Management of the patient and family with neurofibromatosis 2: a consensus conference statement

Evans, D. Gareth; Baser, Michael E.; O’Reilly, Brian F.; Rowe, J; Gleeson, Michael; Saeed, Shakeel R; King, Andrew; Huson, Susan M.; Kerr, Richard; Thomas, Nick; Irving, Richard; Macfarlane, Robert; Ferner, Rosalie E.; McLeod, Renée P.; Moffat, David A.; Ramsden, R. T.

doi:10.1080/02688690500081206

Cited by 240 publications

(190 citation statements)

References 34 publications

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“…In addition, the patient also developed several intramedullary spinal schwannomas. Following the Manchester Clinical Diagnostic Criteria for NF2, 22 this individual was included in a molecular genetic testing program. The patient passed away in 2011, at the age of 52.…”

Section: Patient Descriptionmentioning

confidence: 99%

In vitro antisense therapeutics for a deep intronic mutation causing Neurofibromatosis type 2

et al. 2012

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on behalf of the NF2 Multidisciplinary Clinics HUGTiP-ICO-IMPPC Neurofibromatosis type 2 (NF2) is an autosomal-dominant disorder affecting about 1:33 000 newborns, mainly characterized by the development of tumors of the nervous system and ocular abnormalities. Around 85% of germline NF2 mutations are point mutations. Among them, B25% affect splicing and are associated with a variable disease severity. In the context of our NF2 Multidisciplinary Clinics, we have identified a patient fulfilling clinical criteria for the disease and exhibiting a severe phenotype. The patient carries a deep intronic mutation (g. 74409T4A, NG_009057.1) that produces the insertion of a cryptic exon of 167pb in the mature mRNA between exons 13 and 14, resulting in a truncated merlin protein (p.Pro482Profs*39). A mutation-specific antisense phosphorodiamidate morpholino oligomer was designed and used in vitro to effectively restore normal NF2 splicing in patient-derived primary fibroblasts. In addition, merlin protein levels were greatly recovered after morpholino treatment, decreasing patient's fibroblasts in vitro proliferation capacity and restoring cytoeskeleton organization. To our knowledge, this is the first NF2 case caused by a deep intronic mutation in which an in vitro antisense therapeutic approximation has been tested. These results open the possibility of using this approach in vivo for this type of mutation causing NF2. INTRODUCTIONNeurofibromatosis type 2 (NF2; MIM ID#101000) is an autosomaldominant cancer syndrome caused by mutations in the NF2 gene, located on chromosome 22q12. NF2 has an incidence of 1 in 33 000 live births showing a wide phenotypic variability and a nearly complete penetrance by the age of 60. 1 The NF2 gene codes for the tumorsuppressor protein merlin (69 kDa). Merlin regulates cellular processes that are found to be altered in tumorigenesis including: cell-cell adhesion, cytoskeletal architecture and membrane protein organization. 2,3 NF2 patients are predisposed to develop lesions of the nervous system, eyes and skin. The presence of bilateral vestibular nerve schwannomas is the most distinctive feature of NF2, but patients can develop other clinical manifestations such as schwannomas in other cranial, spinal and peripheral nerves, and also other types of tumors, like meningiomas (both intracranial and intraspinal) and ependymomas (low-grade central nervous system malignancies). Affected individuals can also show peripheral neuropathies (independently of compressive tumors), cataracts, epiretinal membranes, retinal hamartomas and cutaneous tumors, usually schwannomas. 4 Over 50% of patients are familial cases and the other 50% bear de novo mutations. A minimum of 25-33% of these NF2 sporadic cases are mosaic, 5,6 which complicates clinical diagnostics and genetic testing. 7

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Section: Patient Descriptionmentioning

confidence: 99%

In vitro antisense therapeutics for a deep intronic mutation causing Neurofibromatosis type 2

et al. 2012

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“…Since 1997, when the most recent set of diagnostic criteria were proposed, the natural history of NF2 has become more clearly defined, 19 -24 and management of the disease has improved. 1,2,25-27 Molecular testing for NF2 mutations has become clinically available, 1,2,26,28,29 and somatic mosaicism has been found to occur in 25-30% of de novo NF2 patients. 11,12 Schwannomatosis has been defined as a distinct clinical entity, 9 excluded from the NF2 locus, 30 and shown to be related to mutations of the SMARCB1 locus in some patients.…”

Section: Discussionmentioning

confidence: 99%

Empirical development of improved diagnostic criteria for neurofibromatosis 2

Baser¹,

Friedman

Joe

et al. 2011

Genetics in Medicine

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“…However, hearing preservation rates after radical surgery in NF2-associated vestibular schwannomas are lower and the risks of postoperative cranial nerve deficits are higher than those of sporadic vestibular schwannomas. 5,[16][17][18] Furthermore, the bilateral nature of vestibular schwannomas and the presence of other tumors in the central nervous system can increase the likelihood of other interventions and neurologic signs and symptoms in these patients.…”

Section: Discussionmentioning

confidence: 99%

Radiosurgical treatment of vestibular schwannomas in patients with neurofibromatosis type 2

Phi¹,

Kim²,

Chung³

et al. 2009

Cancer

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BACKGROUND:The radiosurgical treatment of vestibular schwannomas in patients with neurofibromatosis type 2 (NF2) is controversial. The authors investigated the radiologically proven tumor control rate after gamma knife radiosurgery. The factors that affect tumor control and serviceable hearing preservation were analyzed.METHODS:Thirty‐six lesions in 30 patients were included. The median lengths of the clinical and radiologic follow‐ups were 48.5 months and 36.5 months, respectively. The median tumor volume was 3.2 cm3. The mean marginal dose was 12.1 grays (Gy) (range, 8–14 Gy) at an isodose line of 50%±0.6%. The Kaplan‐Meier method and Cox proportional hazards model were used for the statistical analyses.RESULTS:The actuarial tumor control rate was 81%, 74%, and 66%, respectively, in the first, second, and fifth years. Five tumors required a salvage surgery because of tumor control failure. A low marginal dose and a young age at radiosurgery were associated with poor tumor control. Of the 16 tumors with which ipsilateral hearing was serviceable, the actuarial serviceable hearing preservation rates were 50%, 45%, and 33%, respectively, in the first, second, and fifth years. Better ipsilateral hearing (Gardner‐Robertson grade 1, compared with grade 2) at the time of radiosurgery was associated with significantly greater serviceable hearing preservation.CONCLUSIONS:Gamma knife radiosurgery for vestibular schwannomas in NF2 patients provided 5‐year tumor control in approximately two‐thirds of patients and preserved serviceable hearing in approximately one‐third. The rates of other cranial nerve deficits were low, and no secondary malignancy was observed. Radiosurgery should be included in treatment options for NF2 patients. Cancer 2009. © 2009 American Cancer Society.

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Management of the patient and family with neurofibromatosis 2: a consensus conference statement

Cited by 240 publications

References 34 publications

In vitro antisense therapeutics for a deep intronic mutation causing Neurofibromatosis type 2

In vitro antisense therapeutics for a deep intronic mutation causing Neurofibromatosis type 2

Empirical development of improved diagnostic criteria for neurofibromatosis 2

Radiosurgical treatment of vestibular schwannomas in patients with neurofibromatosis type 2

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