neurofibromatosis type 2
Summary
Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder caused by loss-of-function mutations in the NF2 tumor suppressor gene (chromosome 22q12) encoding merlin (schwannomin). Hallmark is bilateral vestibular schwannomas (CN VIII), plus meningiomas, ependymomas, and juvenile posterior subcapsular cataracts. Mnemonic: "MISME" (Multiple Inherited Schwannomas, Meningiomas, Ependymomas); 22 = "type 2, chromosome 22, bilateral acoustic neuromas."
Detail
**Genetics/Pathophysiology** - Autosomal dominant, nearly 100% penetrance; ~50% are de novo mutations (mosaicism possible). - NF2 gene on chromosome 22q12 encodes merlin (schwannomin), a cytoskeletal-membrane linking protein (ERM family) that mediates contact inhibition and suppresses mTOR, Hippo/YAP, and Rac/PAK signaling. Biallelic inactivation ("two-hit" hypothesis, Knudson) leads to Schwann cell and meningothelial proliferation. - Contrast: NF1 = chromosome 17q11.2, neurofibromin (negative regulator of Ras, a GTPase-activating protein).
**Clinical features** - Bilateral vestibular schwannomas (CN VIII): sensorineural hearing loss, tinnitus, vertigo/imbalance. Typically presents in late teens to 20s–30s. Arise at the Schwann cell–glial junction (Obersteiner-Redlich zone) of the vestibular portion of CN VIII. - Meningiomas (intracranial and spinal; often multiple). - Spinal ependymomas (and other spinal cord tumors), and other schwannomas (cranial, spinal nerve roots, cutaneous). - Ocular: juvenile posterior subcapsular lenticular opacity/cataract (very common, may be earliest finding), retinal hamartomas. - Skin: few café-au-lait spots (far fewer than NF1), cutaneous schwannomas. - Does NOT typically have Lisch nodules, axillary freckling, cutaneous neurofibromas, or optic gliomas (those are NF1).
**Diagnosis** - Bilateral vestibular schwannomas on MRI with gadolinium (enhancing mass in the cerebellopontine angle widening the internal auditory canal), or a family history plus unilateral VS or other NF2-associated tumors/lesions. Genetic testing confirms. - Audiometry: sensorineural hearing loss.
**Management** - Surveillance MRI and audiology; surgical resection or stereotactic radiosurgery for symptomatic tumors (risk of facial nerve injury). - Bevacizumab (anti-VEGF) can slow tumor growth/improve hearing in some progressive vestibular schwannomas. - Auditory brainstem implant or cochlear implant for hearing rehabilitation. - Genetic counseling.
**High-yield comparisons (NF1 vs NF2)** - NF1 (von Recklinghausen): 17q, café-au-lait spots, Lisch nodules, neurofibromas, axillary/inguinal freckling, optic glioma, pheochromocytoma, scoliosis, sphenoid dysplasia, increased risk of malignant peripheral nerve sheath tumor. - NF2: 22q, bilateral CN VIII schwannomas, meningiomas, ependymomas, cataracts. - Differential for CPA mass: vestibular schwannoma (most common, ~70-80%), meningioma, epidermoid cyst. - Schwannomas are S-100 positive, with Antoni A (hypercellular, Verocay bodies) and Antoni B (hypocellular) areas. - Tuberous sclerosis and von Hippel-Lindau are other phakomatoses (neurocutaneous syndromes) to distinguish: VHL = chromosome 3p, hemangioblastomas, renal cell carcinoma; TSC = TSC1/TSC2, hamartomas, ash-leaf spots, subependymal giant cell astrocytomas, cardiac rhabdomyomas, angiomyolipomas.
Sources
- First Aid for the USMLE Step 1 (Neurocutaneous disorders / Phakomatoses)
- Pathoma (Fundamentals of Pathology) – CNS tumors
- Robbins & Cotran Pathologic Basis of Disease – Nervous system tumors and familial tumor syndromes
- Harrison's Principles of Internal Medicine – Neurofibromatosis
- Plotkin SR et al. Updated diagnostic criteria and nomenclature for neurofibromatosis type 2 and schwannomatosis. Genet Med. 2022
- Sketchy Medical / Boards & Beyond – Neurocutaneous syndromes
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