[Prenatal genetic diagnosis for a fetus with atypical neurofibromatosis type 1 microdeletion].

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.

ERK inhibition rescues defects in fate specification of Nf1-deficient neural progenitors and brain abnormalities.

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.

Neurofibromatosis type 1 is a disorder of dysplasia: the importance of distinguishing features, consequences, and complications.

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.

Mosaicism in sporadic neurofibromatosis type 1: variations on a theme common to other hereditary cancer syndromes?

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.

Chiari I malformation and neurofibromatosis type 1.

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.

Segmental neurofibromatosis follows blaschko's lines or dermatomes depending on the cell line affected: case report and literature review.

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).

Neurofibromatosis segmentaria. A propósito de un caso y revisión bibliográfica / Segmental neurofibromatosis. A case report and bibliographic review

La neurofibromatosis segmentaria es una rara variedad de facomatosis neurocristopática de clínica variable y buen pronóstico, caracterizada por manchas café con leche y/o neurofibromas de distribución unilateral y metamérica, sin afectación visceral. Corresponde al tipo V de las neurofibromatosis de la clasificación de Riccardi, predomina en mujeres y se localiza con frecuencia en la región toracoabdominal, sin sobrepasar la línea media. No es frecuente encontrar nódulos de Lisch ni efélides axilares. La causa es una mutación somática poszigota del gen de la neurofibromatosis tipo I en etapas precoces del desarrollo embrionario de la cresta neural, con mosaicismo somático y, en ocasiones, gonadal, que explicaría los casos hereditarios. Describimos un caso típico de neurofibromatosis segmentaria en una niña de 14 años de edad que consultó por múltiples máculas café con leche desde el segundo mes del nacimiento, sin evidencia de otros hallazgos cutáneos patológicos (AU)

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Neurofibromin-deficient fibroblasts fail to form perineurium in vitro.

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.

Diffuse, multicentric neurogenic tumors in two macerated fetuses: a possible intrauterine form of neurofibromatosis.

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.

[The pathology of factor VIII in von Recklinghausen's disease: a new association]. / Patología del factor VIII en la enfermedad de Recklinghausen: una nueva asociación.

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.

[Association of Recklinghausen's disease with carcinoid of Vater's ampulla. A new nosologic entity: apudoma. A case]. / Association maladie de Recklinghausen et carcinoïde de l'ampoule de Vater. Une nouvelle entité nosologique: les apudomes. Une observation.

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.

[Phacomatoses. Pathogenesis - Classification - Vascular aspects]. / Les phacomatoses. Pathogénie - Classification - Aspects vasculaires.

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.