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      Emerging genotype–phenotype relationships in patients with large NF1 deletions

      review-article
      1 , , 2 , 3
      Human Genetics
      Springer Berlin Heidelberg

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          Abstract

          The most frequent recurring mutations in neurofibromatosis type 1 (NF1) are large deletions encompassing the NF1 gene and its flanking regions ( NF1 microdeletions). The majority of these deletions encompass 1.4-Mb and are associated with the loss of 14 protein-coding genes and four microRNA genes. Patients with germline type-1 NF1 microdeletions frequently exhibit dysmorphic facial features, overgrowth/tall-for-age stature, significant delay in cognitive development, large hands and feet, hyperflexibility of joints and muscular hypotonia. Such patients also display significantly more cardiovascular anomalies as compared with patients without large deletions and often exhibit increased numbers of subcutaneous, plexiform and spinal neurofibromas as compared with the general NF1 population. Further, an extremely high burden of internal neurofibromas, characterised by >3000 ml tumour volume, is encountered significantly, more frequently, in non-mosaic NF1 microdeletion patients than in NF1 patients lacking such deletions. NF1 microdeletion patients also have an increased risk of malignant peripheral nerve sheath tumours (MPNSTs); their lifetime MPNST risk is 16–26%, rather higher than that of NF1 patients with intragenic NF1 mutations (8–13%). NF1 microdeletion patients, therefore, represent a high-risk group for the development of MPNSTs, tumours which are very aggressive and difficult to treat. Co-deletion of the SUZ12 gene in addition to NF1 further increases the MPNST risk in NF1 microdeletion patients. Here, we summarise current knowledge about genotype–phenotype relationships in NF1 microdeletion patients and discuss the potential role of the genes located within the NF1 microdeletion interval whose haploinsufficiency may contribute to the more severe clinical phenotype.

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          Most cited references239

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          Malignant peripheral nerve sheath tumors. A clinicopathologic study of 120 cases.

          A review was done of 120 cases of malignant peripheral nerve sheath tumor (MPNST) seen during a 71-year period. Of the 120 patients, 52 were males and 68 were females with a mean age at diagnosis of 35.3 years; 12 patients were younger than 20 years. The series included 62 (52%) patients with neurofibromatosis, 13 (11%) with postradiation sarcomas, and 19 (16%) with metaplastic foci. The incidence of MPNST arising in neurofibromatosis was 4.6% in the current series and 0.001% in the general clinic population. Tumors greater than 5 cm and the presence of neurofibromatosis adversely affected the prognosis (P less than 0.05). When both features were present, survival was greatly decreased. Patients with tumor in the extremities did better than those with head or neck lesions. Metaplastic foci or previous radiation at the tumor site did not alter the prognosis. Each tumor was graded 1 to 4 on the basis of cellularity, pleomorphism, mitotic index, and necrosis. No significant correlation was noted between survival and either grade or mitotic rate. Survival was improved when total rather than subtotal resection was done. This was most marked in patients with a small lesion, which may reflect the difficulty in adequately excising large tumors. Adjuvant radiation or chemotherapy did not appear to affect survival. The MPNST is an aggressive uncommon neoplasm, and large tumor size, the presence of neurofibromatosis, and total resection are the most important prognostic indicators.
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            Guidelines for the diagnosis and management of individuals with neurofibromatosis 1.

            Neurofibromatosis 1 (NF1) is a common neurocutaneous condition with an autosomal dominant pattern of inheritance. The complications are diverse and disease expression varies, even within families. Progress in molecular biology and neuroimaging and the development of mouse models have helped to elucidate the aetiology of NF1 and its clinical manifestations. Furthermore, these advances have raised the prospect of therapeutic intervention for this complex and distressing disease. Members of the United Kingdom Neurofibromatosis Association Clinical Advisory Board collaborated to produce a consensus statement on the current guidelines for diagnosis and management of NF1. The proposals are based on published clinical studies and on the pooled knowledge of experts in neurofibromatosis with experience of providing multidisciplinary clinical and molecular services for NF1 patients. The consensus statement discusses the diagnostic criteria, major differential diagnoses, clinical manifestations and the present strategies for monitoring and management of NF1 complications.
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              Viral RNA detection by RIG-I-like receptors.

              In higher vertebrates, recognition of the non-self signature of invading viruses by genome-encoded pattern recognition receptors initiates antiviral innate immunity. Retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) detect viral RNA as a non-self pattern in the cytoplasm and activate downstream signaling. Detection of viral RNA also activates stress responses resulting in stress granule-like aggregates, which facilitate RLR-mediated antiviral immunity. Among the three RLR family members RIG-I and melanoma differentiation-associated gene 5 (MDA5) recognize distinct viral RNA species with differential molecular machinery and activate signaling through mitochondrial antiviral signaling (MAVS, also known as IPS-1/VISA/Cardif), which leads to the expression of cytokines including type I and III interferons (IFNs) to restrict viral propagation. In this review, we summarize recent knowledge regarding RNA recognition and signal transduction by RLRs and MAVS/IPS-1. Copyright © 2015 Elsevier Ltd. All rights reserved.
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                Author and article information

                Contributors
                0049 731 50065421 , hildegard.kehrer-sawatzki@uni-ulm.de
                Journal
                Hum Genet
                Hum. Genet
                Human Genetics
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0340-6717
                1432-1203
                17 February 2017
                17 February 2017
                2017
                : 136
                : 4
                : 349-376
                Affiliations
                [1 ]ISNI 0000 0004 1936 9748, GRID grid.6582.9, Institute of Human Genetics, , University of Ulm, ; Albert-Einstein-Allee 11, 89081 Ulm, Germany
                [2 ]ISNI 0000 0001 2180 3484, GRID grid.13648.38, Department of Neurology, , University Hospital Hamburg Eppendorf, ; 20246 Hamburg, Germany
                [3 ]ISNI 0000 0001 0807 5670, GRID grid.5600.3, Institute of Medical Genetics, School of Medicine, , Cardiff University, ; Cardiff, CF14 4XN UK
                Author information
                http://orcid.org/0000-0002-3398-5913
                Article
                1766
                10.1007/s00439-017-1766-y
                5370280
                28213670
                4e2b8a61-2284-4354-a564-78cf323be142
                © The Author(s) 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 27 December 2016
                : 8 February 2017
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                Review
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                © Springer-Verlag Berlin Heidelberg 2017

                Genetics
                Genetics

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