Clinical characteristics.

NF2-related schwannomatosis (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) low-grade 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 bilateral vestibular schwannomas, an identical NF2 pathogenic variant identified in two or more anatomically distinct NF2-related tumors, or a combination of clinical and molecular criteria that fulfill the consensus diagnostic criteria.

Management.

Treatment – targeted therapy: The VEGF antibody bevacizumab for rapidly growing vestibular schwannomas; bevacizumab has also shown some clinical benefit in some individuals with ependymoma.

Treatment – supportive care: 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. Cervical spine MRI prior to cranial surgery; lumbosacral MRI prior to regional analgesia. Treatment for hearing loss includes referral to an audiologist, lipreading and sign language instruction, and possibly hearing aids and/or cochlear or brain stem implants. Surgical treatment for infantile cataracts and patching as needed. Management through rehabilitation medicine, physical therapy, and/or occupational therapy should be considered for hand or foot drop due to mono- or polyneuropathy. Surgical removal as needed for cutaneous schwannomas that are causing disfigurement and/or pain.

Surveillance: For affected or at-risk individuals, annual neurologic examination by a provider with experience in NF2; annual brain MRI beginning at approximately age ten to 12 years and continuing until at least the fourth decade of life; annual hearing evaluation, including BAER testing; annual complete ophthalmology examination.

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

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 diagnosed with NF2 have an affected parent. Approximately 50% of individuals diagnosed with NF2 have the disorder as the result of a de novo NF2 pathogenic variant. As many as 25% to 50% of individuals with a de novo NF2 pathogenic variant have somatic mosaicism for the variant. The possibility that a parent has NF2 can be excluded if the proband is shown to be mosaic. Each child of an individual with NF2 has up to a 50% chance of inheriting the pathogenic variant: offspring of an individual with a germline pathogenic variant have a 50% chance of inheriting the variant, while offspring of an individual who has mosaic NF2 may have a less than 50% risk of inheriting the variant. Once the NF2 pathogenic variant has been identified in the family, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

NF2 should be suspected in individuals with the following clinical, laboratory, and family history findings [Halliday et al 2023].

Clinical 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

Clinical findings 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, ependymoma, cataract in the form of subcapsular lenticular opacities or cortical wedge cataract diagnosed in an individual age <40 years

Laboratory findings. NF2 pathogenic variant identified on tumor tissue testing

Family history. 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 can be established in a proband with ONE of the following:

• Bilateral vestibular schwannomas
• An identical NF2 pathogenic variant in two or more anatomically distinct NF2-related tumors (schwannoma, meningioma, and/or ependymoma)
  Note: If the variant allele fraction (VAF) in an unaffected tissue (e.g., blood) is clearly <50%, the diagnosis is mosaic NF2.
• Two major criteria
• One major and two minor criteria

Major criteria

• Unilateral vestibular schwannoma
• A first-degree relative other than a sib with NF2
• Two or more meningiomas
• NF2 pathogenic variant in an unaffected tissue (e.g., blood)
  Note: If the VAF is clearly <50%, the diagnosis is mosaic NF2.

Minor criteria

• Ependymoma, schwannoma (non-vestibular)
  Note: Two ependymomas or two non-vestibular schwannomas count as two minor criteria.
• A single meningioma
  Note: Two meningiomas count as a major criterion.
• Juvenile subcapsular or cortical cataract, retinal hamartoma, epiretinal membrane in a person age <40 years
  Note: Each ocular manifestation that occurs bilaterally only counts as one minor criterion.

Clinical Description

The average age of onset of findings in individuals with NF2-related schwannomatosis (NF2) is 18 to 24 years (onset range: birth to age 70 years). Almost all affected individuals develop bilateral vestibular schwannomas by age 30 years. In addition to vestibular schwannomas, individuals with NF2 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 may be the first manifestations [Ruggieri et al 2005, Ruggieri et al 2016, Halliday et al 2019].

Genotype-Phenotype Correlations

Intrafamilial variability is much lower than interfamilial variability, suggesting a strong effect of the underlying genotype on the resulting phenotype.

Large deletions of NF2 have been associated with a milder 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 [Evans et al 2019, Forde et al 2021].

• Nonsense and frameshift variants have been associated with severe disease regardless of their position within the gene [Hexter et al 2015, Evans et al 2019, Forde et al 2021].
• 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. 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 2013, Evans et al 2019].

Penetrance

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

Nomenclature

The term "NF2-related schwannomatosis" was proposed by Plotkin et al [2022] to reflect the absence of neurofibroma and glioma (the latter replaced with ependymoma) in current diagnostic criteria and to underscore the importance of molecular testing in diagnosis. Of note, molecular genetic testing is of particular importance for individuals with a unilateral vestibular schwannoma and additional non-vestibular schwannomas in order to distinguish NF2-related schwannomatosis and LZTR1-related schwannomatosis.

Prevalence

The estimated prevalence of NF2 is 1:50,000 [Evans et al 2010, Evans et al 2018], with a birth incidence of 1:28,000.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with NF2, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

There is no cure for NF2.

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations in affected individuals and at-risk individuals in whom the known pathogenic variant in the family has been identified or whose genetic status cannot be clarified by molecular genetic testing, the evaluations summarized in Table 5 are recommended.

Agents/Circumstances to Avoid

Radiotherapy for NF2-associated tumors should be avoided in children when malignancy risks are likely to be substantially higher [Evans et al 2006].

Evaluation of Relatives at Risk

Once the germline NF2 pathogenic variant has been identified in the proband, 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 [Halliday et al 2023].

Proband with mosaic NF2. If an NF2 pathogenic variant is not detected in unaffected tissue (e.g., blood), NF2 molecular analysis on tumor tissue should be done. Identification of the same NF2 pathogenic in more than one tumor allows predictive testing in offspring of the proband.

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 EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

NF2-related schwannomatosis (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.
• As many as 25% to 50% 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]. The possibility that a parent has NF2 can be excluded if the proband is shown to be mosaic (i.e., the NF2 pathogenic variant is not detected in an unaffected tissue [e.g., blood] from the proband or the variant allele fraction [VAF] in an unaffected tissue is clearly <50%).
• If the proband is the only family member known to have NF2 and molecular genetic testing does not suggest that the NF2 pathogenic variant is mosaic, molecular genetic testing is recommended for the parents of the proband to confirm their genetic status. If the pathogenic variant found in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has de novo germline pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
    * If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected.
• 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 DNA extracted from blood and have been clinically affected [Evans et al 2013]. There is one report of two affected children born to apparently unaffected parents before NF2 testing was available [Parry et al 1996]. However, the low likelihood of sib recurrence of unilateral vestibular schwannoma due to parental germline mosaicism (versus the greater likelihood of unilateral vestibular schwannoma in a sib due to chance) is now recognized by exclusion of a sib in the diagnostic criteria [Evans et al 2019, Plotkin et al 2022].
• Because the age of onset of symptoms is typically consistent within families, it is usually not necessary to offer surveillance to asymptomatic parents.
• 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 the proband has mosaic NF2 or molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.

Sibs of a proband. The risk to the sibs of a proband depends on the genetic status of the parents:

• If a parent of the proband is affected and/or is known to have the germline NF2 pathogenic variant identified in the proband, the risk to the sibs is 50%. The age of onset of symptoms within a family is relatively consistent.
• If the proband has a known germline NF2 pathogenic variant that 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. Presumed germline mosaicism in a clinically unaffected parent has been reported in one family to date [Parry et al 1994].
• If the proband has a known germline NF2 pathogenic variant and the parents have not been tested for the 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.
• If the proband has mosaic NF2, it is presumed that the parents do not have the NF2 pathogenic variant identified in the proband and that sibs of the proband are not at risk of inheriting the NF2 pathogenic variant.

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

• If the proband has other affected family members, each child of the proband has a 50% chance of inheriting the pathogenic variant.
• If the proband is the only affected individual in the family:
  • The proband may have a de novo germline pathogenic variant (i.e., present in the egg or sperm at the time of conception). Each offspring of an individual with a de novo germline pathogenic variant has a 50% chance of inheriting the pathogenic variant.
  • The proband may have somatic mosaicism for the pathogenic variant. Offspring of an individual who has mosaic NF2 may have a less than 50% risk of inheriting the pathogenic variant.
    Persons with somatic mosaicism and bilateral vestibular tumors have a less than 50% chance of having an affected child [Evans et al 1998b]. If the pathogenic variant is detected in DNA from multiple tumors, but not in DNA from leukocytes, the risk to offspring is probably less than 1% [Evans et al 2019, Halliday et al 2023].

Other family members. The risk to other family members depends on the genetic status of the proband's parents: if a parent is affected, the parent's 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.

Predictive testing (i.e., testing of asymptomatic at-risk individuals)

• Predictive testing for at-risk asymptomatic family members requires prior identification of the germline NF2 pathogenic variant in the family.
• Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
• 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.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the NF2 pathogenic variant has been identified in the family, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

NF2 encodes a large protein containing FERM (4.1 protein, ezrin, radixin, moesin) domains known as merlin (for moesin-ezrin-radixin-like protein). Although the complete function of merlin remains elusive, studies suggest that merlin coordinates 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 merlin deficiency in mammals [McClatchey & Giovannini 2005]. However, the mechanisms by which pathogenic variants in NF2 cause disease remain unclear due in part to its multiple roles in controlling several signaling pathways, including PI3K-AKT, RAC-PAK, and EGFR-RAS-ERK. More recently, a critical role in the Hippo pathway mediated through suppression of Yap and Taz has also been shown [Reginensi et al 2016].

Abnormal merlin is caused by either somatic or constitutional NF2 pathogenic variants. Attempts to identify truncated protein product have been unsuccessful, 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 these types of variants compared to whole-gene deletions.

Mechanism of disease causation. Loss of function

NF2-specific laboratory technical considerations. Both germline and mosaic variants are seen in NF2. Mosaic genetic variants in NF2 can have low variant allele frequencies (VAFs) and may therefore elude detection using standard sequencing methods. Using high depth of coverage for sequencing as well as pipelines optimized for the detection of variants with low VAFs is recommended for the detection of mosaic pathogenic NF2 variants.

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

Author Notes

Professor D Gareth Evans (ku.shn.tfm@snave.hterag) is actively involved in clinical research regarding individuals with NF2. They would be happy to communicate with persons who have any questions regarding diagnosis of NF2 or other considerations.

Contact Dr Miriam J Smith (ku.ca.retsehcnam@htims.mairim) to inquire about review of NF2 variants of uncertain significance.

Acknowledgments

The author would like to thank Dr Andrew J Wallace and Dr Miriam J Smith for their enormous help in characterizing the molecular pathology of NF2-related schwannomatosis and Dr Scott Plotkin for driving (with Dr Evans) the name change to NF2-related schwannomatosis with further support from the Children's Tumor Foundation.

Author History

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

Revision History

• 20 April 2023 (sw) Comprehensive update posted live
• 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 live
• 6 April 2004 (me) Comprehensive update posted live
• 29 October 2001 (me) Comprehensive update posted live
• 14 October 1998 (pb) Review posted live
• 5 August 1998 (mm) Original submission

Literature Cited

• 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, 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]
• Chang LS, Oblinger JL, Smith AE, Ferrer M, Angus SP, Hawley E, Petrilli AM, Beauchamp RL, Riecken LB, Erdin S, Poi M, Huang J, Bessler WK, Zhang X, Guha R, Thomas C, Burns SS, Gilbert TSK, Jiang L, Li X, Lu Q, Yuan J, He Y, Dixon SAH, Masters A, Jones DR, Yates CW, Haggarty SJ, La Rosa S, Welling DB, Stemmer-Rachamimov AO, Plotkin SR, Gusella JF, Guinney J, Morrison H, Ramesh V, Fernandez-Valle C, Johnson GL, Blakeley JO, Clapp DW, et al. Brigatinib causes tumor shrinkage in both NF2-deficient meningioma and schwannoma through inhibition of multiple tyrosine kinases but not ALK. PLoS One. 2021;16:e0252048. [PMC free article: PMC8282008] [PubMed: 34264955]
• 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, Bowers NL, Tobi S, Hartley C, Wallace AJ, King AT, Lloyd SKW, Rutherford SA, Hammerbeck-Ward C, Pathmanaban ON, Freeman SR, Ealing J, Kellett M, Laitt R, Thomas O, Halliday D, Ferner R, Taylor A, Duff C, Harkness EF, Smith MJ. Schwannomatosis: a genetic and epidemiological study. J Neurol Neurosurg Psychiatry. 2018;89:1215–9. [PubMed: 29909380]
• Evans DG, Halliday D, Obholzer R, Afridi S, Forde C, Rutherford SA, Hammerbeck-Ward C, Lloyd SK, Freeman SM, Pathmanaban ON, Thomas OM, Laitt RD, Stivaros S, Kilday JP, Vassallo G, McBain C, Lavin T, Paterson C, Whitfield G, McCabe MG, Axon PR, Halliday J, Mackeith S, Parry A, Harkness EF, Buttimore J, King AT, et al. Radiation treatment of benign tumors in NF2-related-schwannomatosis: a national study of 266 irradiated patients showing a significant increase in malignancy/malignant progression. Neurooncol Adv. 2023;5:vdad025. [PMC free article: PMC10084499] [PubMed: 37051330]
• Evans DG, Hartley CL, Smith PT, King AT, Bowers NL, Tobi S, Wallace AJ, Perry M, Anup R, Lloyd SKW, Rutherford SA, Hammerbeck-Ward C, Pathmanaban ON, Stapleton E, Freeman SR, Kellett M, Halliday D, Parry A, Gair JJ, Axon P, Laitt R, Thomas O, Afridi SK, Obholzer R, Duff C, Stivaros SM, Vassallo G, Harkness EF, Smith MJ, et al. Incidence of mosaicism in 1055 de novo NF2 cases: much higher than previous estimates with high utility of next-generation sequencing. Genet Med. 2020;22:53–9. [PubMed: 31273341]
• 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, 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, Hartley C, Freeman SR, Lloyd SK, Thomas O, Axon P, Hammerbeck-Ward CL, Pathmanaban O, Rutherford SA, Kellett M, Laitt R, King AT, Bischetsrieder J, Blakeley J, Smith MJ. Familial unilateral vestibular schwannoma is rarely caused by inherited variants in the NF2 gene. Laryngoscope. 2019;129:967–73. [PMC free article: PMC6563429] [PubMed: 30325044]
• 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]
• Forde C, King AT, Rutherford SA, Hammerbeck-Ward C, Lloyd SK, Freeman SR, Pathmanaban ON, Stapleton E, Thomas OM, Laitt RD, Stivaros S, Kilday JP, Vassallo G, McBain C, Kerrigan S, Smith MJ, McCabe MG, Harkness EF, Evans DG. Disease course of neurofibromatosis type 2: a 30-year follow-up study of 353 patients seen at a single institution. Neuro Oncol. 2021;23:1113–24. [PMC free article: PMC8248850] [PubMed: 33336705]
• 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, Evans DGR. Updated protocol for genetic testing, screening and clinical management of individuals at risk of NF2-related schwannomatosis. Clin Genet. 2023;103:540–52. [PubMed: 36762955]
• 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 D, Emmanouil B, Vassallo G, Lascelles K, Nicholson J, Chandratre S, Anand G, Wasik M, Pretorius P, Evans DG, Parry A, et al. Trends in phenotype in the English paediatric neurofibromatosis type 2 cohort stratified by genetic severity. Clin Genet. 2019;96:151–62. [PubMed: 30993672]
• 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, Friedman JM, Evans DG, et al. 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]
• Huang SJ, Amendola LM, Sternen DL. Variation among DNA banking consent forms: points for clinicians to bank on. J Community Genet. 2022;13:389–97. [PMC free article: PMC9314484] [PubMed: 35834113]
• 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, et al. 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]
• Nogué C, Chong AS, Grau E, Han H, Dorca E, Roca C, Mosquera JL, Lázaro C, Foulkes WD, Brunet J, Rivera B. DGCR8 and the six hit, three-step model of schwannomatosis. Acta Neuropathol. 2022;143:115–7. [PubMed: 34821987]
• 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]
• Plotkin SR, Messiaen L, Legius E, Pancza P, Avery RA, Blakeley JO, Babovic-Vuksanovic D, Ferner R, Fisher MJ, Friedman JM, Giovannini M, Gutmann DH, Hanemann CO, Kalamarides M, Kehrer-Sawatzki H, Korf BR, Mautner VF, MacCollin M, Papi L, Rauen KA, Riccardi V, Schorry E, Smith MJ, Stemmer-Rachamimov A, Stevenson DA, Ullrich NJ, Viskochil D, Wimmer K, Yohay K, Huson SM, Wolkenstein P, Evans DG, et al. Updated diagnostic criteria and nomenclature for neurofibromatosis type 2 and schwannomatosis: an international consensus recommendation. Genet Med. 2022;24:1967–77. [PubMed: 35674741]
• 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, 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, 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, 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]