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Theo J. M. Hulsebos - One of the best experts on this subject based on the ideXlab platform.

  • Expanding the mutational spectrum of LZTR1 in Schwannomatosis
    European journal of human genetics : EJHG, 2014
    Co-Authors: Irene Paganini, Roberta Sestini, Theo J. M. Hulsebos, Vivian Y. Chang, Gabriele Lorenzo Capone, Jeremie Vitte, Matteo Benelli, Lorenzo Barbetti, Eva Trevisson, Marco Giovannini
    Abstract:

    Schwannomatosis is characterized by the development of multiple non-vestibular, non-intradermal schwannomas. Constitutional inactivating variants in two genes, SMARCB1 and, very recently, LZTR1, have been reported. We performed exome sequencing of 13 Schwannomatosis patients from 11 families without SMARCB1 deleterious variants. We identified four individuals with heterozygous loss-of-function variants in LZTR1. Sequencing of the germline of 60 additional patients identified 18 additional heterozygous variants in LZTR1. We identified LZTR1 variants in 43% and 30% of familial (three of the seven families) and sporadic patients, respectively. In addition, we tested LZTR1 protein immunostaining in 22 tumors from nine unrelated patients with and without LZTR1 deleterious variants. Tumors from individuals with LZTR1 variants lost the protein expression in at least a subset of tumor cells, consistent with a tumor suppressor mechanism. In conclusion, our study demonstrates that molecular analysis of LZTR1 may contribute to the molecular characterization of Schwannomatosis patients, in addition to NF2 mutational analysis and the detection of chromosome 22 losses in tumor tissue. It will be especially useful in differentiating Schwannomatosis from mosaic Neurofibromatosis type 2 (NF2). However, the role of LZTR1 in the pathogenesis of Schwannomatosis needs further elucidation.

  • SMARCB1 involvement in the development of leiomyoma in a patient with Schwannomatosis.
    The American journal of surgical pathology, 2014
    Co-Authors: Theo J. M. Hulsebos, Susan Kenter, Pieter Wesseling, Ulrike Siebers-renelt, Volkmar Hans, Uta Flucke
    Abstract:

    Germline SMARCB1 mutations predispose in Schwannomatosis patients to the development of multiple benign schwannomas and, in some cases, meningiomas. Here, we report on a 34-year-old female patient who developed multiple schwannomas at various locations and in addition a leiomyoma of the cervix uteri. She carried a c.362+1G>A mutation that inactivates the donor splice site of exon 3. This mutation caused the Schwannomatosis phenotype in this patient and was also demonstrated to be present in her affected mother. The leiomyoma displayed the genetic features that are characteristic for germline SMARCB1 mutation-associated tumors. The mutant allele retained in the tumor, whereas the wild-type allele was lost by loss of heterozygosity. Furthermore, the loss of heterozygosity involved net loss of chromosome 22. An NF2 mutation was not found. However, quantitative polymerase chain reaction suggested that both NF2 copies were lost in the tumor. Immunostaining with a SMARCB1 antibody revealed the mosaic expression pattern that is typical for Schwannomatosis-associated tumors. To our knowledge, this is the first reported case of leiomyoma associated with a germline SMARCB1 mutation. As such, it widens the spectrum of benign tumors associated with a germline SMARCB1 mutation.

  • Update from the 2011 International Schwannomatosis Workshop: From genetics to diagnostic criteria.
    American Journal of Medical Genetics Part A, 2013
    Co-Authors: Scott R. Plotkin, Jaishri O. Blakeley, D. Gareth Evans, Bruce R. Korf, C. Oliver Hanemann, Theo J. M. Hulsebos, Kim Hunter-schaedle, Ganjam V. Kalpana, Ludwine Messiaen, Laura Papi
    Abstract:

    Schwannomatosis is the third major form of neurofibromatosis and is characterized by the development of multiple schwannomas in the absence of bilateral vestibular schwannomas. The 2011 Schwannomatosis Update was organized by the Children's Tumor Foundation (www.ctf.org) and held in Los Angeles, CA, from June 5-8, 2011. This article summarizes the highlights presented at the Conference and represents the "state-of-the-field" in 2011. Genetic studies indicate that constitutional mutations in the SMARCB1 tumor suppressor gene occur in 40-50% of familial cases and in 8-10% of sporadic cases of Schwannomatosis. Tumorigenesis is thought to occur through a four-hit, three-step model, beginning with a germline mutation in SMARCB1 (hit 1), followed by loss of a portion of chromosome 22 that contains the second SMARCB1 allele and one NF2 allele (hits 2 and 3), followed by mutation of the remaining wild-type NF2 allele (hit 4). Insights from research on HIV and pediatric rhabdoid tumors have shed light on potential molecular pathways that are dysregulated in Schwannomatosis-related schwannomas. Mouse models of Schwannomatosis have been developed and promise to further expand our understanding of tumorigenesis and the tumor microenvironment. Clinical reports have described the occurrence of intracranial meningiomas in Schwannomatosis patients and in families with germline SMARCB1 mutations. The authors propose updated diagnostic criteria to incorporate new clinical and genetic findings since 2005. In the next 5 years, the authors expect that advances in basic research in the pathogenesis of Schwannomatosis will lead toward clinical investigations of potential drug therapies.

  • smarcb1 ini1 maternal germ line mosaicism in Schwannomatosis
    Clinical Genetics, 2010
    Co-Authors: Theo J. M. Hulsebos, Susan Kenter, Marja E. Jakobs, Frank Baas, B. Chong, Martin B. Delatycki
    Abstract:

    Hulsebos TJM, Kenter SB, Jakobs ME, Baas F, Chong B and Delatycki MB. SMARCB1/INI1 maternal germ line mosaicism in Schwannomatosis. Schwannomatosis is characterized by the development of multiple schwannomas of the nervous system, but without the occurrence of vestibular schwannomas. Most cases of Schwannomatosis are thought to be sporadic, representing the first case in a family due to a new mutation in the causative gene. We recently identified SMARCB1/INI1 as a Schwannomatosis-predisposing gene. Here, we analyzed this gene in a Schwannomatosis family with two affected children, but with clinically unaffected parents. Both affected individuals carried a constitutional SMARCB1 mutation, c.1118+ 1G>A, that changes the donor splice site sequence of intron 8, causing skipping of exon 8 and resulting in the in-frame deletion of 132 nucleotides in the transcript. The mutation was not evident in constitutional DNA of the parents. Haplotyping revealed that the chromosome 22 segment that carries the mutant SMARCB1 allele originated from the mother. She transferred the same chromosome 22 segment, however, with a wild-type SMARCB1 copy, to a third unaffected child. Our findings indicate that the mother is germ line mosaic for the SMARCB1 mutation. In conclusion, our study shows for the first time that germ line mosaicism may occur in Schwannomatosis, which has implications for genetic counseling in this disease.

  • SMARCB1/INI1 maternal germ line mosaicism in Schwannomatosis.
    Clinical genetics, 2009
    Co-Authors: Theo J. M. Hulsebos, Susan Kenter, Marja E. Jakobs, Frank Baas, B. Chong, Martin B. Delatycki
    Abstract:

    Hulsebos TJM, Kenter SB, Jakobs ME, Baas F, Chong B and Delatycki MB. SMARCB1/INI1 maternal germ line mosaicism in Schwannomatosis. Schwannomatosis is characterized by the development of multiple schwannomas of the nervous system, but without the occurrence of vestibular schwannomas. Most cases of Schwannomatosis are thought to be sporadic, representing the first case in a family due to a new mutation in the causative gene. We recently identified SMARCB1/INI1 as a Schwannomatosis-predisposing gene. Here, we analyzed this gene in a Schwannomatosis family with two affected children, but with clinically unaffected parents. Both affected individuals carried a constitutional SMARCB1 mutation, c.1118+ 1G>A, that changes the donor splice site sequence of intron 8, causing skipping of exon 8 and resulting in the in-frame deletion of 132 nucleotides in the transcript. The mutation was not evident in constitutional DNA of the parents. Haplotyping revealed that the chromosome 22 segment that carries the mutant SMARCB1 allele originated from the mother. She transferred the same chromosome 22 segment, however, with a wild-type SMARCB1 copy, to a third unaffected child. Our findings indicate that the mother is germ line mosaic for the SMARCB1 mutation. In conclusion, our study shows for the first time that germ line mosaicism may occur in Schwannomatosis, which has implications for genetic counseling in this disease.

Said Farschtschi - One of the best experts on this subject based on the ideXlab platform.

  • C-Fiber Loss as a Possible Cause of Neuropathic Pain in Schwannomatosis
    International journal of molecular sciences, 2020
    Co-Authors: Said Farschtschi, Markus Glatzel, Reinhard E Friedrich, Christian Hagel, Tina Mainka, Anna-lena Hannekum, Michael Hauck, Mathias Gelderblom, Martin U. Schuhmann, Alexander Schulz
    Abstract:

    Schwannomatosis is the third form of neurofibromatosis and characterized by the occurrence of multiple schwannomas. The most prominent symptom is chronic pain. We aimed to test whether pain in Schwannomatosis might be caused by small-fiber neuropathy. Twenty patients with Schwannomatosis underwent neurological examination and nerve conduction studies. Levels of pain perception as well as anxiety and depression were assessed by established questionnaires. Quantitative sensory testing (QST) and laser-evoked potentials (LEP) were performed on patients and controls. Whole-body magnetic resonance imaging (wbMRI) and magnetic resonance neurography (MRN) were performed to quantify tumors and fascicular nerve lesions; skin biopsies were performed to determine intra-epidermal nerve fiber density (IENFD). All patients suffered from chronic pain without further neurological deficits. The questionnaires indicated neuropathic symptoms with significant impact on quality of life. Peripheral nerve tumors were detected in all patients by wbMRI. MRN showed additional multiple fascicular nerve lesions in 16/18 patients. LEP showed significant faster latencies compared to normal controls. Finally, IENFD was significantly reduced in 13/14 patients. Our study therefore indicates the presence of small-fiber neuropathy, predominantly of unmyelinated C-fibers. Fascicular nerve lesions are characteristic disease features that are associated with faster LEP latencies and decreased IENFD. Together these methods may facilitate differential diagnosis of Schwannomatosis.

  • distinctive low epidermal nerve fiber density in Schwannomatosis patients provides a major parameter for diagnosis and differential diagnosis
    Brain Pathology, 2020
    Co-Authors: Said Farschtschi, Lan Kluwe, Markus Glatzel, Jakob Matschke, Gerhard Schon, Joachim Weis, Reinhard E Friedrich, Christian Hagel, Victor-felix Mautner
    Abstract:

    Schwannomatosis and neurofibromatosis type 2 (NF2) are two distinct neuro-genetic tumor predisposition disorders, which, however, share some clinical and genetic features. While germline mutations in the NF2 gene are only found in NF2, a majority of Schwannomatosis patients have germline mutations in the SMARCB1 or LZTR1 genes. The overlapping clinical phenotypes pose a serious challenge in differential diagnosis and in risk stratification of these two entities which is further complicated by frequent mosaicism in both disorders. Chronic neuropathic pain which is a typical consequence of small fiber neuropathy, is characteristic for Schwannomatosis. By contrast, NF2 patients do not have chronic pain but may have moderate to severe sensory deficits and paresis which are not characteristic for Schwannomatosis. In the present study, we determined intraepidermal nerve fiber density (IEND) in skin biopsies of 34 clinically ascertained Schwannomatosis and 25 NF2 patients. In the NF2 group, 11/25 (44%) presented with IEND below the age- and gender-matched bottom 5% normative reference IEND. In contrast, nearly all (33/34 = 97%) Schwannomatosis patients showed IEND below or on the bottom 5% normative reference. The reduction of IEND in Schwannomatosis patients was age-independent. Paired t-test revealed no difference between the NF2-IEND and the corresponding bottom 5% normative reference (P = 0.98). By contrast, IEND in the Schwannomatosis patients were highly significantly lower than the corresponding 5% normative reference IEND (P < 0.0001). In addition, the difference between the IEND of our patients and the 5% lowest normative reference IEND was highly significantly larger in Schwannomatosis patients than in NF2 patients (P < 0.0001). IEND of our patients did not correlate with neither the presence nor types of germline mutations in neither the NF2 nor the LZTR1 gene. In conclusion, Schwannomatosis patients have marked low IEND which provides a major parameter for diagnosis and differential diagnosis.

  • Distinctive low epidermal nerve fiber density in Schwannomatosis patients provides a major parameter for diagnosis and differential diagnosis.
    Brain Pathology, 2019
    Co-Authors: Said Farschtschi, Lan Kluwe, Markus Glatzel, Jakob Matschke, Gerhard Schon, Joachim Weis, Reinhard E Friedrich, Christian Hagel, Victor-felix Mautner
    Abstract:

    : Schwannomatosis and neurofibromatosis type 2 (NF2) are two distinct neuro-genetic tumor predisposition disorders, which, however, share some clinical and genetic features. While germline mutations in the NF2 gene are only found in NF2, a majority of Schwannomatosis patients have germline mutations in the SMARCB1 or LZTR1 genes. The overlapping clinical phenotypes pose a serious challenge in differential diagnosis and in risk stratification of these two entities which is further complicated by frequent mosaicism in both disorders. Chronic neuropathic pain which is a typical consequence of small fiber neuropathy, is characteristic for Schwannomatosis. By contrast, NF2 patients do not have chronic pain but may have moderate to severe sensory deficits and paresis which are not characteristic for Schwannomatosis. In the present study, we determined intraepidermal nerve fiber density (IEND) in skin biopsies of 34 clinically ascertained Schwannomatosis and 25 NF2 patients. In the NF2 group, 11/25 (44%) presented with IEND below the age- and gender-matched bottom 5% normative reference IEND. In contrast, nearly all (33/34 = 97%) Schwannomatosis patients showed IEND below or on the bottom 5% normative reference. The reduction of IEND in Schwannomatosis patients was age-independent. Paired t-test revealed no difference between the NF2-IEND and the corresponding bottom 5% normative reference (P = 0.98). By contrast, IEND in the Schwannomatosis patients were highly significantly lower than the corresponding 5% normative reference IEND (P 

  • Distinctive low epidermal nerve fiber density in Schwannomatosis patients provides a major parameter for diagnosis and differential diagnosis.
    Brain Pathology, 2019
    Co-Authors: Said Farschtschi, Lan Kluwe, Markus Glatzel, Jakob Matschke, Gerhard Schon, Joachim Weis, Reinhard E Friedrich, Christian Hagel, Victor-felix Mautner
    Abstract:

    : Schwannomatosis and neurofibromatosis type 2 (NF2) are two distinct neuro-genetic tumor predisposition disorders, which, however, share some clinical and genetic features. While germline mutations in the NF2 gene are only found in NF2, a majority of Schwannomatosis patients have germline mutations in the SMARCB1 or LZTR1 genes. The overlapping clinical phenotypes pose a serious challenge in differential diagnosis and in risk stratification of these two entities which is further complicated by frequent mosaicism in both disorders. Chronic neuropathic pain which is a typical consequence of small fiber neuropathy, is characteristic for Schwannomatosis. By contrast, NF2 patients do not have chronic pain but may have moderate to severe sensory deficits and paresis which are not characteristic for Schwannomatosis. In the present study, we determined intraepidermal nerve fiber density (IEND) in skin biopsies of 34 clinically ascertained Schwannomatosis and 25 NF2 patients. In the NF2 group, 11/25 (44%) presented with IEND below the age- and gender-matched bottom 5% normative reference IEND. In contrast, nearly all (33/34 = 97%) Schwannomatosis patients showed IEND below or on the bottom 5% normative reference. The reduction of IEND in Schwannomatosis patients was age-independent. Paired t-test revealed no difference between the NF2-IEND and the corresponding bottom 5% normative reference (P = 0.98). By contrast, IEND in the Schwannomatosis patients were highly significantly lower than the corresponding 5% normative reference IEND (P 

  • Phenotypic and genotypic overlap between mosaic NF2 and Schwannomatosis in patients with multiple non-intradermal schwannomas.
    Human genetics, 2018
    Co-Authors: Hildegard Kehrer-sawatzki, Lan Kluwe, Said Farschtschi, Reinhard E Friedrich, Anna Summerer, Eleonora Schäfer, Ute Wahlländer, Cordula Matthies, Isabel Gugel, Christian Hagel
    Abstract:

    Schwannomatosis and neurofibromatosis type 2 (NF2) are both characterized by the development of multiple schwannomas but represent different genetic entities. Whereas NF2 is caused by mutations of the NF2 gene, Schwannomatosis is associated with germline mutations of SMARCB1 or LZTR1. Here, we studied 15 sporadic patients with multiple non-intradermal schwannomas, but lacking vestibular schwannomas and ophthalmological abnormalities, who fulfilled the clinical diagnostic criteria for Schwannomatosis. None of them harboured germline NF2 or SMARCB1 mutations as determined by the analysis of blood samples but seven had germline LZTR1 variants predicted to be pathogenic. At least two independent schwannomas from each patient were subjected to NF2 mutation testing. In five of the 15 patients, identical somatic NF2 mutations were identified (33%). If only those patients without germline LZTR1 variants are considered (n = 8), three of them (37.5%) had mosaic NF2 as concluded from identical NF2 mutations identified in independent schwannomas from the same patient. These findings imply that a sizeable proportion of patients who fulfil the diagnostic criteria for Schwannomatosis, are actually examples of mosaic NF2. Hence, the molecular characterization of tumours in patients with a clinical diagnosis of Schwannomatosis is very important. Remarkably, two of the patients with germline LZTR1 variants also had identical NF2 mutations in independent schwannomas from each patient which renders differential diagnosis of LZTR1-associated Schwannomatosis versus mosaic NF2 in these patients very difficult.

Victor-felix Mautner - One of the best experts on this subject based on the ideXlab platform.

  • distinctive low epidermal nerve fiber density in Schwannomatosis patients provides a major parameter for diagnosis and differential diagnosis
    Brain Pathology, 2020
    Co-Authors: Said Farschtschi, Lan Kluwe, Markus Glatzel, Jakob Matschke, Gerhard Schon, Joachim Weis, Reinhard E Friedrich, Christian Hagel, Victor-felix Mautner
    Abstract:

    Schwannomatosis and neurofibromatosis type 2 (NF2) are two distinct neuro-genetic tumor predisposition disorders, which, however, share some clinical and genetic features. While germline mutations in the NF2 gene are only found in NF2, a majority of Schwannomatosis patients have germline mutations in the SMARCB1 or LZTR1 genes. The overlapping clinical phenotypes pose a serious challenge in differential diagnosis and in risk stratification of these two entities which is further complicated by frequent mosaicism in both disorders. Chronic neuropathic pain which is a typical consequence of small fiber neuropathy, is characteristic for Schwannomatosis. By contrast, NF2 patients do not have chronic pain but may have moderate to severe sensory deficits and paresis which are not characteristic for Schwannomatosis. In the present study, we determined intraepidermal nerve fiber density (IEND) in skin biopsies of 34 clinically ascertained Schwannomatosis and 25 NF2 patients. In the NF2 group, 11/25 (44%) presented with IEND below the age- and gender-matched bottom 5% normative reference IEND. In contrast, nearly all (33/34 = 97%) Schwannomatosis patients showed IEND below or on the bottom 5% normative reference. The reduction of IEND in Schwannomatosis patients was age-independent. Paired t-test revealed no difference between the NF2-IEND and the corresponding bottom 5% normative reference (P = 0.98). By contrast, IEND in the Schwannomatosis patients were highly significantly lower than the corresponding 5% normative reference IEND (P < 0.0001). In addition, the difference between the IEND of our patients and the 5% lowest normative reference IEND was highly significantly larger in Schwannomatosis patients than in NF2 patients (P < 0.0001). IEND of our patients did not correlate with neither the presence nor types of germline mutations in neither the NF2 nor the LZTR1 gene. In conclusion, Schwannomatosis patients have marked low IEND which provides a major parameter for diagnosis and differential diagnosis.

  • Distinctive low epidermal nerve fiber density in Schwannomatosis patients provides a major parameter for diagnosis and differential diagnosis.
    Brain Pathology, 2019
    Co-Authors: Said Farschtschi, Lan Kluwe, Markus Glatzel, Jakob Matschke, Gerhard Schon, Joachim Weis, Reinhard E Friedrich, Christian Hagel, Victor-felix Mautner
    Abstract:

    : Schwannomatosis and neurofibromatosis type 2 (NF2) are two distinct neuro-genetic tumor predisposition disorders, which, however, share some clinical and genetic features. While germline mutations in the NF2 gene are only found in NF2, a majority of Schwannomatosis patients have germline mutations in the SMARCB1 or LZTR1 genes. The overlapping clinical phenotypes pose a serious challenge in differential diagnosis and in risk stratification of these two entities which is further complicated by frequent mosaicism in both disorders. Chronic neuropathic pain which is a typical consequence of small fiber neuropathy, is characteristic for Schwannomatosis. By contrast, NF2 patients do not have chronic pain but may have moderate to severe sensory deficits and paresis which are not characteristic for Schwannomatosis. In the present study, we determined intraepidermal nerve fiber density (IEND) in skin biopsies of 34 clinically ascertained Schwannomatosis and 25 NF2 patients. In the NF2 group, 11/25 (44%) presented with IEND below the age- and gender-matched bottom 5% normative reference IEND. In contrast, nearly all (33/34 = 97%) Schwannomatosis patients showed IEND below or on the bottom 5% normative reference. The reduction of IEND in Schwannomatosis patients was age-independent. Paired t-test revealed no difference between the NF2-IEND and the corresponding bottom 5% normative reference (P = 0.98). By contrast, IEND in the Schwannomatosis patients were highly significantly lower than the corresponding 5% normative reference IEND (P 

  • Distinctive low epidermal nerve fiber density in Schwannomatosis patients provides a major parameter for diagnosis and differential diagnosis.
    Brain Pathology, 2019
    Co-Authors: Said Farschtschi, Lan Kluwe, Markus Glatzel, Jakob Matschke, Gerhard Schon, Joachim Weis, Reinhard E Friedrich, Christian Hagel, Victor-felix Mautner
    Abstract:

    : Schwannomatosis and neurofibromatosis type 2 (NF2) are two distinct neuro-genetic tumor predisposition disorders, which, however, share some clinical and genetic features. While germline mutations in the NF2 gene are only found in NF2, a majority of Schwannomatosis patients have germline mutations in the SMARCB1 or LZTR1 genes. The overlapping clinical phenotypes pose a serious challenge in differential diagnosis and in risk stratification of these two entities which is further complicated by frequent mosaicism in both disorders. Chronic neuropathic pain which is a typical consequence of small fiber neuropathy, is characteristic for Schwannomatosis. By contrast, NF2 patients do not have chronic pain but may have moderate to severe sensory deficits and paresis which are not characteristic for Schwannomatosis. In the present study, we determined intraepidermal nerve fiber density (IEND) in skin biopsies of 34 clinically ascertained Schwannomatosis and 25 NF2 patients. In the NF2 group, 11/25 (44%) presented with IEND below the age- and gender-matched bottom 5% normative reference IEND. In contrast, nearly all (33/34 = 97%) Schwannomatosis patients showed IEND below or on the bottom 5% normative reference. The reduction of IEND in Schwannomatosis patients was age-independent. Paired t-test revealed no difference between the NF2-IEND and the corresponding bottom 5% normative reference (P = 0.98). By contrast, IEND in the Schwannomatosis patients were highly significantly lower than the corresponding 5% normative reference IEND (P 

  • dorsal root ganglia volume differentiates Schwannomatosis and neurofibromatosis 2
    Annals of Neurology, 2018
    Co-Authors: Tim Godel, Said Farschtschi, Victor-felix Mautner, Mirko Pham, Isabel Gugel, Daniel Schwarz, Moritz Kronlage, Sabine Heiland, Martin Bendszus, Philipp Baumer
    Abstract:

    Schwannomatosis and neurofibromatosis type 2 are hereditary tumor syndromes, and peripheral neuropathy has been reported in both. We prospectively applied in vivo morphometric measurement of dorsal root ganglia volume in 16 Schwannomatosis patients, 14 neurofibromatosis type 2 patients, and 26 healthy controls by magnetic resonance neurography. Compared to healthy controls, dorsal root ganglia hypertrophy was a consistent finding in neurofibromatosis type 2 (L3, + 267%; L4, + 235%; L5, + 241%; S1, + 300%; S2, + 242%; Bonferroni-adjusted p < 0.001) but not in Schwannomatosis. Dorsal root ganglia may be a vulnerable site in origination of areflexia and sensory loss and a useful diagnostic marker in neurofibromatosis type 2. Ann Neurol 2018;83:854-857.

  • Dorsal root ganglia volume differentiates Schwannomatosis and neurofibromatosis 2.
    Annals of neurology, 2018
    Co-Authors: Tim Godel, Said Farschtschi, Victor-felix Mautner, Mirko Pham, Isabel Gugel, Daniel Schwarz, Moritz Kronlage, Sabine Heiland, Martin Bendszus, Philipp Baumer
    Abstract:

    Schwannomatosis and neurofibromatosis type 2 are hereditary tumor syndromes, and peripheral neuropathy has been reported in both. We prospectively applied in vivo morphometric measurement of dorsal root ganglia volume in 16 Schwannomatosis patients, 14 neurofibromatosis type 2 patients, and 26 healthy controls by magnetic resonance neurography. Compared to healthy controls, dorsal root ganglia hypertrophy was a consistent finding in neurofibromatosis type 2 (L3, + 267%; L4, + 235%; L5, + 241%; S1, + 300%; S2, + 242%; Bonferroni-adjusted p 

Miriam J. Smith - One of the best experts on this subject based on the ideXlab platform.

  • Mutations in LZTR1 add to the complex heterogeneity of Schwannomatosis.
    Neurology, 2014
    Co-Authors: Miriam J. Smith, Bertand Isidor, Christian Beetz, Simon G. Williams, Sanjeev S. Bhaskar, Wilfrid Richer, James O'sullivan, Beverly Anderson, Sarah B. Daly, Jill E. Urquhart
    Abstract:

    Objectives: We aimed to determine the proportion of individuals in our Schwannomatosis cohort whose disease is associated with an LZTR1 mutation. Methods: We used exome sequencing, Sanger sequencing, and copy number analysis to screen 65 unrelated individuals with Schwannomatosis who were negative for a germline NF2 or SMARCB1 mutation. We also screened samples from 39 patients with a unilateral vestibular schwannoma (UVS), plus at least one other schwannoma, but who did not have an identifiable germline or mosaic NF2 mutation. Results: We identified germline LZTR1 mutations in 6 of 16 patients (37.5%) with Schwannomatosis who had at least one affected relative, 11 of 49 (22%) sporadic patients, and 2 of 39 patients with UVS in our cohort. Three germline mutation–positive patients in total had developed a UVS. Mosaicism was excluded in 3 patients without germline mutation in NF2 , SMARCB1 , or LZTR1 by mutation screening in 2 tumors from each. Conclusions: Our data confirm the relationship between mutations in LZTR1 and Schwannomatosis. They indicate that germline mutations in LZTR1 confer an increased risk of vestibular schwannoma, providing further overlap with NF2, and that further causative genes for Schwannomatosis remain to be identified.

  • SMARCB1 mutations in Schwannomatosis and genotype correlations with rhabdoid tumors.
    Cancer genetics, 2014
    Co-Authors: Miriam J. Smith, Naomi L. Bowers, Andrew J. Wallace, Helen Eaton, D. Gareth Evans
    Abstract:

    Mutations in the SMARCB1 gene are involved in several human tumor-predisposing syndromes. They were established as an underlying cause of the tumor suppressor syndrome Schwannomatosis in 2008. There is a much higher rate of mutation detection in familial disease than in sporadic disease. We have performed extensive genetic testing on a cohort of familial and sporadic patients who fulfilled clinical diagnostic criteria for Schwannomatosis. In our updated cohort, we identified novel mutations within the SMARCB1 gene as well as several recurrent mutations. Of the Schwannomatosis screens reported to date, including those in our updated cohort, SMARCB1 mutations have been found in 45% of familial probands and 9% of sporadic patients. The exon 1 mutation, c.41C>A p.Pro14His (10% in our series), and the 3' untranslated region mutation, c.*82C>T (27%), are the most common changes reported in patients with Schwannomatosis to date, indicating the presence of mutation hot spots at both 5' and 3' portions of the gene. Comparison with germline SMARCB1 mutations in patients with rhabdoid tumors showed that the Schwannomatosis mutations were significantly more likely to occur at either end of the gene and be nontruncating mutations (P < 0.0001). SMARCB1 mutations are found in a significant proportion of Schwannomatosis patients, and an even higher proportion of rhabdoid patients. Whereas SMARCB1 alone seems to account for rhabdoid disease, there is likely to be substantial heterogeneity in Schwannomatosis even for familial disease. There is a clear genotype-phenotype correlation, with germline rhabdoid mutations being significantly more likely to be centrally placed, involve multiple exon deletions, and be truncating mutations.

  • Expression of SMARCB1 (INI1) mutations in familial Schwannomatosis
    Human molecular genetics, 2012
    Co-Authors: Miriam J. Smith, James F. Gusella, Anat Stemmer-rachamimov, James A. Walker, Yiping Shen, Scott R. Plotkin
    Abstract:

    Genetic changes in the SMARCB1 tumor suppressor gene have recently been reported in tumors and blood from families with Schwannomatosis. Exon scanning of all nine SMARCB1 exons in genomic DNA from our cohort of families meeting the criteria for 'definite' or 'presumptive' Schwannomatosis previously revealed constitutional alterations in 13 of 19 families (68%). Screening of four new familial Schwannomatosis probands identified one additional constitutional alteration. We confirmed the presence of mRNA transcripts for two missense alterations, four mutations of conserved splice motifs and two additional mutations, in less conserved sequences, which also affect splicing. Furthermore, we found that transcripts for a rare 3'-untranslated region (c.*82C > T) alteration shared by four unrelated families did not produce splice variants but did show unequal allelic expression, suggesting that the alteration is either causative itself or linked to an unidentified causative mutation. Overexpression studies in cells lacking SMARCB1 suggest that mutant SMARCB1 proteins, like wild-type SMARCB1 protein, retain the ability to suppress cyclin D1 activity. These data, together with the expression of SMARCB1 protein in a proportion of cells from Schwannomatosis-related schwannomas, suggest that these tumors develop through a mechanism that is distinct from that of rhabdoid tumors in which SMARCB1 protein is completely absent in tumor cells.

  • Clinical Features of Schwannomatosis: A Retrospective Analysis of 87 Patients
    The oncologist, 2012
    Co-Authors: Vanessa L. Merker, Miriam J. Smith, Sonia Esparza, Anat Stemmer-rachamimov, Scott R. Plotkin
    Abstract:

    Background. Schwannomatosis is a recently recognized form of neurofibromatosis characterized by multiple noncutaneous schwannomas, a histologically benign nerve sheath tumor. As more cases are identified, the reported phenotype continues to expand and evolve. We describe the spectrum of clinical findings in a cohort of patients meeting established criteria for Schwannomatosis.

  • Frequency of SMARCB1 mutations in familial and sporadic Schwannomatosis
    neurogenetics, 2012
    Co-Authors: Miriam J. Smith, Cecilie F. Rustad, Naomi L. Bowers, Andrew J. Wallace, Rosalie E. Ferner, C. Geoff Woods, Guy D. Leschziner, D. Gareth R. Evans
    Abstract:

    Mutations of the SMARCB1 gene have been implicated in several human tumour predisposing syndromes. They have recently been identified as an underlying cause of the tumour suppressor syndrome Schwannomatosis. There is a much higher rate of mutation detection in familial disease than in sporadic disease. We have carried out extensive genetic testing on a cohort of familial and sporadic patients who fulfilled clinical diagnostic criteria for Schwannomatosis. In our current cohort, we identified novel mutations within the SMARCB1 gene and detected several mutations that have been previously identified in other Schwannomatosis cohorts. Of the Schwannomatosis screens reported to date, including our current dataset, SMARCB1 mutations have been found in 45 % of familial probands and 7 % of sporadic patients. The exon 1 mutation, c.41C >A, and the 3′ untranslated region mutation, c.*82C >T, are the most common changes reported in Schwannomatosis disease so far, indicating mutation hotspots at both 5′ and 3′ portions of the gene. SMARCB1 mutations are found in a significant proportion of Schwannomatosis patients, but there remains the possibility that further causative genes remain to be found.

Sylviane Olschwang - One of the best experts on this subject based on the ideXlab platform.