Schwannomatosis

Neurofibromatosis (NF) refers to three different genetic medical conditions, Neurofibromatosis type -1, Schwannomatosis, NF 2 – related Schwannomatosis. involving the development of tumors that may affect the brain, spinal cord, and the nerves that send signals between the brain and spinal cord and all other parts of the body. Most tumors are non-cancerous (benign), although some may become cancerous (malignant).

Overview

Non-NF2-related Schwannomatosis (Non-NF2 SWN), which until recently was simply called Schwannomatosis, includes a group of disorders in which DNA gene abnormalities lead to the tendency to develop multiple benign Schwannomas on peripheral nerves or spinal nerves. These disorders are closely related to NF2-related Schwannomatosis, (NF2 SWN), and the updated classification from 2022 includes these all together under the umbrella term, Schwannomatoses, to highlight this relationship, and also to clearly separate them from Neurofibromatosis Type 1 (NF1) which is clinically and genetically clearly distinct. It is important to note that there is no interconversion between these, meaning NF1 does not turn into NF2-related or other Schwannomatoses. 

Non-NF2-related SWN is rare with estimates of the incidence ranging from 1:40,000 people to as low as 1:126,000. However, some patients go undiagnosed, and the actual incidence may be underestimated. In most adult NF clinics NF2-related SWN is at least ten times more common than nonNF2-related SWN. 

So far two genes have been identified as causing Non-NF2-related SWN. These genes are called SMARCB1 and LZTR1, and the related disorders are now called SMARCB1-related SWN and LZTR1-related SWN. These two genes account for about 80% of familial non-NF2-related SWN and 35% of sporadic cases. Remarkably, both are located on Chromosome 22 near to the NF2 gene and that relation is important in their ability to produce schwannomas. Deletion of a segment of chromosome 22, with these genes and others genes being deleted together, represents another version of nonNF2-SWN and is being called 22q-related SWN. There are still more genes that are very rarely associated non-NF2-related SWN, and good reasons to think some that have not been identified yet.  Patients without defined gene abnormalities are currently called Non-NF2-related SWN-NOS. Only rarely do Non-NF2-related SWN patients develop a single vestibular schwannoma (VS), so the lack of VS in patients with multiple schwannomas is one major clue leading to consideration of non-NF2-related SWN. However, unless genetic testing is done these patients may not be distinguishable from those with mosaic NF2-related schwannomatosis, a distinction that is critical for prognosis, monitoring, and for treatment options. This overlap of clinical features makes genetic testing essential for an accurate diagnosis. Optimal genetic testing for the non-NF2 SWNs often requires testing on unaffected normal tissue, i.e. blood, and two separate distinct schwannomas.   

Over half of Non-NF2 SWN patients develop severe chronic nerve pain syndromes.  The pain may be due to nerves harboring a tumor, but sometimes is more widespread or diffusely distributed. Nerve pain is more often associated with LZTR1-related SWN. Pain and other signs of nerve damage may be present long before any schwannomas are discovered. Typically, patients have pain or other symptoms for many years (average 7-10 years) before the diagnosis is established. The average age at diagnosis as about 40, which is almost twice as old as the average age of diagnosis for NF2-related SWN, and is another important distinguishing features. Onset in childhood has been reported but is very uncommon. The late age of onset and very slow evolution of schwannomas in NonNF2- SWN means that the expected lifespan for non-NF2 related SWN patients is not reduced, however quality of life can be significantly reduced, with pain and neurological problems due to tumor-related nerve damage being the main reasons.  

Also, unlike NF2-related SWN, some patients with a genetic abnormality in either of the SMARCB1 or LZTR1 genes will not develop schwannomatosis. The term penetrance is used to indicate what percentage of patients with a gene abnormality actual develop related symptoms or signs. For the NonNF2 SWNs the penetrance is not 100%. Penetrance for LZTR1 is estimated to be 40-50%, and for SMARCB1 is probably higher. To put it another way, there can be “carriers” of the abnormal gene who do not have any symptoms but can pass the gene along to their children. This is very different from NF2-related SWN where every patient with the abnormal NF2 gene will develop clinical features of the condition, i.e. penetrance is 100% for NF2-related SWN.

A higher percentage of Non-NF2-related SWN patients are sporadic (i.e. 70% lack a family history of the condition) compared with NF2-related SWN where about 50% are sporadic. And a high percentage of these do not have gene abnormalities in blood cells or other normal tissues, and thus may be mosaic, although current information about mosaicism in Non-NF2 SWN is sparse. As noted previously, without NF2 gene testing these patients may not be distinguishable from mosaic NF2. It is estimated that 30-50% of patients that appear to have sporadic non-NF-2 SWN based on clinical features and who do not have SMACRB1 or LZTR1 gene abnormalities, are in fact mosaic NF2-SWN based on genetic testing of tumor tissue.  

MANIFSTATIONS

Initial Symptoms:

Nerve Pain Syndromes – Pain is the most common presenting symptom of nonNF2-related SWN, occurring in over 50% of patients. This occurs more often with germline LZTR1-related SWN than with SMARCB1-related SWN. The pain is sometimes severe and disabling.  It may be localized and related to a particular schwannoma, but as often the pain is widespread or diffuse and not related to a specific schwannoma. Marked changes in tumor-related pain sometimes indicate progression of the tumor to a malignant nature.  This feature is more often observed with germline SMARCB1-related SWN. 

Nodule seen or felt under the skin – A firm nodule, like a marble, seen or felt under the skin that grows very slowly is the first indication of nonNF2-SWN for many patients.  There may be no symptoms, but some are tender or sensitive, or send an electrical sensation when tapped. Lipomas (fatty tumors), lymph nodes, sebaceous cysts, and other nodules are much more common than schwannomas and it is often hard to distinguish among these just by feeling them. 

No symptoms – Schwannomas in deeper locations (ie in muscle or in the abdomen or chest) that are asymptomatic are sometimes an incidental finding on CT scans or MRI scans obtained for other purposes.  They are generally not visible on plain xrays.

Gene Panels used to screen for cancer predisposition syndromes are now commonly obtained for individuals diagnosed with cancers that known as often being hereditary, or who have a strong family history of cancer. These panels may include a few genes or up to a few hundred genes, all of which are related to some form of cancer or cancer predisposition syndrome. The NF1, NF2, SMARCB1 and LZTR1 genes are often included. Germline NF1 and NF2 mutations are sometimes found, although it is uncommon that an adult with either of those diagnoses would be asymptomatic. Still, such patients need to be evaluated. LZTR1 mutations are now recognized as a common finding (1:340) in the general population even though less than 1% of patients with that will develop LZTR1-related SWN.  Why that is the case is not yet understood.     

Tumors:

Benign peripheral and spinal nerve schwannomas, two or more, are the hallmark. Pathologic verification (ie microscopic evaluation) of at least one tumor is required. 

Other tumors are much less common: VS in 10% of LZTR1-related SWN and meningioma in 5% of SMARCB1-related SWN.

Evolution to aggressive cancer (i.e. malignant peripheral nerve sheath tumor or MPNST) is rare and mainly associated with germline SMARCB1-related SWN.  

Other cancer predisposition syndromes and other sporadic cancers are also associated with the Non-NF2-related SWN genes. Rare instances of overlapping of those syndromes with Non-NF2-related SWN in the same family have been reported. 

Multiple Schwannomas: typically 4-12, but highly varied. 

Hybrid Nerve Sheath Tumors (HNST), a closely related benign nerve tumor that under the microscope has features of both schwannoma and neurofibroma, are also seen. True neurofibromas are almost never seen in the nonNF2-related SWNs. 

Schwannoma Locations: 

  • Peripheral Nerve Schwannomas: 89% of patients, most often in limbs (legs 45%, and arms 40%); less often in the trunk (40-50%), and fewer still in the head/neck region (20-25%). 
  • Localized to a single region: 30% (most often one leg) 
  • Spinal nerve root schwannoma: 75%
  • Non-Vestibular Cranial nerve schwannomas: 8%
  • Vestibular Schwannomas: unilateral VS occur in germline LZTR1-related SWN 5%

Other Tumors

  • Meningiomas: occur in germline SMARCB1-related SWN 5%
  • Intradermal schwannomas and ependymomas are seen in NF2-related SWN but not seen in nonNF2-related SWN.
  • Other Syndromes linked to SMARCB1 and LZTR1 Genes: Other tumor predisposition syndromes and developmental disorders that usually do not include schwannomas have been linked to genetic changes in the SMARCB1 and LZTR1 genes. However, very rare instances of overlap of these syndromes and schwannomatosis in the same family or same individual have been reported. 
  • SMARC B1:  Rhabdoid Tumor Predisposition Syndrome (RTPS) – malignant tumor syndrome in infants
  • Coffin-Siris Syndrome – developmental disorder with facial and brain abnormalities
  • LZTR1: Noonan Syndrome
  • Glioblastoma

Diagnostic Criteria

For diagnosis of Schwannomatosis you meet the criteria in path 1 or all of the items in path 2

Path 1
  • For SMARCB1-related SWN or LZTR1-related SWM: one schwannoma or HNST confirmed by microscopic evaluation AND a disease causing SMARCB1 Or LZTR1 gene abnormality (also called “PV” or “pathologic variant”) in normal tissue (i.e. blood)
Path 2
  • Two separate schwannomas or HNSTs with identical SMARCB1 or LZTR1 gene pathologic variants.
  • For 22q-related SWN: two schwannomas or HNSTs with loss of the same chromosome 22q markers AND a different NF2 gene PV in each tumor, which is not present in unaffected tissue (i.e. blood), and there is no evidence for NF2-related, SMARCB1-related or LTZR1-related PV.
  • For SWN-Not Otherwise Specified (SWN-NOS) or SWN- Not Elsewhere Classified (SWN-NEC): two lesions on imaging consistent with nonintradermal schwannomas, and one schwannoma or HNST confirmed by microscopic analysis. 

Genetics

SMARCB1-related SWN and LZTR1-related SWN share some genetic characteristics with NF2-related SWN since all three of the related genes are on chromosome 22, but there are also some important distinctions. In familial cases, the affected parent harbors a germline PV for the related gene on one copy of chromosome 22 and a normal gene on the other copy. When germ cells (egg or sperm cells) are formed they receive one copy of each pair of chromosomes (humans have 23 pairs). This results in a 50% chance of the child inheriting the PV gene. That child will have the PV gene in all cells and thus be affected as a germline patient also. This 50% risk of inheritance is characteristic of Autosomal Dominant genetic disorders. In patients without a family history, also called sporadic or denovo patients, and who do not have germline SMACRB1 or LZTR1 germline PVs on gene testing, the risk of transmission is less than 10%.   

Penetrance

Many types of DNA changes in genes are known to occur, and not all are pathogenic, i.e. cause an illness. Furthermore, some known PVs do not cause an illness in every individual who inherits it, while other PVs are known to cause a related illness in every patient with that PV. Penetrance of the genetic trait is the percentage of patients with the gene PV who actually manifest the related illness. Penetrance for SMARCB1 germline PVs and LZTR1 germline PVs are not 100%. Estimates are still being refined but penetrance of LZTR1 PVs is about 40-50% and SMARCB1 is higher. Thus, some individuals in a family with either of these disorders may have the gene PV but not manifest the illness.  That individual would be an asymptomatic carrier whose children would still be at risk for inheriting the condition.  By contrast, NF2-related SWN has 100% penetrance.  These factors are very important in genetic counseling recommendations about screening at risk family members. 

Another remarkably observation that remains to be understood well is that mutations that reduce LZTR1 gene function are relatively common in the general population (1:310) as demonstrated in genome databases, however less than 1% of those individuals will develop Non-NF2 SWN. 

Mosaicism

Each of the schwannomatoses can arise due to spontaneous mutations in the related gene.  This can occur at conception resulting in a new germline mutation for that individual. However, it is not uncommon for spontaneous mutations to occur in the embryo well after conception, resulting in only some cells in the embryo carrying the PV. Individuals with a mixture of normal and PV-containing cells are called mosaic for the condition. About 70% of non-NF2-related SWN based on clinical diagnoses are nonfamilial, sporadic or denovo patients.  What percentage are mosaic in uncertain. In NF2-related SWN about 50% are nonfamilial, and of those 60% are mosaic.

Mosaic patients tend to have milder versions, and very often the germ cells are not affected, so the likelihood of passing the PV gene to offspring is lower than 50%, and yet cannot be assumed to be zero. The characteristics of mosaic nonNF2-schwannomatosis have not been well studied given the rarity of the condition and the relatively recent identification of the related genes. They would be expected to have a small number of tumors limited to a localized anatomic region. Estimates for segmental nonNF2-SWN are about 30%, although not all of these are mosaic. Some patients with germline NonNF2-SWN might have a localized or regional pattern of tumors.  Some patients with mosaic NF2-related SWN might also have that pattern. Distinguishing these possibilities requires genetic testing. 

Schwannoma Formation

Schwann cells that loose function of both copies of the NF2 gene will start to grow abnormally and produce a tumor, i.e. a schwannoma. In familial NF2-SWN one copy that is lost or shut off is inherited in the egg or sperm, and the other copy is lost or shot off after conception as a sporadic event; often called a somatic mutation. Through whatever mechanism of loss of function, both copies of the gene are inactive and that gives rise to abnormal growth and tumor formation. That “Two Hit” model of tumor formation is known to occur in many hereditary cancer syndromes in addition to NF2-related SWN, including NF1, von Hippel Lindau syndrome, Li Fraumeni Syndrome and many others. 

The gene basis of tumor formation in the Non-NF2-related SWNs is more complex and in part relates to the physical proximity of then SMARCB1 and LZTR1 genes with the NF2 gene on chromosome 22. Testing of tumor DNA samples and DNA from normal tissue in many Non-NF2 SWN patients has shown that tumor activation requires the loss of function of both copies of, for example SMARCB1 PLUS the loss of both copies of the nearby NF2 genes. So, an individual who inherits one mutated copy of the SMARCB1 gene from a parent must have 3 additional genetic events, loss of function of the other SMARCB1 gene and loss of function of both copies of the NF2 gene, i.e. three more steps resulting in “Four Hits”, to initiate a schwannoma. Each of those additional three steps are unique in each individual tumor, and only the inherited SMARCB1 mutation or alteration is shared in all the tumors for that individual. In LZTR1 with same “3 step / 4 hit” model applies. This complexity is central to why testing of tumor DNA is so important in the Non-NF2 SWNs. The genetic basis of schwannomas is still being worked out, and evidence indicates that some other gene are involved in a smaller percentage of patients and families, and schwannoma-related genes on other chromosomes, i.e. Non-22q-related SWN probable exist.  

MONITORING and SCREENING

Individuals who are diagnosed with Non-NF2 SWN or history of Non-NF2 SWN should have regular monitoring focusing on evidence for development of new or progressive schwannomas, assessment of neurological status, pain status and pain control, and quality of life. Guidelines for monitoring have been published based on the consensus of expert panels. MRI is the best imaging method for scwannomas. Baseline assessment at diagnosis should include craniospinal MRI scans. While body MRI is often preferred over MRIs focused on just symptomatic areas, but whole body MRI is not widely done in adult oncology. Special views of the skull base and cranial nerves (internal auditory canal or “IAC” views) look for VSs and help to exclude NF2-related SWN. VS is also relevant in LZTR1-related SWN.  

Patients who are stable and relatively uncomplicated should have annual in office physical examination, pain assessment, and quality of life review. Follow up MRI scans for asymptomatic tumors that are not palpable should be done every 2-3 years. Many patients benefit from consulting with a multidisciplinary pain management team. New or worsening symptoms, especially pain (including headaches and neck or back pain), or neurological symptoms (i.e. progressive weakness or numbness, impaired balance, reduced vision, hearing, change in voice or swallowing, seizures, alteration in cognition, change in bladder control, or others … ) should be carefully evaluated as soon as is feasible.  MRI scanning often would be part of that assessment. In germline SMARCB1-related SWN worsening pain may signal evolution of a schwannoma to a MPNST.

Individuals who are known to be at risk based on a family history of Non-NF2 SWN should undergo germline SMARCB1 or LZTR1 testing on normal tissue based on the knowledge of the germline PV in their family. Individuals with no family history of Non-NF2 SWN who are discovered to have an LZTR1 PV on gene panel testing do not need any further evaluation for Non-NF2 SWN unless they have a suspected tumor or relevant symptoms. 

Treatment

Surgical removal of painful tumors: Often effective at reducing pain; not an option if significant weakness or numbness due to nerve damage is likely to result from surgery.

Medications for Nerve Pain: Gabapentin, Pregabalin, Tricyclic antidepressants (amitriptyline, nortriptyline, and others), Duloxetine all have moderate effectiveness; Narcotics are generally less effective and largely avoided given concern for addiction with chronic use; Acetaminophen and NSAIDS are often not effective. Experimental agents are in testing. 

Chemotherapy: no established effective agents; bevacizumab, which is often helpful in NF2-related SWN,  has anecdotal reports of benefit with reduction in pain for patients with nonNF2-SWN.

Radiation: Not recommended; may increase risk of malignant evolution schwannomas, and of triggering second cancers (meningiomas, gliomas, breast cancer, and others). 

Genetic counseling is an essential part of Non-NF2-related SWN treatment.  Patient education focusing on risk of transmission of autosomal dominant genetic disorders, penetrance, mosaicism, counseling about family planning considerations and options, and identification and assessment of at-risk individuals is essential for high quality care.  These topics are central issues to many genetic disorders, yet the details as applied to Non-NF2 SWN are nuanced and changing rapidly.  The value of seeing specialists with experience in the schwannomatoses is highlighted by the need for patient education regarding these many complex issues.