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1.
Neurology ; 93(10): e964-e967, 2019 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-31363058

RESUMO

OBJECTIVE: To educate providers to recognize the clinical presentation of neurofibromatosis 2 (NF2) in young children. METHODS: A retrospective analysis of 22 children with NF2 from 4 tertiary care NF referral centers was performed. Age and signs/symptoms at initial presentation, age at NF2 diagnosis, family history, clinical/radiographic NF2 features, NF2 genetic testing results, and treatments were assessed. RESULTS: The average age at initial clinical presentation was 48.1 months, while the average age at NF2 diagnosis was 77.2 months. Children with a family history of NF2 (23%) tended to present earlier (mean 39.2 vs 50.7 months) and have shorter times to NF2 diagnosis (mean 1.6 vs 37.2 months). Vision/eye complaints (n = 9; 41%) were the most commonly reported presenting signs/symptoms. Meningiomas (n = 7; 32%) and ocular abnormalities (n = 5; 23%) were the most frequently identified initial NF2 features. Vestibular (n = 17; 77%) and peripheral (n = 15; 68%) schwannomas were the most common abnormalities encountered over the study period. Seventeen (77%) children required treatment, most frequently for vestibular schwannomas (n = 9; 41%), peripheral schwannomas (n = 7; 32%), and meningiomas (n = 7; 32%). Genetic testing was available for 13 individuals, in whom nonsense mutations were most commonly identified (n = 7; 54%). CONCLUSIONS: Although uncommon, a substantial number of individuals with NF2 come to medical attention in early childhood. The finding of meningioma or characteristic ocular abnormalities (retinal hamartomas and epiretinal membranes) in young children should raise clinical suspicion for NF2 and prompt immediate referral to appropriate specialists for diagnosis and management.


Assuntos
Neurofibromatose 2/diagnóstico , Neurofibromatose 2/genética , Neurofibromina 2/genética , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos
2.
Oncogene ; 38(36): 6370-6381, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31312020

RESUMO

Inactivation of the tumor suppressor NF2/merlin underlies neurofibromatosis type 2 (NF2) and some sporadic tumors. Previous studies have established that merlin mediates contact inhibition of proliferation; however, the exact mechanisms remain obscure and multiple pathways have been implicated. We have previously reported that merlin inhibits Ras and Rac activity during contact inhibition, but how merlin regulates Ras activity has remained elusive. Here we demonstrate that merlin can directly interact with both Ras and p120RasGAP (also named RasGAP). While merlin does not increase the catalytic activity of RasGAP, the interactions with Ras and RasGAP may fine-tune Ras signaling. In vivo, loss of RasGAP in Schwann cells, unlike the loss of merlin, failed to promote tumorigenic growth in an orthotopic model. Therefore, modulation of Ras signaling through RasGAP likely contributes to, but is not sufficient to account for, merlin's tumor suppressor activity. Our study provides new insight into the mechanisms of merlin-dependent Ras regulation and may have additional implications for merlin-dependent regulation of other small GTPases.


Assuntos
Neurofibromina 2/fisiologia , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Proteínas Ativadoras de ras GTPase/metabolismo , Animais , Células Cultivadas , Proteínas Ativadoras de GTPase/metabolismo , Genes Supressores de Tumor , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Neurofibromatose 2/genética , Neurofibromatose 2/metabolismo , Neurofibromina 2/metabolismo , Ligação Proteica , Transdução de Sinais/genética
3.
Dev Cell ; 49(3): 425-443.e9, 2019 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-31063758

RESUMO

Merlin/NF2 is a bona fide tumor suppressor whose mutations underlie inherited tumor syndrome neurofibromatosis type 2 (NF2), as well as various sporadic cancers including kidney cancer. Multiple Merlin/NF2 effector pathways including the Hippo-YAP/TAZ pathway have been identified. However, the molecular mechanisms underpinning the growth and survival of NF2-mutant tumors remain poorly understood. Using an inducible orthotopic kidney tumor model, we demonstrate that YAP/TAZ silencing is sufficient to induce regression of pre-established NF2-deficient tumors. Mechanistically, YAP/TAZ depletion diminishes glycolysis-dependent growth and increases mitochondrial respiration and reactive oxygen species (ROS) buildup, resulting in oxidative-stress-induced cell death when challenged by nutrient stress. Furthermore, we identify lysosome-mediated cAMP-PKA/EPAC-dependent activation of RAF-MEK-ERK signaling as a resistance mechanism to YAP/TAZ inhibition. Finally, unbiased analysis of TCGA primary kidney tumor transcriptomes confirms a positive correlation of a YAP/TAZ signature with glycolysis and inverse correlations with oxidative phosphorylation and lysosomal gene expression, supporting the clinical relevance of our findings.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Carcinoma de Células Renais/metabolismo , Neoplasias Renais/metabolismo , Neurofibromina 2/deficiência , Fatores de Transcrição/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Glicólise , Xenoenxertos , Humanos , Neoplasias Renais/genética , Neoplasias Renais/patologia , Sistema de Sinalização das MAP Quinases , Camundongos , Camundongos SCID , Neurofibromatose 2/genética , Neurofibromatose 2/metabolismo , Neurofibromatose 2/patologia , Neurofibromina 2/genética , Neurofibromina 2/metabolismo , Fosforilação Oxidativa , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/genética
4.
Graefes Arch Clin Exp Ophthalmol ; 257(7): 1453-1458, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31089872

RESUMO

PURPOSE: To evaluate ophthalmological and molecular findings in eight patients with a clinical diagnosis of neurofibromatosis type 2 (NF2). New pathological mutations are described and variability in the ophthalmic phenotype and NF2 allelic heterogeneity are discussed. METHODS: Eye examination was performed in eight NF2 patients, and it included the measurement of the visual acuity, biomicroscopy, dilated fundus examination, color fundus photography, infrared photography, and spectral domain optical coherence tomography (SD-OCT). Molecular analysis was performed with whole-exome sequencing using DNA derived from peripheral blood mononuclear cells from each individual. RESULTS: Ophthalmological features were present in all patients, ranging from subtle retinal alterations identified only using SD-OCT to severe ocular damage present at birth. Six mutations were observed: two patients with stop codon mutation as shown on table 1 and result section, three patients with frameshift mutation as shown on table 1 and result section. Three novel mutations were found among them. CONCLUSIONS: It is a descriptive study of a rare disease, with poor previous literature. Clinical and genetic data are shown, reviving the need to further studies to clarify the genotype-phenotype correlations in NF2.


Assuntos
DNA/genética , Oftalmopatias/etiologia , Genes da Neurofibromatose 2/fisiologia , Mutação , Neurofibromatose 2/diagnóstico , Retina/patologia , Tomografia de Coerência Óptica/métodos , Adolescente , Adulto , Análise Mutacional de DNA , Oftalmopatias/diagnóstico , Oftalmopatias/metabolismo , Feminino , Testes Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Neurofibromatose 2/complicações , Neurofibromatose 2/genética , Fenótipo , Retina/metabolismo , Acuidade Visual , Adulto Jovem
5.
Otol Neurotol ; 40(2): e150-e159, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30624408

RESUMO

HYPOTHESIS: We hypothesize that genomic variants including deletions, insertions, inversions, and tandem duplications beyond the changes in tumor suppressor NF2 gene affect gene expression of tumor-specific pathways in vestibular schwannomas (VS) patients with Neurofibromatosis type 2 (NF2), thus contributing to their clinical behavior. BACKGROUND: Genomic variation could reconfigure transcription in NF2 transformation process. Therefore, genome-wide high-resolution characterization of structural variants (SV) landscapes in NF2 tumors can expand our understanding of the genes regulating the clinical phenotypes in NF2-associated VS. METHODS: We performed whole-genome haplotype-specific structural variation analysis using synthetic linked reads generated through microfluidics-based barcoding of high molecular weight DNA followed by high-coverage Illumina paired-end whole-genome sequencing from 10 patients' tumors of different growth rates and their matching blood samples. RESULTS: NF2 tumor-specific deletions and large SVs were detected and can be classified based on their association with tumor growth rates. Through detailed annotation of these mutations, we uncover common alleles affected by these deletions and large SVs that can be associated with signaling pathways implicated in cell proliferation and tumorigenesis. CONCLUSION: The genomic variation landscape of NF2-related VS was investigated through whole-genome linked-read sequencing. Large SVs, in addition to deletions, were identified and may serve as modulators of clinical behavior.


Assuntos
Neurofibromatose 2/genética , Neuroma Acústico/genética , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Mutação
6.
Nat Protoc ; 14(2): 541-555, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30617350

RESUMO

Neurofibromatosis type II (NF2) is a disease that lacks effective therapies. NF2 is characterized by bilateral vestibular schwannomas (VSs) that cause progressive and debilitating hearing loss, leading to social isolation and increased rates of depression. A major limitation in NF2 basic and translational research is the lack of animal models that allow the full spectrum of research into the biology and molecular mechanisms of NF2 tumor progression, as well as the effects on neurological function. In this protocol, we describe how to inject schwannoma cells into the mouse brain cerebellopontine angle (CPA) region. We also describe how to apply state-of-the-art intravital imaging and hearing assessment techniques to study tumor growth and hearing loss. In addition, ataxia, angiogenesis, and tumor-stroma interaction assays can be applied, and the model can be used to test the efficacy of novel therapeutic approaches. By studying the disease from every angle, this model offers the potential to unravel the basic biological underpinnings of NF2 and to develop novel therapeutics to control this devastating disease. Our protocol can be adapted to study other diseases within the CPA, including meningiomas, lipomas, vascular malformations, hemangiomas, epidermoid cysts, cerebellar astrocytomas, and metastatic lesions. The entire surgical procedure takes ~45 min per mouse and allows for subsequent longitudinal imaging, as well as neurological and hearing assessment, for up to 2 months.


Assuntos
Ângulo Cerebelopontino/patologia , Diagnóstico por Imagem/métodos , Modelos Animais de Doenças , Perda Auditiva/patologia , Neurofibromatose 2/patologia , Neuroma Acústico/patologia , Animais , Linhagem Celular Tumoral , Ângulo Cerebelopontino/metabolismo , Ângulo Cerebelopontino/cirurgia , Expressão Gênica , Genes Reporter , Audição/fisiologia , Perda Auditiva/genética , Perda Auditiva/fisiopatologia , Testes Auditivos , Humanos , Injeções Intraventriculares , Luciferases/genética , Luciferases/metabolismo , Camundongos , Camundongos Knockout , Neurofibromatose 2/genética , Neurofibromatose 2/fisiopatologia , Neurofibromina 2/deficiência , Neurofibromina 2/genética , Neuroma Acústico/genética , Neuroma Acústico/fisiopatologia , Técnicas Estereotáxicas
7.
Fam Cancer ; 18(1): 97-100, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29761250

RESUMO

Neurofibromatosis type 2 (NF2) is associated with the development of several types of benign nervous system tumours, while malignancies are rare. We report a 22-year-old man who presented with retroperitoneal and spinal high-grade sarcomas with epithelial features. Samples showed a mixed epithelioid and spindled cell content with little associated matrix and inconclusive immunochemistry. Genetic analysis of a schwannoma and matched blood samples demonstrated a constitutional de novo substitution at the splice donor site of intron 8 of the NF2 gene and aa acquired large deletion of the entire NF2 gene as a second hit, with some loss of SMARCB1. The sarcoma also showed evidence of loss of SMARCB1 and NF2 with loss of INI1 staining. Unfortunately the mass was unresectable and the patient died 6 months after diagnosis. This malignancy was most consistent with SMARCB1-deficient epithelioid malignant peripheral nerve sheath tumour, although a significant differential was proximal-type epithelial sarcoma. Each differential has previously been reported only once with NF2. This demonstrates an extremely rare potential complication of the condition.


Assuntos
Neurofibromatose 2/complicações , Neoplasias Retroperitoneais/diagnóstico , Sarcoma/diagnóstico , Neoplasias da Coluna Vertebral/diagnóstico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Diagnóstico Tardio , Diagnóstico Diferencial , Doxorrubicina/uso terapêutico , Evolução Fatal , Humanos , Masculino , Gradação de Tumores , Neurofibromatose 2/genética , Neurofibromina 2/genética , Cuidados Paliativos/métodos , Neoplasias Retroperitoneais/tratamento farmacológico , Neoplasias Retroperitoneais/genética , Neoplasias Retroperitoneais/patologia , Proteína SMARCB1/genética , Sarcoma/tratamento farmacológico , Sarcoma/genética , Sarcoma/patologia , Sorafenibe/uso terapêutico , Neoplasias da Coluna Vertebral/tratamento farmacológico , Neoplasias da Coluna Vertebral/genética , Neoplasias da Coluna Vertebral/patologia , Adulto Jovem
8.
Hum Mol Genet ; 28(4): 572-583, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30335132

RESUMO

Schwannomas are common, highly morbid and medically untreatable tumors that can arise in patients with germ line as well as somatic mutations in neurofibromatosis type 2 (NF2). These mutations most commonly result in the loss of function of the NF2-encoded protein, Merlin. Little is known about how Merlin functions endogenously as a tumor suppressor and how its loss leads to oncogenic transformation in Schwann cells (SCs). Here, we identify nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-inducing kinase (NIK) as a potential drug target driving NF-κB signaling and Merlin-deficient schwannoma genesis. Using a genomic approach to profile aberrant tumor signaling pathways, we describe multiple upregulated NF-κB signaling elements in human and murine schwannomas, leading us to identify a caspase-cleaved, proteasome-resistant NIK kinase domain fragment that amplifies pathogenic NF-κB signaling. Lentiviral-mediated transduction of this NIK fragment into normal SCs promotes proliferation, survival, and adhesion while inducing schwannoma formation in a novel in vivo orthotopic transplant model. Furthermore, we describe an NF-κB-potentiated hepatocyte growth factor (HGF) to MET proto-oncogene receptor tyrosine kinase (c-Met) autocrine feed-forward loop promoting SC proliferation. These innovative studies identify a novel signaling axis underlying schwannoma formation, revealing new and potentially druggable schwannoma vulnerabilities with future therapeutic potential.


Assuntos
Neurilemoma/genética , Neurofibromatose 2/genética , Neurofibromina 2/genética , Proteínas Serina-Treonina Quinases/genética , Animais , Comunicação Autócrina/genética , Carcinogênese/genética , Caspase 1/genética , Proliferação de Células/genética , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica , Fator de Crescimento de Hepatócito/genética , Humanos , Camundongos , Terapia de Alvo Molecular , NF-kappa B/genética , Neurilemoma/complicações , Neurilemoma/tratamento farmacológico , Neurilemoma/patologia , Neurofibromatose 2/complicações , Neurofibromatose 2/tratamento farmacológico , Neurofibromatose 2/patologia , Complexo de Endopeptidases do Proteassoma/genética , Proteínas Proto-Oncogênicas c-met/genética , Células de Schwann , Transdução de Sinais/genética
9.
Laryngoscope ; 129(4): 974-980, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30456886

RESUMO

OBJECTIVES/HYPOTHESIS: This study set out to describe the progression of hearing loss in patients with neurofibromatosis type 2 (NF2), treated in a quaternary multidisciplinary clinic. It also aimed to compare hearing loss across patients grouped according to a known genetic severity score to explore its utility for prognostication. STUDY DESIGN: Retrospective cohort study. METHODS: We conducted a study of 147 patients with confirmed NF2 diagnosis for a mean observational period of 10 years. Pure-tone average (PTA), optimum discriminations scores (ODS), and genotype data were collected. Patients were classified according to hearing class (American Academy of Otolaryngology), their candidacy for auditory implantation (UK National NF2 consensus) and grouped by genetic severity as: 1 = tissue mosaic, 2A = mild classic, 2B = moderate classic, and 3 = severe. Survival analysis investigated the effect of genetic severity on the age of loss of serviceable hearing. RESULTS: Genetic severity was a significant predictor of hearing outcomes such as ODS, hearing classification, and maximum annual PTA deterioration. Although the overall median age of loss of serviceable hearing was 78 years, there was significant variation according to the genetic severity; the median for severe patients was 32 years compared to a median of 80 for tissue mosaic patients. CONCLUSIONS: This is the first description of long-term hearing outcomes in a clinical setting across a large heterogeneous cohort of patients with NF2. The results highlight the potential importance and benefit of considering the genetic severity score of patients when undertaking treatment decisions, as well as planning future natural history studies. LEVEL OF EVIDENCE: 2c Laryngoscope, 129:974-980, 2019.


Assuntos
Perda Auditiva/etiologia , Neurofibromatose 2/complicações , Neurofibromatose 2/genética , Adulto , Estudos de Coortes , Progressão da Doença , Seguimentos , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Índice de Gravidade de Doença
10.
Pediatr Blood Cancer ; 66(2): e27520, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30408304

RESUMO

Malignant peripheral nerve sheath tumor (MPNST) is a rare soft-tissue sarcoma with an unfavorable prognosis and limited therapeutic options. MPNSTs can be sporadic, but are often associated with neurofibromatosis (NF) 1 and usually arise from preexisting neurofibromas. MPNSTs in patients with NF2 have been reported in only exceedingly rare cases, and the mechanisms underlying transformation into an MPNST have not been fully elucidated. Here, we describe the clinicopathological and genomic features of a peripheral nerve sheath tumor (PNST), with a primary diagnosis of a neurofibroma, as it transforms into a high-grade MPNST in the context of NF2.


Assuntos
Neoplasias da Bainha Neural/patologia , Neurofibromatose 2/patologia , Sarcoma/patologia , Transformação Celular Neoplásica/patologia , Criança , Humanos , Masculino , Neoplasias da Bainha Neural/genética , Neurofibromatose 2/genética , Sarcoma/genética
13.
Hum Genet ; 137(6-7): 543-552, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30006736

RESUMO

Schwannomatosis and neurofibromatosis type 2 (NF2) are both characterized by the development of multiple schwannomas but represent different genetic entities. Whereas NF2 is caused by mutations of the NF2 gene, schwannomatosis is associated with germline mutations of SMARCB1 or LZTR1. Here, we studied 15 sporadic patients with multiple non-intradermal schwannomas, but lacking vestibular schwannomas and ophthalmological abnormalities, who fulfilled the clinical diagnostic criteria for schwannomatosis. None of them harboured germline NF2 or SMARCB1 mutations as determined by the analysis of blood samples but seven had germline LZTR1 variants predicted to be pathogenic. At least two independent schwannomas from each patient were subjected to NF2 mutation testing. In five of the 15 patients, identical somatic NF2 mutations were identified (33%). If only those patients without germline LZTR1 variants are considered (n = 8), three of them (37.5%) had mosaic NF2 as concluded from identical NF2 mutations identified in independent schwannomas from the same patient. These findings imply that a sizeable proportion of patients who fulfil the diagnostic criteria for schwannomatosis, are actually examples of mosaic NF2. Hence, the molecular characterization of tumours in patients with a clinical diagnosis of schwannomatosis is very important. Remarkably, two of the patients with germline LZTR1 variants also had identical NF2 mutations in independent schwannomas from each patient which renders differential diagnosis of LZTR1-associated schwannomatosis versus mosaic NF2 in these patients very difficult.


Assuntos
Genótipo , Mutação em Linhagem Germinativa , Neurilemoma/genética , Neurofibromatoses/genética , Neurofibromatose 2/genética , Neurofibrossarcoma/genética , Neoplasias Cutâneas/genética , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neurilemoma/patologia , Neurofibromatoses/patologia , Neurofibromatose 2/patologia , Neurofibrossarcoma/patologia , Proteína SMARCB1/genética , Neoplasias Cutâneas/patologia , Fatores de Transcrição/genética
14.
PLoS One ; 13(6): e0197350, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29897904

RESUMO

Neurofibromatosis 2 (NF2) is a rare tumor suppressor syndrome that manifests with multiple schwannomas and meningiomas. There are no effective drug therapies for these benign tumors and conventional therapies have limited efficacy. Various model systems have been created and several drug targets have been implicated in NF2-driven tumorigenesis based on known effects of the absence of merlin, the product of the NF2 gene. We tested priority compounds based on known biology with traditional dose-concentration studies in meningioma and schwann cell systems. Concurrently, we studied functional kinome and gene expression in these cells pre- and post-treatment to determine merlin deficient molecular phenotypes. Cell viability results showed that three agents (GSK2126458, Panobinostat, CUDC-907) had the greatest activity across schwannoma and meningioma cell systems, but merlin status did not significantly influence response. In vivo, drug effect was tumor specific with meningioma, but not schwannoma, showing response to GSK2126458 and Panobinostat. In culture, changes in both the transcriptome and kinome in response to treatment clustered predominantly based on tumor type. However, there were differences in both gene expression and functional kinome at baseline between meningioma and schwannoma cell systems that may form the basis for future selective therapies. This work has created an openly accessible resource (www.synapse.org/SynodosNF2) of fully characterized isogenic schwannoma and meningioma cell systems as well as a rich data source of kinome and transcriptome data from these assay systems before and after treatment that enables single and combination drug discovery based on molecular phenotype.


Assuntos
Neoplasias Meníngeas/genética , Neurilemoma/genética , Neurofibromatose 2/genética , Neurofibromina 2/genética , Animais , Carcinogênese/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Meníngeas/tratamento farmacológico , Neoplasias Meníngeas/patologia , Camundongos , Morfolinas/farmacologia , Neurilemoma/tratamento farmacológico , Neurilemoma/patologia , Neurofibromatose 2/tratamento farmacológico , Neurofibromatose 2/patologia , Panobinostat/farmacologia , Pirimidinas/farmacologia , Quinolinas/farmacologia , Sulfonamidas/farmacologia , Biologia de Sistemas , Transcriptoma/genética
15.
J Neurol Neurosurg Psychiatry ; 89(11): 1215-1219, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29909380

RESUMO

OBJECTIVES: Schwannomatosis is a dominantly inherited condition predisposing to schwannomas of mainly spinal and peripheral nerves with some diagnostic overlap with neurofibromatosis-2 (NF2), but the underlying epidemiology is poorly understood. We present the birth incidence and prevalence allowing for overlap with NF2. METHODS: Schwannomatosis and NF2 cases were ascertained from the Manchester region of England (population=4.8 million) and from across the UK. Point prevalence and birth incidence were calculated from regional birth statistics. Genetic analysis was also performed on NF2, LZTR1 and SMARCB1 on blood and tumour DNA samples when available. RESULTS: Regional prevalence for schwannomatosis and NF2 were 1 in 126 315 and 50 500, respectively, with calculated birth incidences of 1 in 68 956 and 1 in 27 956. Mosaic NF2 causes a substantial overlap with schwannomatosis resulting in the misdiagnosis of at least 9% of schwannomatosis cases. LZTR1-associated schwannomatosis also causes a small number of cases that are misdiagnosed with NF2 (1%-2%), due to the occurrence of a unilateral vestibular schwannoma. Patients with schwannomatosis had lower numbers of non-vestibular cranial schwannomas, but more peripheral and spinal nerve schwannomas with pain as a predominant presenting symptom. Life expectancy was significantly better in schwannomatosis (mean age at death 76.9) compared with NF2 (mean age at death 66.2; p=0.004). CONCLUSIONS: Within the highly ascertained North-West England population, schwannomatosis has less than half the birth incidence and prevalence of NF2.


Assuntos
Neurilemoma/epidemiologia , Neurilemoma/genética , Neurofibromatoses/epidemiologia , Neurofibromatoses/genética , Neurofibromina 2/genética , Proteína SMARCB1/genética , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/genética , Fatores de Transcrição/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Bases de Dados Factuais , Inglaterra/epidemiologia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Neurofibromatose 2/epidemiologia , Neurofibromatose 2/genética , Prevalência , Adulto Jovem
16.
Medicine (Baltimore) ; 97(23): e10894, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29879026

RESUMO

RATIONALE: Neurofibromatosis, including type 1 and type 2, is inherited dominant disease that causes serious consequences. The genetic mechanism of these diseases has been described, but germline mutation of checkpoint 2 kinase gene, together with other DNA repair related genes, has not been fully elucidated in the context of neurofibromatosis. PATIENT CONCERNS: In this article, we reported identical germline mutation of CHEK2 gene (p.R180C) in a 7-year-old Tibetan boy with NF1, and in a 12-year-old Chinese girl with NF2. DIAGNOSES: Neurofibromatosis 1 and 2 with CHECK2 gene germline mutation. INTERVENTIONS: Both patients underwent operation to obtain tumor tissue, and peripheral blood of their family was tested. OUTCOMES: Identical germline mutation of CHEK2 gene (p.R180C) was detected in both patients, and germline mutations of POLE, MUTYH and ATR were also detected. LESSONS: This is the first article to describe CHEK2 mutation in both NF1 and NF2. This article highlights a possible role of CHEK2, in association with other germline genetic mutations, in tumorigenesis of NF1 and NF2.


Assuntos
Quinase do Ponto de Checagem 2/genética , Mutação em Linhagem Germinativa/genética , Neurofibromatose 1/genética , Neurofibromatose 2/genética , Grupo com Ancestrais do Continente Asiático/genética , Criança , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino
17.
Dev Med Child Neurol ; 60(12): 1285-1288, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29781505

RESUMO

Unlike adult neurofibromatosis type 2 (NF2), which presents with symptoms related to bilateral vestibular schwannomas, children with NF2 most frequently present with ocular, dermatological, and neurological symptoms. Arteriopathy, a well-established feature in neurofibromatosis type 1, is not a widely recognized feature of NF2. Here we report three children with NF2 with cerebral arteriopathy and/or arterial ischaemic stroke. Bevacizumab, a vascular endothethial growth factor inhibitor, is an established treatment for rapidly growing vestibular schwannomas; however, it carries a risk of both ischaemic and haemorrhagic stroke. Thus, the role of screening and risk to benefit ratio of bevacizumab in NF2 merit further consideration. WHAT THIS PAPER ADDS: Children with neurofibromatosis type 2 (NF2) may be at increased risk of cerebral vasculopathy and arterial ischaemic stroke. Targeted magnetic resonance angiography should be performed in children with NF2 who are being considered for bevacizumab therapy.


Assuntos
Transtornos Cerebrovasculares/etiologia , Neurofibromatose 2/complicações , Adolescente , Transtornos Cerebrovasculares/diagnóstico por imagem , Criança , Pré-Escolar , Feminino , Humanos , Angiografia por Ressonância Magnética , Imagem por Ressonância Magnética , Masculino , Neurofibromatose 2/diagnóstico por imagem , Neurofibromatose 2/genética
18.
Expert Rev Mol Diagn ; 18(6): 577-586, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29685074

RESUMO

OBJECTIVES: Neurofibromatoses (type 1: NF1; type 2: NF2) are autosomal dominant tumor predisposition syndromes mostly caused by loss-of-function mutations in the tumor suppressor genes NF1 and NF2, respectively. Genotyping is important for correct diagnosis of these diseases. The authors aimed to characterize NF1 and NF2 variants in patients from Southern Brazil. METHODS: Ninety-three unrelated probands with NF1 and 7 unrelated probands with NF2 features were recruited from an Oncogenetics center in Southern Brazil. Two next generation sequencing panels were customized to identify point mutations: NF1 (NF1, RNF135, and SUZ12 genes) and NF2 (NF2 and SMARCB1 genes). Large rearrangements were assessed by Multiplex Ligation-dependent Probe Amplification. RESULTS: Sixty-eight heterozygous NF1 variants were identified in 75/93 probands (80%) and 3 heterozygous NF2 variants were identified in 3/7 probands (43%). In NF1, 59 (87%) variants were pathogenic (4 large rearrangements - 6%), 6 (9%) were likely pathogenic, 3 (4%) were variants of uncertain significance and 28 (41%) were novel. In NF2, all variants were pathogenic. No novel genotype-phenotype correlations were observed; however, previously described correlations were confirmed in our cohort. CONCLUSION: The clinical and molecular characterization of neurofibromatoses in different populations is very important to provide further insights into the pathogenesis of these diseases.


Assuntos
Heterozigoto , Neurofibromatose 1 , Neurofibromatose 2 , Fenótipo , Adolescente , Brasil/epidemiologia , Criança , Feminino , Humanos , Masculino , Reação em Cadeia da Polimerase Multiplex , Neurofibromatose 1/epidemiologia , Neurofibromatose 1/genética , Neurofibromatose 2/epidemiologia , Neurofibromatose 2/genética
19.
J Neurooncol ; 138(2): 417-424, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29492767

RESUMO

Surgical treatment of vestibular schwannoma (VS) in patients with neurofibromatosis type 2 (NF2) along with functional preservation of cranial nerves is challenging. The aim of this study was to analyze the outcomes of hearing and facial nerve function in patients with NF2 who underwent large-size VS (> 2 cm) surgery. From 2006 to 2016, one hundred and forty NF2 patients were included with 149 large-size VS resections using retrosigmoid approach. Hearing function was classified according to the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) criteria. Preoperative and one-year postoperative facial nerve function were both assessed using the House-Brackmann (H-B) grading scale. A multivariate logistic regression was performed to identify preoperative predictors for facial function outcomes. No operative death we noted. Total tumor removal was achieved in 82.6% of the operated VSs. The anatomical integrity of the facial nerve was preserved in 67.8% of surgeries. Good facial nerve function (H-B Grades I-III) was maintained in 49.6% of patients at 12 months after surgery. Tumor size larger than 3 cm and preoperative facial weakness related with worse outcome of facial nerve function (P < 0.001; for both). Hearing preservation surgeries were attempted in 31 ears. Class B or C hearing according to the AAO-HNS criteria was maintained in 7 ears (22.5%), and measurable hearing was maintained 11 ears (35.5%). It is challenging to maintain hearing and facial nerve function in NF2 patients with large VSs. Early surgical intervention is an appropriate choice to decrease the risk of neurological functions deficit.


Assuntos
Audição , Neurofibromatose 2/complicações , Neurofibromatose 2/cirurgia , Neuroma Acústico/complicações , Neuroma Acústico/cirurgia , Adolescente , Adulto , Criança , Nervo Facial/fisiopatologia , Feminino , Seguimentos , Testes Auditivos , Humanos , Masculino , Microcirurgia/métodos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Neurofibromatose 2/genética , Neurofibromatose 2/fisiopatologia , Neuroma Acústico/patologia , Neuroma Acústico/fisiopatologia , Procedimentos Neurocirúrgicos/métodos , Complicações Pós-Operatórias , Estudos Retrospectivos , Resultado do Tratamento , Carga Tumoral , Adulto Jovem
20.
Arch Dis Child ; 103(5): 463-469, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29535107

RESUMO

OBJECTIVE: Onset of symptoms in severe sporadic neurofibromatosis type 2 (NF2) is typically within childhood; however, there is poor awareness of presenting features in young children, potentially resulting in delayed diagnosis and poorer outcome. We have reviewed presentation of sporadic paediatric NF2 to raise awareness of early features, highlighting those requiring further investigation. DESIGN: Patients diagnosed with NF2 at age ≤16 and seen between 2012 and 2015 were notified via the British Paediatric Neurology Surveillance Unit or identified through the English NF2 service. RESULTS: Epidemiological data estimate that 1 in 110 611 births are affected with childhood-onset NF2. Notes of 32 patients with sporadic NF2 were reviewed. Of those presenting under the age of 5, 89% (17/19) had ocular, 74% (14/19) dermatological and 58% (11/19) neurological signs; in 84% (16/19) features were multisystemic. Sixty-six per cent (21/32) had ≥1 atypical feature, including cerebellar hypoplasia in three cases (9%) and focal cortical dysplasia in five out of seven seizure-related presentations. Five cases presented with a sometimes transient or intermittent cranial nerve mononeuropathy. The mean delay to diagnosis was 3.16 years; in eight cases (25%) this exceeded 6 years. Most significant delay occurred in mononeuropathy, ophthalmological and/or seizure presentations, with a mean delay of 3, 4.5 and 6 years, respectively. Eighty-four per cent (27/32) of cases needed intervention in childhood. CONCLUSIONS: All non-vestibular schwannoma NF2 presentations in childhood had significant diagnostic delay. We emphasise the importance of detailed assessment of skin and eyes in unusual presentations and propose an aide to prompt timely referral to specialist services.


Assuntos
Neurofibromatose 2/diagnóstico , Adolescente , Fatores Etários , Criança , Pré-Escolar , Diagnóstico Tardio , Inglaterra/epidemiologia , Oftalmopatias/epidemiologia , Oftalmopatias/etiologia , Feminino , Genes da Neurofibromatose 2 , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , Doenças do Sistema Nervoso/epidemiologia , Doenças do Sistema Nervoso/etiologia , Neurofibromatose 2/complicações , Neurofibromatose 2/epidemiologia , Neurofibromatose 2/genética , Vigilância da População , Dermatopatias/epidemiologia , Dermatopatias/etiologia
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