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Schwannomas of the eighth cranial nerve are benign tumours commonly found in the internal auditory meatus or in the cerebellopontine angle. In most cases, they arise from the inferior or vestibular portion of the vestibular nerve. Rarely, these tumours present in the inner ear and are then called intralabyrinthine schwannomas. Bilateral schwannomas are known in neurofibromatosis type 2 (NF2). Bilateral and ipsilateral, multilocular sporadic schwannomas of the eighth cranial nerve have been described as extremely rare findings. This report describes the first case of bilateral sporadic intracochlear schwannomas in a patient with no genetic or clinical features of NF2.Schwannome des achten Hirnnerven sind gutartige Tumoren und präsentieren sich in der Regel im inneren Gehörgang oder/und im Kleinhirnbrückenwinkel. Am häufigsten gehen sie hier von vom N. vestibularis inferior oder superior aus. Selten sind die Tumoren auch im Innenohr lokalisiert; sie werden dann als intralabyrinthäre Schwannome bezeichnet. Bilaterale Tumoren treten bei Neurofibromatose Typ 2 (NF2) auf. Bilaterale und ipsilaterale, multilokuläre, sporadische Vestibularis‑/Cochlearis-Schwannome wurden als extrem seltenes Vorkommen bereits beschrieben. Der vorliegende Bericht beschreibt den ersten Fall beidseitiger intracochleärer Schwannome in einer Patientin ohne genetische oder klinische Zeichen einer NF2.

Intraorbital meningiomas are rare tumors, making up less than 4% of all intraorbital tumors. Intraorbital meningiomas of childhood are curiosities with only few documented cases. We present the case of an 8‑month-old male infant, presenting with strabismus and nystagmus. Magnetic resonance imaging showed a long segment thickening of the optical nerve and an intraocular tumor. The tumor was suspicious for retinal dysplasia and enucleation of the eye was performed to exclude malignancy. Histological examination revealed a meningothelial meningioma (WHO grade I), extending along the optical nerve and into the eye accompanied by retinal dysplasia and epiretinal membranes. Meningiomas of childhood, retinal dysplasia, and epiretinal membranes are regularly associated with neurofibromatosis type 2. Subsequent genetic analysis led to the final diagnosis. This case documents a very unusual early beginning of a neurofibromatosis type 2.

Neurofibromatosis type 2 (NF2) is a genetic condition with an autosomal dominant pattern of inheritance and incomplete penetrance. It is characterized by multiple benign tumors of the central and peripheral nervous system including astrocytomas, ependymomas, meningeomas, and schwannomas, among which bilateral vestibular schwannomas are the most frequent. Among ocular manifestations of NF2, juvenile subcapsular cataract is the most common followed by epiretinal membranes and combined hamartomas of the retina and retinal pigment epithelium.Multimodal imaging was performed in a female patient and her data were compared to an overview of published cases with retinal hamartoma in NF2.We report on a case of a 14-year-old girl with genetically confirmed NF2 who presented with bilateral, asymptomatic hyperplasia of glia cells within the ganglion cell and the nerve fibre layer by spectral domain optical coherence tomography (SD-OCT). A metaanalysis of 25 published cases revealed combined hamartomas of the retina and retinal pigment epithelium (CHRRPE) as the most common (16 cases) retinal tumors followed by retinal astrocytic hamartomas (RAH, 7 cases). Retinal hamartomas were most often reported bilaterally and observed prior to the clinical diagnosis of NF2 in 11 of 25 cases. No correlation to sex was observed. Reduced visual acuity, cataracts and epiretinal membranes were the leading ocular manifestations.There is a large spectrum of ocular-specific findings in NF2. These are seminal, especially at an early age, enabling an early diagnosis and timely therapy of further tumor manifestations. Retinal astrocytic hamartomas may be very discreet and easily missed on routine examination. Fundus infrared imaging is a useful tool allowing to detect even discreet changes rarely seen by ophthalmoscopy in young children. This allows for a more extensive evaluation by SD-OCT.Die Neurofibromatose Typ 2 (NF2) ist eine autosomal-dominant vererbliche Erkrankung mit unvollständiger Penetranz, die durch das Vorkommen von gutartigen Tumoren des zentralen und peripheren Nervensystems charakterisiert ist. Zu diesen zählen Astrozytome, Ependymome, Meningeome und Schwannome, bei denen beidseitige Vestibularisschwannome typisch sind. Okulär manifestiert sich die NF2 durch juvenile subkapsuläre Katarakte, epiretinale Membranen sowie kombinierte Hamartome der Retina und des retinalen Pigmentepithels.Bei einer Patientin mit retinalem Hamartom bei NF2 wurde eine multimodale Bilddokumentation durchgeführt und mit einer Metaanalyse publizierter Fälle retinaler Hamartome bei NF2 verglichen.Berichtet wird über den Fall eines 14-jährigen Mädchens mit molekulargenetisch gesicherter Neurofibromatose Typ 2. In der Spectral-Domain-optischen Kohärenztomografie (SD-OCT) fielen beidseitige, asymptomatische, retinale astrozytäre Hamartome im Bereich der retinalen Ganglienzell- und Nervenfaserschicht auf. Eine Metaanalyse der 25 publizierten Fälle ergab, dass die häufigste Form von Tumoren der Retina das kombinierte Hamartom der Retina und des retinalen Pigmentepithels (CHRRPE, 16 Fälle) war, gefolgt von den retinalen astrozytären Hamartomen (RAH, 7 Fälle). Dabei wurden die retinalen Hamartome meistens beidseitig beschrieben. Es wurden 11 Fälle beschrieben, bei denen retinale Hamartome vor der klinischen Diagnose der NF2 festgestellt wurden. Es konnte keine Geschlechtsprävalenz festgestellt werden. Die 3 häufigsten okulären Befunde bei NF2 waren Sehminderung, Katarakt und epiretinale Membranen.Das Spektrum der spezifisch okulären Befunde bei NF2 ist sehr groß. Deren Feststellung kann gerade im jungen Alter diagnoseweisend für die Erstdiagnose der NF2 sein und somit eine frühzeitige Erkennung und gegebenenfalls eine rechtzeitige und erfolgreichere Therapie weiterer Tumormanifestationen ermöglichen. Retinale astrozytäre Hamartome können sehr dezent ausgeprägt sein und bei einer Routineuntersuchung nicht auffallen. Eine Fundusinfrarotaufnahme ist bei der ophthalmologischen Untersuchung insbesondere von kleinen Kindern ein nützliches Werkzeug und kann in manchen Fällen funduskopisch kaum erkennbare Befunde aufdecken, die dann gezielt mit SD-OCT untersucht werden können.

Schwannomas are benign Schwann cell-derived tumors of the peripheral nerve sheath often involving the vestibular cranial nerve (vestibular schwannoma). Histologically, they consist of bipolar spindle cells and show a moderate cellularity. Typically, Antoni A regions with a storiform pattern and loose Antoni B regions are intermingled. Verocay bodies are the pathognomonic palisading structures. Malignant transformation is rare. Merlin (schwannomin), the protein product of NF2, is inactivated by mutations, loss of heterozygosity or methylation. Within neurofibromatosis type 2, a germline mutation is present in about half of cases, whereas tumors demonstrate an additional second hit of the NF2 gene. A loss of chromosome 22 or 22q is common. Merlin links the cell membrane with the cytoskeleton and regulates intracellular signaling pathways leading to dysorganization when merlin is inactivated. Loss of merlin activates Rac1 and Ras, and the PAK1, mTORC1, EGFR-Ras-ERK, PI3K-Akt, WNT and Hippo pathways as well as receptor tyrosine kinases. Furthermore, merlin locates to the nucleus and inhibits E3 ubiquitin ligase CRL4

Syndromic hearing loss is responsible for approximately 30% of cases of inherited hearing loss. The syndromic form can be differentiated from nonsyndromic hearing loss by the presence of associated symptoms in other organ systems. While for many forms of syndromic hearing loss the individual genes responsible have been identified, the etiology of other associated symptoms remains unclear. The role of the ENT physician is to select appropriate clinical and genetic diagnostic tools based on the presentation of the patient and to subsequently initiate and perform the required hearing loss therapy.

Die Neurofibromatosen zahlen zu den vererbbaren neurokutanen Syndromen, den Phakomatosen, zu deren Gruppe neben der Neurofibromatose Typ 1 (NF1) und Typ 2 (NF2) auch die Schwannomatose zahlt. Als gemeinsames Merkmal weisen sie eine Pradisposition zur Entwicklung von Tumoren, die von den Schwann-Zellen der Nervenscheiden ausgehen, auf. Im Hinblick auf die Genetik und das klinische Erscheinungsbild der Erkrankungen handelt es sich jedoch um unterschiedliche Entitaten, die auch im folgenden Beitrag gesondert abgehandelt werden. Neben der Darstellung der typischen klinischen Befunde und der Diagnosekriterien werden die fur die jeweilige Erkrankung charakteristischen Bildbefunde demonstriert, insbesondere hinsichtlich der Rolle der bildgebenden Verfahren bei der Diagnosestellung, im Verlauf und bei der Prognoseabschatzung dieser multisystemischen Erkrankungen.

The overall aim of this work was to understand, in molecular detail, the interaction between FERM domains and RhoGDIs and the functional consequences for the regulation of Rho-GTPases by RhoGDIs.

Inherited cancer syndromes often involve the central and peripheral nervous system. For the surgical neuropathologist the possibility in individual patients of a familial tumour syndrome needs to be considered in the case of special tumours such as malignant peripheral nerve sheath tumour (MPNST), medulloblastoma with extensive nodularity (MBEN) or even atypical teratoid/rhabdoid tumour (AT/RT) of the brain. Furthermore, tumour location and patient age may point to a familial tumour syndrome as in the case of neurofibromatosis type 2 (NF2) with typical bilateral vestibular schwannoma in young age. This short review discusses some of the diagnostic aspects in this field relating to neurofibromatosis type 1 and 2 (NF1, NF2), as well as the two rare tumors MBEN in Gorlin-Goltz syndrome and AT/RT in particular.

Neurofibromatosis type 2 (NF2) is a highly penetrant, autosomal dominantly inherited disorder. The affected individuals show a predisposition for tumors in the central and the peripheral nervous system. The classical hallmarks are bilateral vestibular schwannomas. NF2 is caused by inactivating mutations in a gene on the chromosome 22q12, which is coding for the protein merlin. The protein shares sequence and function similarity to the ERM proteins and also acts as a molecular linker between the cytoskeleton and the plasma membrane. But only merlin can function as a negative growth regulator. Therefore it is thought to be a tumor suppressor protein. According to this each patient inherits one mutation in the germline found in every cells. Tumor formation follows the inactivation of the remaining wild-type allele. Beside the locally found tumors the NF2 patient often shows a distal symmetric neuropathy, that in most cases cannot be explained as a burder of spinal tumors or toumorlets around peripheral nerves at sites of bonal foramina. Additionally Schwann cells in sural nerve biopsies show abnormalities. The genotype of these cells is so far unknown. Since the increasing evidence of other tumor suppressor genes, haploinsufficiency can give rise to diseases that are related but different from diseases following the complete loss of both alleles. To find out if the second hit has already taken place or merlin shows haploinsufficiency, the gene dosage in peripheral nerve biopsies of patients with neuropathy should be analysed. Therefore a multiplex dosage-PCR assay was established to screen the NF2 gene for the deletion of one or more exons in DNA extracted from paraffin sections. To verify this finding a cell culture model was established. In a mesothelioma cell line, expressing merlin, the expression of the NF2 gene was reduced to a dosage of approximately 50 % using shRNA expressing constructs and the expression of several selected proteins and genes was identified.

Because of its unique anatomy, specific diseases and lesions arise in the upper cervical spine, which differ widely from the rest of the spine. During the last two decades standardised diagnostic and therapeutic algorithms have been defined for most of the craniocervical pathologies often occurring in combination with an underlying disease requiring surgical intervention as well. On the other hand there are some very rare phathological alterations: about 20% of the patients suffering from neurofibromatosis type I develop spinal deformities. These are mostly found in the thoracic and lumbar spine (dystrophic/non-dystrophic type). In rare cases the dystrophic neurofibromatosis type I involves the upper cervical spine leading to bizarre deformities endangering the spinal cord. An aggressive, timely and combined operative therapy is necessary. Patients with Down syndrome should be investigated regularly for affections of the upper cervical spine. Though only in about 1% of all patients with Down syndrome do instabilities require surgical intervention, the upper cervical spine should be screened on a regular basis, since neurological changes due to the pathognomy of the underlying disease often remain undetected for a long time. The operative therapy of the instable os odontoideum in Down syndrome follows the general principles of this pathoanatomical variation. Even though the Klippel-Feil syndrome is generally not linked with neuropathological findings, rare associated deformities of the upper cervical spine should be excluded by proper diagnostic procedures.

Neurofibromatosis 2 is an autosomal-dominant disease, which is characterized by vestibular schwannomas, cataract, retinal hamartomas as well as tumors of the peripheral and central nerve system, demonstrating a variety of expression. The ophthalmologist plays an important role in making the diagnosis, as several ocular manifestations may be shown during childhood, before tumors of the central nerve system become symptomatic. An early diagnosis of NF 2 may prevent deafness by early surgical intervention. Due to primary and secondary reasons such as age-related processes, different sensations like hearing or vision may be compromised. Neuropathy may lead to vestibular disturbances and loss of muscle control. Therapeutic options include cataract surgery, implantation of cochlear or brainstem implants as well as conservative therapy of the ocular surface in paresis of the VIIth cranial nerve or learning to read from the lips. The human NF2 gene was cloned from chromosome 22 in 1993. The major part of the genetic alterations described so far are point mutations as well as deletions or insertions in or around the exons. Geno-phenotype correlations allow some predictions of the course of the disease to be made.

Neurofibromatosis 2 (NF2) is a rare autosomal dominant disorder (prevalence 1:37.000) associated with changes in tumor suppressor genes. Intraocular manifestations have been reported as subcapsular cataract, retinal hamartomas, epiretinal membranes, keratopathy in facial palsy, and tumors of the nerves I-V are typical ocular manifestations of NF2.We prospectively examined 7 patients who met the diagnostic criteria of NF2 with regard to retinal changes using fluorescence angiography and red-free fundus photography.In four patients, we found window defects of the pigment epithelium in the macular or paramacular areas. In one patient we observed a combined pigment epithelial and astrocytic hamartoma. A choked papilla was found in two patients.Presumably, retinal changes in NF2 occur more frequently than has been assumed previously. Our results confirm that in NF2 patients more attention should be paid to abnormalities of the optic disk, the retina and the choroid.

Neurofibromatosis type 2 (NF2) is a disorder with autosomal dominant inheritance which leads to tumor growth in the central and peripheral nervous system. In affected adult patients there is a typical association with ocular abnormalities like juvenile cataract.Ophthalmologic investigation was carried out in ten children aged one to fourteen years with suspected NF2. The diagnosis was confirmed by further clinical examination and-in one patient-by segregation analysis.Nine of these ten children showed ocular abnormalities such as juvenile subcapsular cataracts, retinal hamartomas, optic nerve sheath tumors, fibrotic maculopathies as well as one case of a perineural calcification of the optic nerve and one case of a cerebral hamartoma on the ground of the third ventricle.In six children ophthalmological symptoms were the presenting symptom of the disease. The knowledge of these symptoms allows for the diagnosis of NF2 in children who present with isolated ocular deficits or with other typical criteria of the disease. The early diagnosis of the disease may lead to an improved prognosis with regard to preservation of hearing by surgery of bilateral vestibular schwannoma which occur in more than 90% of the NF2-patients.

Bilateral vestibular schwannomas (VSs) are the hallmark of neurofibromatosis type 2 and the crucial criteria for the diagnosis of this autosomal dominant disorder according to the criteria of the National Institutes of Health Consensus Statement. We describe three patients without VSs aged 47, 52 and 69 years, in whom a NF2 gene carrier status was diagnosed by spinal tumors, a cataract and schwannoma of cranial and peripheral nerves. In one case the diagnosis was ascertained by mutation analysis, which revealed a 163bp deletion in the NF2 cDNA, and by the fact that two daughters had the same deletion and NF2 according to the NIH criteria. Our finding suggests that patients with spinal tumors, multiple brain tumors, associated neurinomas or cataract might be carriers of a mutated NF2-gene. The study suggests that the NIH criteria are too restrictive, since NF2 seems to show up for a broader spectrum of phenotypes.

Neurofibromatosis (NF) is one of the most frequent autosomal-dominant hereditary disorders. The molecular-genetic differentiation of NF 1 and NF 2 has important implications for the ophthalmologist. Among 80 patients with NF 1, Lisch nodules were diagnosed in 83% as typical criteria for the disease. In 6 patients who did not meet the NIH criteria for NF 1 and NF 2, the ophthalmological investigation showed no cataracts or Lisch nodules; thus, the ophthalmological examination can help to confirm a subtype of NF. In 8 out of 22 NF 2 patients a juvenile posterior subcapsular cataract was diagnosed. Our examination demonstrates that the diagnostic value of lens opacities in NF 2 patients--especially for early detection of the disease--must be clarified, especially with regard to the fact that there were no patients with incipient cataract and no neuroradiological criteria for the disease.

Hearing preservation was attempted in eight cases of acoustic neurinomas with good preoperative hearing. This was successful in 3 cases. Brain-stem auditory evoked potentials (BAEP0 were monitored in all cases, and compound nerve action potentials (CNAP) were recorded from the cochlear nerve in the last 3 cases. The BAEP was extremely sensitive to intraoperative manipulation. Intraoperative loss of wave V in BAEP was observed not only in all 5 cases with postoperative hearing loss, but also in 2 out of 3 cases with successful hearing preservation. CNAP correlated better with the hearing outcome than BAEP. In the cases where hearing was preserved, intact CNAP responses were demonstrated at the end of the operation. Conversely, deterioration of CNAP was seen in a case of postoperative hearing loss. CNAP was 10-15 times larger in amplitude than BAEP, so that the new responses were obtainable in shorter intervals. This capability of frequent examination seemed to increase the possibility of avoiding irreversible damage to the hearing by changing surgical tactics. The addition of CNAP monitoring is a good supplement to conventional BAEP monitoring in acoustic neurinoma surgery.

Neurofibromatosis (NF) is subdivided into at least two different forms: NF-1, which is characterized by café-au-lait spots, cutaneous neurofibromas, Lisch nodules and osseous dysplasias, and NF-2, the hallmarks of which are bilateral acoustic neuromas. Neuropathological findings in 5 cases of NF-1 and 3 cases of NF-2 are presented.

The brief article is to correct errors of presentation and erroneous conclusions in the referred publication. It is shown that the neuropsychological resume drawn by the authors is invalidated by statistically significant findings already presented in the two diploma theses, upon which the previous authors drew.

Benign and malign forms of tumors of the peripheral nervous system also occur in the region of jaw and face. They demonstrate a quite different dignity and different courses. Very well known is the neurofibromatosis (Recklinghausen) which can be observed in several variants in face. The possibility is pointed out that primarily benign tumours of the peripheral nervous system may be degenerated to malign ones and the course as well as the therapy with benign and malign tumours are being described.