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PubMed1986

Iris hamartomata as diagnostic criterion in neurofibromatosis.

We have investigated a personal series of 90 patients with the ("classical") peripheral form of neurofibromatosis (NF) for iris hamartomata (IH). Of subjects aged 6 years or older, 97% had IH. IH were unilateral in 8 patients. IH were not found in 44 unaffected first degree relatives of patients with NF or in normal persons seen during the study period. We consider IH a reliable diagnostic criterion to be added to the list of diagnostic features. In childhood the incidence of IH exceeds that of cutaneous neurofibromas and axillary freckling.

Adolescent↗
PubMed1984

[Neurofibromatosis in childhood. Computed tomographic findings in the skull and neck areas].

The value of CT was investigated in sixteen children and adolescents with neurofibromatosis affecting the skull and neck. Its advantage is the simultaneous demonstration of bone and soft tissue changes, which frequently occur together in this condition. Demonstration of the extent of the neurofibromatous soft tissue changes is of crucial importance to the surgeon when planning treatment. Serial observations provide information on progress of the disease and helps in the decision of the optimal time for surgery. The differential diagnosis is discussed.

Adolescent↗
PubMed1981

Malignant abdominal schwannoma associated with von Recklinghausen's neurofibromatosis.

A 4-year-old boy with neurofibromatosis was operated on for abdominal tumor and a malignant Schwannoma adhering to the bladder was completely resected. Four months later he died with multiple liver metastases. The authors comment on the main features of this rate tumor and on the problems of malignancy associated with von Recklinghausen's disease.

Abdominal Neoplasms↗
PubMed1993

Gastrointestinal manifestations of neurofibromatosis in childhood.

Von Recklinghausen's neurofibromatosis (VRN) is a familial disorder characterised by a generalized neuroectodermal dysplasia--symptomatic involvement of the gastrointestinal tract is rare. We report on our experience with two children who had proven gastrointestinal neurofibromas and highlight the need for careful assessment in children with VRN who develop abdominal pain.

Child↗
PubMed1989

[Neurofibrosarcomas in neurofibromatosis 1].

Between 1983 and 1987 three patients (mean age 31 years) with neurofibrosarcoma were seen among 22 with von Recklinghausen neurofibromatosis (NF-1) at the Department of Neurology, University of Berne, Switzerland. There was an average interval of 14 months between onset of symptoms and treatment. The first presenting sign was a rapidly enlarging mass or unusual persistent pain. The occurrence of either sign, in the known presence of NF-1, should lead to immediate neuroradiological investigation. The mean survival time of the three patients was 37 months. Only early diagnosis provides any chance of curative treatment.

Adult↗
PubMed1990

Hemimegalencephaly and neurofibromatosis.

Hemimegalencephaly, which previously has been associated with a poor clinical course characterized by intractable seizures and severe encephalopathy, was found without these conditions in two children with neurofibromatosis. These children showed relatively similar and favourable prognostic features: no presence of seizures before one month, seizures controlled or absent, no focal neurological signs and peculiar EEG findings. In our opinion the absence of heterotopias and hamartomas can be related with less severe outcome.

Brain↗
PubMed1994

Follow-up of optic pathway gliomas in children with neurofibromatosis type 1.

Optic pathway gliomas (OPG) are found in about 15% of patients with neurofibromatosis Type 1 (NF-1). The natural history of OPG is not yet well documented. Treatment in cases with growing tumors is still controversial. Twenty-one patients with NF-1 and OPG, diagnosed over a 20-year period, and followed neuroradiologically and ophthalmologically for at least two years, were reevaluated. The diagnosis of OPG was made at a mean age of 7.1 years (range 0-14.5 years); six children were asymptomatic, 15 were symptomatic. The mean follow-up was 9.0 years (2.0-18.5 (years). In eight initially operated or biopsied patients (three optic nerve and five chiasmal gliomas) tumor regrowth was found in one patient without progression on subsequent follow-up. Improvement of visual acuity occurred in one child after operation of a large suprasellar tumor and deterioration in one patient after biopsy of a chiasmal glioma. The neuroradiological follow-up of the 13 not-operated and not-radiated patients (four optic nerve and nine chiasmal gliomas) was stable in 10, progressive in three, resulting in visual loss in one patient. In 11 children (52%) a second tumor outside the optic pathway was found at a mean age of 4.0 years after the diagnosis of an OPG. Until now they are mostly asymptomatic. Second site tumors were operated in two children because of rapid tumor growth, one child died of a brainstem tumor. OPG are a frequent complication in children with NF-1, appearing within the first decade.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed2002

The heart in neurofibromatosis type 1: an echocardiographic study.

BACKGROUND: Comprehensive data are unavailable for cardiac abnormalities in patients with neurofibromatosis type 1 (NF1). The goal of this study was to evaluate the prevalence of cardiovascular abnormalities with echocardiography with color Doppler scan (ECHO) in a large, consecutive series of patients with NF1. METHODS: We studied 48 patients with NF1 (mean age, 10 years). Thirty healthy subjects comparable for age and sex served as the control group. All ECHO studies were performed by the same cardiologist and reviewed by a second cardiologist blinded to the physical findings of the subjects. RESULTS: Cardiac abnormalities were found in 13 of the 48 young patients (27%). A secundum atrial septal defect with a left to right shunt was found in 2 children. ECHO evidence of mild left pulmonary artery stenosis was found in 1 participant. A moderate coarctation of the thoracic aorta was found in 1 patient. ECHO criteria for mitral valve prolapse and evidence of trivial mitral regurgitation with myxomatous mitral valve was present in 1 case. Mild mitral regurgitation was found in 2 patients. A regurgitant mild flow signal was detected from the aortic valve in 2 subjects. Atrial septal aneurysm was found in 2 patients without patent foramen ovale. Two patients had septal to posterior left ventricular free wall ratio greater than 1.5, suggesting hypertrophic cardiomyopathy. CONCLUSION: This is the first attempt to evaluate the prevalence of cardiovascular abnormalities in patients with NF1 with ECHO. The study's most striking finding is the high prevalence of cardiovascular abnormalities. Congenital lesions have potential long-term hemodynamic consequences that justify an early diagnosis. Thus, a cardiologic assessment at regular intervals, including ECHO study, is mandatory for patients with NF1.

Adolescent↗
PubMed2003

Neurofibromatosis type I: clinical and imaging features of Von Recklinghausen's disease.

OBJECTIVE: To discuss the case of a 45-year-old woman, with a prior diagnosis of neurofibromatosis type 1 (NF-1), complaining of low back and cervical spine pain with bilateral upper extremity paresthesias. CLINICAL FEATURES: The patient had a dull, achy, constant low-back pain of 4 months' duration, with mild headaches and upper extremity paresthesias. Multiple skin lesions and spinopelvic postural imbalances were present. Diagnostic radiography, along with advanced imaging, demonstrated multilevel dysplastic osseous changes, with dural ectasia, scoliosis, and tumor extension. In addition to the previous diagnosis of NF-1, our clinical diagnosis included segmental dysfunction with resultant cervicalgia, lumbalgia, and myospasm. INTERVENTION AND OUTCOME: Treatment consisted of a course of spinal manipulation of the lumbopelvic region, with adjunctive therapy consisting of interferential therapy, heat, and rehabilitative exercise. Marked reduction in pain and paresthesia with improved function were achieved. CONCLUSIONS: NF-1 is a multisystem disease with neoplasia of the skin and nervous system. Patients experience a lifetime of morbidity and increased risk of mortality, depending on the extent of the disease. A multitude of therapeutic regimens may be engaged to improve NF-1-associated symptomatology and morbidity. Chiropractic spinal manipulation may have a positive effect in pain reduction and improved function in patients who have NF-1 without spinal instability.

Female↗
PubMed2001

An anterior tibial artery aneurysm in a patient with neurofibromatosis.

Von Recklinghausen's Type 1 neurofibromatosis (NF) is a genetic disorder of neuroectodermal tissue. Arterial involvement has also been recognized. Stenotic lesions predominate, but aneurysms have been documented as well. Aortoiliac, visceral, and cervical aneurysms are well represented in the literature. Rarely noted, however, have been peripheral aneurysms. Typically in more proximal vessels, subclavian, femoral, and popliteal aneurysms have been mentioned. We present the case of a patient with type 1 NF and an anterior tibial artery aneurysm that was subsequently resected. neurofibromatous invasion of the vessel was confirmed by means of pathological tests. We think this is the first reported case of a tibial artery aneurysm associated with NF.

Adult↗
PubMed2001

Spontaneous aortic dissection and rupture in a patient with neurofibromatosis.

Vascular involvement in neurofibromatosis type I is a well-recognized but rare feature of the disease. This case report is the first such describing acute aortic dissection and rupture in a patient who also had incidental aneurysms of his carotid and iliac arteries. A review of the literature about pathogenesis and management strategies is also presented.

Adult↗
PubMed2004

Neurofibromatosis 2 (NF2) tumor suppressor merlin inhibits phosphatidylinositol 3-kinase through binding to PIKE-L.

Neurofibromatosis 2 (NF2) is a tumor suppressor, although the molecular mechanism accounting for this effect remains unknown. Here, we show that merlin exerts its activity by inhibiting phosphatidylinositol 3-kinase (PI3-kinase), through binding to PIKE-L. Wild-type merlin, but not patient-derived mutant (L64P), binds PIKE-L and inhibits PI3-kinase activity. This suppression of PI3-kinase activity results from merlin disrupting the binding of PIKE-L to PI3-kinase. In addition, merlin suppression of PI3-kinase activity as well as schwannoma cell growth is abrogated by a single PIKE-L point mutation (P187L) that cannot bind merlin but can still activate PI3-kinase. Knocking down PIKE-L with RNA interference abolishes merlin's tumor-suppressive activity. Our data support the hypothesis that PIKE-L is an important mediator of merlin growth suppression.

Adenoviridae↗
PubMed1990

Chromosome 17p deletions and p53 gene mutations associated with the formation of malignant neurofibrosarcomas in von Recklinghausen neurofibromatosis.

von Recklinghausen neurofibromatosis (NF1) is a common hereditary disorder characterized by neural crest-derived tumors, particularly benign neurofibromas whose malignant transformation to neurofibrosarcomas can be fatal. The NF1 gene has been mapped to a small region of chromosome 17q, but neither the nature of the primary defect nor the mechanisms involved in tumor progression are understood. We have tested whether NF1 might be caused by the inactivation of a tumor suppressor gene on 17q, analogous to that on chromosome 22 in NF2, by searching for deletions of chromosome 17 in NF1-derived tumor specimens. Both neurofibrosarcomas from patients with "atypical" NF and 5 of 6 neurofibrosarcomas from NF1 patients displayed loss of alleles for polymorphic DNA markers on chromosome 17. However, the common region of deletion was on 17p and did not include the NF1 region of 17q. Since no loss of markers on chromosome 17 was observed in any of 30 benign tumors from NF1 patients, the 17p deletions seen in neurofibrosarcomas are probably associated with tumor progression and/or malignancy. This region contains a candidate gene for tumor progression, p53, which has recently been implicated in the progression of a broad array of human cancers. In a preliminary search for p53 aberrations by direct sequencing of polymerase chain reaction-amplified DNA from 7 neurofibrosarcomas, 2 tumors that contained point mutations in exon 4 of the p53 gene were found, suggesting a role for this gene in at least some neurofibrosarcomas. Thus the formation of malignant neurofibrosarcomas may result from several independent genetic events including mutation of the NF1 gene, whose mechanism of tumorigenesis remains uncertain, and subsequent loss of a "tumor suppressor" gene on 17p, most likely p53.

Base Sequence↗
PubMed1990

Genetic and physical map of the von Recklinghausen neurofibromatosis (NF1) region on chromosome 17.

The von Recklinghausen neurofibromatosis 1 (NF1) locus has been previously assigned to the proximal long arm of chromosome 17, and two NF1 patients have been identified who have constitutional balanced translocations involving 17q11.2. We have constructed a cosmid library from a chromosome-mediated gene transfectant, KLT8, that contains approximately 10% of chromosome 17, including 17q11.2. Cosmids isolated from this library have been mapped across a panel of somatic cell hybrids, including the hybrids from the two patients, and have been localized to seven small regions of proximal 17q. We have 5 cosmids that map directly above the two NF1 translocations, and 11 cosmids that map directly below. Of these, 2 cosmids in each region are linked to the disease locus and 3 of these cosmids show no recombination. One distal cosmid, 2B/B35, detects the two NF1 translocations by pulsed-field gel analysis and has been used to produce a long-range restriction map that covers the translocations.

Blotting, Southern↗
PubMed1993

Suppression of oncogenic Ras by mutant neurofibromatosis type 1 genes with single amino acid substitutions.

NF1 was first identified as the gene responsible for the pathogenesis of the human genetic disorder neurofibromatosis type 1. cDNA cloning revealed that its putative protein product has a domain showing significant sequence homology with the mammalian Ras GTPase activating protein and two yeast Saccharomyces cerevisiae proteins, Ira1 and Ira2. The Ras GTPase activating protein-related domain of the NF1 gene product (NF1-GRD) stimulates GTPase activity of normal Ras proteins but not of oncogenic mutant Ras from both mammalian and yeast cells. Thus, in yeast, NF1-GRD can suppress the heat-shock-sensitive phenotype of ira- cells but not the same phenotype of activated RAS such as RAS2Val19 and RAS2Leu68. We have screened a pool of mutagenized NF1 expression plasmids and obtained two mutant NF1 cDNA clones that can suppress the heat-shock-sensitive phenotype of RAS2Val19 cells. One clone (NF201) suppressed RAS2Leu68, RAS2Ser41, and RAS2Val19, whereas another clone (NF204) preferentially suppressed RAS2Val19. When expressed in mammalian cells, these mutant NF1-GRDs were able to induce the morphological reversion of v-ras-transformed NIH 3T3 cells. Both wild-type and mutant NF1-GRDs can stimulate the GTPase activity of normal but not transforming Ras. We suggest that mutant NF1-GRDs may bind tightly to transforming Ras, which stays in GTP-bound conformation, thus preventing the interaction with the putative effector molecule. On the other hand, normal Ras cannot be sequestered since the bound GTP is rapidly hydrolyzed upon interaction with mutant NF1-GRD to yield Ras-GDP, which is readily released from the NF1-GRD and recycled.

3T3 Cells↗
PubMed1995

High frequency of inactivating mutations in the neurofibromatosis type 2 gene (NF2) in primary malignant mesotheliomas.

Malignant mesotheliomas (MMs) are aggressive tumors that develop most frequently in the pleura of patients exposed to asbestos. In contrast to many other cancers, relatively few molecular alterations have been described in MMs. The most frequent numerical cytogenetic abnormality in MMs is loss of chromosome 22. The neurofibromatosis type 2 gene (NF2) is a tumor suppressor gene assigned to chromosome 22q which plays an important role in the development of familial and spontaneous tumors of neuroectodermal origin. Although MMs have a different histogenic derivation, the frequent abnormalities of chromosome 22 warranted an investigation of the NF2 gene in these tumors. Both cDNAs from 15 MM cell lines and genomic DNAs from 7 matched primary tumors were analyzed for mutations within the NF2 coding region. NF2 mutations predicting either interstitial in-frame deletions or truncation of the NF2-encoded protein (merlin) were detected in eight cell lines (53%), six of which were confirmed in primary tumor DNAs. In two samples that showed NF2 gene transcript alterations, no genomic DNA mutations were detected, suggesting that aberrant splicing may constitute an additional mechanism for merlin inactivation. These findings implicate NF2 in the oncogenesis of primary MMs and provide evidence that this gene can be involved in the development of tumors other than nervous system neoplasms characteristic of the NF2 disorder. In addition, unlike NF2-related tumors, MM derives from the mesoderm; malignancies of this origin have not previously been associated with frequent alterations of the NF2 gene.

Base Sequence↗
PubMed1998

Regulation of the neurofibromatosis type 2 tumor suppressor protein, merlin, by adhesion and growth arrest stimuli.

The neurofibromatosis type 2 tumor suppressor gene is inactivated in the development of familial and sporadic schwannomas and meningiomas. The encoded protein, Merlin, is closely related to the Ezrin, Radixin, and Moesin family of membrane/cytoskeletal linker proteins. Examination of Merlin in several cell lines revealed that the protein migrates as two distinct species near 70 kDa. Phosphatase treatment and orthophosphate labeling demonstrated that the species with decreased mobility is phosphorylated. Given Merlin's localization to cortical actin structures, we examined the effect of cell-cell contact or other forms of growth arrest on Merlin expression and post-translational modification. Under conditions of confluency or serum deprivation, the levels of phosphorylated and unphosphorylated Merlin species increased significantly. Cells arrested in G1 by other methods or other phases of the cell cycle did not show changes in Merlin levels. Furthermore, loss of adhesion resulted in a nearly complete dephosphorylation of Merlin, which was reversed upon re-plating of cells, suggesting Merlin phosphorylation may be responsive to cell spreading or changes in cell shape. Thus, the tumor suppressor function of Merlin may involve the regulation of cellular responses to cues such as cell-cell contact, growth factor microenvironment, or changes in cell shape.

3T3 Cells↗
PubMed2002

The motor protein kinesin-1 links neurofibromin and merlin in a common cellular pathway of neurofibromatosis.

Mutations in either of the two tumor suppressor genes NF1 (neurofibromin) and NF2 (merlin) result in Neurofibromatosis, a condition predisposing individuals to developing a variety of benign and malignant tumors of the central and peripheral nervous systems. Here we report the identification of two distinct NF1-containing complexes, one in the soluble and the other in the particulate fraction of HeLa extract. We show that the soluble NF1 complex delineates a large holo-NF1 complex (2 MDa) encompassing the components of a smaller particulate core-NF1 complex (400 kDa). Purification of the core-NF1 complex followed by mass spectrometric analysis revealed the motor protein, kinesin-1 heavy chain (HsuKHC/KIF5B), as a catalytic subunit of both NF-1-containing complexes. Importantly, although NF1 and NF2 are not in a stable association, NF2 is also a component of a distinct kinesin-1-containing complex. These results point to kinesin-1 as a common denominator between NF1 and NF2.

Animals↗