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PubMed1992

Aberrant regulation of ras proteins in malignant tumour cells from type 1 neurofibromatosis patients.

Defects in the NF1 gene have been implicated in the inherited disorder neurofibromatosis type 1, which is characterized by several developmental abnormalities including an increased frequency of benign and malignant tumours of neural crest origin (neurofibromas and neurofibrosarcomas respectively). The NF1 gene encodes a ubiquitous protein homologous to p120GAP, the GTPase-activating protein (GAP) for the products of the ras protooncogenes. When expressed in non-mammalian systems, the region of the NF1 gene homologous to p120GAP produces a protein with GAP-like activity. Here we present evidence that the ras proteins in malignant tumour cell lines from patients with type 1 neurofibromatosis are in a constitutively activated state, as judged by the guanine nucleotide bound to them, and are necessary for cellular proliferation. These cells contain p21ras and p120GAP that are both functionally wild type, but barely any functional NF1 protein. Our results show that the NF1 protein is normally essential for correct negative regulation of ras proteins in the cell, even in the presence of normal p120GAP, and they support the hypothesis that NF1 is a tumour-suppressor gene whose product acts upstream of ras.

Antibodies, Monoclonal↗
PubMed2002

Malignant peripheral nerve sheath tumors are t(X;18)-negative sarcomas. Molecular analysis of 25 cases occurring in neurofibromatosis type 1 patients, using two different RT-PCR-based methods of detection.

To verify the absence of the synovial sarcoma translocation t(X;18) (SYT-SSX) in malignant peripheral nerve sheath tumors, 34 tumor samples from 25 neurofibromatosis type 1 patients were examined in two independent laboratories (Bordeaux, France, and Lausanne, Switzerland) using reverse transcriptase polymerase chain reaction (RT-PCR)-based techniques. RNA was extracted from paraffin blocks using standard methods, reverse transcribed, and conventional (in one laboratory) versus real-time (in the other laboratory) PCR performed. Twenty-seven tumor samples from 19 patients were negative for the t(X;18) in both laboratories; six additional tumors that were t(X;18)-negative in one laboratory gave noninterpretable results in the other, due to lack of internal positive controls; one case was noninterpretable in both places. In conclusion, malignant peripheral nerve sheath tumors in neurofibromatosis type 1 patients do not bear the synovial sarcoma t(X;18) (SYT-SSX). Laboratories that use PCR-based techniques for diagnostic purposes would benefit from quality assurance programs.

Adolescent↗
PubMed2004

Neurofibromatosis type I with periodontal manifestation. A case report and literature review.

The term neurofibromatosis (NF) is used for a group of genetic disorders that primarily affect the cell growth of neural tissues. Neurofibromatosis type 1 (NF1), also known as von Recklinghausen's disease, is the most common type of NF and accounts for about 90% of all cases. It is one of the most frequent human genetic diseases, with a prevalence of one case in 3,000 births. The expressivity of NF1 is extremely variable, with manifestations ranging from mild lesions to several complications and functional impairment. Oral manifestations can be found in almost 72% of NF1 patients. A case of a NF1 patient with a gingival neurofibroma in the attached gingiva of the lingual aspect of the lower central incisors is presented. The lesion was nodular, with sessile base, non-ulcerated, non-painful, with normal colour and measured 1 cm in diameter. An excisional biopsy of the oral lesion was performed. Histopathological and immunohistochemical analysis confirmed the clinical hypothesis of neurofibroma. Because NF1 is one of the most common genetic diseases and oral manifestations are very common, dentists should be aware of the characteristics of this disease.

Biopsy↗
PubMed1999

Site-specific DNA methylation in the neurofibromatosis (NF1) promoter interferes with binding of CREB and SP1 transcription factors.

Tumour suppressor genes and growth regulatory genes are frequent targets for methylation defects that can result in aberrant expression and mutagenesis. We have established a methylation map of the promoter region of the neurofibromatosis (NF1) gene and demonstrated functional sensitivity for methylation at specific sites for the SP1 and CRE binding (CREB) proteins in the NF1 regulatory region. We evaluated the methylation status of CpG dinucleotides within five promoter subregions in the human and mouse homologues of the neurofibromatosis (NF1) genes. Three 5' subregions were found to be consistently methylated in all the tissues analysed. In contrast, DNA methylation was absent in the vicinity of the transcription start site bounded by SP1 recognition sequences. Gelshift assays showed that methylation specifically inhibits the CREB transcription factor from binding to its recognition site at the NF1 transcription start site. Furthermore, SP1 elements within the NF1 promoter are methylation sensitive, particularly when methylation is present on the antisense strand. We propose that for NF1 as with several other tumour suppressor genes, CpG methylation occurs in a complex, site-specific manner with the maintenance of a methylation-free promoter region bounded by SP1 binding sites that allow an accessible promoter to be retained. When these SP1 boundaries are breached, methylation can sweep in, rendering the promoter inaccessible for specific methylation-sensitive transcription factors and leading to a loss of functional integrity of the methylation-free CpG island.

Animals↗
PubMed2002

Loss of neurofibromatosis-1 and p19(ARF) cooperate to induce a multiple tumor phenotype.

Inactivation of the neurofibromatosis-1 (NF1) gene de-regulates RAS and cooperates with mutation or loss of the p53 tumor suppressor to induce tumorigenesis. p19(ARF) acts upstream of p53 in an oncogene checkpoint to induce apoptosis in response to activated RAS and other factors that stimulate proliferation. Therefore, we bred p19(ARF-/-) to NF1(+/-) mice to determine if loss of these genes collaborates in tumorigenesis. As expected from the embryonic lethality of NF1 null mice, no mice lacking both p19(ARF) and NF1 were born. Unexpectedly, the loss of one allele of NF1 did not greatly shorten the time to tumor formation in a p19(ARF) null background. The tumor types observed were characteristic of p19(ARF) null animals, not those associated with neurofibromatosis or those observed with NF1(+/-)/p53(+/-) mice. However, seven out of 12 animals developed multiple tumors, some with metastases. This multiple tumor phenotype was not previously observed with p19(ARF)-null mice and suggests a distinct form of cooperation between the loss of these tumor suppressors.

Animals↗
PubMed1996

Headache in patients with neurofibromatosis type 1.

A study of headache in a homogeneously ascertained population of 181 subjects suffering from neurofibromatosis type 1 is described. All subjects underwent a diagnostic protocol including imaging studies (for subjects over 5 years old up until 1992). Headache data were collected by means of a questionnaire. Headache was present in 55 of 181 subjects (25 males). Overall headache frequency was 30%, which is not significantly different from the frequency of headache reported in the general population. Headache was primary in 52 cases (5 migraine and 47 tension-type) and secondary to obstructive hydrocephalus with brain tumor-induced intracranial hypertension in 3 with a tension-type pattern. It was concluded that headache is not a specific feature of neurofibromatosis type 1, it is not significantly related to central nervous system abnormalities, and in itself, it is not an indication for neuroradiological examination.

Adolescent↗
PubMed1999

Malignant peripheral nerve sheath tumours associated with von Recklinghausen's neurofibromatosis.

AIMS: A retrospective study was conducted of patients with von Recklinghausen's neurofibromatosis who developed malignant peripheral nerve sheath tumours to determine their clinical characteristics, treatment outcome and prognostic factors. METHODS: During the period 1987-1995, 29 patients with von Recklinghausen's neurofibromatosis (VRN) were seen at the Royal Marsden Hospital, of whom 23 had malignant peripheral nerve sheath tumours (MPNSTs). RESULTS: The median age of the patients with MPNSTs was 30 years and the sex distribution was equal. The commonest site was the lower extremity, with a tendency for tumours to occur in the proximal parts. A nerve of origin was identified in 59% of the tumours and heterologous differentiation was present in 26%. Multiple primary MPNSTs occurred in four patients (17%) and other malignant tumours developed in three (13%). The overall 5-year survival was 35% with a median survival of 36 months. The incidence of local recurrence was 38% and 75% of them occurred within 2 years. CONCLUSIONS: MPNSTs which develop in association with VRN occur in a younger age group, tend to be of a higher histological grade and are associated with a very poor prognosis. Tumour size > or = 10 cm (P=0.003) and high tumour grade (P=0.003) were adverse independent prognostic factors for overall survival.

Diagnosis, Differential↗
PubMed1977

[Renovascular hypertension in neurofibromatosis. Simultaneous occurrence of multiple abdominal and cerebral vascular abnormalities (author's transl)].

Vascular involvement in von Recklinghausen's neurofibromatosis has been known since the work of Reubi (1944, 1946). We found 72 cases of neurofibromatosis with renovascular hypertension reported in the literature. We have observed three female patients, of whom two had unilateral renal artery abnormalities consisting of stensoses and small aneurysms. The third patient, who had a right-sided nephrectomy for probable occlusion of the renal artery, had a coarctation of the abdominal aorta and complete occlusion of the left renal artery and of the coeliac-mesenteric trunk. There were, in addition, large, bilateral aneurysms in the circle of Willis.

Adult↗
PubMed2000

[Ganglioglioma of optic nerve in neurofibromatosis type 1. Case report and review of the literature].

BACKGROUND: Gangliogliomas are rare tumors of the central nervous system. In only seven cases they have been found within the optic nerve. Two of these cases were associated with neurofibromatosis (NF), but a pathogenic link between gangliogliomas of the optic nerve and NF still remains controversial. PATIENT: Here we report on a 71-year-old patient with a ganglioglioma of the optic nerves and NF type 1. Post mortem examination revealed multiple neurofibromas of the vagal and left femoral nerves, multiple schwannomas of the small bowel and Lisch noduli of both irides. In addition, a spindle shaped thickening of the right optic nerve was observed in its intracranial portion. The left optic nerve was normal on gross inspection. RESULT: Histologically, tumoral tissue was found in both optic nerves. The tumor was composed of two cell types: highly differentiated, partly stellate, partly pilocytic astrocytes and, at the rim of the axon bundles of the optic nerve, fully developed synaptophysin- and neurofilament-antigen-positive ganglion-cells with short corkscrew-shaped processes. No mitosis could be found in the neuronal or in the glial cell population. In spite of the tumoral involvement of the optic nerves, there has been no evidence of visual disturbance. CONCLUSION: Optic nerve tumors in NF most often are of glial origin (astrocytomas, pilocytic astrocytomas). Our case illustrates the rare condition of a glioneuronal tumor associated with neurofibromatosis type 1.

Aged↗
PubMed2000

Generalized nerve sheath tumors in neurofibromatosis type 1 (NF1). A case report.

We describe a case of chronic distal sensorimotor neuropathy associated with neurofibromatosis type 1 (NF1) in a 15-year old girl. The patient showed a striking clinical picture consisting of diffuse nodular enlargements of peripheral nerves. Motor conduction velocities were decreased and sensory responses were absent after maximal stimulation. Magnetic resonance imaging (MRI) was performed throughout the body and disclosed generalized nerve sheath neurofibromas affecting all peripheral nerves. Intracranially, the patient had a glioma of the left optic nerve, but no other cranial nerve involvement. These results demonstrate the value of MRI for visualization of the peripheral nervous system in neurofibromatosis.

Child, Preschool↗
PubMed2000

[A young woman with neurofibromatosis 1 (Recklinghausen disease), abdominal tumor and hypertension].

HISTORY AND ADMISSION FINDINGS: A 38-year-old woman, known to have type 1 neurofibromatosis (NF1; von Recklinghausen's disease) and recurrence of a malignant haemangiopericytoma in the lower abdomen developed hypertension. She also had headaches and marked perspiration. Physical examination revealed tachycardia and paleness of the distal digits, in addition to multiple neurofibromas and café-au-lait spots. INVESTIGATIONS: A tumour was found in the region of the right adrenal gland, in addition to the known haemangiopericytoma. The levels of epinephrine and dopamine were elevated, suggesting an orthotopic phaeochromocytoma as the cause of the hypertension. Mutation analysis confirmed the neurofibromatosis by demonstrating a splice mutation of the NF1 gene in exon 8. She also was found to have emphysema of the right upper and middle lobes of the lung. TREATMENT AND COURSE: Because of the extensive local changes the recurrent haemangiopericytoma was only partially resected. At the same time a right adrenalectomy was performed without complication. However, the patient's postoperative recovery was slow, but she was now normotensive. Planned radiotherapy was omitted because of her poor general state. Instead she was given weekly palliative chemotherapy with adriamycin, with little improvement. She died several weeks later from the malignancy. CONCLUSION: This case emphasizes that in a patient with NF1 a phaeochromocytoma must be considered as a possible cause of hypertension. It is likely that the patient's emphysema was associated with the NF1, while the haemangiopericytoma was presumably unconnected with the NF1.

Abdominal Neoplasms↗
PubMed2004

[Gastrointestinal stromal tumours (GIST) of the jejunum in a patient with neurofibromatosis type 1 (von Recklingshausen's disease)].

CASE REPORT: A 72-year-old female patient with known neurofibromatosis type 1 was admitted to the hospital with symptomatic anaemia and a history of melaena. Upper and lower endoscopy did not show any signs of bleeding. Ultrasound and computed tomography revealed an abdominal mass. The histological analysis of a US-guided puncture showed a mesenchymal tumour with spindle-shaped appearance. Laparotomy revealed two jejunal tumours which could be classified as gastrointestinal stromal tumours (GIST) by immunohistochemistry. CONCLUSION: Patients with neurofibromatosis type 1 have an increased risk of developing gastrointestinal tumours including rare types such as GIST. Because the localisation in the small intestine by conventional endoscopy can be difficult, further diagnostic means such as ultrasound, computed tomography or possibly capsule endoscopy should be considered.

Aged↗
PubMedDate not supplied

[Posteromedial bowing of the lower leg and neuroblastoma with possible neurofibromatosis type I: a case report and literature review].

BACKGROUND: The posteromedial bowing of the tibia is a rare condition that is not yet known to be related to neurofibromatosis. The case of a three month-old boy with the tentative diagnosis of neurofibromatosis is described. He developed paraplegia due to an abdominal neuroblastoma at the age of 9 months. This led us to a review of the literature. METHOD: 122 cases of posteromedial bowing of the tibia in 20 publications of the years 1949 - 2000 were analysed under special respect to gender, side of affection, shortening of the lower leg, treatment and possible cause. RESULTS: The posteromedial bowing of the lower leg seems to affect more boys as well as the left side. As far as described in all but one case it was the first delivery. Regularly, a limb shortening and pes calcaneovalgus is to be found. 99 children were treated conservatively, 21 got an operation of the affected side. In 19 performed osteotomies no pseudarthrosis occurred. One case of a fracture due to an adequate trauma without healing problems is described.

Abdominal Neoplasms↗
PubMed1999

Neurofibromatosis type 1: the role of neuroradiology.

Neurofibromatosis type 1 is the commonest of the phakomatoses with a prevalence of 1 in 3-4000. In common with most of the other phakomatoses it is a genetic disorder with typical dermatological manifestations. Many organ systems can be affected but brain, spine, cranial nerve and peripheral nerve involvement is frequent. In this review we will describe the central nervous system manifestations of neurofibromatosis type 1 and discuss some of the controversies raised by investigating children with this disorder.

Brain↗
PubMed1997

Prenatal ultrasound abnormalities in a patient with generalized neurofibromatosis type 1.

We describe a patient with an unusual neonatal disseminated form of neurofibromatosis (NF1). Prenatal ultrasound studies, at 35 weeks of gestation, revealed ambiguous external genitalia, an increased biparietal diameter and a decreased growth of long bones. Postnatal examination displayed generalized neurofibromatosis, with perineal, thoracic and spinal cord invasion by tumors. Spinal cord compression was responsible for paraparesis. The child died of a pulmonary infection at five years of age. No previous report of such prenatal abnormalities has been described. Genetic counselling is difficult because of the variable expression of the illness.

Abnormalities, Multiple↗
PubMed1997

An association between optic glioma and other tumours of the central nervous system in neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) has a very heterogeneous phenotype. It is not currently possible to predict which patients will have mild disease and which will develop serious complications. Medical management of patients with NF1 might be improved if subgroups of patients who are at especially high (or low) risk for particular complications could be identified. We have begun an analysis of NF1 patients in the National Neurofibromatosis Foundation International Database (NNFFID) to identify possible associations between the occurrence of clinical features. A striking association has been observed between the presence of optic glioma and of other central nervous system (CNS) tumours in NF1 patients. This association is not dependent on the effect of age. No association is seen between optic glioma and non-CNS neoplasms. The association of optic glioma and other intracranial neoplasms in patients with NF1 suggests that there are fundamental pathophysiological differences between patients with and without optic glioma.

Age Factors↗
PubMed1990

[The MR tomographic findings in cranial manifestations of neurofibromatosis].

Twelve patients with central neurofibromatosis underwent MR examination of the head. Among these, chiasma glioma was the most common CNS tumour (6/12). Seven patients had multifocal areas of increased T2-signal without mass effect predominantly involving the region of the basal ganglia. No corresponding CT abnormalities were present. These lesions may represent multifocal dysplasia and seem to be characteristic of central neurofibromatosis.

Adolescent↗