78.1 Introduction

Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder characterized by the development of multiple tumors of the nervous system, most typically bilateral vestibular schwannomas.s. Literatur ^,​ s. Literatur Other tumors may also occur including schwannomas of other cranial, spinal, peripheral, and intracutaneous nerves; cranial and spinal meningiomas; and ependymomas. NF2 is also associated with ocular changes including cataract formation, epiretinal membranes, and retinal hamartomas, as well as cutaneous changes such as skin plaques. The symptomatic prevalence of NF2 is approximately 1 per 60,000 people.s. Literatur The Manchester criteria has been used for the clinical diagnosis of NF2 (Table 78‑1 ).s. Literatur

78.2 Inheritance of Neurofibromatosis Type 2

The genetic nature of NF2 was first described by Feiling and Ward in 1920s. Literatur and its autosomal dominant inheritance was described by Gardner and Frazier in 1930.s. Literatur While many patients inherit the disease from their parents, more than half of patients with NF2 have de novo mutations.s. Literatur Of these, approximately 35% display mosaicism. First described in 1995 by Bourn et al,s. Literatur mosaicism is a phenomenon in which only some cells within the affected individual carry the NF2 gene mutation.s. Literatur ^,​ s. Literatur ^,​ s. Literatur It results from postzygotic mutation of the NF2 gene such that two distinct cell lines develop—one normal and the other carrying the NF2 gene mutation. Mosaicism is more common in NF2 than in almost any other condition. In NF2 patients with unilateral vestibular schwannomas, the rate of mosaicism is as high as 60%.s. Literatur The remaining 65% of de novo cases have the NF2 gene mutation throughout their body.

In order to develop NF2-related tumors, both alleles of the NF2 gene must become mutated/deleted. NF2 patients carry a germline mutation that constitutes the first hit. The second hit is not, however, present as a germline mutation but is acquired at a later stage. This second hit is especially likely in Schwann cells where Merlin expression is particularly high, hence the propensity of NF2 patients to develop vestibular schwannomas.

78.3 The NF2 Gene

NF2 results from inactivation of the NF2 gene. There is no current evidence that a mutation of any other gene is implicated in classical NF2. However, cases with unilateral vestibular schwannomas and other schwannomas may have an underlying LZTR1 mutation.s. Literatur The NF2 gene was identified by two separate groups in 1993s. Literatur ^,​ s. Literatur and is located on chromosome 22, band 22q12.2. Its promoter and major transcription ignition sites have also been described.s. Literatur Its protein product is called Merlin, also known as Schwannomin. Merlin is a 69-kDa protein with 595 amino acids and is part of the band 4.1 family of cytoskeletal proteins known as ERM proteins, ERM being an abbreviation of ezrin–radixin–moesin-like protein.s. Literatur ^,​ s. Literatur It has three functional domains: a conserved FERM (4.1 ERM) amino terminal domain (exons 1–9), an alpha-helical domain (exons 10–13), and a carboxy terminal domain (exons 14–17).s. Literatur Most truncating mutations map to the FERM domain suggesting that this has a particularly important tumor suppression role.

Merlin is found ubiquitously throughout the body, but it is particularly well expressed in the cell membranes of Schwann cell, in nerve tissue, in lens tissue, and in meningeal tissues.s. Literatur It has two isoforms, Merlin-1 and Merlin-2, resulting from alternative splicing of exons 16 and 17. Its activity is regulated by phosphorylation of serine 518.s. Literatur Phosphorylation results in conformational change such that Merlin becomes open and inactive. Dephosphorylation results in a closed confirmation and activation of the molecule. This is controlled by a family of ras-related kinases including protein kinase A and p21 activated kinases. The unphosphorylated active form may have a number of roles, all of which act to inhibit cell growths. Literatur:

1. 
   

   Linkage of cell surface glycoproteins such as CD44, β1integrin, and β catenin to intracellular adhesion molecules and cytoskeletal actin regulating cell:cell adhesion and contact inhibition.s. Literatur

   
   
2. 
   

   An upstream regulator of the Hippo pathway, a regulator of cell growth by contact inhibition.s. Literatur This may be mediated through translocation of Merlin to the nucleus where it inhibits E3 ubiquitin ligase CRL4^DCAF1.s. Literatur

   
   
3. 
   

   Promotion of inactivation of membrane growth factor receptors, e.g., EGFR, PDGFR.s. Literatur

Loss of this tumor suppressor function is the underlying reason for the propensity for tumor development in individuals carrying a mutated form of the gene.

78.4 Types of Mutation and the Association with Phenotype

Traditionally, NF2 patients have been divided into two broad phenotypic groups: those with milder disease, termed “Gardner type,” and those with more severe disease, termed “Wishart type.” These terms have now become outdated in the knowledge that there is a spectrum of disease severity with enormous variability in disease location and severity between and within individuals.

Members of the same family tend to have similar disease severity, but there is significant variability in the phenotype of unrelated patients with NF2.s. Literatur ^,​ s. Literatur This partly relates to the presence of mosaicism but is also dependent on the type of mutation.

Patients with mosaicism often have less severe disease and the severity of disease is related to the proportion of cells affected.s. Literatur This is, in turn, related to the point during development at which the mutation takes place. The earlier the mutation takes place, the more affected cells are present and the more severe the disease. Mosaic patients may also have segmental involvement resulting from proliferation of cells with the mutated form of the NF2 gene in isolated areas of the body.s. Literatur

There are a number of different types of mutations of the NF2 gene that have been described and the frequencies of the recorded mutations from the Manchester cohort are shown in Table 78‑2 .

While it is not an invariable correlation, the type of mutation often determines disease severity. Truncating mutations, including non-sense and frameshift mutations, are associated with a younger age of disease presentation and more severe phenotypes. Literatur ^,​ s. Literatur ^,​ s. Literatur ^,​ s. Literatur and poorer survivals. Literatur than that seen with missense mutations, in-frame mutations, or large deletions. Splice-site mutations, in contrast, can result in a range of disease severity depending on the site of the mutation. For example, mutations in the first five exons are associated with more severe disease than those occurring in exons 11 to 15.s. Literatur The reason why truncating mutations are associated with more severe phenotypes is unclear. It has been hypothesized that the mutant protein dimerizes with the normal product resulting in less normal product to suppress tumor development. Ring 22 is another genetic defect that can lead to NF2 and is associated with mental retardation.s. Literatur

Paradoxically, truncating mutations are more common in mosaic cases than in inherited cases, presumably because of reduced “genetic fitness.” Conversely, missense mutations are much less frequent in mosaic cases compared to inherited cases. Truncating mutations have a higher prevalence of meningioma compared to missense or splice-site mutations.s. Literatur Truncating and nonsense mutations are associated with a higher risk of developing spinal tumors.s. Literatur Nonsense and frameshift mutations are also associated with greater mortality.s. Literatur

The site of mutation may also influence disease severity. For example, splice-site mutations in exons 11 to 15 are associated with less severe disease than splice-site mutations in exons 1 to 5s. Literatur and risk of meningioma development is higher if a mutation is in exons 1 to 3 compared to exons 14 to 15.s. Literatur Recently, a positional effect has also been shown for truncating mutations with those in exons 1 and 14 to 15 being associated with milder disease, less meningiomas, and improved survival.s. Literatur

There may also be epigenetic factors that influence NF2 gene inactivation as well as gene mutation. For example, it has been suggested that methylation of the NF2 gene may be responsible for inactivation in some cases.s. Literatur

Although disease severity is often determined by the type of mutation, it is not unusual to see differences in phenotype between individuals in the same family and even between monozygotic twins.s. Literatur There is also variability in the behavior of tumors within individuals.s. Literatur This suggests that there are certainly other factors involved in determining severity other than mutation type and mosaicism. This may relate to expression of cytokine or hormone receptors such as vascular endothelial growth factor (VEGF) receptors. Literatur or androgen receptor. The interested reader may also review Chapter 5, further detailing the molecular biology of sporadic and NF2-associated vestibular schwannomas.