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 JovemRESUMO
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/genéticaRESUMO
Part 1 of this guideline addressed the differential diagnosis of the neurofibromatoses (NF): neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2) and schwannomatosis (SCH). NF shares some features such as the genetic origin of the neural tumors and cutaneous manifestations, and affects nearly 80 thousand Brazilians. Increasing scientific knowledge on NF has allowed better clinical management and reduced rate of complications and morbidity, resulting in higher quality of life for NF patients. Most medical doctors are able to perform NF diagnosis, but the wide range of clinical manifestations and the inability to predict the onset or severity of new features, consequences, or complications make NF management a real clinical challenge, requiring the support of different specialists for proper treatment and genetic counseling, especially in NF2 and SCH. The present text suggests guidelines for the clinical management of NF, with emphasis on NF1.
A primeira parte desta diretriz abordou o diagnóstico diferencial das neurofibromatoses (NF): neurofibromatose do tipo 1 (NF1), neurofibromatose do tipo 2 (NF2) e schwannomatose (SCH). As NF compartilham algumas características, como a origem neural dos tumores e sinais cutâneos, e afetam cerca de 80 mil brasileiros. O aumento do conhecimento científico sobre as NF tem permitido melhor manejo clínico e redução da morbidade das complicações, resultando em melhor qualidade de vida para os pacientes com NF. A maioria dos médicos é capaz de realizar o diagnóstico das NF, mas a variedade de manifestações clínicas e a dificuldade de se prever o surgimento e a gravidade de complicações, torna o manejo da NF um desafio para o clínico e envolve diferentes especialistas para o tratamento adequado e aconselhamento genético, especialmente a NF2 e a SCH. O presente texto sugere algumas orientações para o acompanhamento dos portadores de NF, com ênfase na NF1.
Assuntos
Humanos , Neurilemoma/terapia , Neurofibromatoses/terapia , Neurofibromatose 1/terapia , /terapia , Neoplasias Cutâneas/terapia , Gerenciamento Clínico , Neurilemoma/complicações , Neurilemoma/patologia , Neurofibromatoses/complicações , Neurofibromatoses/patologia , Neurofibromatose 1/complicações , Neurofibromatose 1/patologia , /complicações , /patologia , Glioma do Nervo Óptico/patologia , Glioma do Nervo Óptico/terapia , Fatores de Risco , Neoplasias Cutâneas/complicações , Neoplasias Cutâneas/patologiaRESUMO
Neurofibromatoses (NF) are a group of genetic multiple tumor growing predisposition diseases: neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2) and schwannomatosis (SCH), which have in common the neural origin of tumors and cutaneous signs. They affect nearly 80 thousand of Brazilians. In recent years, the increased scientific knowledge on NF has allowed better clinical management and reduced complication morbidity, resulting in higher quality of life for NF patients. In most cases, neurology, psychiatry, dermatology, clinical geneticists, oncology and internal medicine specialists are able to make the differential diagnosis between NF and other diseases and to identify major NF complications. Nevertheless, due to its great variability in phenotype expression, progressive course, multiple organs involvement and unpredictable natural evolution, NF often requires the support of neurofibromatoses specialists for proper treatment and genetic counseling. This Part 1 offers step-by-step guidelines for NF differential diagnosis. Part 2 will present the NF clinical management.
Neurofibromatoses (NF) constituem um grupo de doenças genéticas com predisposição ao crescimento de múltiplos tumores: tipo 1 (NF1), tipo 2 (NF2) e schwannomatose (SCH). Estas doenças têm em comum a origem neural dos tumores e os sinais cutâneos. Afetam cerca de 80 mil brasileiros. O maior conhecimento científico sobre as NF tem permitido melhor manejo clínico, redução da morbidade das complicações e melhor qualidade de vida. Na maioria dos casos, os especialistas em neurologia, dermatologia, genética clínica, oncologia e medicina interna estão capacitados a realizar o diagnóstico diferencial e identificar suas principais complicações. Devido à sua variabilidade fenotípica, curso progressivo, multiplicidade de órgãos acometidos e evolução imprevisível, as NF frequentemente necessitam de especialistas em NF para o acompanhamento. A Parte 1 deste texto oferece orientações para o diagnóstico de cada tipo de NF e discute os diagnósticos diferenciais com outras doenças. A Parte 2 oferecerá orientações em relação ao manejo clínico das NF.
Assuntos
Humanos , Neurilemoma/patologia , Neurofibromatoses/patologia , Neurofibromatose 1/patologia , /patologia , Neoplasias Cutâneas/patologia , Diagnóstico Diferencial , Testes Genéticos , Gradação de Tumores , Fatores de RiscoRESUMO
Although there is an ongoing debate about the ideal management of vestibular schwannomas, radiosurgical treatment has become popular in the past decade with good to excellent results reported. Given the young age at presentation, the bilateral nature of vestibular schwanomas, the presence of other associated central nervous system tumors, patients with neurofibromatosis Type 2 (NF2) are very complex and present significant management challenges. Although results do not seem to be as good as for patients with sporadic unilateral tumors, stereotactic radiosurgery has proven a safe, attractive, and effective management modality for NF2 vestibular schwannomas. An overview of the impact stereotactic radiosurgery has had in the management of these tumors is discussed.
RESUMO
Los schwannomas vestibulares son tumores benignos que habitualmente se presentan en forma esporádica y unilateral, pero pueden aparecer de manera bilateral en el contexto de una neurofibromatosis tipo 2 (NF2). En aquellos asociados a NF2 se han identificado mutaciones del gen NF2 que codifica para merlina, una proteína citoplasmática que se localiza primariamente en protrusiones celulares ricas en actina, y en sitios de contacto entre células y matriz extracelular. La evidencia sugiere que merlina ejerce un rol como proteína supresora de tumores ya que regula la cascada de activación de diversos tipos de receptores de factores de crecimiento celular De esta manera, el déficit de merlina provoca un patrón de proliferación celular aumentado, alteraciones del citoesqueleto, apoptosis disminuida, y un incremento de la adhesión a la matriz extracelular. Se han desarrollado terapias clínicas para la NF2 con anticuerpos monoclonales e inhibidores dirigidos contra distintas moléculas involucradas en las cascadas de señalización celular moduladas por merlina. En este artículo se revisan y discuten los mecanismos celulares dependientes de merlina y los diversos estudios clínicos y experimentales que se han probado en pacientes con NF2.
Vestibular schwannomas are benign tumors that may occur bilaterally in the context of neurofibromatosis type 2 (NF2). A mutation in the NF2 gene coding for merlin protein has been identified in those cases associated with NF2. Merlin is a cytoplasmic protein localized in actin rich cell protrusions, and near contact sites between cells and extracellular matrix. The evidence suggests that merlin plays a role as tumor suppressor protein, regulating the activation cascade of different types of receptors for cell growth factors. Thus, merlin deficiency causes a pattern of increased cell proliferation, cytoskeletal alterations, decreased apoptosis and increased cell adhesion to the extracellular matrix. Several clinical therapies have been developed for NF2 patients including monoclonal antibodies and inhibitors directed against different molecules involved in cell signaling cascades modulated by merlin. In this article we review and discuss cellular mechanisms dependent of merlin and some clinical and experimental studies that have been studied in patients with NF2.
Assuntos
Humanos , Neuroma Acústico/terapia , Neurofibromatose 2/terapia , Neurofibromina 2/deficiência , Neuroma Acústico/complicações , Neuroma Acústico/tratamento farmacológico , Neurofibromatose 2/complicações , Neurofibromatose 2/tratamento farmacológico , Neoplasias/etiologiaRESUMO
Los tumores cerebrales son infrecuentes durante el embarazo. Los neurinomas del acústico pueden ser sintomáticos por primera vez durante la gestación y representan el 6-8 por ciento de las neoplasias intracraneales. El objetivo de esta comunicación es presentar el caso de una primigesta adolescente que presentó sintomatología neurológica de afectación del VIII par y de fosa posterior, característica de la neurofibromatosis tipo 2.
Brain tumors are infrequent during pregnancy. Neurinomas of auditive nerve can get to be symptomatic during gestation, representing 6-8 percent of the intracranial neoplasias. The objective is to report a case of a pregnant adolescent who present a neurological symptoms of VIII pair affectation and posterior cranial fossa, characteristic of the neurofibromatosis type 2.
Assuntos
Humanos , Adolescente , Feminino , Gravidez , Complicações Neoplásicas na Gravidez/diagnóstico , Neoplasias Encefálicas/diagnóstico , /diagnóstico , Neuroma Acústico/diagnósticoRESUMO
O implante auditivo de tronco cerebral foi desenvolvido para restaurar alguma audição útil em pacientes que apresentam ausência de nervo coclear bilateralmente. OBJETIVOS: Discutir a indicação, cirurgia e resultados em quatro pacientes submetidos à cirurgia para colocação de implante auditivo de tronco cerebral. CASUÍSTICA E MÉTODOS: Quatro pacientes com diagnóstico de schwannomas vestibulares bilaterais foram submetidos à cirurgia para colocação de Implante Auditivo de Tronco Cerebral durante o mesmo ato cirúrgico utilizado para a exérese de um dos tumores. Aspectos clínicos e técnicos e as referências anatômicas da cirurgia e os resultados auditivos foram analisados. RESULTADOS: Em todos os casos foram identificados as referências anatômicas ao forame de Luschka. As complicações cirúrgicas se resumiram à fístula liquórica em dois pacientes. Os eletrodos foram bem posicionados e a sensação auditiva foi suficiente para reconhecimento de sons e auxílio à leitura labial. CONCLUSÃO: Os resultados auditivos de nossos pacientes abrem uma perspectiva importante aos pacientes com surdez profunda bilateral sem integridade anatômica das vias auditivas centrais.
Auditory Brainstem Implants were developed to partially restore the hearing capabilities of patients without cochlear nerves bilaterally. AIM: this paper aims to discuss the clinical and surgical findings of four ABI patients. MATERIALS AND METHOD: four patients diagnosed with bilateral schwannomas received auditory brainstem implants (ABI) and had one of their tumors resected in the same surgical procedure. Clinical aspects, surgical technique, anatomic landmarks, and outcomes were analyzed. RESULTS: the anatomic landmarks were identified in all four patients in relation to the foramina of Luschka. Two patients had CSF leaks. The electrodes were well positioned and hearing sensation was good enough to allow for sound recognition and assist patients perform lip reading. CONCLUSION: the outcomes observed in our patients were quite encouraging and offer great perspectives for those suffering from deep bilateral deafness and impaired central auditory pathways.