RESUMO
OBJECTIVE: To analyze the correlation between atypical neurofibromatosis type 1(NF1) microdeletion and fetal phenotype. METHODS: Fetal blood sampling was carried out for a woman bearing a fetus with talipes equinovarus. G-banded karyotyping and single nucleotide polymorphism array (SNP-array) were performed on the fetal blood sample. Fluorescence in situ hybridization (FISH) was used to confirm the result of SNP array analysis. FISH assay was also carried out on peripheral blood specimens from the parents to ascertain the origin of mutation. RESULTS: The karyotype of fetus was found to be 46, XY by G-banding analysis. However, a 3.132 Mb microdeletion was detected in chromosome region 17q11.2 by SNP array, which overlaped with the region of NF1 microdeletion syndrome. Analyzing of the specimens from the fetus and its parents with FISH has confirmed it to be a de novo deletion. CONCLUSION: Talipes equinovarus may be an abnormal sonographic feature of fetus with atypical NF1 microdeletion which can be accurately diagnosed with SNP array.
Assuntos
Anormalidades Craniofaciais/embriologia , Anormalidades Craniofaciais/genética , Deficiência Intelectual/embriologia , Deficiência Intelectual/genética , Deficiências da Aprendizagem/genética , Neurofibromatoses/embriologia , Neurofibromatoses/genética , Neurofibromatose 1/embriologia , Neurofibromatose 1/genética , Adulto , Bandeamento Cromossômico , Deleção Cromossômica , Cromossomos Humanos Par 17/genética , Anormalidades Craniofaciais/diagnóstico , Feminino , Deleção de Genes , Humanos , Deficiência Intelectual/diagnóstico , Cariotipagem , Deficiências da Aprendizagem/diagnóstico , Masculino , Neurofibromatoses/diagnóstico , Neurofibromatose 1/diagnóstico , Gravidez , Diagnóstico Pré-NatalRESUMO
Germline mutations in the RAS/ERK signaling pathway underlie several related developmental disorders collectively termed neuro-cardio-facial-cutaneous (NCFC) syndromes. NCFC patients manifest varying degrees of cognitive impairment, but the developmental basis of their brain abnormalities remains largely unknown. Neurofibromatosis type 1 (NF1), an NCFC syndrome, is caused by loss-of-function heterozygous mutations in the NF1 gene, which encodes neurofibromin, a RAS GTPase-activating protein. Here, we show that biallelic Nf1 inactivation promotes Erk-dependent, ectopic Olig2 expression specifically in transit-amplifying progenitors, leading to increased gliogenesis at the expense of neurogenesis in neonatal and adult subventricular zone (SVZ). Nf1-deficient brains exhibit enlarged corpus callosum, a structural defect linked to severe learning deficits in NF1 patients. Strikingly, these NF1-associated developmental defects are rescued by transient treatment with an MEK/ERK inhibitor during neonatal stages. This study reveals a critical role for Nf1 in maintaining postnatal SVZ-derived neurogenesis and identifies a potential therapeutic window for treating NF1-associated brain abnormalities.
Assuntos
Encéfalo/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Células-Tronco Neurais/patologia , Neurofibromatose 1/patologia , Neurofibromina 1/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Corpo Caloso/patologia , Humanos , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/metabolismo , Neurofibromatose 1/embriologia , Neurofibromatose 1/metabolismo , Neurofibromina 1/genética , Neuroglia/patologia , Fator de Transcrição 2 de OligodendrócitosRESUMO
BACKGROUND: The disorder neurofibromatosis type 1 (NF1) is caused by mutations in the NF1 gene, which influences the availability of activated Ras and the latter's control of cellular proliferation. Emphasis on this aspect of NF1 has focused attention on the tumor suppression function of NF1 and thereby displaced attention from the gene's role in initial normal tissue formation, maintenance, and repair. METHODS: Clinical and neuroimaging data systematically compiled over more than 30 years are analyzed to document the involvement of multiple organs and tissues, often with an embryonic origin. In addition, recent literature based on selective knockout mouse experiments is cited to corroborate embryonic dysplasia as an element of NF1 pathogenesis. RESULTS: Tissue dysplasia, both ab initio and as part of tissue maintenance and wound healing, is a key clinical and pathogenetic aspect of NF1 and thereby provides a rationale for differentiating the elements of NF1 into features, consequences, and complications. CONCLUSIONS: NF1 is a histogenesis control gene that also has properties that overlap with those of a tumor suppressor gene. Both its neoplastic and dysplastic manifestations become more amenable to understanding and treatment if they are differentiated at three levels--specifically, features, consequences and complications.
Assuntos
Embrião de Mamíferos/anormalidades , Desenvolvimento Embrionário/fisiologia , Desenvolvimento Fetal/fisiologia , Genes da Neurofibromatose 1 , Neurofibromatose 1/diagnóstico , Animais , Proliferação de Células , Modelos Animais de Doenças , Regulação da Expressão Gênica no Desenvolvimento , Inativação Gênica , Genes Supressores de Tumor , Humanos , Camundongos , Camundongos Knockout , Crista Neural/anormalidades , Neurofibromatose 1/embriologia , Neurofibromatose 1/genéticaRESUMO
Mosaicism constitutes a frequent complication of the genotype-phenotype relationship in genetic disease and is an important consideration for the estimation of transmission risk. Mosaicism has been identified in several hereditary cancer syndromes including retinoblastoma, familial adenomatous polyposis coli, von Hippel-Lindau disease and neurofibromatosis type 2. Recent data support the postulate that the frequency of mosaicism is increased in cancer predisposition syndromes characterised by high new mutation rates. Since the new mutation rate is very high in neurofibromatosis type 1 (NF1), mosaicism might reasonably be expected to be frequent among sporadic cases but this remains to be formally demonstrated. Here we summarise current knowledge of mosaicism in NF1, focusing on the types of mutations identified as well as their inferred developmental timing and representation in different cell types, and assess the potential impact of high frequency mosaicism on mutation screening in patients with apparent de novo NF1.
Assuntos
Mosaicismo , Neurofibromatose 1/genética , Epigênese Genética , Genes da Neurofibromatose 1 , Testes Genéticos , Humanos , Mutação , Síndromes Neoplásicas Hereditárias/genética , Neurofibromatose 1/embriologia , Neurofibromatose 1/patologiaAssuntos
Aberrações Cromossômicas , Genes Dominantes/genética , Haplótipos , Leiomiomatose/genética , Perda de Heterozigosidade , Dermatopatias Genéticas/genética , Neoplasias Cutâneas/genética , Alelos , Feminino , Humanos , Leiomiomatose/embriologia , Neurofibromatose 1/embriologia , Neurofibromatose 1/genética , Gravidez , Dermatopatias Genéticas/embriologia , Neoplasias Cutâneas/embriologiaRESUMO
Single case reports exist in the medical literature of patients with tonsillar ectopia, i.e., the Chiari I malformation and neurofibromatosis type 1. However, large series of patients with either of these entities have not been examined for the presence of both defects. We have retrospectively examined two large groups of pediatric patients: Group I, with the primary diagnosis of Chiari I malformation, who have undergone posterior fossa decompression for symptomatology; and Group II patients, who have been observed in our hospital's neurofibromatosis clinic for evaluation. Of 130 surgically addressed Chiari I malformations (Group I), we determined that 5.4% of these patients had the additional diagnosis of neurofibromatosis type 1. Of Group II patients (198) who underwent imaging of the brain, 8.6% were found to have a concomitant Chiari I malformation. These data suggest that Chiari I malformation and neurofibromatosis type 1 are not spurious findings but rather true associations. We hypothesize that the same early dysgenesis of mesoderm that is widely accepted as a culprit in the genesis of many Chiari I malformations is the same pathology affecting primitive development of tissues involved in many patients with neurofibromatosis type 1. Perhaps these data will aid in the determination of a genetic locus for the Chiari I malformation.
Assuntos
Malformação de Arnold-Chiari/complicações , Neurofibromatose 1/complicações , Adolescente , Adulto , Malformação de Arnold-Chiari/diagnóstico , Malformação de Arnold-Chiari/embriologia , Malformação de Arnold-Chiari/cirurgia , Criança , Pré-Escolar , Fossa Craniana Posterior/embriologia , Fossa Craniana Posterior/cirurgia , Descompressão Cirúrgica , Feminino , Humanos , Lactente , Masculino , Mesoderma/patologia , Neurofibromatose 1/diagnóstico , Neurofibromatose 1/embriologia , Exame Neurológico , Gravidez , Estudos RetrospectivosRESUMO
BACKGROUND: Segmental neurofibromatosis type 1 (NF-1) has the characteristic features of generalized NF-1 but is isolated to a particular segment of the body. Segmental NF-1 results from a postzygotic mutation during embryogenesis in the NF-1 gene on chromosome 17. The embryologic timing of the mutation and cell types affected predict the clinical phenotype. OBJECTIVE: We present a case of a 52-year-old woman with segmental neurofibromas isolated to the right cheek and neck. We review the recent literature on the genetic and cellular differences between the various clinical manifestations of segmental NF-1. METHODS: A MEDLINE search for cases of segmental neurofibromatosis was conducted. RESULTS: In patients with segmental NF-1 presenting as neurofibromas-only, the distribution follows a neural distribution in dermatomes because the genetic mutation appears to be limited to Schwann cells. In patients with pigmentary changes only, the NF-1 mutation has been shown to occur in fibroblasts and the distribution tends to follow the lines of Blaschko. CONCLUSION: Our patient's neurofibromas were secondary to a postzygotic mutation in the NF-1 gene of neural crest-derived cells. This mutation most likely occurred later in embryogenesis in cells that had already differentiated to Schwann cells and were committed to the dermatomal distribution of the right neck and cheek region (C2).
Assuntos
Neurofibromatose 1/diagnóstico , Fenótipo , Neoplasias Cutâneas/diagnóstico , Bochecha , Feminino , Humanos , Pessoa de Meia-Idade , Mosaicismo , Mutação , Pescoço , Neurofibromatose 1/embriologia , Neurofibromatose 1/genética , Células de Schwann , Neoplasias Cutâneas/embriologia , Neoplasias Cutâneas/genética , Fatores de TempoRESUMO
To identify cell type(s) that might contribute to nerve sheath tumors (neurofibromas) in patients with neurofibromatosis type 1, we generated cell cultures containing neurons. Schwann cells and fibroblasts from transgenic mouse embryos in which the type 1 neurofibromatosis gene was disrupted by homologous recombination (Brannan et al. (1994) Genes Development, 8,1019-1029). Normal fascicle formation by perineurial cells failed to occur in the absence of neurofibromin. Fascicles were reduced in number and showed abnormal morphology when normal neurons and Schwann cells were cultured up to 37 days with fibroblasts lacking neurofibromin. Proliferation was increased in a majority of fibroblast cell strains analyzed from embryos lacking neurofibromin. These observations suggest that mutations in the neurofibromatosis type I gene affect fibroblast behavior that might contribute to neurofibroma formation in patients with neurofibromatosis type 1.
Assuntos
Fibroblastos/patologia , Neurofibroma/embriologia , Neurofibromatose 1/embriologia , Nervos Periféricos/embriologia , Proteínas/fisiologia , Animais , Técnicas de Cultura de Células , Divisão Celular/fisiologia , Células Cultivadas , Genes ras , Camundongos , Camundongos Transgênicos , Microscopia de Contraste de Fase , Modelos Neurológicos , Mutação , Neurofibroma/patologia , Neurofibromatose 1/genética , Neurofibromatose 1/patologia , Neurofibromina 1 , Neurônios/patologia , Células de Schwann/patologiaRESUMO
Two tiny macerated fetuses with a remarkably similar pattern of multicentric neurogenic neoplasms of both paravertebral autonomic structures and peripheral nerves are described. Maceration precluded further histologic classification of the neoplasms in either fetus. The first fetus had a Meckel's diverticulum, short attachment of the small bowel mesentery, pulmonary hypoplasia, and intrauterine growth retardation. The second had the sympus bipus variant of sirenomelia sequence. The multicentric neoplasms in these two fetuses are very similar to those previously described in a few neonates and one stillborn with well-documented or suspected neurofibromatosis. It is reasonable to hypothesize that these two fetuses may represent an early intrauterine expression of neurofibromatosis characterized by multicentric neurogenic neoplasms of autonomic structures and peripheral nerves. Detailed examination of early abortuses, especially those from families with neurofibromatosis, may help to confirm or disprove the hypothesis.
Assuntos
Doenças Fetais , Neoplasias do Sistema Nervoso/congênito , Neurofibromatose 1/congênito , Doenças do Sistema Nervoso Autônomo , Feminino , Humanos , Neoplasias do Sistema Nervoso/embriologia , Neoplasias do Sistema Nervoso/patologia , Neurofibromatose 1/embriologia , Neurofibromatose 1/patologia , Nervos Periféricos , GravidezRESUMO
A Von Willebrand's disease associated to Von Recklinghausen's disease is described. A an common alteration in the mesenchima is suggested as pathogenic mechanism. DDAVP was used as supportive treatment for bleeding, in preparation for surgery.
Assuntos
Neurofibromatose 1/complicações , Neoplasias Cutâneas/complicações , Doenças de von Willebrand/complicações , Vasos Sanguíneos/embriologia , Criança , Endotélio/embriologia , Feminino , Humanos , Neurofibromatose 1/embriologia , Neoplasias Cutâneas/embriologia , Estrabismo/complicações , Doenças de von Willebrand/embriologiaRESUMO
The coexistence of neurofibromatous skin lesions and carcinoid of Vater's ampulla is not fortuitous. The melanocytes in the brownish pigmented skin lesions bind DOPA, while the chromaffin cells in the digestive tumour contain cytoplasmic granules where precursors of amines with digestive activity are synthetized and stored. DOPA is one of these precursors. Both diseases, therefore, are interrelated by a common embryological origin: the neural crest.
Assuntos
Ampola Hepatopancreática/patologia , Apudoma/patologia , Tumor Carcinoide/patologia , Neoplasias do Ducto Colédoco/patologia , Neoplasias Primárias Múltiplas/patologia , Neurofibromatose 1/patologia , Neoplasias Cutâneas/patologia , Adulto , Apudoma/embriologia , Tumor Carcinoide/embriologia , Neoplasias do Ducto Colédoco/embriologia , Feminino , Humanos , Neurofibromatose 1/embriologiaAssuntos
Células APUD/fisiologia , Crista Neural/citologia , Células APUD/patologia , Síndrome do Nevo Basocelular/embriologia , Doenças do Sistema Endócrino/embriologia , Humanos , Defeitos do Tubo Neural/embriologia , Neurofibromatose 1/embriologia , Esclerose Tuberosa/embriologia , Síndrome de Werner/embriologiaAssuntos
Crista Neural/fisiologia , Animais , Ciclo Celular , Diferenciação Celular , Movimento Celular , Embrião de Galinha , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Mutantes , Crista Neural/citologia , Neurofibromatose 1/embriologia , Neurofibromatose 1/etiologia , Neurofibromatose 1/patologiaRESUMO
The pathogenesis of the phacomatoses, developmental diseases of the embryonic plates, permits an understanding of the different manifestations which characterize these disorders. This pathogenesis also constitutes the best basis for a rational classification. The author sets out the main features of this pathogenesis and its practical applications, and then considers the principal vascular aspects of the phacomatoses, especially in Osler-Rendu disease, Blue Rubber Bleb Naevi, Mafussi's syndrome, the haemangioblastomatoses, Bailey's glomangiomatosis, the Louis-Bar syndrome, Struge-Weber angiomatosis, the syndrome of Bonnet-Dechaume and Blanc, Cobb's syndrome, the angio-osteo-hypertrophic syndromes, von Recklinghausen's neurofibromatosis, Bourneville's tuberous sclerosis, and the melanic phacomatoses.
Assuntos
Angiomatose/embriologia , Camadas Germinativas/patologia , Neurofibromatose 1/embriologia , Nevo Pigmentado/embriologia , Esclerose Tuberosa/embriologia , Adolescente , Adulto , Angiomatose/classificação , Humanos , Neurofibromatose 1/classificação , Nevo Pigmentado/classificação , Esclerose Tuberosa/classificaçãoRESUMO
The authors review various of the derivatives of the neural crest, consider their relationship with the APUD System, and deduce the physiopathological consequences applicable to these cells, whose only similarity lies in their common embryologic origin. They propose a system of classification of interrelated pathological conditions that these cells may show, an detail clinical information as well as the mode of genetic transmission of the principal neurocristopathic syndroms.