Clinical characteristics.

Schwannomatosis is characterized by a predisposition to develop multiple schwannomas and, less frequently, meningiomas. Individuals with schwannomatosis most commonly present between the second and fourth decade of life. The most common presenting feature is localized or diffuse pain or asymptomatic mass. Schwannomas most often affect peripheral nerves and spinal nerves. Meningiomas occur in about 5% of individuals with schwannomatosis and have only been reported in individuals with SMARCB1-related schwannomatosis. Malignancy remains a theoretic risk especially in individuals with a SMARCB1 pathogenic variant.

Diagnosis/testing.

The diagnosis of schwannomatosis is established based on clinical criteria or combined molecular and clinical criteria. Combined criteria include identification of a heterozygous germline pathogenic variant in SMARCB1 or LZTR1 in an individual with a pathologically confirmed schwannoma or meningioma.

Management.

Treatment of manifestations: Comprehensive, multimodal approach to pain management, guided by a pain management specialist or neurologist; referral to mental health professionals as needed for anxiety and/or depression; surgery for schwannomas associated with uncontrolled localized pain or a neurologic deficit; meningioma treatment as for sporadic meningioma.

Surveillance: At least annual imaging of intracranial schwannomas and spinal schwannomas as they can potentially cause spinal cord compression.

Evaluation of relatives at risk: It is appropriate to evaluate apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from surveillance and clinical management.

Genetic counseling.

Schwannomatosis is inherited in an autosomal dominant manner. Fewer than 20% of individuals have an affected parent. The proportion of cases caused by de novo pathogenic variants is approximately 30% for LZTR1-related schwannomatosis and 10% for SMARCB1-related schwannomatosis. Penetrance is less than 100%. The risk to each offspring of inheriting the pathogenic variant is 50%. Once the LZTR1 or SMARCB1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

Schwannomatosis should be suspected in a proband with the following:

• Two or more non-intradermal tumors suggestive of schwannomas
• No history of vestibular schwannomas
• A family history of schwannomatosis

Establishing the Diagnosis

A diagnosis of schwannomatosis is established in a proband with the following clinical criteria or combined molecular and clinical criteria recently proposed by Kehrer-Sawatzki et al [2017].

Clinical Description

Schwannomatosis is an autosomal dominant tumor suppressor syndrome with reduced penetrance, characterized by a predisposition to develop multiple schwannomas (histologically benign nerve sheath tumors) and much less frequently meningiomas [Merker et al 2012]. Individuals with schwannomatosis most commonly present between the second and fourth decade of life. Individuals with sporadic schwannomatosis usually present later than those with familial schwannomatosis [Antinheimo et al 2000, Gonzalvo et al 2011, Koontz et al 2013]. The most common clinical symptom is either localized or diffuse pain [Merker et al 2012, Li et al 2016, Ostrow et al 2017]. Another presenting symptom can be an asymptomatic mass. Focal weakness and/or muscle atrophy rarely occur as the only presenting sign of schwannomatosis [Ostrow et al 2017].

Schwannomas most often affect peripheral nerves (90%) and spinal nerves (75%) [Merker et al 2012]. Among the spinal nerves, the lumbar spine is most commonly affected [Li et al 2016]. Although cranial nerve involvement is rare, the most common cranial nerve affected is the trigeminal nerve [Gonzalvo et al 2011]. Unilateral vestibular schwannomas can occur in individuals with schwannomatosis, but bilateral vestibular schwannoma is an exclusion criterion as these individuals fulfill diagnostic criteria for neurofibromatosis 2 [Smith et al 2017].

In a study of 51 individuals with schwannomatosis imaged by whole-body MRI examination, 36 (71%) of the 51 individuals had internal nerve sheath tumors –81% of which were discrete; three (8%) individuals had plexiform neurofibromas, and the remaining individuals had both tumor types [Plotkin et al 2012].

Meningiomas occur in about 5% of individuals with schwannomatosis [Merker et al 2012] and have only been reported in individuals with SMARCB1 pathogenic variants [Bacci et al 2010, Christiaans et al 2011].

Malignancy. Malignant transformation of schwannomas remains a theoretic risk as in other tumor suppressor syndromes [Evans et al 2012]. Malignant schwannomas were identified in two individuals with clinically diagnosed familial schwannomatosis [Gonzalvo et al 2011]. In a large retrospective analysis of 87 individuals with schwannomatosis, three individuals were diagnosed with malignant peripheral nerve sheath tumors (MPNSTs) but subsequent reanalysis by an experienced neuropathologist led to reclassification of these MPNSTs to cellular schwannoma (2 tumors) and melanoma (1 tumor) [Merker et al 2012]. Thus, the exact risk of malignant transformation remains unclear. Rapid growth of a schwannoma and intractable pain should raise concern for the possibility of malignancy.

Pain is a very common comorbid condition in individuals with schwannomatosis and may not always localize to the site of the schwannoma. Increased tumor volume was associated with higher levels of pain in an analysis of 51 individuals with schwannomatosis imaged with whole-body MRI examination [Merker et al 2014]. Pain often becomes chronic and is associated with anxiety and depression [Gonzalvo et al 2011, Merker et al 2012]. Quality of life measurement scores are decreased in individuals with schwannomatosis [Merker et al 2014].

Segmental schwannomatosis. In about one third of individuals with schwannomatosis, schwannomas are limited to one extremity, one side of the body, or a limited region of the spine (typically <5 contiguous segments) [Koontz et al 2013]. Somatic mosaicism has been proposed as a mechanism for segmental schwannomatosis, although this is not yet established. A recent study of five individuals with clinically diagnosed segmental schwannomatosis identified subtle fascicular lesions by magnetic resonance neurography in four of five individuals in clinically unaffected limbs; two of the five individuals had germline LZTR1 pathogenic variants. The presence of subtle disease beyond the clinically affected region argues against a purely segmental disease and suggests the possibility of other genetic modifiers [Farschtschi et al 2016].

Note: Cutaneous manifestations including café au lait macules, skin-fold freckling, and cutaneous schwannomas typical of other forms of neurofibromatosis are not features of schwannomatosis.

Phenotype Correlations by Gene

SMARCB1. Meningiomas have been reported in individuals with SMARCB1-related schwannomatosis [Bacci et al 2010, Christiaans et al 2011, Melean et al 2012, van den Munckhof et al 2012].

LZTR1. To date no individuals with LZTR1-related schwannomatosis have been reported to have meningiomas.

Genotype-Phenotype Correlations

In general, SMARCB1 pathogenic variants that predispose to familial schwannomatosis are more likely to be nontruncating (e.g., missense, splice site) and are most commonly located at either the 5' or 3' end of the gene. Individuals with sporadic schwannomatosis are more likely to have truncating (e.g., frameshift, nonsense) SMARCB1 pathogenic variants [Rousseau et al 2011].

Germline truncating SMARCB1 variants (e.g., frameshift, nonsense), deletions of one or more exons, or deletion of the entire SMARCB1 gene is found in 15%-60% of individuals with rhabdoid tumors [Bourdeaut et al 2011, Eaton et al 2011]. Truncating SMARCB1 variants and deletions of one or more exons are most commonly seen in the central part of the gene (see Genetically Related Disorders) [Smith et al 2014]. Rhabdoid and atypical teratoid tumors have rarely also been reported in some members of families with SMARCB1-related schwannomatosis [Swensen et al 2009, Eaton et al 2011].

Penetrance

The data on penetrance are limited, though it is less than 100% for both SMARCB1- and LZTR1-related schwannomatosis [Swensen et al 2009, Plotkin et al 2013]. Reduced penetrance is more frequently reported in individuals with LZTR1-related schwannomatosis [Piotrowski et al 2014, Paganini et al 2015, Smith et al 2015, Gripp et al 2017].

Nomenclature

Schwannomatosis has been referred to as the third form of neurofibromatosis.

Previous terminology for this condition has included multiple neurilemomas, multiple schwannomas, and congenital neurilemomatosis.

Prevalence

Schwannomatosis is a rare disorder with an estimated prevalence of around 1/70,000. This is likely an underestimate given difficulty in identifying affected individuals [MacCollin et al 2005, Koontz et al 2013, Plotkin et al 2013, Kehrer-Sawatzki et al 2017, Smith et al 2017].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with schwannomatosis, the following evaluations are recommended if they have not already been completed:

• Detailed family and personal clinical history
• Brain and spine MRI examination to establish the extent of disease
• MRI examination of peripheral nervous system based on symptoms
• Consultation with a neurologist and a neurosurgeon as symptoms indicate
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Pain management. Various pain medications (e.g., calcium channel alpha 2 delta ligands such as gabapentin, tricyclic antidepressants such as amitriptyline, serotonin-norepinephrine reuptake inhibitors such as venlafaxine) may be helpful individually or as adjuncts. No class of pain medication appears to be better than another [Author, personal communication]. A comprehensive, multimodal approach to pain management guided by a pain management specialist or neurologist provides an opportunity for long-term management of symptoms without surgical intervention.

Emotional health. Pain management may improve anxiety and depression. Referral to mental health professionals may also be warranted.

Surgical management of peripheral nerve tumors. Surgery is indicated for symptomatic schwannomas (e.g., uncontrolled localized pain related to a schwannoma, schwannoma resulting in a neurologic deficit). The principles for surgical resection of peripheral nerve tumors are similar to those utilized for resection of sporadic nerve sheath tumors:

• The potential benefits of surgery must be weighed carefully against the potential risks.
• Given the technical challenges involved in surgery, referral to an expert center with a peripheral nerve surgeon is recommended.
• It is important that surgery be performed in conjunction with ongoing pharmacologic pain management, as pain relief following tumor resection is not ensured.

Management of spinal and cranial nerve tumors. Performing surgery for each newly identified tumor is impractical and inadvisable. Therefore, delineation of "presymptomatic" tumors at initial evaluation (and each subsequent evaluation) is requisite to establishing a paradigm of expectant management for longitudinal observation. Affected individuals should be educated on the most common, early symptoms that suggest that an existing tumor is becoming problematic. Early identification and intervention for problematic tumors improves outcomes for many central nervous system tumors. Intraspinal schwannomas >5 mm in size warrant longitudinal imaging and clinical surveillance. Growing intraspinal schwannomas may cause significant impact to adjacent neural structures, and surgical removal at the time of early onset of symptoms remains the mainstay of treatment. This approach balances the need to maximize functional outcome and to avoid unnecessary prophylactic surgical intervention.

When considering surgical intervention for a cerebellopontine angle cranial nerve schwannoma it is important to consider historical cues, physical exam findings, and imaging observations that may help delineate a facial nerve etiology. Because hearing preservation and facial nerve preservation are significant considerations when making a decision to intervene on schwannomas of the internal auditory canal, these become critical in determining the timing of intervention. In general hearing preservation rates are dramatically reduced when vestibular schwannomas exceed 1 cm in size, and facial nerve function significantly declines when schwannomas exceed 2.5-3 cm. It remains unclear how best to translate the success seen with radiosurgery for sporadic vestibular schwannoma management to those with schwannomatosis [Kondziolka et al 1998].

Management of meningiomas. There is a paucity of outcome data from surgical, radiosurgical, and radiation therapy for meningiomas in individuals with schwannomatosis. Therefore, management recommendations in individuals with schwannomatosis and meningioma are the same as for those with sporadic meningioma.

Radiation therapy. There is a theoretic risk that radiation exposure can increase the risk for malignant transformation; however, this has not yet been demonstrated in individuals with schwannomatosis [Evans et al 2006]. The exact role of this modality needs to be established.

Surveillance

Based on the 2016 American Association for Cancer Research Childhood Cancer Predisposition Workshop, surveillance guidelines have been proposed [Evans et al 2017].

SMARCB1-related schwannomatosis

• Baseline MRI examination of the brain and spine at diagnosis, then every two to three years beginning at age ten years
• Consideration of whole-body MRI examination and increasing surveillance frequency if symptomatic

LZTR1-related schwannomatosis [Plotkin et al 2012, Merker et al 2014, Evans et al 2017]

• Baseline MRI examination of the brain and spine at diagnosis, then every two to three beginning at age 15 to 19 years
• Consideration of whole-body MRI examination and increasing surveillance frequency if symptomatic

High cost and poor insurance reimbursement limit the wider use of whole-body MRI.

Agents/Circumstances to Avoid

There is a theoretic risk that radiation exposure can increase the risk for malignant transformation; however, this has not yet been demonstrated in individuals with schwannomatosis [Evans et al 2006].

Evaluation of Relatives at Risk

It is appropriate to evaluate apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from surveillance and clinical management. Evaluations can include:

• Molecular genetic testing (after appropriate genetic counseling) if the pathogenic variant in the family is known;
• A through neurologic examination and history if the pathogenic variant in the family is not known.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Schwannomatosis is inherited in an autosomal dominant manner with incomplete penetrance.

Risk to Family Members

Parents of a proband

• Fewer than 20% of individuals diagnosed with schwannomatosis have an affected parent. There is clinical variability within families and reduced penetrance [Antinheimo et al 2000, Kehrer-Sawatzki et al 2017].
• Some individuals diagnosed with schwannomatosis have the disorder as the result of a de novo LZTR1 or SMARCB1 pathogenic variant [Kehrer-Sawatzki et al 2017]. The proportion of simplex cases caused by a de novo pathogenic variant is approximately 30% for LZTR1-related schwannomatosis and 10% for SMARCB1-related schwannomatosis [Kehrer-Sawatzki et al 2017].
• Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant.
• If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent. Germline mosaicism for a SMARCB1 pathogenic variant has been reported in one family, and thus is far less frequent than in neurofibromatosis 2 [Hulsebos et al 2010].
• The family history of some individuals diagnosed with schwannomatosis may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband.
• Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to be heterozygous for the LZTR1 or SMARCB1 pathogenic variant, the risk to the sibs is 50%. However, penetrance is reduced and there is phenotypic variability within families.
• If the LZTR1 or SMARCB1 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is presumed to be slightly greater than that of the general population (though still <1%) because of the possibility of parental germline mosaicism [Hulsebos et al 2010].
• The absence of clinical symptoms in parents whose genetic status is unknown cannot be used to predict risk to sibs of a proband because of the possibility of reduced penetrance in a heterozygous parent or the possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with schwannomatosis has a 50% chance of inheriting the LZTR1 or SMARCB1 pathogenic variant. However, penetrance is reduced and there is phenotypic variability within families.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the LZTR1 or SMARCB1 pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the LZTR1 or SMARCB1 pathogenic variant in the family.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption should also be considered.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).

Prenatal Testing and Preimplantation Genetic Testing

Once the LZTR1 or SMARCB1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

The classic Knudson two-hit model of tumorigenesis does not suffice for tumor initiation or growth in LZTR1- or SMARCB1-related schwannomatosis. LZTR1- or SMARCB1-related schwannomatosis is caused by biallelic inactivation of at least two tumor suppressor genes.

A hypothesis has been proposed for both LZTR1- and SMARCB1-related familial schwannomatosis. The first hit is a germline inactivating SMARCB1 or LZTR1 mutation event. The second event involves loss of heterozygosity through contiguous deletion on 22q including the wild-type LZTR1, SMARCB1, and NF2 alleles. Thirdly, somatic inactivating mutation of the remaining NF2 allele, in cis with the SMARCB1 or LZTRI first hit, occurs. Therefore, these events result in either biallelic inactivation of SMARCB1 (in SMARCB1-related schwannomatosis) or LZTR1 (in LZTR1-related schwannomatosis) as well as the inactivation of both NF2 alleles (in SMARCB1- as well as LZTR1-related schwannomatosis) [Hadfield et al 2008, Hadfield et al 2010, Piotrowski et al 2014].

Revision History

• 8 March 2018 (sw) Review posted live
• 14 July 2017 (rd) Original submission

Published Guidelines / Consensus Statements

• Evans DGR, Salvador H, Chang VY, Erez A, Voss SD, Druker H, Scott HS, Tabori U. Cancer and central nervous system tumor surveillance in pediatric neurofibromatosis 2 and related disorders. Clin Cancer Res. 2017;23:e54–e61. [PubMed: 28620005]

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