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.

Key Data

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Synonym NF3
Genes SMARCB1 (INI1), LZTR1 -> schwannomatosis
SMARCE1 -> meningiomatosis
Gene products • SMARCB1
• LZTR1
• SMARCE1
Functions 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
Heredity 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
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Diagnosis

Clinical Diagnostic Criteria

  • ≥ 2 non-intradermal schwannomas (at least 1 histopathologically confirmed), no vestibular schwannomas in the high-resolution MRI
    or
    ≥ 2 non-intradermal schwannomas (at least 1 histopathologically confirmed), no vestibular schwannomas in the high-resolution MRI

    or

  • A histopathologically confirmed schwannoma or intracranial meningioma
    and
    a first-degree relative with schwannomatosis

The presence of ≥ 2 non-intradermal schwannomas without supportive histopathological evidence confirms the suspected diagnosis, especially if associated with chronic pain.

Segmental schwannomatosis: schwannomas in 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.

Therapeutic Considerations

Surgical intervention, pain management

Surveillance Recommendations

Surveillance Recommendations

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