The protean nature of the central nervous system tumors in NF2, incomplete understanding of their natural history, and undefined mechanism of symptom formation have resulted in a strategy of treating patients after they develop neurologic deficits. By that time, tumors are typically large and neurological deficits irreversible. Surgical removal of large tumors often adds deficits. Better knowledge of NF2 natural history and tumor growth patterns could improve surgical timing and outcomes. We started a natural history study of NF2 patients 10 years ago to gain clinical and molecular insights into the effects of the type (missense, nonsense, deletion) of NF2 gene mutation on tumor development/progression and to identify features associated with symptom evolution in patients with NF2-associated tumors. This prospective natural history study should find factors that influence tumor biology, symptom formation, and treatment outcome. The natural history study of NF2 enrolled 169 subjects. So far, 119 subjects have competed the 5-year study. The final subjects will complete the study by November 20, 2018. Previous work in the study showed that elevated intralabyrinthine protein and larger tumor size by MRI-scanning correlated with hearing loss. A saltatory growth pattern of periodic tumor growth was more often seen (59%) than linear (30%) or exponential growth (11%). Because tumor growth and symptom production are unpredictable and new tumors develop in NF2 patients over their lifetime, we have not found a better method for timing of tumor resection than the present practice of resecting only symptom-producing tumors. This year our study of NF2 resulted in 3 published manuscripts. The first publication reported the first comprehensive whole exome sequencing study of NF2-related meningiomas. Sequencing of 2 adjacent intracranial meningiomas removed from the same patient showed that the second copy of the NF2 gene was inactivated in both tumors. The faster growing tumor, a Grade II meningioma, had a higher level of genomic instability than the slower-growing, Grade I meningioma. The second article explored the audiologic natural history of small volume cochleovestibular schwannomas in patients with NF2 in the natural history study. The third article described the many possible etiologies of peripheral nerve tumors and the radiographic and histologic findings that differentiate them.
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