NF2-related schwannomatosis

The average age of onset is 18 to 24 years, with a reported range from birth to 70 years. Almost all affected individuals develop bilateral vestibular schwannomas by age 30 years; initial symptoms include tinnitus, hearing loss, and balance dysfunction. At least two thirds develop spinal tumours, most commonly schwannomas arising on the dorsal nerve root with a characteristic dumbbell configuration. Meningiomas are present in approximately half of individuals in cross-sectional cohorts, with lifetime risk approaching 80%. One-third have decreased visual acuity, with posterior subcapsular lens opacities frequently appearing in childhood, sometimes preceding vestibular schwannoma symptoms. Cohort data from a single specialist centre report bilateral vestibular schwannomas in 88%, meningioma in 48%, and ependymoma in 25% of 353 individuals followed annually. Expressivity is highly variable in tumour size, location, and number, and although tumours are histologically benign, anatomical location and multiplicity drive substantial morbidity.

The estimated prevalence is 1/50,000.

NF2-related schwannomatosis is caused by germline pathogenic variants in NF2 (22q12.2), with post-zygotic mosaic variants accounting for a substantial proportion of de novo cases. NF2 encodes merlin, a FERM-domain tumour-suppressor protein that coordinates growth-factor receptor signalling, cell adhesion, and the Hippo pathway through suppression of YAP/TAZ. Tumour formation typically follows somatic loss of the second NF2 allele, consistent with a classical two-hit tumour-suppressor mechanism.

NF2-related schwannomatosis is inherited in an autosomal dominant manner. Each child of an affected individual has a 50% risk of inheriting the familial pathogenic variant. Approximately 50% of affected individuals represent de novo cases, with a substantial proportion of these occurring as somatic mosaicism. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

Diagnosis is established by the , which recognise NF2 through specified combinations of bilateral vestibular schwannomas, family history, and additional NF2-associated tumours. Meeting these criteria constitutes the clinical diagnosis. Brain and, where indicated, spinal MRI detects vestibular schwannomas, meningiomas, ependymomas, and other tumours; ophthalmological examination identifies subcapsular cataract, retinal hamartoma, and epiretinal membrane.

Main differential diagnoses include:

• LZTR1-related schwannomatosis: unilateral vestibular schwannoma and other (typically non-intradermal) schwannomas, without intradermal plaques, cataract, or ependymoma; LZTR1
• SMARCB1-related schwannomatosis: multiple schwannomas, less frequently meningiomas; vestibular schwannomas, intradermal plaques, cataract, and ependymoma absent; SMARCB1
• : dumbbell configuration of spinal tumors; café au lait macules, Lisch nodules and cutaneous neurofibromas; NF1

• Establishing the diagnosis: confirming the molecular cause ends the diagnostic odyssey and underpins accurate prognosis and counselling for the affected individual and family.
• Specific and individualised surveillance: identifying the underlying molecular cause enables condition-specific surveillance and monitoring, a prerequisite for targeted medical care, and is determined by the treating physicians in consultation with the affected individual.
• Family member testing: once the familial pathogenic variant is identified, predictive and carrier testing of at-risk relatives becomes available, supporting timely entry into surveillance pathways.

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