Version August 2025
INTRODUCTION —
NF2-related schwannomatosis (NF2-SWN, formerly neurofibromatosis type 2) is an autosomal dominantly inherited syndrome that predisposes individuals to bilateral vestibular schwannomas as well as multiple other tumors of the nervous system [1-3]. NF2-SWN is caused by pathogenic variants in the NF2, moesin-ezrin-radixin like (MERLIN) tumor suppressor (NF2) gene, which produces merlin, a tumor suppressor.
The molecular pathogenesis, clinical features, diagnosis, and management of NF2-SWN are reviewed here. Neurofibromatosis type 1 (NF1; von Recklinghausen disease) and other schwannomatoses are discussed separately. (See "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis" and "Schwannomatoses related to genetic variants other than NF2".)
TERMINOLOGY —
In 2022, the nomenclature for neurofibromatosis type 2 and schwannomatosis was revised to recognize the complete spectrum of schwannoma predisposition syndromes, which are defined in many cases by pathogenic variants in one of several genes on chromosome 22 [4]:
●NF2-related schwannomatosis (NF2-SWN), formerly neurofibromatosis type 2
●SMARCB1-related schwannomatosis (SMARCB1-SWN)
●LZTR1-related schwannomatosis (LZTR1-SWN)
●Other schwannomatoses, including those related to loss of heterozygosity of chromosome 22q (22q-SWN)
MOLECULAR PATHOGENESIS
NF2 gene — NF2-SWN is consistently linked with abnormalities of the NF2 gene, which is located on chromosome 22q [5]. The NF2 gene produces merlin, also known as schwannomin, a cell membrane-related protein that acts as a tumor suppressor [6,7].
Individuals with NF2-SWN may inherit an abnormal NF2 allele from a parent. Alternatively, a de novo variant may arise after fertilization, resulting in a mosaic expression of two cell lines. For individuals thought to harbor a de novo variant, somatic mosaicism may prevent the molecular diagnosis from being established by germline testing alone, instead requiring tumor tissue to be analyzed [8-12]. A study of over 1000 patients with de novo NF2-SWN found that more than 50 percent of such cases are potentially due to mosaicism [13].
The development of schwannomas and other NF2-SWN-associated tumors requires inactivation of both NF2 alleles in a given cell. The ”second hit” usually occurs through loss of the entire healthy NF2 gene and most or all of chromosome 22q (ie, a loss of heterozygosity event), although a point pathogenic variant or promoter methylation in the normal NF2 copy may also be sufficient to cause tumor development. Loss of the normal copy of NF2 may also occur by mitotic recombination, where the mutated copy is doubled up without loss of chromosomal material [14].
Genotype-phenotype correlation — NF2-SWN is fully penetrant, meaning that any individual who carries a germline pathogenic NF2 variant will develop the clinical disorder [4]. Within a family that includes multiple members with NF2-SWN, the phenotypic expression and natural history of the disease are similar. However, significant differences have been observed among families harboring different abnormalities of NF2.
Frameshift or nonsense variants cause truncated protein expression, which has been associated with more severe manifestations of NF2-SWN; missense or in-frame deletions have been associated with milder manifestations of disease [15]. In an analysis of 268 patients in whom the NF2 abnormality was characterized, the presence of a truncated protein was associated with younger age at diagnosis and a higher prevalence of meningiomas, spinal tumors, and tumors of cranial nerves other than cranial nerve VIII [16]. Patients with variants causing truncated protein also had vestibular schwannomas at a younger age and had more cutaneous schwannomas. There is also a positional effect, with variants in the later parts of the gene (especially exons 14 and 15) being associated with milder disease and fewer meningiomas [17].
There is also evidence that different NF2 pathogenic variants may have markedly different effects on life expectancy, with missense variants being associated with the best life expectancy and truncating variants in exons 2 to 13 having the poorest overall survival [18]. A genetic severity score was derived from the NF2 variant identified, which predicts the clinical severity of NF2-SWN disease (table 1) [18,19]. An updated genotype classification based on the functional impact of pathogenic variants on merlin function has been proposed [20].
EPIDEMIOLOGY —
The estimated incidence of NF2-SWN derived from population-based studies in England and Finland is as high as 1 in 25,000, with disease prevalence as high as 1 in 58,000 in England [21-25].
CLINICAL FEATURES —
NF2-SWN is an autosomal dominant schwannoma predisposition syndrome that affects the nervous system as well as eyes and skin. In addition to schwannomas, individuals may develop meningiomas and ependymomas, and most have one or more ophthalmic and cutaneous manifestations.
Age of onset — Individuals with NF2-SWN typically present with symptoms due to one or more NF2-SWN-related tumors around age 20 to 25 years [15,26], although age of onset is variable depending on genetic severity scoring [19].
The presentation of NF2-SWN in children is associated with severe genotype and may often be delayed, since the earliest manifestations may be skin tumors and ocular findings [27,28]. Rare patients with a mild genotype or mosaic genetics are diagnosed as late as the eighth decade of life with unusually indolent tumor growth patterns [29].
Patients typically present around 20 to 25 years of age [15]. Initial or presenting symptoms vary by age at presentation.
Clinical spectrum — Children diagnosed with NF2-SWN often have an atypical, but more severe, presentation [27]. In childhood, patients most commonly present with visual/eye problems, hearing loss, weakness, pain, mononeuropathy, cutaneous tumors, and/or seizures [15,30,31]. In adults, hearing loss and tinnitus are the presenting symptoms in over one-half of patients.
The most frequent clinical features of NF2-SWN include:
●Neurologic lesions [26,32,33]
•Bilateral vestibular schwannomas, generally developing by 30 years of age – 90 to 95 percent
•Schwannomas of other cranial nerves – 24 to 51 percent
•Intracranial meningiomas – 45 to 77 percent [17]
•Spinal tumors (both intramedullary ependymomas and extramedullary meningiomas or schwannomas) – 63 to 90 percent
•Peripheral neuropathy – Up to 66 percent
●Ocular lesions [34-36]
•Posterior subcapsular cataracts – 60 to 81 percent
•Epiretinal membranes – 12 to 40 percent
•Retinal hamartomas – 6 to 22 percent
●Skin lesions [26,32,37,38]
•Cutaneous schwannomas – 59 to 68 percent
•Skin plaques – 41 to 48 percent
•Subcutaneous schwannomas – 43 to 48 percent
Vestibular schwannomas — Vestibular schwannomas in NF2-SWN are typically bilateral and cause tinnitus, hearing loss, and balance dysfunction (image 1) [2]. The course of hearing loss is usually gradual and progressive, leading to deafness, although sudden hearing loss can occur. NF2-SWN-related vestibular schwannomas are usually multifocal and occur equally on the superior and inferior vestibular nerve [39].
The mechanism of hearing loss from vestibular schwannomas in NF2-SWN is not well understood, and there is poor correlation between tumor size and/or growth rate and degree of hearing loss [40-43]. One proposed mechanism of hearing loss in this population is the accumulation of intralabyrinthine protein as a result of cochlear aperture obstruction, which can be visualized by high-resolution magnetic resonance imaging (MRI) [44]. If left untreated, vestibular schwannomas can extend medially and cause brainstem compression and hydrocephalus. (See "Vestibular schwannoma (acoustic neuroma)", section on 'Clinical presentation'.)
Almost all vestibular schwannomas in individuals with NF2-SWN are histopathologically benign. However, they are an important cause of morbidity because of their anatomic location and bilaterality.
Meningiomas — Approximately one-half of individuals with NF2-SWN have meningiomas, and multiple meningiomas are often present [45]. The incidence increases with age, and lifetime risk may be as high as 75 percent [26]. Most meningiomas are intracranial, although spinal meningiomas are also seen. The presence of multiple meningiomas is a leading cause of morbidity in NF2-SWN due to the cumulative mass effect of the tumors.
Individuals with NF2-SWN tend to develop meningiomas at an earlier age than those with sporadic meningiomas. When patients are diagnosed with meningioma during childhood, approximately 20 percent will be found to have NF2-SWN [27,46]. Histopathologically, the meningiomas seen in patients with NF2-SWN are more frequently atypical or anaplastic compared with sporadic tumors [47,48]. (See "Epidemiology, pathology, clinical features, and diagnosis of meningioma", section on 'Clinical presentation' and "Spinal cord tumors", section on 'Meningioma'.)
Spinal tumors — Most individuals with NF2-SWN eventually develop a spinal tumor, which can cause debilitating pain, muscle weakness, or paresthesias [2,49,50].
●Schwannomas are most common (image 2). These arise from the dorsal root and can take on a characteristic “dumbbell” shape. (See "Spinal cord tumors", section on 'Presentation' and "Intradural nerve sheath tumors", section on 'Clinical presentation'.)
●Meningiomas can also arise on the spinal cord in the extramedullary space. (See "Spinal cord tumors", section on 'Meningioma'.)
●Intramedullary tumors, particularly ependymomas (image 3), are seen in 5 to 33 percent of individuals with NF2-SWN. (See "Spinal cord tumors", section on 'Ependymomas'.)
Neuropathies — Neuropathies can be manifested in a variety of ways in individuals with NF2-SWN [1,51]. Some people develop a mononeuropathy, often involving the facial nerve, which can precede the development of other NF2-SWN manifestations. Others may develop a peripheral mononeuropathy associated with a specific tumor compressing or disrupting nerve function. Finally, in 3 to 5 percent of adults, a more severe polyneuropathy not directly related to tumors is seen, and this can progress to severe muscle wasting [1,2,52].
Ophthalmic manifestations — Individuals with NF2-SWN may have visual impairment due to cataracts, optic nerve meningiomas, retinal hamartomas, and epiretinal membrane [1,2,31,36,53]. Cataracts are seen in 60 to 80 percent of patients and typically are manifested as posterior subcapsular lenticular opacities. Ophthalmic manifestations are more severe with increased genetic severity score [54]. (See 'Genotype-phenotype correlation' above.)
Development of cataracts and other ocular manifestations can lead to visual abnormalities in early childhood in those with NF2-SWN [31]. In addition, particular attention is required to differentiate optic nerve meningiomas or hamartomas from retinoblastoma. (See "Retinoblastoma: Clinical presentation, evaluation, and diagnosis", section on 'Clinical presentation'.)
Due to the exceedingly high risk of deafness with NF2-SWN and the potential impact of ophthalmic manifestations on vision, patients should be monitored routinely by an ophthalmologist. (See 'Tumor surveillance and follow-up' below.)
Cutaneous manifestations — Approximately 70 percent of individuals with NF2-SWN have cutaneous manifestations, although only 10 percent have more than 10 skin tumors [1,55,56]. These skin lesions can take several forms:
●Plaque-like lesions, which are intracutaneous and slightly raised [12]. These may be more pigmented than the surrounding skin and may be associated with increased hair.
●Subcutaneous nodules can often be palpated, sometimes along the course of a peripheral nerve. These tumors represent a swelling of the nerve.
●Intracutaneous tumors, similar to those observed in patients with neurofibromatosis type 1 (NF1), are also seen occasionally. These tumors generally represent schwannomas rather than neurofibromas.
DIAGNOSIS —
The diagnosis of NF2-SWN is based upon standardized criteria that include both clinical features and genetic testing. Genetic testing is recommended in all individuals with suspected schwannomatosis predisposition syndromes but is not required for the diagnosis of NF2-SWN in those who fulfill clinical criteria.
Clinical and radiologic evaluation — For individuals suspected of having NF2-SWN, the initial evaluation should include a detailed clinical and family history, neurologic examination, careful cutaneous and eye examinations, and contrast-enhanced MRI of the brain and whole spine [1].
●Skin examination – A full skin examination should be performed to assess for cutaneous tumor burden. Suspicious lesions should be palpated. (See 'Cutaneous manifestations' above.)
●Eye examination – All individuals should have a slit lamp examination and ophthalmoscopy, ideally by an ophthalmologist with experience in NF2-SWN.
●Neuroimaging – High-resolution, contrast-enhanced MRI of the brain with thin cuts (<3 mm with no skipping) through the internal auditory canal should be performed for optimal resolution to detect small vestibular schwannomas. Contrast-enhanced MRI of the spine is recommended for all patients at the time of diagnosis to assess the burden of spinal cord involvement and rule out spinal cord impingement.
Diagnostic criteria — The clinical diagnosis of NF2-SWN is based upon the presence of any one of the following criteria [4,57,58]:
●Bilateral vestibular schwannomas
●An identical pathogenic NF2 variant in at least two anatomically distinct NF2-SWN-related tumors (schwannoma, meningioma, and/or ependymoma); if the variant allele fraction in blood is clearly <50 percent, the diagnosis is mosaic NF2-SWN
●Two of the following major criteria:
•Unilateral vestibular schwannoma
•First-degree relative other than sibling with NF2-SWN
•Multiple meningiomas
•A pathogenic NF2 variant in nontumor material (eg, blood)
●One major criterion and two of the following minor criteria:
Can be counted twice (eg, two distinct schwannomas would count as two minor criteria):
•Nonvestibular schwannoma (at least one dermal if unilateral vestibular schwannoma used as major criterion)
•Ependymoma
Can only be counted once:
•Juvenile subcapsular or cortical cataract
•Retinal hamartoma
•Epiretinal membranes
•Single meningioma (only if multiple meningiomas not used as major criterion)
In a patient with NF2-SWN-associated tumors who does not otherwise meet diagnostic criteria for constitutional NF2-SWN, criteria for mosaic NF2-SWN are met in the presence of either of the following:
●Clearly <50 percent pathogenic variant allele fraction in blood or saliva
●Pathogenic variant not detected in blood or saliva but a shared pathogenic variant is found in two or more anatomically unrelated tumors
Clinical criteria for NF2-SWN were initially established by a National Institutes of Health (NIH) consensus conference [59]. These were subsequently modified into the Manchester criteria, which substantially improved the sensitivity for making the diagnosis without affecting specificity [26,60]. These were further adapted by an international consensus group [4].
Revisions to the NF2-SWN diagnostic criteria take into account the possibility that unilateral vestibular schwannomas may be due to LZTR1 germline variants (ie, LZTR1-related schwannomatosis) rather than NF2-SWN (see "Schwannomatoses related to genetic variants other than NF2"). Although the diminishing likelihood of NF2-SWN in patients with vestibular schwannomas diagnosed after 70 years of age [57,61] was considered, no age limit was set in the 2022 criteria, due in part to the possibility of mosaic disease as the driver of late or mild clinical presentation [4]. In addition, ependymoma has replaced glioma in the diagnostic criteria based on the absence of high-grade gliomas [62] and predominance of ependymomas in NF2-SWN [58].
Genetic testing — Genetic testing is recommended in all individuals with suspected schwannomatosis predisposition syndromes. Although it is not required for the diagnosis of NF2-SWN in those who fulfill clinical criteria, it can help in assessing disease severity, among other roles.
Genetic testing is particularly helpful in younger individuals who do not otherwise meet diagnostic criteria without genetic data (algorithm 1 and algorithm 2). De novo NF2-SWN cases are common, and patients may present before the clinical diagnostic criteria are fulfilled. Early identification of patients who have NF2-SWN is important to minimize the complications associated with disease manifestations.
Genetic testing is also important for non-sibling first-degree relatives of an individual with NF2-SWN, who can be diagnosed with NF2-SWN based on an NF2 pathogenic variant, even in the absence of clinical features. Of note, standard analysis to detect variants in the NF2 gene using second-generation next-generation sequencing and a test for copy number variants only detects a likely pathogenic variant in 87 percent of families [63]. This can be improved to 95 percent by using additional techniques such as long-range polymerase chain reaction (PCR), ribonucleic acid (RNA) testing, and cytogenetic testing.
Referral to a clinical geneticist or genetic counselor is recommended for individuals in whom genetic testing is being considered. Physician-directed testing is increasing, but involvement of a genetic expert remains very important for a holistic approach to patient and family counseling.
Given the frequency of mosaic disease, the ideal genetic testing method for NF2-SWN involves testing tumor tissue plus blood lymphocytes to maximize the likelihood of identifying the causative pathogenic variant [64]. When possible, molecular testing for NF2-SWN should start with tumor deoxyribonucleic acid (DNA) (if available) and then proceed to targeted testing of blood lymphocytes by sequencing of any NF2 aberration identified. If two tumors are available, identification of an identical NF2 variant in two tumors that is either clearly <50 percent minor allele frequency or not present at all in blood confirms mosaicism. LZTR1 should be assessed if individuals have only unilateral vestibular schwannoma or otherwise meet NF2-SWN criteria with only non-intradermal schwannoma disease [58]. (See 'Diagnostic criteria' above.)
Comprehensive molecular genetic evaluation is recommended in all individuals suspected of having NF2-SWN, including those with any of the following [65,66]:
●A first-degree relative with NF2-SWN (ie, affected parent, sibling, or offspring)
●Multiple spinal tumors (schwannomas, meningiomas)
●Cutaneous schwannomas
●An apparently sporadic vestibular schwannoma in an individual younger than 30 years of age
●A solitary meningioma or nonvestibular schwannoma in an individual younger than 25 to 30 years of age [67]
●Two or more anatomically distinct meningiomas in an individual aged 25 to 69 years and three or more meningiomas at any age [65,68]
The role of genetic testing for NF2-SWN in all patients with a unilateral vestibular schwannoma is less certain. Although these patients appear to be at increased risk for the development of NF2-SWN, routine screening for germline variants does not appear to be indicated except in those younger than 30 years of age [65,66]. Moreover, germline testing alone, especially in this context, may not be sufficiently sensitive in light of the possibility of genetic mosaicism [64]. There is also evidence that NF2-SWN is unlikely in first-degree relatives who only manifest unilateral vestibular schwannoma [69].
Of note, some individuals have been identified who carry a likely pathogenic variant in NF2 in blood but do not have clinical features of NF2-SWN (eg, in an asymptomatic individual who underwent genetic sequencing for another indication). Given the complete penetrance of NF2 pathogenic variants, such individuals and their at-risk relatives should be referred to a tertiary care center with expertise in schwannomatosis for further evaluation; testing to determine whether the variant is constitutional (germline), mosaic, or somatic; and genetic counseling [4]. Neuraxial imaging and specialized ophthalmologic evaluation may be considered to identify any occult clinical signs of disease.
Differential diagnosis — The major entities in the differential diagnosis of NF2-SWN are sporadic vestibular schwannomas, other schwannomatoses, neurofibromatosis type 1 (NF1), and a familial syndrome of multiple meningiomas [2].
Sporadic vestibular schwannomas — Sporadic vestibular schwannomas are relatively common in the general population. Although these tumors are unilateral, their diagnosis can cause confusion in some cases. (See "Vestibular schwannoma (acoustic neuroma)".)
The possibility that a unilateral vestibular schwannoma represents the first manifestation of NF2-SWN is related to the age of the patient. For younger individuals who are less than 30 years of age, there is a substantial risk of developing a contralateral vestibular schwannoma, and patients should be monitored carefully for that possibility. Even with a negative family history, these may represent a de novo somatic variant with mosaicism [66,70]. The likelihood that an individual diagnosed with a vestibular schwannoma after the age of 30 will have constitutional NF2-SWN is low, although mosaic cases may present later in life.
In patients with a unilateral vestibular schwannoma and multiple noncutaneous schwannomas, schwannomatosis due to variants in LZTR1 must also be considered. (See 'Other schwannomatoses' below.)
Other schwannomatoses — NF2-SWN is the most common form of schwannomatosis, but additional forms also exist that may lead to multiple noncutaneous peripheral and intracranial schwannomas in the absence of bilateral vestibular schwannomas.
These syndromes may be caused by variants in SMARCB1 (ie, SMARCB1-SWN), LZTR1 (ie, LZTR1-SWN), or larger genetic events on chromosome 22q (ie, 22q-SWN); or they may arise without an identifiable germline or mosaic variant (ie, schwannomatosis, NEC). Among these, LZTR1-SWN has the greatest diagnostic overlap with NF2-SWN, because individuals may have unilateral vestibular schwannomas, in addition to other tumors [71].
Because of the critical role of NF2 loss of function in schwannoma development, detailed genetic analysis of schwannomas or meningiomas from non-NF2-related schwannomatosis will still contain somatic variants in the NF2 gene, but such variants are not present in the germline. This is considered a required genetic loss of function for individual tumors to form [72].
The clinical features, diagnosis, and management of non-NF2-related schwannomatoses are reviewed separately. (See "Schwannomatoses related to genetic variants other than NF2".)
Neurofibromatosis type 1 — NF2-SWN and NF1 are caused by variants in genes on different chromosomes. Nonetheless, partial overlap in the clinical manifestations of these inherited disorders can occasionally lead to confusion. (See "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis".)
Key differences between NF1 and NF2-SWN include:
●Lisch nodules (raised, pigmented hamartomas of the iris) are characteristic of NF1 and are not seen in significant numbers in NF2-SWN.
●The schwannomas associated with NF2-SWN rarely, if ever, undergo malignant transformation into a neurofibrosarcoma (malignant peripheral nerve sheath tumor [MPNST]) [73], whereas MPNST risk is much higher in patients with NF1.
●The "dumbbell" spinal root tumors that are seen with both NF2-SWN and NF1 are schwannomas in NF2-SWN and neurofibromas in NF1.
●NF2-SWN is not associated with the cognitive impairment that is often seen with NF1.
●Gliomas, especially astrocytomas, are common in NF1 but not NF2-SWN. Ependymomas, primarily involving the spine, are common with NF2-SWN.
Familial meningioma — Familial meningioma is a rare disorder that is not associated with abnormalities of the NF2 gene. Some cases may be associated with germline variants in SMARCE1, SUFU, or BAP1, while others have no identified genetic cause to date.
MANAGEMENT —
The management of individuals with NF2-SWN is complex and involves multiple disciplines to prevent or treat the various complications that may develop. Whenever possible, they should be cared for by a multidisciplinary team with expertise in the care of individuals with NF2-SWN and their families and caregivers [74]. Multidisciplinary teams are a requirement for high-quality care for NF2-SWN and may include a neurosurgeon, neuro-otologist, neuroradiologist, neurologist or neuro-oncologist, radiation oncologist, audiologist, and geneticist or genetic counselor.
Tumor surveillance and follow-up — For individuals known to harbor an NF2 pathogenic variant, there is little data to guide surveillance intervals, but expert opinion suggests that follow-up should include [1,2,74]:
●Annual history and physical examination, including:
•Audiology with measurement of pure-tone thresholds and word recognition scores
•Ophthalmologic evaluation
•Cutaneous examination
●Annual brain MRI, beginning at 10 years of age. If baseline imaging shows no characteristic sites of involvement, frequency can be reduced to every two years. If tumors are detected, brain MRI should be performed twice yearly in the first year, then annually. Brain MRI protocol should include high-resolution (1 to 3 mm slice thickness) postcontrast imaging through the internal auditory meatus, preferably in at least two orthogonal planes.
●Surveillance spinal MRI every 24 to 36 months beginning at 10 years of age. The interval between scans may be reduced to every three to five years if there is no disease detected on baseline imaging. If tumors are detected, imaging should be repeated in six months to evaluate tumor growth rate.
●Whole-body MRI, including brain and spine, is used at some centers for surveillance.
●18F-fluorodeoxyglucose positron emission tomography (FDG-PET) is not recommended for routine screening, as the risk of malignant peripheral nerve sheath tumor (MPNST) is extremely small in an individual with NF2-SWN who has not received radiation. In addition, FDG-PET does not discriminate well between a cellular schwannoma and MPNST.
Treatment of vestibular schwannomas — The goal of treatment for vestibular schwannomas in individuals with NF2-SWN is preservation of function and maintenance of quality of life [1]. As such, the identification of a tumor per se is not an indication for treatment, and the potential benefits must be balanced against the risks of active intervention. Treatment is generally indicated when there is a risk of brainstem compression, deterioration of hearing, and/or facial nerve dysfunction [2].
Surgery — Vestibular schwannomas are generally managed surgically if treatment is indicated, although first-line bevacizumab plays a role in select cases (see 'Bevacizumab' below). Surgery in patients with NF2-SWN can be more complex than in patients with sporadic tumors, since NF2-SWN-associated tumors are often multifocal [39,75]. In addition, the entire vestibular nerve is at risk of developing schwannomas in patients with NF2-SWN; thus, early or complete removal of a schwannoma does not preclude future development of schwannomas on the same side, which are generally genetically distinct [75].
Vestibular schwannomas may extend to involve fibers of the facial nerve, and there is a significant risk of damage to the facial nerve during surgery [1]. This is particularly problematic, since the facial nerve controls the blink reflex and innervates the lacrimal gland. Loss of the blink reflex or loss of tearing may complicate other eye problems. Moreover, individuals with NF2-SWN are at risk of complete deafness, and iatrogenic risk to vision may significantly complicate their well-being and cannot be taken lightly. (See 'Ophthalmic manifestations' above.)
Radiation therapy — The role of radiation therapy in managing vestibular schwannomas in patients with NF2-SWN is debated [76-79]. Radiation therapy is primarily used for the purposes of controlling tumor growth when surgery alone is not an option or has been unsuccessful.
Because hearing loss is a very common sequela with radiation therapy, treatment must be carefully weighed in this population that often has significantly compromised hearing and/or is at risk for further impairment with future tumor growth. Similar to sporadic vestibular schwannomas, surgical resection may be more difficult following radiation therapy.
Added complexity arises from concerns that NF2-SWN, as a genetic tumor predisposition syndrome, increases the risk of radiation-induced secondary tumor formation. Long-term follow-up data support this concern [80-84]. In a study of 1345 patients with NF2-SWN that included 266 individuals who had undergone radiation therapy, the risk of malignancy at 20 years was increased among patients who had received radiation therapy compared with untreated matched controls (6 versus <1 percent) [80]. Risk may also be increased with conventional fractionated radiation therapy, which is used to treat larger target volumes and likewise entails larger normal tissue collateral irradiation compared with more conformal techniques.
Despite the risks, the benefit of radiation therapy often outweighs the risk when surgical and/or drug treatments are exhausted and there is a need to control tumor growth that can otherwise become debilitating and life-threatening due to brainstem compression by tumor.
We avoid treating younger patients whenever possible because the risk of radiation-induced secondary tumors increases with time from radiation exposure and with younger age at radiation exposure. When radiation therapy is compelling, proton therapy at an experienced center can be considered to reduce normal tissue collateral radiation exposure.
Bevacizumab — Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), can induce both tumor shrinkage and hearing improvement in patients with NF2-SWN-associated vestibular schwannomas, and there is growing experience at multidisciplinary NF2-SWN centers with using bevacizumab as a first-line medical therapy for rapidly growing vestibular schwannomas that are a threat to function, before committing a patient to surgery or radiation therapy [85].
Given the risk of toxicities that may limit the duration of the safe use of bevacizumab, as well as its potential effectiveness in controlling tumor size and/or hearing, it may be reasonable to withhold initiation of bevacizumab for a patient with NF2-SWN until there is a single hearing ear that begins to lose hearing and/or a single hearing ear with a growing ipsilateral tumor.
The dose and schedule of bevacizumab in NF2-SWN has not been standardized. A proposed regimen is bevacizumab 5 to 7.5 mg/kg every two to three weeks for at least six months or until no further tumor response on successive three-month interval MRIs, followed by maintenance therapy at 2.5 to 5 mg/kg every four weeks [85]. A multicenter trial of an alternative, higher-dose “induction” regimen (10 mg/kg every two weeks for six months) offered no clear advantage over the historical experience with lower-dose regimens [86], and higher doses may increase the risk of renal impairment.
The efficacy of bevacizumab for progressive vestibular schwannomas in NF2-SWN is supported by retrospective case series and a limited number of prospective single-arm studies [85-95]. In a meta-analysis of eight observational studies in a total of 161 patients with NF2-SWN-associated vestibular schwannomas, the best response to bevacizumab was partial regression in 41 percent, no change in 47 percent, and progression in 7 percent [94]. The median treatment duration was 16 months. In the subset of patients with audiometric data, hearing was improved in 20 percent, stable in 69 percent, and worse in 6 percent. The pooled rate of serious toxicity was 17 percent, including one fatal intracranial hemorrhage. The most common toxicities of any severity were amenorrhea (70 percent), proteinuria (43 percent), and hypertension (33 percent).
There may also be a role for bevacizumab in cystic progressive ependymoma, as shown by a systematic review of treatment reports [96].
Other targeted therapies — The NF2 gene product appears to affect multiple molecular pathways involved in cell growth. An understanding of this provides a potential opportunity for targeted therapy in the treatment of NF2-SWN-related tumors. Examples including the following:
●Everolimus – There are mixed reports on the efficacy of everolimus, an oral inhibitor of the mammalian target of rapamycin complex 1 (mTORC1), for progressive vestibular schwannomas in patients with NF2-SWN [97,98].
●Lapatinib – Lapatinib, a dual human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, showed evidence of objective activity in 4 out of 17 patients with NF2-SWN-related progressive vestibular schwannoma in a small phase II trial [99]. By contrast, erlotinib, an EGFR inhibitor, was not effective in a retrospective series that included 11 patients with NF2-SWN [100].
●Brigatinib – In the phase II INTUITT-NF2 basket-platform trial [101], the anaplastic lymphoma kinase (ALK) inhibitor brigatinib was evaluated in 40 patients with progressive target tumors, of which 10 were vestibular schwannomas [102]. Although none of the 10 target vestibular schwannomas responded (defined as ≥20 percent decrease in tumor volume) and 6 progressed, the response rate for all 43 evaluable vestibular schwannomas in the trial was 23 percent. Hearing improved in 35 percent of evaluable ears as measured by word-recognition scores and pure-tone averages, and approximately three-quarters of patients had no decrease in hearing at 12 months. These rates are comparable to those observed with bevacizumab, as reviewed above. (See 'Bevacizumab' above.)
Hearing impairment — Hearing impairment in patients with NF2-SWN is associated with decreased quality of life and increased risk for social avoidance and isolation, unemployment, and decreased social support [103]. For patients with severe hearing impairment, strategies such as cochlear or brainstem implants may offer some benefit [104,105]. Pilot studies have demonstrated the feasibility of novel psychosocial interventions delivered to deafened individuals with NF2-SWN via teleconferencing with captioning technology [106]. (See "Hearing amplification in adults", section on 'Cochlear implants'.)
Meningioma management — Meningiomas can arise both at intracranial sites and at intradural, extramedullary sites in the spinal cord. (See "Epidemiology, pathology, clinical features, and diagnosis of meningioma", section on 'Clinical presentation'.)
Many meningiomas in NF2-SWN grow to a certain size, stop growing, and do not require active treatment. Risk factors for more rapid growth (eg, ≥2 cm3 per year) are similar to those for sporadic meningiomas and include large tumor size, peritumoral edema, absence of calcifications, and isointense or hyperintense T2-weighted MRI signal [107].
For rapidly growing meningiomas and those threatening functional loss, meningiomas are managed surgically when possible. Radiation therapy is used in patients whose tumors are not surgically accessible, in those with symptomatic progression of a partially resected tumor, and for higher grade (grade 2 and 3) meningiomas [108,109]. However, long-term follow-up is lacking in this population. As with the use of radiation in patients with vestibular schwannomas, there is concern about the development of secondary neoplasia. (See 'Radiation therapy' above.)
Targeted therapies under investigation have a relatively low objective response rate but show some ability to slow the growth trajectory of tumors, including some that have failed prior therapies. One example is the ALK inhibitor, brigatinib. Supporting data come from the brigatinib platform of the INTUITT-NF2 trial, in which 20 of 40 patients had progressive meningioma as the target lesion and an additional 31 non-target meningiomas were evaluable for radiographic response (≥20 percent decrease in volume) [102]. Three of 20 target meningiomas met criteria for response (15 percent), and the response rate of all 53 evaluable meningiomas was 25 percent. The annualized growth rate for all meningiomas on treatment was 3 percent, which is lower than a pretreatment rate of 139 percent derived from a multicenter NF2 natural history study.
Lapatinib also showed some activity in a small series of patients with NF2-SWN-associated progressive meningiomas [110]. Bevacizumab also has modest activity in NF2-SWN-related meningiomas [111]. The INTUITT-NF2 trial has a neratinib platform for NF2-SWN-associated meningiomas that is ongoing [101]. A histone deacetylase inhibitor is also under investigation [112].
Intramedullary spinal tumors — Approximately 75 percent of intramedullary spinal tumors in patients with NF2-SWN are ependymomas. These are often diagnosed with screening imaging studies and usually grow very slowly without symptoms for a prolonged period. Careful neurologic surveillance for evidence of progression is indicated in this situation.
If symptoms require intervention, which is relatively uncommon, first-line treatment is generally surgical resection [113]. There is some evidence that cystic elements of the tumors respond to bevacizumab [114]. There is also a basket of the INTUITT-NF2 trial looking at targeted drug effects for NF2-SWN-associated ependymomas [101]; the brigatinib platform enrolled only two target ependymomas, neither of which responded, but the response rate in all five evaluable ependymomas was 20 percent (one patient) [102].
Radiation therapy is also an effective option when surgical management has been exhausted and merits multidisciplinary discussion to determine the best timing relative to the alternatives of surveillance and medical therapies.
Screening of at-risk family members — For families in which there is a documented index case of NF2-SWN, screening of at-risk family members is important so that a diagnosis can be established in affected individuals as early as possible [1,65].
When a specific pathogenic variant has been identified in the index case, this information provides a 100 percent specific marker to test other family members. Prenatal testing is possible in settings where a known variant has been identified [2]. However, variant screening is not 100 percent sensitive in patients with NF2-SWN.
For children who have not inherited NF2-SWN, no further testing or prospective evaluation is necessary. Tumor surveillance and follow-up for individuals with an NF2 pathogenic variant is reviewed above. (See 'Tumor surveillance and follow-up' above.)
PROGNOSIS AND COMPLICATIONS —
Despite surveillance for the development of tumors in patients with NF2-SWN and the aggressive management of any abnormalities that are detected, NF2-SWN is associated with substantial morbidity and shortened survival [1].
The most common morbidities include the following:
●Deafness – The vestibular schwannomas associated with NF2-SWN are more difficult to manage than their sporadic counterparts. In NF2-SWN, the lesions are often multifocal, and histologically these are less vascular and more lobular [115]. Because of this and the bilaterality of the tumors, the majority of patients eventually become completely deaf.
●Decreased mobility – Poor balance due to eighth nerve involvement, visual problems, and muscle weakness can all contribute to immobility, and many patients require use of a wheelchair or other assistive devices in early adulthood.
●Swallowing and speech dysfunction – There is frequent loss of lower cranial nerve function leading to swallowing and speech problems, which may contribute to shortened life expectancy [116,117].
Overall survival appears to be shortened in patients with NF2-SWN due to complications of their tumors. In studies from the 1970s and 1980s, the actuarial survival after establishing the diagnosis was 15 years, with an average age at death of 36 years [26,118,119]. Earlier diagnosis and advances in treatment may have improved outcomes [120,121]. Subsequent data suggest that patients with a mild genotype may live on average to mid-40s or 50s, while those with a severe phenotype have an average age at death of 32.5 years [19].
INFORMATION FOR PATIENTS —
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Vestibular schwannoma (acoustic neuroma) (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Definition – NF2-related schwannomatosis (NF2-SWN; formerly known as neurofibromatosis type 2) is a dominantly inherited syndrome that predisposes individuals to bilateral vestibular schwannomas as well as multiple other tumors of the nervous system. (See 'Introduction' above and 'Terminology' above.)
●Pathogenesis – NF2-SWN is due to pathogenic variants in the NF2 gene, which produces merlin, a cell membrane-related protein that acts as a tumor suppressor. (See 'Molecular pathogenesis' above.)
●Clinical manifestations – The clinical manifestations of NF2-SWN include bilateral vestibular schwannomas in almost all patients. Other commonly observed nervous system tumors include intracranial meningiomas, schwannomas of other cranial nerves, and spinal tumors (especially schwannomas of the dorsal nerve roots, meningiomas, and ependymomas). Neuropathies and ocular and cutaneous manifestations are also frequent. (See 'Clinical features' above.)
●Diagnosis – The diagnosis of NF2-SWN is based upon standardized criteria that include both clinical features and genetic testing. (See 'Clinical and radiologic evaluation' above and 'Diagnostic criteria' above.)
Early identification of NF2-SWN is important to minimize the complications associated with the disease. Evaluation for NF2-SWN, including genetic testing (algorithm 1 and algorithm 2), is recommended in all individuals suspected of having NF2-SWN, including those with any of the following:
•A first-degree relative with NF2-SWN (ie, parent, sibling, or offspring)
•Multiple spinal tumors (schwannomas, meningiomas)
•Schwannomas of the skin
•A solitary vestibular schwannoma in an individual younger than 30 years of age
•A solitary meningioma or nonvestibular schwannoma in an individual younger than 25 to 30 years of age
•Two or more meningiomas in an individual aged 25 to 69 years and three or more meningiomas at any age
●Differential diagnosis – The differential diagnosis includes sporadic unilateral vestibular schwannomas, other schwannoma predisposition syndromes, neurofibromatosis type 1 (NF1), and familial meningiomas. (See 'Diagnosis' above.)
●Management – Whenever possible, patients should be cared for by a multidisciplinary team with expertise in the care of NF2-SWN-affected individuals and families. (See 'Management' above.)
•All individuals with NF2-SWN require brain and spinal tumor surveillance and annual clinical follow-up that includes audiology, eye evaluation, neurologic examination, and skin examination. (See 'Tumor surveillance and follow-up' above.)
•Vestibular schwannomas are generally managed surgically if treatment is indicated, although first-line medical therapy with bevacizumab plays a role in select cases. For patients with severe hearing impairment, strategies such as cochlear or brainstem implants may offer some benefit. (See 'Treatment of vestibular schwannomas' above and 'Hearing impairment' above.)
•Many meningiomas in NF2-SWN grow to a certain size and stop, and do not require active treatment. For rapidly growing meningiomas and those threatening functional loss, meningiomas are managed surgically when possible. (See 'Meningioma management' above.)
•Spinal ependymomas are often diagnosed with screening imaging studies and usually grow very slowly without symptoms for a prolonged period. (See 'Intramedullary spinal tumors' above.)
●Prognosis – NF2-SWN is associated with substantial morbidity and shortened survival due to complications of central nervous system tumors. (See 'Prognosis and complications' above.)
