An update on the CNS manifestations of neurofibromatosis type 2

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 FDAapproved 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.

Canine Primary Intracranial Cancer: A Clinicopathologic and Comparative Review of Glioma, Meningioma, and Choroid Plexus Tumors

“…The molecular pathogenesis of meningioma in humans is better understood than in the dog. There is an association between patients that have neurofibromatosis type 2 and the development of meningioma due to variable mutations in the NF2 gene and the subsequent production of a non-functional protein known as merlin (142). Although NF2 clearly illustrates that there are familial inheritance tendencies for meningioma, the majority of meningiomas in humans occur as sporadic tumors.…”

Genomics and Functional Genomics of Malignant Pleural Mesothelioma

“…The inactivation of the NF2 gene is associated with homozygous chromosomal loss and focal deletions of the 22q12 locus. High rates of gene fusions; splicing defects; and frameshift, missense, and nonsense mutations that result in low expression or absence of the 70 kDa tumor suppressor protein Merlin (moesin-ezrin-radixin-like protein), the protein encoded by the NF2 gene, have also been reported [ 53 , 54 ]. Merlin shares a similar domain organization with, and therefore belongs to, the Ezrin, Radixin, and Moesin (ERM) protein family [ 55 ].…”

Long-Term Outcomes of Stereotactic Radiosurgery for Vestibular Schwannoma Associated with Neurofibromatosis Type 2 in Comparison to Sporadic Schwannoma

“…Patients with NF2 develop multiple tumors in the nervous system, and NF2-associated tumors often contribute to earlier-than-expected death [5]. In particular, bilateral vestibular schwannomas (VS) are the most pathognomonic and diagnostic [6,7]. VSs are also the most common cause of morbidity, potentially resulting in bilateral sensorineural hearing loss, tinnitus, balance difficulty, and ultimately deafness, facial nerve weakness, and possible brainstem compression [8,9].…”