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Detection of spontaneous schwannomas by MRI in a transgenic murine model of neurofibromatosis type 2.

Spontaneous schwannomas were detected by magnetic resonance imaging (MRI) in a transgenic murine model of neurofibromatosis type 2 (NF2) expressing a dominant mutant form of merlin under the Schwann cell-specific P0 promoter. Approximately 85% of the investigated mice showed putative tumors by 24 months of age. Specifically, 21% of the mice showed tumors in the intercostal muscles, 14% in the limb muscles, 7% in the spinal cord and spinal ganglia, 7% in the external ear, 14% in the muscle of the abdominal region, and 7% in the intestine; 66% of the female mice had uterine tumors. Multiple tumors were detected by MRI in 21% of mice. The tumors were isointense with muscle by T1-weighted MRI, showed strong enhancement following administration of gadolinium-DTPA, and were markedly hyperintense by T2-weighted MRI, all hallmarks of the clinical manifestation. Hematoxylin and eosin staining and immunohistochemistry indicated that the tumors consisted of schwannomas and Schwann cell hyperplasias. The lesions stained positively for S-100 protein and a marker antigen for the mutated transgenic NF2 protein, confirming that the imaged tumors and areas of hyperplasia were of Schwann cell origin and expressed the mutated NF2 protein. Tumors were highly infectable with a recombinant herpes simplex virus type 1 vector, hrR3, which contains the reporter gene, lacZ. The ability to develop schwannoma growth with a noninvasive imaging technique will allow assessment of therapeutic interventions.

Animals↗
PubMed1998

Expression of Kit in neurofibromin-deficient human Schwann cells: role in Schwann cell hyperplasia associated with type 1 neurofibromatosis.

Type 1 Neurofibromatosis (NF1) is characterized by the formation of neurofibromas, benign tumors composed mainly of Schwann cells, which can turn malignant to form neurofibrosarcomas. Neurofibromin, the protein product of the Nf1 gene, is believed to act as a tumor suppressor, accelerating the conversion of the oncogene Ras to its inactive form. The absence of neurofibromin could therefore lead to higher Ras activity in Schwann cells, resulting in uncontrolled growth through a cascade of events not yet elucidated. We describe the abnormal expression of high levels of the Kit tyrosine kinase receptor in both NF1-derived Schwann cell lines and tissue, as compared to primary Schwann cells or schwannoma-derived cells. High levels of Kit expression in the neurofibrosarcoma-derived Schwann cells correlate with a decrease in neurofibromin expression. Using inhibitors of tyrosine kinase receptors, we found that proliferation of the neurofibrosarcoma-derived cells is dependent upon activation of a subclass of tyrosine-kinase receptors. The proliferation of these cells is not dependent upon an autocrine loop involving typical Schwann cell mitogens. Finally, the proliferation of the neurofibrosarcoma-derived Schwann cells can be increased by stimulation with Kit ligand. These data implicate Kit as one of the components leading to the Schwann cell hyperplasia observed in NF1.

Animals↗
PubMed2003

Mlh1 deficiency accelerates myeloid leukemogenesis in neurofibromatosis 1 (Nf1) heterozygous mice.

Defects in DNA mismatch repair (MMR) have been implicated in the genesis of a diverse set of human cancers. Recent studies have suggested that one of the targets of MMR is the neurofibromatosis 1 (NF1) gene. To evaluate the contribution of Mlh1 MMR deficiency to Nf1 tumorigenesis, Mlh1-/-;Nf1+/- mice were generated. All Mlh1-/-;Nf1+/- mice (n=21) were dead by 260 days compared to none of the Nf1+/- mice. In all, 50% of the Mlh1-/-;Nf1+/- mice were dead at 150 days compared to 252 days for Mlh1-/- mice. Nine of the Mlh1-/-;Nf1+/- mice were found to harbor intrathoracic NOS2-immunoreactive myeloid leukemias similar to the hematopoietic malignancies observed in older Nf1+/- mice. As expected, significant microsatellite instability was observed in six of six tumors and neurofibromin expression was lost in all tumors analysed. These results suggest that MMR deficiency can accelerate myeloid leukemogenesis in Nf1+/- mice, presumably by inactivating Nf1 gene expression.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Characterization of functional elements in the neurofibromatosis (NF1) proximal promoter region.

An essential requirement to understand how genes contribute to genetic disease is the thorough knowledge of the transcriptional regulation of gene expression. Here, we have characterized transcription factor binding sites within the type 1 neurofibromatosis (NF1) proximal regulatory region, and addressed the molecular mechanisms that regulate NF1 transcription. Overlapping regions of the NF1 proximal promoter have been cloned and characterized for use in luciferase reporter assays. These assays have identified a 500 bp region displaying activities up to 80-fold higher than control reporter levels. Mutations at putative CRE and SP1-binding sites immediately 5' to the transcription start site have dramatic effects that lead to a 70-90% decrease in reporter activity in all cell lines tested. Gelshift assays confirm binding of CREB and SP1/KLF family members to their putative recognition sequences, and provide the first evidence identifying functional sites likely involved in regulating NF1 transcription. These assays have also revealed a putative repressor region within the NF1 promoter region corresponding to CCCTC-rich sequences between the transcription and translation start sites. This work provides new information concerning the transcriptional regulation of the NF1 gene, and is the most thorough attempt to date to map functionally relevant regions within the NF1 proximal promoter region.

Cell Line↗
PubMed2003

Spinal subarachnoid hematoma compressing the conus medullaris and associated with neurofibromatosis type 2.

STUDY DESIGN: Report of a case of subarachnoid hematoma associated with neurofibromatosis type 2 (NF2) in a 10-year-old girl. OBJECTIVE: To report a rare case of subarachnoid spontaneous hematoma associated with NF2, with no evidence of trauma. SETTING: Gifu, Japan. METHODS: The patient presented with severe leg pain. MRI revealed a subarachnoid hematoma at the level of L2 and a spinal cord tumor at the level of T6. The subarachnoid hematoma had low and high heterogeneous signal intensity on the T1-weighted image and low signal intensity on the T2-weighted image, indicating the presence of extracellular methemoglobin. The tumor and hematoma were resected. RESULTS: Pathological analysis demonstrated that the surgical specimen removed from the area of L2 was a hematoma and the specimen from T6 was a neurinoma. At follow-up 1 year after surgery, the girl remained neurologically asymptomatic. CONCLUSIONS: This rare case of spinal subarachnoid hematoma was associated with NF2. MRI was useful in establishing the diagnosis.

Child↗
PubMed2001

The neurofibromatosis 2 protein product merlin selectively binds F-actin but not G-actin, and stabilizes the filaments through a lateral association.

The neurofibromatosis 2 protein product merlin, named for its relatedness to the ezrin, radixin and moesin (ERM) family of proteins, is a tumour suppressor whose absence results in the occurrence of multiple tumours of the nervous system, particularly schwannomas and meningiomas. Merlin's similarity to ERMs suggests that it might share functions, acting as a link between cytoskeletal components and the cell membrane. The N-terminus of merlin has strong sequence identity to the N-terminal actin-binding region of ezrin; here we describe in detail the merlin-actin interaction. Employing standard actin co-sedimentation assays, we have determined that merlin isoform 2 binds F-actin with an apparent binding constant of 3.6 microM and a stoichiometry of 1 mol of merlin per 11.5 mol of actin in filaments at saturation. Further, solid-phase binding assays reveal that merlin isoforms 1 and 2 bind actin filaments differentially, suggesting that the intramolecular interactions in isoform 1 might hinder its ability to bind actin. However, merlin does not bind G-actin. Studies of actin filament dynamics show that merlin slows filament disassembly with no influence on the assembly rate, indicating that merlin binds along actin filament lengths. This conclusion is supported by electron microscopy, which demonstrates that merlin binds periodically along cytoskeletal actin filaments. Comparison of these findings with those reported for ERM proteins reveal a distinct role for merlin in actin filament dynamics.

Actins↗
PubMed2001

Binding of the merlin-I product of the neurofibromatosis type 2 tumour suppressor gene to a novel site in beta-fodrin is regulated by association between merlin domains.

The mechanism underlying the tumour-suppressor activity of the neurofibromatosis type 2 (NF2) gene product, merlin, is largely undefined but there is evidence that the biological function of the protein might be mediated partly through interactions with the cytoskeleton. Merlin is expressed predominantly as two isoforms that differ at their C-termini owing to alternative splicing of exon 16. By expressing merlin isoform I as bait in a yeast two-hybrid screen, we isolated a clone encoding a region of the cytoskeletal protein beta-fodrin. Confirmation of the merlin-fodrin interaction was provided by using the mammalian two-hybrid system and binding assays in vitro. In addition, these assays and co-immunoprecipitation from mammalian cells revealed that the binding site for fodrin is located in the C-terminal half of merlin at a site that is masked in the native protein. Co-expression of the N-terminus of merlin decreased the interaction of its C-terminus with fodrin, implicating homophilic interactions of merlin isoform I in masking the fodrin-binding site. The effect of three disease-associated mutations on the merlin-fodrin interaction and merlin dimerization was also investigated. The mutation L535P, but not L360P or K413E, significantly decreased the merlin-fodrin interaction but not dimerization, indicating that the tumour suppressor ability of merlin might reside partly in its ability to interact with the cytoskeleton via fodrin.

Amino Acid Sequence↗
PubMed1999

Fetal antigen 1, a member of the epidermal growth factor superfamily, in neurofibromas and serum from patients with neurofibromatosis type 1.

Fetal antigen 1 (FA1) is a 26-32 kDa glycoprotein containing six epidermal growth factor-like repeats closely related to the delta/notch/serrate proteins in Drosophila. FA1 has been shown to be involved in cell differentiation in a juxtacrine/paracrine manner. As neurofibromatosis type 1 (NF-1), also called von Recklinghausen disease, involves aberrant growth of tissues derived from the neural crest, the expression of FA1 was examined in neurofibroma skin biopsies and serum from patients with NF-1. FA1 was found in the spindle cells of all (n = 10) skin tumour specimens from adult NF-1 patients, whereas normal dermis was FA1 negative. In adults, the serum FA1 levels were significantly higher in NF-1 patients (n = 13) than in normal healthy controls (n = 177) (P = 0.037). In the group of children with NF-1 (n = 9), significantly higher serum FA1 levels were observed in those known to have complications with cerebral or spinal involvement (n = 4) (P = 0.014). The presence of FA1 in neurofibroma specimens and the elevated serum levels in patients with NF-1 suggests that FA1 may be involved in the pathogenesis of NF-1, perhaps acting as a growth promoting factor.

Adolescent↗
PubMed2000

Cost evaluation of the medical management of neurofibromatosis 1: a prospective study on 201 patients.

Neurofibromatosis 1 (NF1) is associated with many internal complications as well as skin manifestations, and patients may require a variety of medical and surgical interventions. We aimed to assess the medical needs of NF1 patients, and to evaluate the financial cost of the resources used for them in relation to the severity of the disease. We conducted a prospective analysis on a cohort of 201 patients in our referral centre for adults. Severity of the disease was assessed. Therapeutic management was considered as multidisciplinary if it required more than three different specialists. Plastic and dermatological surgery procedures performed were recorded. Hospital costs were computed over a 3-year period and included all hospitalization days, clinic visits and procedures performed in all departments where the patients were admitted. One hundred and thirty-seven patients had at least one out-patient procedure or one hospitalization during the follow-up period. The mean cost per patient per year was pound810 (median 240; range 0-13, 860). Multidisciplinary procedures were more frequent in moderately and severely affected NF1 patients than in milder cases (P < 0. 0001); hence, the costs for moderate and severe cases were higher than for less severe groups (P = 0.005). Plastic and/or dermatological surgery was performed with the same frequency in the different severity groups (71%). Regardless of the presence of serious intractable complications, the patients' priority is for treatment of the disfigurement due to the disease. The management of these patients can be considered relatively inexpensive from the viewpoint of the healthcare system.

Adolescent↗
PubMed2002

Epidermodysplasia verruciformis associated with neurofibromatosis type 1: coincidental association or model for understanding the underlying mechanism of the disease?

We describe a 25-year-old man with epidermodysplasia verruciformis (EV) associated with neurofibromatosis type 1 (NF1). The lesions, persisting for more than 15 years, consisted of widespread planar warts on the backs of the hands and wrists, and reddish-brown macules on the trunk, neck and face. During the last 5 years, our patient developed several epithelial tumours, namely solar keratoses, plaques of Bowen's disease and squamous cell carcinomas (SCCs). He also presented with NF1 lesions with neurofibromas, café-au-lait macules, axillary freckling and Lisch nodules. He had left tibial bowing. Polymerase chain reaction analysis of the skin lesions demonstrated the presence of human papillomavirus (HPV) 15 in a flat wart, HPV 20 in a plaque of Bowen's disease, and HPV 15 and HPV 20 in an SCC lesion. Both EV and NF1 show an inherited predisposition to malignancy but the molecular mechanism underlying tumour development is not fully understood. The appearance of both diseases in our patient may be a coincidental association but may also contribute to the identification of loci for susceptibility to NF1 and EV on chromosome 17.

Adult↗
PubMed2003

A possible paracrine hedgehog signalling pathway in neurofibromas from patients with neurofibromatosis type 1.

BACKGROUND: Hedgehogs (Hhs) and their receptors are involved in organ development as well as in tumorigenesis observed in basal cell carcinoma. Among Hhs, Desert hedgehog secreted from Schwann cells mediates the formation of peripheral nerve sheaths. However, there has been no study on the role of Hhs and their receptors in tumorigenesis of neurofibromas in neurofibromatosis type 1 (NF1). OBJECTIVES: To clarify the expression and localization of Hhs and their receptors in neurofibromas of NF1 patients. METHODS: Expression of Hhs and their receptors was studied by immunohistochemistry using neurofibromas from NF1 patients and control normal skin samples. RESULTS: In neurofibromas, CD57-positive tumour cells with delicate elongated processes were positive for the receptor PTCH2. Perineurial cells of involved nerves within neurofibromas as well as those of normal cutaneous nerves expressed Indian hedgehog and Sonic hedgehog. Schwann cells of normal cutaneous nerves were positive for PTCH2. CONCLUSIONS: Our study suggests that a paracrine Hh signalling pathway may be involved in tumorigenesis of neurofibromas in NF1.

CD57 Antigens↗
PubMed2003

The mechanism of epidermal hyperpigmentation in café-au-lait macules of neurofibromatosis type 1 (von Recklinghausen's disease) may be associated with dermal fibroblast-derived stem cell factor and hepatocyte growth factor.

BACKGROUND: The mechanism of the accentuated melanization in café-au-lait macules (CALMs) in patients with neurofibromatosis type 1 (NF1; von Recklinghausen's disease) has not been elucidated. OBJECTIVES: To clarify the mechanism involved in the hyperpigmentation of CALMs in NF1. METHODS: Using enzyme-linked immunosorbent assay (ELISA) and reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of cultured cells, we measured the levels of cytokines produced and secreted by keratinocytes and fibroblasts derived from CALMs (group RC: Recklinghausen CALM) skin, compared with cells derived from the skin of normal individuals (group NN: Normal skin of Normal individuals) and cells derived from non-CALM skin of NF1 patients (group RN: Recklinghausen Non-CALM). RESULTS: ELISA revealed that the secretion of hepatocyte growth factor (HGF) and stem cell factor (SCF) by cultured fibroblasts was significantly elevated in group RC compared with groups RN and NN. In parallel, semiquantitative real-time RT-PCR of HGF and SCF mRNAs demonstrated increased expression of both types of transcripts by cultured fibroblasts in group RC compared with group NN. In contrast, the secretion of endothelin-1 and granulocyte/macrophage colony-stimulating factor by cultured keratinocytes occurred at a similar level among all three groups, RC, RN and NN. CONCLUSIONS: These findings suggest that increased secretion of HGF and SCF by dermal fibroblasts may be associated with the accentuated epidermal melanization observed in CALMs in the skin of NF1 patients.

Adult↗
PubMed2000

A clinical study of vestibular schwannomas in type 2 neurofibromatosis.

All 13 patients with neurofibromatosis 2 (NF2) who presented over a period of 17 years at the Institute of Neurological Sciences, Glasgow were reviewed and compared to patients with sporadic vestibular schwannomas. The NF2 patients presented at a younger age than those with sporadic vestibular schwannomas. A significant number had normal pure tone audiograms and a small number also had normal auditory brainstem responses at presentation. Vestibular schwannomas in NF2 patients grow more often and more rapidly than sporadic unilateral ones. They are more liable to infiltrate the cochlear and facial nerves making hearing and facial nerve preservation more difficult to achieve. Because the relatives of these patients often have normal audiograms and normal auditory brain stem responses in the presence of a schwannoma, our recommended method of screening of relatives of NF2 patients is magnetic resonance image scanning with Gd-DTPA enhancement.

Adolescent↗
PubMed2000

Loss of neurofibromatosis 1 (NF1) gene expression in NF1-associated pilocytic astrocytomas.

The critical role of the neurofibromatosis 1 (NF1) gene as a tumour suppressor has been clearly demonstrated for malignancies arising in NF1 patients. However, little is known about the more common benign tumours, such as the pilocytic astrocytoma. Most NF1-associated astrocytomas are benign and clinically non-progressive, though aggressive tumours are occasionally encountered. In this study, eight pilocytic astrocytomas from six individuals affected with NF1 were analysed for NF1 expression. All eight tumours demonstrated loss of neurofibromin expression by immunohistochemistry, which was confirmed in one case using Western blot analysis. Microsatellite analysis showed loss of a single NF1 allele (LOH) in two of four NF1-associated tumours. These results demonstrate that, in contrast to sporadic astrocytomas, loss of NF1 expression is an important primary genetic event in the pathogenesis of NF1-associated pilocytic astrocytomas.

Adolescent↗
PubMed2003

Endovascular treatment for bilateral vertebral arteriovenous fistulas in neurofibromatosis 1.

We report a rare case of a 36-year-old woman with neurofibromatosis 1 (NF1) with bilateral vertebro-vertebral arteriovenous fistulas. The patient presented with quadriparesis and had neck pain. Angiography revealed vertebral arteriovenous fistulas bilaterally with dilated epidural venous plexuses compressing the cervical cord resulting in quadriparesis. Endovascular treatment using coils and balloons resulted in successful occlusion of both fistulas. At 6-months postembolization, the patient had improved significantly and is now able to walk with support.

Adult↗
PubMed2001

Neurofibromatosis type 1-associated unusual pleomorphic astrocytoma displaying continual malignant progression.

Patients with neurofibromatosis type 1 (NF1) often have gliomas as a complication, most of which are benign pilocytic astrocytomas which have arisen in optic pathways. In the present case, a 17-year-old girl (at death) with stigmata of NF1, initially had a bulky tumor mass in the left thalamus, developing into the lateral ventricle, at 13 years of age. Partially resected tissue samples showed pleomorphic astrocytoma with abundant xanthoma cells and degenerative structures such as Rosenthal fibers (RF) and eosinophilic granular bodies. Fine eosinophilic granules identical to RF, both immunophenotypically and ultrastructurally, were also seen. The residual tumor was subtotally resected 6 months later, and the tumor histology was essentially similar as before, accompanying the regenerative structures; this was believed to be a good prognostic indicator. However, several anaplastic features such as mitosis, necrosis and vascular proliferation appeared even in areas rich in the regenerative structures. After a 2-year, disease-free interval, multiple tumor relapse occurred in June 1997. Partially resected tumor tissues were composed of monotonous small anaplastic cells with prominent proliferative activity. Surprisingly, the tumor cells had retained eosinophilic granules within the cell bodies. Postoperative chemotherapy with procarbazine, MCNU and vincristine (PCV) suppressed the residual tumor dramatically, but the regrowing tumor finally became uncontrollable, leading to the patient's death. TP53 mutation was not detected, while p27 immunopositivity was constantly high during malignant progression, suggesting acquisition of proliferative activity to overcome p53 and p27 inhibitory functions. A review of previously published reports failed to reveal any cases of this type.

Adolescent↗