Cerebrovascular Insult as Presenting Symptom of Neurofibromatosis Type 2 in Children, Adolescents, and Young Adults

Background and Purpose: Neurofibromatosis Type 2 (NF2) is an autosomal-dominant tumor-prone disorder characterized by the manifestations of central nervous system lesions. However, the first clinical signs of disease are often non-tumorous. Cerebrovascular insults are known in NF2, however, not yet described as first symptom in young NF2 patients.Methods: Magnetic resonance image scans of 298 NF2 patients treated in our neurofibromatosis center in Tübingen from 2003 to 2017 were retrospectively evaluated focusing on presence of aneurysms and ischemic stroke. Clinical data were used to clarify whether or not ischemic stroke or aneurysm rupture were the first presentation of disease. Blood of the patients were subjected to genetic screening for constitutional NF2 mutations.Results: We identified 5 cases under age of 25 years with aneurysms or ischemic stroke. Among them three had ischemic strokes of the brain stem and one aneurysmal subarachnoid hemorrhage as the first symptom of the disease. Incidental finding of 2 intracranial aneurysm occurred in one patient. All aneurysms were clipped. Patients with ischemia suffered from dysarthria, gait disturbances, dizziness, and hemiparesis. Residual signs of hemiparesis and dysarthria persisted in one patient. All others fully recovered from the cerebrovascular insult. Bilateral vestibular schwannomas and intracranial meningiomas were found in all five patients.Conclusions: A cerebrovascular insult in the vertebrobasilar territory may occur as first symptom of disease in young NF2 patients. The brain stem seems to be especially prone to ischemic stroke. Multicenter studies on large NF2 cohorts are needed to determine the prevalence and pattern of cerebrovascular insults and disease in NF2 patients

Phenotypic and genotypic overlap between mosaic NF2 and schwannomatosis in patients with multiple non-intradermal schwannomas

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

cDNA microarray analysis and gene expression profiling of sporadic vestibular schwannomas compared to healthy post-mortem tissue: a look at the molecular level using Ingenuity Pathway Analysis Software

Ziel: Die vorliegende Studie wurde durchgeführt um differentiell exprimierte Gene und Signalwege zwischen Tumor- und Kontrollgewebe zu identifizieren, die eine möglicherweise wichtige Rolle in der Krankheitsentstehung spielen. Zur Bestimmung des Expressionsprofils diente uns eine cDNA Microarray und die Auswertung der resultierenden Daten erfolgte mit der Ingenuity Pathway Analysis Software (IPA, www.ingenuity.com). Hintergrund: Vestibularisschwannome sind benigne Tumore, die von den Schwannzellen des VIII. Hirnnerven ausgehen. Mit einem Anteil von 80-86% aller raumfordernden Läsionen des Kleinhirnbrückenwinkels stellen sie somit die am häufigsten dort anzutreffende Tumorentität dar. Unter den Vestibularisschwannomen werden eine unilateral sporadische Form, eine zystische Variante und eine bilateral oder auch Neurofibromatose Typ 2 (NF2)-assoziierte Form unterschieden. Letztere ist eine charakteristische Manifestation innerhalb des autosomal-dominant vererbten Tumorsyndroms, der Neurofibromatose Typ 2 (NF2). Zudem weisen die Patienten mit einer NF2 weitere benigne Tumore des Nervensystems (z.B. Meningeome), okuläre Veränderungen (z.B. Katarakte) aber auch Hautläsionen, wie beispielsweise die typischen Café-au-lait Flecken, auf. In den letzten Jahren wurden zahlreiche Mutationen innerhalb des Tumorsuppressorgens NF2 und deren Effekte auf dessen Proteinprodukt Merlin ausfindig gemacht. Im Laufe der Zeit kamen neue, molekulardiagnostische Methoden hinzu, die es uns ermöglichten weitere Gene zu identifizieren, welche potentiell eine wichtige Rolle in der Tumorgenese spielen könnten. Methoden: Eine globale Genexpressionsanalyse (HG-U219 Array Plate, Affymetrix®), wurde für eine Gruppe von 36 sporadischen Vestibularisschwannomen und sieben postmortal gewonnenen Proben an Nn. vestibulocochlearis durchgeführt. Unter Zuhilfenahme der Ingenuity Pathway Analysis Software (www.ingenuity.com), wurden in den Tumoren deregulierte Signalwege detektiert. Ergebnisse: Durch die Festlegung eines p-Wertes von =1 als signifikante cut-off-Werte, erhielten wir aus der Genexpressionsanalyse 4021 differentiell exprimierte Gene, worunter sich 2276 über- und 1745 unterexprimierte Gene fanden. Unter Berücksichtigung eines statistischen Schwellenwerts (Threshold) von 0.0001 identifizierte IPA 13 signifikant deregulierte Signalwege, unter denen sich sechs Signalwege vorfanden, die in Kategorien des Immunsystems (Zytokin-Signalkaskaden, zelluläre und humorale Immunantwort) involviert waren. Der am signifikantesten deregulierte Signalweg The Role of NFAT in Regulation of the Immune Response ließ den Nuclear factors of activated T cells (NFAT) und der T-Zellantwort eine zentrale Rolle in der Bildung von sporadischen Vestibularisschwannomen zukommen. Schlussfolgerung: Eine wichtige Rolle bei der Formation von sporadischen Vestibularisschwannomen spielen die Genen und Signalwegen, die in Prozessen des Immunsystems involviert sind. Es gibt Hinweise darauf, dass eine gestörte Regulation dieser auf molekularer Ebene, zu einem Ungleichgewicht zwischen Tumorgenese und der Immunantwort führt. Im Speziellen scheinen die Nuclear factors of activated T cells (NFAT) und deren Transkriptionspartner eine wichtige Position darin einzunehmen. Nichtsdestotrotz bedarf es weiterer Validierungsmethoden (z.B. RT-PCR und Proteinanalysen) um die vorliegenden Ergebnisse weiter zu prüfen und um an die gewonnenen Erkenntnisse anzuknüpfen.Objective: In this study we investigated the gene expression profile between tumor and control tissue in search of underlying disease-causing deregulated genes and pathways, using cDNA microarray technology and Ingenuity Pathway Analysis Software. Background: Vestibular schwannomas are benign tumors arising from the Schwann cells of the 8th cranial nerve. With an amount of 80-86% of all space consuming lesions of the cerebellopontine angle, they represent the most common tumors in this location. There are different types of vestibular schwannomas which can be grouped into unilateral sporadic vestibular schwannomas, cystic schwannomas and bilateral or neurofibromatosis type 2 (NF2)-associated schwannomas. The latter are characteristic for the autosomal dominant disorder neurofibromatosis type 2 (NF2). Frequently, in patients suffering from NF2, other noncancerous tumors in the nervous system (e.g. meningiomas), ophthalmologic abnormalities (e.g. cataracts), and skin lesions (e.g. Café au lait macules) occur. Mutations within the tumor suppressor gene NF2 and their effects on its protein product merlin have been identified over the past years. Recently, novel molecular diagnostic technologies and bioinformatics tools also help us to identify other genes playing a role in tumorigenesis. Methods: Whole-genome gene expression profiling was performed (HG-U219 Array Plate, Affymetrix®) of tissue samples from 36 patients with sporadic vestibular schwannomas versus seven postmortem samples of the vestibulocochlear nerve. Canonical pathway analysis (Ingenuity Pathway Analysis, IPA) was utilized to determine the most significantly associated pathways. . Results: A total of 4021 probe sets (2276 probe sets were up- and 1745 downregulated) showed significant difference based on the criteria of P value = 1. With a threshold of 0.0001, IPA identified 13 significantly deregulated canonical pathways. Among them six were involved in categories of the immune response (cytokine signaling, celullar and humoral immune response). We focused on the highest ranked canonical pathway The Role of NFAT in Regulation of the Immune Response which reveals an important role for Nuclear factors of activated T cells (NFAT) and T cell response in the formation of sporadic vestibular schwannoma. Conclusions: An important role in vestibular schwannoma formation is attributed to pathways and genes of the immune system and there is evidence that these findings may lead to an imbalance between tumorigenesis and immune response. Specifically, Nuclear factors of activated T cells (NFAT) and their transcriptional partners seem to be of potential importance. Nevertheless, results obtained with cDNA microarray analysis require further validation steps by alternative and reliable technologies (e.g. RT-PCR and protein analysis)

Management of Sporadic Vestibular Schwannomas in Children—Volumetric Analysis and Clinical Outcome Assessment

Vestibular schwannomas (VS) usually manifest between the 5th and 8th decade of life. Most pediatric cases are associated with Neurofibromatosis type 2 and sporadic VS are rare in this age group. Few case series have been published. We report on our institutional series of sporadic VS in children. We included all cases between 2003 and 2021; 28 of 1635 patients harbored a sporadic VS and were younger than 21 years old. A retrospective review of clinical parameters and surgical data as well as outcomes was performed. All procedures were performed via a retrosigmoid approach. Preoperative imaging was assessed, and tumor volumetry was performed. Mean follow-up was 28 months, symptomatology was diverse. Most children and adolescents presented with hearing loss and tinnitus. All cases with multiple preoperative magnetic resonance imaging scans showed volumetric tumor growth between 1 and 18%/month (mean 8.9 ± 5.6%). Cystic tumor morphology and bone erosion was seen in larger tumors. Gross total resection was possible in 78% of patients and no recurrence was observed. All patients with subtotal resection showed tumor regrowth. Sporadic VS in children are rare and present with a high clinical variability. Surgical resection is the primary therapy and is feasible with favorable results comparable to the adult age group