Diagnostic Criteria

Diagnostic criteria established by international consensus in 2022 (Plotkin SR et al., Genetics in Medicine; International Consensus Group on Neurofibromatosis Diagnostic Criteria). A clinical diagnosis requires pathology confirmation — imaging alone is not sufficient. Comprehensive molecular testing must include both unaffected tissue (blood or saliva) and tumor tissue from anatomically distinct sites; blood and saliva alone are not adequate.

Schwannomatosis

Applies to SWN-SMARCB1, SWN-LZTR1, SWN-SMARCE1, and SWN-DGCR8.

Diagnosis is established through one of three pathways depending on what genetic testing reveals. In all pathways, bilateral vestibular schwannomas must be absent on high-quality MRI.

Pathway 1 — Genetic confirmation (most common):

One pathologically confirmed non-intradermal schwannoma or hybrid nerve sheath tumor
No bilateral vestibular schwannomas on high-quality MRI
A pathogenic or likely pathogenic germline variant in SMARCB1, LZTR1, SMARCE1, or DGCR8

In Pathway 1, the gene variant carries the diagnosis. A second surgery is not required to establish it. Additional tumors may be visible on imaging — and should be mapped — but only one pathologically confirmed tumor is required when the germline variant is confirmed.

Pathway 2 — Family history:

One pathologically confirmed non-intradermal schwannoma or hybrid nerve sheath tumor
No bilateral vestibular schwannomas on high-quality MRI
A first-degree relative with a confirmed schwannomatosis diagnosis — genetic (named subtype) or clinical (SWN-NOS or SWN-NEC). A gene-negative relative who meets clinical criteria counts. Science has not found all the genes yet; a clinical diagnosis is a real diagnosis.

Pathway 3 — Clinical criteria only (when no genetic confirmation and no family history):

Two or more lesions on appropriate imaging (MRI or ultrasound) consistent with non-intradermal schwannomas
At least one of those lesions pathologically confirmed as a schwannoma or hybrid nerve sheath tumor
No bilateral vestibular schwannomas on high-quality MRI

Pathway 3 without a germline variant identified leads to a working classification of SWN-NOS or SWN-NEC (see below), not a named genetic subtype. Two surgically removed and confirmed tumors are not required — one confirmed by pathology plus one visible on imaging satisfies this pathway.

SWN-22q — Chromosome 22q–Related

Applies to patients who do not meet criteria for NF2-related, SMARCB1-related, or LZTR1-related schwannomatosis, and whose tumor molecular testing reveals both of the following: (1) loss of heterozygosity (LOH) of the same chromosome 22q markers in at least two anatomically distinct schwannomas or hybrid nerve sheath tumors, and (2) a different somatic NF2 pathogenic variant in each of those tumors — variants that are not detectable in unaffected tissue (blood or saliva). These are tumor-only somatic NF2 variants, not a germline NF2 mutation, and they are different in each tumor. Tumor tissue from at least two separate sites is required; blood alone cannot confirm this subtype.

SWN-NOS — Testing Not Yet Performed

SWN-NOS (not otherwise specified) applies when genetic testing has not been performed or is not available, and the following clinical criteria are met:

Two or more lesions on appropriate imaging (MRI or ultrasound) consistent with non-intradermal schwannomas
Pathologic confirmation of at least one of those lesions as a schwannoma or hybrid nerve sheath tumor — removed and reviewed by a pathologist
No bilateral vestibular schwannomas on high-quality MRI

SWN-NOS is a working diagnosis: two or more tumors visible on imaging, with one confirmed by pathology. The second tumor does not need to be surgically removed to meet NOS criteria — seen on imaging is sufficient. You do not need two surgically removed and confirmed tumors to qualify. Comprehensive molecular testing — of blood or saliva and tumor tissue from at least two anatomically distinct sites — is the required next step to reach a definitive subtype classification or establish SWN-NEC.

SWN-NEC — Comprehensively Tested, No Variant Found

SWN-NEC (not elsewhere classified) applies when the SWN-NOS clinical criteria are met AND comprehensive molecular testing of both unaffected tissue (blood or saliva) and tumor tissue from at least two anatomically distinct sites does not reveal a pathogenic variant in any known SWN gene.

The two-tumor-site requirement for SWN-NEC is a molecular testing requirement, not an additional diagnostic criterion for surgical removal. It means that to reach a formal SWN-NEC classification, tissue from at least two separate tumors must have been submitted for molecular analysis — not simply that two tumors must have been removed. In practice, this often does require access to tissue from a second tumor, but the purpose is testing for mosaic variants, not confirming a second diagnosis.

Blood and saliva alone are not sufficient to establish SWN-NEC. The tumor tissue requirement is not optional. Mosaic variants — present in some tumor cells but absent from blood — are frequently missed by germline testing alone and require tumor analysis to detect. Until tissue from at least two separate, anatomically distinct tumor sites has been tested, a negative blood result does not meet the criteria for SWN-NEC. If you have had only blood or saliva tested, ask specifically for tumor tissue molecular analysis.

SWN-NEC is a formal diagnostic category, not a placeholder or a ruling-out. A significant proportion of schwannomatosis cases remain gene-negative even after comprehensive testing. This does not invalidate the diagnosis. Your negative result is not final — science continues to look for the missing genes of schwannomatosis.

If you are SWN-NEC or SWN-NOS — your negative result is not final

Several conditions are known pointers to specific SWN genes. If you have any of the following alongside a schwannomatosis diagnosis or strong clinical suspicion, your prior genetic testing may be incomplete by current 2022 standards — and a targeted re-evaluation at UAB is warranted.

Points to LZTR1

Noonan syndrome or Noonan-like features

LZTR1 causes both Noonan syndrome and SWN-LZTR1 schwannomatosis — through different variants in the same gene. Testing done in the Noonan context screens for Noonan-associated LZTR1 variants; it does not necessarily screen for the schwannomatosis-relevant variants. If you have Noonan syndrome or Noonan-like features (short stature, characteristic facial features, heart defects, learning differences) and schwannomas, ask UAB specifically to evaluate LZTR1 variants in the schwannomatosis context — with tumor tissue, not only blood.

Points to SMARCB1 or SMARCE1

Coffin-Siris syndrome features

SMARCB1 and SMARCE1 cause both Coffin-Siris syndrome and schwannomatosis through different variants in the same genes. If you have features of Coffin-Siris (absent or underdeveloped fifth fingernail, coarse facial features, intellectual disability) alongside schwannomas, your panel should specifically evaluate schwannomatosis-relevant SMARCB1 and SMARCE1 variants in tumor tissue.

Your panel is incomplete

Tested before 2022, or without SMARCE1 and DGCR8

SMARCE1 and DGCR8 are recent enough discoveries that they are not included in most standard panels — including UAB’s current standard schwannomatosis panel. If your prior testing returned negative on NF2, SMARCB1, and LZTR1 only, those two subtypes were never evaluated. A targeted add-on or research panel at a lab that includes SMARCE1 and DGCR8 is the next appropriate step.

Tumor tissue was never tested

Blood or saliva only — no tumor molecular analysis

Mosaic variants — present in some or all tumor cells but absent from blood — are found only in tumor tissue. Blood testing alone cannot detect them. Until tissue from at least two anatomically distinct tumors has been analyzed alongside blood or saliva, a negative result does not meet the 2022 criteria for SWN-NEC. You remain SWN-NOS, and comprehensive re-testing is the indicated next step.

What to ask UAB specifically:

“I have a working diagnosis of SWN-NEC/NOS. I also have [Noonan syndrome / Coffin-Siris features / a prior panel that did not include SMARCE1 and DGCR8 / testing done without tumor tissue]. I would like a re-evaluation using 2022 I-NF-DC criteria, including tumor tissue from at least two anatomically distinct sites, with explicit evaluation of LZTR1 schwannomatosis variants, SMARCE1, and DGCR8.”

UAB Medical Genomics Laboratory — Schwannomatosis Panel →

LZTR1-Noonan syndrome and SMARCB1/SMARCE1-Coffin-Siris cross-condition associations: Dhamija R et al. GeneReviews Dec 2025; Johnston JJ et al. Genet Med 2018 (LZTR1-Noonan); Plotkin SR et al. Genet Med 2022 (I-NF-DC consensus criteria).

Pathology and tumor tissue testing are both required. A tumor must be confirmed as a schwannoma or hybrid nerve sheath tumor by a pathologist — imaging alone does not fulfill the criteria. And if you are working toward a definitive molecular subtype or SWN-NEC classification, tumor tissue from at least two distinct anatomical sites must be tested alongside your blood or saliva sample.

NF2-SWN (formerly NF2)

Either:

Bilateral vestibular schwannomas on MRI — this is the defining criterion
An identical NF2 pathogenic variant in at least two anatomically distinct NF2-related tumors (schwannoma, meningioma, or ependymoma)
A combination of major and minor criteria including: unilateral VS, first-degree relative with NF2-SWN, two or more meningiomas, NF2 pathogenic variant in blood; minor criteria include ependymoma, meningioma, schwannoma, juvenile cataract, retinal hamartoma, epiretinal membrane in a person under 40

Source: Plotkin SR et al. Genet Med 2022 — International Consensus Group on Neurofibromatosis Diagnostic Criteria (I-NF-DC); Dhamija R et al. GeneReviews Dec 2025. Full citations in the Knowledge Bank →