What causes multiple schwannomas?

Causes of Multiple Schwannomas

Multiple schwannomas are most commonly caused by genetic syndromes, primarily Neurofibromatosis type 2 (NF2) and Schwannomatosis, with NF2 being the predominant cause due to pathogenic variants in the NF2 gene on chromosome 22q. 1

Genetic Causes of Multiple Schwannomas

Neurofibromatosis Type 2 (NF2)

• Primary cause: Autosomal dominant condition due to pathogenic variants in the NF2 gene on chromosome 22q 1, 2
• Prevalence: Approximately 1 in 60,000 individuals 2
• Key features:
  • Bilateral vestibular schwannomas (hallmark feature) 1
  • Additional schwannomas affecting cranial, spinal, and peripheral nerves 2
  • Meningiomas (intracranial and intraspinal)
  • Ependymomas
  • Skin tumors in about 70% of patients 2
• Genetic mechanism:
  • More than 50% of cases represent new mutations 2
  • Up to one-third of patients are mosaic for the disease-causing mutation 2
  • NF2 inactivation occurs in 77% of vestibular schwannomas via loss of chromosome 22q or NF2 gene mutation 1

Schwannomatosis

• Genetic basis: Pathogenic variants in the LZTR1 gene 1, 3
• Distinguishing features:
  • Multiple schwannomas without vestibular schwannomas 4
  • Often presents with pain as the predominant symptom 4
  • May affect peripheral nerves, spinal nerve roots, and cranial nerves 4
  • Some cases show segmental distribution (limited to a single limb) 4
• Genetic counseling: Less likely to have positive family history compared to NF2 4

Other Genetic Considerations

• DGCR8 microprocessor defect can cause schwannomatosis 3
• In patients under 25 years with apparently isolated vestibular schwannoma:
  • 8.5% have NF2 pathogenic variants
  • 2.9% have LZTR1 pathogenic variants 1

Diagnostic Considerations

When to Suspect a Genetic Syndrome

• Multiple schwannomas at any age
• Unilateral vestibular schwannoma in patients under 30 years 1
• Bilateral vestibular schwannomas (strongly suggestive of NF2) 1, 2
• Family history of NF2 or schwannomatosis 1

Important Caveats

• Chance occurrence: In older patients (>50 years) with only bilateral vestibular schwannomas and no other NF2 features:
  • ~25% of cases over age 50 may represent chance occurrence rather than NF2
  • ~50% of cases over age 70 may be sporadic rather than syndromic 5
• Mosaicism: Up to one-third of NF2 patients with new mutations are mosaic for the disease-causing mutation, which can complicate genetic testing 2

Clinical Evaluation

• Complete baseline MRI of brain and spine to evaluate for multiple lesions 3
• Genetic testing should be considered in:
  • Young patients
  • Those with multiple schwannomas
  • Patients with specific histological subtypes 3
• Regular surveillance imaging is recommended for patients with multiple schwannomas 3

Management Implications

• Surgical excision is the primary treatment for symptomatic schwannomas 6
• Watchful waiting with careful surveillance is appropriate for asymptomatic lesions 2, 7
• Genetic counseling is essential for patients with multiple schwannomas 3
• Syndrome-specific surveillance protocols should be implemented if a genetic syndrome is identified 3

Understanding the genetic basis of multiple schwannomas is crucial for proper management, surveillance, and genetic counseling of affected individuals and their families.