NF2-related schwannomatosis …

Neuro-Oncology

Updated 12.13.2024
Released 03.21.1995
Expires For CME 12.13.2027

NF2-related schwannomatosis

Authors: Stefania Maraka MD, Mariam/Myriam Markouli MD

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Editor: Rimas V Lukas MD

NF2-related schwannomatosis

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Introduction

Overview

NF2-related schwannomatosis is a tumor predisposition syndrome most commonly associated with the development of multiple schwannomas (classically bilateral vestibular schwannomas), meningiomas, and ependymomas. This disorder is caused by mutations in the neurofibromatosis 2 (NF2) gene, a tumor suppressor gene that encodes for merlin/schwannomin and is located on chromosome 22.

Key points

	• NF2-related schwannomatosis is an autosomal dominant disorder caused by mutations of the neurofibromatosis 2 gene, a tumor suppressor gene located on chromosome 22, whose normal protein product is merlin/schwannomin.
	• The average age of diagnosis for NF2-related schwannomatosis is in one’s 20s, but patients may also present across a spectrum of ages. The majority of affected children do not present with the vestibular or auditory complaints typical of adult patients.
	• Classically, patients have bilateral vestibular schwannomas (CN VIII), which are frequently responsible for the initial presenting complaints (ie, hearing loss and tinnitus) in adult patients. Other associated sequelae include nervous system tumors (ie, meningiomas, schwannomas affecting other cranial nerves or spinal nerve roots, and gliomas), lens abnormalities, and peripheral neuropathy, among others.
	• Although patients with NF2-related schwannomatosis sometimes display cutaneous features (eg, pigmented skin lesions called “cafe au lait” spots) typical of neurofibromatosis type 1 (NF1), these skin findings are typically less common and less numerous than in NF1 patients.
	• Treatments currently target specific disease manifestations (ie, tumors, cataracts, neuropathy) rather than the underlying disease process. Genetic counseling is recommended to first-degree relatives of affected individuals.
	• Treatment options include conservative management (observation), surgery, radiosurgery, and systemic therapy, with novel and repurposed targeted therapeutics, immunotherapy, adoptive T-cell therapy, tumor vaccines, as well as in vivo and ex vivo gene therapeutic strategies. A number of these approaches are undergoing continued investigation.

Historical note and terminology

NF2-related schwannomatosis has also been called central or acoustic neurofibromatosis because of its characteristic involvement of the central nervous system (CNS) with tumors, especially meningiomas and acoustic neuromas that are now termed vestibular schwannomas (37). It is much less common than NF1, with which, historically, it was often confused (114). This is less of an issue in contemporary times, as it is more broadly understood to be a distinct disease. NF2-related schwannomatosis is now well characterized clinically as an autosomal dominant disorder with genetic origins on the long arm of chromosome 22 (103; 133).

Wishart reported the first patient with probable neurofibromatosis type 2 who had multiple intracranial tumors and no recorded cutaneous features (134). Cushing reported a case of acoustic neuromas in 1917 and considered it to be a form of neurofibromatosis because the pathological changes were so similar to those seen in von Recklinghausen cases (31). However, since von Recklinghausen's report in 1865 and for many years later, NF1 and neurofibromatosis type 2 were frequently classified as the same disease and referred to as von Recklinghausen disease or multiple neurofibromatosis (114). The perception that NF1 and neurofibromatosis type 2 were one disease arose because café au lait spots and peripheral nerve tumors can occur in either condition (114). Following the recognition of the autosomal dominant inheritance pattern of acoustic neuromas, these tumors were considered one of the complications of NF1 (62).

Gardiner and Frazier reported a large family from Pennsylvania with neurofibromatosis type 2 and suggested that the bilateral acoustic neuromas represented a separate form of neurofibromatosis (53). However, the subclassification was not adopted at that time. A large study of neurofibromatosis in 1956 reported 5% of patients with what was called multiple neurofibromatosis, who had bilateral acoustic neuromas and, in retrospect, probably had neurofibromatosis type 2 (114).

A follow-up study of the Gardiner and Frazier family in 1970 again concluded that the condition was different from von Recklinghausen disease and suggested that it be called central neurofibromatosis (136). This subclassification was more widely accepted by the 1980s (69; 101), and the natural history of neurofibromatosis type 2, with its greater morbidity and mortality in the majority of affected individuals, was recognized (63; 79). Moreover, the absence of acoustic schwannomas in neurofibromatosis type 1 was also appreciated (102). The NIH Consensus Panel agreed in 1987 on clinical guidelines for diagnosis and nomenclature, recommending the name neurofibromatosis type 2 rather than central or acoustic neurofibromatosis (86). The mapping of the neurofibromatosis type 2 gene to chromosome 22 confirmed the impression of neurofibromatosis type 2 as a distinct entity (103). The most widely known clinical diagnostic criteria for neurofibromatosis type 2 are the Manchester criteria, first established in 1992. Research surrounding neurofibromatosis type 2 has been dominated by gene studies and the process in which these gene abnormalities impact disease course. This translational research has guided current research efforts in neurofibromatosis type 2 and has subsequent powerful clinical impact in future potential therapeutic options.

Updated nomenclature and diagnostic criteria were proposed for neurofibromatosis type 2. The current diagnostic criteria for neurofibromatosis type 2 and schwannomatosis classify patients primarily on the basis of their clinical features. Because the phenotype of neurofibromatosis type 2 and schwannomatosis spans a continuum without complete clinical delineation of these subtypes, the umbrella term “schwannomatosis” was introduced, and neurofibromatosis type 2 was proposed to be replaced by “NF2-related schwannomatosis” (95).

Clinical manifestations

Presentation and course

Adults. Most adult patients present with symptoms of hearing loss, tinnitus, and impaired balance related to vestibular schwannomas. The average age of symptom onset is 18 to 24 years, and most patients will present by age of 30 years. Approximately 20% to 30% of patients present with symptoms related to cranial and spinal meningiomas with headaches, seizures, weakness, and paresthesias (40). Peripheral neuropathies, mostly axonal in nature, are also common in NF2-related schwannomatosis (106). Ocular findings can affect a majority of patients with NF2-related schwannomatosis and include cataracts, epiretinal membranes, hamartomas, and optic nerve sheath meningiomas (40). Dermatologic manifestations in NF2-related schwannomatosis are less common compared to NF1 but can affect nearly 70% of patients, including cutaneous and subcutaneous nodules, which are usually schwannomas (30) or tumors of mixed type (neurofibroma/schwannoma). The tumors can be subtle and easily overlooked.

Children. Although NF2-related schwannomatosis most commonly presents in adulthood, approximately 20% of patients will present before the age of 15. Symptoms referable to vestibular schwannomas are uncommon in children at presentation and account for only 15% to 30% of patients; however, schwannomas at any other location and skin plaques should raise high suspicion for NF2-related schwannomatosis in children. Visual symptoms are common presenting complaints for children, such as strabismus secondary to a cranial nerve schwannoma, cortical wedge cataract, visual loss due to a retinal lesion, such as a retinal hamartoma, or proptosis due to an orbital ridge meningioma. Mononeuropathies, especially unilateral facial or third nerve palsies, foot or wrist drops due to nerve schwannomas, or seizures due to meningiomas (usually of non-meningothelial/arachnoidal origin), are also presenting complaints in some children (40).

A diagnosis of NF2-related schwannomatosis was made based on fulfilling a set of clinical criteria, otherwise known as the Manchester criteria (Table 1) (40). Baser and colleagues proposed updated criteria to improve diagnostic accuracy by assigning different points for presence of spinal tumors, cutaneous schwannomas, cranial nerve schwannomas, mononeuropathy, cataracts, or peripheral neuropathies before or after the age of 30 (10). The suggested criteria estimate a 9% to 15% increase of diagnostic sensitivity without affecting specificity. Further revisions of the clinical criteria emphasize the need of identification of germline leucine zipper like transcription regulator 1 (LZTR1) mutations for patients with unilateral vestibular schwannoma to evaluate for schwannomatosis. Additionally, suggestions of revised criteria include the replacement of the term “glioma' to “ependymoma” and the removal of the term “neurofibroma” (46). In this context, Smith and colleagues suggested that neurofibromatosis type 2 should not be diagnosed until germline LZTR1 testing has been conducted in patients presenting only with unilateral vestibular schwannoma or other schwannomas unless they also demonstrate other disease-suggestive features (116). This led them to an update of the previous Manchester criteria (Table 2). Lastly, Plotkin and colleagues proposed new updated criteria for the disease (95) (see Table 3).

Table 1. Clinical Criteria (Manchester Criteria) for Diagnosis of Neurofibromatosis 2

Main Criteria

Additional Criteria

Bilateral vestibular schwannomas or

Unilateral vestibular schwannoma plus any two of the following: meningioma, schwannoma, glioma, neurofibroma, cataract in the form of posterior subcapsular lenticular opacities, or cortical wedge cataract or

First-degree relative with neurofibromatosis type 2 plus:

1. Unilateral vestibular schwannomas or

2. Any two of the following: meningioma, schwannoma, or glioma, neurofibroma, cataract in the form of posterior subcapsular lenticular opacities, or cortical wedge cataract

At least two meningiomas plus

1. Unilateral vestibular schwannoma

2. Any two of the following: meningioma, schwannoma, glioma, neurofibroma, cataract in the form of posterior subcapsular lenticular opacities, or cortical wedge cataract

Table 2. Revised Manchester Criteria

	Revised Manchester criteria for the diagnosis of neurofibromatosis 2 (any of the following):
	• Bilateral vestibular schwannomas for patients younger than 70 years of age • First-degree relative with NF2 and unilateral vestibular schwannoma younger than 70 years of age • First-degree relative with NF2 or unilateral vestibular schwannoma and two of any of the following: meningioma, cataract, ependymoma, nonvestibular schwannoma (if unilateral vestibular schwannoma need negative LZTR1 testing*) • Multiple meningiomas and two of unilateral vestibular schwannoma, cataract, ependymoma, nonvestibular schwannoma • Constitutional or mosaic pathogenic neurofibromatosis 2 mutation in blood or identical mutations in two distinct tumors
*LZTR1 testing should be carried out on tumor tissue, but as mosaicism does not appear as common in LZTR1-affected individuals, blood can still be used to exclude germline schwannomatosis.

Table 3. Revised 2022 Criteria

A diagnosis of neurofibromatosis 2-related schwannomatosis (previously termed neurofibromatosis 2, NF2) can be made when an individual has one of the following:
	1. Bilateral vestibular schwannomas
	2. An identical NF2 pathogenic variant in at least two anatomically distinct neurofibromatosis 2-related tumors (schwannoma, meningioma, and/or ependymoma). Note: if the variant allele fraction (VAF) in unaffected tissues such as blood is clearly <50%, the diagnosis is mosaic neurofibromatosis 2-related schwannomatosis
	3. Either two major or one major and two minor criteria as follows:
		Major criteria:
			• Unilateral vestibular schwannoma
			• First-degree relative other than sibling with neurofibromatosis 2-related schwannomatosis
			• Two or more meningiomas (Note: single meningioma qualifies as minor criteria)
			• NF2 pathogenic variant in an unaffected tissue such as blood (Note: if the VAF is clearly < 50%, the diagnosis is mosaic neurofibromatosis 2-related schwannomatosis)
		Minor criteria:
			Can count more than one of a type: (eg, two distinct schwannomas would count as two minor criteria)
			• Ependymoma, meningioma (Note: multiple meningiomas qualify as a major criteria), schwannoma (Note: if the major criterion is unilateral vestibular schwannoma, at least one schwannoma must be dermal in location)
			Can count only once: (eg, bilateral cortical cataracts count as a single minor criterion)
			•Juvenile subcapsular or cortical cataract, retinal hamartoma, epiretinal membrane in a person aged <40 years, meningioma
Adapted from (95)

The diagnosis of NF2-related schwannomatosis can also be made using genetic testing. However, one third to one half of all nonfamilial cases is due to de novo mutations causing somatic mosaicism and may, thus, be falsely negative. Rigorous genetic testing often involves the genetic blood test plus testing of tumor sample.

miRNAs have also emerged as promising biomarkers for noninvasive disease detection with high specificity and sensitivity. Distinctive miRNA profiles in the serum of patients with NF2-related schwannomatosis were discovered using miRNA sequencing in both sporadic and familial cases (64).

Prognosis and complications

Cranial tumors.

Vestibular schwannomas. Vestibular schwannomas arise from the vestibular portion of the eighth cranial nerve. They occur in up to 95% of patients with NF2-related schwannomatosis (05). The most common symptom associated with vestibular schwannomas is sensorineural hearing loss, which ultimately leads to deafness. Tinnitus and vertigo may also be seen (05). As the vestibular schwannomas grow, they can impact adjacent nervous tissue, producing twitching or facial weakness (CN VII), facial paresthesias (CN V), dysphonia, and dysphagia (CN IX and X), or they compress the cerebellum and cause gait ataxia and incoordination. Such growth may also cause increased intracranial pressure, leading to headaches, nausea, and vomiting (56). Vestibular schwannomas are multifocal, and pathologic studies reveal multiple tumors along the eighth nerve in the majority of patients. It is also important to recognize that new tumors occur over time (120).

Growth rate for vestibular schwannomas is variable and difficult to predict (90). The median time to 20% growth in vestibular schwannomas was 21 months, with nearly 50% of vestibular schwannomas showing a saltatory growth pattern. Vestibular schwannomas showed more rapid growth compared to other cranial nerve schwannomas (76). In a study evaluating conservative management for vestibular schwannoma, a median growth rate of 1.4 mm per year with patients younger than 20 having a faster growth rate was demonstrated (2.6 mm per year compared to 0.9 mm per year) (91). The mean time for developing radiological evidence of bilateral vestibular schwannomas in patients with NF2-related schwannomatosis with an existing unilateral vestibular schwannoma is about 6.5 years for adults and 3.25 years for children, and it takes 7.3 years for the hearing loss to become bilateral (05).

The clinical course for hearing loss is progressive but unpredictable and can occur in a gradual, stepwise, or sudden fashion. There is limited understanding of the mechanism for hearing loss. Tumor size or growth rate does not seem to correlate with hearing loss. Other postulated mechanisms include intralabyrinthine hemorrhage, causing disruption of the cochlear blood supply, as well as secretion of oto- and neurotoxic metabolites by the tumor (100). One study suggests that hearing loss may be related to accumulation of intralabyrintine protein in some patients due to an inflammatory response that may cause cochlear aperture obstruction (06).

Other cranial nerve schwannomas. Schwannomas can grow along any of the cranial nerves, most commonly in the trigeminal nerve with the exception of cranial nerve I and II. These other schwannomas may or may not be symptomatic and are commonly detected incidentally on screening MRIs. Based on a study by the Neurofibromatosis 2 Natural History Consortium, about 50% of patients had nonvestibular cranial nerve schwannomas, with the oculomotor (CNIII) and trigeminal nerve (CN V) most commonly affected. Neuropathies of these cranial nerves are rare; however, schwannomas of the lower cranial nerves can cause dysphonia, dysphagia, and aspiration (16).

Cranial meningiomas. Meningiomas are the second most common tumor type in NF2-related schwannomatosis and occur throughout the CNS in 50% to 75% of patients (05). Symptoms are related to compression of adjacent neural tissue and include headaches, weakness, seizures, and visual disturbance. Patients with NF2-related schwannomatosis are likely to have multiple meningiomas, and they have a 2.5-fold higher relative risk of mortality compared to those without (09). In a long-term natural history study of meningiomas in NF2-related schwannomatosis patients, 52% of patients had three or fewer meningiomas, whereas almost 30% had seven or more. The most common location for meningiomas are along the falx (72%), skull base (25%), and orbital ridge, whereas only 3% were intraventricular.

Meningiomas in NF2-related schwannomatosis tend to be higher grade than sporadic meningiomas (05). It used to be believed that although meningiomas in NF2-related schwannomatosis are more aggressive compared to sporadic meningiomas, the vast majority are grade I. Grade 2 and grade 3 tumors were reported to represent 24% and 5% of meningiomas requiring resection, respectively. However, a new study that included clinical, transcriptomic, and histological analyses of meningiomas in patients with NF2-related schwannomatosis showed that meningiomas in NF2-related schwannomatosis were characterized by less aggressive behavior than sporadic altered meningiomas in NF2-related schwannomatosis and caused a marked immune response with increased myeloid cell and particularly macrophage infiltration (125).

There can be multiple histological subtypes within the same meningioma specimen. Among the grade 1 meningiomas, 55% are reported to be transitional, 35% fibroblastic, and 10% meningothelial. In Goutagny’s study, 66% of meningiomas showed no growth over 110 months of observation (54). Younger age at diagnosis of NF2-related schwannomatosis and female sex have been associated with increased growth rate (34).

A genotype-phenotype analysis of patients showed that patients with truncation mutations in NF2-related schwannomatosis and mutations at the 5’ end of the gene were more likely to develop cranial meningiomas. Mutations in exons 1 to 13 carried a higher risk of cranial meningioma formation compared to exons 14 to 15. Men under the age of 20 have a higher risk of meningioma formation (117). Dewan and colleagues performed whole exosome sequencing on grade 1 and grade 2 meningiomas from a single NF2-related schwannomatosis patient that demonstrated increased chromosomal translocations as well as mutations in ADAMTSL3 and CAPN (32). Chromosomal loss and homozygous deletions are also commonly observed and may explain a more aggressive growth rate.

Glial cell tumors. These tumors include ependymomas and astrocytomas and do not tend to cause symptoms frequently. They usually affect the lower brain stem and upper cervical cord. Their prevalence in adults with neurofibromatosis 2 is around 1.6% to 4.1% and 2.5% to 6% for intracranial astrocytomas and ependymomas, respectively, but the prevalence is much higher (24%) in pediatric patients (05).

Spinal tumors.

Spinal tumors, both intramedullary and extramedullary, are common in NF2-related schwannomatosis. The incidence is as high as 90% of patients (80). They can occur along any portion of the spine, although the cervical and lumbosacral spine are the more common locations. Extramedullary tumors include schwannomas and meningiomas, whereas intramedullary tumors are ependymomas. About 30% of spinal tumors are intramedullary ependymomas (05). It is important to understand that all three types are commonly present in the same patient. Differentiation can be challenging based solely on radiographic appearance, but careful MR imaging is an essential step in characterizing spinal tumors.

Spinal schwannoma. Spinal schwannomas are the most common spinal tumors (51). These are intradural, extramedullary tumors that grow from dorsal nerve roots. They are commonly multiple and can grow in a multicentric pattern (59). In a retrospective analysis by Malis of nearly 100 extramedullary spinal tumors, 58 of them were schwannomas, whereas the rest were meningiomas (78). It is also important to recognize that although 90% of patients have extramedullary spinal tumors, only 33% of them presented with localizable symptoms. The most frequent symptoms are motor and sensory deficits followed by sensory only deficits (87).

Spinal meningioma. The incidence of spinal meningiomas is estimated to be similar to schwannomas (80; 78). In the retrospective analysis by Malis, spinal meningiomas were associated with higher morbidity and mortality, with death attributed to growth of multiple meningiomas (78). This is presumably due to high cervical spine tumors.

Spinal ependymoma. Ependymomas are intramedullary spinal tumors in NF2-related schwannomatosis and can be seen in approximately 33% to 53% of patients (23). Some intramedullary tumors in NF2-related schwannomatosis were incorrectly described as astrocytomas in the older literature. Ependymomas occur most frequently in the cervical spine and cervicomedullary junction (86%), followed by thoracic (62%) and lumbar spine (8%) (96). Although ependymomas usually are asymptomatic, they can grow and produce symptoms based on their location, and those symptoms can be life-threatening for tumors involving the medulla. In a retrospective analysis of 55 NF2-related schwannomatosis patients with spinal ependymomas, almost 60% had multiple ependymomas, and nearly 76% were asymptomatic. In that study, only 20% of patients underwent surgery for symptomatic progression. All the resected ependymomas were low grade (WHO grade 1 or 2) (96). Ependymomas commonly have a cystic component, and most patients with multiple ependymomas have a unique MRI appearance described as a “string of pearls” (87). The presence of spinal ependymomas is highly associated with other extramedullary spinal tumors and intracranial meningiomas (87).

Peripheral tumors.

Peripheral schwannoma. Nearly 70% of patients with NF2-related schwannomatosis have peripheral schwannomas affecting the paraspinal and cutaneous nerves as well as the nerve trunks and plexi. Symptoms include sensory loss, pain, and weakness (40). Plexiform schwannomas occur in the cutaneous and subcutaneous tissue and are most commonly located in the head and neck region. Patients with plexiform schwannomas are more likely to have NF2-related schwannomatosis, but they can also occur in the absence of neurofibromatosis (14; 13). Small Schwann cell neoplasms, otherwise referred to as tumorlets, have been seen within the paraspinal nerve roots in patients with NF2-related schwannomatosis and may be precursors to schwannomas (74).

Peripheral neuropathy. Peripheral neuropathy is a potential complication in NF2-related schwannomatosis and can occur in the absence of visible tumor cells. A potential mechanism for peripheral neuropathy in NF2-related schwannomatosis is deficiency in merlin isoform 2, which is implicated in maintaining axonal integrity (106). Peripheral neuropathy can be asymptomatic. Careful evaluations including EMG of patients with NF2-related schwannomatosis indicate that as many as 67% of patients can have peripheral neuropathies. Patients with absent reflexes, unexplained muscle weakness, or atrophy should be evaluated for peripheral neuropathy (107).

Ophthalmic manifestations.

Ophthalmologic changes that affect the majority of patients with NF2-related schwannomatosis include the following: 70% to 80% cataracts, 20% to 44% retinal changes, 12% to 50% strabismus, 12% amblyopia, 10% to 27% optic nerve sheath meningiomas or other optic pathway tumors, and 10% extraocular movement abnormalities (05). A study of 30 patients, with 60% being children, documented more frequent ophthalmologic abnormalities in pediatric patients (94%) compared to adults (67%) (18). This study also reported significantly poorer vision outcomes in children, with only 14% versus 78% of adults having normal visual acuity at the end of similar follow-up periods (18).

Cataracts. The most common ophthalmic complication of NF2-related schwannomatosis is cataracts, which is often bilateral and may occur at an early age (including infancy or childhood) (40). Cataracts in patients under 50 years of age are specific to NF2-related schwannomatosis and are most commonly located in the posterior subcapsular lenticular space, but they can also occur in the capsular and peripheral regions (20). Most patients are asymptomatic; however, up to 25% have visual difficulty due to cataracts requiring removal (22).

Epiretinal membranes, retinal hamartomas, optic disc tumors. Epiretinal membranes are developmental abnormalities that are reported in NF2-related schwannomatosis with a frequency of 20% to 80% and are often detectable at an early age. These are proliferations at the vitreoretinal interface borders (38). They are usually not a cause of vision loss but can rarely cause macular impairment and retinal detachment (05). In a long-term retrospective study of ophthalmologic findings in NF2-related schwannomatosis patients, 44% of patients had epiretinal membranes (18). Ocular findings can precede the discovery of other neurologic issues by an average of 5 years (115).

Retinal hamartomas are raised masses along the macula that appear as areas of thickening and disorganization of the retinal layers, sometimes combining involvement of the retinal pigment epithelium (38). They occur in 6% to 22% of patients with NF2-related schwannomatosis and are associated with visual acuity loss (21). Optic disc tumors have been reported in as many as 13% of patients with NF2-related schwannomatosis. Early onset manifestations of NF2-related schwannomatosis and increased severity are found in patients with early onset visual problems. Retinal hamartomas and optic nerve sheath meningiomas in NF2-related schwannomatosis have been misdiagnosed as retinoblastomas in early childhood and resulted in an unnecessary enucleation of the globe (05).

Optic nerve sheath, cavernous sinus, orbital ridge meningiomas. Optic nerve sheath meningiomas are strongly associated with NF2-related schwannomatosis (18a; 18b). They are usually unilateral though 5% may be bilateral (36). Symptoms include loss of visual acuity and color perception from optic nerve compression. The triad of optic atrophy, optociliary vein shunting, and vision loss are pathognomonic for optic nerve sheath meningiomas, with proptosis and strabismus arising later in the disease course (18).

Cavernous sinus meningiomas in children are rare and if present should prompt an evaluation for NF2-related schwannomatosis. Presenting symptoms include strabismus, visual dysfunction, and oculomotor nerve dysfunction (49).

Skin findings.

Skin tumors are estimated to occur in up to 70% of NF2-related schwannomatosis patients, although only a minority of patients (10%) have greater than 10 skin tumors (39). There are three main types: plaque-like intracutaneous lesion, which are hyperpigmented with excess hair; subcutaneous nodules (neurofibromas) formed by thickened nerves; and intracutaneous tumors, which are usually schwannomas (30). Café au lait spots, a frequently found abnormality in NF1, sometimes occur in NF2-related schwannomatosis but are usually not multiple. They occur in approximately 30% to 50% of patients and are fewer in number and not associated with freckling as in NF1 patients (30). A high number of skin tumors are associated with increased disease severity (05).

Neuropsychology and quality of life.

Although patients with NF2-related schwannomatosis typically have slow-growing tumors, the tumors can cause significant neurologic morbidity, which compromises patients’ quality of life. Patients with NF2-related schwannomatosis are more likely than the general population to report lower quality of life with an incidence similar to cancer patients. Patients with hearing impairment, facial weakness, and gait instability reported lower quality of life, with greater vestibular schwannoma tumor volume correlating with greater impact on quality of life (29; 81). A primary concern of patients with NF2-related schwannomatosis is deafness, which affects communication and socialization. Patients with neurofibromatosis 2 also demonstrated greater psychosocial stress given uncertainty of their disease course as well as pain (29). A multidisciplinary approach with participation of neuropsychologist in the care of patients with NF2-related schwannomatosis has been deemed to be highly beneficial (24).

An anonymous survey of 630 adults with NF2-related schwannomatosis demonstrated that the majority (91%) of participants reported that their disease symptoms somehow impacted their daily life, with 51% endorsing a diagnosed mental health condition, whereas 27% believed they had an undiagnosed mental health issue (135). NF2-related schwannomatosis appeared to highly affect the emotional (44%), physical (38%), and social (35%) function of these patients. Of note, few reported having participated in a drug (6%) or psychosocial (7%) clinical trial, and 68% would "probably" or "definitely" want to participate in a psychosocial trial that would target their concern (mostly anxiety, healthier lifestyle, and daily stress).

Clinical vignette

A 21-year-old, previously healthy man presented with a complaint of tinnitus and decreased hearing in his right ear. On neurologic examination he was found to have sensorineural hearing loss in the right ear that was confirmed to be of a moderate degree in audiometric testing. The only other finding was that of a 2 by 2.5 cm café au lait spot on his left shoulder. There was no family history of hearing loss, other neurologic problems, or skin lesions. He was found to have bilateral eighth nerve masses, small in size on the left and moderate on the right. These appeared to be vestibular schwannomas and confirmed a diagnosis of neurofibromatosis type 2. He was thought to have the disease by occurrence of a spontaneous mutation because there was an absence of a family history of NF2-related schwannomatosis.

He was referred to a center with a dedicated NF2-related schwannomatosis program and underwent surgery for resection of each of the tumors sequentially. The left-side, small tumor was gross totally resected without postoperative hearing or facial nerve deficit. The right-side, larger tumor could be radically but not totally resected with a residual postoperative mild facial nerve palsy and slightly greater hearing deficit in the right ear. He had had stable hearing and surveillance MR imaging for 8 years when the hearing in his right ear significantly decreased further. The right side tumor had markedly increased in size with no evidence of growth of the left tumor, whereas audiometric testing of hearing was decreased (though not absent) on the right and still normal on the left. He underwent a total resection of the right-side tumor at that time with postoperative total deafness in the right ear, but no worsening of the facial nerve deficit. He did well following the surgery, with no further hearing loss or other neurologic problems until the age of 36 years when he had a focal motor seizure that secondarily generalized. MRI showed an enhancing mass at the surface of the posterior right frontal lobe that was a benign meningioma that was gross totally resected. At the age of 42 years, he had remained without progression of any neurologic symptoms or further seizures since the last surgery.

Biological basis

Etiology and pathogenesis

Chromosomal localization and merlin. NF2-related schwannomatosis is caused by a mutation in the NF2 gene located at chromosome 22q12. NF2-related schwannomatosis is due to inactivation of the neurofibromatosis 2 gene (28). Loss of the second allele is thought to occur in the majority of patients.

The protein product is merlin, which is a member of the FERM gene family (ezrin, radixin, moesin) and regulates multiple proliferative signaling pathways. Merlin shares 64% sequence similarity to the other members of the family of proteins. FERM proteins link plasma membrane receptors to the cortical actin cytoskeleton. Thus, merlin can be regarded as a scaffold protein indirectly linking F-actin, transmembrane receptors, and intracellular effectors to modulate receptor-mediated signaling pathways controlling cell growth, proliferation, and survival. The receptors linked to Merlin include tyrosine kinase, cell adhesion, and small GTPase pathways. More specifically, Merlin inhibits downstream pathways, such as the Wnt/β-catenin, p21, Ras/Raf/MEK/ERK, Rac/PAK/JNK, PI3K/AKT, FAK/Src, and mTORC1 pathways. Merlin does not stay at the cell membrane but also migrates to the nucleus and induces growth suppression through inhibition of CRL4DCAF1, the E3 ubiquitin ligase, which regulates integrin and tyrosine receptor kinase expression (123). Merlin also increases YAP by inhibiting Lats1 and Lats2 in the nucleus. YAP and TAZ are major effectors of the tumor suppressor Hippo pathway. Abnormalities in the Hippo pathway are linked to a number of cancers as well as disorders of Schwann cell proliferation and myelination (28; 89; 99).

A de novo mutation results in somatic mosaicism, which may hinder a molecular diagnosis unless the specific tumor tissue is examined. Schwannoma growth requires the inactivation of both the two neurofibromatosis 2 alleles. This mutation may be a nonsense, a splice-site, or a missense mutation, or it may be a frameshift deletion or insertion. Nonsense and frameshift mutations resulting in protein-truncating changes are the most commonly identified germline events and result in the most severe phenotype with a younger age at diagnosis and a higher tumor burden. On the other hand, missense and in-frame deletions are linked to milder disease courses. Similarly, mutations in exons 14 and 15 in the latter parts of the NF2 gene are associated with a milder disease and smaller incidence of meningiomas (111).

Differential diagnosis

Associated or underlying disorders

The group of neurofibromatosis syndromes includes NF1, NF2-related schwannomatosis, and schwannomatosis, all of which are caused by mutations in different tumor suppressor genes, resulting in multiple nervous system tumors that arise in various locations depending on their distinct genetic etiology (04). NF2-related schwannomatosis appears to be most frequently misdiagnosed, especially when the cutaneous manifestations of the disease are prominent. The clinical features most useful in distinguishing NF2-related schwannomatosis from NF1 are usually the lower number or complete absence of café au lait spots, the absence of axillary freckling, the presence of schwannomas, and luck of neurofibromas (114). Interestingly, NF2-related schwannomatosis is not genetically related to NF1 but is closely related to schwannomatosis that is caused by mutations in either INI1 (SMARCB1) or LZTR1, located near NF2 gene on chromosome 22 (07). Schwannomatosis is characterized by the presence of multiple schwannomas sparing the vestibular nerves, which distinguishes it from NF2-related schwannomatosis (04). Of note, the most severe clinical manifestations are thought to be observed in patients with disruption of semantic sequences and reading frame shifts in exons 2 to 13 of the NF2 gene. On the other hand, patients with somatic mosaicism are characterized by a more favorable course, with a smaller number of tumors (77). All of these points underline the importance of evaluation by a genetics counselor and accompanied genetic testing.

Patients with NF2-related schwannomatosis have also rarely been misdiagnosed as having isolated vestibular or spinal schwannomas or meningiomas when other signs of NF2-related schwannomatosis were not sought. Isolated vestibular schwannomas generally occur in older individuals (4th or 5th decade), with no other family members affected and with no other manifestations of NF2-related schwannomatosis (127). Younger patients with unilateral vestibular schwannoma should be monitored for contralateral vestibular schwannoma and the possibility of neurofibromatosis 2 (25). The use of genetic testing has limited the risk of misdiagnosis of NF2-related schwannomatosis.

Of note, there also seems to be an association between NF2-related schwannomatosis and multiple sclerosis, with the number of multiple sclerosis cases among individuals with NF2-related schwannomatosis being remarkably higher than the general population. It is hypothesized that genetic predisposition for peripheral nerve vulnerability together with repeated nerve repair processes possibly pose an independent risk factor for the pathogenesis of multiple sclerosis and explain the evident over-representation of multiple sclerosis in patients with NF2-related schwannomatosis (108).

Diagnostic workup

The diagnostic assessment of patients suspected of having NF2-related schwannomatosis should include a detailed clinical and family history. The physical examination should focus on the skin for detection of characteristic cutaneous lesions, and the neurologic examination should focus on cranial nerve function. Ophthalmologic examination is helpful to confirm the typical posterior lens abnormalities of NF2-related schwannomatosis when they are present (126).

A contrast-enhanced MRI of the brain and entire spine can be completed for identification of schwannomas and meningiomas (126). Patients with intramedullary spinal tumors (primarily ependymomas, but also astrocytomas) should have annual follow-up imaging. Those with dumbbell neural foraminal tumors, spinal meningiomas, and cauda equina tumors probably can be followed with repeat imaging if symptoms change or appear (57). Whole-body MRI use is being investigated as a way to better measure tumor burden (94). Characteristic MRI features of vestibular schwannomas include hypointense lesions on T1 and hyperintense lesions on T2-weighted images with intense contrast enhancement, causing widening of the internal auditory canal with possible extension into the cerebellopontine angle, leading to an "ice cream cone" appearance. Cystic changes are seen with large tumors (126). Meningiomas on the other hand are dural-based lesions with isointense and iso- to hyperintense signaling on T1 and T2-weighted images, respectively, with intense contrast enhancement and an enhancing dural tail (126).

Standard audiometric testing, including vestibular testing, is an important perioperative measure of eighth nerve function and facilitates management decisions. In contrast, audiometric testing is not particularly useful for early detection of vestibular schwannomas in neurofibromatosis 2 because imaging abnormalities or abnormal brainstem auditory-evoked responses precede the hearing loss (15).

Genetic testing. Genetic testing of blood samples in second-generation members of NF2-related schwannomatosis families is at least 93% diagnostic. However, diagnosis is more difficult in the first generation where as many as 30% of patients are mosaics. Mosaics can carry the mutation in too small a proportion (or even none) of their lymphocytes to make the diagnosis via blood tests. Testing of tumor samples is often required in first-generation individuals (01; 111). A wide variety of mutations has been identified including missense, nonsense, splice-site and point mutations, and large and small deletions. Missense mutations (which result in a complete protein product), large deletions (which result in no protein product), and mutations in the latter exons 9 to 15 are associated with milder phenotype. Missense mutations are associated with longer survival than patients with nonsense and frameshift mutations. Extensive lists of NF2-related schwannomatosis mutations are available. Careful assessment of patients with multiple schwannomas, particularly where there is a family history, should include genetic testing for NF2-related schwannomatosis as well as MRIs of the brain with internal acoustic protocol. Genetic testing provides important information for patient management and should be done in all at-risk patients (40). Due to the increased frequency of de novo cases, early genetic testing should be considered not only in patients with first-degree relatives with the disease, but also with a sporadic vestibular schwannoma at the age of 30 years or younger or a solitary nonvestibular schwannoma or meningioma at the age of 25 years or younger, multiple spinal tumors, and cutaneous schwannomas (48; 40). Genetic testing should include tumor and then blood lymphocyte DNA sequencing and NF2 mutation testing. If identical NF2 variants are identified in more than one tumor but not in blood samples, mosaicism can be confirmed (43). LZTR1 status should also be assessed to differentiate from schwannomatosis (116).

Management

Vestibular schwannoma. Vestibular schwannomas present the most frequent challenge in patient management. Although most vestibular schwannomas are benign tumors, they cause significant morbidity primarily due to hearing loss, which has a major impact on quality of life. Patients with NF2-related schwannomatosis consistently indicate that hearing loss is their major concern. However, removal of vestibular schwannomas is difficult. Pathologic studies demonstrate that vestibular schwannomas are multifocal. Removal of vestibular schwannoma is associated with significant potential complications including hearing loss and facial nerve injury (33). The main indications for intervention are brainstem compression, progressive hearing loss, and other cranial nerve (most commonly facial) dysfunction (40). Treatment options include conservative management (observation), surgery, radiosurgery, and systemic therapy with novel and repurposed targeted therapeutics, immunotherapy, including checkpoint inhibitors, adoptive T-cell therapy, tumor vaccines, as well as in vivo and ex vivo gene therapeutic strategies (83).

Surgery. Surgery is favored over radiosurgery due to the increased rate of recurrence, more aggressive growth pattern compared to sporadic vestibular schwannoma and younger age of presentation (27). In a retrospective review, 20% of patients initially treated with radiotherapy required surgery, whereas another 13% were managed conservatively despite growth (129). It is important to recognize that small tumors may remain stable for years and that surgery for all small tumors would result in overtreatment of some tumors that may never grow or produce hearing loss. Surgery should be considered when there is evidence of growth on serial MRIs or when significant brainstem compression is present. In patients with bilateral vestibular schwannoma where one tumor is growing, management decisions become more complicated.

Surgical approach for vestibular schwannoma is commonly retrosigmoid or translabyrinthine. Delayed facial palsy can be a common complication after retrosigmoid surgery, which can be associated with the formation of a postoperative hematoma in the cerebellopontine angle (67). A translabyrinthine approach is commonly performed due to lack of useful hearing at time of surgery as well as low likelihood of hearing preservation. This approach also allows for excision of an adjacent facial nerve tumor with reinnervation anastomosis (129). However, the translabyrinthine approach can be done with good hearing preservation. The middle fossa approach to vestibular schwannoma should be considered only in small tumors. Injury of the adjacent facial nerve is a possible complication with all surgical approaches and can lead to inability to close the ipsilateral eye, causing corneal ulcerations and potentially blindness (129; 40). Thus, surgical operations for neurofibromatosis 2-related vestibular schwannomas are ideally referred to centers with experience and expertise. Considerations for operating must take into account hearing dysfunction, tumor size, tumor growth rate, extent of brainstem compression, facial nerve function (40), and the presence of a contralateral vestibular schwannoma.

Surgical management of vestibular schwannoma has started to become truly revolutionized and redefined by innovations that allow for real-time feedback of nerve location and functionality that augments tissue-specific visualization and guides the surgeon to perform safer nerve dissections and more complete tumor resections. One example is intracochlear electrically evoked auditory neuromonitoring that can guide cochlear microdissection and is currently being studied in a clinical trial (NCT04241679). The most promising visualization technology is the use of optical imaging methods to guide surgery, also known as “fluorescence-guided surgery,” which uses fluorescence agents (fluorophores) and compatible imaging systems to visually distinguish a tissue of interest (83).

Radiotherapy. Stereotactic radiosurgery is a widely accepted treatment option for small-sized (less than 3 cm) vestibular schwannomas, whereas for larger tumors microsurgery or a combination of therapeutic strategies are mostly recommended (104). The advantage of stereotactic radiosurgery compared to surgery is its minimally invasive nature and its potential for reasonable hearing and facial nerve function preservation (128). Tumor control rates with stereotactic radiosurgery for sporadic versus neurofibromatosis 2-related vestibular schwannomas were similar at 87% at 5 years (75). In a series by Kruyt and colleagues, a lower marginal dose of radiation was used (11 Gy compared to greater than 12 Gy), with good hearing preservation at 1 to 6 years as well as lower reported complications, namely facial neuropathy (113; 75). However, although short-term hearing preservation is good with stereotactic radiosurgery, long-term hearing loss is a significant risk due to cochlear radiation. Stereotactic radiosurgery may also make subsequent surgery more difficult. There is the additional risk of malignant transformation from radiation in a tumor predisposition syndrome. Malignant peripheral nerve sheath tumors have been reported in patients with NF2-related schwannomatosis who have had stereotactic radiosurgery. Although the numbers are small, this is a uniformly fatal complication rarely seen in NF2-related schwannomatosis patients without stereotactic radiosurgery. In an extensive review of the literature, the estimated overall risk for malignant transformation in vestibular schwannoma in neurofibromatosis patients is 25 per 100,000 compared to 1 to 2 per 100,000 without radiation (42; 110). Despite these risks, a retrospective analysis showed that stereotactic radiosurgery is characterized by high success rates of long-term local tumor control with low neurologic injury risks (119; 97).

Conservative management. Neurofibromatosis 2-related vestibular schwannomas have a variable growth rate and may even slow down with age (11; 12). Given potential risks of surgery and radiotherapy, a conservative management approach is advisable in asymptomatic patients with serviceable hearing and stable imaging (91). Patients should undergo annual MRIs of the brainstem as well as audiological assessments for close follow up (100). In a study of patients with bilateral vestibular schwannomas and serviceable hearing, 66% of patients maintained serviceable hearing after 6 years of follow-up, and there was no correlation between growth rate and hearing preservation (91). In a careful review of the literature, Sughrue and colleagues concluded that patients with tumor growth greater than 2.5 mm/year had a nearly doubled rate of hearing loss at 7 years compared to almost 15 years for the other patients (121). Patients with less than 2.5 mm/year of growth and stable hearing may be ideal candidates for conservative management.

Systemic therapy. In a landmark study by Plotkin and colleagues, vestibular schwannomas were shown to be enriched in vestibular endothelial growth factor (VEGF) receptors, and at least 40% of patients responded to bevacizumab with either tumor shrinkage or improvement in hearing. Bevacizumab is an antiangiogenic agent inhibiting VEGF (100). In a retrospective analysis of bevacizumab use in neurofibromatosis 2 vestibular schwannomas, 90% of patients had stable or improved hearing after 1 year of treatment and 61% at 3 years. Radiographic response, defined as stable or decreased tumor size, was seen in 88% at 1 year and 54% at 3 years (94). In a prospective study performed in the United Kingdom, use of bevacizumab (7.5 mg/kg every 3 weeks) lead to hearing stability or improvement in 86% of patients and partial radiographic response in almost 40% of patients (84). In general, treatment with bevacizumab is well tolerated, with the most common toxicities being fatigue, myalgias, proteinuria, amenorrhea, and hypertension (85). Relapse after cessation of therapy as well as possible kidney injury are concerns. A study further examined the effects of bevacizumab withdrawal. It was demonstrated that there is a high risk of increased vestibular schwannoma rebound growth following bevacizumab discontinuation. It was therefore proposed that heightened surveillance imaging and symptom monitoring are pursued for at least 6 months after stopping anti-VEGF therapy (131). In a similar context, a phase II study on maintenance bevacizumab (5 mg/kg every 3 weeks) showed an association with high rates of hearing and tumor stability on 18 months follow-up (93). Finally, a study examined the use of VEGF receptor peptide vaccines in seven NF2-related schwannomatosis patients with progressive schwannomas, resulting in greater than or equal to 20% tumor size reduction in two patients, including one for whom bevacizumab had not been effective (124).

Additionally, pathologic studies indicate that vestibular schwannoma is associated with a significant inflammatory response. A retrospective study of vestibular schwannoma suggested that patients who took aspirin regularly had reduced growth of vestibular schwannoma (68). A subsequent retrospective analysis of 564 patients with vestibular schwannoma using aspirin or other nonsteroidal anti-inflammatory drugs disputes this finding (61). Nevertheless, the findings indicate that the inflammatory response in vestibular schwannoma could be a potential therapeutic target. Both the bevacizumab trial and the aspirin study have at least partially shifted the focus for management of vestibular schwannoma in NF2-related schwannomatosis.

Multiple other therapies have also been evaluated for NF2-related schwannomatosis. A phase II study using lapatinib, a dual human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor 1 (EGFR1) tyrosine kinase inhibitor, showed promising results with objective activity in four of 17 patients with progressive vestibular schwannomas in NF2-related schwannomatosis (71). Treatment of patients with NF2-related schwannomatosis remains of unmet need, and many clinical trials have already been completed or are currently ongoing that include various molecular-targeted agents besides bevacizumab, such as the EGFR inhibitor, icotinib; the EGFR inhibitor, erlotinib; the VEGFR inhibitor, axitinib; the mTOR1 inhibitor, everolimus; the c-Met and ALK inhibitor, crizotinib; the dual mTORC1/2 inhibitor, vistusertib; the ALK and EGFR inhibitor, brigatinib; and the MEK inhibitor, selumetinib, with the primary measured outcomes being volumetric or hearing response (123). The responses have been promising so far but have not met the expectations (132). For example, the study on vistusertib did not meet the primary endpoint, but it was associated with high rates of stable disease in progressive NF2-related tumors even though the dosing regimen was poorly tolerated (65). Moreover, CUDC907, a dual histone deacetylase (HDAC)/PI3K inhibitor is a novel candidate for clinical trial because it was shown to have cytotoxic activity in neurofibromatosis 2 schwannoma models and primary vestibular schwannoma cells (60). Interestingly, a preclinical study screened combinations of 13 PI3K and FAK inhibitors in Schwann cell lines and found that the combination of the PI3K/mTOR inhibitor omipalisib and the SRC/FAK inhibitor dasatinib was the most efficacious, promoting G1 cell-cycle arrest and producing a 44% decrease in tumor growth over a 2-week period (58). The first phase III randomized clinical trial is being conducted in Japan using bevacizumab (50).

Gene therapy. A study by Ahmed and colleagues showed reduced tumor volume and pain in a human xenograft schwannoma model after the use of the adeno-associated virus serotype 1 (AAV1) vector in order to deliver the inflammasome adaptor protein, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) under the control of the P0 promoter (02). The minimum effective dose of AAV1-P0-hASC required to induce an anti-tumor effect was also determined, and it appeared not to be associated with neuronal toxicity, suggesting the possible use of AAV1-P0-ASC schwannoma gene therapy in clinical trials (02).

Hearing preservation. Despite conservative and aggressive management with surgery and radiation, hearing loss remains a persistent problem in NF2-related schwannomatosis. Because hearing loss is a major contributor to morbidity in NF2-related schwannomatosis, hearing preservation is a critical focus of management. Hearing preservation dictates choices in terms of surgical management of vestibular schwannomas. Consideration of hearing preservation plays a role in when and how to do surgery in patients with bilateral disease where one tumor is growing. In patients with unilateral hearing loss and a growing contralateral tumor, bevacizumab may be considered. Alternatively, surgery with implantation of an augmented hearing device should be considered.

Hearing implants are auditory brainstem implants (ABI) and cochlear implants (CI). The choice of implant depends upon the extent of hearing preoperatively as well as intraoperative assessment of cochlear nerve response through electrophysiological testing. If patients have cochlear nerve action potential then a cochlear implant may be placed; however, neuropraxia from surgical manipulation can cause absent responses; thus, repeat testing 6 to 8 weeks after surgery is recommended. If no response is noted after 6 to 8 weeks, auditory brainstem implant is indicated (130).

Auditory brainstem implants are electrodes that are placed on the brainstem over the cochlear nuclear complex during vestibular schwannoma surgery (109). Outcomes from auditory brainstem implants are variable (72), with only a small amount of patients recovering function to understand conversational speech (109). Much of the benefit with understanding speech with auditory brainstem implants has been seen in combination with lip reading (105). A novel 2023 study on patients with progressive bilateral tumor growth and associated profound hearing loss who underwent surgical intervention via partial cochleoectomy, tumor removal, modiolus preservation, and simultaneous cochlear implantation with lateral wall electrode carrier with basal double electrode contacts demonstrated that the aided speech recognition for consonant-nucleus-consonant (CNC) phonemes in quiet improved hearing from 57% to 83% 12 months after bilateral cochlear implantation (98). Another study that compared cochlear implantation to auditory brainstem implants showed that some auditory benefit can be achieved with either cochlear implantation or auditory brainstem implants, but cochlear implantation is associated with significantly better outcomes. When disease and anatomy permit, hearing rehabilitation with cochlear implantation should be considered over auditory brainstem implants in these patients (35). Thus, if cochlear nerve function is intact, cochlear implants should be considered the first choice for hearing rehabilitation. Of note, only larger tumor size seems to be associated with longitudinal cochlear implantation failure (112).

Peripheral nerve schwannomas. Surgery and, particularly, subcapsular resection, is considered to be the most safe and effective method for treating peripheral nerve schwannomas in NF2-related schwannomatosis that are symptomatic. Rare multinodular tumors with multifascicular involvement have increased surgical risks (92; 122).

Cranial meningioma. Approaches to managing cranial meningiomas in NF2-related schwannomatosis are similar to patients with sporadic meningiomas, with standard of care consisting of conservative management for asymptomatic and slowly growing tumors and surgical resection for those that are symptomatic or show rapid growth. In a longitudinal study by Goutagny and colleagues, 66% of meningiomas in 74 patients showed minimal to no growth in over 9 years of follow up. Thus, conservative management is a safe management strategy (55). The multiplicity of meningiomas and their location in higher-risk anatomical areas in NF2-related schwannomatosis, such as optic nerve sheath and skull base, may present a surgical challenge. A study by Osorio and colleagues suggested that lapatinib, an EGFR/ErbB2 inhibitor with antitumor properties against vestibular schwannoma in patients with NF2-related schwannomatosis, may be used to inhibit meningioma growth in these patients as well (88). Radiosurgery has also been suggested as a potential treatment alternative. Gao and colleagues presented a series of patients with neurofibromatosis 2 with meningiomas treated with GKRS with a median dose of 13 Gy (52). Meningiomas in NF2-related schwannomatosis seemed to successfully be locally controlled by GKRS, but their distant control rate was lower. Preclinical studies support the use of proteasomal pathway inhibitors as a treatment for meningiomas and schwannomas models (17).

Ependymoma. The optimal management of ependymomas in NF2-related schwannomatosis is usually conservative. A significant number of patients are asymptomatic despite potentially having multiple ependymomas (96). Surgery can be considered for symptomatic patients. A retrospective study compared outcomes of conservative management versus surgical intervention of spinal ependymoma based on differing practice patterns in NF2-related schwannomatosis centers in the United Kingdom and France. In the conservatively managed group from the United Kingdom, 27% experienced neurologic deterioration on follow-up, whereas 11% of those patients operated in an NF2-related schwannomatosis specialty center experienced postoperative decline. Based on these findings, patients with growing symptomatic ependymomas may be considered for surgery; however, surgery should be done in a center with significant expertise with this problem (66). Bevacizumab is a reasonable surgery-deferring option for ependymomas with cystic components or patients at risk for cumulative surgical morbidity (118).

Eye lesions. NF2-related schwannomatosis patients require an annual dilated funduscopic examination to monitor for potential ocular complications, which as previously discussed include cataracts, epiretinal membranes, and hamartomas. Approximately 10% to 25% of patients with cataracts experience vision degradation for which extraction can be performed (20; 18). Hamartomas remain a significant problem that can progress over time and cause visual loss.

Cutaneous findings. The removal of cutaneous schwannomas is not necessary but may be indicated if they are causing notable disfigurement or pain, or if removal can help diagnostically (41).

Outcomes

Patients with NF2-related schwannomatosis have a decreased life expectancy. For patients diagnosed in the 1970s and 80s, the life expectancy after diagnosis was a dismal 15 years with an average age of death of 36 years (45). A retrospective study of patients with NF2-related schwannomatosis in the United Kingdom found that earlier age of diagnosis, presence of meningiomas, and treatment at a non-specialty center were associated with poorer outcomes (09). Although it is clear that life expectancy has improved over the last 10 years, early death is still a reality for the most severely affected patients.

Special considerations

Pregnancy

A deleterious effect of pregnancy on the natural history of NF2-related schwannomatosis has been suggested by a few studies (03; 70). Even though there is not enough evidence that the size of schwannomas increases during pregnancy, hormones may affect the size of meningiomas (41). In addition, the determination of genetic risk in high-risk individuals, the clarification of a possible carrier status, as well as prenatal genetic testing discussions, should be conducted before pregnancy. Genetic counseling including discussions about potential risks to the offspring and other reproductive options should also be offered to at-risk or affected young adults (41).

Pediatric age group

This group usually presents with nonspecific features that are different from adult patients and usually unrelated to vestibular schwannomas, which hinders the correct diagnosis of NF2-related schwannomatosis. Most pediatric patients experience ocular and skin changes or nonvestibular schwannoma-related neurologic symptoms. NF2-related schwannomatosis suspicion should, thus, always be raised when children present with neurologic changes, which are usually attributed to tumors such as intracranial or spinal meningiomas, or nonvestibular or peripheral schwannomas. In this context, an MRI of the spine to detect schwannomas or ependymomas, an MRI of the posterior fossa to detect any small intracanalicular vestibular schwannomas, and a detailed skin and ocular examination should follow. A correct diagnosis is critical because childhood onset usually signifies more severe disease and higher risk of early morbidity and mortality (05).

Anesthesia

The use of nitrous oxide as an anesthetic agent during vestibular schwannoma surgery has been implicated in the development of tension pneumocephalus (82). The exact pathophysiology associated with the use of nitrous oxide in this setting is debated but may be related to its greater solubility than nitrogen in blood, which results in changes in middle ear pressure leading to the pneumocephalus. Before cranial surgery, a spinal imaging should be considered to evaluate for spinal tumors posing patient risk from spine manipulation while under anesthesia. Spinal tumors may further complicate epidural analgesia, and lumbosacral imaging should, thus, be obtained before local analgesia (41).

COVID-19

Patients with NF2-related schwannomatosis should follow the latest COVID-19-related public health measures and vaccination guidelines. These individuals do not seem to be at an increased risk for being infected with COVID-19 or developing severe complications because there is no evidence of immune dysfunction (08). However, patients with concurrent underlying medical problems such as large plexiform neurofibromas of the chest cavity, chronic lung diseases, or severe scoliosis might be at increased risk for complications from COVID-19 infection (73).

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Authors

Stefania Maraka MD

Dr. Maraka of University of Illinois Brain Tumor Center has no relevant financial relationships to disclose.
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Mariam/Myriam Markouli MD

Dr. Markouli of Boston University has no relevant financial relationships to disclose.
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Editor

Rimas V Lukas MD

Dr. Lukas of Northwestern University Feinberg School of Medicine received honorariums from Novartis and Novocure for speaking engagements, honorariums from Cardinal Health, Novocure, and Merck for advisory board membership, and research support from BMS as principal investigator.
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Former Authors

Patricia L Robertson MD
Sonal G Patel MD
Priya Kumthekar MD
Jay Gavvala MD
Renee Buchanan MD
Jeffrey J Raizer MD
Karan S Dixit MD
James H Tonsgard MD

Patient Profile

Age range of presentation: 0 month to 65+ years
Sex preponderance: male=female
Heredity: heredity may be a factor

autosomal dominant
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-9: Neurofibromatosis type 2 acoustic neurofibromatosis: 237.72
ICD-10: Neurofibromatosis (nonmalignant): Q85.0
OMIM: Neurofibromatosis, type II: #101000

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NF2-related schwannomatosis

Associated Disorders

Meningiomatosis
Neurofibromatosis
Schwannomatosis
Von Hippel Lindau

Differential Diagnosis

Mosaic neurofibromatosis type 2
neurofibromatosis type 1
schwannomatosis

Also Relevant

Ependymoma
Meningiomas
Neurocutaneous syndromes
Neurofibromatosis 1
Sporadic schwannomas and neurofibromas
- Vestibular schwannoma
- Von Hippel-Lindau disease

NF2-related schwannomatosis

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Table 1. Clinical Criteria (Manchester Criteria) for Diagnosis of Neurofibromatosis 2

Table 2. Revised Manchester Criteria

Table 3. Revised 2022 Criteria

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Associated or underlying disorders

Diagnostic workup

Management

Outcomes

Special considerations

Pregnancy

Pediatric age group

Anesthesia

COVID-19

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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Questions or Comment?

Also in This Category

Familial dysautonomia

Tumors of the skull base

Common maculopathies

Breath-holding spells

Toxic and nutritional deficiency optic neuropathies

Third nerve palsy

Nystagmus

Neuropathies associated with cytomegalovirus infection

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