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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 -
Current Opinion in Oncology Nov 2023In 2022, an international consensus recommendation revised the nomenclature for neurofibromatosis type 2 ( NF2 ) and Schwannomatosis (SWN), now grouped under the... (Review)
Review
PURPOSE OF REVIEW
In 2022, an international consensus recommendation revised the nomenclature for neurofibromatosis type 2 ( NF2 ) and Schwannomatosis (SWN), now grouped under the umbrella term Schwannomatosis, and defined new diagnostic criteria.
RECENT FINDINGS
This review describes the molecular criteria for diagnosis of schwannomatosis and the subsequent diagnosis strategy, while setting out the most recent advances in our understanding of the natural history, pathology, molecular biology and treatment of schwannomatosis-associated tumors, including schwannomas, meningiomas and ependymomas.
SUMMARY
Somatic mutation screening should become a new standard for the diagnosis of NF2 -, LTZTR1 -, SMARCB1 - and 22q-schwannomatosis to discriminate those conditions. Constitutional events in NF2 -Schwannomatosis have a major influence on disease severity and justifiably motivate ongoing efforts on gene replacement therapy research. On the other hand, underlying mechanisms of disease severity and associated pain remain largely unknown in non- NF2 -SWN and independent of germline mutation. Research efforts therefore focus on pain relief in ongoing trials and the discovery of new molecular mechanisms underlying schwannoma tumorigenesis/pain/neuropathies.
Topics: Humans; Neurilemmoma; Neurofibromatoses; Skin Neoplasms; Neurofibromatosis 2; Pain
PubMed: 37820090
DOI: 10.1097/CCO.0000000000000994 -
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 -
British Journal of Neurosurgery Apr 2022Schwannomatosis is a relatively rare disorder and is related to neurofibromatosis type 2. Although there is clinical overlap between schwannomatosis and... (Review)
Review
BACKGROUND
Schwannomatosis is a relatively rare disorder and is related to neurofibromatosis type 2. Although there is clinical overlap between schwannomatosis and neurofibromatosis type 2, these diseases have to be regarded as separate entities due to the genetic origin and course of the disease.
METHODS
A comprehensive review of the literature was conducted for relevant studies using Pubmed and Cochrane databases to discuss the epidemiology, clinical presentation, diagnostic criteria, pathological and imaging features, treatment and genetics of schwannomatosis.
RESULTS
Germline mutations SMARCB1 and LZTRI together with the gene play a role in the pathophysiology of schwannomatosis. The most common symptom is pain with affection of the spine and peripheral nerves in the majority of patients. High quality contrast enhanced MRI scan is the imaging modality of choice. Treatment is conservative if asymptomatic and surgical if symptomatic. The goal is symptom control with preservation of neurological function.
CONCLUSION
Schwannomatosis is a relatively rare disorder in which the main goal is to preserve neurological function.
Topics: Humans; Neurilemmoma; Neurofibromatoses; Neurofibromatosis 2; Skin Neoplasms
PubMed: 33263426
DOI: 10.1080/02688697.2020.1836323 -
European Journal of Human Genetics :... Jul 2015Schwannomatosis is characterized by the development of multiple non-vestibular, non-intradermal schwannomas. Constitutional inactivating variants in two genes, SMARCB1...
Schwannomatosis is characterized by the development of multiple non-vestibular, non-intradermal schwannomas. Constitutional inactivating variants in two genes, SMARCB1 and, very recently, LZTR1, have been reported. We performed exome sequencing of 13 schwannomatosis patients from 11 families without SMARCB1 deleterious variants. We identified four individuals with heterozygous loss-of-function variants in LZTR1. Sequencing of the germline of 60 additional patients identified 18 additional heterozygous variants in LZTR1. We identified LZTR1 variants in 43% and 30% of familial (three of the seven families) and sporadic patients, respectively. In addition, we tested LZTR1 protein immunostaining in 22 tumors from nine unrelated patients with and without LZTR1 deleterious variants. Tumors from individuals with LZTR1 variants lost the protein expression in at least a subset of tumor cells, consistent with a tumor suppressor mechanism. In conclusion, our study demonstrates that molecular analysis of LZTR1 may contribute to the molecular characterization of schwannomatosis patients, in addition to NF2 mutational analysis and the detection of chromosome 22 losses in tumor tissue. It will be especially useful in differentiating schwannomatosis from mosaic Neurofibromatosis type 2 (NF2). However, the role of LZTR1 in the pathogenesis of schwannomatosis needs further elucidation.
Topics: Adult; Aged; Amino Acid Sequence; Exome; Family Health; Female; Genetic Predisposition to Disease; Humans; Immunohistochemistry; Male; Middle Aged; Molecular Sequence Data; Mutation; Neurilemmoma; Neurofibromatoses; Pedigree; Sequence Analysis, DNA; Sequence Homology, Amino Acid; Skin Neoplasms; Transcription Factors; Young Adult
PubMed: 25335493
DOI: 10.1038/ejhg.2014.220 -
Seminars in Neurology Feb 2018Neurofibromatosis 1, neurofibromatosis 2, and schwannomatosis are a group of related classically inherited but often times sporadic tumor suppressor syndromes.... (Review)
Review
Neurofibromatosis 1, neurofibromatosis 2, and schwannomatosis are a group of related classically inherited but often times sporadic tumor suppressor syndromes. Neuro-oncologists should recognize these syndromes, initiate necessary tests in patients with a clinical suspicion, and support genetic counseling of patients and families. In this review, clinical presentation, diagnostic criteria, day-to-day management including supportive care as well as updates on genetics, and experimental treatment strategies are discussed.
Topics: Humans; Nervous System Neoplasms; Neurilemmoma; Neurofibromatoses; Skin Neoplasms
PubMed: 29548054
DOI: 10.1055/s-0038-1627471 -
BMC Medical Genomics Jul 2022Noonan syndrome (NS) is a genetic disorder characterized by developmental delays, typical facial gestalt and cardiovascular defects. LZTR1 variants have been recently... (Review)
Review
BACKGROUND
Noonan syndrome (NS) is a genetic disorder characterized by developmental delays, typical facial gestalt and cardiovascular defects. LZTR1 variants have been recently described in patients with NS and schwannomatosis, but the association, inheritance pattern and management strategy has not been fully elucidated. Here, we review the contribution of LZTR1 in NS and describe a patient with a novel, likely pathogenic variant in LZTR1.
CASE PRESENTATION
A female patient was diagnosed with clinical NS at 8 months of age. She presented in adulthood when a brain and spine MRI identified plexiform neurofibromas; however, she did not meet the clinical criteria for Neurofibromatosis type 1. No pathogenic variants were identified through molecular genetic analysis of NF1, SPRED1 and a multigene NS panel. Whole exome sequencing at age 23 identified a novel de novo likely pathogenic heterozygous variant in the LZTR1 gene denoted as c.743G>A (p.Gly248Glu). Serial MRIs have shown stable imaging findings and the patient is being followed clinically by cardiology, neurology and medical genetics.
CONCLUSIONS
We identified a novel mutation in the LZTR1 gene, not previously reported in association with NS. This report provides additional evidence to support for the assessment of schwannomatosis in patients with LZTR1-NS and may have overlap with Neurofibromatosis type 1.
Topics: Adult; Female; Humans; Molecular Biology; Mutation; Neurilemmoma; Neurofibromatoses; Neurofibromatosis 1; Noonan Syndrome; Skin Neoplasms; Transcription Factors; Young Adult
PubMed: 35840934
DOI: 10.1186/s12920-022-01304-x -
AJR. American Journal of Roentgenology Jun 2013Schwannomas are typically benign tumors that occur sporadically, in neurofibromatosis type 2 (NF2), or in an entity called "schwannomatosis." Schwannomatosis patients... (Review)
Review
OBJECTIVE
Schwannomas are typically benign tumors that occur sporadically, in neurofibromatosis type 2 (NF2), or in an entity called "schwannomatosis." Schwannomatosis patients develop multiple schwannomas without involvement of the vestibular apparatus. Geneticists, neurologists, and pathologists have recognized that schwannomatosis is distinct from NF2, but schwannomatosis remains unfamiliar to many radiologists. This article reviews the current medical literature, highlighting the similarities and differences between the schwannomatosis and NF2 phenotypes, genotypes, clinical manifestations, management considerations, and imaging findings.
CONCLUSION
Imaging plays a critical role in diagnosing schwannomatosis, and a basic understanding of this syndrome is of interest to diagnostic radiologists. Moreover, it is imperative that radiologists be able to differentiate schwannomatosis from NF2 on imaging because there are significant differences in the management of these two diseases and clinical outcomes for affected patients.
Topics: Diagnosis, Differential; Diagnostic Imaging; Humans; Neurilemmoma; Neurofibromatoses; Neurofibromatosis 2; Phenotype; Skin Neoplasms
PubMed: 23701098
DOI: 10.2214/AJR.12.8577