforme after stereotactic radiotherapy for acoustic neuroma: case report and review of the literature. Neuro Oncol. 2007;9:447–53. [PMC free article: PMC1994102] [PubMed: 17704364]
  • Baser ME, Evans DG, Jackler RK, Sujansky E, Rubinstein A. Malignant peripheral nerve sheath tumours, radiotherapy and neurofibromatosis 2. Br J Cancer. 2000;82:998. [PMC free article: PMC2374414] [PubMed: 10732777]
  • Baser ME, Friedman JM, Aeschliman D, Joe H, Wallace AJ, Ramsden RT, Evans DG. Predictors of the risk of mortality in neurofibromatosis 2. Am J Hum Genet. 2002;71:715–23. [PMC free article: PMC378530] [PubMed: 12235555]
  • Baser ME, Friedman JM, Evans DG. Increasing the specificity of diagnostic criteria for schwannomatosis. Neurology. 2006;66:730–2. [PubMed: 16534111]
  • Baser ME, Kuramoto L, Joe H, Friedman JM, Wallace AJ, Gillespie JE, Ramsden RT, Evans DG. Genotype-phenotype correlations for nervous system tumors in neurofibromatosis 2: a population-based study. Am J Hum Genet. 2004;75:231–9. [PMC free article: PMC1216057] [PubMed: 15190457]
  • Baser ME, Kuramoto L, Woods R, Joe H, Friedman JM, Wallace AJ, Ramsden RT, Olschwang S, Bijlsma E, Kalamarides M, Papi L, Kato R, Carroll J, Lazaro C, Joncourt F, Parry DM, Rouleau GA, Evans DG. The location of constitutional neurofibromatosis 2 (NF2) splice site mutations is associated with the severity of NF2. J Med Genet. 2005;42:540–6. [PMC free article: PMC1736092] [PubMed: 15994874]
  • Christiaans I, Kenter SB, Brink HC, van Os TA, Baas F, van den Munckhof P, Kidd AM, Hulsebos TJ. Germline SMARCB1 mutation and somatic NF2 mutations in familial multiple meningiomas. J Med Genet. 2011;48:93–7. [PubMed: 20930055]
  • Chung LK, Nguyen TP, Sheppard JP, Lagman C, Tenn S, Lee P, Kaprealian T, Chin R, Gopen Q, Yang I. A systematic review of radiosurgery versus surgery for neurofibromatosis type 2 vestibular schwannomas. World Neurosurg. 2018;109:47–58. [PubMed: 28882713]
  • Cordeiro NJ, Gardner KR, Huson SM, Stewart H, Elston JS, Howard EL, Tullus KO, Pike MG. Renal vascular disease in neurofibromatosis type 2: association or coincidence? Dev Med Child Neurol. 2006;48:58–9. [PubMed: 16359595]
  • Dow G, Biggs N, Evans G, Gillespie J, Ramsden R, King A. Spinal tumors in neurofibromatosis type 2. Is emerging knowledge of genotype predictive of natural history? J Neurosurg Spine. 2005;2:574–9. [PubMed: 15945431]
  • Evans DG, Baser ME, O'Reilly B, Rowe J, Gleeson M, Saeed S, King A, Huson SM, Kerr R, Thomas N, Irving R, MacFarlane R, Ferner R, McLeod R, Moffat D, Ramsden R. Management of the patient and family with neurofibromatosis 2: a consensus conference statement. Br J Neurosurg. 2005a;19:5–12. [PubMed: 16147576]
  • Evans DG, Birch JM, Ramsden RT. Paediatric presentation of type 2 neurofibromatosis. Arch Dis Child. 1999;81:496–9. [PMC free article: PMC1718148] [PubMed: 10569966]
  • Evans DG, Birch JM, Ramsden RT, Sharif S, Baser ME. Malignant transformation and new primary tumours after therapeutic radiation for benign disease: substantial risks in certain tumour prone syndromes. J Med Genet. 2006;43:289–94. [PMC free article: PMC2563223] [PubMed: 16155191]
  • Evans DG, Bowers N, Huson SM, Wallace A. Mutation type and position varies between mosaic and inherited NF2 and correlates with disease severity. Clin Genet. 2013;83:594–5. [PubMed: 22989157]
  • Evans DG, Howard E, Giblin C, Clancy T, Spencer H, Huson SM, Lalloo F. Birth incidence and prevalence of tumour prone syndromes: estimates from a UK genetic family register service. Am J Med Genet. 2010;152A:327–32. [PubMed: 20082463]
  • Evans DG, Huson SM, Donnai D, Neary W, Blair V, Newton V, Harris R. A clinical study of type 2 neurofibromatosis. Q J Med. 1992;84:603–18. [PubMed: 1484939]
  • Evans DG, Kalamarides M, Hunter-Schaedle K, Blakeley J, Allen J, Babovic-Vuskanovic D, Belzberg A, Bollag G, Chen R, DiTomaso E, Golfinos J, Harris G, Jacob A, Kalpana G, Karajannis M, Korf B, Kurzrock R, Law M, McClatchey A, Packer R, Roehm P, Rubenstein A, Slattery W 3rd, Tonsgard JH, Welling DB, Widemann B, Yohay K, Giovannini M. Consensus recommendations to accelerate clinical trials for neurofibromatosis type 2. Clin Cancer Res. 2009;15:5032–9. [PMC free article: PMC4513640] [PubMed: 19671848]
  • Evans DG, Ramsden RT, Gokhale C, Bowers N, Huson SM, Wallace A. Should NF2 mutation screening be undertaken in patients with an apparently isolated vestibular schwannoma? Clin Genet. 2007a;71:354–8. [PubMed: 17470137]
  • Evans DG, Ramsden RT, Shenton A, Gokhale C, Bowers NL, Huson SM, Pichert G, Wallace A. Mosaicism in neurofibromatosis type 2: an update of risk based on uni/bilaterality of vestibular schwannoma at presentation and sensitive mutation analysis including multiple ligation-dependent probe amplification. J Med Genet. 2007b;44:424–8. [PMC free article: PMC2598002] [PubMed: 17307835]
  • Evans DG, Ramsden RT, Shenton A, Gokhale C, Bowers N, Huson SM, Wallace AJ. What are the implications in individuals with unilateral vestibular schwannoma and other neurogenic tumors? J Neurosurg. 2008;108:92–6. [PubMed: 18173316]
  • Evans DG, Sainio M, Baser ME. Neurofibromatosis type 2. J Med Genet. 2000;37:897–904. [PMC free article: PMC1734496] [PubMed: 11106352]
  • Evans DG, Trueman L, Wallace A, Collins S, Strachan T. Genotype/phenotype correlations in type 2 neurofibromatosis (NF2): evidence for more severe disease associated with truncating mutations. J Med Genet. 1998a;35:450–5. [PMC free article: PMC1051337] [PubMed: 9643284]
  • Evans DG, Wallace AJ, Wu CL, Trueman L, Ramsden RT, Strachan T. Somatic mosaicism: a common cause of classic disease in tumor-prone syndromes? Lessons from type 2 neurofibromatosis. Am J Hum Genet. 1998b;63:727–36. [PMC free article: PMC1377392] [PubMed: 9718334]
  • Evans DG, Watson C, King A, Wallace AJ, Baser ME. Multiple meningiomas: differential involvement of the NF2 gene in children and adults. J Med Genet. 2005b;42:45–8. [PMC free article: PMC1735900] [PubMed: 15635074]
  • Farschtschi S, Merker VL, Wolf D, Schuhmann M, Blakeley J, Plotkin SR, Hagel C, Mautner VF. Bevacizumab treatment for symptomatic spinal ependymomas in neurofibromatosis type 2. Acta Neurol Scand. 2016;133:475–80. [PubMed: 26369495]
  • Feucht M, Griffiths B, Niemüller I, Haase W, Richard G, Mautner VF. Neurofibromatosis 2 leads to higher incidence of strabismological and neuro-ophthalmological disorders. Acta Ophthalmol. 2008;86:882–6. [PubMed: 18976311]
  • Goutagny S, Kalamarides M. Meningiomas and neurofibromatosis. J Neurooncol. 2010;99:341–7. [PubMed: 20714782]
  • Hadfield KD, Smith MJ, Trump D, Newman WG, Evans DG. SMARCB1 mutations are not a common cause of multiple meningiomas. J Med Genet. 2010;47:567–8. [PubMed: 20472658]
  • Hagel C, Lindenau M, Lamszus K, Kluwe L, Stavrou D, Mautner VF. Polyneuropathy in neurofibromatosis 2: clinical findings, molecular genetics and neuropathological alterations in sural nerve biopsy specimens. Acta Neuropathol (Berl). 2002;104:179–87. [PubMed: 12111361]
  • Halliday D, Emmanouil B, Pretorius P, MacKeith S, Painter S, Tomkins H, Evans DG, Parry A. Genetic Severity Score predicts clinical phenotype in NF2. J Med Genet. 2017;54:657–64. [PMC free article: PMC5740551] [PubMed: 28848060]
  • Halliday J, Rutherford SA, McCabe MG, Evans DG. An update on the diagnosis and treatment of vestibular schwannoma. Expert Rev Neurother. 2018;18:29–39. [PubMed: 29088993]
  • Hexter A, Jones A, Joe H, Heap L, Smith MJ, Wallace AJ, Halliday D, Parry A, Taylor A, Raymond L, Shaw A, Afridi S, Obholzer R, Axon P, King AT. English Specialist NF2 Research Group, Friedman JM, Evans DG. Clinical and molecular predictors of mortality in neurofibromatosis 2: a UK national analysis of 1192 patients. J Med Genet. 2015;52:699–705. [PubMed: 26275417]
  • Kluwe L, MacCollin M, Tatagiba M, Thomas S, Hazim W, Haase W, Mautner VF. Phenotypic variability associated with 14 splice-site mutations in the NF2 gene. Am J Med Genet. 1998;77:228–33. [PubMed: 9605590]
  • Kluwe L, Mautner V, Heinrich B, Dezube R, Jacoby LB, Friedrich RE, MacCollin M. Molecular study of frequency of mosaicism in neurofibromatosis 2 patients with bilateral vestibular schwannomas. J Med Genet. 2003;40:109–14. [PMC free article: PMC1735360] [PubMed: 12566519]
  • Kros J, de Greve K, van Tilborg A, Hop W, Pieterman H, Avezaat C, Lekanne Dit Deprez R, Zwarthoff E. NF2 status of meningiomas is associated with tumour localization and histology. J Pathol. 2001;194:367–72. [PubMed: 11439370]
  • Masuda A, Fisher LM, Oppenheimer ML, Iqbal Z, Slattery WH. Hearing changes after diagnosis in neurofibromatosis type 2. Otol Neurotol. 2004;25:150–4. [PubMed: 15021775]
  • McClatchey AI, Giovannini M. Membrane organization and tumorigenesis--the NF2 tumor suppressor, Merlin. Genes Dev. 2005;19:2265–77. [PubMed: 16204178]
  • Morris KA, Afridi SK, Evans DG, Hensiek AE, McCabe MG, Kellett M, Halliday D, Pretorius PM, Parry A. UK NF2 Research Group. The response of spinal cord ependymomas to bevacizumab in patients with neurofibromatosis Type 2. J Neurosurg Spine. 2017;26:474–82. [PubMed: 27982762]
  • Morris KA, Golding JF, Axon PR, Afridi S, Blesing C, Ferner RE, Halliday D, Jena R, Pretorius PM, Evans DG, McCabe MG, Parry A, et al. Bevacizumab in neurofibromatosis type 2 (NF2) related vestibular schwannomas: a nationally coordinated approach to delivery and prospective evaluation. Neurooncol Pract. 2016;3:281–9. [PMC free article: PMC5909937] [PubMed: 29692918]
  • Mohyuddin A, Baser ME, Watson C, Purcell S, Ramsden RT, Heiberg A, Wallace AJ, Evans DG. Somatic mosaicism in neurofibromatosis 2: prevalence and risk of disease transmission to offspring. J Med Genet. 2003;40:459–63. [PMC free article: PMC1735486] [PubMed: 12807969]
  • Mohyuddin A, Neary WJ, Wallace A, Wu CL, Purcell S, Reid H, Ramsden RT, Read A, Black G, Evans DG. Molecular genetic analysis of the NF2 gene in young patients with unilateral vestibular schwannomas. J Med Genet. 2002;39:315–22. [PMC free article: PMC1735110] [PubMed: 12011146]
  • Nguyen DQ, Chatterjee S, Bates R. Persistent hyperplastic primary vitreous in association with neurofibromatosis 2. J Pediatr Ophthalmol Strabismus. 2005;42:247–9. [PubMed: 16121558]
  • North HJ, Mawman D, O'Driscoll M, Freeman SR, Rutherford SA, King AT, Hammerbeck-Ward C, Evans DG, Lloyd SK. Outcomes of cochlear implantation in patients with neurofibromatosis type 2. Cochlear Implants Int. 2016;17:172–7. [PubMed: 27691934]
  • Pathmanaban ON, Sadler KV, Kamaly-Asl ID, King AT, Rutherford SA, Hammerbeck-Ward C, McCabe MG, Kilday JP, Beetz C, Poplawski NK, Evans DG, Smith MJ. Association of genetic predisposition with solitary schwannoma or meningioma in children and young adults. JAMA Neurol. 2017;74:1123–9. [PMC free article: PMC5710179] [PubMed: 28759666]
  • Patronas NJ, Courcoutsakis N, Bromley CM, Katzman GL, MacCollin M, Parry DM. Intramedullary and spinal canal tumors in patients with neurofibromatosis 2: MR imaging findings and correlation with genotype. Radiology. 2001;218:434–42. [PubMed: 11161159]
  • Parry DM, Eldridge R, Kaiser-Kupfer MI, Bouzas EA, Pikus A, Patronas N. Neurofibromatosis 2 (NF2): clinical characteristics of 63 affected individuals and clinical evidence for heterogeneity. Am J Med Genet. 1994;52:450–61. [PubMed: 7747758]
  • Parry DM, MacCollin MM, Kaiser-Kupfer MI, Pulaski K, Nicholson HS, Bolesta M, Eldridge R, Gusella JF. Germ-line mutations in the neurofibromatosis 2 gene: correlations with disease severity and retinal abnormalities. Am J Hum Genet. 1996;59:529–39. [PMC free article: PMC1914910] [PubMed: 8751853]
  • Perry A, Giannini C, Raghavan R, Scheithauer BW, Banerjee R, Margraf L, Bowers DC, Lytle RA, Newsham IF, Gutmann DH. Aggressive phenotypic and genotypic features in pediatric and NF2-associated meningiomas: a clinicopathologic study of 53 cases. J Neuropathol Exp Neurol. 2001;60:994–1003. [PubMed: 11589430]
  • Plotkin SR, Stemmer-Rachamimov AO, Barker FG 2nd, Halpin C, Padera TP, Tyrrell A, Sorensen AG, Jain RK, di Tomaso E. Hearing improvement after bevacizumab in patients with neurofibromatosis type 2. N Engl J Med. 2009;361:358–67. [PMC free article: PMC4816642] [PubMed: 19587327]
  • Reginensi A, Enderle L, Gregorieff A, Johnson RL, Wrana JL, McNeill H. A critical role for NF2 and the Hippo pathway in branching morphogenesis. Nat Commun. 2016;7:12309. [PMC free article: PMC4974664] [PubMed: 27480037]
  • Rowe JG, Radatz MW, Walton L, Soanes T, Rodgers J, Kemeny AA. Clinical experience with gamma knife stereotactic radiosurgery in the management of vestibular schwannomas secondary to type 2 neurofibromatosis. J Neurol Neurosurg Psychiatry. 2003;74:1288–93. [PMC free article: PMC1738689] [PubMed: 12933938]
  • Ruggieri M, Iannetti P, Polizzi A, La Mantia I, Spalice A, Giliberto O, Platania N, Gabriele AL, Albanese V, Pavone L. Earliest clinical manifestations and natural history of neurofibromatosis type 2 (NF2) in childhood: a study of 24 patients. Neuropediatrics. 2005;36:21–34. [PubMed: 15776319]
  • Ruggieri M, Praticò AD, Serra A, Maiolino L, Cocuzza S, Di Mauro P, Licciardello L, Milone P, Privitera G, Belfiore G, Di Pietro M, Di Raimondo F, Romano A, Chiarenza A, Muglia M, Polizzi A, Evans DG. Childhood neurofibromatosis type 2 (NF2) and related disorders: from bench to bedside and biologically targeted therapies. Acta Otorhinolaryngol Ital. 2016;36:345–67. [PMC free article: PMC5225790] [PubMed: 27958595]
  • Sakai T, Vallejo MC, Shannon KT. A parturient with neurofibromatosis type 2: anesthetic and obstetric considerations for delivery. Int J Obstet Anesth. 2005;14:332–5. [PubMed: 16140520]
  • Slattery WH 3rd, Fisher LM, Iqbal Z, Oppenhiemer M. Vestibular schwannoma growth rates in neurofibromatosis type 2 natural history consortium subjects. Otol Neurotol. 2004;25:811–7. [PubMed: 15354016]
  • Slusarz KM, Merker VL, Muzikansky A, Francis SA, Plotkin SR. Long-term toxicity of bevacizumab therapy in neurofibromatosis 2 patients. Cancer Chemother Pharmacol. 2014;73:1197–204. [PubMed: 24710627]
  • Smith MJ, Higgs JE, Bowers NL, Halliday D, Patterson J, Gillespie J, Huson SM, Freeman SR, Lloyd S, Rutherford SA, King AT, Wallace AJ, Ramsden RT, Evans DG. Cranial meningiomas in 411 NF2 patients with proven gene mutations: Clear positional effect of mutations, but absence of female severity effect on age at onset. J Med Genet. 2011;48:261–5. [PubMed: 21278391]
  • Smith MJ, Bowers NL, Bulman M, Gokhale C, Wallace AJ, King AT, Lloyd SK, Rutherford SA, Hammerbeck-Ward CL, Freeman SR, Evans DG. Revisiting neurofibromatosis type 2 diagnostic criteria to exclude LZTR1-related schwannomatosis. Neurology. 2017;88:87–92. [PMC free article: PMC5200853] [PubMed: 27856782]
  • Smith MJ, Urquhart JE, Harkness EF, Miles EK, Bowers NL, Byers HJ, Bulman M, Gokhale C, Wallace AJ, Newman WG, Evans DG. The Contribution of Whole Gene Deletions and Large Rearrangements to the Mutation Spectrum in Inherited Tumor Predisposing Syndromes. Hum Mutat. 2016;37:250–6. [PubMed: 26615784]
  • Sperfeld AD, Hein C, Schroder JM, Ludolph AC, Hanemann CO. Occurrence and characterization of peripheral nerve involvement in neurofibromatosis type 2. Brain. 2002;125:996–1004. [PubMed: 11960890]
  • Spiegel JE, Hapgood A, Hess PE. Epidural anesthesia in a parturient with neurofibromatosis type 2 undergoing cesarean section. Int J Obstet Anesth. 2005;14:336–9. [PubMed: 16154348]
  • Wallace AJ, Watson CJ, Oward E, Evans DG, Elles RG. Mutation scanning of the NF2 gene: an improved service based on meta-PCR/sequencing, dosage analysis, and loss of heterozygosity analysis. Genet Test. 2004;8:368–80. [PubMed: 15684865]

Suggested Reading

  • Hanemann CO, Evans DG. News on the genetics, epidemiology, medical care and translational research of Schwannomas. J Neurol. 2006;253:1533–41. [PubMed: 17219030]
  • 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]
  • MacCollin M, Gusella J. Neurofibromatosis 2. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). Chapter 40.

Chapter Notes

Author History

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

Revision History

  • 15 March 2018 (ha) Comprehensive update posted live
  • 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
Copyright © 1993-2018, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source (http://www.genereviews.org/) and copyright (© 1993-2018 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.

For more information, see the GeneReviews® Copyright Notice and Usage Disclaimer.

For questions regarding permissions or whether a specified use is allowed, contact: ude.wu@tssamda.

Bookshelf ID: NBK1201PMID: 20301380

Views

Tests in GTR by Gene

Related information

  • MedGen
    Related information in MedGen
  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed
  • Gene
    Locus Links

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...