Laryngeal plexiform schwannoma as first symptom in a patient with neurofibromatosis type 2

Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder characterized by bilateral vestibular schwannomas. The initial symptoms of NF2 are usually hearing loss and tinnitus caused by vestibular schwannomas. Although other intracranial, spinal, or skin tumors also occur in NF2, laryngeal lesions are very rare. We report a rare case of NF2 with laryngeal plexiform schwannoma as first symptom. A 38-year-old man presented with a smooth-surfaced submucosal supraglottic mass. Two round masses in the left chest wall and left supraclavicular fossa were noted incidentally during investigation of the laryngeal mass. Magnetic resonance imaging (MRI) findings for these masses were identical to those of the laryngeal mass. No typical symptoms related to NF2 were identified. Histologically, the laryngeal tumor represented plexiform schwannoma. We thus considered that the two round masses in the left chest wall and left supraclavicular fossa might also represent plexiform schwannomas. NF2 was suspected, as a high incidence of multiple plexiform schwannomas has been suggested for patients with NF2. MRI of brain lesions demonstrated bilateral vestibular schwannomas and multiple meningiomas. Finally, NF2 with laryngeal plexiform schwannoma was diagnosed. Recognizing that multiple plexiform schwannomas could be associated with NF2 is important.     

Superficial neurofibromas in the setting of schwannomatosis: nosologic implications

First described in the past decade, schwannomatosis is a syndrome distinct from neurofibromatosis 2 (NF2). It is characterized by the development of multiple schwannomas, sparing the vestibular division of cranial nerve VIII, and may also predispose to develop meningiomas. We report two female patients, a 27 and a 44 years old who developed multiple peripheral schwannomas, but without involvement of the vestibular nerves, satisfying clinical criteria for schwannomatosis. Lack of vestibular nerve involvement was confirmed with MRI using an internal auditory canal protocol with 3 mm thick slices in both patients after age 30. Both patients developed a small neurofibroma in axillary subcutaneous tissues and a diffuse cutaneous neurofibroma of the left buttock, respectively. This report highlights that superficial neurofibromas may arise in the setting of schwannomatosis, which may have implications for the diagnostic criteria of this unique syndrome. In particular, the presence of a cutaneous neurofibroma in a patient with multiple schwannomas should not lead to a diagnosis of NF2.     

Earliest clinical manifestations and natural history of neurofibromatosis type 2 (NF2) in childhood: a study of 24 patients

BACKGROUND: Neurofibromatosis type 2 (NF2) is an autosomal dominant disease characterised by the development of multiple nervous system tumours, ocular abnormalities, and skin tumours. Although classically considered a disease of adults, initial signs and/or symptoms may be evident in childhood and are often unrecognised. OBJECTIVES: The aim of this study was to identify the earliest clinical presentations of NF2 and to characterise the clinical course and outcome in children with NF2. METHODS: We have performed a retrospective (years 1990-1998) and prospective (years 1998-2004) study of 24 patients (10 males, 14 females; currently aged 4 to 22 years) fulfilling the revised (Manchester) NF2 criteria seen at the Universities of Catania and Rome, Italy. RESULTS: Causes of referral prior to a definitive diagnosis of NF2 were: 1) Ophthalmologic problems: early onset lens opacities (n = 3); strabismus (n = 3) and amblyopia (n = 3) (due to underlying cranial nerves and/or brain tumours); 2) Otolaryngology problems: hearing loss and tinnitus (n = 2) in early teens disregarded or treated as ear infections; hoarse (n = 1) or bitonal (n = 1) voice; 3) Neurological dysfunction: seizures secondary to intracranial meningioma (n = 1) or vestibular schwannomas (VS) (n = 1), neurological dysfunction related to brainstem and/or spinal cord tumours (n = 7), isolated and multiple cranial nerve deficits (n = 10), and peripheral neuropathy secondary to schwannomas (n = 4); 4) Skin manifestations: schwannomas misdiagnosed as neurofibromas because of associated café-au-lait spots (n = 2); café-au-lait spots (n = 8) and skin tumours (n = 3). A family history was relevant in 20 % of the patients. Molecular genetic analysis of the NF2 gene revealed typical truncating mutations in all the 5 familial cases and in 2/10 sporadic cases analysed. CONCLUSIONS: Children with NF2 often first come to medical attention because of ocular, subtle skin, or neurological problems the significance of which is realised when they later present with more classical symptoms due to bilateral VS or other intracranial tumours. The clinical course at this young age is highly variable, depending on tumour burden, early surgical intervention, surgical outcome after tumour resection, and complications.     

Probability of bilateral disease in people presenting with a unilateral vestibular schwannoma

BACKGROUND: Some 4%-5% of those who develop vestibular schwannomas have neurofibromatosis type 2 (NF2). Although about 10% of these patients present initially with a unilateral vestibular schwannoma, the risk for a patient with a truly sporadic vestibular schwannoma developing contralateral disease is unknown. METHODS: A United Kingdom survey of 296 patients with NF2 was reviewed for laterality of vestibular schwannoma at presentation and the presence of other NF2 related features. The time to presentation of bilateral disease was calculated for patients presenting with a unilateral tumour. Mutation analysis of the NF2 gene was carried out on all available cases presenting initially with unilateral disease. RESULTS: Of 240 patients with NF2 with vestibular schwannomas, 45 (18%; 32 sporadic, 13 familial) had either a unilateral tumour or delay in detection between the first and contralateral tumours. Among those tested for NF2 mutations, eight of 27 and nine of 13 were identified among sporadic and familial cases respectively. Sporadic cases showed a high female to male ratio and 19 of 32 have not as yet developed a contralateral tumour (mean 4.1 years after diagnosis of the first). Thirteen of 32 sporadic patients developed a contralateral tumour (mean 6.5 years after the first tumour diagnosis, range 0-22 years) compared with 11 of 13 familial patients (mean delay 5 years, range 0-16 years). Seven of the 45 patients had neither a family history of NF2 nor evidence of related tumours at initial presentation (six before the age of 35 years). CONCLUSION: The risk of patients with sporadic unilateral vestibular schwannomata developing a contralateral tumour in the absence of family history or other features of NF2 is low, but those presenting with other neurogenic tumours in addition to vestibular schwannoma are at high risk of harbouring an NF2 mutation in at least a proportion of their somatic cells.     

Diagnostic criteria for schwannomatosis

The neurofibromatoses are a diverse group of genetic conditions that share a predisposition to the development of tumors of the nerve sheath. Schwannomatosis is a recently recognized third major form of neurofibromatosis (NF) that causes multiple schwannomas without vestibular tumors diagnostic of NF2. Patients with schwannomatosis represent 2.4 to 5% of all patients requiring schwannoma resection and approximately one third of patients with schwannomatosis have anatomically localized disease with tumors limited to a single limb or segment of spine. Epidemiologic studies suggest that schwannomatosis is as common as NF2, but that familial occurrence is inexplicably rare. Patients with schwannomatosis overwhelmingly present with pain, and pain remains the primary clinical problem and indication for surgery. Diagnostic criteria for schwannomatosis are needed for both clinicians and researchers, but final diagnostic certainly will await the identification of the schwannomatosis locus itself.     

Use of "unidentified bright objects" on MRI for diagnosis of neurofibromatosis 1 in children

BACKGROUND: "Unidentified bright objects" (UBOs) have been observed as areas of increased T2-weighted signal intensity on MRI in 43% to 93% of children with neurofibromatosis 1 (NF1). Because of this high frequency and the fact that the NIH diagnostic criteria often do not permit diagnosis of NF1 in early childhood, UBOs have been proposed as an additional diagnostic criterion. METHODS: The authors examined the sensitivity and specificity of UBOs for NF1 in 19 affected children and 19 age-matched controls. Eleven of the control patients had CNS pathology that might be classified as UBOs on MRI scan. The authors measured the agreement in recognition of UBOs between two pediatric neuroradiologists who independently examined the MRI studies of these patients. They also assessed the effect of adding UBOs to the NIH diagnostic criteria on ability to diagnose NF1 in young patients. RESULTS: Sensitivity and specificity of UBOs for NF1 averaged 97% and 79%, respectively. Agreement between the two radiologists was 84% overall, but varied greatly from one brain region to another. Adding UBOs as a diagnostic criterion permitted the diagnosis of 30% of young patients with NF1 mutations who do not meet the existing NIH diagnostic criteria for NF1. The value of including UBOs is less in older patients because a larger proportion of them meet the existing diagnostic criteria. CONCLUSIONS: UBOs are difficult to identify with certainty and occur in children with suspected CNS disorders who do not have NF1, but they tend to occur in different brain regions. UBOs may be more useful for diagnosis of NF1 in young children if they can be defined precisely and if only the cerebellum, brainstem, and basal ganglia are considered.     

Neurofibromatosis 1 and neurofibromatosis 2: a twenty first century perspective

Historically, neurofibromatosis 1 (NF1) has been inextricably linked with neurofibromatosis 2 (NF2). Both are inherited autosomal-dominant neurocutaneous disorders that have high de novo mutation rates and carry a high risk of tumour formation. However, they are clinically and genetically distinct diseases and should be considered as seperate entities. NF1 is a common disease that mainly affects the skin and peripheral nervous system and causes characteristic bony dysplasia. By contrast, NF2 is a rare disorder with a relative paucity of skin manifestations and high-grade malignancy is unusual. Neurological symptoms are the predominant problem and the cardinal sign is bilateral vestibular schwannomas. In this Review, I discuss the pertinent diagnostic, clinical, and genetic symptoms of NF1 and NF2. I also examine the current views on the pathogenesis of these neurocutaneous disorders in the wake of advances in molecular genetics and the development of mouse models of disease.     

Linear accelerator radiosurgery for treatment of vestibular schwannomas in neurofibromatosis 2.

Management of vestibular schwannomas in patients with neurofibromatosis 2 (NF2) balances growth control against preservation of hearing with the primary aim of maintaining patient quality of life. Surgical resection of these lesions carries greater risk of functional deterioration than in sporadic cases. Stereotactic radiosurgery is a less invasive option that provides comparable, if not superior outcomes to resection. Previous studies on the efficacy of stereotactic radiosurgery for vestibular schwannomas in NF2 have reported results from delivery by Gamma Knife systems. The efficacy of linear accelerator (LINAC) delivered treatment has not been specifically addressed. Modelling studies suggest that lesional conformality is superior with Gamma Knife, but clinical studies on sporadic vestibular schwannomas show equivalent results between the two systems. Our experience with LINAC radiosurgery in NF2 reported here shows good long-term growth control in four patients with vestibular schwannomas.     

Spinal and cutaneous schwannomatosis is a variant form of type 2 neurofibromatosis: a clinical and molecular study.

OBJECTIVE: To delineate the clinical phenotype, molecular basis, and implications for screening in patients and families with multiple schwannomas not generally involving the cranium. METHODS: As part of a United Kingdom clinical and genetic study of type 2 neurofibromatosis (NF2) patients and families with multiple schwannomas who do not fulfil diagnostic criteria for NF2 have been identified. The clinical phenotype was studied in the extended families and molecular analysis was carried out at the NF2 gene locus on chromosome 22. RESULTS: Patterns of inheritance in five families with schwannomatosis are consistent with inheritance of an autosomal dominant gene. The consistency of phenotype, with relative sparing of the cranium, is constant in these families. However, families which initially seem to be indicative of schwannomatosis may develop into classic NF2 as shown by a sixth family. Many of the tumours found in these families were referred to as "neurofibroma" when they were clearly schwannomas. This difference in classification has major implications for the relative risk of each particular type of neurofibromatosis and neuropathological review may be important in some cases. Genetic linkage analysis in the two largest families is entirely consistent with primary involvement of the NF2 gene. CONCLUSIONS: Variant forms of neurofibromatosis have presented a dilemma in classification and determination of recurrence risks in families. Previous reports have suggested that schwannomatosis is a sporadic non-hereditary condition. Patients with multiple schwannomas are likely to have a variant form of NF2 and up to a 50% risk of passing on a gene predisposing to multiple schwannoma.     

Clinical presentation,immunohistochemistry and electron microscopy indicate neurofibromatosis type 2‐associated gliomas to be spinal ependymomas

Neurofibromatosis type 2 (NF2) is a hereditary tumor syndrome. The hallmark of NF2 is bilateral vestibular schwannoma. In addition, glioma is one of the diagnostic criteria of NF2. In this retrospective study the clinical presentation and histopathological features of 12 spinal gliomas from NF2 patients were assessed. Ten tumors were previously diagnosed as ependymomas and two as astrocytomas. However, upon re‐evaluation both astrocytomas expressed epithelial membrane antigen in a dot‐like fashion and in one case it was possible to perform electron microscopy revealing junctional complexes and cilia typical for ependymoma. The findings suggest that NF2‐associated spinal gliomas are ependymomas. Based on the fact that NF2‐associated gliomas are almost exclusively spinal and that no NF2 mutations have been found in sporadic cerebral gliomas, we suggest that “glioma” in the current diagnostic criteria for NF2 should be specified as “spinal ependymoma”.     

Infratentorial meningioma in an 8-year-old child as first sign of neurofibromatosis type 2

Meningiomas are rare intracranial tumors in pediatric patients. In contrast to meningiomas in adults, childhood ones have a poorer prognosis because of their high growth potential and tendency to recur. Meningiomas are often associated with neurofibromatosis type 2 (NF2) which is an autosomal-dominant disorder. In contrast to adults who primarily present with symptoms due to vestibular tumors, the initial symptoms in children with NF2 are subtle skin tumors, posterior capsular cataracts, or neurological signs secondary to cranial nerve(s) schwannoma excluding vestibular nerve, and/or brainstem or spinal cord compression. Here we report on the clinical, radiological, and histological findings in an 8-year-old boy who was diagnosed with an isolated infratentorial meningioma and a novel splice site mutation in the NF2 gene. The same mutation was detected in the boy's mother who suffered from hearing loss and tinnitus due to a bilateral vestibular schwannoma. Our patient demonstrates the need for molecular testing for NF2 gene mutations even in isolated childhood meningiomas although they do not fulfill the clinical criteria of NF2.     

From sound to silence: a case study of neurofibromatosis type II

Neurofibromatosis is a disease that occurs in both males and females of all races and ethnic groups. It is inherited as a dominant disorder but can also occur as a new mutation. Neurofibromatosis was formerly considered a single disorder with at least two variations. However, it is currently known to be two distinct entities, Neurofibromatosis Type I (NF I), which is caused by a defective gene localized to chromosome 17 and Neurofibromatosis Type II (NF II), which is caused by a defective gene localized to chromosome 22. NF II is the less common form, affecting 1 in 40,000 persons. The distinguishing clinical feature of NF II is the presence of bilateral vestibular schwannomas. This is a case of a 15-year-old boy who presented with a mild hearing loss in the left ear and a nine month history of prominent hearing loss in the right ear. Brain magnetic resonance imaging (MRI) showed bilateral enhancing lesions in the cerebellopontine angle which extend into the internal auditory canal, consistent with vestibular schwannoma. He has no family history of Neurofibromatosis.     

Imaging features of neurofibromatosis type 2

Neurofibromatosis type 2 (NF2) is a separate entity from von Recklinghausen's disease (NF1) and is much less frequent than NF1. The major feature of NF2 is the presence in nearly all affected individuals of bilateral vestibular schwannomas. Imaging of the entire central nervous system is necessary, including evaluation of the cerebral parenchyma, the pontocerebellar angles, the spinal cord as well as the lumbar nerve roots, because the affected individuals can develop tumours from schwann cells, meningeal cells and from ependymocytes.     

Acute Deterioration Of Charcot-Marie-Tooth Disease IA (CMT IA) Following 2 MG Of Vincristine Chemotherapy

Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder characterised by bilateral vestibular schwannomas and other CNS tumours including meningiomas and spinal schwannomas. Occasionally, peripheral neuropathy occurs in these patients but this is the first report of focal amyotrophy. Clinical, electrophysiological, and imaging data from four NF2 patients seen at a specialist neurofibromatosis clinic over a 4 year period are described in whom symptomatic focal amyotrophy preceded the diagnosis of NF2. Two presented with wasting and weakness of a single muscle group, several years before NF2 was diagnosed. In one patient a mononeuritis multiplex was the presenting feature of NF2, and in one patient focal wasting and weakness developed after the diagnosis of NF2 was made. In none of the four cases could a focal peripheral nerve or root neurofibroma be identified despite extensive imaging with MRI, and the limitations of neuroimaging for identifying a structural cause in patients with NF2 with a focal peripheral nerve lesion is discussed. It is likely that NF2 may affect peripheral nerve structures in a manner distinct from a compressive schwannoma.     

Focal amyotrophy in neurofibromatosis 2

Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder characterised by bilateral vestibular schwannomas and other CNS tumours including meningiomas and spinal schwannomas. Occasionally, peripheral neuropathy occurs in these patients but this is the first report of focal amyotrophy. Clinical, electrophysiological, and imaging data from four NF2 patients seen at a specialist neurofibromatosis clinic over a 4 year period are described in whom symptomatic focal amyotrophy preceded the diagnosis of NF2. Two presented with wasting and weakness of a single muscle group, several years before NF2 was diagnosed. In one patient a mononeuritis multiplex was the presenting feature of NF2, and in one patient focal wasting and weakness developed after the diagnosis of NF2 was made. In none of the four cases could a focal peripheral nerve or root neurofibroma be identified despite extensive imaging with MRI, and the limitations of neuroimaging for identifying a structural cause in patients with NF2 with a focal peripheral nerve lesion is discussed. It is likely that NF2 may affect peripheral nerve structures in a manner distinct from a compressive schwannoma.     

Neurofibromatosis 2 in the pediatric population

Neurofibromatosis 2 is a severe autosomal dominant disorder characterized by the occurrence of bilateral vestibular schwannomas and other benign tumors of the nervous system. Excellent natural history studies exist for adults with neurofibromatosis 2, but limited outcome data are available for children with neurofibromatosis 2. In this study, we present clinical data on 12 patients with neurofibromatosis 2 and age at diagnosis before 18 years. Full record review included surgical reports, pathology reports, and imaging studies; all patients were personally examined by a single author. One third of the patients presented with hearing impairment and another third presented with other cranial nerve dysfunction. Tumor load was extensive, including cranial meningiomas in 75%, cranial schwannomas other than vestibular schwannomas in 83%, and spinal cord tumors in 75%. Family history was present in two thirds of the patients. Surgical removal of vestibular schwannomas was performed in 58%; none had full preservation of hearing postsurgery. Functionally, 75% of children had hearing loss, 83% had visual impairment, 25% had abnormal ambulation, and 25% were performing below grade level. In conclusion, increased clinical awareness, better imaging techniques, and molecular diagnostics have made pediatric diagnosis of neurofibromatosis 2 feasible, but outcomes appear to be worse than in adult patients. Further work is needed to determine optimal management of pediatric neurofibromatosis 2.     

Effect of bevacizumab on intracranial meningiomas in patients with neurofibromatosis type 2 – a retrospective case series

Purpose: The hallmark of neurofibromatosis type 2 (NF2) is bilateral vestibular schwannomas (VS). Approximately 80% of NF2 patients also have intracranial meningiomas. Vascular endothelial growth factor (VEGF) is expressed in both NF2-related and sporadic occurring meningiomas and anti-VEGF therapy (bevacizumab) may, therefore, be beneficial in NF2-related meningiomas. The purpose of the study was to report the effect of bevacizumab on meningiomas in NF2 patients. Materials and methods: We retrospectively reviewed the effect of bevacizumab on the cross-sectional area (CSA) of 14 intracranial meningiomas in 7 NF2 patients. Bevacizumab 10 mg/kg was administered intravenously every two weeks for six months and 15 mg/kg every three weeks thereafter. Patients were evaluated according to the modified Macdonald criteria with repeated magnetic resonance (MR) scans. Results: The median duration of therapy was 27 months (range 16–34) and 42 MR scans (median 8, range 4–11) were reviewed. The median annual change in meningioma CSA prior to bevacizumab was 2% (range –4%–+76%). During treatment, a decrease in meningioma CSA was observed in 5 of 14 meningiomas (36%) in 5 of 7 patients (71%). The median decrease in CSA was –10% (range –3%––25%). One meningioma (7%) progressed and the remaining (93%) had stable disease. Conclusions: Bevacizumab may slow or reverse the growth of some NF-related meningiomas. However, we have previously reported a fatal case of intracerebral hemorrhage following bevacizumab in NF2 patients, wherefore, this effect needs to be balanced carefully against the risk of side effects.     

Central nervous system metastases of pulmonary adenocarcinoma mimicking neurofibromatosis type 2

We report a case of a 51-year-old man presenting with rapidly progressive unilateral tinnitus, hearing loss and imbalance. Neuroimaging revealed bilateral VIIIth cranial nerve masses and multiple cerebral and spinal cord lesions that were interpreted as being acoustic schwannomas and multiple meningeomas. An initial tentative diagnosis of neurofibromatosis type 2 (NF2) was made. Both clinical and radiological evolution were atypical for NF2 and the initial diagnosis of NF2 was questioned. Additional technical investigations demonstrated a pulmonary adenocarcinoma. Postmortem examination confirmed that this patient had multiple central nervous system metastases of a primary pulmonary adenocarcinoma, presenting clinically and neuroradiologically as a probable neurofibromatosis type 2. Clinicians should be aware of the rare possibility of central nervous system metastases mimicking NF2.     

Evidence for a cytoskeleton attachment domain at the N-terminus of the NF2 protein

Neurofibromatosis type 2 is a hereditary cancer syndrome characterized by the development of bilateral vestibular schwannomas. Underlying the disease are inactivating mutations of the NF2 tumor suppressor gene, located on chromosome 22, encoding a 595-amino-acid protein. The NF2 protein, also known as merlin or schwannomin, is reported to act as a membrane-cytoskeleton linking protein. This assumption is based on the homology of the NF2 protein to a group of band 4.1-related proteins, ezrin, radixin, and moesin. The cytoskeletal association of the NF2 protein has in part been confirmed by its ability to resist extraction from cells by nonionic detergents. We performed detergent extraction on COS cells transfected with NF2 cDNA constructs. The extracts were analyzed by Western blotting and immunofluorescent staining with monoclonal anti-NF2 antibodies. The results provide evidence for a high-affinity cytoskeleton attachment domain at amino acids 29-131 and a putative lower affinity domain between amino acids 321 and 470.     

First experience of stereotactic radiation therapy for vestibular schwannoma using CyberKnife

Currently stereotactic radiosurgery has become the treatment of choice in small vestibular schwannomas. This paper discusses our first experience of application of CyberKnife system for stereotactic irradiation of these tumors. From April 2009 till June 2011 we treated 62 patients (35 female and 27 male) with vestibular schwannomas. Stereotactic radiosurgery using CyberKnife system was performed in 33 patients. Mean tumor volume was 2 +/- 1.4 cm3. Hypofractionated treatment was used in 30 cases (31 tumor). Mean tumor volume reached was 7 +/- 6.2 cm3 (range - 0.5-31.3 cm3). In a case of a patient with NF2 simultaneous irradiation of bilateral tumors was performed. Most frequently we applied 3 fractions 6 Gy each (17 observations of 31, or 55%) and 5 fractions with mean dose 5 Cy (10 cases, or 32%). Follow-up period varied from 1 to 26 months (mean 9 +/- 4.5 months). By the end of this study (June 30, 2011) surgical resection was required in the only case of 47-years old male patient with cystic schwannoma of left vestibular nerve 5 months after radiation treatment, due to progressive growth of the cyst and increased brainstem compression. Tumor growth control was established in 97.5% of cases. Stabilization of auditory function was achieved in 77.5% of series. Effective hearing was preserved in 75% of patients. Facial nerve palsy after stereotactic radiation treatment was observed in 2 cases (3%). Incidence of trigeminal nerve dysfunction was significantly higher: sensation disturbances occurred in 6 (10%) patients: 3% after radiosurgery and 16.7% after hypofractionation. We did not obtain significant correlations between risk of cranial nerve complications and dosimetric or demographic factors. However we observed stable tendency: larger initial volume of the tumor and presence of trigeminal nerve dysfunction before treatment were poor prognostic factors for trigeminal neuropathy. Stereotactic irradiation using CyberKnife system is effective and sufficiently safe technique for management of vestibular schwannoma. The paper demonstrates high rates of tumor stabilization, hearing preservation and minimal incidence of complications associated with trigeminal or facial nerve.