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. Genotype–phenotype correlation
Many people with NF2 were included in studies that were designed to compare disease type and progression with exact determination of the associated mutation. The goal of such comparisons of genotype and phenotype is to determine whether specific mutations cause respective combinations of symptoms. This would be extremely valuable for the prediction of disease progression and the planning of therapy starting at a young age. The results of such studies are the following:
In most cases the mutation in the NF2 gene causes shortened peptides. There are no mutational hot spots. People with frameshift mutations or nonsense mutations have poor prognosis. People with missense mutations have a better prognosis. In cases with mutations in the splice-acceptor-region, there is no good correlation to determine. Point mutations may have only minor effects. Cases are published in which exactly the same mutation is associated with clearly different outcomes.These results suggest that other factors (environment, other mutations) will probably determine the clinical outcome. Diagnosis
NF2 is a genetically transmitted condition. Diagnosis is most common in early adulthood (20–30 years); however, it can be diagnosed earlier. NF2 can be diagnosed due to the presence of a bilateral vestibular schwannoma, or an acoustic neuroma, which causes a hearing loss that may begin unilaterally.
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).