Neurofibromatosis Type 2 (NF2). 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 treatment being reserved until neurologic deficits develop. Based on this treatment paradigm, tumors at the time of treatment are typically large and associated with irreversible neurologic decline and increased risk of treatment-induced morbidity. Subsequently, knowledge of the natural history of these tumors associated with NF2 is critical to determine the optimal treatment of patients with these lesions and to gain insight into the development of these tumors. To gain clinical and molecular insights into the effects of NF2 gene mutations on tumor development/progression and to identify features associated with symptom evolution in patients with NF2-associated tumors, we have been conducting a natural history study of NF2 patients. This prospective natural history study should be useful in identifying the stochastic factors that influence tumor biology, symptom formation, and treatment outcome. To gain insight into the pathophysiologic basis for hearing loss in NF2, we performed a prospective cross-sectional study of 89 untreated ears in 56 consecutive NF2 patients (age range of 8 to 68 years;mean age of 30 years). The 89 untreated ears harbored 84 untreated cochleovestibular schwannomas (CVSs). Thirty-four (38%) ears had varying degrees of hearing loss. Elevated intralabyrinthine protein was identified in 70 (75%) ears by FLAIR MR-imaging and was strongly associated with the presence of hearing loss (32/34 hearing loss ears;94%)(Fishers exact test;P=.005). Elevated intralabyrinthine protein was associated with the presence of CVS-associated cochlear aperture obstruction (64 of 67 ears with elevated protein;96%)(Fishers exact test;P<0.0001) in both normal and hearing-loss ears. Elevated intralabyrinthine protein was not identified in ears without CVS (5 ears). While larger tumor size was associated with hearing loss (P=0.006), 16 hearing-loss ears (47%) harbored CVSs less than 0.5 cm3, including 14 ears (88%) with block of the cochlear aperture and elevated protein. Findings from this study are consistent with a model in which hearing loss develops as a result of cochlear aperture obstruction and accumulation of intralabyrinthine protein. MRI based identification of elevated intralabyrinthine protein may help identify the ear at-risk for developing hearing loss. Consecutive NF2 patients with a minimum of 4 years (range 4 to 21 years) of serial clinical and MRI follow-up were analyzed. Seventeen patients, 9 males and 8 females, age 12-57 (mean 33) years, were included in this analysis. Patients harbored 182 intracranial neoplasms, 164 of which were assessable for growth rate analysis (18 vestibular schwannomas VSs, 11 nonvestibular cranial nerve CN schwannomas, and 135 meningiomas) and 152 of which were assessable for growth pattern analysis (15 VSs, 9 nonvestibular CN schwannomas, and 128 meningiomas). New tumors developed in patients over the course of the imaging follow-up: 66 meningiomas, 2 VSs, and 2 nonvestibular CN schwannomas. Overall, 45 tumors (29.6%) exhibited linear growth, 17 tumors (11.2%) exhibited exponential growth, and 90 tumors (59.2%) displayed a saltatory growth pattern characterized by alternating periods of growth and quiescence (mean quiescent period 2.3 +/- 2.1 years, range 0.4 to 11.7 years). Further, the saltatory pattern was the most frequently identified growth pattern for each tumor type: meningiomas 60.9%, VSs 46.7%, and nonvestibular schwannoma 55.6%. A younger age at the onset of NF2-related symptoms (p = 0.01) and female sex (p = 0.05) were associated with an increased growth rate in meningiomas. The identification of saltatory growth in meningiomas increased with the duration of follow-up (p = 0.01). Neurofibromatosis Type 2-associated intracranial tumors most frequently demonstrated a saltatory growth pattern. Because new tumors can develop in NF2 patients over their lifetime and because radiographic progression and symptom formation are unpredictable, resection may be best reserved for symptom-producing tumors. Moreover, establishing the efficacy of nonsurgical therapeutic interventions must be based on long-term follow-up (several years). To gain insight into the mechanisms underlying loss of merlin function in NF2, we investigated mutated merlin homeostasis and function in NF2-associated tumors and cell lines. Quantitative protein and RT-PCR analysis revealed that whereas merlin protein expression was significantly reduced in NF2-associated tumors, mRNA expression levels were unchanged. Transfection of genetic constructs of common NF2 missense mutations into NF2 gene-deficient meningioma cell lines revealed that merlin loss of function is due to a reduction in mutant protein half-life and increased protein degradation. Transfection analysis also demonstrated that recovery of tumor suppressor protein function is possible, indicating that these mutants maintain intrinsic functional capacity. Further, increased expression of mutant protein is possible after treatment with specific proteostasis regulators, implicating protein quality control systems in the degradative fate of mutant tumor suppressor proteins. These findings provide direct insight into protein function and tumorigenesis in NF2 and indicate a unique treatment paradigm for this disorder.

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