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An update on the CNS manifestations of neurofibromatosis type 2

  • Shannon Coy
  • Rumana Rashid
  • Anat Stemmer-Rachamimov
  • Sandro SantagataEmail author
Review

Abstract

Neurofibromatosis type II (NF2) is a tumor predisposition syndrome characterized by the development of distinctive nervous system lesions. NF2 results from loss-of-function alterations in the NF2 gene on chromosome 22, with resultant dysfunction of its protein product merlin. NF2 is most commonly associated with the development of bilateral vestibular schwannomas; however, patients also have a predisposition to development of other tumors including meningiomas, ependymomas, and peripheral, spinal, and cranial nerve schwannomas. Patients may also develop other characteristic manifestations such as ocular lesions, neuropathies, meningioangiomatosis, and glial hamartia. NF2 has a highly variable clinical course, with some patients exhibiting a severe phenotype and development of multiple tumors at an early age, while others may be nearly asymptomatic throughout their lifetime. Despite the high morbidity associated with NF2 in severe cases, management of NF2-associated lesions primarily consists of surgical resection and treatment of symptoms, and there are currently no FDA-approved systemic therapies that address the underlying biology of the syndrome. Refinements to the diagnostic criteria of NF2 have been proposed over time due to increasing understanding of clinical and molecular data. Large-population studies have demonstrated that some features such as the development of gliomas and neurofibromas, currently included as diagnostic criteria, may require further clarification and modification. Meanwhile, burgeoning insights into the molecular biology of NF2 have shed light on the etiology and highly variable severity of the disease and suggested numerous putative molecular targets for therapeutic intervention. Here, we review the clinicopathologic features of NF2, current understanding of the molecular biology of NF2, particularly with regard to central nervous system lesions, ongoing therapeutic studies, and avenues for further research.

Keywords

Neurofibromatosis type 2 Neurofibromatosis type II NF2 Epidemiology of familial tumor syndromes Schwannomatosis Merlin Schwannomin ERM (ezrin/radixin/moesin) family scaffolding Vestibular schwannoma Meningioma Glioma Ependymoma Neurofibroma Plexiform schwannoma Intraneural schwannoma Cellular schwannoma Posterior subcapsular lenticular opacities LZTR1 SH3PXD2A-HTRA1 Verocay body SUFU SMARCE1 SMARCB1 Meningioangiomatosis Glial micro-hamartoma Glial hamartia Wishart Gardner Von Recklinghausen Manchester (NIH) Criteria Manchester Criteria Schwannoma Central neurofibromatosis Neurofibromin 2 Acoustic neuroma 

Notes

Acknowledgements

We thank David Solomon, Sarah Becker, Nicole Ullrich, and Hart Lidov for assistance with the manuscript. Sandro Santagata is supported by U2C-CA233262 and U54-CA225088. We thank Jeremy Muhlich and Yu-An Chen for assistance with website development and Peter Sorger for guidance and valuable suggestions. We thank Dana-Farber/Harvard Cancer Center in Boston, MA, for the use of the Specialized Histopathology Core, which provided slide scanning services. Dana-Farber/Harvard Cancer Center is supported in part by an NCI Cancer Center Support Grant #NIH 5 P30 CA06516.

Compliance with ethical standards

Conflict of interest

The authors declare no conflicts of interest.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Division of Neuropathology, Department of PathologyBrigham and Women’s Hospital, Hale Building for Transformative Medicine, BTM8002PBostonUSA
  2. 2.Department of PathologyBoston Children’s HospitalBostonUSA
  3. 3.Harvard Medical SchoolBostonUSA
  4. 4.Laboratory for Systems Pharmacology, Harvard Program in Therapeutic ScienceBostonUSA
  5. 5.Department of PathologyMassachusetts General HospitalBostonUSA
  6. 6.Ludwig Center at HarvardBostonUSA

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