Version May 2024
INTRODUCTION — Schwannomatosis is the name originally coined for a neurocutaneous syndrome that is genetically distinct from neurofibromatosis type 1 (NF1) and neurofibromatosis type 2 (NF2). It was first recognized as distinct from NF2 in the late 1990s [1].
In 2022, the nomenclature for NF2 and schwannomatosis was further updated to recognize the disorders as part of a spectrum of schwannoma predisposition syndromes with extensive clinical overlap, defined in many cases by pathogenic variants in one of several genes on chromosome 22 [2]:
●NF2-related schwannomatosis (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 (LOH) of chromosome 22q
This topic will cover the non-NF2-related schwannomatoses, which we will continue to refer to as "schwannomatosis" in this topic for brevity and consistency, unless otherwise noted.
Schwannomatosis is characterized by a predisposition to form benign nerve sheath tumors called schwannomas, in the absence of intradermal and bilateral vestibular schwannomas. The majority of familial cases are caused by inactivating pathogenic variants in either SMARCB1 or LZTR1, tumor suppressor genes on chromosome 22, but these variants are associated with <50 percent of sporadic cases. Most patients present in adulthood with multiple schwannomas and pain, and approximately 20 percent of patients have a family history of schwannomas or schwannomatosis. Treatment is symptomatic, focused primarily on pain management.
The epidemiology, pathology, clinical manifestation, diagnosis, and treatment of schwannomatosis will be reviewed here. The following related topics are reviewed separately:
●(See "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis".)
●(See "NF2-related schwannomatosis (formerly neurofibromatosis type 2)".)
●(See "Peripheral nerve tumors".)
●(See "Intradural nerve sheath tumors".)
EPIDEMIOLOGY — Schwannomatosis is a rare disorder with a prevalence approximately half that of NF2-related schwannomatosis (NF2) [3,4]. In a northwest England population, the prevalence was estimated at 1 in 126,000 [3]. There is no known predilection based on sex, race, or ethnicity.
Family history is the only known risk factor. The disorder is familial in approximately 20 percent of patients [4-6], although this may be an underestimate, as there may be incomplete penetrance for SMARCB1 or LZTR1 pathogenic variants. An understanding of the phenotypic spectrum is still evolving.
Patients with schwannomatosis account for 2 to 10 percent of all individuals undergoing schwannoma resection [4,5,7,8]. In a retrospective surgical series of over 200 schwannoma excisions, for example, 90 percent of patients had solitary (nonsyndromic) tumors, 9 percent met diagnostic criteria for definite or probable schwannomatosis, and 1 percent had NF2 [7].
PATHOGENESIS — Schwannomatosis is a genetic tumor suppressor syndrome that leads to formation of multiple noncutaneous schwannomas on peripheral nerves, spinal roots, and cranial nerves.
SMARCB1 inactivation — Inactivating germline pathogenic variants in SMARCB1 on chromosome 22 are the most common cause of familial schwannomatosis [9]. SMARCB1 pathogenic variants are present in 40 to 50 percent of families with schwannomatosis and up to 10 percent of sporadic cases [10-14].
SMARCB1, previously called INI1, is thought to act as a tumor suppressor gene that affects the expression of genes regulating the cell cycle, growth, and differentiation.
In schwannomas containing SMARCB1 pathogenic variants, additional genetic alterations are almost always present, including loss of one copy of chromosome 22 and inactivating pathogenic variants in NF2, moesin-ezrin-radixin like (MERLIN) tumor suppressor (NF2) [15]. Such cases suggest a four-hit, three-step model of tumorigenesis, in which the altered germline SMARCB1 gene copy is present in the tumor (hit 1), part or all of chromosome 22 containing the wildtype SMARCB1 gene copy and a wildtype copy of the NF2 gene is lost (hits 2 and 3), and the remaining wildtype NF2 gene copy is altered (hit 4) [12,16].
Some loss-of-function germline pathogenic variants in SMARCB1 can cause an inherited predisposition to rhabdoid tumors that occur in childhood, including malignant rhabdoid tumors of the kidney, atypical teratoid/rhabdoid tumors (ATRT) of the central nervous system, and extrarenal rhabdoid tumors [9,17]. There are rare reports of families with both schwannomatosis and rhabdoid tumor phenotypes [18-20], mostly in families with hypomorphic partially functioning variants [21]. (See "Uncommon brain tumors", section on 'Atypical teratoid/rhabdoid tumor'.)
SMARCB1 has also been implicated in Coffin-Siris syndrome and a condition causing severe intellectual disability and choroid plexus hyperplasia [22,23]. These conditions are likely caused by germline missense variants acting through a gain-of-function mechanism.
There are conflicting data about the role of SMARCB1 pathogenic variants in patients with multiple meningiomas [24-27]. Somatic variants in SMARCB1 have been reported in less than 3 percent of sporadic meningiomas [28-31], but no germline variants were identified in a series of 47 patients with multiple meningiomas [27]. In other reports, pathogenic variants in SMARCB1 have been identified in families with schwannomatosis and multiple meningiomas [24-26].
LZTR1 inactivation — Pathogenic variants in LZTR1 predispose to schwannomatosis in many patients without pathogenic variants in SMARCB1 [32,33]. A study in individuals without SMARCB1 or NF2 pathogenic variants identified LZTR1 pathogenic variants in 6 of 16 patients with familial schwannomatosis (38 percent), 11 of 49 sporadic patients (22 percent), and 2 of 39 patients with unilateral vestibular schwannoma [33].
As with SMARCB1-related cases, the pattern of genetic alterations suggests a four-hit, three-step model of tumorigenesis in which the altered germline LZTR1 gene copy is present in the tumor (hit 1), a segment of chromosome 22 containing the wildtype SMARCB1 gene copy and a wildtype copy of the NF2 gene is lost (hits 2 and 3), and the remaining wildtype NF2 gene copy is altered (hit 4).
LZTR1 is located on chromosome 22q11.21, centromeric to both SMARCB1 (22q11.23) and NF2 (22q12.2). LZTR1 has been identified as a tumor suppressor gene and a driver in a subset of glioblastomas [34]. Additionally, somatic LZTR1 pathogenic variants have been found in several other cancers [35] as well as individuals with both dominant and possible recessive Noonan syndrome [36,37]. (See "Noonan syndrome".)
Consistent with other late-onset tumor predisposition genes, loss-of-function variants in LZTR1 are also seen in control populations, suggesting that LZTR1 may exhibit reduced or incomplete penetrance [32].
Other genetic causes — A third gene on chromosome 22q, DGCR8, has been identified in two families with schwannomatosis [38].
In other cases, loss of heterozygosity (LOH) of chromosome 22q is present, but no pathogenic variants are identified in NF2, SMARCB1, or LZTR1. These cases are referred to as "22q-related schwannomatosis" in the updated diagnostic criteria [2].
CLINICAL FEATURES
Clinical presentation — Most patients with schwannomatosis present in adulthood with one or more symptomatic schwannomas and pain that may or may not localize to known tumors. The average age of symptom onset is 25 to 30 years, and the median age of diagnosis is 40 years [1,6,7,39]. Delays in diagnosis are common.
Presenting symptoms include the following [39]:
●Pain – Pain is reported by over half of patients at the time of presentation. In the majority of patients, pain does not correlate with a specific, identifiable schwannoma. (See 'Chronic pain' below.)
●Palpable mass – A mass is the presenting symptom in approximately 40 percent of patients. Masses are more often painless than painful.
●Other symptoms – Other presenting symptoms vary based on the location of the tumors but can include focal numbness, weakness, and muscle atrophy [1,6,39]. Some patients may be asymptomatic and diagnosed only incidentally based on an imaging study or as a result of a positive family history.
Schwannomas — Multiple schwannomas are the hallmark feature of schwannomatosis. Schwannomas are benign tumors of the nerve sheath, typically occurring as solitary, encapsulated masses on cranial nerves, peripheral nerves, or spinal roots. Schwannomas in schwannomatosis can be discrete or plexiform.
Distribution and burden
●Peripheral nerves – Nearly all patients with schwannomatosis have one or more peripheral nerve schwannomas, which are most often located within the arms or legs. Peripheral nerve schwannomas are commonly found in the head and neck region, and can also be seen in the chest, abdomen, and pelvis.
●Cranial nerves – Nonvestibular cranial nerve schwannomas are reported in up to 10 percent of patients. Unilateral vestibular schwannomas are uncommon but have been reported, primarily in the setting of LZTR1 pathogenic variants [3,33,39-41]. Symptoms of cranial nerve schwannomas depend upon the nerve involved. As an example, a trigeminal schwannoma typically presents with pain, numbness, and/or paresthesias in the distribution of one or more branches of the fifth cranial nerve.
●Spinal nerve roots – Spinal nerve root schwannomas are present in approximately 75 percent of patients, most commonly in the lumbar spine (image 1) [39]. LZTR1 pathogenic variants may be associated with an increased incidence of spinal schwannomas [42].
Spinal tumors involve a single area of the spine (ie, cervical, thoracic, or lumbar) in approximately one-half of patients, two areas in one-third, and the entire spine in a small minority. Spinal nerve root schwannomas usually arise from the dorsal sensory roots and present with radicular sensory changes (pain, paresthesias). Radiculopathy with motor manifestations is not common. (See "Intradural nerve sheath tumors", section on 'Clinical presentation'.)
●Subcutaneous nerves – Subcutaneous schwannomas are seen in 20 to 30 percent of patients, usually fewer than five in number [43]. Subcutaneous schwannomas are palpable or visible masses located beneath the skin, and when palpated, the skin moves freely over the mass.
This is in contrast with cutaneous or intradermal schwannomas, which are common in NF2-related schwannomatosis (NF2) but are not part of the phenotype of schwannomatosis. Cutaneous schwannomas are located within the skin itself, move with the skin when palpated, and often protrude superficially.
●Segmental disease – Anatomically limited or segmental disease, defined as multiple schwannomas limited to a single limb or two spinal segments, is described in approximately 30 percent of patients [39].
●Overall tumor burden – The overall tumor burden in patients with schwannomatosis has not been well characterized and is difficult to assess clinically, since some tumors may not be visible or palpable on physical examination and may be asymptomatic.
In a study of whole-body magnetic resonance imaging (MRI) that included 51 patients with schwannomatosis, 36 patients had one or more internal tumors visualized by MRI [16,43]. The median tumor count in patients with tumors was 4 (range, 1 to 27 tumors), and the median whole-body tumor volume was 39 mL (range, 7 to 1372 mL). Internal tumors were discrete-appearing in 81 percent of patients, plexiform in 8 percent, and both discrete and plexiform in 11 percent.
Radiographic appearance — Radiographically, schwannomas and neurofibromas have a similar appearance and often cannot be distinguished by imaging.
MRI is the best method for visualizing nerve sheath tumors, which typically have an intermediate signal intensity on T1-weighted images, very high signal intensity on T2-weighted images, and uniform contrast enhancement with a low-intensity rim (image 2) [44]. Nerve sheath tumors are particularly well visualized on short tau inversion recovery (STIR) sequences (image 3). A heterogeneous appearance with cystic degeneration can also be seen and is more typical of schwannoma than neurofibroma.
Other tumors — Beyond schwannomas, patients with schwannomatosis may be at increased risk for certain other tumors.
●Meningiomas – The incidence of meningioma in patients with schwannomatosis was 5 percent in one large series [39]. There have been several documented families with germline SMARCB1 pathogenic variants who manifest schwannomatosis as well as multiple meningiomas [24-26].
●Malignant peripheral nerve sheath tumors (MPNSTs) – MPNSTs have been reported in a small number of patients with schwannomatosis [7,19,45,46]. The overall risk of malignant transformation is not well established, however, in part because the pathologic diagnosis of malignant nerve sheath tumors can be challenging. In the largest cohort of patients with schwannomatosis described to date, 3 out of 87 patients (3 percent) were diagnosed with MPNST; upon subsequent neuropathologic review, however, all three tumors were reclassified (two as schwannoma, one as melanoma) [39].
●Rhabdoid tumors – Rare families with both multiple schwannomas and rhabdoid tumors, including atypical teratoid/rhabdoid tumors (ATRT) of the central nervous system, in the presence of a germline pathogenic variant in SMARCB1 have been reported [18-20]. (See 'Pathogenesis' above.)
Chronic pain — Chronic pain is very common in patients with schwannomatosis, affecting approximately two-thirds of patients [5,7,39]. The etiology of the pain is often complex, with a mix of neuropathic and nociceptive features.
Risk factors for pain are not well characterized. Tumor size, location, and number do not correlate well with pain-related morbidity [5]. However, total tumor volume correlated with increased pain scores in one study [42]. Additionally, individuals with LZTR1 pathogenic variants may have higher pain and worse quality-of-life scores compared with those with SMARCB1 pathogenic variants [42].
Some patients experience pain that does not seem to correlate with specific tumors and may be diffuse in nature. The pain may be difficult to manage medically and can become disabling [5]. (See 'Pain management' below.)
DIAGNOSIS — The diagnosis of schwannomatosis should be considered in a patient presenting with multiple schwannomas, particularly in the presence of an affected family member.
Evaluation — The initial evaluation should include a detailed clinical and family history, review of available tumor pathology, and a high-resolution brain MRI with fine cuts through the internal auditory canal. Family history that could be indicative of schwannomatosis includes the presence of schwannomas, meningiomas, and atypical teratoid/rhabdoid tumors (ATRT). Genetic testing is recommended in the majority of patients with a suspected schwannoma predisposition syndrome [2].
The most common diagnostic scenario is that of a patient who undergoes biopsy or resection of a nerve sheath tumor that is pathologically confirmed to be a schwannoma, and then additional schwannomas are recognized by clinical history, examination, or imaging in a patient without bilateral vestibular tumors.
Diagnostic criteria — The diagnosis of schwannomatosis is based on clinical criteria first proposed in 2005, modified in 2006, and revised to include molecular genetic criteria in 2022 [2,5,47]. As of the 2022 criteria, schwannomatosis is further classified according to the available genetic data into one of several diagnoses:
●SMARCB1-related schwannomatosis – The diagnosis can be made when an individual meets one of the following criteria:
•At least one pathologically confirmed schwannoma or hybrid nerve sheath tumor and a SMARCB1 pathogenic variant in an unaffected tissue such as blood or saliva
•A common SMARCB1 pathogenic variant in two anatomically distinct schwannomas or hybrid nerve sheath tumors
●LZTR1-related schwannomatosis – The diagnosis can be made when an individual meets one of the following criteria:
•At least one pathologically confirmed schwannoma or hybrid nerve sheath tumor and an LZTR1 pathogenic variant in an unaffected tissue such as blood or saliva
•A common LZTR1 pathogenic variant in two anatomically distinct schwannomas or hybrid nerve sheath tumors
●22q-related schwannomatosis – The diagnosis can be made when an individual meets all of the following criteria:
•Individual does not meet criteria for NF2-, SMARCB1-, or LTZR1-related schwannomatosis and does not have a germline DGCR8 pathogenic variant
•Both of the following molecular features:
-Loss of heterozygosity (LOH) of the same chromosome 22q markers in two anatomically distinct schwannomas or hybrid nerve sheath tumors
-A different NF2 pathogenic variant in each tumor, which cannot be detected in unaffected tissue
●Schwannomatosis not otherwise specified (NOS) – A diagnosis of schwannomatosis-NOS can be made if both of the following criteria are met and genetic testing was not performed or is not available:
•Two or more lesions on appropriate imaging consistent with nonintradermal schwannomas
•Pathologic confirmation of at least one schwannoma or hybrid nerve sheath tumor
●Schwannomatosis not elsewhere classified (NEC) – A diagnosis of schwannomatosis-NEC can be made if both of the above criteria for schwannomatosis-NOS are met and genetic testing has been performed but does not reveal a pathogenic variant in a known schwannomatosis-related gene.
●Mosaic schwannomatosis – Mosaicism for SMARCB1- and LZTR1-related schwannomatosis is confirmed by either of the following in the appropriate clinical context:
•At least one pathologically confirmed schwannoma or hybrid nerve sheath tumor and clearly less than 50 percent pathogenic variant allele fraction in blood or saliva
•Pathogenic variant not detected in blood or saliva but a shared pathogenic variant is present in two or more anatomically unrelated tumors
It is important to note that there is extensive clinical overlap between mosaic NF2-related schwannomatosis (NF2) and other schwannomatoses, which can lead to misdiagnosis. This underscores the importance of molecular testing in the setting of diagnostic evaluation. (See 'Differential diagnosis' below and 'Genetic testing' below.)
Tumor pathology — Pathologic evaluation of a tumor specimen, when available, is essential for the diagnosis of schwannomatosis in order to differentiate schwannomas from other tumors that can arise in the setting of neurofibromatosis (eg, neurofibroma), and increasingly for molecular characterization.
Schwannomas are benign peripheral nerve sheath tumors composed entirely of neoplastic Schwann cells, arising from cranial nerves, spinal roots, or peripheral nerves. They are typically situated eccentrically to the nerve, displacing the nerve fibers [10]. They may be encapsulated or plexiform in configuration.
The hallmark pathologic feature is the presence of alternating areas of compact spindle cells arranged in compact fascicles called Antoni A areas, and less cellular and more disorganized areas called Antoni B areas (picture 1) [48].
There are no reliable histologic features that distinguish a sporadic (nonsyndromic) schwannoma from a schwannoma related to a schwannomatosis or NF2. However, the presence of abundant myxoid stroma or a hybrid tumor (one with characteristics of both neurofibroma and schwannoma) may be clues to an underlying syndromic diagnosis [16].
Immunohistochemistry can also help to signal a syndromic diagnosis. Mosaic loss of immunohistochemical expression of SMARCB1/INI1 is a reliable marker of schwannomatosis (regardless of the involved gene) and can assist in distinguishing schwannomatosis from an isolated (nonsyndromic) schwannoma. This same mosaic immunohistochemical pattern can be seen in the setting of NF2, and so does not help in distinguishing between schwannomatosis and NF2 [49]. (See 'Differential diagnosis' below.)
Neuroimaging — Patients with suspected schwannomatosis require the following imaging studies to assess extent of disease and exclude alternative diagnoses:
●Brain MRI with contrast and thin cuts – High-resolution, contrast-enhanced MRI of the brain with thin cuts (<3 mm with no skipping) through the internal auditory canal should be performed to exclude bilateral eighth nerve tumors, which are not compatible with the diagnosis of schwannomatosis and would suggest the alternative diagnosis of NF2. Patients with schwannomatosis can develop unilateral vestibular schwannomas (image 4) or other cranial nerve tumors in the cerebellopontine angle (CPA), although this is relatively uncommon. (See 'Differential diagnosis' below.)
●Whole-spine MRI – Contrast-enhanced MRI of the entire spine with coronal short tau inversion recovery (STIR) is recommended for all patients at the time of diagnosis to assess the burden of spinal cord involvement and rule out spinal cord impingement.
●Focused tumor MRI – Focused MRI of known symptomatic masses or of neurologic findings should also be performed. MRI with STIR sequences is especially helpful to visualize nerve sheath tumors (image 3). (See 'Radiographic appearance' above.)
●Whole-body MRI – Where available, whole-body MRI with quantitative apparent diffusion coefficient (ADC) mapping may be useful for delineating extent of disease and tumor characteristics, and for ongoing surveillance of tumors [50].
Genetic testing — For individuals with a known or suspected schwannoma predisposition syndrome, genetic testing is recommended to establish the specific diagnosis, which may have implications for prognosis and family planning. There may be some circumstances in which a clinical diagnosis is sufficient and genetic testing is not necessary. If genetic testing for schwannomatosis is being considered, we recommend referral to a clinical geneticist or genetic counselor who is knowledgeable about the testing protocol and the relevant issues for discussion with patients and their families. (See 'Counseling and prognosis' below and "Genetic counseling: Family history interpretation and risk assessment".)
Aside from SMARCB1 and LZTR1, there are likely other causative genes and molecular regulatory mechanisms in schwannomatosis that have not yet been identified, which limits the ability of genetic testing to exclude the diagnosis of schwannomatosis [51]. Additionally, genetic testing for schwannomatosis is not yet helpful in determining prognosis or informing medical management.
The decision to pursue genetic testing for SMARCB1 and/or LZTR1 is individualized and depends on a variety of factors, including the age and reproductive status of the patient, the presence or absence of additional family members who might be at risk, the cost of the test and insurance coverage, whether there are other affected family members, and preferences with regard to reproductive decision-making.
The protocol for genetic testing in the setting of schwannomatosis can also be complex and depends on both the individual and family history (algorithm 1 and algorithm 2). Clinicians must select the appropriate tissue to submit for testing; coordinate testing for the NF2, SMARCB1, and LZTR1 genes; and interpret results accurately [52]. In addition to deoxyribonucleic acid (DNA) testing, ribonucleic acid (RNA) testing should be considered to evaluate for a deep intronic SMARCB1 variant in patients with suspected schwannomatosis who have negative testing for NF2, SMARB1, and LZTR1 [53].
Of note, some individuals have been identified who carry a variant in NF2, SMARCB1, or LZTR1 in blood but do not have clinical features of a schwannomatosis predisposition syndrome (eg, in an asymptomatic individual who underwent genetic sequencing for another indication). Given the incomplete penetrance of SMARCB1 and LZTR1 pathogenic variants, such an incidental finding cannot be used as a standalone criterion to diagnose schwannomatosis [2]. Such individuals and their at-risk relatives should be referred to a tertiary care center with expertise in schwannomatosis for further evaluation and genetic counseling.
DIFFERENTIAL DIAGNOSIS — Multiple schwannomas can also be seen in association with NF2-related schwannomatosis (NF2). In particular, there is extensive clinical overlap between mosaic NF2 and other schwannomatoses.
Differentiating schwannomatosis from NF2 can be challenging but is critical, as management decisions and counseling are very different for the two disorders. Whenever possible, patients in whom any of these diagnoses are being considered should be referred to a multidisciplinary team with experience in the diagnosis and management of neurofibromatosis.
The cardinal feature that distinguishes NF2 from schwannomatosis is the presence of bilateral vestibular schwannomas, which are a key clinical feature of NF2 and incompatible with a diagnosis of schwannomatosis. The absence of bilateral vestibular schwannomas on high-resolution brain MRI is particularly reliable for ruling out NF2 in patients over the age of 30 years. Patients younger than 30 years with a unilateral vestibular schwannoma may still go on to develop a contralateral tumor. The clinical criteria for the diagnosis of NF2 are reviewed separately. (See "NF2-related schwannomatosis (formerly neurofibromatosis type 2)", section on 'Diagnostic criteria'.)
Differentiating schwannomatosis from NF2 can be difficult, and molecular testing may be helpful to reach a definitive diagnosis in these circumstances (see 'Genetic testing' above):
●Mosaic NF2 – Individuals who have a mosaic form of NF2 (approximately 30 percent of all people with NF2) can present with multiple schwannomas and no vestibular schwannomas, thereby mimicking the presentation of schwannomatosis [54]. In one study, mosaic NF2 misdiagnosed as schwannomatosis accounted for at least 9 percent of clinically diagnosed schwannomatosis cases [3].
●Unilateral vestibular schwannoma – Individuals with schwannomatosis can develop unilateral vestibular schwannomas, thereby mimicking the presentation of NF2 [33,40,41]. One study found that 1 to 2 percent of individuals with schwannomatosis were misdiagnosed with mosaic NF2 [3]. This phenotype is most common with LRTZ1-related schwannomatosis [3].
●Meningiomas – Multiple meningiomas are common in NF2 and have been described in some individuals with schwannomatosis, making it difficult to distinguish between schwannomatosis and NF2 based on the presence or absence of meningiomas.
A detailed family history, probing for the presence of symptoms consistent with either schwannomatosis or NF2, is imperative. Schwannomas and meningiomas can be seen in families with either syndrome. In the setting of NF2, however, there may be an additional family history of vestibular schwannomas, hearing loss, tinnitus, or ependymomas, which would be unlikely to occur within a schwannomatosis pedigree. (See "NF2-related schwannomatosis (formerly neurofibromatosis type 2)", section on 'Clinical features'.)
Aside from NF2, segmental or spinal forms of neurofibromatosis type 1 (NF1) may occasionally be considered in the initial differential diagnosis but are typically ruled out by other clinical findings (such as cutaneous features of NF1) or by pathologic diagnosis of a neurofibroma as opposed to a schwannoma. (See "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis".)
TREATMENT — Treatment of patients with schwannomatosis is primarily symptomatic. There are no established medical therapies that target the underlying disease at the present time. Whenever possible, patients should be cared for by a multidisciplinary team with expertise in the care of patients with schwannoma predisposition syndromes.
Pain management — Pain is one of the most common symptoms of schwannomatosis. Severity of pain varies widely between patients and can often be severe and incapacitating. Pain can be localized or diffuse and often does not correlate well with the location of known schwannomas.
Early involvement of a multidisciplinary pain team should be considered. As a last resort, surgical resection of painful schwannomas may be considered if pain is not satisfactorily controlled by other means. (See 'Surgery' below.)
Pharmacologic therapy — Painful schwannomas have a significant neuropathic component. In our experience, treatment with gabapentin or pregabalin and use of short-acting opioids and/or nonsteroidal anti-inflammatories for breakthrough pain can be successful for many patients.
Additional agents, including tricyclic antidepressants such as amitriptyline, serotonin-norepinephrine reuptake inhibitors such as duloxetine, cannabinoids, or antiepileptics such as topiramate or carbamazepine, may be used as adjuncts or independently. (See "Pharmacologic management of chronic non-cancer pain in adults", section on 'General principles of drug selection' and "Use of opioids in the management of chronic non-cancer pain".)
Nonpharmacologic therapy — There are a variety of nonpharmacologic options to treat pain that may be effective, although no clinical trials have examined such modalities specifically for schwannomatosis.
In our experience, patients may benefit from meditation, yoga, and mindfulness-based stress reduction (MBSR) techniques to help with relaxation, stress reduction, dealing with difficult emotions, examining thoughts and beliefs about pain, and training the mind to be less reactive to painful sensations [55-59]. Biofeedback and hypnosis can assist with managing the anxiety that often accompanies pain and train the brain to be less reactive to pain [60-62]. Many patients have used acupuncture, and in several clinical trials acupuncture has shown promise in alleviating chronic and neuropathic pain [63,64]. (See "Approach to the management of chronic non-cancer pain in adults".)
Surgery — When surgery is necessary, indications include medically refractory local pain, spinal cord compression, or impingement of other organs. Surgical resection of these tumors is often complex and may put patients at risk of additional neurologic compromise.
Surgical therapy for schwannomatosis is highly individualized and depends on the size, location, and complexity of tumors; the need for pathologic conformation for diagnosis; the presence and/or progression of neurologic or systemic symptoms; and pain.
The goals of surgery should be explicitly discussed with the patient. In general, the goal of surgery is to prevent progression of symptoms, as neurologic dysfunction is unlikely to be reversed by tumor resection. If pain is the primary indication, patients should be counseled that, though surgery may relieve pain, it is also possible that it will be ineffective or could even worsen pain and dysfunction.
SURVEILLANCE — The optimal type and frequency of surveillance imaging has not been established in schwannomatosis. We suggest the following approach, which is closely aligned with that of a European clinical practice guideline for patients with schwannomatosis [53]:
●MRI is the preferred imaging modality for schwannoma surveillance. We find that MRI with and without gadolinium and multiplanar short tau inversion recovery (STIR) imaging provides the most useful information. Some centers use ultrasound for monitoring superficial tumors.
●We do not find positron emission tomography (PET) useful for monitoring schwannomas as it is not a reliable predictor of malignant conversion [65].
●For asymptomatic, molecularly confirmed individuals with a relative with schwannomas, we recommend screening imaging of whole spine and brain/internal auditory canal (IAC) with and without gadolinium at the time of diagnosis or at an age at which the patient can undergo MRI without the need for anesthesia (typically age 12 and older). If initial screening imaging is negative, our practice is to repeat imaging every five years or sooner if symptoms develop. Others have suggested performing brain and spine MRI every two to three years in all patients, starting at age 10 for those with SMARCB1 pathogenic variants and age 15 to 19 for those with LZTR1 pathogenic variants [66].
●For patients with symptomatic tumors, the frequency of MRI is dependent on the severity of symptoms, tumor location, and clinical evidence of progression. For patients with intradural spinal schwannomas and/or cranial nerve schwannomas, we typically image on an annual basis at minimum. For many patients with tumors in multiple body regions, we use whole-body MRI at the time of diagnosis to establish the location of tumors and then serially for monitoring. A changing tumor, especially one causing functional impairment in a patient with SMARCB1-related schwannomatosis, requires prompt evaluation with focused tumor contrast-enhanced MRI to look for signs of malignant transformation [53].
●For patients with known but asymptomatic schwannomas, surveillance with serial imaging is not necessary unless they are considered to be high risk for future neurologic compromise, such as those with intradural spinal schwannomas causing spinal cord compression or intracranial schwannomas.
COUNSELING AND PROGNOSIS — Individuals with schwannomatosis are at risk of having other affected family members, including children.
●Transmission risk – For individuals with a known germline SMARCB1 or LZTR1 pathogenic variant, the transmission risk to offspring is 50 percent. For individuals with no known SMARCB1 or LZTR1 pathogenic variant who have an affected parent, the transmission risk is also considered to be 50 percent.
For individuals with no affected parent and no known pathogenic variant (ie, sporadic schwannomatosis), estimating the transmission risk is more complicated. Many of these patients will be mosaic for a de novo variant, and if the variant is also present in the germline, there may be an appreciable (but hard to quantify) transmission risk (0 to 50 percent). An additional source of uncertainty is that schwannomatosis is probably not fully penetrant, meaning that individuals can carry a pathogenic variant that causes schwannomatosis but never develop the condition. Rates of nonpenetrance and mosaicism are not yet well characterized.
●Sharing the diagnosis with family members – Patients diagnosed with schwannomatosis are counseled to consider sharing the diagnosis with family members, particularly those who have symptoms consistent with the condition. Asymptomatic family members can be screened with whole-body MRI or genetic testing (if a pathogenic variant has been identified within the family) but should first be counseled about issues regarding presymptomatic testing and the possible impact on insurability (health and life) based on the results of screening. (See "Genetic testing", section on 'Ethical, legal, and psychosocial issues'.)
●Natural history – The natural history of schwannomatosis is not well documented, and the phenotypic spectrum remains to be fully characterized. It appears that patients with schwannomatosis do not have a decreased lifespan, which is in marked contrast to patients with NF2-related schwannomatosis (NF2) [3,5]. However, more data are needed to understand the risk of malignant peripheral nerve sheath tumors (MPNSTs) and other malignancies in patients with schwannomatosis, especially those related to SMARCB1 [53].
An international database has been established to facilitate progress in understanding the natural history of schwannomatosis. Another resource for patients and families with schwannomatosis is the Children's Tumor Foundation.
SUMMARY AND RECOMMENDATIONS
●What is schwannomatosis? – Schwannomatosis is the name originally coined for a neurocutaneous syndrome that is genetically distinct from neurofibromatosis type 1 (NF1) and neurofibromatosis type 2 (NF2), in which patients develop multiple noncutaneous nerve sheath tumors, called schwannomas, in the absence of bilateral vestibular schwannomas.
In 2022, the nomenclature was updated to recognize NF2 (now called NF2-related schwannomatosis) and schwannomatosis as part of a spectrum of schwannoma predisposition syndromes with extensive clinical overlap, defined in many cases by pathogenic variants in one of several genes on chromosome 22. This topic will continue to use the term "schwannomatosis" to refer to the non-NF2-related schwannomatoses for brevity and consistency, unless otherwise noted. (See 'Introduction' above.)
●Genetics – Schwannomatosis is familial in approximately 20 percent of cases and sporadic in the remaining. Germline pathogenic variants in either SMARCB1 or LZTR1 are responsible for a majority of familial cases and up to 40 percent of sporadic cases. (See 'Pathogenesis' above.)
●Clinical presentation – Most patients present in their 20s or 30s with a symptomatic nerve sheath tumor and localized pain that may or may not be associated with a discrete mass. The median age of diagnosis is 40 years. (See 'Clinical presentation' above.)
●Tumor distribution – Schwannomas can form along the course of any peripheral nerve. The most common locations are the extremities and spinal roots; tumors can also be seen intracranially (along cranial nerves) and in the trunk (along peripheral nerves in the chest, abdomen, or pelvis). (See 'Schwannomas' above.)
●Diagnosis – The diagnosis of schwannomatosis is based on characteristic clinical and genetic findings, family history, and exclusion of a diagnosis of NF2. Patients require high-resolution brain MRI, spine MRI, and genetic testing in selected cases (algorithm 1 and algorithm 2). (See 'Diagnosis' above.)
●Differential diagnosis – The most important alternative diagnosis to consider in patients with multiple schwannomas is NF2. The distinction can be challenging in many patients but carries important implications for management and prognosis. (See 'Differential diagnosis' above.)
●Referral – Patients in whom the diagnosis is being considered should be referred to a multidisciplinary team with experience in the diagnosis and management of neurofibromatosis and schwannomatosis, whenever possible. (See 'Counseling and prognosis' above.)
●Treatment – Management of patients with schwannomatosis is primarily symptomatic, focusing on chronic pain management in many patients. Indications for surgical resection of schwannomas include refractory local pain, spinal cord compression, or impingement of other organs. (See 'Pain management' above and 'Surgery' above.)
●Surveillance – Where available, whole-body MRI is preferred for monitoring of multiple schwannomas. For patients with symptomatic tumors or tumors in critical locations (eg, spinal cord), we obtain imaging yearly for surveillance. (See 'Surveillance' above.)
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