Familial Schwannomatosis Research Articles

Improved sensitivity for detection of pathogenic variants in familial NF2-related schwannomatosis

PurposeTo determine the impact of additional genetic screening techniques on the rate of detection of pathogenic variants leading to familial NF2-related schwannomatosis.MethodsWe conducted genetic screening of a cohort of 168...

ERN GENTURIS clinical practice guidelines for the diagnosis, treatment, management and surveillance of people with schwannomatosis

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.

Malignant Peripheral Nerve Sheath Tumor with Loss of SMARCB1 and Diffuse S1000 Expression Arising in a Trigeminal Nerve Schwannoma

Abstract Malignant peripheral nerve sheath tumors (MPNSTs) are rare sarcomas of the nerve sheath that infrequently involve the head and neck region. The few reports of MPNSTs arising from benign schwannoma precursors typically exhibit epithelioid morphology. We describe an exceptional case of a conventional MPNST arising in a benign trigeminal nerve schwannoma of a 21-year-old man without neurofibromatosis or familial schwannomatosis. Histologically, the tumor consisted of spindle-shaped cells in a fascicular and focal whorling growth pattern, with extensive geographic necrosis, cytologic atypia, rare atypical mitotic figures and focal histologic features of cellular schwannoma. Immunohistochemically, the tumor cells showed strong and diffuse S100 positivity and loss of SMARCB1. Subsequent genomic sequencing revealed a single nucleotide deletion (c.1148delC) in the SMARCB1/INI1 gene Diffuse S100 positivity and/or loss of SMARCB1 expression is extremely rare in conventional MPNST. We discuss diagnostic considerations for MPNSTs and review the literature concerning treatment of these rare neoplasms.

Oligo-astrocytoma in LZTR1-related Noonan syndrome

Mutations in LZTR1, already known to be causal in familial schwannomatosis type 2, have been recently involved in a small proportion of patients with autosomal dominant and autosomal recessive Noonan syndrome. LZTR1 is also a driver gene in non syndromal glioblastoma. We report a 26-year-old patient with typical Noonan syndrome, and the dominantly transmitted c.850C > T (p.(Arg284Cys)) variant in LZTR1. An oligoastrocytoma was diagnosed in the patient at the age of 22 years; recurrence of the tumor occurred at age 26, as a ganglioblastoma. The patient had been transiently treated with growth hormone between ages 15 and 17. Considering the implication of LZTR1 in sporadic tumors of the nervous system, we hypothesize that gliomas are a possible complication of LZTR1-related Noonan syndrome. This report also supports a possible link between occurrence of a cerebral tumor in Noonan syndrome and a previous treatment with growth hormone.

Hereditary SWI/SNF complex deficiency syndromes.

The SWItch Sucrose non-fermentable (SWI/SNF) complex is a highly conserved multi-subunit complex of proteins encoded by numerous genes mapped to different chromosomal regions. The complex regulates the process of chromatin remodelling and hence plays a central role in the epigenetic regulation of gene expression, cell proliferation and differentiation. During the last three decades, the SWI/SNF complex has been increasingly recognized as a central molecular event driving the initiation and/or progression of several benign and malignant neoplasms of different anatomic origin and having diverse histomorphological appearance. Atypical teratoid/rhabdoid tumors (AT/RT) and renal/extrarenal malignant rhabdoid tumors of childhood, epithelioid sarcoma and small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) represent the most commonly recognized SWI/SNF-driven neoplasms. Approximately one-third of pediatric malignant rhabdoid tumors are linked to germline SWI/SNF alterations (SMARCB1/INI1, rarely SMARCA4) resulting in occasional familial clustering of these highly aggressive malignancies (so-called rhabdoid tumor predisposition syndrome, RTPS, types 1 and 2, respectively). However, more recently, inherited SWI/SNF-deficiency has been linked to several benign syndromic tumors including a subset of familial schwannomatosis (linked to SMARCB1) and multiple meningiomas (linked to SMARCE1) as well as others. Beyond neoplasms, several congenital developmental functional disorders such as Coffin-Siris syndrome and intellectual disability are now known to be SWI/SNF-related. The latter are essentially not associated with SWI/SNF-driven neoplasms, although at least anecdotal cases have documented concurrence of both neoplastic and developmental disorders. This review summarizes the most important SWI/SNF-driven diseases with a main focus on neoplasms.

Timing of Smarcb1 and Nf2 inactivation determines schwannoma versus rhabdoid tumor development

Germline mutations of the SMARCB1 gene predispose to two distinct tumor syndromes: rhabdoid tumor predisposition syndrome, with malignant pediatric tumors mostly developing in brain and kidney, and familial schwannomatosis, with adulthood benign tumors involving cranial and peripheral nerves. The mechanisms by which SMARCB1 germline mutations predispose to rhabdoid tumors versus schwannomas are still unknown. Here, to understand the origin of these two types of SMARCB1-associated tumors, we generated different tissue- and developmental stage-specific conditional knockout mice carrying Smarcb1 and/or Nf2 deletion. Smarcb1 loss in early neural crest was necessary to initiate tumorigenesis in the cranial nerves and meninges with typical histological features and molecular profiles of human rhabdoid tumors. By inducing Smarcb1 loss at later developmental stage in the Schwann cell lineage, in addition to biallelic Nf2 gene inactivation, we generated the first mouse model developing schwannomas with the same underlying gene mutations found in schwannomatosis patients.

A mosaic pattern of INI1/SMARCB1 protein expression distinguishes Schwannomatosis and NF2-associated peripheral schwannomas from solitary peripheral schwannomas and NF2-associated vestibular schwannomas.

The INI1/SMARCB1 gene protein product has been implicated in the direct pathogenesis of schwannomas from patients with one form of schwannomatosis [SWNTS1; MIM # 162091] showing a mosaic pattern of loss of protein expression by immunohistochemistry [93% in familial vs. 55% in sporadic cases]. To verify whether such INI1/SMARCB1 mosaic pattern could be extended to all schwannomas arising in the sporadic and familial schwannomatoses [i.e. to SMARCB1-related (SWNTS1) or LZTR1-related (SWNTS2) schwannomatosis or to SMARCB1/LZTR1-negative schwannomatosis] and whether it could be involved in classical NF2 or solitary peripheral schwannomas METHODS: We blindly analysed schwannoma samples obtained from a total of 22 patients including (a) 2 patients (2 males; aged 38 and 55years) affected by non-familial SMARCB1-associated schwannomatosis (SWTNS1); (b) 1 patient (1 female; aged 33years) affected by familial schwannomatosis (SWTNS1/ SMARCB1 germ line mutations); (c) 5 patients (3 males, 2 females; aged 33 to 35years) affected by non-familial (sporadic) LZTR1-associated schwannomatosis (SWNTS2); (d) 3 patients (3 males; aged 35 to 47years) affected by familial schwannomatosis (SWTNS2/ LZTR1 germ line mutations); (e) 2 patients (1 male, 1 female; aged 63 and 49years, respectively) affected by non-familial schwannomatosis (SWTNS, negative for SMARCB1, LZTR1 and NF2 gene mutations); (f) 4 patients (3 males, 1 females; aged 15 to 24years) affected by classical NF2 (NF2: harbouring NF2 germ line mutations; and (g) 5 patients (3 males, 2 females; aged 33 to 68years) who had solitary schwannomas. [follow-up=15-30years; negative for constitutional/somatic mutation analysis for the SMARCB1, LZTR1 and NF2 genes] were (blindly) analyzed. The INI1/SMARCB1 immunostaining pattern was regarded as (1) diffuse positive nuclear staining [= retained expression] or (2) mosaic pattern [mixed positive/negative nuclei = loss of expression in a subset of tumour cells]. All solitary peripheral schwannomas and NF2-associated vestibular schwannomas showed diffuse nuclear INI1/SMARCB1 staining in 97-100% of neoplastic cells; schwannomas obtained from all cases of non-familial and familial schwannomatosis and NF2-associated non-vestibular schwannomas showed a mosaic pattern ranging from 10 to 70% of INI1/SMARCB1-positive expression. We did not record a complete lack of nuclear staining. The present data suggests that (a) mosaic loss of immunohistochemical INI1/SMARCB1 expression, despite the interlesional variability, is a reliable marker of schwannomatosis regardless of the involved gene and it might help in the differential diagnosis of schwannomatosis vs. solitary schwannomas and (b) INI1/SMARCB1 expression is not useful in the differential with mosaic NF2, since NF2-associated peripheral schwannomas show the same immunohistochemical pattern.

PM-02 * CONDITIONAL INACTIVATION OF SMARCB1 IN P0 PERMISSIVE MOUSE CELLS GENERATES RHABDOID TUMORS IN THE PERIPHERAL NERVOUS SYSTEM AND IN THE BRAIN

Inactivation of the SMARCB1/Snf5/Ini1 tumor-suppressor gene was originally described as a hallmark of malignant rhabdoid tumors (MRT), an aggressive tumor of early childhood. Recently, SMARCB1 germline mutations have been found in patients with familial or sporadic schwannomatosis, which is characterized by the onset of multiple schwannomas, benign tumors occurring during adolescence and adulthood. The mechanisms by which SMARCB1 germline mutations predispose to schwannomatosis versus MRT are still unknown. Schwannomas are benign neoplasms of the peripheral nerve sheath and are believed to have their origin in embryonic neural crest cells. We used conditional mutagenesis to investigate the role of Smarcb1 biallelic inactivation in mouse neural crest and Schwann cell lineage. In this model, Cre recombinase expression was under the control of the protein zero (P0) gene promoter. P0Cre;Smarcb1flox/flox mice showed reduced viability and at 5 months of age most of the mice presented tumors arising from different cranial nerves (olfactory, trigeminal, vestibulocochlear) or developing in the brain. Brain tumors were mostly found very close to or in contact with the meninges of the rostral part of the cortex leading to the hypothesis that these tumors would arise from the cranial neural crest cell-derived meninges. Analysis of the tumors demonstrated typical histological features of rhabdoid tumors with a histologic spectrum from a primitive neuroectodermal pattern to a more differentiated mesenchymal pattern with extensive spindle shape cell differentiation. Typical rhabdoid cells were found isolated or in nest in most of the tumors. Molecular analysis of the tumors showed derepression of cyclin D1 as found in mouse and human MRT. Altogether, our data not only establish a new model of Smarcb1-related tumorigenesis, but also provide important insight into the cell of origin of MRT.

P16.07 * BEVACIZUMAB AS PALLIATIVE TREATMENT OF FAMILIAL SCHWANNOMATOSIS

Familial schwannomatosis is a rare genetic disorder characterized by multiple schwannomas and chronic pain. There are, except for the schwannomas, no characteristic findings of neurofibromatosis type II. The only established treatments involve repeated surgery, radiotherapy including gamma knife radiosurgery, and analgesics. We describe a 42-year old female patient with familial schwannomatosis with numerous schwannomas. She underwent 12 resections for symptomatic schwannomas in the past two decades, and was treated with external beam radiotherapy at the skull base and the pelvic region in 2006 and 2010, respectively. Based on reports in neurofibromatosis type II and the expression of VEGF, the patient was treated after written informed consent with bevacizumab at a dose of 5 mg/kg every two weeks. She started treatment in November 2013. The treatment was well tolerated, and the patient observed a decreasing volume of a cervical schwannoma. The patient is free of pain, three months after the start of treatment. CT imaging confirmed an average volume reduction of about 25% in all lesions. In irradiated areas, the volume reduction seemed less pronounced than in previously untreated lesions. To our knowledge, this is the first report of a response to systemic treatment, observed in an adult patient with familial schwannomatosis. Treatment with bevacizumab could be considered as a palliative treatment in patients with this rare but debilitating disease.

Whole exome sequencing reveals that the majority of schwannomatosis cases remain unexplained after excluding SMARCB1 and LZTR1 germline variants.

familial and ~10 % of sporadic schwannomatosis patients [4, 10, 12]. recently, another schwannomatosis-predisposing gene within the 22q candidate region has been identified. piotrowski et al. [9] reported germline loss-of-function mutations in LZTR1 in 80 % of familial and sporadic schwannomatosis cases with combined chr22 loss and somatic NF2 mutation (MIM #615670). LZTr1 functions as an adaptor of the cullin 3-containing e3 ubiquitin ligase complex and has recently been implicated in glioblastoma multiforme development [3], indicating a broader role in tumorigenesis. We therefore sought to further explore the prevalence of LZTR1 mutations in a cohort of 23 sporadic schwannomatosis patients. eight tumor-blood DNA pairs from de novo schwannomatosis patients were subjected to whole exome schwannomatosis (MIM #162091) is characterized by the development of multiple schwannomas without vestibular nerve involvement (which is a characteristic of neurofibromatosis type 2—NF2—MIM #101000). About 10 % of patients have a family history of the disease, with the remaining 90 % presumed to be sporadic [7]. Germline mutations of NF2 are not observed [8], although schwannomas frequently harbor somatic NF2 mutations and often display chromosome 22 loss [6]. rare cases with somatic mosaicism for NF2 alterations have also been described [5]. Germline mutations in SMARCB1 (INI1), located proximal to NF2 on chromosome 22, are found in ~30–60 % of

Multimodal Magnetic Resonance Imaging Evaluation of Primary Brain Tumors

Gliomas comprise 80% of primary brain neoplasms, with glioblastoma multiforme being the most commonly diagnosed glioma. The annual incidence is 5.26 per 100,000, or 17,000 newly diagnosed cases per year in the United States. The incidence increases with age, peaking between the 6th and 8th decades. Gliomas are more common among Caucasians and occur more often in men. They can be associated with certain rare hereditary syndromes including Cowden, Turcot, Li-Fraumeni, neurofibromatosis type 1 and type 2, tuberous sclerosis, and familial schwannomatosis. Known risk factors include a history of ionizing radiation, family history of glioma, and certain genetic susceptibility variants that are weakly associated with glioma. Preventative measures have not been shown to decrease the risk of later development. In addition, screening tests are unwarranted since early diagnosis and treatment have not been shown to improve outcome.

A germline missense mutation in COQ6 is associated with susceptibility to familial schwannomatosis.

Purpose:Schwannomatosis, a subtype of neurofibromatosis, is characterized by multiple benign, nonvestibular, nonintradermal schwannomas. Although the tumor suppressor SMARCB1 gene has been frequently identified as the underlying genetic cause of half of familial and ~10% of sporadic schwannomatosis, for most other cases, further causative genes remain to be discovered. Herein, we characterize the genome of a schwannomatosis family without constitutional inactivation of the SMARCB1 gene to explore novel genomic alterations predisposing individuals to the familial disease.Methods:We performed whole-genome/exome sequencing on genomic DNA of both schwannomatosis-affected and normal members of the family.Results:We identified a novel missense mutation (p.Asp208His; c.622G>C) in the coenzyme Q10 (CoQ10) biosynthesis monooxygenase 6 gene (COQ6) in schwannomatosis-affected members. The deleterious effects of the COQ6 mutations were validated by their lack of complementation in a coq6-deficient yeast mutant. Our study further indicated that the resultant haploinsufficiency of COQ6 might lead to CoQ10 deficiency and chronic overproduction of reactive oxygen species in Schwann cells.Conclusion:Although the exact oncogenetic mechanisms in this schwannomatosis family remain to be elucidated, our data strongly indicate a probable role of COQ6 mutation and CoQ10 deficiency in the development of familial schwannomatosis.

Does hereditary neuropathy with liability to pressure palsy predispose to schwannomatosis?

Does hereditary neuropathy with liability to pressure palsy predispose to schwannomatosis?

Rac1 is required for Prkar1a-mediated Nf2 suppression in Schwann cell tumors

Schwannomas are peripheral nerve sheath tumors that often occur in the setting of an inherited tumor predisposition syndrome, including Neurofibromatosis Types 1 (NF1) and 2 (NF2), Familial Schwannomatosis (FS) and Carney Complex (CNC). Loss of the NF2 tumor suppressor (encoding NF2, or Merlin) is associated with upregulation of the Rac1 small GTPase, which is thought to play a key role in mediating tumor formation. In prior studies, we generated a mouse model of schwannomas by performing tissue-specific knockout of the CNC gene Prkar1a, which encodes the type 1A regulatory subunit of Protein Kinase A. These tumors exhibited down-regulation of Nf2 protein and an increase in activated Rac1. To assess the requirement for Rac1 in schwannoma formation, we generated a double knockout of Prkar1a and Rac1 in Schwann cells and monitored tumor formation. Loss of Rac1 reduced tumor formation by reducing proliferation and enhancing apoptosis. Surprisingly, the reduction of tumor formation was accompanied by re-expression of the Nf2 protein. Furthermore, activated Rac1 was able to downregulate Nf2 in vitro in a Pak-dependent manner. These in vivo data indicate that activation of Rac1 is responsible for suppression of Nf2 protein production; deficiency of Nf2 in Schwann cells leads to loss of cellular growth control and tumor formation.. Further, PKA activation through mutation in Prkar1a is sufficient to initiate Rac1 signaling, with subsequent reduction of Nf2 and schwannomagenesis. Although in vitro evidence has shown that loss of Nf2 activates Rac1, our data indicates that signaling between Nf2 and Rac1 occurs in a bidirectional fashion, and these interactions are modulated by PKA.

Expression of SMARCB1 (INI1) mutations in familial schwannomatosis

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.

RNA-based analysis of two SMARCB1 mutations associated with familial schwannomatosis with meningiomas

Germline mutations in the SMARCB1 gene cause familial schwannomatosis, a condition characterized by the presence of multiple schwannomas, although mutations in SMARCB1 have also been associated with rhadboid tumor predisposition syndrome 1 (RTPS1). Both schwannomatosis and RTPS1 are autosomal dominant conditions that predispose individuals to develop distinct types of tumors. We clinically and genetically characterized two families with schwannomatosis associated with SMARCB1 mutations. Eight affected members of these families developed different numbers of schwannomas and/or meningiomas at distinct ages, evidence that meningiomas are variably expressed in this condition. We identified two germline mutations in SMARCB1 associated with the familial disease, c.233-1G>A and the novel c.207_208dupTA mutation, which both proved to affect the main SMARCB1 isoforms at the RNA level distinctly. Interestingly, the c.207_208dupTA mutation had no effect on the coding sequence, pre-mRNA splicing or the level of expression of the SMARCB1 isoform 2. Furthermore, SMARCB1 isoforms harboring a premature termination codon were largely eliminated via the nonsense-mediated mRNA decay pathway. Our results highlight the importance of RNA-based studies to characterize SMARCB1 germline mutations in order to determine their impact on protein expression and gain further insight into the genetic basis of conditions associated with SMARCB1 mutations.

SMARCB1 Deficiency in Tumors From the Peripheral Nervous System

Inactivation of SMARCB1 tumor-suppressor gene was originally described as highly specific for rhabdoid tumors (RTs). Nevertheless, recent reports have illustrated that SMARCB1 alterations also characterize other tumors; in particular, some familial schwannomatosis and epithelioid malignant peripheral nerve sheath tumors, both from peripheral nervous system (PNS) origin, lack BAF47 expression. To document the putative role of SMARCB1 in PNS, we reviewed PNS tumors referred to our institution for a molecular analysis of SMARCB1 because of histologic features compatible with RT. Clinicopathologic, radiologic, and molecular characteristics were detailed for the 12 cases showing loss of expression and/or biallelic inactivation of SMARCB1. The status of the NF2 gene, likely to synergize with SMARCB1 in PNS tumors, was also analyzed. Patients' age ranged from 0 to 45 years (median age, 6.6 y). Neurological symptoms were observed in 7/12 cases with radiologic features evoking a neuroblastic tumor in 6 cases and a peripheral nerve tumor in 4 cases. The mean delay before diagnosis was 3 months. Histologic examination revealed rhabdoid features in 11/12 tumors. All tumors showed a complete loss of SMARCB1 expression. Interestingly, adjacent nervous proliferation resembling neurofibromas were observed in 3 cases, suggesting a multistep transformation. Three tumors harbored a hemizygous deletion at the NF2 locus, but all NF2 sequences were normal. We report the first series of PNS RT. In patients with aggressive PNS tumors, RT should be suspected, and anti-SMARCB1 immunohistochemical analysis should be performed. SMARCB1 inactivation, occasionally associated with NF2 deletion, might have oncogenic effects in peripheral nerves.

Frequency of SMARCB1 mutations in familial and sporadic schwannomatosis

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.

Dissecting genetic pathways in schwannomatosis and malignant rhabdoid tumour

Schwannomatosis is a form of Neurofibromatosis type 2 (NF2) characterized by multiple schwannomas without vestibular involvement, affecting the cranium, spine and periphery. Several recent genetic studies have implicated the SMARCB1/INI1 tumour suppressor gene in familial schwannomatosis. SMARCB1 is located centromeric to NF2 on 22q and loss of function of SMARCB1 is also a hallmark of malignant rhabdoid tumour (MRT), a highly aggressive tumour of infancy. Both familial and sporadic schwannoma tumours show a mosaic pattern of SMARCB1 protein expression, suggestive of tumour cells either haploinsufficient, or null for SMARCB1 protein. Familial schwannomas linked to constitutional SMARCB1 mutation can also have somatic mutation of NF2, and conversely, schwannoma tumours associated with constitutional NF2 mutation show mosaic loss of SMARCB1, suggesting the involvement of a four-hit mechanism. Molecular analysis for evidence of constitutional SMARCB1 mutation is important in both familial and sporadically occurring schwannomatosis because of the transmission risk for a mutation predisposing to the incurable MRT, in early childhood. However as for NF2, recent evidence suggests that constitutional SMARCB1 mutations have variable penetrance and exhibit mosaicism, highlighting the importance of examining multiple tumour tissue samples as well as blood in affected individuals to ascertain germline predisposition and to provide accurate counseling for transmission risk. Further studies are needed to define the SMARCB1 mutation spectrum in schwannomatosis and to dissect the strikingly different biology between schwannoma and MRT.

Cribriform neuroepithelial tumour: novel clinicopathological, ultrastructural and cytogenetic findings

Cribriform neuroepithelial tumour (CRINET) is a recently described tumour of neuroectodermal origin with distinct cribriform non-rhabdoid histological features and loss of INI1 protein expression [2]. The INI protein is encoded by the hSNF/INI1/BAF47 (SMARCB1) tumour suppressor gene, which is located on chromosome 22q.11.2 [4]. The gene product is a subunit of the adenosine triphosphate (ATP)-dependent SWI/SNF chromatin-remodelling complex, which normally regulates cell proliferation [7, 8]. Biallelic loss of SMARCB1 is seen in peripheral rhabdoid tumours, atypical teratoid/rhabdoid tumours (AT/RTs) of the central nervous system as well as familial schwannomatosis [1, 3, 10]. In contrast to AT/RTs, CRINETs lack rhabdoid tumour cells, and may be associated with a more favourable prognosis [2]. Here, we present a third case of CRINET with complete clinicopathological, ultrastructural and cytogenetic features. A 21-month-old boy presented with a 1-week history of imbalance, discoordination, recurrent falls and torticollis, as well as progressive nausea, vomiting and irritability. The family history was significant for possible ependymomas in the maternal great uncle and two maternal second cousins. Computed tomography (CT) and magnetic resonance (MR) imaging demonstrated a large heterogeneously enhancing mass within the fourth ventricle extending into the left cerebellopontine angle and associated with mild hydrocephalus and brainstem compression (Fig. 1a). The patient experienced an acute neurological deterioration and an urgent CT scan demonstrated haemorrhage into the tumour causing obliteration of the fourth ventricle and acute obstructive hydrocephalus (Fig. 1b). The patient underwent an urgent posterior fossa decompression and gross total tumour resection. Post-operatively, he underwent chemotherapy according to the Children’s Oncology Group (COG) 99703 protocol, which includes cisplatin, cyclophosphamide, etoposide and vincristine with stem cell rescue followed by the maintenance chemotherapy with tamoxifen and cis-retinoic acid. Fourteen months following the presentation, he remains in remission. On histology, the specimen showed a cellular neoplasm, in which mitotic activity was scattered and MIB-1 index was high. Cells were found to have oval nuclei with occasional notable nucleoli (Fig. 2a). Cuboidal to polygonal cells were arranged in sheets and chords occasionally forming tubule-like or rosette-like structures. The specimen contained punched out foci of necrosis. Typical rhabdoid cells were not appreciated. Immunohistochemistry showed neoplastic cells to be non-reactive for BAF47 (Fig. 2b). These cells were reactive for Vimentin, S100, beta-catenin (nucleus and cytoplasm), c-erbB2 and MAP2. Isolated cells reacted for p53, GFAP, cytokeratin (rare), EMA (scattered foci) and SMA (usually vasocentric). Studies for synaptophysin were negative. A summary of the current and previous immunohistochemical findings is presented in Table 1. Electron G. M. Ibrahim P. B. Dirks Division of Neurosurgery, The Hospital for Sick Children, Toronto, ON, Canada