Did you mean: neurofibromatosis
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International Journal of Molecular... May 2021Neurofibromatosis (NF) is a neurocutaneous syndrome characterized by the development of tumors of the central or peripheral nervous system including the brain, spinal... (Review)
Review
Neurofibromatosis (NF) is a neurocutaneous syndrome characterized by the development of tumors of the central or peripheral nervous system including the brain, spinal cord, organs, skin, and bones. There are three types of NF: NF1 accounting for 96% of all cases, NF2 in 3%, and schwannomatosis (SWN) in <1%. The NF1 gene is located on chromosome 17q11.2, which encodes for a tumor suppressor protein, neurofibromin, that functions as a negative regulator of Ras/MAPK and PI3K/mTOR signaling pathways. The NF2 gene is identified on chromosome 22q12, which encodes for merlin, a tumor suppressor protein related to ezrin-radixin-moesin that modulates the activity of PI3K/AKT, Raf/MEK/ERK, and mTOR signaling pathways. In contrast, molecular insights on the different forms of SWN remain unclear. Inactivating mutations in the tumor suppressor genes SMARCB1 and LZTR1 are considered responsible for a majority of cases. Recently, treatment strategies to target specific genetic or molecular events involved in their tumorigenesis are developed. This study discusses molecular pathways and related targeted therapies for NF1, NF2, and SWN and reviews recent clinical trials which involve NF patients.
Topics: Animals; Biomarkers, Tumor; Clinical Trials as Topic; Disease Models, Animal; Disease Susceptibility; Genes, Neurofibromatosis 1; Genes, Neurofibromatosis 2; Genetic Predisposition to Disease; Humans; Models, Biological; Molecular Targeted Therapy; Mutation; Neurilemmoma; Neurofibromatoses; Neurofibromatosis 1; Neurofibromatosis 2; Protein Kinase Inhibitors; Skin Neoplasms; Treatment Outcome
PubMed: 34072574
DOI: 10.3390/ijms22115850 -
Genetics in Medicine : Official Journal... Sep 2022Neurofibromatosis type 2 (NF2) and schwannomatosis (SWN) are genetically distinct tumor predisposition syndromes with overlapping phenotypes. We sought to update the...
PURPOSE
Neurofibromatosis type 2 (NF2) and schwannomatosis (SWN) are genetically distinct tumor predisposition syndromes with overlapping phenotypes. We sought to update the diagnostic criteria for NF2 and SWN by incorporating recent advances in genetics, ophthalmology, neuropathology, and neuroimaging.
METHODS
We used a multistep process, beginning with a Delphi method involving global disease experts and subsequently involving non-neurofibromatosis clinical experts, patients, and foundations/patient advocacy groups.
RESULTS
We reached consensus on the minimal clinical and genetic criteria for diagnosing NF2 and SWN. These criteria incorporate mosaic forms of these conditions. In addition, we recommend updated nomenclature for these disorders to emphasize their phenotypic overlap and to minimize misdiagnosis with neurofibromatosis type 1.
CONCLUSION
The updated criteria for NF2 and SWN incorporate clinical features and genetic testing, with a focus on using molecular data to differentiate the 2 conditions. It is likely that continued refinement of these new criteria will be necessary as investigators study the diagnostic properties of the revised criteria and identify new genes associated with SWN. In the revised nomenclature, the term "neurofibromatosis 2" has been retired to improve diagnostic specificity.
Topics: Consensus; Humans; Neurilemmoma; Neurofibromatoses; Neurofibromatosis 1; Neurofibromatosis 2; Skin Neoplasms
PubMed: 35674741
DOI: 10.1016/j.gim.2022.05.007 -
Lancet (London, England) Jun 2009Neurofibromatosis type 2 is an autosomal-dominant multiple neoplasia syndrome that results from mutations in the NF2 tumour suppressor gene located on chromosome 22q. It... (Review)
Review
Neurofibromatosis type 2 is an autosomal-dominant multiple neoplasia syndrome that results from mutations in the NF2 tumour suppressor gene located on chromosome 22q. It has a frequency of one in 25,000 livebirths and nearly 100% penetrance by 60 years of age. Half of patients inherit a germline mutation from an affected parent and the remainder acquire a de novo mutation for neurofibromatosis type 2. Patients develop nervous system tumours (schwannomas, meningiomas, ependymomas, astrocytomas, and neurofibromas), peripheral neuropathy, ophthalmological lesions (cataracts, epiretinal membranes, and retinal hamartomas), and cutaneous lesions (skin tumours). Optimum treatment is multidisciplinary because of the complexities associated with management of the multiple, progressive, and protean lesions associated with the disorder. We review the molecular pathogenesis, genetics, clinical findings, and management strategies for neurofibromatosis type 2.
Topics: Cataract; Chromosomes, Human, Pair 22; Disease Progression; Gene Frequency; Genes, Neurofibromatosis 2; Genetic Testing; Humans; Molecular Biology; Mutation; Nervous System Neoplasms; Neurofibromatosis 2; Neurofibromin 2; Patient Care Team; Pedigree; Penetrance; Peripheral Nervous System Diseases; Skin Neoplasms; Survival Rate
PubMed: 19476995
DOI: 10.1016/S0140-6736(09)60259-2 -
International Journal of Molecular... Jan 2021Patients diagnosed with neurofibromatosis type 2 (NF2) are extremely likely to develop meningiomas, in addition to vestibular schwannomas. Meningiomas are a common... (Review)
Review
Patients diagnosed with neurofibromatosis type 2 (NF2) are extremely likely to develop meningiomas, in addition to vestibular schwannomas. Meningiomas are a common primary brain tumor; many NF2 patients suffer from multiple meningiomas. In NF2, patients have mutations in the gene, specifically with loss of function in a tumor-suppressor protein that has a number of synonymous names, including: Merlin, Neurofibromin 2, and schwannomin. Merlin is a 70 kDa protein that has 10 different isoforms. The Hippo Tumor Suppressor pathway is regulated upstream by Merlin. This pathway is critical in regulating cell proliferation and apoptosis, characteristics that are important for tumor progression. Mutations of the NF2 gene are strongly associated with NF2 diagnosis, leading to benign proliferative conditions such as vestibular schwannomas and meningiomas. Unfortunately, even though these tumors are benign, they are associated with significant morbidity and the potential for early mortality. In this review, we aim to encompass meningiomas and vestibular schwannomas as they pertain to NF2 by assessing molecular genetics, common tumor types, and tumor pathogenesis.
Topics: Animals; Apoptosis; Brain Neoplasms; Cell Proliferation; Humans; Meningeal Neoplasms; Meningioma; Mutation; Neurofibromatosis 2; Neuroma, Acoustic
PubMed: 33445724
DOI: 10.3390/ijms22020690 -
Acta Neuropathologica Apr 2020Neurofibromatosis type II (NF2) is a tumor predisposition syndrome characterized by the development of distinctive nervous system lesions. NF2 results from... (Review)
Review
Neurofibromatosis type II (NF2) is a tumor predisposition syndrome characterized by the development of distinctive nervous system lesions. NF2 results from loss-of-function alterations in the NF2 gene on chromosome 22, with resultant dysfunction of its protein product merlin. NF2 is most commonly associated with the development of bilateral vestibular schwannomas; however, patients also have a predisposition to development of other tumors including meningiomas, ependymomas, and peripheral, spinal, and cranial nerve schwannomas. Patients may also develop other characteristic manifestations such as ocular lesions, neuropathies, meningioangiomatosis, and glial hamartia. NF2 has a highly variable clinical course, with some patients exhibiting a severe phenotype and development of multiple tumors at an early age, while others may be nearly asymptomatic throughout their lifetime. Despite the high morbidity associated with NF2 in severe cases, management of NF2-associated lesions primarily consists of surgical resection and treatment of symptoms, and there are currently no FDA-approved systemic therapies that address the underlying biology of the syndrome. Refinements to the diagnostic criteria of NF2 have been proposed over time due to increasing understanding of clinical and molecular data. Large-population studies have demonstrated that some features such as the development of gliomas and neurofibromas, currently included as diagnostic criteria, may require further clarification and modification. Meanwhile, burgeoning insights into the molecular biology of NF2 have shed light on the etiology and highly variable severity of the disease and suggested numerous putative molecular targets for therapeutic intervention. Here, we review the clinicopathologic features of NF2, current understanding of the molecular biology of NF2, particularly with regard to central nervous system lesions, ongoing therapeutic studies, and avenues for further research.
Topics: Central Nervous System Diseases; Genetic Predisposition to Disease; Humans; Neurofibromatosis 2
PubMed: 31161239
DOI: 10.1007/s00401-019-02029-5 -
International Journal of Molecular... May 2022Vestibular schwannoma (VS) is a benign tumor that originates from Schwann cells in the vestibular component. Surgical treatment for VS has gradually declined over the... (Review)
Review
Vestibular schwannoma (VS) is a benign tumor that originates from Schwann cells in the vestibular component. Surgical treatment for VS has gradually declined over the past few decades, especially for small tumors. Gamma knife radiosurgery has become an accepted treatment for VS, with a high rate of tumor control. For neurofibromatosis type 2 (NF2)-associated VS resistant to radiotherapy, vascular endothelial growth factor (VEGF)-A/VEGF receptor (VEGFR)-targeted therapy (e.g., bevacizumab) may become the first-line therapy. Recently, a clinical trial using a VEGFR1/2 peptide vaccine was also conducted in patients with progressive NF2-associated schwannomas, which was the first immunotherapeutic approach for NF2 patients. Targeted therapies for the gene product of SH3PXD2A-HTRA1 fusion may be effective for sporadic VS. Several protein kinase inhibitors could be supportive to prevent tumor progression because merlin inhibits signaling by tyrosine receptor kinases and the activation of downstream pathways, including the Ras/Raf/MEK/ERK and PI3K/Akt/mTORC1 pathways. Tumor-microenvironment-targeted therapy may be supportive for the mainstays of management. The tumor-associated macrophage is the major component of immunosuppressive cells in schwannomas. Here, we present a critical overview of targeted therapies for VS. Multimodal therapy is required to manage patients with refractory VS.
Topics: High-Temperature Requirement A Serine Peptidase 1; Humans; Neurilemmoma; Neurofibromatosis 2; Neuroma, Acoustic; Phosphatidylinositol 3-Kinases; Tumor Microenvironment; Vascular Endothelial Growth Factor A
PubMed: 35628268
DOI: 10.3390/ijms23105462 -
Chinese Clinical Oncology Jul 2017Meningiomas are frequent intracranial and intraspinal tumors. They are tumors of the elderly, and meningioma growth at certain localizations, as well as recurrent tumors... (Review)
Review
Meningiomas are frequent intracranial and intraspinal tumors. They are tumors of the elderly, and meningioma growth at certain localizations, as well as recurrent tumors or primary aggressive biology may pose a therapeutic challenge. To understand the growth characteristics of meningiomas, animal models can provide insights both from a biological and therapeutical point of view. Using genetically-engineered mouse models (GEMM), it has been proven that alterations of the neurofibromatosis type 2 (NF2) gene are key steps for benign meningioma development. Aggressive meningiomas can be induced by simultaneous activation of Nf2 and the PDGF (platelet-derived growth factor)/-PDGF-Receptor (R) system, or inactivation of Tp53 and cdkn2ab in mice. However, mechanisms acting in NF2 wild-type meningiomas are poorly understood so far, because appropriate models are lacking. Xenograft models have been used either by implantation of primary cultures derived from human meningiomas, or immortalized human cell lines, respectively. While the value of primary cells is limited due to low rate of overall tumor growth and slow proliferation, xenograft approaches have been shown to be helpful for the evaluation of potential medical treatment options. Future studies must incorporate new molecular meningioma tumor drivers, as well as potential treatment options based on recurrent genetic alterations into the generation of meningioma models.
Topics: Animals; Disease Models, Animal; Genes, Neurofibromatosis 2; Heterografts; Humans; Meningeal Neoplasms; Meningioma; Mice; Neoplasm Recurrence, Local
PubMed: 28595424
DOI: 10.21037/cco.2017.05.03 -
Brain Pathology (Zurich, Switzerland) Apr 2014Schwannomas may occur spontaneously, or in the context of a familial tumor syndrome such as neurofibromatosis type 2 (NF2), schwannomatosis and Carney's complex.... (Review)
Review
Schwannomas may occur spontaneously, or in the context of a familial tumor syndrome such as neurofibromatosis type 2 (NF2), schwannomatosis and Carney's complex. Schwannomas have a variety of morphological appearances, but they behave as World Health Organization (WHO) grade I tumors, and only very rarely undergo malignant transformation. Central to the pathogenesis of these tumors is loss of function of merlin, either by direct genetic change involving the NF2 gene on chromosome 22 or secondarily to merlin inactivation. The genetic pathways and morphological features of schwannomas associated with different genetic syndromes will be discussed. Merlin has multiple functions, including within the nucleus and at the cell membrane, and this review summarizes our current understanding of the mechanisms by which merlin loss is involved in schwannoma pathogenesis, highlighting potential areas for therapeutic intervention.
Topics: Animals; Brain Neoplasms; Carney Complex; Humans; Neurilemmoma; Neurofibromatosis 2
PubMed: 24450866
DOI: 10.1111/bpa.12125 -
Arquivos de Neuro-psiquiatria Mar 2014
Topics: Humans; Neurilemmoma; Neurofibromatoses; Neurofibromatosis 1; Neurofibromatosis 2; Skin Neoplasms
PubMed: 24676432
DOI: 10.1590/0004-282x20140012 -
Neuro-oncology Apr 2015
Topics: Genes, Neurofibromatosis 2; Humans; Neurofibromatosis 2; Neuroma, Acoustic
PubMed: 25537020
DOI: 10.1093/neuonc/nou338