Radiation-induced rhabdomyosarcoma of the brainstem in a patient with neurofibromatosis Type 2

Neurofibromatosis Type 2 (NF2) is a rare autosomal dominant disorder characterized by the development of benign tumors of the peripheral nervous system and the CNS, including schwannomas, meningiomas, and ependymomas. The gene responsible for the development of NF2 acts as a tumor suppressor gene. Stereotactic radiotherapy (SRT) or single-fraction stereotactic radiosurgery has been increasingly used in the past decades to treat benign tumors in patients with NF2. These radiotherapy methods are less invasive and can be potentially used to treat multiple tumors in a single session. The risk of inducing malignancy is unclear. Few reports exist of malignant peripheral nerve sheath tumors, meningiomas, or ependymomas occurring after SRT or stereotactic radiosurgery in patients with NF2. The authors present the first documented case of rhabdomyosarcoma following SRT for multiple NF2-associated schwannomas. Compared with patients with sporadic tumors, NF2 patients having a germline tumor suppressor gene defect may be more prone to secondary malignancies after treatment involving radiation therapy.

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Molecular genetic investigation of the neurofibromatosis type 2 tumor suppressor gene in sporadic meningioma

Journal of Neurosurgery ◽

10.3171/jns.1996.84.5.0847 ◽

1996 ◽

Vol 84 (5) ◽

pp. 847-851 ◽

Cited By ~ 58

Author(s):

Takehiko Harada ◽

Richard M. Irving ◽

John H. Xuereb ◽

David E. Barton ◽

David G. Hardy ◽

...

Keyword(s):

Tumor Suppressor ◽

Tumor Suppressor Gene ◽

Molecular Genetic ◽

Gene Mutations ◽

Neurofibromatosis Type ◽

Suppressor Gene ◽

Neurofibromatosis Type 2 ◽

Chromosome 22 ◽

Sporadic Meningioma

✓ The authors investigated the role of somatic mutations of the neurofibromatosis type 2 (NF2) gene in sporadic meningioma. Neurofibromatosis 2 is a dominantly inherited familial tumor syndrome predisposing affected patients to a variety of central nervous system tumors including vestibular schwannoma and meningioma. Neurofibromatosis type 2 is caused by germline mutations in the NF2 tumor suppressor gene. In addition, the authors and others have reported that somatic NF2 gene mutations occur frequently in nonfamilial vestibular schwannoma. In this study, molecular genetic analysis was performed on 23 nonfamilial meningiomas. Paired DNA samples extracted from the blood and tumors of the patients were analyzed for loss of heterozygosity (LOH) in the region of the NF2 gene on chromosome 22 using closely linked DNA markers. The NF2 gene mutations were sought by single-stranded conformation polymorphism analysis and DNA sequencing. Fourteen (61%) of 23 meningiomas showed LOH in the region of the NF2 gene on chromosome 22. Somatic NF2 gene mutations were detected in eight meningiomas (35%) after screening all 17 exons. All tumors with NF2 gene mutations showed simultaneous chromosome 22 LOH. Review of the histopathological findings of the cases studied did not demonstrate any predominance of genetic abnormalities in a particular histological type of meningioma. These results are compatible with the hypothesis that the NF2 gene acts as a tumor suppressor and that its inactivation is important in the pathogenesis of sporadic meningioma.

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New Developments in Neurofibromatosis Type 2 and Vestibular Schwannoma

Neuro-Oncology Advances ◽

10.1093/noajnl/vdaa153 ◽

2020 ◽

Author(s):

Yin Ren ◽

Divya A Chari ◽

Sasa Vasilijic ◽

D Bradley Welling ◽

Konstantina M Stankovic

Keyword(s):

Treatment Options ◽

Neurofibromatosis Type ◽

Suppressor Gene ◽

Severe Form ◽

Neurofibromatosis Type 2 ◽

Future Research ◽

Autosomal Dominant Disorder ◽

Management Options ◽

Stereotactic Radiation

Abstract Neurofibromatosis type 2 (NF2) is a rare autosomal dominant disorder characterized by the development of multiple nervous system tumors due to mutation in the NF2 tumor suppressor gene. The hallmark feature of the NF2 syndrome is the development of bilateral vestibular schwannomas (VS). Although there is nearly 100% penetrance by 60 years of age, some patients suffer from a severe form of the disease and develop multiple tumors at an early age, while others are asymptomatic until later in life. Management options for VS include surgery, stereotactic radiation, and observation with serial imaging; however, currently there are no FDA-approved pharmacotherapies for NF2 or VS. Recent advancements in the molecular biology underlying NF2 have led to a better understanding of the etiology and pathogenesis of VS. These novel signaling pathways may be used to identify targeted therapies for these tumors. This review discusses the clinical features and treatment options for sporadic- and NF2-associated VS, the diagnostic and screening criteria, completed and ongoing clinical trials, quality of life metrics, and opportunities for future research.

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Neurofibromatosis Type 2

Journal of Child Neurology ◽

10.1177/0883073816666736 ◽

2016 ◽

Vol 32 (1) ◽

pp. 9-22 ◽

Cited By ~ 30

Author(s):

Simone Ardern-Holmes ◽

Gemma Fisher ◽

Kathryn North

Keyword(s):

Vision Loss ◽

Clinical Signs ◽

Neurofibromatosis Type ◽

Neurofibromatosis Type 2 ◽

Careful Examination ◽

Benign Tumors ◽

Autosomal Dominant Disorder ◽

Timely Initiation ◽

Disease Specific

Neurofibromatosis type 2 (NF2) is a rare autosomal dominant disorder (incidence 1:33 000-40 000) characterized by formation of central nervous system tumors, due to mutation in the NF2 gene on chromosome 22q12. Vestibular schwannomas are the hallmark lesion, affecting 95% of individuals and typically occur bilaterally. Schwannomas commonly occur on other nerves intracranially and in the spinal compartment, along with meningiomas, ependymomas, and gliomas. Although histologically benign, tumors are associated with significant morbidity due to multiple problems including hearing and vision loss, gait abnormalities, paralysis, pain, and seizures. Risk of early mortality from brainstem compression and other complications is significant. Severity of disease is higher when NF2 presents during childhood. Children have a more variable presentation, which can be associated with significant delays in recognition of the condition. Careful examination of the skin and eyes can identify important clinical signs of NF2 during childhood, allowing timely initiation of disease-specific surveillance and treatment. Monitoring for complications comprises clinical evaluation, along with functional testing including audiology and serial neuroimaging, which together inform decisions regarding treatment. Evidence for disease-specific medical treatment options is increasing, nevertheless most patients will benefit from multimodal treatment including surgery during their lifetime. Patient enrolment in international natural history and treatment trials offers the best opportunity to accelerate our understanding of the complications and optimal treatment of NF2, with a view to improving outcomes for all affected individuals.

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Neurofibromatosis Type 2: A Pandora’s Box of Variable Presentations

Indian Journal of Neurosurgery ◽

10.1055/s-0041-1722832 ◽

2021 ◽

Author(s):

Ashok Gandhi ◽

Swarup Sohan Gandhi ◽

Surendra Jain ◽

Shashikant Jain ◽

Paresh Sukhani

Keyword(s):

Nervous System ◽

Incidental Finding ◽

Significant Proportion ◽

Young Patients ◽

Neurofibromatosis Type ◽

Suppressor Gene ◽

Neurofibromatosis Type 2 ◽

Spinal Tumors ◽

Benign Tumors

Abstract Introduction Neurofibromatosis type 2 (NF2) also known as MISME syndrome stands for multiple inherited schwannomas, meningiomas, and ependymomas in the peripheral and central nervous system. It is a rare disorder of autosomal dominant inheritance due to mutations of a tumor-suppressor gene on the chromosome 22q12. Clinically, it is characterized by multiple benign tumors arising in both the central and peripheral nervous system, particularly from the bilateral vestibular nerve, in more than 90% of the patients, with more than two thirds of them developing spinal tumors. Materials and Methods Here, we studied the variable presentations of cases of NF2, and thorough evaluation of patients was done by contrast MRI of brain and spine. Also, evaluation of ocular manifestations and cutaneous features was done in cases of NF2, and a follow-up was done for a period of 18 months with monitoring of cranial and spinal lesions. Conclusion We studied the various presentations of NF2 and found that a significant proportion of the patients presented with nonvestibular tumors as the initial presentation, with bilateral cerebellopontine angle lesions being an incidental finding; also, the age of presentation in half of the patients was less than 30 years, and so we can conclude that in young patients with spinal tumors or multiple meningiomas, a thorough evaluation regarding family history and various features of NF2 should be done, so that early identification of the disease could be done and patients can be benefitted from timely interventions.

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Clinical and molecular genetic features of neurofibromatosis type

Nauchno-prakticheskii zhurnal «Medicinskaia genetika» ◽

10.25557/2073-7998.2021.10.3-12 ◽

2021 ◽

pp. 3-12

Author(s):

К.О. Карандашева ◽

Е.С. Макашова ◽

А.А. Мартьянова ◽

К.И. Аношкин ◽

С.В. Золотова ◽

...

Keyword(s):

Tumor Suppressor ◽

Binding Sites ◽

Genetic Disorder ◽

Molecular Genetic ◽

Neurofibromatosis Type ◽

Suppressor Gene ◽

Neurofibromatosis Type 2 ◽

Post Translational Modifications ◽

Genetic Features

Нейрофиброматоз 2 типа - редкое генетическое заболевание, этиологическим фактором развития которого являются мутации в гене-онкосупрессоре NF2, кодирующем белок мерлин. В обзоре подробно описаны структура, функции и посттрансляционные модификации мерлина, освещены клинические особенности нейрофиброматоза 2 типа, известные клинико-генетические корреляции, а также представлена информация о сайтах связывания мерлина и о функциональном вкладе расположенных в них мутаций, что закладывает базис персонализированной терапии нейрофиброматоза 2 типа. Neurofibromatosis type 2 is a rare genetic disorder caused by pathogenic mutations in the NF2 tumor suppressor gene which encodes a protein called merlin. This review describes the structure, functions, and post-translational modifications of merlin, highlights clinical features and known genotype-phenotype correlations of neurofibromatosis type 2, and provides information on the merlin binding sites and the functional contribution of mutations they harbor, which lays the basis for personalized therapy for neurofibromatosis type 2.

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Hypofractionated CyberKnife stereotactic radiosurgery for acoustic neuromas with and without association to neurofibromatosis Type 2

Reconstructive Neurosurgery - Acta Neurochirurgica Supplementum ◽

10.1007/978-3-211-78205-7_29 ◽

2009 ◽

pp. 169-173 ◽

Cited By ~ 17

Author(s):

D. T. Ju ◽

J. W. Lin ◽

M. S. Lin ◽

L. M. Lee ◽

H. M. Tseng ◽

...

Keyword(s):

Stereotactic Radiosurgery ◽

Neurofibromatosis Type ◽

Neurofibromatosis Type 2 ◽

Acoustic Neuromas

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Primary meningeal melanoma masquerading as neurofibromatosis type 2: illustrative case

Journal of Neurosurgery: Case Lessons ◽

10.3171/case21444 ◽

2021 ◽

Vol 2 (20) ◽

Author(s):

Melanie Lang-Orsini ◽

Julian Wu ◽

Carl B. Heilman ◽

Alina Kravtsova ◽

Gene Weinstein ◽

...

Keyword(s):

Internal Auditory Canal ◽

Primary Melanoma ◽

Neurofibromatosis Type ◽

Neurofibromatosis Type 2 ◽

Proliferation Index ◽

Illustrative Case ◽

Radiographic Findings ◽

Peripheral Nerve Sheath Tumors ◽

Spinal Lesion

BACKGROUND Primary meningeal melanocytic neoplasms are exceedingly rare tumors, representing only 0.06% to 0.1% of all primary brain tumors and ranging in spectrum from benign localized tumors to highly aggressive malignant lesions. The diagnosis of these tumors is often challenging from clinical, radiological, and pathologic standpoints. Equally challenging is the distinction between primary meningeal melanocytic neoplasm and metastatic melanoma. OBSERVATIONS The authors reported the case of a 41-year-old man with imaging findings diagnostic of neurofibromatosis type 2: bilateral internal auditory canal lesions (most consistent with bilateral vestibular schwannomas), two dura-based lesions presumed to be meningiomas, multiple spinal lesions consistent with peripheral nerve sheath tumors, and one intramedullary spinal lesion consistent with an ependymoma. Biopsy of these lesions revealed melanocytic neoplasms with mild to moderate atypia and a mildly elevated proliferation index, which made the distinction between benign and malignant challenging. In addition, the disseminated nature of these tumors made it difficult to determinate whether they arose from the meninges or represented metastases from an occult primary melanoma. LESSONS This case illustrated the challenges presented by the diagnosis of meningeal melanocytic neoplasms and highlighted the importance of integrating the clinical and radiographic findings with histologic appearance and molecular studies.

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