A 28-year-old woman presents with progressive bilateral asymmetric sensorineural hearing loss and tinnitus over the past 2 years. Gadolinium-enhanced MRI brain shows bilateral cerebellopontine angle (CPA) enhancing masses. The structure marked **A** (right CPA enhancing mass) is a vestibular schwannoma. Which of the following genetic and pathophysiological features is PATHOGNOMONIC for the underlying diagnosis in this patient?
A. Inactivating mutations in the TP53 tumor suppressor gene predisposing to Li-Fraumeni syndrome with bilateral acoustic neuromas
B. Loss-of-function mutations in the CDKN2A gene on chromosome 9p21 resulting in multiple cutaneous neurofibromas and optic nerve gliomas
C. Activating mutations in the BRAF gene causing neurofibromatosis with unilateral vestibular schwannoma and café-au-lait macules
D. Inactivating mutations in the NF2 tumor suppressor gene on chromosome 22q12.2 encoding MERLIN, causing bilateral vestibular schwannomas in an autosomal dominant disorder
Explanation
Why option 1 is right
Bilateral vestibular schwannomas are pathognomonic of Neurofibromatosis Type 2 (NF2), an autosomal dominant disorder caused by inactivating mutations in the NF2 tumor suppressor gene on chromosome 22q12.2, which encodes MERLIN (schwannomin). The presence of the right CPA enhancing mass (A) as part of a bilateral presentation, combined with the clinical history of progressive bilateral asymmetric sensorineural hearing loss (the most common presenting feature in adults), is diagnostic of NF2. This is the only genetic-pathophysiological feature that directly explains bilateral vestibular schwannomas.
Why each distractor is wrong
Option 2 (CDKN2A mutations): CDKN2A mutations are associated with familial melanoma and pancreatic cancer predisposition, not neurofibromatosis or bilateral vestibular schwannomas. This is not a recognized cause of bilateral acoustic neuromas.
Option 3 (BRAF mutations): BRAF mutations are found in sporadic melanomas and some low-grade gliomas, not in neurofibromatosis. BRAF is not implicated in bilateral vestibular schwannoma pathogenesis.
Option 4 (TP53 mutations): TP53 mutations cause Li-Fraumeni syndrome, predisposing to diverse malignancies (breast, sarcoma, brain tumors), but NOT bilateral vestibular schwannomas. Unilateral acoustic neuromas may rarely occur in TP53 carriers, but bilateral presentation is not characteristic.
High-YieldNEET PG
Bilateral vestibular schwannomas = NF2 until proven otherwise; NF2 = NF2 gene (chromosome 22q12.2) inactivation → MERLIN loss → loss of contact inhibition and tumor suppression.
Harrison's 21e Ch 86; Manchester Criteria; NF2 Clinical Care Guidelines
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