RESUMEN

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.

Asunto(s)

ADN/genética , Oftalmopatías/etiología , Genes de la Neurofibromatosis 2/fisiología , Mutación , Neurofibromatosis 2/diagnóstico , Retina/patología , Tomografía de Coherencia Óptica/métodos , Adolescente , Adulto , Análisis Mutacional de ADN , Oftalmopatías/diagnóstico , Oftalmopatías/metabolismo , Femenino , Pruebas Genéticas , Humanos , Masculino , Persona de Mediana Edad , Neurofibromatosis 2/complicaciones , Neurofibromatosis 2/genética , Fenotipo , Retina/metabolismo , Agudeza Visual , Adulto Joven

RESUMEN

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.

Asunto(s)

Heterocigoto , Neurofibromatosis 1 , Neurofibromatosis 2 , Fenotipo , Adolescente , Brasil/epidemiología , Niño , Femenino , Humanos , Masculino , Reacción en Cadena de la Polimerasa Multiplex , Neurofibromatosis 1/epidemiología , Neurofibromatosis 1/genética , Neurofibromatosis 2/epidemiología , Neurofibromatosis 2/genética

RESUMEN

BACKGROUND/AIM: Individuals with type 2 Neurofibromatosis are predisposed for the appearance of schwannomas. In the present study we analyzed the loss of heterozygosity and mutations in the NF2 gene in patients with sporadic Schwannoma without Neurofibromatosis type 2. MATERIALS AND METHODS: We analyzed 39 patients with sporadic spinal schwannoma. We quantified the number of alleles by FISH and sequenced the NF2 gene. RESULTS: We identified 16/39 patients with point mutations and/or LOHs in the tumor samples analyzed. The LOHs were found in 7/39 patients. Two homozygous mutations were detected in 4/39 tumors, and the presence of the mutation in heterozygosis was revealed in 3/39 patients. In two tumors, we detected the loss of one allele of the NF2 gene, with no mutation. CONCLUSION: The genetic alterations observed in the NF2 gene indicated that spinal schwannomas are associated with genetic alterations also found in other schwannomas and type 2 Neurofibromatosis, which reinforces the etiological role of this gene.

Asunto(s)

Genes de la Neurofibromatosis 2 , Pérdida de Heterocigocidad , Neurilemoma/epidemiología , Neurilemoma/genética , Neoplasias de la Columna Vertebral/epidemiología , Neoplasias de la Columna Vertebral/genética , Adulto , Brasil/epidemiología , Femenino , Frecuencia de los Genes , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Neurofibromatosis 2/epidemiología , Neurofibromatosis 2/genética

RESUMEN

Neurofibromatosis 2 is a familial syndrome characterized by the development of schwannomas, meningiomas and ependymomas. Most of them are benign however, their location in the nervous system has harmful effects on important cranial and spinal structures. These tumors are developed as the outcome of NF2 gene (22q12) inactivation. The NF2 protein, merlin or schwannomin belongs to the Ezrin, Radixin, Moesin (ERM) family involved in the cytoskeletal network and has a tumor suppressor function. Inactivating mutations occur as "de novo" (more frequently) or as inherited, and most of them are frameshift or nonsense. Our aim is to study NF2 gene alterations in Argentine patients and relate them to clinical features. 10 families and 29 single patients were analyzed for: 1) at-risk haplotype by STR-segregation analysis and 2) NF2 gene mutations by SSCP/heteroduplex/sequencing. The at-risk haplotype was uncovered in 8 families and mutations were identified in 5 patients. The molecular data are in full agreement with the clinical features supporting previous reports. The obtained results were important for the detection of mutation-carrying relatives and exclusion of other individuals from risk.

Asunto(s)

Neurofibromatosis 2/genética , Neurofibromina 2/genética , Adolescente , Adulto , Anciano , Argentina , Niño , Ependimoma/genética , Ependimoma/fisiopatología , Femenino , Haplotipos , Humanos , Masculino , Neoplasias Meníngeas/genética , Neoplasias Meníngeas/fisiopatología , Meningioma/genética , Meningioma/fisiopatología , Persona de Mediana Edad , Técnicas de Diagnóstico Molecular , Mutación , Neurofibromatosis 2/fisiopatología , Linaje , Adulto Joven

RESUMEN

Atualmente neurofibromatose faz parte de um grupo de doenças heterogêneas. A neurofibromatose NF-1 é a mais comum das facomatoses ocorrendo em aproximadamente 90 por cento dos casos. A anomalia anastomótica mais comum entre as áreas supridas pela artéria carótida e a artéria vertebral é uma artéria de grosso calibre que se localiza ao nível do seio cavernoso. Esta comunicaçäo vascular na opiniäo de muitos pesquisadores é a primitiva artéria trigeminal. É apresentada uma paciente com neurofibromatose tipo NF-1 periférico que apresentou uma cefaléia explosiva seguida de agitaçäo psicomotora. A punçäo lombar revelou-se hemorrágica e o estudo angiográfico revelou um aneurisma de artéria carótida interna direita e uma larga comunicaçäo entre os sistemas carótido-basilar ao nível do seio cavernoso

Asunto(s)

Humanos , Femenino , Adulto , Arteria Carótida Interna/anomalías , Arteria Carótida Interna , Genes de Neurofibromatosis 1/genética , Genes de la Neurofibromatosis 2/genética , Cefalea/etiología , Aneurisma Intracraneal/genética , Neurofibromatosis 1/genética , Neurofibromatosis 2/genética , Seno Cavernoso