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

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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Rare variant of misme syndrome – a case report with review of literature

Romanian Neurosurgery ◽

10.1515/romneu-2016-0069 ◽

2016 ◽

Vol 30 (3) ◽

pp. 444-450

Author(s):

Ashish Kumar Dwivedi ◽

Shashi Kant Jain ◽

Ashok Gandhi

Keyword(s):

Nervous System ◽

Autosomal Dominant ◽

Neurofibromatosis Type ◽

Suppressor Gene ◽

Initial Presentation ◽

Spinal Tumors ◽

Simultaneous Occurrence ◽

Benign Tumors ◽

Review Of Literature

Abstract MISME syndrome, also known as neurofibromatosis type-2 (NF2), stands for multiple inherited schwannomas, meningiomas, and ependymomas (MISME) 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 the peripheral nervous system, particularly from the bilateral vestibular nerve in more than 90% of the patients and more than two thirds of them develop spinal tumors. Simultaneous occurrence of bilateral vestibular schwanoma with cervical and lumbar ependymoma without neuro cutaneous marker with weakness of limb as initial presentation is rare finding in single patient. Here, we are reporting a rare case of MISME syndrome harbouring bilateral vestibular schwanoma with cervical and lumbar ependymoma tumors in a 45 year old male patient having no other lesion and neurocutaneous marker with weakness of limb as initial presentation without posterior subcapsular cataract.

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

Journal of Neurosurgery ◽

10.3171/2009.6.jns09105 ◽

2010 ◽

Vol 112 (1) ◽

pp. 81-87 ◽

Cited By ~ 29

Author(s):

Matthew L. Carlson ◽

Dusica Babovic-Vuksanovic ◽

Ludwine Messiaen ◽

Bernd W. Scheithauer ◽

Brian A. Neff ◽

...

Keyword(s):

Tumor Suppressor ◽

Stereotactic Radiosurgery ◽

Tumor Suppressor Gene ◽

Neurofibromatosis Type ◽

Suppressor Gene ◽

Neurofibromatosis Type 2 ◽

Benign Tumors ◽

Autosomal Dominant Disorder ◽

Peripheral Nerve Sheath Tumors

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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Role of the neurofibromatosis Type 2 gene in the development of tumors of the nervous system

Neurosurgical FOCUS ◽

10.3171/foc.2005.19.5.7 ◽

2005 ◽

Vol 19 (5) ◽

pp. 1-5 ◽

Cited By ~ 12

Author(s):

Martin H. Ruttledge ◽

Guy A. Rouleau

Keyword(s):

Nervous System ◽

Somatic Mutations ◽

Germ Line ◽

Large Body ◽

Neurofibromatosis Type ◽

Suppressor Gene ◽

Neurofibromatosis Type 2 ◽

Sporadic Tumors

Germ line and somatic mutations in the neurofibromatosis Type 2 (NF2) tumor suppressor gene predispose individuals to tumors of the nervous system, including schwannomas and meningiomas. Since identification of the NF2 gene more than a decade ago, a large body of information has been collected on the nature and consequences of these alterations in patients with NF2 and in individuals in whom sporadic tumors associated with NF2 develop. The catalog of mutations identified thus far has facilitated extensive genetic analysis, including studies of patients with mosaicism and phenotype–genotype correlations, and has also led to experiments that have begun to unravel the molecular biology of the NF2 gene and its role in tumorigenesis. The authors describe some of the most significant findings in NF2 genetics and biology over the last decade.

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Spinal tumors in patients with neurofibromatosis type 2: MR imaging study of frequency, multiplicity and variety.

American Journal of Roentgenology ◽

10.2214/ajr.166.5.8615282 ◽

1996 ◽

Vol 166 (5) ◽

pp. 1231-1231 ◽

Cited By ~ 12

Author(s):

V F Mautner

Keyword(s):

Mr Imaging ◽

Imaging Study ◽

Neurofibromatosis Type ◽

Neurofibromatosis Type 2 ◽

Spinal Tumors

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Management of spinal tumors in neurofibromatosis type 2 patients

Neurologia i Neurochirurgia Polska ◽

10.1016/j.pjnns.2015.11.004 ◽

2016 ◽

Vol 50 (1) ◽

pp. 31-35 ◽

Cited By ~ 1

Author(s):

Arkadiusz Nowak ◽

Tomasz Dziedzic ◽

Tomasz Czernicki ◽

Przemysław Kunert ◽

Andrzej Marchel

Keyword(s):

Neurofibromatosis Type ◽

Neurofibromatosis Type 2 ◽

Spinal Tumors

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Unilateral vestibular schwannoma with other neurofibromatosis Type 2–related tumors: clinical and molecular study of a unique phenotype

Journal of Neurosurgery ◽

10.3171/jns.2006.104.2.201 ◽

2006 ◽

Vol 104 (2) ◽

pp. 201-207 ◽

Cited By ~ 16

Author(s):

Manish Aghi ◽

Lan Kluwe ◽

Micah T. Webster ◽

Lee B. Jacoby ◽

Fred G. Barker ◽

...

Keyword(s):

Molecular Genetic ◽

Neurofibromatosis Type ◽

Molecular Study ◽

Molecular Genetic Analysis ◽

Neurofibromatosis Type 2 ◽

Spinal Tumors ◽

Rapid Progression ◽

Eighth Cranial Nerve ◽

Cranial Nerve Dysfunction

Object Although the manifestations of neurofibromatosis Type 2 (NF2) vary, the hallmark is bilateral vestibular schwannomas (VSs). The authors studied the clinical course and genetic basis of unilateral VSs associated with other NF2-related tumors. Methods Forty-four adults presenting with unilateral VSs and other NF2-related tumors were identified. A comprehensive review of patient records and cranial imaging was conducted. Molecular analysis of the NF2 locus was performed in available tumors and paired blood specimens. Patient age at symptomatic onset ranged from 11 to 63 years (mean 32 years). Twenty-two patients (50%) presented with eighth cranial nerve dysfunction. Twenty-six presented with multiple lesions. Thirty-eight harbored other intracranial tumors and 27 had spinal tumors, with most lesions situated ipsilateral to the VS. No patient had a relative with NF2, although two of 63 offspring had isolated NF2-related findings. A contralateral VS developed in four patients 3 to 46 years after the symptomatic onset of a unilateral VS, and two of these patients experienced rapid progression to total deafness. Results of a Kaplan–Meier analysis identified actuarial chances of developing contralateral VS: 2.9% (3–17 years after the VS symptomatic onset of unilateral VS), 11% (18–24 years), and 28.8% (25–40 years). Mosaicism for the NF2 gene mutation was proven in eight patients. Conclusions The authors describe the clinical features of this unique phenotype—unilateral VS with other NF2-related tumors. Persons with this phenotype should undergo evaluation and monitoring similar to that conducted in patients with NF2, and the possibility of aggressive contralateral VS formation should be considered in their treatment. Molecular genetic analysis is best performed using resected tumor specimens and will enable future studies to determine the genetic risks of individuals with mosaicism.

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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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