Clinical characteristics.

LZTR1- and SMARCB1-related schwannomatosis are characterized by a predisposition to develop multiple non-intradermal schwannomas. Individuals 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 have only been reported in individuals with SMARCB1-related schwannomatosis. Malignancy remains a risk especially in individuals with SMARCB1-related schwannomatosis.

Diagnosis/testing.

The diagnosis of LZTR1- or SMARCB1-related schwannomatosis is established in a proband with characteristic clinical findings and a heterozygous germline pathogenic variant in LZTR1 or SMARCB1 identified by molecular genetic testing.

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: Annual neurologic examination and pain assessment; brain and spine MRI or whole-body MRI every two to three years beginning at age 12 years, with fine cuts through internal auditory canal in those w/LZTR1-related schwannomatosis; assessment for anxiety and depression annually or as needed.

Agents/circumstances to avoid: Radiation can increase the risk for malignant transformation and should be avoided when possible.

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.

LZTR1- and SMARCB1-related schwannomatosis are inherited in an autosomal dominant manner with reduced penetrance. Fewer than 20% of individuals diagnosed with LZTR1- or SMARCB1-related schwannomatosis have an affected parent. In families in which the proband represents a simplex case, the proportion of probands with a de novo pathogenic variant is approximately 30% for LZTR1-related schwannomatosis and 10% for SMARCB1-related schwannomatosis. Each child of an individual with LZTR1- or SMARCB1-related schwannomatosis has up to a 50% chance of inheriting a pathogenic variant. Once a germline LZTR1 or SMARCB1 pathogenic variant has been identified in an affected family member, predictive testing for at-risk asymptomatic family members and prenatal and preimplantation genetic testing are possible.

Suggestive Findings

LZTR1- or SMARCB1-related schwannomatosis should be suspected in a proband with the following:

• Two or more non-intradermal tumors suggestive of schwannomas
• Absence of bilateral vestibular schwannomas
• A family history of schwannomatosis consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

A diagnosis of LZTR1- or SMARCB1-related schwannomatosis is established in a proband with suggestive findings by identification of a heterozygous germline pathogenic (or likely pathogenic) variant in LZTR1 or SMARCB1 by molecular genetic testing (see Table 1); or identification of identical pathogenic (or likely pathogenic) variants in SMARCB1 or LZTR1 in two or more anatomically distinct schwannomatosis-related tumors.

Note: In some instances, it may be difficult to distinguish between LZTR1- or SMARCB1-related schwannomatosis and mosaic NF2-related schwannomatosis (see Differential Diagnosis).

See Molecular Pathogenesis for a hypothesis regarding the development of LZTR1- or SMARCB1-related schwannomatosis resulting from biallelic inactivation of LZTR1 or SMARCB1 and biallelic inactivation of NF2.

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include concurrent LZTR1 and SMARCB1 gene testing or use of a multigene panel:

• Concurrent gene testing. Sequence analysis of LZTR1 and SMARCB1 is performed first to detect missense, nonsense, and splice site variants and small intragenic deletions/insertions. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis of LZTR1 and SMARCB1 to detect exon and whole-gene deletions or duplications.
• A multigene panel that includes LZTR1, SMARCB1, NF2, and other genes of interest (see Differential Diagnosis) may be considered to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Clinical Description

LZTR1- and SMARCB1-related schwannomatosis are characterized by a predisposition to develop multiple schwannomas (histologically benign nerve sheath tumors) [Merker et al 2012]. Individuals most commonly present between the second and fourth decade of life. The most common presenting symptoms are localized or diffuse pain or an asymptomatic mass. Focal weakness and/or muscle atrophy rarely occur as the only presenting sign of LZTR1- or SMARCB1-related schwannomatosis [Ostrow et al 2017].

Schwannomas most often affect peripheral nerves and spinal nerves [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 LZTR1-related schwannomatosis, but presence of bilateral vestibular schwannomas are an exclusion criterion, as individuals with bilateral vestibular schwannomas fulfill diagnostic criteria for NF2-related schwannomatosis [Pathmanaban et al 2017, Smith et al 2017].

In a study of 51 individuals with LZTR1- or SMARCB1-related schwannomatosis imaged by whole-body MRI examination, 36/51 (71%) had internal nerve sheath tumors, 81% of which were discrete; three individuals (8%) had plexiform neurofibromas; and the remaining individuals had both tumor types [Plotkin et al 2012].

Meningiomas have only been reported in individuals with SMARCB1-related schwannomatosis [Bacci et al 2010, Christiaans et al 2011].

Malignancy. Malignant transformation of schwannomas remains a risk in SMARCB1-related schwannomatosis [Eelloo et al 2019]. 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 LZTR1- or SMARCB1-related schwannomatosis and may not always localize to the site of the schwannoma [Merker et al 2012].

Note: Cutaneous manifestations including café au lait macules, skin fold freckling, and cutaneous schwannomas typical of other forms of neurofibromatosis are not common features of LZTR1- or SMARCB1-related schwannomatosis.

Phenotype Correlations by Gene

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

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

Genotype-Phenotype Correlations

SMARCB1. In general, SMARCB1 pathogenic variants that predispose to familial schwannomatosis are more likely to be non-truncating (e.g., missense, splice site) and are most commonly located at either the 5' or 3' end of the gene. Individuals without a family history of 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, Kehrer-Sawatzki et al 2018].

Penetrance

The data on penetrance are limited, though it is less than 100% for both SMARCB1- and LZTR1-related schwannomatosis. Penetrance is estimated to be between 40% and 50% with penetrance higher in SMARCB1 pathogenic variants [Swensen et al 2009, Plotkin et al 2013, Piotrowski et al 2014, Paganini et al 2015, Smith et al 2015, Gripp et al 2017, Evans et al 2022].

Nomenclature

Schwannomatosis is now used as an umbrella term for individuals with predisposition to multiple schwannomas.

In the revised nomenclature [Plotkin et all 2022], schwannomatosis is termed:

• SMARCB1-related schwannomatosis (individuals with a germline pathogenic variant in SMARCB1 or a shared SMARCB1 pathogenic variant in two independent schwannomas);
• LZTR1-related schwannomatosis (individuals with a germline pathogenic variant in LZTR1 or a shared LZTR1 pathogenic variant in two independent schwannomas);
• NF2-related schwannomatosis (individuals with a germline pathogenic variant in NF2 or a shared NF2 pathogenic variant in two independent schwannomas);
• 22q-related schwannomatosis (individuals with multiple schwannomas with shared loss of heterozygosity along chromosome 22q on the same allele for each tumor along with biallelic inactivation of NF2);
• Schwannomatosis-not otherwise specified (NOS) (individuals who have clinical features of SMARCB1-, LZTR1-, and NF2- related schwannomatosis but have not had molecular analysis);
• Schwannomatosis-not elsewhere classified (NEC) (individuals in whom molecular analysis of blood and tumors has failed to detect a pathogenic variant).

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

Prevalence

LZTR1- and SMARCB1-related schwannomatosis are rare disorders with a combined estimated prevalence of around one in 126,000. This is likely an underestimate given difficulty in identifying affected individuals [Kehrer-Sawatzki et al 2017, Smith et al 2017, Evans et al 2022].

Cancer and Benign Tumors

LZTR1. Sporadic glioblastomas occurring as single tumors in the absence of any other findings of schwannomatosis may contain a somatic variant in LZTR1 that is not present in the germline. In these circumstances predisposition to these tumors is not heritable. Somatic LZTR1 pathogenic variants are identified in about one fifth of glioblastomas [Frattini et al 2013].

SMARCB1. Sporadic meningiomas occurring as single tumors in the absence of any other findings of schwannomatosis may contain a somatic variant in SMARCB1 that is not present in the germline [Schmitz et al 2001, Rieske et al 2003]. In these circumstances predisposition to these tumors is not heritable.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with LZTR1- or SMARCB1-related schwannomatosis, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Incidental diagnosis of LZTR1- or SMARCB1-related schwannomatosis. If a pathogenic variant in LZTR1 or SMARCB is identified in an individual not otherwise known to be at risk for predisposition to develop schwannomas, the individual should be informed about reduced penetrance and referred for genetic counseling (as described in Table 4). Baseline imaging can be dictated by symptoms [Evans et al 2022].

Treatment of Manifestations

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 5).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended by a multispecialty guideline group [Evans et al 2022].

Agents/Circumstances to Avoid

Radiation can increase the risk for malignant transformation and should be avoided when possible [Evans et al 2022].

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of 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.

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

Therapies Under Investigation

A Phase II study of tanezumab (an investigational humanized monoclonal antibody that inhibits nerve growth factor) in individuals with moderate to severe pain due to schwannomatosis is active. It is the first therapeutic clinical trial for schwannomatosis, targeting biological drivers of schwannomatosis-related pain [Da et al 2022].

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.

Mode of Inheritance

LZTR1- and SMARCB1-related schwannomatosis are inherited in an autosomal dominant manner with reduced penetrance.

Risk to Family Members

Parents of a proband

• Fewer than 20% of individuals diagnosed with LZTR1- or SMARCB1-related schwannomatosis have an affected parent. Because LZTR1- and SMARCB1-related schwannomatosis are associated with both intrafamilial clinical variability and reduced penetrance, a parent with an LZTR1 or SMARCB1 pathogenic variant may not have clinical symptoms [Antinheimo et al 2000, Kehrer-Sawatzki et al 2017].
• Some individuals diagnosed with LZTR1- or SMARCB1-related schwannomatosis have the disorder as the result of a de novo pathogenic variant [Kehrer-Sawatzki et al 2017]. In families in which the proband represents a simplex case (i.e., the only family member known to be affected), the proportion of probands with a de novo pathogenic variant is approximately 30% for LZTR1-related schwannomatosis and 10% for SMARCB1-related schwannomatosis [Kehrer-Sawatzki et al 2017].
• If the proband is the only family member known to have schwannomatosis and molecular genetic testing does not suggest that the LZTR1 or SMARCB1 pathogenic variant identified in the proband is mosaic, molecular genetic testing can be considered for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the LZTR1 or SMARCB1 pathogenic variant found in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has de novo germline pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The family history of some individuals diagnosed with LZTR1- or SMARCB1-related 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 molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.

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 identified in the proband, the risk to the sibs of inheriting an LZTR1 or SMARCB1 pathogenic variant is 50%. However, the risk of developing schwannomas and/or meningiomas may be less than 50% because penetrance is reduced (see Penetrance). Phenotypic variability may also be observed among affected family members.
• If the LZTR1 or SMARCB1 pathogenic variant detected in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism. Presumed germline mosaicism in a clinically unaffected parent has been reported in one family to date [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 and the possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with LZTR1- or SMARCB1-related schwannomatosis has up to a 50% chance of inheriting an LZTR1 or SMARCB1 pathogenic variant:

• If the proband has other affected family members, each child of the proband has a 50% chance of inheriting an LZTR1 or SMARCB1 pathogenic variant.
• If the proband is the only affected individual in the family:
  • And the proband has a de novo germline pathogenic variant (i.e., present in the egg or sperm at the time of conception), offspring have a 50% chance of inheriting the pathogenic variant.
  • And the proband has somatic mosaicism for the pathogenic variant, offspring may have a less than 50% risk of inheriting the pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has an 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 (i.e., testing of asymptomatic at-risk individuals)

• Predictive testing for at-risk asymptomatic family members requires prior identification of the germline LZTR1 or SMARCB1 pathogenic variant in the family.
• Potential consequences of such testing as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
• Because early detection of at-risk individuals affects surveillance, testing of at-risk asymptomatic individuals younger than age 18 years may be beneficial. Parents often want to know the genetic status of their children prior to initiating screening in order to avoid unnecessary procedures for a child who has not inherited the pathogenic variant. Special consideration should be given to education of the children and their parents prior to genetic testing. A plan should be established for the manner in which results are to be given to the parents and children.

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.

Prenatal Testing and Preimplantation Genetic Testing

Once the germline 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. 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- and SMARCB1-related schwannomatosis. LZTR1- and SMARCB1-related schwannomatosis are 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 LZTR1 or SMARCB1 mutation event. The second event involves loss of heterozygosity through contiguous deletion on 22q including the wild type LZTR1, SMARCB1, and NF2 alleles. Third, somatic inactivating mutation of the remaining NF2 allele, in cis with the LZTR1 or SMARCB1 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 both SMARCB1- and LZTR1-related schwannomatosis) [Hadfield et al 2008, Hadfield et al 2010, Piotrowski et al 2014].

Author Notes

The authors are actively involved in clinical research regarding individuals with schwannomatosis. They would be happy to communicate with persons who have any questions regarding diagnosis of schwannomatosis or other considerations.

Contact Alicia Gomes (ude.cmbau@semoga) to inquire about review of LZTR1 or SMARCB1 variants of uncertain significance.

Acknowledgments

The authors would like to thank Children's Tumor Foundation for their continued work on neurofibromatosis and schwannomatosis.

Author History

Ashok Asthagiri, MD; University of Virginia (2018-2023)
Dusica Babovic-Vuksanovic, MD (2018-present)
Radhika Dhamija, MD (2018-present)
Alicia Gomes, MS, LCGC (2023-present)
Ludwine Messiaen, PhD; University of Alabama (2018-2023)
Scott Plotkin, MD, PhD (2018-present)

Revision History

• 25 April 2024 (sw) Revision: clarification of when first brain MRI is recommended (Table 4)
• 27 July 2023 (sw) Comprehensive update posted live
• 8 March 2018 (sw) Review posted live
• 14 July 2017 (rd) Original submission

Published Guidelines / Consensus Statements

• Evans DG, Mostaccioli S, Pang D, Fadzil O Connor M, Pittara M, Champollion N, Wolkenstein P, Thomas N, Ferner RE, Kalamarides M, Peyre M, Papi L, Legius E, Becerra JL, King A, Duff C, Stivaros S, Blanco I. ERN GENTURIS clinical practice guidelines for the diagnosis, treatment, management and surveillance of people with schwannomatosis. Eur J Hum Genet. 2022;30:812-7. [PubMed]
• Plotkin SR, Messiaen L, Legius E, Pancza P, Avery RA, Blakeley JO, Babovic-Vuksanovic D, Ferner R, Fisher MJ, Friedman JM, Giovannini M, Gutmann DH, Hanemann CO, Kalamarides M, Kehrer-Sawatzki H, Korf BR, Mautner VF, MacCollin M, Papi L, Rauen KA, Riccardi V, Schorry E, Smith MJ, Stemmer-Rachamimov A, Stevenson DA, Ullrich NJ, Viskochil D, Wimmer K, Yohay K; International Consensus Group on Neurofibromatosis Diagnostic Criteria (I-NF-DC); Huson SM, Wolkenstein P, Evans DG. Updated diagnostic criteria and nomenclature for neurofibromatosis type 2 and schwannomatosis: an international consensus recommendation. Genet Med. 2022;24:1967-77. [PubMed]

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