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PubMed2002

Losses in chromosomes 17, 19, and 22q in neurofibromatosis type 1 and sporadic neurofibromas: a comparative genomic hybridization analysis.

Neurofibromatosis type 1 (von Recklinghausen's NF1) is an autosomal dominant disease associated with an increased risk of benign and malignant neoplasia including malignant peripheral nerve sheath tumors (MPNSTs). In this study, we employed comparative genomic hybridization (CGH) to determine changes in the relative chromosome copy number in 24 patients with neurofibromas, including 12 NF1-associated and 12 sporadic cases. Differences in the frequency and distribution of chromosomal imbalances were observed in both NF1-asociated and sporadic neurofibromas. Chromosomal imbalances were more common in NF1-associated tumors than in sporadic neurofibromas. In both groups, the number of losses was higher than the number of gains, suggesting a predominant role of tumor suppressor gene in tumorigenesis. A number of new chromosomal imbalances were noted including chromosomes 17, 19, and chromosome arm 22q, which may be related to oncogenes or tumor suppressor genes in neurofibromas. In NF1-associated neurofibromas, the most frequent losses were found in chromosome 17 (the minimal common regions were 17p11.2-->p13 in nine cases and 17q24-->q25 in six cases) and 19p (19p13.2 in nine cases). In addition, both NF1-associated and sporadic neurofibromas often exhibited losses at chromosome arms 19q and 22q (in NF1 tumors, the minimal common regions were 19q13.2-->qter in seven cases).

Adult↗
PubMed2003

Modified allelic replication in lymphocytes of patients with neurofibromatosis type 1.

Transcription activity of genes is related to their replication timing, accordingly gene activation is coupled with a shift from late replication to early replication and vice versa. The relationship between replication timing and gene expression is best manifested by monoallelically expressed genes which show an asynchronous pattern of allelic replication, with the active allele replicating earlier than the inactive counterpart. Biallelically expressed genes, which normally replicate highly synchronously, when present in lymphocytes derived from patients with various types of malignancies or premalignancies, replicate highly asynchronously, similar to monoallelically expressed genes. Since neurofibromatosis-type 1 (NF1) patients are at an increased risk to develop malignancies, we used the fluorescence in situ hybridization (FISH) replication assay and evaluated the level of replication synchrony of three cancer-implicated genes (RB1, AML1, and CMYC) in lymphocytes derived from patients with NF1 without malignancy. Each gene, which normally displayed synchrony in allelic replication, in the patients' cells displayed loss of synchrony. The loss of replication synchrony, of each gene, in the patients' cells was achieved by an advanced replication of a single allele, which replicated remarkably earlier than its normal scheduled timing. In addition, the second allele showed slightly earlier replication timing than that normal for the gene. Thus, it is assumed that the NF1 condition is associated with activation of cancer-implicated genes that may be the cause for increased risk of patients to develop malignancies. As loss of synchrony in allelic replication timing differentiates well between NF1 patients and control subjects, this marker may have a potential use for identification of presymptomatic carriers of NF1 disorders.

Adolescent↗
PubMed1996

Loss of heterozygosity on chromosome 22 in human gliomas does not inactivate the neurofibromatosis type 2 gene.

The molecular genetic alterations that underlie development of gliomas, the most common neoplasm of the human central nervous system, include activation of cellular proto-oncogenes as well as inactivation of tumor suppressor genes. Although research has identified some affected loci, others clearly remain to be identified. We have investigated loss of heterozygosity on chromosome 22 in a panel of sporadic gliomas, and have assessed the possibility that inactivation of the neurofibromatosis type 2 (NF2) tumor suppressor gene on 22q plays a role in development of sporadic gliomas in humans. Loss of heterozygosity for loci on chromosome 22 loci was observed in 15 of 47 informative blood-tumor pairs, although no common area of loss of heterozygosity shared by all of these tumors could be identified. The most frequently affected segment, distal to the NF2 locus and bounded proximally by D22S15 and distally by a gene for myoglobin, was shared by as many as 11 tumors. Loss of heterozygosity at the NF2 locus was observed in 10 tumors. No rearrangements of the NF2 gene could be detected by Southern analysis of restriction endonuclease-digested genomic DNA, and no abnormally migrating bands were detected on single strand conformation analysis of individual exons of the NF2 gene. Thus, although frequent loss of heterozygosity on chromosome 22 suggests that inactivation of a tumor suppressor gene on this chromosome plays a role in development of gliomas, there is no evidence that inactivation of the NF2 gene is implicated in this process, confirming the results of other studies of the NF2 gene in human gliomas. The identity of the putative tumor suppressor gene on 22q involved in development of gliomas remains unknown.

Brain Neoplasms↗
PubMed1998

Structure-function relationships in the ezrin family and the effect of tumor-associated point mutations in neurofibromatosis 2 protein.

Ezrin, radixin and moesin (ERM proteins) link cell adhesion molecules to the cytoskeleton, modulate cell morphology and cell growth and are involved in Rho-mediated signal transduction. Merlin, the tumor suppressor in neurofibromatosis 2, is a diverged member of the ezrin family, but its function is at least partially similar to the ERM proteins. In the N-domain, the ezrin family belongs to the band 4.1 superfamily. Secondary structure predictions made separately for the ezrin and band 4.1-tyrosine phosphatase families give a similar pattern for the homologous N-domains, indicating that both families have a similar binding site for the integral membrane proteins. The alpha-domain shows a strong coiled-coil prediction, that can be involved in the protein dimerization. The C-terminal actin-binding site in the ERM proteins and the actin-binding helix in the villin headpiece have a common amino acid motif. In merlin, the published tumor-associated single amino acid mutations in the N-domain are located in the conserved sites, and they affect mainly the predicted helices and strands, indicating that these mutations cause the disease primarily by disturbing the protein structure. In the alpha- and C-domains, some of the mutations break the helical structures. Some known mutations are observed at a site potentially interacting with cell adhesion molecules. We will also discuss the implications of the evolutionary information and the actin-binding models in the ezrin family.

Animals↗
PubMed2005

[Dragged disc syndrome in a patient presenting neurofibromatosis type II: a case study].

We report a case of dragged disc syndrome associated with neurofibromatosis type II (NF2). A 5-year-old girl with amblyopia (right eye, 20/200; left eye, 20/40) presented with dragged disk syndrome and a posterior subcapsular cataract in the left eye associated with an epiretinal membrane in the right eye. Five years later, she developed exophthalmos in the right eye associated with a cervical mass. MRI revealed schwannoma developing in the left optic nerve sheath associated with a cervicothoracic schwannoma. The child was diagnosed with NF2. Association of posterior subcapsular cataract with macular epiretinal membranes is highly suggestive of NF2, although the dragged disk syndrome has not been previously reported in NF2 to our knowledge. It may also be an ocular feature of this disease.

Cataract↗
PubMed2000

Intracranial sarcoma in a patient with neurofibromatosis type 2 treated with gamma knife radiosurgery for vestibular schwannoma.

OBJECTIVE: To discuss the possible relationship between stereotactic radiation therapy and the development of a meningosarcoma. STUDY DESIGN: Retrospective case review. PATIENT: A 19-year-old woman with bilateral vestibular schwannomas (neurofibromatosis type 2). One large tumor was removed totally by the translabyrinthine approach; the other smaller tumor was treated with stereotactic radiation (SRT). Six years after SRT, a malignant tumor (meningosarcoma) developed at the exact site of radiation. The patient subsequently died of this tumor. OUTCOME MEASURE: On the basis of literature surveys, the possibility and risk of postirradiation neoplasia after SRT is discussed. Furthermore, the possible causal association between SRT and the development of the meningosarcoma in this case is evaluated. CONCLUSION: On the basis of statistical considerations, the development of the reported mesenchymal sarcoma was most likely caused by the stereotactic radiation therapy.

Adult↗
PubMed1975

Changes of the facial skeleton in cases of neurofibromatosis.

In 12 patients with neurofibromatosis of the maxillofacial region distinct changes of the facial skeleton were found, which in localisation and extent largely conformed to the more or less wide soft tissue hyperplasias. In pronounced cases, a combined maxillo-zygomatico-temporo-mandibular hypoplasia was present radiographically. These skeletal changes hardly can be interpreted as pressure atrophy caused by the adjacent neurofibromatous tumours; more likely they are the result of complex developmental disorders. A more detailed explanation possibly will be obtained, when development and skeletal changes are controlled radiographically over a long period of time.

Adult↗
PubMed1984

Neurofibromatosis of the head and neck: clinical presentation and treatment.

The clinical features of neurofibromatosis of the head and neck in 28 Nigerians are presented. The disease produced varying degrees of cosmetic and functional deformity. Total excision of the lesions, where feasible, with skin grafting, when indicated, gave satisfactory cosmetic and functional results. Incomplete excision was unsatisfactory for all eyelid and other more extensive lesions. Intraoperative bleeding was prominent and postoperative follow-up poor.

Adolescent↗
PubMed1987

Von Recklinghausen neurofibromatosis (VRNF) and pregnancy. A single case study.

A case of Von Recklinghausen neurofibromatosis (VRNF) with progression during two pregnancies and obstetrical complications is described to illustrate the effect of pregnancy on VRNF and vice versa. The interaction between VRNF and pregnancy is discussed. The obstetrical complications and progression of VRNF lesions during pregnancy necessitate close follow-up of these patients by neurologist and obstetrician.

Adult↗
PubMed1993

Genetic alterations in a malignant schwannoma from a patient with neurofibromatosis (NF1).

In a patient with neurofibromatosis (von Recklinghausen disease; NF1), normal lymphocytes, five cutaneous neurofibromas, and tumour tissue from a recurrence of a malignant schwannoma were analysed for genetic alterations. Eleven DNA markers located on chromosome 17 and nine randomly chosen markers representing chromosomes 1, 2, 3, 4, 5, 6, and 11, were analysed. High resolution Giemsa banding of lymphocytes revealed no chromosomal rearrangement. The DNA from the neurofibromas were all found to have the same restricted fragment length polymorphism pattern as the constitutional DNA from the patient. In the malignant schwannoma a complete loss of one allele was found at polymorphic loci on chromosome arm 17p. One gene copy of the TP53 gene (17p13.1) and the NF1 gene (17q11.2) was lost, as was one copy of the PGA gene (11q13). No mutations were detected in the mutational hotspots of the TP53 gene. Partial losses were detected at three loci on chromosomes 1, 2 and 6, indicating a clonal variation within the tumour since histological evaluation disclosed no normal tissue in the analysed specimen. Our data indicate that the NF1 gene may function as a tumour suppressor gene, and that, either by effect of dose reduction or complete inactivation, both the NF1 gene and the TP53 gene may be critical for the progression of a neurofibroma to a malignant schwannoma. The observations made are consistent with the concept of stepwise multigenetic changes in tumour progression.

Adult↗
PubMed1989

Two epithelioid malignant schwannomas in a patient with neurofibromatosis. Cytology, histology and DNA-flow-cytometry.

Cytological, histological and DNA-ploidy findings of 2 epithelioid malignant schwannomas arising in a patient with von Recklinghausen's neurofibromatosis are described. In both primary tumors, i.e. in the thigh and in the thoracic wall, origin from a neurofibromatous nerve could be established. Within 2 years after the manifestation of the first malignant tumor the patient died of widely metastasized disease. DNA-flow cytometry of several neurofibromas revealed diploid stemlines, but both malignant primary tumors and a lung metastasis appeared to be aneuploid. Presumably, the primary tumors also contained cell populations with a diploid stem line.

Adult↗
PubMed1987

Massive neurofibromatosis of the upper extremity with paralysis.

Tendon transfer and bulk reduction procedures are an alternative to amputation of the elephantoid enlarged limb with neurofibromatosis and paralysis. A patient with this progressive disease has been followed-up for 10 years and retains sufficient function to work as a computer operator.

Adolescent↗
PubMed1998

Genomic characterization of the Neurofibromatosis Type 1 gene of Fugu rubripes.

The genomic structure of the Neurofibromatosis Type1 (NF1) gene of Fugu rubripes was investigated by sequence analysis of two overlapping cosmids. The Fugu NF1 gene spans 27 kb and is 13 times smaller than the human counterpart owing primarily to reduced intron size. The predicted amino acid sequence is highly related to that of human neurofibromin, exhibiting an overall similarity of 91.5%. Nearly all exons described for the human NF1 gene could be identified, except exon 12b and the alternatively spliced exons 9br and 48a. With the exception of the splice acceptor site in front of exon 16, all splice sites are in identical positions to those found in the human gene. Intron 1, which is 100-140 kb long in humans, spans 2575 bp in the Fugu NF1 gene. Another large intron of the human NF1 gene, intron 27b (45-50 kb), is 3942 bp of size in Fugu. Sequences related to the OMgp gene (Oligodendrocyte-Myelin-glycoprotein) or the EVI2A gene (ecotropic viral integration site), which are inserted into human NF1 intron 27b, were not detected in the corresponding Fugu intron. However, a single exon gene with similarity to the human EVI2B gene has been found on the reverse strand of Fugu intron 27b. This suggests that the human EVI2B gene and the Fugu gene in intron 27b have a common ancestor. We found the expression of this inserted gene in liver and kidney, but not in brain tissue of Fugu rubripes.

Amino Acid Sequence↗
PubMed1999

A case of laryngeal neurinoma with neurofibromatosis 2.

We present a case of a laryngeal neurinoma in a patient with neurofibromatosis 2. A 39-year-old man presented to our hospital with multiple complaints including progressive bilateral hearing loss, dizziness, dyspnea, dysphagia, and a 9-year history of right lower leg weakness. Magnetic resonance imaging demonstrated multiple lesions including bilateral cerebellopontine angle tumors, a foremen magnum tumor, multiple tumors of the spinal cord, a laryngeal tumor, and several retrocervical tumors. Fiberoptic laryngoscopy revealed a large submucosal supraglottic tumor. The laryngeal tumor was visualized through microlaryngoscopy and excised with a KTP laser directed through a quartz fiber.

Adult↗
PubMed1988

Optic glioma with progressive occlusion of the aqueduct of Sylvius in monozygotic twins with neurofibromatosis.

Monozygotic twins sisters with optic glioma "in mirror image" (one with involvement of the left optic nerve and the other with the right optic nerve) and hydrocephalus secondary to progressive stenosis of the aqueduct have been found in a series of 128 cases below 14 years of age with neurofibromatosis. The optic glioma was diagnosed in each of the twins at 2 years of age. In one twin the tumor involved only the optic nerve but in the other the glioma affected the optic nerve and spread to the homolateral zone of the optic chiasm. First symptoms of hydrocephalus appeared at 8 years and 11 years of age respectively but ventriculo-peritoneal shunting procedures were performed to relieve intracranial hypertension at 11 years and 15 years of age respectively. At 2 years of age both twins had pneumoencephalography which demonstrated normal air passage through the aqueduct and cerebral ventricles of normal size and morphology. Posterior studies with CT-scan demonstrated progressive obstruction of the aqueduct with very slow progression of the hydrocephalus in each twin, although it was not observed simultaneously. The increased intracranial pressure was tolerated for many years in each twin without obvious symptoms which could be attributed to the slow progression of the aqueduct obstruction.

Adolescent↗
PubMed1998

Neurofibromatosis type 1 in children: MR imaging and follow-up studies of central nervous system findings.

PURPOSE: To determine the frequency, evolution and diagnostic impact of characteristic central nervous system MR imaging lesions in children with neurofibromatosis type 1 (NF1). SUBJECTS: We reviewed 89 children with established or clinically suspected disease. A final diagnosis of NF1 was made in 72 (age range, 10 months to 14 years). RESULTS: Hyperintense lesions on long TR images were detected in 78% of patients, principally involving the basal ganglia, cerebellum and brain stem. In 30% of the globus pallidus lesions, hyperintensity was seen on short TR images, being usually isointense on IR T1 weighted images. Globus pallidus lesions did not enhance. Eight patients presented atypical unenhanced lesions showing either edema, mass effect or hypointensity on short TR images; 2 of them were considered symptomatic brain stem gliomas. Six other children showed one or more growing enhanced cerebral lesions classified as tumors. Other child developed a growing enhanced lesion that markedly decreased in the follow-up studies. Twenty patients (28%) had optic gliomas. In two children, under 6 years old, this tumor appeared de novo. Forty-five children had several follow-up MR imaging studies (mean interval, 3 years). Regression of the basal ganglia lesions, both in size and/or intensity was noticed in 42% of cases, enlargement or new appearance of lesions in 24.5%, mixed increased/decreased in 7%, and stability in 26.5%. White matter lesions of the cerebellum and brain stem decreased in size in 40%, grew in 15.5%, showed a mixed increased/decreased pattern in 11%, and remained unchanged in 33.5% of cases. An involutional tendency of these lesions occurred in children older than 10 years, while progression was more frequent in younger children (P<0.05). CONCLUSIONS: Hyperintense lesions are highly prevalent and characteristic in patients with NF1. MR imaging contributed to a definitive diagnosis of NF1 in 53% of suspected cases. Follow-up studies are necessary in the evaluation of suspected NF1, even if the first examination is negative.

Adolescent↗
PubMed2003

Proton MR spectroscopy features of normal appearing white matter in neurofibromatosis type 1.

To determine whether differences exist between neurofibromatosis type 1 (NF1) patients with or without focal lesions and healthy normal volunteers in the metabolite ratios of normal appearing white matter, 27 patients with NF1 (with parenchymal lesion, MR positive, n: 17; without parenchymal lesions, MR negative, n: 10) and 20 healthy volunteers underwent MRI and short TE (31 ms) proton MR spectroscopy (MRS). In 17 patients with parenchymal lesions, 61 focal lesions were detected by MRI. MRS was performed from normal appearing frontal and posterior parietal white matter (FWM and PWM) in NF1 and from control groups. NAA/Cr, Cho/Cr and MI/Cr ratios were calculated. Significant increase in Cho/Cr and MI/Cr ratios were found in FWM and PWM in MR negative and positive groups when compared to control group. NAA/Cr ratio in MR positive group was significantly decreased in FWM compared to control group. There were no significant differences between FWM and PWM in all metabolite ratios of MR negative group. MI/Cr ratio in MR positive group was significantly elevated in PWM compared to FWM. Metabolite changes detected by MRS could indicate demyelination and gliosis in normal appearing white matter in all NF1 patients, and additionally neuroaxonal damage in the FWM of NF1 patients with focal lesions. For that reason, in the clinical evaluation and follow-up of these patients MRS features of normal appearing white matter should be considered in addition to focal lesions.

Adolescent↗
PubMed2002

Neurofibromatosis 1.

Neurofibromatosis 1 is one of the most common genetic conditions affecting the nervous system. Individuals with NF1 are predisposed to the development of peripheral nerve sheath tumors (neurofibromas and MPNSTs), astrocytomas (optic pathway gliomas), learning disabilities, seizures, strokes, macrocephaly, and vascular abnormalities. The NF1 tumor suppressor gene encodes a large protein (neurofibromin) that functions primarily as a RAS negative regulator, suggesting that targeted therapy for NF1 might derive from inhibition of the RAS signaling pathway.

Adult↗