Schwannomatosis

Individuals most commonly present between the second and fourth decade of life, typically with localised or diffuse pain or an asymptomatic mass. Schwannomas most often affect peripheral and spinal nerves, with the lumbar spine most commonly involved; cranial nerve involvement is rare and most often affects the trigeminal nerve. Chronic pain, which does not always localise to a schwannoma, is a common and disabling comorbidity. Unilateral vestibular schwannomas can occur, whereas individuals with bilateral vestibular schwannomas fulfill diagnostic criteria for NF2-related schwannomatosis. Meningiomas have been reported only in SMARCB1-related disease, in which malignant transformation of a schwannoma also remains a risk; rapid growth with intractable pain should raise this concern. Café au lait macules, skin fold freckling, and Lisch nodules typical of are uncommon.

The estimated combined prevalence of LZTR1– and SMARCB1-related schwannomatosis is 1/126,000. This figure is likely an underestimate, given the difficulty of identifying affected individuals. The estimated prevalence of NF2-related schwannomatosis is 1/50,000, with a birth incidence of 1:28,000.

Schwannomatosis is associated with germline pathogenic variants in several tumour suppressor genes. NF2-related schwannomatosis is caused by pathogenic variants in NF2. Among the LZTR1– and SMARCB1-related forms, SMARCB1 accounts for about 60% of families and LZTR1 for about 40%. Tumorigenesis departs from the classic two-hit model. A germline inactivating SMARCB1 or LZTR1 variant constitutes the first hit. Loss of heterozygosity through a contiguous 22q deletion then removes the wild-type SMARCB1 or LZTR1 and NF2 alleles, followed by somatic inactivation of the remaining NF2 allele. The result is biallelic inactivation of both tumour suppressor loci. The panel additionally assesses genes implicated in related schwannoma-predisposing and overlapping conditions, including DGCR8, SMARCE1, SUFU, and PRKAR1A.

NF2-related schwannomatosis, as well as LZTR1– and SMARCB1-related schwannomatosis are inherited in an autosomal dominant manner. Among simplex cases, the pathogenic variant is de novo in about 50% of NF2-related, 30% of LZTR1-related and 10% of SMARCB1-related disease. Parental mosaicism has been reported and can underlie apparently de novo cases, with implications for sib recurrence risk. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

The diagnosis rests on established . Updated consensus diagnostic criteria and nomenclature for schwannomatosis were published in 2022; meeting these criteria establishes the clinical diagnosis. Whole-body MRI detects internal nerve sheath tumours, and molecular genetic testing of blood or at least two anatomically distinct tumours defines the genetic subtype.

Main differential diagnoses include:

• Mosaic NF2-related schwannomatosis: multiple schwannomas with unilateral vestibular schwannoma; NF2
• 22q-related schwannomatosis: shared 22q loss of heterozygosity with biallelic NF2 inactivation; chromosome 22q
• DGCR8-related schwannomatosis: dominant peripheral nerve sheath tumour predisposition; DGCR8
• : neurofibromas rather than schwannomas, with café au lait macules; NF1

• Establishing the diagnosis: identifying the underlying germline pathogenic variant confirms the clinical diagnosis at the molecular level.
• Surveillance and management: identification of the pathogenic germline variant supports condition-specific monitoring and management decisions made by the treating physicians in consultation with the affected individual.
• Testing of family members: once the familial pathogenic variant is known, at-risk relatives can be offered predictive testing to clarify their variant status.

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