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A case report of bilateral acoustic neurofibromatosis (NF-2) is presented with temporal bone histopathology. The distinct clinical and genetic features of NF-2 are reviewed in the context of recent data that show it to be a disorder distinct from classic von Recklinghausen's disease (NF-1).
The neurofibromatoses comprise at least two autosomal dominant disorders affecting an estimated 100,000 Americans with clinical manifestations that may require care from every type of clinician. Neurofibromatosis 1 and neurofibromatosis 2 have in common the occurrence of many neurofibromas but are distinctly different clinical disorders. The disease genes are on different chromosomes. Magnetic resonance imaging, particularly with gadolinium enhancement, has generally supplanted other techniques for visualizing brain, spinal, and other neural tumors in both disorders. The technique has rekindled the controversy over the nature and frequency of optic pathway tumors in patients with neurofibromatosis 1 and has revealed, throughout the brains of young patients, bright lesions that have uncertain clinical consequences and unknown pathologic bases. In patients with neurofibromatosis 2, small acoustic neuromas can be seen, leading to the possibility of excision with preservation of hearing and facial nerve function. Abnormal hearing may occur to excess in patients with neurofibromatosis 1, but acoustic neuroma has never been documented. In patients with neurofibromatosis 2, a battery of audiologic tests has a high positive predictive power. Lisch nodules or iris hamartomas, probably a universal sign in adults with the neurofibromatosis 1 gene, cause no problem with vision. Posterior capsular lens opacity in patients with neurofibromatosis 2 is a helpful diagnostic sign and a potential source of additional handicap in persons at risk for impaired hearing. Progress in the clinical delineation of the disorders has been matched with considerable research into the still obscure pathogenesis of the disorders. Such rapid advances may necessitate reconsideration of the conclusions of the National Institutes of Health Consensus Development Conference on Neurofibromatosis, especially those on the categories of persons in which a neurofibromatosis should be considered and the need for caution in recommending surgery. Watchful waiting may often be the best management for acoustic neuromas in neurofibromatosis 2.
OBJECTIVE: Neurofibromatosis 1 and neurofibromatosis 2 are autosomal dominant genetic disorders in which affected individuals develop both benign and malignant tumors at an increased frequency. Since the original National Institutes of Health Consensus Development Conference in 1987, there has been significant progress toward a more complete understanding of the molecular bases for neurofibromatosis 1 and neurofibromatosis 2. Our objective was to determine the diagnostic criteria for neurofibromatosis 1 and neurofibromatosis 2, recommendations for the care of patients and their families at diagnosis and during routine follow-up, and the role of DNA diagnostic testing in the evaluation of these disorders. DATA SOURCES: Published reports from 1966 through 1996 obtained by MEDLINE search and studies presented at national and international meetings. STUDY SELECTION: All studies were reviewed and analyzed by consensus from multiple authors. DATA EXTRACTION: Peer-reviewed published data were critically evaluated by independent extraction by multiple authors. DATA SYNTHESIS: The main results of the review were qualitative and were reviewed by neurofibromatosis clinical directors worldwide through an Internet Web site. CONCLUSIONS: On the basis of the information presented in this review, we propose a comprehensive approach to the diagnosis and treatment of individuals with neurofibromatosis 1 and neurofibromatosis 2.
Detailed clinical, ophthalmological, and molecular studies were performed on a multigeneration family in which there were many subjects with type 1 neurofibromatosis, a common autosomal dominant disorder. Affected family members displayed a wide range of clinical findings including, in two subjects, features seen in Noonan syndrome (triangular facies, downward slanting palpebral fissures, micrognathia, short stature, and learning disability). Subjects have been described previously whose features have overlapped with neurofibromatosis and Noonan syndrome, and it has been suggested that these persons might represent a separate condition. DNA haplotype analysis showed linkage of the neurofibromatosis phenotype seen in this family to the proximal long arm of chromosome 17 in the region where the type 1 neurofibromatosis gene has been mapped. These results imply that the Noonan phenotype seen in some patients with type 1 neurofibromatosis might be the result of variable or variant expression of the neurofibromatosis gene on chromosome 17. The possible role of non-specific factors, such as fetal hypotonia, in producing the neurofibromatosis-Noonan phenotype needs further investigation. The availability of closely linked and intragenic molecular markers for neurofibromatosis could potentially be useful in the diagnosis and characterisation of patients and families with atypical forms of neurofibromatosis.
Bilateral acoustic neurofibromatosis (neurofibromatosis 2, NF2) accounts for less than 10% of all cases of neurofibromatosis and manifests itself with bilateral acoustic schwannomas, multiple schwannomas of spinal nerve roots, meningiomas, glial tumors and hamartomatous CNS lesions. We have observed dysplastic foci of immature neuroectodermal cells in the cerebral cortex and basal ganglia of six patients afflicted with neurofibromatosis 2, ranging from occasional clusters of immature, dysplastic cells to numerous, confluent lesions. These cells, although often polymorphic and multinuclear did not show mitotic activity or a tendency for neoplastic transformation. To determine the histogenesis of these foci, extensive immunocytochemical reactions were carried out with antibodies to a variety of glial, neuronal and non-neural cell lineages. With the exception of S-100 protein, no immunoreactivity was detectable. S-100 was consistently expressed in these foci, irrespective of their size, location, and degree of polymorphism. On the basis of cytological appearance, distribution and immunoreactivity we tentatively designate these foci as glial micro-hamartomas. Although we did not systematically analyze the CNS of patients with von Recklinghausen neurofibromatosis (neurofibromatosis 1, NF1), the present study strongly suggests that these micro-hamartomas constitute a morphological hallmark of bilateral acoustic neurofibromatosis (NF2).
Although acknowledged as separate entities in the neurologic literature, central neurofibromatosis and peripheral neurofibromatosis, which is also known as von Recklinghausen's disease, have not been commonly distinguished by otologists as two separate diseases. An NIH Conference statement has reclassified these diseases as neurofibromatosis-1 and neurofibromatosis-2. Genetic, biochemical, and clinical variants of these two related diseases are presented and discussed. Patients with bilateral acoustic neuromas may have either the central or peripheral form of the disease; central neurofibromatosis is much more rare than the peripheral form of the disease.
Neurofibromatosis includes the common "peripheral" form and a recently documented "central" form. We describe the central form in 130 cases from 9 kindreds personally studied and 15 reported kindreds. Central neurofibromatosis with bilateral acoustic neuroma is an autosomal dominant disorder beginning about 20 years of age, accompanied by mild skin changes. In three kindreds with central neurofibromatosis, we measured nerve growth factor in serum by radioimmunoassay and radioreceptor assay. Only the antigenic activity of nerve growth factor was increased. In contrast, in peripheral neurofibromatosis, only the functional activity of nerve growth factor has been reported increased. Central and peripheral forms of neurofibromatosis are closely related but discrete diseases which appear to have separate alterations in nerve growth factor activity.
Neurofibromatosis in cattle is typically a noncutaneous disease. A small group of cows in a Holstein dairy herd developed cutaneous neurofibromatosis. This unique condition was investigated and compared with neurofibromatosis type 1 (NF1) in humans. All cutaneous lesions but one were consistent with neurofibromas in noncutaneous sites in cattle and neurofibromas in patients with NF1. One bovine lesion was classified as a neurofibrosarcoma. Immunohistochemistry and electron microscopy supported Schwannian differentiation in benign and malignant lesions. Linkage analysis with a polymorphism in the bovine NF1 gene confirmed that two affected animals from the same sire inherited the same paternal NF1 allele. Bovine cutaneous neurofibromatosis is a naturally occurring disease in this group of animals, characterized by skin tumors morphologically identical to those of NF1. An informative polymorphism at the NF1 locus of two animals and their sire suggests this disorder may be caused by hereditary mutations at the bovine NF1 locus.
Neurofibromatosis 1, neurofibromatosis 2, and tuberous sclerosis are a set of dominantly transmitted disorders that have in common the tendency towards formation of tumors of the nervous system and other tissues. The genes for neurofibromatosis 1, neurofibromatosis 2, and one of two forms of tuberous sclerosis have been identified and appear to act as tumor suppressor genes. Information is accumulating about pathogenesis that may eventually improve our ability to diagnose and treat these disorders.
A large four-generation family with Noonan syndrome (NS) and neurofibromatosis-type 1 (NF1) was studied for clinical association between the two diseases and for linkage analysis with polymorphic DNA markers of the NF1 region in 17q11.2. Nonrandom segregation between NS and NF1 phenotypes was observed. Neurofibromatosis was tightly linked to NF1 markers, whereas Noonan syndrome was found not be allelic to NF1. These results suggest that two mutations at two independent but closely linked loci are the cause of neurofibromatosis-Noonan syndrome (NF-NS) association in this family.
The authors present a case of mesenteric neurofibromatosis in a child, which is a rare complication of neurofibromatosis type 1 (NF1). This case is presented to illustrate the clinical features and the radiological appearance of mesenteric neurofibromatosis, which, in the appropriate clinical setting of NF1, are diagnostic. The authors also discuss the long-term complications of this condition, which includes the potential risk of malignant degeneration.
Spinal neurofibromatosis (SNF) has been considered to be an alternative form of neurofibromatosis in which spinal cord tumors are the main clinical characteristic. Familial SNF has been reported, elsewhere, in three families-two linked to markers within the gene for neurofibromatosis type 1 (NF1) and the other not linked to NF1-but no molecular alterations have been described in these families. We describe a three-generation family that includes five members affected by SNF. All the affected members presented multiple spinal neurofibromas and café au lait spots, one member had cutaneous neurofibromas, and some members had other signs of NF1. Genetic analysis, performed with markers within and flanking the NF1 gene, showed segregation with the NF1 locus. Mutation analysis, performed with the protein-truncation test and SSCP/heteroduplex analysis of the whole coding region of the NF1 gene, identified a frameshift mutation (8042insA) in exon 46, which should result in a truncated NF1 protein. The 8042insA mutation was detected in all five family members with the SNF/NF1 phenotype. To our knowledge, this is the first time that a mutation in the NF1 gene has been associated with SNF. The clinical homogeneity in the severity of the disease among the affected members of the family, which is unusual in NF1, suggests that a particular property of the NF1 mutation described here, a gene closely linked to NF1, or posttranscriptional events are involved in this severe neurological phenotype.
OBJECTIVES: The purpose of this study was to investigate the natural history of the high signal intensities shown on long TR sequences-neurofibromatosis type 1 bright objects (NBO)-in children with neurofibromatosis type 1 (NF1). We have paid particular attention to the development of tumors in these areas of abnormality. METHODS: During a 12-month period in 1992 to 1993, 46 children with clinically proven NF1 had a magnetic resonance (MR) examination at our institution. These were reviewed along with any previous or subsequent MR examinations that had been performed. We recorded the number, volume, and distribution of the abnormal high signal intensities and their change with time when serial examinations were performed. RESULTS: NBO were found in 93% of 46 children with NF1 on the original cross-sectional study. The most common anatomic sites were the globus pallidus (30.4%), cerebellum (23.5%), and midbrain (16.2%). The number and volume of NBO varied significantly with age. NBO were uncommon in children younger than 4 years but were very common and extensive between 4 to 10 years. A significant reduction in the number and volume of NBO was demonstrated in children older than 10 years as shown on both the cross-sectional and longitudinal portions of the study. Eight brain tumors (nonoptic pathway) were demonstrated in the 46 children (17%) with 1 child having two tumors. Only 1 child had symptoms referable to the tumor at the time of diagnosis. Five tumors developed in NBO that were documented on serial MR examinations. All those cases developed in children aged 7 to 12 years, and all these children had higher than average numbers and volumes of NBO. CONCLUSIONS: NBO occur commonly in children with NF1 and are most prevalent between the ages of 4 and 10. We have shown a high frequency of brain tumors in our children with NF1, but the majority of these were asymptomatic. We have demonstrated proliferative change NBO in 11% of 46 children. Most NBO regress with age and seem to be benign, however, young children with a large number and volume of NBO should be followed closely with regular MR examinations because of an increased risk of proliferative change. neurofibromatosis type 1, magnetic resonance, tumor, astrocytoma, childhood.
INTRODUCTION: Neurofibromatosis is a term used for two disorders: NF-1 and NF-2. NF-1 is Von Recklinghasusen's neurofibromatosis and comprises characteristic skin lesions (cafe au lait spots, intertriginous freckles, neurofibromatous skin tumors) and other congenital and hamartomatous bone, endocrine glands and central nervous system lesions. Its incidence is one in every 2500 to 3300 births. CASE REPORT: Two female patients, a 20 years old daughter and her mother 46 years of age were admitted to the Clinic of Dermatovenereology in Novi Sad due to appearance of many sessile and pedunculated neurofibromas, cafe au lait spots and freckles on their trunks, axillary and inguinal regions. Laboratory findings showed no abnormalities. Both of them were examined by many specialists. No systemic disturbances were established. The daughter was sent to plastic surgery for operative treatment. DISCUSSION: The clinical presentation of NF-1 is very variegated. Beside characteristic skin lesions, other clinical features include skeletal bony abnormalities, mental deficiency, seizures, neurofibromas of the spinal and cranial nerve roots, iris hamartomas, optic nerve gliomas, endocrine disorders, endocrine tissue tumors, other visceral tumors, etc. Some of these disorders can be life-threatening. Malignant transformations of the NF-1 lesions occur approximately in 5% of patients, most often as neurofibrosarcomas, Wilms' tumors, rhabdomyosarcomas or various forms of leukemias. CONCLUSION: We present familial cases of Von Recklingausen's neurofibromatosis without systemic abnormalities so far. The clinical course of this disease is unpredictable and a multidiscipline clinical assessment is necessary during whole life.
Mutations at splice sites or surrounding sequences have been reported to cause aberrant splicing. However, splicing errors can also occur without sequence alterations. We investigated three tumor suppressor genes for aberrant splicing in tumors. At a low frequency per exon it was found in five of seven of the investigated in-frame exons of the neurofibromatosis type 1 (NF1) gene, in two of three exons of the neurofibromatosis type 2 (NF2) gene, and in one of three exons of the tuberous sclerosis 2 gene. It was detectable in all of the human tumor tissues tested (NF1 neurofibroma, sporadic intramedullar neurinoma, sporadic meningiomas, NF2 schwannoma, NF2 meningioma, basalioma, and naevus) as well as in cultured tumor cell lines and cultured primary cells. Hence, our data show that aberrant splicing is a very common process. According to simulations of the secondary structures of the pre-mRNA, we suggest that aberrant splicing is attributable to the rare occurrence of alternative structures at the splice donor site, which are not recognized by the splice machinery. In HeLa cells, aberrant splicing is found to be increased at elevated temperatures and low pH in vitro, conditions often found in tumor tissues. In three tumor tissues tested for one NF1 exon, we found approximately twice the amount of aberrant transcript as in normal tissues. Therefore, we suggest that the increase in aberrant splicing caused by environmental factors represents an additional mechanism for the reduction of the amount of tumor suppressor mRNA in the absence of relevant mutations in the tumor.
Neurofibromatosis type 1 (NF-1) was incidentally diagnosed in a 1-year-old girl. Her father was found to show the cutaneous signs of segmental neurofibromatosis (NF-5). This observation supports the possibility that subjects with NF-5 can transmit NF-1 to their offsprings in some cases, which has to be considered in genetic counseling.
Mast cells (MC) are a conspicous component of neurofibromas in humans. The present study is based on damselfish neurofibromatosis (DNF) a naturally occurring animal model of neurofibromatosis type 1. Investigations of leukocytes of fishes have generally concluded that these animals lack metachromatic, basophilic mast cells and that the apparent analog in fishes is an eosinophilic granule containing cell (EGC). EGC were found at high densities in both naturally occurring neurofibromas in DNF and in those produced in laboratory transmission experiments. Tumors induced by injection of cells from cultured DNF tumor cell lines exhibited significantly higher densities of EGC than did spontaneously occurring tumors or those induced by injection of homogenized tumor tissue. EGC were significantly more common in the outer 200 microns edge of the tumors. We believe that these EGC are the piscine equivalent of the mammalian MC and that their presence in tumors in DNF will provide the first opportunity to experimentally manipulate this type of cell in neurofibromas.
Segmental neurofibromatosis (NF) is generally thought to result from a postzygotic NF1 (neurofibromatosis type 1) gene mutation. However, this has not yet been demonstrated at the molecular level. Using fluorescence in situ hybridisation (FISH) we identified an NF1 microdeletion in a patient with segmental NF in whom café-au-lait spots and freckles are limited to a single body region. The mutant allele was present in a mosaic pattern in cultured fibroblasts from a café-au-lait spot lesion, but was absent in fibroblasts from normal skin as well as in peripheral blood leukocytes. These findings prove the hypothesis that the molecular basis of segmental cutaneous NF is a mutation in the NF1 gene and that the regional distribution of manifestations reflects different cell clones, commensurate with the concept of somatic mosaicism.