Neurofibromatosis Type 1

Symptoms, Treatment and Prognosis

Author: Matthias A. Karajannis

Publisher: Nova Science Pub Incorporated

ISBN:

Category: Science

Page: 211

View: 418

Neurofibromatosis Type 1 (NF1) is a relatively common genetic disorder that predisposes affected individuals for developing multiple tumors, predominantly neurofibromas. NF1 is caused by a loss of the tumor suppressor protein neurofibromin, which was discovered over 20 years ago. NF1 patients develop a wide spectrum of benign tumors, including in the skin, deep soft tissues and brain, as well as malignant tumors including malignant peripheral nerve sheath tumors, malignant gliomas and acute myeloblastic leukemia. NF1 patients are also at risk for a spectrum of orthopedic and neurological disorders, including bone abnormalities and speech and learning disorders. This book, edited by Matthias Karajannis, MD, MS and Jeffrey Allen, MD, who direct the Comprehensive NF Center at NYU Langone Medical Center in New York, represents a valuable resource for both scientists and clinicians involved in NF1 research and patient care. Each chapter is written by expert authors in the field and addresses one or several specific topics in NF1 with a focus on disease biology, genetics, diagnostics and/or clinical management. The latest scientific advances in the field of NF1 are discussed, along with practical management recommendations and an outlook on future avenues of NF1 research.

Peripheral Nerve Disorders

Chapter 53. Neurofibromatosis type 1 (NF1): diagnosis and management

Author: Rosalie E. Ferner

Publisher: Elsevier Inc. Chapters

ISBN:

Category: Medical

Page: 1008

View: 682

Neurofibromatosis 1 (NF1) is an inherited neurocutaneous disease that has a major impact on the nervous system, eye, skin, and bone. Individuals with NF1 have a predisposition to benign and malignant tumor formation and the hallmark lesion is the neurofibroma, a benign peripheral nerve sheath tumor. The gene for NF1 was cloned on chromosome 17q11.2 and neurofibromin, the NF1 protein, controls cell growth and proliferation by regulating the proto-oncogene Ras and cyclic adenosine monophosphate (AMP). Advances in molecular biology and mouse models of disease have enhanced our understanding of the pathogenesis of NF1 complications and facilitated targeted therapy. Progress has been made in developing robust clinical and radiological outcome measures and clinical trials are underway for children with learning difficulties and for individuals with symptomatic plexiform neurofibromas.

Neurofibromatosis Type 1

Molecular and Cellular Biology

Author: Meena Upadhyaya

Publisher: Springer Science & Business Media

ISBN:

Category: Medical

Page: 717

View: 949

Neurofibromatosis type 1 (NF1), caused by mutational inactivation of the NF1 tumour suppressor gene, is one of the most common dominantly inherited human disorders, affecting 1 in 3000 individuals worldwide. This book presents in concise fashion, but as comprehensively as possible, our current state of knowledge on the molecular genetics, molecular biology and cellular biology of this tumour predisposition syndrome. Written by internationally recognized experts in the field, the 44 chapters that constitute this edited volume provide the reader with a broad overview of the clinical features of the disease, the structure and expression of the NF1 gene, its germ line and somatic mutational spectra and genotype-phenotype relationships, the structure and function of its protein product (neurofibromin), NF1 modifying loci, the molecular pathology of NF1-associated tumours, animal models of the disease, psycho-social aspects and future prospects for therapeutic treatment.

Neurofibromatosis Type 1

Symptoms, Treatment and Prognosis

Author: Allen Jeffrey Karajannis Matthias a

Publisher:

ISBN:

Category: Medical

Page: 212

View: 770

Neurofibromatosis Type 1 (NF1) is a relatively common genetic disorder that predisposes affected individuals for developing multiple tumors, predominantly neurofibromas. NF1 is caused by a loss of the tumor suppressor protein neurofibromin, which was discovered over 20 years ago. NF1 patients develop a wide spectrum of benign tumors, including in the skin, deep soft tissues and brain, as well as malignant tumors including malignant peripheral nerve sheath tumors, malignant gliomas and acute myeloblastic leukemia. NF1 patients are also at risk for a spectrum of orthopedic and neurological disorders, including bone abnormalities and speech and learning disorders. This book, edited by Matthias Karajannis, MD, MS and Jeffrey Allen, MD, who direct the Comprehensive NF Center at NYU Langone Medical Center in New York, represents a valuable resource for both scientists and clinicians involved in NF1 research and patient care. Each chapter is written by expert authors in the field and addresses one or several specific topics in NF1 with a focus on disease biology, genetics, diagnostics and/or clinical management. The latest scientific advances in the field of NF1 are discussed, along with practical management recommendations and an outlook on future avenues of NF1 research.

Multidisciplinary Approach to Neurofibromatosis Type 1

Author: Gianluca Tadini

Publisher: Springer

ISBN:

Category: Medical

Page: 313

View: 362

This volume offers an update of the clinical signs, diagnostic criteria (including molecular diagnosis) and targeted therapies for a particular type of genodermatosis, providing a handy and unique tool for early diagnosis. In recent years, our understanding of genodermatosis and neurocutaneous syndromes has increased, but although Type 1 Neurofibromatosis (NF1) is the most common neuroectodermal disorder and involves a large number of patients and medical disciplines, this syndrome remains underestimated, often misdiagnosed thus leading to inaccurate treatment. The literature on the molecular and pathogenetic aspects is ample, but current clinical approaches, classification, diagnostic criteria and treatment protocols are outdated, creating difficulties in early diagnosis and treatment. As such, a chapter is devoted renewing current diagnostic criteria; it includes clinical and molecular data, to offer a sound, updated discussion basis for a consensus conference. NF1 is a “time-dependent” disorder, meaning that the onset of clinical signs are closely linked to patient age and the book discusses this particularly neglected aspect extensively, as well as the latest molecular diagnosis techniques, which are highly sensitive have not been included in the diagnostic criteria. It also explains the role of the RAS-MAPK pathway and genotype-phenotype correlations. In addition it explores new concepts concerning the pathogenesis of neurofibromas and other hamarthomas and their relevance for a modern therapeutical approach with targeted molecular drugs, as well as newly discovered aspects of NF1 in all internal organs, together with their diagnostic counterparts. A chapter on mosaic neurofibromatosis is also included. There is a particular focus on differential diagnosis (i.e. other diseases with café-au-lait macules), and the recently described Legius syndrome will be presented directly by Prof Eric Legius. All chapters are easy-to-understand, up-to-date, comprehensive and concise tools and are intended for a wide range of professionals involved with genetic disorders of the skin and neurocutaneous diseases: dermatologists, pediatricians, neurologists, oncologists and general practitioners.

Neurofibromatosis Type 1 in Childhood

Author: Kathryn North

Publisher: Cambridge University Press

ISBN:

Category: Medical

Page: 132

View: 663

A thoughtful and clinically valuable account which will aid both treatment of and research into this difficult disorder.

Neurofibromatosis Type 1: New Insights for the Healthcare Professional: 2011 Edition

ScholarlyPaper

Author:

Publisher: ScholarlyEditions

ISBN:

Category: Medical

Page: 14

View: 537

Neurofibromatosis Type 1: New Insights for the Healthcare Professional: 2011 Edition is a ScholarlyPaper™ that delivers timely, authoritative, and intensively focused information about Neurofibromatosis Type 1 in a compact format. The editors have built Neurofibromatosis Type 1: New Insights for the Healthcare Professional: 2011 Edition on the vast information databases of ScholarlyNews.™ You can expect the information about Neurofibromatosis Type 1 in this eBook to be deeper than what you can access anywhere else, as well as consistently reliable, authoritative, informed, and relevant. The content of Neurofibromatosis Type 1: New Insights for the Healthcare Professional: 2011 Edition has been produced by the world’s leading scientists, engineers, analysts, research institutions, and companies. All of the content is from peer-reviewed sources, and all of it is written, assembled, and edited by the editors at ScholarlyEditions™ and available exclusively from us. You now have a source you can cite with authority, confidence, and credibility. More information is available at http://www.ScholarlyEditions.com/.

Neurofibromatosis Type 1(NF1)

Author: Johnson Mbabazi Frsph

Publisher:

ISBN:

Category:

Page: 32

View: 646

Neurofibromatosis type 1 is a multifaceted autosomal dominant disorder caused by germline mutations in the NF1 tumour suppressor gene. Approximately all people with neurofibromatosis type 1 develop pigmentary lesions and dermal neurofibromas. Some individuals develop skeletal abnormalities (scoliosis, tibial pseudarthrosis and orbital dysplasia), brain tumours (optic pathway gliomas and glioblastoma), peripheral nerve tumours (spinal neurofibromas, plexiform neurofibromas and malignant peripheral nerve sheath tumours), learning disabilities, attention deficits, and social and behavioural problems, which can negatively affect quality of life. With the identification of NF1 and the generation of accurate preclinical mouse strains that model some of these clinical features, therapies that target the underlying molecular and cellular pathophysiology for neurofibromatosis type 1 are becoming available. Even though no single treatment exists, current clinical management strategies include early detection of disease phenotypes (risk assessment) and biologically targeted therapies. Likewise, new medical and behavioural interventions are emerging to improve the quality of life of patients. Although considerable progress has been made in understanding this condition, various challenges remain; a collaborative and interdisciplinary method is required to manage individuals with neurofibromatosis type1 and to develop effective treatments.

Neurofibromatosis Type 1: New Insights for the Healthcare Professional: 2012 Edition

ScholarlyPaper

Author:

Publisher: ScholarlyEditions

ISBN:

Category: Medical

Page: 23

View: 161

Neurofibromatosis Type 1: New Insights for the Healthcare Professional / 2012 Edition is a ScholarlyPaper™ that delivers timely, authoritative, and intensively focused information about Neurofibromatosis Type 1 in a compact format. The editors have built Neurofibromatosis Type 1: New Insights for the Healthcare Professional / 2012 Edition on the vast information databases of ScholarlyNews.™ You can expect the information about Neurofibromatosis Type 1 in this eBook to be deeper than what you can access anywhere else, as well as consistently reliable, authoritative, informed, and relevant. The content of Neurofibromatosis Type 1: New Insights for the Healthcare Professional / 2012 Edition has been produced by the world’s leading scientists, engineers, analysts, research institutions, and companies. All of the content is from peer-reviewed sources, and all of it is written, assembled, and edited by the editors at ScholarlyEditions™ and available exclusively from us. You now have a source you can cite with authority, confidence, and credibility. More information is available at http://www.ScholarlyEditions.com/.

Neurofibromatosis Type 1 Tumourigenesis

Author: Isis M. Atallah

Publisher: Sudwestdeutscher Verlag Fur Hochschulschriften AG

ISBN:

Category:

Page: 144

View: 474

Neurofibromatosis type 1 (NF1) is one of the most frequent dominantly inherited diseases. NF1 patients harbour an increased risk of developing benign nerve sheath tumours and a 10% lifetime risk of developing malignant peripheral nerve sheath tumours. Molecular mechanisms involved in NF1 malignant transformation are still largely unknown. This book provides an insight into the pathways disrupted in NF1 associated tumourigenesis. First, a panel of genes useful for subclassification of nerve sheath tumours was identified by cDNA array technology. Second, dysregulated expression of several genes, known to play important roles in tumour formation, was confirmed on the protein level. Third, the prognosis relevance of gene misregulation was assessed and several genes were pointed out as potential targets of new therapeutic strategies.

Study Neurofibromatosis Type 1 Disease with Patient-Specific Induced Pluripotent Stem Cells

Author: Dajiang Qin

Publisher:

ISBN:

Category:

Page:

View: 353

This dissertation, "Study Neurofibromatosis Type 1 Disease With Patient-specific Induced Pluripotent Stem Cells" by Dajiang, Qin, 秦大江, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Abstract of thesis entitled "Study neurofibromatosis type 1 disease with patient-specific induced pluripotent stem cells." Submitted by Dajiang Qin for the degree of Doctor of Philosophy at The University of Hong Kong in April 2016 The autosomal dominant disease Neurofibromatosis type 1(NF1) results from mutations in the neurofibromin tumor suppressor gene that encodes a protein activated by GTPase, enabling the negative regulation on Ras signaling. This disorder is reported to affect 1 in 3500 people all over the world, and approximately 90% of such patients develop plexiform and/or dermal neurofibromas that constitute a mixture of fibroblasts, Schwann cells, neuronal axons, mast cells, and perineurial cells. Characterizing the somatic mutation in several mouse models of NF1 as well as clinical NF1 tumor samples has suggested that neurofibromas potentially orginate from the Nf1-/- Schwann cells (Carroll SL et al. Glia. 56, 2008). In this study, we managed to identify the same novel stop mutation site from a NF1 donor family in exon 53 of Nf1 gene from donor #1, #3 and #5, and found that 15 genes possibly participated in the tumorigenesis of NF1, whereas another 25 were associated with the formation of huge tumors in clinical NF1 cases. Notably, most of these mutated genes were either tumor-suppresser genes, or involved in neural, dermal development or related diseases like malignant peripheral nerve sheath tumors (MPNST). Induced pluripotent stem cells (iPSCs) derived specifically from skin fibroblasts of five NF1 donors were generated by transduction with pMX retroviruses containing Oct4, Sox2, Klf4 and c-Myc genes, and subsequent characterization with multiple stem cell markers. The data have confirmed the expression of stem cell markers Nanog, SSEA4, Sox2, TRA-81, Oct4 and TRA-60 in these NF1-iPSCs by immunofluorescence. In addition, the teratoma formation assay showed that all of these iPSCs were capable of differentiation into three germ layers. By use of the + + defined NSB culture system, HNK1 and P75 neural crest cells (NCs) were obtained from the iPSCs by FACS, and Schwann cells characterized by expressing S100 were differentiated from NCs by maintenance in the Neurobasal medium. Compared with Schwann cells derived from normal iPSCs, those from NF1-mut iPSCs exhibited a lower level of Nf1 proteins and a higher activity in Ras. The NF1-mut iPSC-derived Schwann cells were more sensitive to the Ras inhibitor farnesylthiosalicylic acid (FTS). Hence, inhibitors of Ras are potentially therapeutic to NF1 cases with huge tumors, where the Schwann cells differentiated from these patient-specific iPSCs may be useful for screening the Ras pathway modulators. In future, more clinically samples are in need to allow the exon sequencing and functional confirmation of the mutated genes we've found.Besides, other inhibitors of the Ras signaling pathways could be evaluated on the Schwann cell screening platform we have established. The NF1-iPSCs could be a new method to study the tumorigenesis of NF1 and drug discovery. Word count:433 Subjects: Neurofibromatosis

The Molecular Biology of Neurofibromatosis Type 1

Author: Meena Upadhyaya

Publisher: Morgan & Claypool Life Sciences

ISBN:

Category: Science

Page: 80

View: 962

Neurofibromatosis type 1 (NF1) is a common autosomal dominantly inherited, tumour predisposition syndrome affecting 1/3,000-4,000 individuals worldwide. This inherited disorder results from the mutational inactivation of the NF1 gene on human chromosome 17. The NF1 gene contains 61 exons that give rise to 12kb mRNA encoding neurofibromin. The 327kDa (2,818 amino acid) neurofibromin protein is expressed in most tissues and has a number of alternative isoforms. Neurofibromin is a tumour suppressor protein and down-regulates cellular Ras. Increased active Ras- GTP levels also stimulate the important PI3K/AKT/mTOR signalling pathway that protects cells from apoptosis. The major clinical features of NF1 include multiple café-au-lait rmacules, skinfold freckles, iris Lisch nodules, and neurofibromas. The diagnostic criteria for clinical diagnosis have been well established. However, there are a small number of cases in which the diagnosis is not certain. The germline mutation rate for the NF1 gene is 10-fold higher than that observed for most other inherited diseases. Using a combination of different techniques, almost 95% of germline mutations can be detected. To date, only two firm genotype phenotype correlations have been reported. NF1 phenotype exhibits large variations within a family, evidence for modifying loci regulating the expression of an NF1 gene is beginning to emerge. We also are gaining knowledge on the molecular mechanisms associated with the development of different types of tumours. It is encouraging that the results of recent laboratory and clinical research are finally being translated into clinical trials. With the availability of high-throughput technologies, sophisticated animal models, and multi-centre clinical trials, the future for NF1 sufferers is looking optimistic. This book aims to provide an overview of the genetic and clinical aspects of NF1 and its role in both NF1-associated and sporadic tumour development. It emphasizes the recent developments in this field and some of the promising on-going clinical trials.

Neurofibromatosis Type 1- Unearthing the Hidden Treasure

Author: Rupak Sethuraman

Publisher: LAP Lambert Academic Publishing

ISBN:

Category:

Page: 92

View: 682

Neurofibromatosis Type 1 (NF 1) although not a very uncommon tumor presents difficulties in understanding because of lack of in depth knowledge about the etiopathogenesis of the disease at a molecular level, which mainly encompasses knowledge regarding the NF 1 Gene and the protein Neurofibromin.The disease affects several organs in the body and produces a plethora of clinical manifestations. A good percentage of cases also transform into the Malignant peripheral nerve sheath tumors (MPNSTs)thus establishing this entity as a premalignant condition. Hence, this calls for an early and accurate diagnosis in order to decrease the morbidity of the patient.However, this may not be always easy because a good number of other conditions frequently overlap this disease entity.The oral manifestations of this disease seldom receive importance. Thus the aim of the present study was to focus on the etiopathogenesis of the disease along with the oral manifestations.

Neurofibromatosis Type 1

From Genotype to Phenotype

Author: Meena Upadhyaya

Publisher: Garland Science

ISBN:

Category: Medical

Page: 230

View: 177

Neurofibromatosis type 1 is a common inherited neurogenetic disorder affecting one in 4000 individuals worldwide. Symptoms include facial and body disfigurement, mental retardation, and abnormalities of the cardiovascular, renal and endocrine systems. Beginning with an overview of what is known about the disease, this text goes on to provide information on developments and clinical implications.

Ras Signalling in Schwann Cell Tumor Formation

Neurofibromatosis Type 1

Author:

Publisher:

ISBN:

Category:

Page:

View: 945

Patients with Neurofibromatosis Type 1 (NF1) carry a germline mutation in the NF1 gene and have an increased risk for developing a variety of benign and malignant tumors. Neurofibromin, the protein encoded by the NF1 gene, is a GTPase activating protein that negatively regulates Ras activity. NF1 -deficient tumors display elevated levels of Ras-GTP suggesting that inappropriate Ras activation contributes to tumor formation. While many abnormal phenotypes of NF1 mutant cells can be ascribed to H-, N-, and K-Ras-GTP excess, Ras-independent phenotypes have been described. The major objective of this work is to explore the contribution of Ras-dependent and Ras-independent signaling pathways to tumor formation in neurofibromin deficient cells. The first set of studies demonstrates that Schwann cells derived from Nf1 null mice have enhanced migration in comparison to wildtype controls. Nf1 -/- mouse Schwann cell migration is not reversed by inhibition of the classical Ras proteins, suggesting that migration is independent of their increased H-, N-, and/or K-Ras activation. We find that TC21/R-Ras2 and its downstream effectors play a role in the migration of neurofibromin-deficient Schwann cells. These studies are the first to implicate TC21 activity in benign tumor formation. The second set of studies investigates Ras signaling in the context of malignant transformation in NF1. NF1 patients are at a greater risk for the development of malignant peripheral nerve sheath tumors (MPNST) than the general population. We hypothesize that a NF1 -specific pathway contributes to the pathogenesis of NF1-associated MPNST. To better understand the molecular events involved in MPNST formation, we characterize 6 NF1-associated MPNST cell lines, 2 sporadic MPNST lines, and 7 normal human Schwann cell samples. We demonstrated that NF1-associated MPNSTs, but not sporadic MPNSTs, had elevated levels of Ras-GTP and loss of p16 INK4a expression. Ras-GTP levels of NF1-associated MPNSTs correlate with their rates of proliferation. In addition, we identify a molecular signature that distinguishes NF1-associated MPNSTs from sporadic MPNSTs. Taken together, these data reveal that each of the Ras isoforms contributes to different aspects of NF1 tumor formation.