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
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
- Neurofibromatosis Type 1
- Neurofibromatosis Type 2
- Carney complex
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
According to the latest AACR guidelines, the following screening tests are recommended for patients with LZTR1– and SMARCB1-associated schwannomatosis:
Baseline: at 10 years of age or at diagnosis (whichever is later)
- Contrast-enhanced MRI of the head, including dedicated high-resolution imaging of the internal auditory canal (3 Tesla, 1-3mm slices)
- MRI of the spine
- Full body MRI (cannot replace other MRI scans)
- Hearing screening
- Ophthalmological examination
- Dermatological examination for Schwannomatous plaques
Regular examinations for asymptomatic patients or patients with stable findings
- Physical examination, including neurological examination, with recording of any pain since diagnosis, annually
- Head MRI from age 13 years or 3 years after baseline imaging, every 3 years
- LZTR1 only: including dedicated high-resolution imaging of the internal auditory canal
- If brain tumour is detected on initial MRI, repeat MRI after 1 year, then every 3 years if findings are stable
- MRI of the spine and whole body starting at 13 years or 3 years after baseline imaging, alternating every 3 years
Regular examinations for symptomatic patients
- Dedicated MRI of the painful or symptomatic region
- In SMARCB1 patients, 18F-FDG-PET can be considered for rapidly growing, changing, painful or function-restrictin tumours
