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.

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

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 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 probands 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 contain 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

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