NF2-related schwannomatosis (formerly neurofibromatosis type 2)

INTRODUCTION — NF2-related schwannomatosis (formerly neurofibromatosis type 2), hereafter referred to as "NF2" [1], is a dominantly inherited syndrome that predisposes individuals to bilateral vestibular schwannomas as well as multiple other tumors of the nervous system [2-4]. NF2 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 patient management of NF2 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 NF2 and schwannomatosis was updated to recognize NF2 and schwannomatosis as parts of a spectrum of schwannoma predisposition syndromes, which are defined in many cases by pathogenic variants in one of several genes on chromosome 22 [1]:

●NF2-related schwannomatosis (and shortened to NF2 in this topic and others for brevity), formerly neurofibromatosis type 2

●SMARCB1-related schwannomatosis

●LZTR1-related schwannomatosis

●Other schwannomatoses, including those related to loss of heterozygosity of chromosome 22q

MOLECULAR PATHOGENESIS

NF2 gene — NF2 is consistently linked with abnormalities of the NF2 gene, which is located on chromosome 22 [5]. The NF2 gene produces merlin, also known as schwannomin, a cell membrane-related protein that acts as a tumor suppressor [6,7].

Detailed molecular testing will identify an abnormality in NF2 in over 93 percent of families with multiple members affected with NF2 [8]. Individuals with NF2 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 unless tumor tissue is analyzed [8-12]. A study of over 1000 patients with de novo NF2 found that more than 50 percent of such cases are potentially due to mosaicism [13].

The development of schwannomas and other tumors requires inactivation of both NF2 alleles, since tumors only develop in cells that have lost function of their normal NF2 allele. The "second hit" usually occurs through loss of the entire healthy NF2 gene and most or all of chromosome 22, although a point pathogenic variant or promoter methylation may also occur. Loss of the normal copy may also occur by mitotic recombination, where the mutated copy is doubled up without loss of chromosomal material [14].

Genotype-phenotype correlation — NF2 is fully penetrant, meaning that any individual who carries a germline pathogenic NF2 variant will develop the clinical disorder [1]. Within a family that includes multiple members with NF2, 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; missense or inframe 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 VIII [16]. Patients with variants causing truncated protein also had vestibular schwannomas at a younger age and had more cutaneous tumors. 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 these differences have marked 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 survival [18]. A genetic severity score can be derived from the variant identified, which predicts the clinical severity of NF2 disease (table 1) [18,19].

EPIDEMIOLOGY — The estimated incidence of NF2 derived from population-based studies in England and Finland is as high as 1 in 25,000 [20-23].

CLINICAL FEATURES — NF2 is an autosomal dominant schwannoma predisposition syndrome that affects the nervous system as well as eyes and skin. In addition to schwannomas and other nervous system tumors, most patients have one or more ophthalmic and cutaneous manifestations.

Age of onset and clinical spectrum — Patients typically present around 20 to 25 years of age [15]. Initial or presenting symptoms vary by age at presentation.

Children diagnosed with NF2 often have an atypical, but more severe, presentation [24]. In childhood, patients most commonly present with visual/eye problems, hearing loss, weakness, pain, mononeuropathy, cutaneous tumors, and/or seizures [15,25,26]. In adults, hearing loss and tinnitus are the presenting symptoms in over one-half of patients.

The most frequent clinical features of NF2 include:

●Neurologic lesions [27-29]

•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 and extramedullary) – 63 to 90 percent

•Peripheral neuropathy – Up to 66 percent

●Eye lesions [30-32]

•Cataracts – 60 to 81 percent

•Epiretinal membranes – 12 to 40 percent

•Retinal hamartomas – 6 to 22 percent

●Skin lesions [27,29,33,34]

•Cutaneous tumors – 59 to 68 percent

•Skin plaques – 41 to 48 percent

•Subcutaneous tumors – 43 to 48 percent

Vestibular schwannomas — Vestibular schwannomas in NF2 are typically bilateral and cause tinnitus, hearing loss, and balance dysfunction (image 1) [3]. The onset of hearing loss is usually gradual and progressive, leading to deafness, although sudden hearing loss can occur. NF2-related vestibular schwannomas are usually multifocal and occur equally on the superior and inferior vestibular nerve [35].

The mechanism of hearing loss from vestibular schwannomas in NF2 is not well understood, and there is poor correlation between tumor size and/or growth rate and degree of hearing loss [36-39]. One proposed mechanism is the accumulation of intralabyrinthine protein as a result of cochlear aperture obstruction, which can be visualized by high-resolution magnetic resonance imaging (MRI) [40]. 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 patients with NF2 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 have meningiomas, and multiple meningiomas are often present [41]. The incidence increases with age, and lifetime risk may be as high as 75 percent [29]. Most meningiomas are intracranial, although spinal meningiomas are also seen. (See "Epidemiology, pathology, clinical features, and diagnosis of meningioma", section on 'Clinical presentation' and "Spinal cord tumors", section on 'Meningioma'.)

Patients with NF2 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 [24,42]. Histopathologically, the meningiomas seen in patients with NF2 are more frequently atypical or anaplastic compared with sporadic tumors [43,44].

Spinal tumors — Most individuals with NF2 eventually develop a spinal tumor, which can cause debilitating pain, muscle weakness, or paresthesias [3,45,46].

●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 cases. (See "Spinal cord tumors", section on 'Ependymomas'.)

Neuropathies — Neuropathies can be manifested in a variety of ways in individuals with NF2 [2,47]. Some people develop a mononeuropathy, often involving the facial nerve, which can precede the development of other NF2 manifestations. 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 [2,3,48].

Ophthalmic manifestations — Patients with NF2 may have visual impairment due to cataracts, optic nerve meningiomas, retinal hamartomas, and epiretinal membrane [2,3,26,32,49]. 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 [50]. (See 'Genotype-phenotype correlation' above.)

Development of cataracts and other ocular manifestations can lead to visual abnormalities in early childhood in those with NF2 [26]. 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'.)

Cutaneous manifestations — Approximately 70 percent of patients with NF2 have cutaneous manifestations, although only 10 percent have more than 10 skin tumors [2]. 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 is based upon the presence of characteristic clinical and molecular genetic features. Genetic testing is recommended in all patients with suspected schwannomatosis predisposition syndromes but is not required for the diagnosis of NF2 in patients who fulfill clinical criteria. Genetic testing is particularly helpful in younger patients who do not meet diagnostic criteria without genetic data. Genetic testing is also important for first-degree relatives of an individual with NF2, who can be diagnosed with NF2 based on an NF2 pathogenic variant, even in the absence of clinical features.

Clinical and radiologic evaluation — For individuals suspected of having NF2, 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 [2].

●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 patients should have a slit lamp examination and ophthalmoscopy, ideally by an ophthalmologist with experience in NF2.

●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 is based upon the presence of any one of the following criteria [1,51,52]:

●Bilateral vestibular schwannomas

●An identical pathogenic NF2 variant in at least two anatomically distinct NF2-related tumors (schwannoma, meningioma, and/or ependymoma); if the variant allele fraction in blood is clearly <50 percent, the diagnosis is mosaic NF2

●Two of the following major criteria:

•Unilateral vestibular schwannoma

•First-degree relative other than sibling with NF2

•Multiple meningiomas

•A pathogenic NF2 variant in nontumorous 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)

Criteria for mosaic NF2 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 shared pathogenic variant in two or more anatomically unrelated tumors

Clinical criteria for NF2 were initially established by a National Institutes of Health (NIH) consensus conference [53]. These were subsequently modified into the Manchester criteria, which substantially improved the sensitivity for making the diagnosis without affecting specificity [29,54]. These were further adapted by an international consensus group [1].

Revisions to the NF2 criteria take into account the possibility that unilateral vestibular schwannomas may be due to LZTR1 germline variants (ie, LZTR1-related schwannomatosis) rather than NF2 (see "Schwannomatoses related to genetic variants other than NF2"). Although the diminishing likelihood of NF2 in patients with vestibular schwannomas diagnosed after 70 years of age [51,55] was considered, no age limit was set in the 2022 criteria [1]. In addition, ependymoma has replaced glioma in the diagnostic criteria based on the absence of high-grade gliomas [56] and predominance of ependymomas in NF2 [52].

Genetic testing — Genetic testing is recommended in all patients with suspected schwannomatosis predisposition syndromes but is not required for the diagnosis of NF2 in patients who fulfill clinical criteria. Genetic testing is particularly helpful in younger patients who do not meet diagnostic criteria without genetic data (algorithm 1 and algorithm 2). Genetic testing is also important for first-degree relatives of an individual with NF2, who can be diagnosed with NF2 based on an NF2 pathogenic variant, even in the absence of clinical features.

There is a high frequency of de novo NF2 cases, and patients may present before the clinical diagnostic criteria are fulfilled. Early identification of patients who have NF2 is important to minimize the complications associated with disease manifestations.

Referral to a clinical geneticist or genetic counselor is recommended for patients in whom genetic testing is being considered. Ideally, molecular testing for NF2 should start with tumor deoxyribonucleic acid (DNA) and then 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 not present in blood confirms mosaicism. LZTR1 should be assessed if individuals meet NF2 criteria with only nonintradermal schwannoma disease. (See 'Diagnostic criteria' above.)

Comprehensive molecular genetic evaluation for NF2 is recommended in all patients suspected of having NF2, including individuals with any of the following [57,58]:

●A first-degree relative with NF2 (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 years of age [59]

●Two or more anatomically distinct meningiomas in an individual aged 25 to 69 years and three or more meningiomas at any age [57,60]

The role of genetic testing for NF2 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, routine screening for germline variants does not appear to be indicated except in those younger than 30 years of age [57,58]. There is also evidence that NF2 is unlikely in first-degree relatives who only manifest unilateral vestibular schwannoma [61].

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 (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 [1].

Differential diagnosis — The major entities in the differential diagnosis of NF2 are sporadic vestibular schwannomas, other schwannomatoses, neurofibromatosis type 1 (NF1), and a familial syndrome of multiple meningiomas [3].

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 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 [58,62]. The likelihood that an individual diagnosed with a vestibular schwannoma after the age of 30 will have NF2 is minimal.

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 — Distinct from NF2, there are rare sporadic or familial schwannomatoses characterized by multiple noncutaneous peripheral and intracranial schwannomas in the absence of bilateral vestibular schwannomas.

These syndromes are caused by variants in genes other than NF2 on chromosome 22, including SMARCB1 and LZTR1. Among these, LZTR1-related schwannomatosis has the greatest diagnostic overlap with NF2, because individuals may have unilateral vestibular schwannomas, in addition to other tumors [63].

The schwannomas seen in individuals with non-NF2-related schwannomatosis contain somatic variants in the NF2 gene, but such variants are not present in the germline.

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 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 include:

●Lisch nodules (raised, pigmented hamartomas of the iris) are characteristic of NF1 and are not seen in significant numbers in NF2.

●The schwannomas associated with NF2 rarely, if ever, undergo malignant transformation into a neurofibrosarcoma (malignant peripheral nerve sheath tumor [MPNST]) [64].

●The "dumbbell" spinal root tumors that are seen with both NF2 and NF1 are schwannomas in NF2 and neurofibromas in NF1.

●NF2 is not associated with the cognitive impairment that is often seen with NF1.

Familial meningioma — Familial meningioma is a rare disorder with only a few families described in the literature. This entity is not associated with abnormalities of the NF2 gene.

Multiple meningiomas can occur sporadically, especially in older adults. The occurrence of a single meningioma in a patient less than 25 years of age should prompt evaluation for NF2 [42]. Individuals aged 25 to 69 with at least two anatomically distinct meningiomas and at any age with three meningiomas should also be assessed for NF2 [57,60]. (See 'Genetic testing' above.)

MANAGEMENT — The management of patients with NF2 is complex and involves multiple disciplines to prevent or treat the various complications that may develop. Whenever possible, patients should be cared for by a multidisciplinary team with expertise in the care of NF2-affected individuals and families [65]. Multidisciplinary teams should include, at a minimum, a neurosurgeon, neuro-otologist, neuroradiologist, neurologist or neuro-oncologist, audiologist, specialist nurse, and geneticist.

Tumor surveillance and follow-up — For individuals known to harbor an NF2 pathogenic variant, follow-up should include [2,3,65]:

●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 unirradiated patient with NF2. 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 is preservation of function and maintenance of quality of life [2]. 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 [3].

Surgical management — 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 can be more complex than in patients with sporadic tumors, since NF2 tumors are often multifocal [35,66]. 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 [2]. 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. (See 'Ophthalmic manifestations' above.)

The role of radiation therapy in managing vestibular schwannomas in patients with NF2 is less clear [67-70]. Reports using radiation in patients with NF2 have shown variable outcomes, and long-term follow-up is lacking. Furthermore, surgical resection may be more difficult following stereotactic radiosurgery. There are also concerns that such patients may have an increased risk of second malignancies [71-73]. The risk of second malignancies may also be increased with fractionated radiation therapy, with one report of a rhabdomyosarcoma occurring in the radiation field in an NF2 patient [74].

Bevacizumab — Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), can induce both tumor shrinkage and hearing improvement in patients with NF2-associated vestibular schwannomas, and there is growing experience at multidisciplinary NF2 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 [75].

The efficacy of bevacizumab for progressive vestibular schwannomas in NF2 is supported by retrospective case series and a limited number of prospective single-arm studies [75-85]. In a meta-analysis of eight observational studies in a total of 161 patients with NF2-associated vestibular schwannomas, the best response to bevacizumab was partial regression in 41 percent, no change in 47 percent, and progression in 7 percent [83]. 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 [86].

The dose and schedule of bevacizumab in NF2 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 [75]. 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 [84], and higher doses may increase the risk of renal impairment.

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-related tumors.

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 [87,88]. 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-related progressive vestibular schwannoma in a small phase II trial [89], whereas erlotinib, an EGFR inhibitor, was not effective in a retrospective series that included 11 patients with NF2 [90]. A phase II trial of the anaplastic lymphoma kinase (ALK) inhibitor brigatinib is underway in the United States [91]. A histone deacetylase inhibitor is also under investigation for treatment of NF2 patients [92].

Hearing impairment — Hearing impairment in patients with NF2 is associated with decreased quality of life and increased risk for social avoidance and isolation, unemployment, and decreased social support [93]. For patients with severe hearing impairment, strategies such as cochlear or brainstem implants may offer some benefit [94]. Pilot studies have demonstrated the feasibility of novel psychosocial interventions delivered to deaf individuals with NF2 via teleconferencing with captioning technology [95]. (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 grow to a certain size and stop, 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 [96].

For rapidly growing meningiomas and those threatening functional loss, meningiomas are managed surgically when possible. Radiation therapy has been used in patients whose tumors are not surgically accessible or in those in whom only a partial resection is possible [97]. 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 "Spinal cord tumors", section on 'Meningioma'.)

Targeted therapies are under investigation. Lapatinib showed some activity in a small series of patients with NF2-associated progressive meningiomas [98]. There is little evidence that bevacizumab has activity in NF2-related meningiomas [99].

Intramedullary spinal tumors — Approximately 75 percent of intramedullary spinal tumors 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, treatment is generally surgical resection rather than radiation therapy [100]. There is some evidence that cystic elements of the tumors respond to bevacizumab [101].

Screening of at-risk family members — For families in which there is a documented index case of NF2, screening of at-risk family members is important so that a diagnosis can be established in affected individuals as early as possible [2,57].

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 [3]. However, variant screening is not 100 percent sensitive in patients with NF2.

For children who have not inherited NF2, 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 NATURAL HISTORY — Individuals typically present with symptoms due to the NF2-related tumors around age 20 to 25 years [15,29]. The diagnosis of NF2 in children is often delayed, since the earliest manifestations may be skin tumors and ocular findings [24,102]. Rare patients are diagnosed as late as the eighth decade of life with unusually indolent tumor growth patterns [103].

Despite surveillance for the development of tumors in patients with NF2 and the aggressive management of any abnormalities that are detected, NF2 is associated with substantial morbidity and shortened survival [2].

●The vestibular schwannomas associated with NF2 are more difficult to manage than their sporadic counterparts. In NF2 the lesions are often multifocal, and histologically these are less vascular and more lobular [104]. Because of this and the bilaterality of the tumors, the majority of patients eventually become completely deaf.

●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.

●There is frequent loss of lower cranial nerve function leading to swallowing and speech problems, which may contribute to shortened life expectancy [105,106].

●Overall survival appears to be shortened in patients with NF2 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 [29,107,108]. Earlier diagnosis and advances in treatment may have improved outcomes [109,110].

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 5^th to 6^th 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 10^th to 12^th 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

●What is NF2? – NF2-related schwannomatosis (NF2; 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 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 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 is based upon consensus criteria that incorporate both clinical features and genetic testing. (See 'Clinical and radiologic evaluation' above and 'Diagnostic criteria' above.)

Early identification of patients who have NF2 is important to minimize the complications associated with disease manifestations. Evaluation for NF2, including comprehensive molecular genetic evaluation (algorithm 1 and algorithm 2), is recommended in all patients suspected of having NF2, including individuals with any of the following:

•A first-degree relative with NF2 (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 years of age

•Two or more anatomically distinct 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-affected individuals and families. (See 'Management' above.)

•All patients with NF2 require brain and spinal tumor surveillance and annual clinical follow-up that includes audiology, ophthalmologic evaluation, neurologic examination, and cutaneous examination. (See 'Tumor surveillance and follow-up' above.)

•Vestibular schwannomas are generally managed surgically if treatment is indicated, although first-line 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 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 is associated with substantial morbidity and shortened survival due to complications of central nervous system tumors. (See 'Prognosis and natural history' above.)