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Multiple primary malignancies associated with a germline SMARCB1 pathogenic variant

Authors:
Judith Eelloo at Manchester University NHS Foundation Trust
Judith Eelloo
Miriam J Smith at The University of Manchester
Miriam J Smith
Naomi L. Bowers
Naomi L. Bowers
Naomi L. Bowers
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John Edward Paul Ealing at The University of Manchester
John Edward Paul Ealing
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Abstract and Figures

A 51-year old presented with a 6-month history of increasing pelvic/lower back pain with nocturnal waking and episodes of anorexia and vomiting. Examination revealed right torticollis and Horner’s syndrome, and a large abdominal mass arising from the pelvis. Magnetic resonance and positron emission tomography imaging revealed (A) a 14 cm heterogeneous enhancing mass, abutting the left kidney with standardised uptake value max = 2.9, (B) a large heterogeneous enhancing pelvic mass (C) mesenteric adenopathy standardised uptake value max = 10.3 and (D) 6 cm right lung apex mass standardised uptake value max = 4.3. Computerised tomography-guided biopsy of lesion A was reported as neurofibroma with occasional atypia, lesion B a benign uterine leiomyoma and lesion C follicular lymphoma world health organisation Grade 2. Although she had been given the diagnosis of Neurofibromatosis Type-1 (NF1) 25-years previously following removal of an intradural extramedullary schwannoma she had no cutaneous stigmata of NF1. Genetic analysis of blood lymphocyte DNA identified a pathogenic variant in SMARCB1 confirming a diagnosis of schwannomatosis. Following 6-months chemotherapy for lymphoma, surgery was performed to remove lesion A. Histology revealed a malignant peripheral nerve sheath tumour with areas of low and high-grade change. An incidental, well-differentiated small bowel neuroendocrine carcinoma was also excised. Close surveillance continues with no recurrence after 6 years. This case study describes a novel finding of three separate synchronous primary malignancies in a patient with schwannomatosis and a proven SMARCB1 pathogenic variant.
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Familial Cancer (2019) 18:445–449
https://doi.org/10.1007/s10689-019-00138-4
ORIGINAL ARTICLE
Multiple primary malignancies associated withagermline SMARCB1
pathogenic variant
JudithA.Eelloo1· MiriamJ.Smith1,2· NaomiL.Bowers1· JohnEaling1,3· PaulHulse4· JamesP.Wylie5·
PatrickShenjere6· NoelW.Clarke7· CalvinSoh8· RichardW.Whitehouse8· MarkJones9· ChristopherDu10·
AnthonyFreemont11· D.GarethEvans1,2
Published online: 25 June 2019
© Springer Nature B.V. 2019
Abstract
A 51-year old presented with a 6-month history of increasing pelvic/lower back pain with nocturnal waking and episodes
of anorexia and vomiting. Examination revealed right torticollis and Horner’s syndrome, and a large abdominal mass aris-
ing from the pelvis. Magnetic resonance and positron emission tomography imaging revealed (A) a 14cm heterogeneous
enhancing mass, abutting the left kidney with standardised uptake value max = 2.9, (B) a large heterogeneous enhancing
pelvic mass (C) mesenteric adenopathy standardised uptake value max = 10.3 and (D) 6cm right lung apex mass stand-
ardised uptake value max = 4.3. Computerised tomography-guided biopsy of lesion A was reported as neurofibroma with
occasional atypia, lesion B a benign uterine leiomyoma and lesion C follicular lymphoma world health organisation Grade 2.
Although she had been given the diagnosis of Neurofibromatosis Type-1 (NF1) 25-years previously following removal of an
intradural extramedullary schwannoma she had no cutaneous stigmata of NF1. Genetic analysis of blood lymphocyte DNA
identified a pathogenic variant in SMARCB1 confirming a diagnosis of schwannomatosis. Following 6-months chemotherapy
for lymphoma, surgery was performed to remove lesion A. Histology revealed a malignant peripheral nerve sheath tumour
with areas of low and high-grade change. An incidental, well-differentiated small bowel neuroendocrine carcinoma was also
excised. Close surveillance continues with no recurrence after 6years. This case study describes a novel finding of three
separate synchronous primary malignancies in a patient with schwannomatosis and a proven SMARCB1 pathogenic variant.
Keywords Schwannomatosis· Neurofibromatosis type 1· Neurofibromatosis type 2· Malignancy· SMARCB1· Follicular
lymphoma· MPNST
* Judith A. Eelloo
judith.eelloo@mft.nhs.uk
1 Manchester Centre forGenomic Medicine, St Mary’s
Hospital, Manchester University Hospitals Foundation Trust,
ManchesterM139WL, UK
2 Division ofEvolution andGenomic Sciences, School
ofBiological Sciences, University ofManchester,
Manchester, UK
3 Department ofNeurology, Salford Royal Foundation Trust,
Manchester, UK
4 Department ofRadiology, The Christie NHS Foundation
Trust, Manchester, UK
5 Departments ofMedical Oncology, The Christie NHS
Foundation Trust, Manchester, UK
6 Department ofHistopathology, The Christie NHS Foundation
Trust, Manchester, UK
7 Department ofClinical Urology, The Christie NHS
Foundation Trust, Manchester, UK
8 Department Radiology, Manchester Royal Infirmary,
Manchester University Hospitals Foundation Trust,
Manchester, UK
9 Department ofCardiothoracic Surgery, Wythenshawe
Hospital, Manchester Universities Foundation Trust,
Manchester, UK
10 Department ofPlastic Surgery, Wythenshawe Hospital,
Manchester Universities Foundation Trust, Manchester, UK
11 Department ofHistopathology, Manchester Royal Infirmary,
Manchester Universities Foundation Trust, Manchester, UK
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
... Life expectancy is not usually reduced, unlike in NF2 [2], but quality of life is strongly affected. Whilst there exists some concern over malignant potential in SMARCB1-related schwannomatosis [26,27], this does not appear to be a feature of other types of schwannomatosis. Other common features of NF2 such as ependymomas and ocular features such as retinal hamartoma, epiretinal folds and juvenile cataracts have not been reported in schwannomatosis [1,2]. ...
... Recently several cases have been described mainly in patients harbouring germline mutations in SMARCB1 gene. A clear increased risk of a malignant-peripheral nerve-sheath tumour has been established [26] although it is possible that a more extended malignancy phenotype associated with a SMARCB1 pathogenic variant does exist [27]. Due to this increased risk, we have recommended that a changing tumour, in someone with SMARCB1 germline pathogenic variant, especially one causing functional impairment, should prompt exclusion of malignant transformation. ...
ERN GENTURIS clinical practice guidelines for the diagnosis, treatment, management and surveillance of people with schwannomatosis
Article
Full-text available
  • Apr 2022
A Guideline Group (GG) was convened from multiple specialties and patients to develop the first comprehensive schwannomatosis guideline. The GG undertook thorough literature review and wrote recommendations for treatment and surveillance. A modified Delphi process was used to gain approval for recommendations which were further altered for maximal consensus. Schwannomatosis is a tumour predisposition syndrome leading to development of multiple benign nerve-sheath non-intra-cutaneous schwannomas that infrequently affect the vestibulocochlear nerves. Two definitive genes ( SMARCB1 / LZTR1 ) have been identified on chromosome 22q centromeric to NF2 that cause schwannoma development by a 3-event, 4-hit mechanism leading to complete inactivation of each gene plus NF2 . These genes together account for 70–85% of familial schwannomatosis and 30–40% of isolated cases in which there is considerable overlap with mosaic NF2. Craniospinal MRI is generally recommended from symptomatic diagnosis or from age 12–14 if molecularly confirmed in asymptomatic individuals whose relative has schwannomas. Whole-body MRI may also be deployed and can alternate with craniospinal MRI. Ultrasound scans are useful in limbs where typical pain is not associated with palpable lumps. Malignant-Peripheral-Nerve-Sheath-Tumour-MPNST should be suspected in anyone with rapidly growing tumours and/or functional loss especially with SMARCB1- related schwannomatosis. Pain (often intractable to medication) is the most frequent symptom. Surgical removal, the most effective treatment, must be balanced against potential loss of function of adjacent nerves. Assessment of patients’ psychosocial needs should be assessed annually as well as review of pain/pain medication. Genetic diagnosis and counselling should be guided ideally by both blood and tumour molecular testing.
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... Among the patients diagnosed with other SWNs, approximately 5% were reported to have meningiomas 31) . 16 The malignant transformation of schwannomas remains a potential risk in individuals with SMARCB1-SWN 8) . Rapid growth of schwannomas and intractable pain should prompt suspicion of possible malignancy. ...
Genetic Basis and Clinical Management of Schwannomatosis
Article
  • Mar 2025
  • J KOREAN NEUROSURG S
Schwannomatosis (SWN) is now recognized as a broad classification that includes neurofibromatosis (NF) type 2, reflecting their shared genetic and phenotypic characteristics. Previously, SWN and NF type 2 were considered distinct clinical entities; however, the 2022 classification revision has unified them under the umbrella of SWN, with NF type 2 now referred to as NF2-related SWN. SWN arises from mutations in NF2, SMARCB1 or LZTR1. Recent diagnostic criteria for SWN incorporate molecular classification, including "NF2-related SWN", "SMARCB1-related SWN", "LZTR1-related SWN", "22q-related SWN", "SWN-not otherwise specified", or "SWN-not elsewhere classified". NF2-related SWN is a genetic condition where all individuals with a germline or constitutional NF2 mutation are destined to develop the disease. The pathogenesis of SMARCB1- or LZTR1-related SWN follows a three-step, four-hit model. This involves retention of the mutated germline SMARCB1 or LZTR1 allele in the tumor, loss of the wild-type chromosome 22, and somatic mutation in the NF2 gene. Clinically, NF2-related SWN involves bilateral vestibular schwannomas, with treatment options including microsurgery, radiotherapy, and bevacizumab, each with specific benefits and limitations. Patients with SWN frequently present with chronic pain caused by schwannomas, which often does not correlate with tumor size, location, or burden. Management of SWN is primarily symptom-based. Surgical intervention is reserved for symptomatic lesions, particularly in cases of spinal cord compression or significant functional impairments. Multidisciplinary approaches to pain management are critical for enhancing quality of life. Although malignant transformation of schwannomas is a potential risk, the life expectancy of individuals with SWN is nearly normal. Despite advancements in understanding SWN, further research is necessary to elucidate the underlying genetic mechanisms and to develop targeted therapeutic strategies for this complex disorder.
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... MPNST was remarkably absent from other common CPS like hereditary breast and ovarian cancer (HBOC) syndrome and Lynch syndrome [34] . While MPNST has been rarely reported in association with rhabdoid tumor predisposition syndrome [35,36] , investigation of rhabdoid tumor predisposition syndrome amongst unselected cohorts of MPNST has not been reported. MPNST risk in individuals with NF2 remains controversial. ...
Germline predisposition to soft tissue sarcoma
Article
Full-text available
  • Aug 2022
Soft tissue sarcoma (STS) most often occurs sporadically, but can also arise in the setting of a germline cancer predisposition syndrome (CPS). There is significant diversity amongst STS diagnoses as these tumors exhibit a variety of histologies, occur in all age groups, and can occur in any location in the body. This diversity is also reflected in the many known associated germline cancer predisposition associations. Some STS diagnoses, such as anaplastic rhabdomyosarcoma, are associated with high heritability and other STS, such as Ewing sarcoma, are notably absent from known CPS. Recognizing when a STS is more likely to be hereditary can influence clinical management. Individuals diagnosed with STS due to CPS may be at risk for other malignancies and should undergo additional surveillance for early detection. Additionally, family members should undergo genetic testing as they also may be at risk to develop STS and other CPS-associated malignancies. Some underlying cancer predisposition diagnoses may have implications for the treatment of a concurrent malignancy as in the case of PARP inhibitor therapy in the setting of homologous recombination deficiency. This review summarizes current knowledge of selected STS and their associations with CPS.
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... Interestingly, a well-differentiated small bowel NEN was also identified in a patient with a pathogenic variant in SMARCB1 (22q11.23) [121], while another patient with germline BRCA1 (17q21.31) was found to have a small bowel mixed adenocarcinoma and neuroendocrine carcinoma [122]. ...
Inherited Neuroendocrine Neoplasms
Chapter
Full-text available
  • Jan 2021
Inherited neuroendocrine neoplasms (NENs) represent a heterogeneous group of disorders that often present with subtle clinical or biochemical features. The well-recognized entities include a spectrum of associated neoplasms harboring various degrees of biologic aggressiveness, which often show variable degrees of genotype-phenotype correlations and penetrance. The rate of germline susceptibility in endocrine neoplasms is generally underestimated as most healthcare providers do not routinely consider the possibility of germline disease in a seemingly sporadic presentation in adults over the age of 50–60 years. Variations in disease penetrance and de novo pathogenic variants can lead to late-onset manifestations of inherited NENs that can simulate sporadic disease in the absence of family history. Some of these also manifest with a non-syndromic presentation as seen in patients with familial isolated hyperparathyroidism (FIHP), familial isolated pituitary adenoma (FIPA), as well as in a subset of multiple endocrine neoplasia type 2 (MEN2) patients manifesting only with medullary thyroid carcinoma (formerly known as familial isolated medullary thyroid carcinoma syndrome). The suspicion of an underlying germline susceptibility for NENs should be based on tumor multifocality and morphology including non-tumorous parenchyma, identification of hyperplasia-to-neoplasia progression sequence, early-onset, and coexistence of synchronous or asynchronous endocrinopathies, including endocrine neoplasias. The delivery of genetic care for hereditary inherited disorders is multifaceted and involves multiple healthcare practitioners, including laboratory geneticists, physician geneticists, and genetic counsellors.
View
Update on Cancer and Central Nervous System Tumor Surveillance in Pediatric NF2-, SMARCB1-, and LZTR1-Related Schwannomatosis
Article
  • Feb 2025
  • CLIN CANCER RES
Schwannomatoses (SWN) are distinct cancer predisposition syndromes caused by germline pathogenic variants in the genes NF2, SMARCB1, or LZTR1. There is significant clinical overlap between these syndromes with the hallmark of increased risk for cranial, spinal and peripheral schwannomas. Neurofibromatosis type 2 was recently renamed as NF2-related SWN and is the most common SWN syndrome with increased risk for bilateral vestibular schwannomas, intradermal schwannomas, meningiomas and less commonly ependymoma. SMARCB1-related SWN is a familial SWN-syndrome associated with peripheral and spinal schwannomas and an increased risk for meningiomas and malignant peripheral nerve sheath tumors, even in the absence of radiation. These individuals do not develop bilateral vestibular schwannomas. Finally, patients with LZTR1-related SWN typically present with peripheral schwannomas, and unilateral vestibular schwannomas have been reported. The following perspective is intended to highlight the clinical presentation and international tumor surveillance recommendations across these SWN-syndromes.
View
Classification of schwannomas and the new naming convention for "neurofibromatosis-2": Genetic updates and international consensus recommendation
Article
  • Jan 2025
Despite their similar nomenclature, Neurofibromatosis type 1 (NF1) and “Neurofibromatosis type 2” are discrete and clinically distinguishable entities. The name of “neurofibromatosis type 2” has been changed to NF2-related schwannomatosis, to reflect the fact that neurofibromas do not occur in this syndrome and therefore the name “Neurofibromatosis” is factually incorrect. Furthermore, multiple schwannomas, a hallmark feature of NF2, can also occur in patients with mutations in genes including SMARCB1 and LZTR1, all exhibiting overlapping clinical features. Current understanding suggests that schwannomatosis (SWN) encompasses a range of clinical presentations consisting of clearly defined, separate subtypes which share a common phenotype of schwannomas. Recognizing these newly emerging subtypes, the International Consensus Group on Neurofibromatosis Diagnostic Criteria (I-NF-DC) proposed a revised nomenclature for NF2 and related disorders in 2022. This review article focuses on this critical update in diagnostic terminology, highlighting the key gene-related SWN subtypes relevant to neuroradiologists. By emphasizing molecular testing alongside clinical features, the revised system facilitates a more precise diagnosis, potentially paving the way for personalized treatment strategies. Additionally, the flexible structure accommodates future discoveries of genes associated with SWN.
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Premature termination of SMARCB1 translation may be followed by reinitiation in schwannomatosis-associated schwannomas, but results in absence of SMARCB1 expression in rhabdoid tumors
Article
Full-text available
  • Apr 2014
  • ACTA NEUROPATHOL
In schwannomatosis, germline SMARCB1 mutations predispose to the development of multiple schwannomas, but not vestibular schwannomas. Many of these are missense or splice-site mutations or in-frame deletions, which are presumed to result in the synthesis of altered SMARCB1 proteins. However, also nonsense and frameshift mutations, which are characteristic for rhabdoid tumors and are predicted to result in the absence of SMARCB1 protein via nonsense-mediated mRNA decay, have been reported in schwannomatosis patients. We investigated the consequences of four of the latter mutations, i.e. c.30delC, c.34C>T, c.38delA, and c.46A>T, all in SMARCB1-exon 1. We could demonstrate for the c.30delC and c.34C>T mutations that the respective mRNAs were still present in the schwannomas of the patients. We hypothesized that these were prevented from degradation by translation reinitiation at the AUG codon encoding methionine at position 27 of the SMARCB1 protein. To test this, we expressed the mutations in MON cells, rhabdoid cells without endogenous SMARCB1 protein, and found that all four resulted in synthesis of the N-terminally truncated protein. Mutation of the reinitiation methionine codon into a valine codon prevented synthesis of the truncated protein, thereby confirming its identity. Immunohistochemistry with a SMARCB1 antibody revealed a mosaic staining pattern in schwannomas of the patients with the c.30delC and c.34C>T mutations. Our findings support the concept that, in contrast to the complete absence of SMARCB1 expression in rhabdoid tumors, altered SMARCB1 proteins with modified activity and reduced (mosaic) expression are formed in the schwannomas of schwannomatosis patients with a germline SMARCB1 mutation.
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Malignant peripheral nerve sheath tumours in inherited disease
Article
Full-text available
  • Oct 2012
Background Malignant peripheral nerve sheath tumours (MPNST) are rare tumours known to occur at high frequency in neurofibromatosis 1 (NF1), but may also occur in other cancer prone syndromes. Methods The North West Regional Genetic Register covers a population of 4.1 million and was interrogated for incidence of MPNST in 12 cancer prone syndromes. Age, incidence and survival curves were generated for NF1. Results Fifty two of 1254 NF1 patients developed MPNST, with MPNST also occurring in 2/181 cases of schwannomatosis and 2/895 NF2 patients. Three cases were also noted in TP53 mutation carriers. However, there were no cases amongst 5727BRCA1/2 carriers and first degree relatives, 2029 members from Lynch syndrome families, nor amongst 447 Familial Adenomatous Polyposis, 202 Gorlin syndrome, nor 87 vHL cases. Conclusion MPNST is associated with schwannomatosis and TP53 mutations and is confirmed at high frequency in NF1. It appears to be only increased in NF2 amongst those that have been irradiated. The lifetime risk of MPNST in NF1 is between 9–13%.
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Schwannomatosis: A genetic and epidemiological study
Article
  • Jun 2018
Objectives Schwannomatosis is a dominantly inherited condition predisposing to schwannomas of mainly spinal and peripheral nerves with some diagnostic overlap with neurofibromatosis-2 (NF2), but the underlying epidemiology is poorly understood. We present the birth incidence and prevalence allowing for overlap with NF2. Methods Schwannomatosis and NF2 cases were ascertained from the Manchester region of England (population=4.8 million) and from across the UK. Point prevalence and birth incidence were calculated from regional birth statistics. Genetic analysis was also performed on NF2, LZTR1 and SMARCB1 on blood and tumour DNA samples when available. Results Regional prevalence for schwannomatosis and NF2 were 1 in 126 315 and 50 500, respectively, with calculated birth incidences of 1 in 68 956 and 1 in 27 956. Mosaic NF2 causes a substantial overlap with schwannomatosis resulting in the misdiagnosis of at least 9% of schwannomatosis cases. LZTR1-associated schwannomatosis also causes a small number of cases that are misdiagnosed with NF2 (1%–2%), due to the occurrence of a unilateral vestibular schwannoma. Patients with schwannomatosis had lower numbers of non-vestibular cranial schwannomas, but more peripheral and spinal nerve schwannomas with pain as a predominant presenting symptom. Life expectancy was significantly better in schwannomatosis (mean age at death 76.9) compared with NF2 (mean age at death 66.2; p=0.004). Conclusions Within the highly ascertained North-West England population, schwannomatosis has less than half the birth incidence and prevalence of NF2.
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Broadening the spectrum of SMARCB1-associated malignant tumors: A case of uterine leiomyosarcoma in a patient with schwannomatosis
Article
  • May 2015
Schwannomatosis is a tumor predisposition syndrome characterized by development of multiple intracranial, spinal, and peripheral schwannomas. Constitutional alterations in either SMARCB1 or LZTR1 on 22q are responsible of the phenotype. We describe a 34-year-old woman who developed multiple benign peripheral sheath tumors and a uterine leiomyosarcoma. The patient carried a de novo constitutional alteration in exon 8 of SMARCB1, c.1118G > A, which destroyed the splice donor site of intron 8. Two schwannomas and the leiomyosarcoma of the patient retained the SMARCB1 mutation; in addition, the tumors showed loss of the normal chromosome 22. In conclusion, our findings enlarged the spectrum of SMARCB1-predisposing tumors and demonstrated, for the first time, the association of a malignant smooth muscle tumor to schwannomatosis. Therefore, clinicians should definitely be aware that a constitutional SMARCB1 mutation, which mainly predisposes to benign nerve sheath tumors, may also predispose to aggressive neoplasms throughout life, within an unexpected spectrum. Copyright © 2015. Published by Elsevier Inc.
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SMARCB1 Involvement in the Development of Leiomyoma in a Patient With Schwannomatosis
Article
  • Mar 2014
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.
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Hybrid Neurofibroma/Schwannoma is Overrepresented Among Schwannomatosis and Neurofibromatosis Patients
Article
  • Mar 2012
We analyzed the histologic features of peripheral nerve sheath tumors occurring in 14 patients with schwannomatosis. Among a total of 31 tumors, 19 tumors (61%) showed schwannoma-like nodules within a neurofibroma-like tumor, corresponding to hybrid neurofibroma/schwannoma. At least 1 hybrid tumor occurred in 10 of 14 (71%) schwannomatosis patients. We then retrieved cases of hybrid tumors without documented relation to schwannomatosis from our database and identified 41 tumors arising in 23 patients. More than half of these patients (14/23) were reported to suffer from multiple peripheral nerve sheath tumors, favoring a tumor syndrome. Indeed, analysis of clinical records revealed the diagnosis of neurofibromatosis type 2 (NF2) in 26% (6/23), neurofibromatosis type 1 (NF1) in 9% (2/23), definite schwannomatosis in 4% (1/23), and possible schwannomatosis in 13% (3/23) of patients with multiple nerve sheath tumors. Our findings suggest that hybrid neurofibroma/schwannoma represents a common tumor type in schwannomatosis and shows a striking association with neurofibromatoses.
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Frequency of SMARCB1 mutations in familial and sporadic schwannomatosis
Article
  • Mar 2012
  • NEUROGENETICS
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.
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Epithelioid Malignant Peripheral Nerve Sheath Tumor Arising in a Schwannoma, in a Patient With “Neuroblastoma-like” Schwannomatosis and a Novel Germline SMARCB1 Mutation
Article
  • Nov 2011
Epithelioid malignant peripheral nerve sheath tumors arising in preexisting schwannomas are extremely rare. We report an unusual example occurring in a patient with multiple schwannomas (schwannomatosis), all but 1 of which showed "neuroblastoma-like" histology. By immunohistochemistry, both the epithelioid malignant peripheral nerve sheath tumor and the schwannomas showed a complete loss of the Smarcb1 protein. Subsequent genetic evaluation revealed the presence of a novel germline mutation in the SMARCB1/INI1 gene in the patient and in 3 of her children, 2 of whom were diagnosed with atypical teratoid/rhabdoid tumors of the brain.
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Spectrum of SMARCB1/INI1 mutations in familial and sporadic rhabdoid tumors
Article
  • Jan 2011
  • PEDIATR BLOOD CANCER
Germline mutations and deletions of SMARCB1/INI1 in chromosome band 22q11.2 predispose patients to rhabdoid tumor and schwannomatosis. Previous estimates suggested that 15-20% of rhabdoid tumors were caused by an underlying germline abnormality of SMARCB1. However, these studies were limited by case selection and an inability to detect intragenic deletions and duplications. One hundred matched tumor and blood samples from patients with rhabdoid tumors of the brain, kidney, or soft tissues were analyzed for mutations and deletions of SMARCB1 by FISH, multiplex ligation-dependent probe amplification (MLPA), sequence analysis and high resolution Illumina 610K SNP-based oligonucleotide array studies. Thirty-five of 100 patients were found to have a germline SMARCB1 abnormality. These abnormalities included point and frameshift mutations, intragenic deletions and duplications, and larger deletions including regions both proximal and distal to SMARCB1. There were nine cases that demonstrated parent to child transmission of a mutated copy of SMARCB1. In eight of the nine cases, one or more family members were also diagnosed with rhabdoid tumor or schwannoma, and two of the eight families presented with multiple affected children in a manner consistent with gonadal mosaicism. Approximately one-third of newly diagnosed patients with rhabdoid tumor have an underlying genetic predisposition to tumors due to a germline SMARCB1 alteration. Families may demonstrate incomplete penetrance and gonadal mosaicism, which must be considered when counseling families of patients with rhabdoid tumor.
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