germ­ -line NF2 mutations, the risk of passing NF2 caused by mosaicism to future offspring is low [42].

The NF2 gene is located on chromosome 22q11 and encodes a 587 amino acid protein known as merlin or schwannomin. It is activated in most NF2-associated tumors such as schwannoma and meningioma. Merlin is structurally related to ezrin, radixin, and moesin, which are proteins that link the actin cytoskeleton to cell surface glycoproteins that control growth and cellular remodeling. Merlin is widely expressed in Schwann cells, meningeal cells, peripheral nerves, and the lens [43, 44]. The NF2 gene functions as a tumor suppressor of Schwann cell and leptomeningeal cell proliferation. Inactivation of NF2 and the loss of merlin expression have been detected in sporadic meningiomas, schwannomas, mesothelioma, and in NF2-associated tumors. In mice, loss of function of the NF2 gene in Schwann cells results in schwannomas [45]. The precise mechanisms of tumor formation in NF2 have not been determined, but it is likely that merlin interacts with multiple intercellular signaling pathways to maintain growth suppression.

There is some evidence for genotype-phenotype correlation in NF2. Patients with frame-shift or nonsense NF2 mutations are usually associated with severe phenotype and those with single codon alterations have mild NF2 [46, 47]. However, the NF2 expression is also influenced by some unknown epigenetic factors [46]. These findings support the observations of minimal intrafamilial variability in the manifestations of NF2 as compared to wide variations in the manifestations of NF2 in different families, i.e., interfamilial variability.

7.2.4.6  Incidence

The birth incidence of NF2 is about one in 25,000 and the diagnostic prevalence is one in 210,000. In a study of incidence of familial occurrences of meningiomatosis and schwannomatosis, only 1% of the patients with meningioma and 3% of the patients with schwannoma were associated with NF2 [48].

7.2.4.7  Natural History and Prognosis

Overall, about 5% of patients with VN have NF2. Over 90% of patients with NF2 present with bilateral VN. The risk of developing a contralateral tumor in the absence of family history or other features of NF2 in patients with sporadic unilateral VN is low.

7.2.4.8  Signs and Symptoms

Ocular Findings

The ophthalmic manifestations of NF2 are posterior subcapsular cataracts, peripheral cortical cataracts, combined hamartoma of the retina and retinal pigment epithelium, and epiretinal membranes (Fig. 7.4) [49– 51]. In a clinical study of 49 patients with NF2 and their offsprings, posterior subcapsular/capsular, cortical, or mixed lens opacities were the most common ocular abnormalities, seen in 67% of patients. Therefore, early onset cortical cataract and posterior subcapsular/capsular cataracts are included in the diagnostic criteria of NF2 [36]. Retinal hamartomas are less common and are seen in about 20% of cases [52].

Systemic Findings

Vestibular Schwannoma

Schwannomas are benign encapsulated tumors that arise from the Schwann cells of the peripheral nervous system. Malignant transformation of these lesions is rare. The mean age at onset is less than 25 years and presentation beyond the age of 55 years is unusual. Bilateral VNs develop in 95% of patients. Progressive, sensorineural deafness is the most common presenting symptom. The degree of hearing impairment is not associated with tumor size [53]. Schwannomas can develop on other cranial nerves, and oculomotor and trigeminal nerves are most commonly involved. Intracranial and spinal involvement is common in Wishart phenotype and is the major cause of mortality and morbidity.

Fig. 7.4  Fundus photograph of a combined hamartoma of the retina and the retinal pigment epithelium. Reproduced with permission from: Singh et al. [228]