mTORC1 inhibition delays growth of neurofibromatosis type 2 schwannoma.

BACKGROUND: Neurofibromatosis type 2 (NF2) is a rare autosomal dominant genetic disorder, resulting in a variety of neural tumors, with bilateral vestibular schwannomas as the most frequent manifestation. Recently, merlin, the NF2 tumor suppressor, has been identified as a novel negative regulator of mammalian target of rapamycin complex 1 (mTORC1); functional loss of merlin was shown to result in elevated mTORC1 signaling in NF2-related tumors. Thus, mTORC1 pathway inhibition may be a useful targeted therapeutic approach. METHODS: We studied in vitro cell models, cohorts of mice allografted with Nf2(-/-) Schwann cells, and a genetically modified mouse model of NF2 schwannoma in order to evaluate the efficacy of the proposed targeted therapy for NF2. RESULTS: We found that treatment with the mTORC1 inhibitor rapamycin reduced the severity of NF2-related Schwann cell tumorigenesis without significant toxicity. Consistent with these results, in an NF2 patient with growing vestibular schwannomas, the rapalog sirolimus induced tumor growth arrest. CONCLUSIONS: Taken together, these results constitute definitive evidence that justifies proceeding with clinical trials using mTORC1-targeted agents in selected patients with NF2 and in patients with NF2-related sporadic tumors.

Neurofibromatosis type 2-living with the complications: a case study.

Neurofibromatosis is a disease caused by a chromosomal defect that can occur spontaneously or be inherited. The disease is grossly disfiguring and carries with it significant psychological sequelae. It is characterized by tumors on nerve sheaths that can arise anywhere in the body. The rate and frequency of occurrence is unpredictable. More than nine different types of neurofibromatosis have been identified, but other than types 1 and 2, they are quite rare. All types of neurofibromatosis persist for a lifetime, so nurses from different backgrounds may encounter such a patient for various reasons. Nursing care should focus not only on the medical issues the patient presents with, but also on the psychosocial needs that may arise.

Clinical manifestations of mutations in the neurofibromatosis type 2 gene in vestibular schwannomas (acoustic neuromas).

Vestibular schwannomas (acoustic neuromas) continue to cause significant facial nerve and hearing morbidity, despite marked improvement in diagnosis and treatment. Mutation of a tumor-suppressor gene on human chromosome 22 has been found to be associated with vestibular schwannoma formation. The central hypothesis of this study is that specific mutations in the neurofibromatosis type 2 (NF2) gene may produce specific clinical characteristics or phenotypic expressions. The purposes of this investigation are: 1. to determine what proportion of vestibular schwannomas from patients with spontaneous unilateral and familial bilateral schwannomas have mutations present within the NF2 gene; 2. to determine whether specific types of mutations are associated with a specific clinical manifestation of this disease; and 3. to further define the relationship between newly discovered mutations within the NF2 tumor-suppressor gene and possible clinical applications of this knowledge to advance diagnosis and treatment of patients with NF2 and spontaneous vestibular schwannomas. DNA from 61 schwannomas (29 unilateral vestibular schwannomas and 32 from patients with bilateral vestibular schwannomas [NF2]) were examined, and 33 unique mutations were identified. Significant differences were found in the frequency, distribution, and type of mutation between the NF2 schwannomas and the spontaneous vestibular schwannomas. Three clinical subtypes of NF2 were identified. In tumors from 28 patients, no mutations were identified. Of the 33 mutations identified in the NF2 gene, 30 were likely to result in loss of tumor-suppressor function from protein truncation; however, three milder mutations termed missense mutations were associated with milder clinical manifestations of the disease and had a slower estimated growth rate. Variable clinical presentation in patients whose tumors had severe or truncating types of mutations suggest that factors in addition to the mutation class are likely to be responsible for a portion of the clinical expression of disease. New diagnostic options are now available for NF2 that will improve the likelihood of hearing and facial nerve preservation and ultimately have significant impact on the management of vestibular schwannomas.

Spinal and cutaneous schwannomatosis is a variant form of type 2 neurofibromatosis: a clinical and molecular study.

OBJECTIVE: To delineate the clinical phenotype, molecular basis, and implications for screening in patients and families with multiple schwannomas not generally involving the cranium. METHODS: As part of a United Kingdom clinical and genetic study of type 2 neurofibromatosis (NF2) patients and families with multiple schwannomas who do not fulfil diagnostic criteria for NF2 have been identified. The clinical phenotype was studied in the extended families and molecular analysis was carried out at the NF2 gene locus on chromosome 22. RESULTS: Patterns of inheritance in five families with schwannomatosis are consistent with inheritance of an autosomal dominant gene. The consistency of phenotype, with relative sparing of the cranium, is constant in these families. However, families which initially seem to be indicative of schwannomatosis may develop into classic NF2 as shown by a sixth family. Many of the tumours found in these families were referred to as "neurofibroma" when they were clearly schwannomas. This difference in classification has major implications for the relative risk of each particular type of neurofibromatosis and neuropathological review may be important in some cases. Genetic linkage analysis in the two largest families is entirely consistent with primary involvement of the NF2 gene. CONCLUSIONS: Variant forms of neurofibromatosis have presented a dilemma in classification and determination of recurrence risks in families. Previous reports have suggested that schwannomatosis is a sporadic non-hereditary condition. Patients with multiple schwannomas are likely to have a variant form of NF2 and up to a 50% risk of passing on a gene predisposing to multiple schwannoma.

Prevention and control of neurofibromatosis: memorandum from a joint WHO/NNFF meeting.

Neurofibromatosis (NF) is a serious, common, genetically determined neurological disorder; with a prevalence of about 1:4000 births it affects both sexes and all races and ethnic groups. The two major forms are referred to as NF1 and NF2, as suggested in 1987 by a National Institutes of Health Consensus Development Conference on Neurofibromatosis. In NF1, the disease phenotype is more variable and complex than in NF2. Complications can occur in any of the body systems in tissues of ectodermal, mesodermal and neural tube origin; there is marked variation of disease phenotype even within families. The NF2 gene, in contrast, only seems to be expressed in tissues of ectodermal origin and its expression is more uniform both within and between families. The recent discovery and isolation of the gene responsible for the NF1 mutation has practical applications in the field of molecular genetics which could modify the approaches for diagnosis, treatment and prevention of NF. This Memorandum summarizes the discussions and recommendations of the participants at a joint WHO/National Neurofibromatosis Foundation (NNFF) meeting, held in Jacksonville, Florida, USA, on 27-28 January 1991.