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V F Mautner

Publications and source records attributed to V F Mautner.

At least 19 recordsLinked to original sources
PubMed2006

MRI growth patterns of plexiform neurofibromas in patients with neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder with an incidence of 1:3000. Approximately 30% of NF1 patients develop plexiform neurofibromas (PNF) which often cause severe clinical deficits. We studied the growth patterns of 256 plexiform neurofibromas (PNF) by magnetic resonance imaging (MRI) and associated disfigurement and functional deficits to determine whether there are definable growth types of these tumors. Retrospectively, we evaluated MRI scans obtained during 1997 to 2003 of 256 plexiform neurofibromas from 202 patients with NF1. Clinical investigation was carried out at the same time as the MRI scans. We identified three growth patterns: superficial in 59, displacing in 76, and invasive growth in 121 tumors. The majority (52%) of invasive PNF were found in the face, head and neck area. While superficial PNF primarily caused aesthetic problems, displacing PNF led in most cases to aesthetic problems and pain, while invasive PNF led mainly to functional deficits and disfigurement. Our study demonstrates that PNF have different growth patterns that are associated with specific clinical features. Classification of PNF may open new opportunities in clinical management, especially regarding decisions and options associated with surgical intervention.

Adolescent↗
PubMed2005

Diagnostic criteria for schwannomatosis.

The neurofibromatoses are a diverse group of genetic conditions that share a predisposition to the development of tumors of the nerve sheath. Schwannomatosis is a recently recognized third major form of neurofibromatosis (NF) that causes multiple schwannomas without vestibular tumors diagnostic of NF2. Patients with schwannomatosis represent 2.4 to 5% of all patients requiring schwannoma resection and approximately one third of patients with schwannomatosis have anatomically localized disease with tumors limited to a single limb or segment of spine. Epidemiologic studies suggest that schwannomatosis is as common as NF2, but that familial occurrence is inexplicably rare. Patients with schwannomatosis overwhelmingly present with pain, and pain remains the primary clinical problem and indication for surgery. Diagnostic criteria for schwannomatosis are needed for both clinicians and researchers, but final diagnostic certainly will await the identification of the schwannomatosis locus itself.

Diagnosis, Differential↗
PubMed2004

Methylation analysis of the neurofibromatosis type 1 (NF1) promoter in peripheral nerve sheath tumours.

Peripheral nerve sheath tumours are hallmarks of neurofibromatosis type 1 (NF1). Development of plexiform neurofibromas to malignant peripheral nerve sheath tumours (MPNST) is common. The NF1 gene promoter harbours a hypomethylated CpG island. Thus, methylation changes may be involved in the development of different types of neurofibromas and malignant transformation. We investigated NF1-associated dermal (n=9) and plexiform neurofibromas (n=7), MPNST (n=5) and non-NF1 leucocyte samples (n=20) for their methylation pattern by bisulphite genomic sequencing. We could not find global hypermethylation in the NF1 promoter in our series. Nevertheless, site-specific methylation, involving transcription factor binding sites for SP1, CRE (-10), and AP-2, was observed. One region of the 5'-UTR (untranslated region) overlapping with a putative AP-2 binding site was methylated at 30-100% in 4/20 control samples. In conclusion, we did not find hypermethylation in NF1-associated tumours. Instead, low level methylation could parallel a global genomic hypomethylation in malignancy.

Antioxidants↗
PubMed2003

Malignant peripheral nerve sheath tumours in neurofibromatosis type 1: MRI supports the diagnosis of malignant plexiform neurofibroma.

Plexiform neurofibroma (PNF) is a typical feature of neurofibromatosis 1 (NF1). About 10% of patients with NF1 develop malignant peripheral nerve-sheath tumours (MPNST), usually arising from PNF, and this is the major cause of poor survival. A better prognosis can be achieved if the tumours are diagnosed at an early stage. Our objective was to establish MRI criteria for MPNST and to test their usefulness in detecting early malignant change in PNF. MRI was performed on 50 patients with NF1 and nerve-sheath tumours, of whom seven had atypical pain, tumour growth or neurological deficits indicative of malignancy; the other 43 were asymptomatic. On MRI all seven symptomatic patients had inhomogeneous lesions, due to necrosis and haemorrhage and patchy contrast enhancement. In one patient, the multiplicity of confluent tumours with inhomogeneous areas in addition to central lesions did not allow exclusion of malignancy. Only three of the 43 asymptomatic patients had comparable changes; the other 40 patients had tumours being of relatively homogeneous structure on T1- and T2-weighted images before and after contrast enhancement. All three asymptomatic patients with inhomogeneous lesions were shown to have MPNST.

Adolescent↗
PubMed2003

Multiple unilateral schwannomas: segmental neurofibromatosis type 2 or schwannomatosis?

Schwannomas are benign solitary tumours of the peripheral nerve sheaths. The occurrence of multiple schwannomas usually implies hereditary disease. The most frequent syndrome associated with multiple schwannomas is neurofibromatosis type 2 (NF2), which is defined by bilateral vestibular schwannomas. Schwannomatosis is a distinct disease characterized by multiple pathologically proven schwannomas in the absence of vestibular schwannomas. It is not currently known if the presence of multiple schwannomas confined to a limb may represent a mosaic form of NF2 or a distinct disease, because mutation analysis of these tumours is not routinely performed. We report a 31-year-old patient who presented with multiple slowly growing subcutaneous tumours on his left arm. His family history was negative for cutaneous tumours or central nervous system disease, and he did not have additional features of NF2. Magnetic resonance tomography and ophthalmological examination excluded vestibular schwannoma and eye stigmata of NF2. After resection of three tumours, histological analysis confirmed the diagnosis of benign schwannomas. Molecular genetic analysis by temperature gradient gel electrophoresis and microsatellite marker analysis demonstrated two distinct mutations of the NF2 gene (NF2) in two different schwannomas, with concomitant loss of heterozygosity in both tumours. In contrast, neither normal skin nor peripheral blood lymphocytes revealed mutations of NF2. The clinical and molecular genetic findings suggest that the diagnosis in our patient is schwannomatosis rather than segmental NF2 because the mutations found in different tumours were not identical. The possibility of a localized predisposition for the acquisition of NF2 mutations is discussed.

Adult↗
PubMed2002

Intrafamilial correlation of clinical manifestations in neurofibromatosis 2 (NF2).

Measuring correlation in clinical traits among relatives is important to our understanding of the causes of variable expressivity in Mendelian diseases. Random effects models are widely used to estimate intrafamilial correlations, but such models have limitations. We incorporated survival techniques into a random effects model so that it can be used to estimate intrafamilial correlations in continuous variables with right censoring, such as age at onset. We also describe a negative-binomial gamma mixture model to determine intrafamilial correlations of discrete (e.g., count) data. We demonstrate the utility of these methods by analyzing intrafamilial correlations among patients with neurofibromatosis 2 (NF2), an autosomal-dominant disease caused by mutations of the NF2 tumor-suppressor gene. We estimated intrafamilial correlations in age at first symptom of NF2, age at onset of hearing loss, and number of intracranial meningiomas in 390 NF2 nonprobands from 153 unrelated families. A significant intrafamilial correlation was observed for each of the three features: age at onset (0.35; 95% confidence interval (CI) 0.23-0.47), age at onset of hearing loss (0.51; 95% CI, 0.35-0.64), and number of meninginomas (0.29; 95% CI, 0.15-0.43). Significant correlations were also observed for age at first symptom within NF2 families with truncating mutations (0.41; 95% CI, 0.06-0.68) or splice-site mutations (0.29; 95% CI, 0.03-0.51), for age at onset of hearing loss within families with missense mutations (0.67; 95% CI, 0.18-0.89), and for number of meningiomas within families with splice-site mutations (0.39; 95% CI, 0.13-0.66). Our findings are consistent with effects of both allelic and nonallelic familial factors on the clinical variability of NF2.

Adolescent↗
PubMed2002

[Abnormalities of the maxillary sinus in type 1 neurofibromatosis].

AIM: The aim of this study was to determine the malformations of the maxillary sinus in neurofibromatosis type 1 patients (NF1). MATERIAL AND METHODS: Twenty-two patients with NF1 were investigated clinically and radiologically: 11 had an unilateral trigeminal plexiform neurofibroma and 11 had multiple cutaneous neurofibromas. The histological type of NF was ascertained in all cases following tumor resections. The malformation of the maxillary sinus was assessed on plain radiographs and computed or magnetic resonance tomograms. Intraindividual side comparison was used to judge the size of the sinus and its position in the midface. RESULTS: In patients with cutaneous neurofibromas the maxillary sinus appeared symmetrical in size and position. The pneumatization of the sinus had no abnormalities on the radiographs. Malformations of the maxillary sinus were restricted to plexiform neurofibromas. On the side affected by a plexiform NF, the sinus appeared hypoplastic and caudally displaced due to an enlarged ipsilateral orbit. The expansion of the sinus to the lateral side was impaired, obviously due to tumor masses. Consecutively, the alveolar process of the affected side was also displaced leading to a complex malocclusion. DISCUSSION: Malformations of the face are frequently presented as case reports in the literature. Emphasis is given to the elephantiasis-like tumor growth of the face in certain patients with NF1. The underlying pathology has not yet been fully understood. This report provides evidence that in the midfacial region the overgrowth is predominantly caused by the plexiform neurofibroma itself and that the bones can even be hypoplastic and show scoliosis-like malformation compared to the nonaffected side. These findings are relevant when debulking procedures of the face are planned for NF1 patients.

Adolescent↗
PubMed2001

Loss of NF1 alleles distinguish sporadic from NF1-associated pilocytic astrocytomas.

Pilocytic astrocytomas classified as WHO grade I typically arise in childhood and upon complete surgical removal carry a favorable prognosis. Children with neurofibromatosis 1 (NF1) have a vastly increased risk for pilocytic astrocytomas, especially for those of the optic nerve. Using 4 intragenic NF1 microsatellite markers, we examined losses of NF1 alleles on the long arm of chromosome 17 in 12 NF1-associated and 25 sporadic pilocytic astrocytomas. The TP53 gene region on the short arm of chromosome 17 was also examined in these tumors using 3 markers. Loss of 1 NF1 allele was detected in 11 of 12 (92%) informative NF1-associated pilocytic astrocytomas. In contrast, only 1 of 24 informative (4%) sporadic pilocytic astrocytomas exhibited allelic loss in the NF1 region. Among the 11 NF1-associated tumors with NF1 loss, 5 had also lost alleles on 17p. The high rate of NF1 allele loss in NF1-associated pilocytic astrocytomas suggests a tumor initiating or promoting action of the NF1 gene in these patients. On the other hand, the much lower rate of NF1-allele loss in sporadic pilocytic astrocytomas argues for only minor importance of NF1 in that patient group. The present data support different mechanisms in the formation of NF1-associated and sporadic pilocytic astrocytomas.

Adolescent↗
PubMed2000

Supporting evidence of a gene for partial epilepsy on 10q.

A four-generation family with nine individuals with temporal partial epilepsy was studied. Detailed epilepsy history was investigated by structured interview. All putatively affected family members underwent a standardized electroencephalographic examination. The phenotype in the family was characterized by a short acoustic aura followed by rapid secondary generalization. To examine if the trait is linked to a region on 10q (interval D10S185-D10S1671), which has been reported in two other epilepsy families with similar phenotypes, linkage analysis was performed using nine markers covering the previously reported region. A maximum two-point LOD score of 2.1 at a recombination fraction of zero was obtained. All living affected individuals shared the same haplotype, while three unaffected at-risk adults did not. This result presents supporting evidence of a gene for partial epilepsy on 10q.

Adult↗
PubMed2000

Mutations and allelic loss of the NF2 gene in neurofibromatosis 2-associated skin tumors.

Schwannomas in the skin are frequently observed in neurofibromatosis 2 patients. In about one-quarter of the cases, skin tumors are the first clinical symptoms of this disease. Recognizing neurofibromatosis-2-related skin tumors is therefore important for early diagnosis of neurofibromatosis 2, especially in pediatric patients. In this study, we examined 40 skin tumors (36 schwannomas and four neurofibromas) from 20 neurofibromatosis 2 patients for NF2 mutations and allelic loss. NF2 mutations have been identified in blood from 15 (75%) of the 20 patients. We found NF2 mutations in five (13%) and NF2 allelic loss in 18 (45%) of the 40 analyzed tumors. Genetic alterations (allelic loss or mutation) were thus found in 50 (63%) out of the total of 80 examined alleles. In 17 (43%) tumors, alterations were found on both NF2 alleles. These results suggest that, as in the case of vestibular schwannomas and meningiomas, loss of functional NF2 gene product is also the critical event in the development of skin schwannomas. Identification of genetic alterations of the NF2 gene in skin tumors may help to identify neurofibromatosis-2-associated skin tumors, thus assisting in the diagnosis of neurofibromatosis 2 in ambiguous cases, and excluding neurofibromatosis 1 in unclear cases. We also report that the detection rate of constitutional mutations was higher in patients with skin tumors (65%) than in patients without skin tumors (40%).

Genes, Neurofibromatosis 2↗
PubMed2000

Allelic losses in neurofibromatosis 2-associated meningiomas.

More than 50% of patients with neurofibromatosis 2 (NF2) develop meningiomas. Recently, a higher proliferative activity, more mitotic figures, and greater nuclear pleomorphism have been described for NF2-associated meningiomas compared with sporadic ones. To analyze whether such histological differences could reflect underlying genetic differences, we examined 30 meningiomas from 22 NF2 patients for allelic losses on those chromosome arms that are frequently affected by deletions in sporadic meningiomas. In addition, we assessed the proliferative activity of the tumors and studied NF2 germline mutations. Twenty-three meningiomas corresponded to WHO grade I (10 fibrous, 6 psammomatous, 4 transitional, 3 meningothelial) and 7 to WHO grade II. The average MIB-1 index was 1.60 +/- 0.85 (WHO grade I: 1.41 +/- 0.80, WHO grade II: 2.13 +/- 0.82). When compared with several published studies of sporadic meningiomas, the MIB-1 index in NF2-associated meningiomas was not higher. Loss of heterozygosity (LOH) flanking or within the NF2 locus at 22q12 was detected in 100% of the tumors. LOH on 1p was the second most frequent abnormality (40%), followed by losses on 10q (27%), 6q and 14q (24%), 18q (23%), and 9p (17%). LOH on 19q and 17p, which is not commonly seen in sporadic meningiomas, was also only rarely detected in NF2-associated meningiomas. NF2 gene mutations were detected in 8 of 15 patients analyzed and were located in exons 2, 5, 6, 7, and 8. We conclude that sporadic and NF2-associated meningiomas share a common spectrum and frequency of allelic deletions as well as, in contrast to previous observations, a similar proliferative activity.

Adolescent↗
PubMed1999

Loss of NF1 allele in Schwann cells but not in fibroblasts derived from an NF1-associated neurofibroma.

Neurofibromas, the hallmark of neurofibromatosis 1, are composed mainly of Schwann cells and fibroblasts. Inactivation of both NF1 alleles is the cause of these benign tumors, but it is unknown which cell type is the progenitor. In this study, we selectively cultured Schwann cells from an NF1-associated neurofibroma. Fibroblasts were also obtained by culturing the tumor cells under standard conditions. Using four intragenic markers, we genotyped the NF1 locus in the original tumor and in the derived Schwann cells and fibroblasts. Loss of heterozygosity for two informative markers, which indicates loss of one NF1 allele, was found in Schwann cells but not in fibroblasts. This result suggests that genetic alterations of the NF1 gene in Schwann cells are responsible for the development of neurofibromas.

Alleles↗
PubMed1999

Spinal tumours in neurofibromatosis type 1: an MRI study of frequency, multiplicity and variety.

In neurofibromatosis type 1 (NF1) spinal tumours cause neurological symptoms in about 2 % of patients. Among over 1400 patients with NF1 we saw symptomatic spinal tumours in 23 (1.6 %). MRI of the entire spinal canal was obtained in 54 patients aged 5-56 years with NF1. The number, site, morphology and signal characteristics of the spinal tumours were recorded and analysed. There were 24 patients with symptoms such as sensory impairment or paralysis; 30 patients had no neurological deficits. Of the 24 symptomatic patients, 23 (96 %) had spinal tumours, while we saw spinal tumours in 12 (40 %) of the 30 patients without neurological deficits. No spinal segment was preferred in symptomatic or asymptomatic patients. Most intraspinal extramedullary tumours were primarily extradural and intraforaminal. MRI showed intramedullary tumours in 3 patients (6 %), intraspinal extramedullary tumours in 18 (33 %) and intraforaminal tumours in 31 (57 %). Only neurological deficits in patients with NF1 should prompt further diagnostic clarification. In patients with neurological symptoms there may be a multiplicity of masses in the spinal canal, which can lead to difficulties in attaching symptoms to a certain tumour. In patients who do not satisfy the NIH criteria, it can be a helpful observation that spinal tumours in NF1 are primarily intraforaminal, extending into the spinal canal, while in NF2 they are mostly intraspinal intradural tumours.

Adolescent↗
PubMed1999

Quantitative analysis of NF1 and OMGP gene transcripts in sporadic gliomas, sporadic meningiomas and neurofibromatosis type 1-associated plexiform neurofibromas.

The close association of neurofibromatosis type 1 (NF1) with gliomas raises the question of whether the NF1 gene may be involved in the pathogenesis of sporadic astrocytic brain tumors. However, no frequent mutations within NF1 have been described in these tumors. Recent data on a limited series of gliomas indicate that NF1 expression may even be increased, thereby questioning the role of NF1 as a tumor suppressor in astrocytomas. In the present study, we examined the expression of NF1 in a series of 96 tumors including astrocytomas, meningiomas and plexiform neurofibromas. NF1 RNA transcription levels were compared to those of the reference genes B2M, ACTB and GAPD. The expression of OMGP, which is interposed in the NF1 gene, served as an additional control. NF1 expression did not significantly diverge among different malignancy stages of astrocytomas. As expected, the plexiform neurofibromas showed only very low NF1 expression. A striking finding was the highly variable expression of those genes selected to serve as references. While B2M and ACTB exhibited comparable levels of expression within different grades of astrocytomas and meningiomas, GAPD showed an inverse pattern in these tumors. In conclusion, NF1 expression is strongly reduced in NF1-associated plexiform neurofibromas but not in astrocytic tumors. The significant differences between B2M, ACTB and GAPD transcript levels brings into question the common practice of defining gene expression as a ratio between the transcripts of interest and those of these reference genes.

Base Sequence↗
PubMed1999

Allelic loss of the NF1 gene in NF1-associated plexiform neurofibromas.

Neurofibromatosis 1 (NF1) is an autosomal dominant disorder with a complex variety of clinical symptoms. Genetic alteration of the NF1 gene on 17q11.2 is the disease. Neurofibromas of the peripheral nervous system are one main manifestation. A variant of neurofibroma is the plexiform neurofibroma which can be found in about 30% of NF1-patients, often causing severe clinical symptoms. In this study, we examined 14 such tumors from 10 NF1-patients for allele loss of the NF1 gene (LOH: loss of heterozygosity) using four intragenic polymorphic markers. Loss of heterozygosity was found in eight tumors from five patients, and suspected in one additional tumor from another patient. This finding suggests that loss of the second allele, and thus inactivation of both alleles of the NF1 gene, is associated with the development of plexiform neurofibromas. The 14 plexiform neufibromas were also examined for mutation in the TP53 gene by screening exons 5 through 8 using temperature gradient gel electrophoresis. No mutation was found in any of the tumors.

Adult↗
PubMed1999

[Long-term outcome of gliomas of the visual pathway in type 1 neurofibromatosis].

BACKGROUND: Optic gliomas are frequently associated with neurofibromatosis type 1 (NF1) and belong to the diagnostic criteria of NF1. Different growth rates require differentiated strategies for screening and observation. PATIENTS AND METHODS: 29 patients (25 children < 11 years, 4 adults > 18 years) with visual pathway tumors and NF1 were examined neurologically, ophthalmogically, by means of MRI and VEP. Results were set into context with preceding investigations (mean follow up time 6.5 years). RESULTS: 11 children showed a stable condition, 14 an unfavorable process with substantial loss of vision. Children with an unfavorable process showed a lower age at diagnosis (3.2 versus 5.8 years; p < 0.05), more frequently strabism (11/14 versus 1/11; p < 0.05), optic atrophy (12/14 versus 1/11; p < 0.05), pathological VEP (9/9 versus 2/10; p = 0.001), visual field defects (9/9 versus 1/9) and involvement of the optic chiasm (11/14 versus 3/11; p < 0.05) than children with a stable condition. 3 of 4 adults had no visual symptoms despite involvement of the optic chiasm. CONCLUSIONS: The crucial prognostic factor is the patient's age at the time of diagnosis. Optic gliomas which become symptomatic in early childhood (< 6 years) grow rapidly and require frequent ophthalmologic investigations and MRI. Tumors diagnosed in late childhood (> 6 years) do not progress, allowing for gradual extension of intervals between ophthalmological investigations.

Adolescent↗