Schwannomatosis – Definition

Schwannomatosis (OMIM #162091 (SMARCB1), #615670 (LZTR1), #607174 (SMARCE1)) is a newly identified rare form of neurofibromatosis, also known as neurofibromatosis type 3, which is associated with the development of benign nerve sheath tumors, called schwannomas, that form along spinal and peripheral nerves. The disease frequently does not occur until adulthood and exhibits clinical symptoms of chronic and often diffuse pain.

Synonym:

NF3

Genes:

SMARCB1 (INI1), LZTR1 -> schwannomatosis
SMARCE1 -> meningiomatosis

Gene ­products:

• SMARCB1

• LZTR1

• SMARCE1

Function:

Regulators of gene expression and, thus tumor suppression

  • SMARCB1: SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1
  • LZTR1: leucine-zipper-like transcriptional regulator 1
  • SMARCE1: SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily E member 1

Pattern of inheritance:

Autosomal dominant, 80% de novo mutations

Prevalence:

< 1 : 40.000

Genotype-phenotype correlation:

SMARCB1 schwannomatosis:

  • Loss of function mutation -> rhabdoid tumor
  • Hypomorphic mutation -> schwannomatosis

Penetrance:

Incomplete

Overview of the Chapters on This Page:

  • Schwannomatosis – Definition (This Section)
  • Schwannomatosis – Diagnosis

  • Clinical Presentation

  • Special Features of Treatment

  • Recommendations for Early Detection in Your Patients

  • Further Information (e.g., Links to Support Groups)

  • Schwannomatosis – Definition (This Section)
  • Schwannomatosis – Diagnosis

  • Clinical Presentation

  • Special Features of Treatment

  • Recommendations for Early Detection in Your Patients

  • Further Information (e.g., Links to Support Groups)

Schwannomatosis – Diagnosis

Clinical Suspicion

  • At least one schwannoma or one mixed nerve sheath tumor in the pathology report
  • ≥ 2 non-intradermal schwannomas in the imaging

Clinical Diagnostic Criteria

  • At least one histologically confirmed schwannoma or hybrid nerve sheath tumor AND a pathogenic SMARCB1 or LZTR1 variant in an unaffected tissue (e.g. blood)
    or
  • A shared pathogenic SMARCB1 or LZTR1 variant in two schwannomas or hybrid nerve sheath tumors

If there are ≥ 2 non-intradermal schwannomas without histopathological confirmation, the tentative diagnosis is likely, especially in association with chronic pain.

Segmental schwannomatosis: schwannomas on only one extremity or over 2 spinal segments (30%).

Differential Diagnoses

Clinical Presentation

Depending on the location of the genetic changes, schwannomatosis presents itself in 3 clinically distinct forms:

  • SMARCB1 schwannomatosis is associated with the development of many, often painful, yet benign tumors of the sheaths of peripheral or central nerves (located in the head or spinal canal). The risk of malignant degeneration is probably slightly elevated. In addition, the risk of developing benign tumors of the meninges (meningiomas) is slightly elevated (5%) as well.
  • LZTR1 schwannomatosis can cause unilateral tumors of cranial nerve 8, the auditory vestibular nerve (vestibular schwannoma).
  • Meningiomatosis (SMARCE1 schwannomatosis) leads to a predisposition to isolated benign central or spinal tumors of the meninges (meningiomas) during childhood.

Special Features of Treatment

Surgical intervention, pain management

Diagnosis of Schwannomatosis- What's Next?

Once diagnosed, it is recommended that a cancer predisposition specialist manage the patient. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. Some additional information, including links to support groups, is also included at the end of this page.

Diagnosis of Schwannomatosis- What's Next?

Once diagnosed, it is recommended that a cancer predisposition specialist manage the patient. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. Some additional information, including links to support groups, is also included at the end of this page.

Recommendations for Early Detection in Your Patients

For patients with NF3, starting once the clinical or genetic diagnosis has been established, throughout life (examination recommendations from AACR 2016)

SMARCB1

  • Baseline MRI (craniospinal) when the diagnosis is made, and then every 2-3 years from the age of 10, with reduced intervals if the clinical symptoms allow
  • Consider performing a whole-body MRI.

LZTR1

  • Baseline MRI (craniospinal) when the diagnosis is established, and then every 2-3 years from the age of 15-19, with reduced intervals if the clinical symptoms allow
  • Consider performing a whole-body MRI.

SMARCE1

  • Neurological examination, baseline MRI (craniospinal), annually as of the diagnosis until the age of 18, and then every 3 years if there are mild clinical symptoms
  • Shorten the interval if there is evidence of a tumor or clinical symptoms

Schwannomatosis – Further Information

Open Clinical Trials/ Registries

Additional Resources