Unilateral VS <30 years plus at least one of the following: meningioma, glioma, schwannoma, juvenile posterior subcapsular lenticular opacities/juvenile cortical cataract

Multiple meningiomas (≥2) plus unilateral VS <30 years or one of the following: glioma, schwannoma, juvenile posterior subcapsular lenticular opacities/juvenile cortical cataract

VS, vestibular schwannomas.

There may be significant heterogeneity in the presentation of the disease from one individual to the next. Some individuals may have a very mild form of the disease with small vestibular schwannomas manifesting in an older individual. Meanwhile, some children present with multiple intracranial tumors at a very young age. Despite the heterogeneity of the disease within a family, the expression of NF2 tends to be very similar.² There is a significant genetic component to the disease with much variability within the parameters of the observed phenotype. Studies have shown that a truncating mutation (nonsense and frame shift) may be linked with a more severe form of NF2.³^–⁵ The more severe form of NF2 is termed Wishart form. Individuals with this severe form present with early onset of the disease with multiple intracranial schwannomas and meningiomas that result in blindness, deafness, paralysis, and death by age 40. Despite the strong genotype-phenotype correlation, individual differences in tumor growth occur within subjects, making it difficult to predict how an individual will change over time even when the genotype is known.

The milder form, or Gardner form, of NF2 is less debilitating. The schwannomas may remain stable for many years, few meningiomas develop, and patients may not develop symptoms until later in life and often have fewer disabilities. The genetic basis of the mild form has not been well characterized. Many of these may be mosaic forms of the disease, however.^2-^4,^6-¹²

Prevalence and Incidence

The average age of diagnosis of NF2 is 25 years; however, many patients present with symptoms before the diagnosis. There is an average delay of diagnosis of approximately 7 years (Fig. 57-1). There is no difference in the proportion of men versus women who develop NF2, and no prevalence has been described based on ethnicity. Epidemiologic studies place the incidence of NF2 between 1 in 40,000 live births¹³ and 1 in 87,410 live births.¹⁴

FIGURE 57-1 Time from first symptoms to first surgery.

Imaging Studies

All patients suspected to have NF2 should have a high-quality magnetic resonance imaging (MRI) scan performed with thin cuts through the internal auditory canal (IAC). All patients diagnosed with a unilateral vestibular schwannoma should have a dedicated IAC series to ensure there is not another tumor on the opposite side. Patients diagnosed with NF2 should have a complete spine series to evaluate the spine and stage the disease. Small spinal tumors commonly may be found in the cauda equina area, and occasionally a large asymptomatic schwannoma or meningioma may be found in the spine that could require treatment. Early treatment of spine tumors can significantly reduce the mortality associated with these tumors. Older patients who present with bilateral IAC tumors must be worked up for other carcinomas. It is unusual for patients older than 40 years to present with NF2, although with more sensitive MRI scanning techniques, more of these individuals are being diagnosed at an older age. Metastasis may rarely manifest with bilateral IAC lesions, and it is important that carcinoma be ruled out in any patient older than 40 years who presents with bilateral IAC lesions.

A patient identified with NF2 should have a complete cranial MRI scan with cervical thoracic and lumbar spinal imaging. This scan serves as a baseline. A 6-month follow-up MRI scan is recommended for the intracranial tumors. If the tumors exhibit stability, a yearly MRI scan is performed on the intracranial structures. Large tumors in the spine may be monitored with a similar frequency. If no spinal tumors are present, spinal imaging should be performed if the patient becomes symptomatic. Monitoring spinal tumors every 3 years is recommended when these are present. Intracranial imaging is performed on a yearly basis unless studies over several years indicate stability of the tumors.

The NF2 gene was mapped to chromosome 22 q 12-2in 1993.¹⁵^–¹⁷ The NF2 gene located at chromosome 22 codes for a tumor suppressive protein termed Merlin or Schwannomin. This protein negatively regulates Schwann cell production. The loss of this protein allows overproduction of Schwann cells. The mutation in the NF2 chain predisposes individuals to developing a schwannoma when the second hit occurs to the gene; control of Schwann cells is lost or mutated within the cell. Various types of mutations have been identified, including single base substitutions, insertions, and deletions.^4,¹⁸^–²⁰ The mild, or Gardner, type of NF2 may be associated with missense mutations, whereas associations between the other mutations and phenotypes are not as clear.²¹ The occurrence of NF2 is not restricted to families known to carry the mutation. Frequently, genetic mosaicism occurs, which may not be detected by common mutation analysis techniques.²² Unilateral vestibular schwannomas may exhibit the same type of genetic markers as NF2.²³ The mutations in unilateral vestibular schwannomas are confined to the affected tumor tissue. In patients with NF2, the mutation is present in all cell types.²²

Family History

NF2 is an autosomal dominant disease, and 50% of children of affected individuals are at risk for developing the disease. Of patients in whom NF2 is diagnosed, 50% present with a family history of NF2. Half of all NF2-affected patients have no family history of NF2 and are considered founder cases. NF2 presentation and phenotype tend to be similar within families. The likelihood of NF2 occurring in related individuals who do not exhibit similar clinical symptoms to an affected family member is small. Consideration must still be given to screening these individuals for risks despite the lack of clinical symptoms. Individuals at risk for developing NF2 must be screened to provide an early diagnosis. Individuals at risk include children of NF2-affected patients and their siblings. Fifty percent of all children of NF2 patients are found to have the disease. Siblings of a diagnosed NF2 patient are at risk, especially if the parent also has NF2.

The type of screening and timing of screening depend on each NF2 center’s preference. Early screening is advocated so that tumors may be diagnosed presymptomatically. Screening may occur via MRI or genetic blood testing.

Screening

MRI screening of potentially affected individuals uses a postcontrast T1-weighted sequence of the full head with thin cuts through the IAC. A dedicated IAC MRI scan identifies most NF2 patients by showing any vestibular schwannomas. Screening of the spine and ophthalmologic examination should be considered if the cranial MRI scan is positive. An audiogram (pure tone thresholds) or current clinical standard auditory brainstem response (ABR) testing is likely to miss small vestibular schwannomas. MRI can diagnose presymptomatically.

Identification of the NF2 gene and chromosome 22 has made genetic testing possible. It is recommended that patients with NF2 see a genetic counselor to discuss the hereditary consequences of the disease. Blood testing for the mutation is able to identify the defect of the NF2 gene in approximately 70% to 75% of patients with a known diagnosis of NF2. If the defect is identified in the affected individual, potential family members may be screened. If the gene is not identified in the affected individuals, blood screening of family members cannot be performed. The use of blood screening for patients without a diagnosis of NF2 or with a suspected diagnosis of NF2 is not recommended. New mutations in patients with mild presentation are most likely to be missense mutations, and this is difficult to identify with genetic testing of NF2 patients.

Tumor Types

Bilateral vestibular schwannomas (acoustic neuromas) are benign neoplasms of the acoustic or eighth cranial nerve (Fig. 57-2).²⁴ The tumors are thought to arise at the glioma–Schwann’s cell junction within the internal auditory meatus. The tumors most commonly arise from the superior vestibular nerve, although with NF2, tumors may be found on the cochlear and facial nerves within the internal auditory meatus. The consequences of a vestibular schwannoma are numerous, including hearing loss progressing to deafness, dizziness and balance problems, tinnitus, facial nerve paralysis, brainstem compression, and, if left untreated, death.