
==== Front
Neurol Med Chir (Tokyo)
Neurol Med Chir (Tokyo)
Neurologia medico-chirurgica
0470-8105
1349-8029
The Japan Neurosurgical Society

38897938
10.2176/jns-nmc.2024-0067
Special Topic
Historical Development of Diagnostic Criteria for NF2-related Schwannomatosis
TAMURA Ryota 1
YO Masahiro 1
TODA Masahiro 1
1 Department of Neurosurgery, Keio University School of Medicine, Tokyo, Japan
Corresponding author: Ryota Tamura, M.D., Ph.D.

Department of Neurosurgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.

e-mail: moltobello-r-610@keio.jp

19 6 2024
8 2024
64 8 299308
27 3 2024
16 4 2024
© 2024 The Japan Neurosurgical Society
https://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives International License.
NF2-related schwannomatosis (NF2; previously termed neurofibromatosis type 2) is a tumor-prone disorder characterized by development of multiple schwannomas and meningiomas. The diagnostic criteria of NF2 have been regularly revised. Clinical criteria for NF2 were first formulated at the National Institutes of Health Consensus Conference in 1987 and revised in 1990. Revised criteria were also proposed by the Manchester group in 1992 and by the National Neurofibromatosis Foundation (NNFF) in 1997. The 2011 Baser criteria improved the sensitivity of diagnostic criteria, particularly for patients without bilateral vestibular schwannomas. Revisions to the Manchester criteria were published in 2019, with replacement of “glioma” by “ependymoma,” removal of “neurofibroma,” addition of an age limit of 70 years for development of vestibular schwannomas, and introduction of molecular criteria, which led to the most widely used criteria. In 2022, the criteria were reviewed and updated by the international committee of NF experts. In addition to changes in diagnostic criteria, the committee recommended the use of “schwannomatosis” as an umbrella term for conditions that predispose to schwannomas. Each type of schwannomatosis was classified by the gene containing the disease-causing pathogenic variant. Molecular data from NF2 patients led to further clarification of the diagnostic criteria for NF2 mosaic phenotypes. Given all these changes, the diagnostic criteria of NF2 may be confusing. Herein, to help healthcare professionals who diagnose NF2 conditions in the clinical setting, we review the historical development of diagnostic criteria.

NF1
NF2
schwannoma
schwannomatosis
diagnostic criteria
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pmcIntroduction

Neurofibromatosis was considered as a disease of familial syndromes showing neoplastic and dysplastic lesions in the central and peripheral nervous systems.1) Historically, the term “neurofibromatosis” was widely used to described three syndromes-neurofibromatosis type I (NF1), neurofibromatosis type II (NF2), and schwannomatosis.2,3) Patients with NF2 present with bilateral vestibular schwannomas (BVS) and multiple other tumors (such as meningiomas) in the central nervous system (Fig. 1).4-6) NF2 is considered as a dominantly inherited syndrome caused by pathogenic variants in the moesin-ezrin-radixin-like (merlin) tumor suppressor gene, which produces merlin protein.7,8)

Fig. 1 Typical radiographic image of NF2.

NF2-associated tumors, which include schwannoma and meningioma, are shown on contrast-enhanced T1-weighted image.

Further, the diagnostic criteria for NF2 have been regularly revised. Epidemiologic and molecular analysis of NF2 patients led to further clarification of diagnostic criteria for delineation of related syndromes such as schwannomatosis and the identification of mosaic phenotypes in NF2. The most recent updated diagnostic criteria classify each disorder that predisposes to schwannoma according to the specific gene harboring a pathogenic variant. Therefore, NF2 is now termed NF2-related schwannomatosis.9)

Healthcare professionals in the field of neurology, neurosurgery, dermatology, orthopedics, and oncology can diagnose NF2 conditions in the clinical setting,10) and they are responsible for providing cutting-edge treatments for every facet of NF2. Herein, to aid clinicians in use of the latest diagnostic criteria, we review the historical development of diagnostic criteria for NF2.

Historic Overview of NF2

Before establishment of the restrictive criteria

A disease consistent with NF2 was first described by Wishart in 1822, while NF1 was first described as a different entity by von Recklinghausen in 1882.11,12) In the 19th and 20th centuries, many reports of NF2 were combined with NF1.13) NF1 and NF2 were regarded as alternate presentations of a single syndrome by Cushing et al.,14) who established the importance of BVS and multiple meningiomas as components of NF.

Next, BVS were the traditional pathognomonic diagnostic characteristics of NF2. In 1920, hereditary development of vestibular schwannomas was recognized by Feiler and Ward.15) In 1930, an autosomal dominant mode of transmission was reported by Gardner and Frazier.16) The term “schwannomatosis” first appeared in the 1950s. Other terms, such as neurilemmomatosis, have also been used in Japan. In early literature, both schwannomatosis and neurilemmomatosis were used to describe patients who were suspected as presenting with NF2 with BVS.17)

National Institutes of Health (NIH) criteria

In the late 1980s, genetic analyses demonstrated linkage of neurofibromatosis to distinct regions on chromosomes 17 and 22.18,19) In 1987, a working group from the National Institutes of Health (NIH) proposed a distinct diagnostic consensus for NF1 and NF2 based on those clinicopathologic and genetic analyses (Supplementary Table 1), with NF2 and NF1 classified as clinically and molecularly distinct syndromes.20) These criteria were revised in 1990 (Supplementary Table 2),21,22) with an emphasis on the presence of BVS in a high percentage of patient with NF2. Furthermore, patients could qualify for a diagnosis of NF2 if they presented with a family history of NF2 and either unilateral vestibular schwannomas or any one (in 1990; Supplementary Table 2) or two (in 1987; Supplementary Table 1) other tumors (e.g., neurofibroma, meningioma, glioma, schwannoma, or juvenile posterior subcapsular lenticular opacity) typically associated with NF2. By contrast, patients without BVS or a family history of NF2 could not qualify for a diagnosis of NF2.23)

Manchester criteria and NNFF criteria

In 1992, the above criteria were amended to establish the Manchester criteria (Supplementary Table 3).24) This modification included patients lacking BVS or a family history of NF2 but who were diagnosed with multiple schwannomas and/or meningiomas. The Manchester criteria increased the sensitivity of the diagnostic framework, and they have been widely used in the clinical setting.23) Nevertheless, these diagnostic criteria may be overly restrictive because the additional characteristics are not observed in all NF2 patients (e.g., they may be absent in younger patients at the time of diagnosis).

As such, in 1997, revised criteria were proposed by the National Neurofibromatosis Foundation (NNFF) (Supplementary Table 4).25) The goal of these revisions was to improve the sensitivity for patients with NF2-associated features who did not completely reach NIH criteria. The NNFF recommended differentiating between “confirmed or definite NF2” and “presumed or probable NF2” to encourage regular clinical evaluation of patients suspected with NF2. For instance, the finding of a vestibular schwannoma or meningioma in patients <30 years of age raises suspicion for NF2, and based on these clinical criteria, young patients may eventually develop NF2. At that time, mutational analysis could not replace the clinical criteria for NF2 diagnosis because no causative mutation was detected in a high percentage of affected children with NF2.

Baser criteria

In 2011, the Baser criteria were developed as a revision of the Manchester criteria. Specifically, Baser, et al. attempted to overcome all the aforementioned problems by evaluating the natural history and genetic characteristics of NF2 to increase sensitivity while maintaining high specificity (Supplementary Table 5).23,26) In particular, patients without BVS, but who later met criteria for NF2, were reviewed using the United Kingdom NF2 registry, which resulted in acceptance of a fifth set of clinical diagnostic criteria for NF2. The previous four criteria demonstrated a specificity of 100% and a sensitivity <70%, while the Baser criteria demonstrated a specificity of 100% and a sensitivity of 79%.

The Baser criteria include several points for various clinical features, from which a total score is calculated (<4 points, 4 or 5 points, ≥6 points). A diagnosis of definite NF2 is established if the total number of points is ≥6 (Supplementary Figure 1). Next, NF2 mutation testing is indicated if the total number of points is 4 or 5. Also, a diagnosis of definite NF2 is established if a constitutional pathogenic NF2 mutation is found on mutation testing. A diagnosis of mosaic NF2 is established if mosaicism for a pathogenic NF2 mutation is found in the blood or if no detectable pathogenic NF2 mutation is found in the blood but the same pathogenic NF2 mutation is found in two separate NF2-associated tumors. Pending further clarification, a temporary diagnosis of possible NF2 is made. Clarification may occur if the patient shows a different condition (e.g., schwannomatosis of multiple meningiomas) by standard diagnostic criteria or if evolution of the patient's disease over time permits a diagnosis of definite NF2 or mosaic NF2 according to the criteria. These criteria permitted early diagnosis in a greater proportion of NF2 patients than previous diagnostic criteria.23,26)

Schwannomatosis and revised Manchester criteria

In 1996-1997, increasing consensus was found that schwannomatosis showed some clinical overlap with NF2, which included development of multiple nonvestibular schwannomas.27-30) Schwannomatosis was first officially defined as a different entity in 2005 by MacCollin et al.,31) whereby schwannomatosis was regarded as a group of mainly isolated patients, but with occasional families presenting with noncranial, nonintradermal, and painful schwannomas on imaging studies.29,30) These criteria only required the presence of ≥2 schwannomas (one proven histologically) with exclusion of the vestibular part after >18 years of age. Application of these criteria did not exclude individuals with NF2 who presented with nonvestibular schwannomas at a young age.32) Unilateral vestibular schwannoma was subsequently shown to occur rarely in schwannomatosis, which led to further modifications of the original criteria in 2013 they were refined to include molecular diagnostic criteria.33,34) Further, the molecular mechanisms of schwannomatosis were shown to involve different somatic point mutations from NF2.35-37) In 2007, a separate gene on chromosome 22 termed SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily b, member 1 (SMARCB1) was found to cause a subset of familial and sporadic cases of schwannomatosis.35,38-40) This gene was also linked to development of meningiomas.39,41) Seven years after identification of SMARCB1, a second 22q gene leucine zipper-like transcription regulator 1 (LZTR1) was identified as another cause of schwannomatosis.42) These two definitive genes (SMARCB1/LZTR1) cause schwannoma development by a three-event, four-hit mechanism, which leads to complete inactivation of each gene plus NF2.43) This again raised the overlap with NF2 patients who developed unilateral vestibular schwannoma and met the Manchester diagnostic criteria for NF2.35,42,44-46)

Thereafter, in 2017, combined clinical and molecular criteria were proposed by Kehrer-Sawatzki et al.47) Also, to identify the complete mutational spectra and number of mutational hits, the authors recommended a comprehensive mutation analysis of all three genes (LZTR1, SMARCB1, and NF2) in patients with schwannomatosis.47) Furthermore, many sporadically affected individuals who do not present with either LZTR1 or SMARCB1 germline pathogenic variants, but who meet schwannomatosis criteria,31,33) present with mosaic NF2 with identical pathogenic variants in two separate schwannomas.48,49) Together, these genes account for 70%-85% of familial schwannomatosis and 30%-40% of isolated cases in which considerable overlap with mosaic NF2 is found.46,50)

Thus, revised diagnostic criteria for NF2 were recommended to include these genomic alterations. Revisions to the UK Manchester criteria were published in 2019, which included replacing “glioma” with “ependymoma,” removal of “neurofibroma,” creating an age limit of 70 years for development of vestibular schwannomas, and introducing molecular criteria (Supplementary Table 6).45,51,52)

The latest clinical criteria

The overlap from the vestibular schwannomas occurring in LZTR1-related schwannomatosis and the mosaic NF2 mimicking schwannomatosis necessitated a reevaluation of existing diagnostic criteria,51) and an international collaboration defined new criteria in 2022. With sponsorship from the Children's Tumor Foundation, an international panel of NF and schwannomatosis experts was assembled in 2017, and they were charged with reviewing the diagnostic criteria for NF1, NF2, and schwannomatosis.13) The updated diagnostic criteria for schwannomatosis classify each disorder according to the specific gene harboring a pathogenic variant. Therefore, NF2 is now termed NF2-related schwannomatosis (Table 1).9) Also, the committee recommended the term “schwannomatosis” be used as an umbrella term for conditions that predispose to schwannoma. An advantage of this format is that it allows addition of other types of schwannomatosis when and if new genes are identified. Although the diminishing likelihood of NF2 in patients with vestibular schwannomas diagnosed after 70 years of age was considered,45,53) no age limit was set in the 2022 criteria.9) Also, the committee recommended that the name of NF1 remain unchanged, and that NF2 and the other cluster of NF-related conditions be renamed as follows (see details in the “Genetic testing” section below): NF2-related schwannomatosis (formerly termed NF2), SMACRB1-related schwannomatosis, LZTR1-related schwannomatosis, 22q-related schwannomatosis, schwannomatosis not otherwise specified for patients who have not received genetic testing, and schwannomatosis not elsewhere classified for patients in whom genetic testing of blood/saliva and tumors failed to detect a pathogenic variant.

Table 1 The latest criteria (2022)

A diagnosis of NF2-related schwannomatosis can be made when a patient has one of the following:	
1. Bilateral VS	
2. An identical NF2 pathogenic variant in at least two anatomically distinct NF2-related tumors (schwannoma, meningioma, and/or ependymoma)	
3. When either two Major OR one Major and two Minor criteria are present as follows:	
Major criteria:	
・Unilateral VS	
・First-degree relative other than a sibling with NF2-related schwannomatosis	
・Two of more meningiomas (Note: single meningioma qualifies as a minor criterion)	
・NF2 pathogenic variant* in an unaffected tissue such as blood or saliva (*When the variant is present at significantly less than 50%, the diagnosis is mosaic NF2-related schwannomatosis)	
Minor criteria:	
・Can count more than once of each type (e.g., two schwannomas = two minor criteria)	
⇒Ependymoma; schwannoma (Note: if the major criterion is unilateral VS, at least one schwannoma must be dermal in location)	
・Can count only once	
⇒Juvenile subcapsular or cortical cataract; retinal hamartoma; epiretinal membrane in a person aged less than 40 years; meningioma (Note: multiple meningiomas qualify as a major criteria; meningioma cannot be used as both a major and minor criterion)	
Additional genetic criteria:	
・Genetic analysis may identify pathogenic NF2 variants in blood in 66%–90% of individuals	
・Genetic analysis is not required for diagnosis. Diagnosing NF2-related schwannomatosis based on clinical criteria without genetic analysis will be possible	
・Genetic analysis with family history will be sufficient to diagnose NF2-related schwannomatosis (no requirement to present with tumors)	
Mosaicism	
Mosaicism is confirmed for NF2-related schwannomatosis by either of the following:	
・Clearly less than 50% pathogenic variant allele fraction in blood or saliva	
・Pathogenic variant not detected in clinically unaffected tissue but shared pathogenic variant in two or more anatomically unrelated tumors	
VS, vestibular schwannoma

NF2 Gene and Somatic Mosaic

NF2 is caused by inactivating alterations in the NF2 gene on chromosome 22q12.2. The 100 kb NF2 gene is encoded by 17 exons, and 10 isoforms resulting from alternative splicing have been described in humans. Next, alternative isoforms frequently result from alterations in the C-terminal exons 16 and 17.54,55) The growth of schwannomas requires inactivation of both NF2 alleles. NF2-associated tumors form when additional somatic genetic alterations in vulnerable cells result in bi-allelic loss of NF2 function (Knudson's two-hit hypothesis).56) However, to promote tumorigenesis, NF2 mutations alone may be insufficient, and additional genetic alterations are required.57) The “second hit” occurs via loss of the entire NF2 gene or most of chromosome 22.

Various types of mutations, such as protein truncating alterations (frameshift deletions/insertions and nonsense mutations), splice-site mutations, and missense mutations, have been identified.58) Truncating mutations (nonsense and frameshifts) are the most frequent germline event and cause the most severe disease. Further, the presence of a truncated protein is associated with younger age at diagnosis and a higher prevalence of meningiomas, spinal tumors, and cranial nerve tumors other than of the VIII nerve.59) Deletions in the NH2-terminal domain of merlin proteins are associated with early tumor onset and disease progression.59) Next, the most common alterations are splice-site mutations or nonsense mutations in exons 1-8. Missense or in-frame deletions have been associated with milder clinical courses. A positional effect with mutations in the latter parts of the gene (exons 14 and 15) is associated with milder disease and fewer meningiomas.60)

The Wishart phenotype is a more aggressive form that involves formation of multiple neoplasms in patients <20 years of age. Presentation with nonvestibular tumors in early life may be a forerunner to a more severe multi-tumor disease.61,62) By contrast, the Gardner phenotype is mild with fewer slow-growing tumors arising later in life. The phenotype severity depends on the type of NF2 gene alteration. For example, alterations in the conserved N-terminal FERM domain and truncating mutations are typically associated with the Wishart phenotype, which includes younger age at diagnosis, a higher incidence of meningiomas, ophthalmologic and cutaneous lesions, and poor outcomes. Next, missense and splice-site mutations occur predominantly in the 30 end of the gene, are associated with the Gardner phenotype, and demonstrate a better prognosis with fewer meningiomas.63-65)

Pathogenic NF2 alterations exhibit a nearly 100% penetrance. Fifty percent of NF2 patients present with symptoms and/or neoplastic manifestations by 20 years of age, while nearly all NF2 patients present by 60 years of age.64) Large-population-based analyses suggested that germline mutations in NF2 are present in 1 in 25,000 individuals (with no gender predilection). Further, fifty percent of NF2 cases are suspected to result from hereditary transmission from a parent with NF2, while the remainder appear to be due to de novo mutations in patients with no family history.66,67) More than 50% of NF2 patients are sporadic, and they may therefore represent de novo or new mutations68) that occur in the germline cells of their parents (prezygotic) or in any cell after fertilization and cell division (postzygotic). A postzygotic mutation can result in mosaicism.69) The symptoms of mosaic NF2 are milder and often restricted to a certain area or side of the body. Next, mosaic patients may present with unilateral vestibular schwannomas or segmental disease.5,70-72) Patients with germline NF2 mutations demonstrate a 50% probability of passing the disease to their children, while mosaic patients demonstrate a reduced chance of further transmission to their offspring because of the absence of germ cell alterations in some cases. However, if affected, the children of mosaic patients will typically develop a more severe form of the disease than the parent because of the greater number of affected cells following germline transmission.73)

Note that the mutation analysis should also include methods (e.g., next generation sequencing) that are well suited to detect somatic mosaicism with mutant cells present in low proportions. This approach helps to distinguish between mosaic NF2 and schwannomatosis.48)

Genetic Testing

Genetic testing for NF2 is considered not medically indispensable if a diagnosis can be made by clinical characteristics. Genetic testing may be considered medically necessary when any of the following conditions are met. (A) The diagnosis is clinically suspected because of signs and symptoms of the disease, but a clinical diagnosis has not been made. (B) At-risk relatives show no signs of disease when a first-, second-, or third-degree relative has been diagnosed with NF2, especially important for first-degree relatives of patients with NF2.74,75) (C) Young patients do not meet diagnostic criteria without genetic data. (D) An asymptomatic individual who received genetic sequencing for another indication is identified with a pathogenic variant in NF2 in the blood but exhibits no clinical features of NF2. Such individuals and their at-risk relatives should be referred to a tertiary care center with expertise in schwannomatosis, the variant should be determined as constitutional (germline), mosaic, or somatic, and they should receive genetic counseling.9,13) Next, when genetic testing is performed, updated diagnostic criteria should be adapted.9) The algorithm for genetic testing according to the updated diagnostic criteria is shown in Fig. 2.9,76)

Fig. 2 Genetic testing.

The first step involves testing of unaffected tissues (i.e., blood or saliva) for pathogenic variants (PVs) in NF2, SMARCB1, and LZTR1. If heterozygous mutations are identified for each gene and clinical features are also present, the disease is classified as full NF2-, SMARCB1-, or LZTR1-related schwannomatosis. If the PVs in NF2, SMARCB1, or LZTR1 exhibit a variant allele fraction clearly <50% and clinical features are also present, the disease is classified as mosaic NF2-, SMARCB1-, or LZTR1-related schwannomatosis. If no PVs are found in NF2, SMARCB1 or LZTR1, the second step involves testing of two or more anatomically unrelated tumors. If the tumors share PVs in NF2, SMARCB1, or LZTR1, the disease is classified as mosaic NF2-, SMARCB1-, or LZTR1-related schwannomatosis. If no shared PVs are found, the third step involves testing loss of heterozygosity of chr 22 q in the tumors. Loss of heterozygosity is classified as 22q-related schwannomatosis. Otherwise, the patient is classified as schwannomatosis-not elsewhere classified. Importantly, an uninformative genetic test (i.e., negative or uncertain clinical significance PV) does not exclude the diagnosis of schwannomatosis, and a referral to a schwannomatosis specialist should be considered.

LOH, loss of heterozygosity; PV, pathogenic variant; SWN, schwannomatosis; VAF, variant allele frequency

Note that 15%-30% of familial schwannomatosis patients lack germline pathogenic variants in SMARCB1 or LZTR1, which suggests the existence of another schwannomatosis-causing gene.47,48) Molecular testing of blood in patients with sporadic schwannomatosis who meet diagnostic criteria, but who did not exhibit SMARCB1 or LZTR1 germline pathogenic variants, identified mosaic NF2-related schwannomatosis in 37%-57% of patients by testing the two anatomically unrelated tumors.9,77)

Summary and Future Directions

We reviewed the historical development of diagnostic criteria of NF2 (Fig. 3). Genetic analysis is of increasing importance in the diagnosis, classification, and prognosis of brain tumors. Recently, molecular diagnosis was needed for the correct diagnosis of malignant glioma.78) By contrast, in the clinical setting, imaging and histological examination is sufficient for a diagnosis of NF2. Nevertheless, advanced molecular diagnostics are now required to accurately guide complex diagnosis of patients with NF2 including the mosaic type. Next, molecular diagnostics can offer important benefits including the expected clinical course, which allows personalized medicine in health care systems. However, several problems are found that need to be resolved. Genetic analysis is complicated and may involve several specialists, while molecular analysis is not available at every hospital. Value assessment remains the main barriers to providing patients with equal access to molecular diagnostics.79) We must continue to routinely collect specific cases and build on international experience in successful integration of molecular diagnostics into clinical practice. Further, equal access is required to ensure the appropriate molecular diagnostics. For patients with NF2, national centers are required to help accelerate advancements in rare disease diagnosis, treatment, and research.

Fig. 3 Previous sets of diagnostic criteria for NF2.

Seven main sets of clinical diagnostic criteria have been proposed for NF2. The characteristics of each diagnostic criterion were described.

Author Contributions

R.T. conceptualized, designed, and wrote the manuscript. M.Y. and M.T. assisted with discussion and review of the manuscript. All authors approved the final version.

Funding

This work was supported in part by grants from the Japan Society for the Promotion of Science (JSPS) (22K15531 to R.T.).

Availability of Data and Code

All data supporting the findings of this study are available within the article and from the corresponding author upon reasonable request.

Conflicts of Interest Disclosure

All authors have no conflict of interest.

Supplementary Material

Appendix

Acknowledgments

We thank Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.
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