General
- Umbrella term for both NF2 and schwannomatosis
- Since they share a genetic predisposition for schwannoma formation
- Molecular analysis is clinically indicated for all patients suspected to have SPS (except for those with bilateral vestibular schwannoma).
4 hit, three-step model of tumorigenesis in schwannomatosis
- Hit 1: (inherited) SMARCB1 germline mutation
- Hit 2 and 3: loss of the other chromosome 22 with the wildtype copy of SMARCB1 and wildtype one copy of NF2
- Hit 4: somatic mutation of the remaining copy of the NF2 gene
- This model, with somatic mutations of the NF2 gene as the last step, explains the observation of different forms of NF2 mutations in multiple schwannomas in a single patient with schwannomatosis
- This four-hit model of genetic events also occurs in meningiomas in patients with SMARCB1 germline mutation
Classify type of SPS according to pathogenic gene variant based on the 4 hit hypothesis
NF2 (Aka MERLIN-SPS or Merlin syndrome)
- A patient has one of the following:
- Bilateral vestibular schwannoma (VS) OR
- An identical NF2 pathogenic variant in at least two anatomically distinct NF2 related tumours (schwannoma, meningioma and/or ependymoma).
- Genetic analysis is sensitive: able to identify pathogenic NF2 variants in blood in 66%-90% of individuals
- Note:
- Genetic analysis is not REQUIRED for diagnosis. It will be possible to diagnose NF2 based on clinical criteria without genetic analysis
- Genetic analysis ALONE will not be sufficient to diagnose NF2 (diagnosis will also require a diagnostic feature of NF2 or a family history of NF2)
- OR when either 2 Major OR 1 Major and 2 Minor criteria as follows: (clarification)
- Unilateral VS
- First degree relative other than sibling with SPS-MERLIN (clarification)
- 2 or more meningiomas.
- Note: single meningioma qualifies as minor criteria.
- NF2 pathogenic variant* in an unaffected tissue such as blood (when the variant is present at significantly less than 50% this confirms mosaicism) (addition)
- If a likely pathogenic variant is identified, tumour analysis may aid upward classification
- Can count more than one of a type (e.g. two schwannomas)
- Ependymoma;
- Schwannoma (require at least one dermal if major criterion is unilateral VS)
- (Clarification – removed neurofibroma, glioma)
- The term “glioma” will be updated to specify “ependymoma”
- RATIONALE: Ependymomas are relatively common in NF2 patients. In contrast, other types of glioma are rare or unreported (including especially high-grade glioma)
- The feature “neurofibroma” will be removed from the diagnostic criteria.
- RATIONALE: True neurofibromas are rare in the setting of NF2. Thus, use of this tumour type in diagnosis may lead to more confusion among clinicians. There are still many pathologists who report ‘neurofibroma’ when it is a schwannoma
- Can count only once
- Juvenile subcapsular or cortical cataract;
- Aka: presenile posterior lenticular opacity
- Age-related cataracts (over age 40) are not associated with NF2.
- Retinal hamartoma
- RATIONALE: Diagnosis of children with NF2 remains a challenge. Children with NF2 are less likely to present with symptoms referable to a vestibular schwannoma and more likely to present with ophthalmologic findings
- Epiretinal membrane aged less than 40 years (clarification),
- Meningioma
Major criteria:
Minor criteria:
SMARCB1-SPS
- SMARCB1
- 22q11.23
- Involved in
- 50% of familial cases
- <10% of sporadic cases
- Function
- A core subunit of mammalian SWI/SNF chromatin remodelling complexes → regulate the expression of many genes by using ATP for sliding the nucleosomes along the DNA helix → act as a tumour suppressor gene for
- Repression of CCND1 gene expression,
- Induction of the CDKN2A gene,
- Hypophosphorylation of retinoblastoma protein
- All leading to G0/G1 cell cycle arrest
- Previously classified as “schwannomatosis with SMARCB1 mutation”
- Diagnostic criteria: one of the following criteria:
- At least one pathologically confirmed schwannoma or hybrid nerve sheath tumor AND a SMARCB1 pathogenic variant in an unaffected tissue such as blood.
- A common SMARCB1 pathogenic variant in two schwannomas or hybrid nerve sheath tumors.
ㅤ | Tumor 1 | Tumor 2 | Comment |
SMARCB1 | ㅤ | ㅤ | ㅤ |
Allele 1 | Mut1 | Mut1 | Common SMARCB1 pathogenic variant |
Allele 2 | LOH | LOH | Tumor-specific partial loss of 22q in trans position |
NF2 | ㅤ | ㅤ | ㅤ |
Allele 1 | Mut2 | Mut3 | Tumor-specific pathogenic NF2 variant in cis to pathogenic SMARCB1 variant |
Allele 2 | LOH | LOH | Tumor-specific partial loss of 22q in trans position |
SPS-LZTR1 (aka previously classified as “schwannomatosis with LZTR1 mutation”
- LZTR1
- 22q11.21
- Involved in (in patients without SMARCB1 mutation)
- 40% familial
- 25% sporadic cases
- Function: substrate adaptor in cullin-3 ubiquitin ligase complexes, binding to cullin-3 and to substrates targeted for ubiquitination
- One of the following criteria:
- At least one pathologically confirmed schwannoma or hybrid nerve sheath tumour AND an LZTR1 pathogenic variant in an unaffected tissue such as blood.
- A common LZTR1 pathogenic variant in two anatomically distinct tumours.
ㅤ | Tumor 1 | Tumor 2 | Comment |
LZTR1 | ㅤ | ㅤ | ㅤ |
Allele 1 | Mut1 | Mut1 | Common LZTR1 pathogenic variant |
Allele 2 | LOH | LOH | Tumor-specific partial loss of 22q in trans position |
NF2 | ㅤ | ㅤ | ㅤ |
Allele 1 | Mut2 | Mut3 | Tumor-specific NF2 pathogenic variant in cis to LZTR1 pathogenic variant |
Allele 2 | LOH | LOH | Tumor-specific partial loss of 22q in trans position |
22q-SPS (aka previously classified as “schwannomatosis without identified mutation in blood)
- A diagnosis of SPS-22q can be made when a patient does not meet criteria for MERLIN-SPS, SMARCB1-SPS or LTZR1-SPS and has both molecular features:
- LOH of the same chromosome 22q markers in two anatomically distinct schwannomas or hybrid nerve sheath tumors AND
- A different NF2 pathogenic variant in each tumor which cannot be detected in unaffected tissue.
ㅤ | Tumor 1 | Tumor 2 | Comment |
SMARCB1/LZTR1 | ㅤ | ㅤ | ㅤ |
Allele 1 | None found | None found | No common pathogenic LZTR1 or SMARCB1 variant |
Allele 2 | LOH | LOH | Tumor-specific partial loss of the same chromosome 22q |
NF2 | ㅤ | ㅤ | ㅤ |
Allele 1 | Mut1 | Mut2 | Tumor-specific pathogenic NF2 variant trans to the 22q del |
Allele 2 | LOH | LOH | Tumor-specific partial loss of the same chromosome 22q, a single somatic event results in LOH of LZTR1-SMARCB1-NF2 |
SPS-Not Otherwise Specified (NOS): (Previously classified as “schwannomatosis”)
- If genetic testing was not performed, is not available, or did not reveal a pathogenic variant, a diagnosis of SPS-NOS can be made if the following criteria are met:
- Presence of two or more lesions on appropriate imaging consistent with non-intradermal schwannomas
- At least one schwannoma is pathologically confirmed
Mosaicism
- General definition: individual composed of ≥2 genetically different cell populations/ lineages derived from the same zygote
- NF1: 5-10%; NF2: ~30%; SMARCB1/ LZTR1: unknown
- Confirmed by either of following
- Significantly lower than 50% pathogenic variant in clinically unaffected tissue (e.g. NGS <35% variant allele frequency, VAF , in blood) ? Mosaicism
- Pathogenic variant not detected in clinically unaffected tissue but common pathogenic variant in ≥2 anatomically unrelated affected lesions = Mosaic disorder
Risk of transmission to offspring in
- Germline mutation of SMARCB1 or LZTR1: 50%
- Sporadic mutation of SMARCB1 or LZTR1: unknown
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