Neurofibromatosis type II (NF2 or NF II; also known as MISME syndrome – multiple inherited schwannomas, meningiomas, and ependymomas) is a genetic condition that may be inherited or may arise spontaneously, and causes benign tumors of the brain, spinal cord, and peripheral nerves. The types of tumors frequently associated with NF2 include vestibular schwannomas, meningiomas, and ependymomas. The main manifestation of the condition is the development of bilateral benign brain tumors in the nerve sheath of the cranial nerve VIII, which is the "auditory-vestibular nerve" that transmits sensory information from the inner ear to the brain. Besides, other benign brain and spinal tumors occur. Symptoms depend on the presence, localisation and growth of the tumor(s). Many people with this condition also experience vision problems. NF2 is caused by mutations of the "Merlin" gene, which seems to influence the form and movement of cells. The principal treatments consist of neurosurgical removal of the tumors and surgical treatment of the eye lesions. Historically, the underlying disorder has not had any therapy due to the cell function caused by the genetic mutation.
Classification NF2 is an inheritable disorder with an autosomal dominant mode of transmission. There are two forms of the NF2:
The Wishart-phenotype form is characterized by multiple cerebral and spinal lesions in people younger than 20 years and with rapid progression of the tumours. People with NF2 who develop single central tumours with slow progression after the age of 20 are thought to have the Feiling–Gardner phenotype.
Symptoms and signs Symptoms can occur at any age, typically in adolescence and early adulthood, and rarely seen in children, and the severity depends on the location of the tumours. Symptoms include, but are not limited to:
Tinnitus Loss/problems of balance Glaucoma Seizures Hearing loss Vision impairment Numbness or weakness in arms and legs
Hearing loss Because hearing loss in those with NF2 almost always occurs after acquisition of verbal language skills, people with NF2 do not always integrate well into Deaf culture and are more likely to resort to auditory assistive technology. One of these devices is the cochlear implant, which can sometimes restore a high level of auditory function even when natural hearing is totally lost. However, the amount of destruction to the cochlear nerve caused by the typical NF2 schwannoma often precludes the use of such an implant. In these cases, an auditory brainstem implant (ABI) can restore some level of hearing, supplemented by lip reading.
Cause
NF2 is caused by inactivating mutations in the NF2 gene located at 22q12.2 of chromosome 22, type of mutations vary and include protein-truncating alterations (frameshift deletions/insertions and nonsense mutations), splice-site mutations, missense mutations and others. Deletions, too, in the NH2-terminal domain of merlin proteins have been associated with early tumor onset and poor prognosis in people with NF2. Protein truncating mutations correlate with more severe phenotype. There is a broad clinical spectrum known, but all people with the condition who have been checked have been found to have some mutation of the same gene on chromosome 22. Through statistics, it is suspected that one-half of cases are inherited, and one-half are the result of new, de novo mutations.
Pathogenesis NF2 is caused by a defect in the gene that normally gives rise to a product called Merlin or Schwannomin, located on chromosome 22 band q11-13.1. Merlin was first discovered as a structural protein functioning as an actin cytoskeleton regulator. Later merlin's tumour suppressant role was described. Merlin regulates multiple proliferative signalling cascades such as receptor tyrosine kinase signalling, p21-activated kinase signalling, Ras signalling, MEK-ERK cascade, MST-YAP cascade. In a normal cell, the concentrations of active (dephosphorylated) merlin are controlled by processes such as cell adhesion (which would indicate the need to restrain cell division). It has been shown that Merlin inhibits Rac1 which is crucial for cell motility and tumour invasion. Also, merlin's interaction with cyclin D was described. It is known that Merlin's deficiency can result in unmediated progression through the cell cycle due to the lack of contact-mediated tumour suppression, mainly because of the cell:cell junction disruption, sufficient to result in the tumors characteristic of Neurofibromatosis type II. Recent studies showed that besides its cytoskeletal and cytoplasmic functions Merlin also translocates to the nucleus and suppresses proliferation by inhibiting E3 ubiquitin ligase CRL4(DCAF1). Finally, most recent studies indicated that Merlin also plays important role in energy metabolism regulation. Mutations of NF2 is presumed to result in either a failure to synthesize Merlin or the production of a defective peptide that lacks the normal tumor-suppressive effect. The Schwannomin-peptide consists of 595 amino acids. Comparison of Schwannomin with other proteins shows similarities to proteins that connect the cytoskeleton to the cell membrane. Mutations in the Schwannomin-gene are thought to alter the movement and shape of affected cells with loss of contact inhibition. Ependymomas are tumors arising from the ependyma, an epithelium-like tissue of the central nervous system. In people with NF2 and ependymomas, the tumor suppressant function of Merlin may be compromised. Loss of function mutations occurring in chromosome 22q, where Merlin proteins are coded, can promote tumorigenesis, or the creation of new tumorous cells. Deletions, too, in the NH2-terminal domain of merlin proteins have been associated with early tumor onset and poor prognosis in affected people.
Pathology
The so-called acoustic neuroma of NF2 is in fact a schwannoma of the nervus vestibularis, or vestibular schwannoma. The misnomer of acoustic neuroma is still often used. The vestibular schwannomas grow slowly at the inner entrance of the internal auditory meatus (meatus acousticus internus). They derive from the nerve sheaths of the upper part of the nervus vestibularis in the region between the central and peripheral myelin (Obersteiner-Redlich-Zone) within the area of the porus acousticus, 1 cm from the brainstem.
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