Neurofibromatosis 2

Introduction

Neurofibromatosis 2 (NF2) is a rare syndrome characterized by bilateral vestibular schwannomas, multiple meningiomas, cranial nerve tumors, spinal tumors, and eye abnormalities. NF2 presents unique challenges to the otologist because hearing loss may be the presenting complaint leading to the diagnosis of the disorder. NF2 is quite invasive, requiring a multispecialist team approach for the evaluation and treatment of the disorder. The primary impairment is hearing loss resulting from bilateral vestibular schwannomas. NF2 must be differentiated from neurofibromatosis 1 (NF1); although the names are linked, the disease entities are distinctly different. This chapter reviews the clinical characteristics of NF2 and the current recommendations for evaluation and treatment.

Neurofibromatosis 2 Differentiated from Neurofibromatosis 1

NF1 has distinctly different characteristics from NF2. NF1 and NF2 have been differentiated as completely different genetic diseases based on the chromosome responsible for the disease. NF1 has been localized to chromosome 17 and NF2 to chromosome 22.

NF1 is a multisystem disorder in which some features may be present at birth and others are age-related manifestations. A National Institutes of Health (NIH) Consensus Development Conference identified the following seven features of the disease, of which two or more are required to establish the diagnosis of NF1:

• • Six café-au-lait spots equal to or greater than 5 mm in the longest diameter in prepubertal patients and 15 mm in the longest diameter in postpubertal patients

  • Two or more neurofibromas of any type or one plexiform neurofibroma

  • Freckling in the axilla or inguinal regions

  • Optic glioma (optic pathway glioma)

  • Two or more Lisch nodules (iris hamartoma)

  • Distinct osseous lesions, such as sphenoid wing dysplasia or cortical thinning of the cortex of long bones with or without pseudoarthrosis

  • First-degree relative (parent, sibling, or child) with NF1 according to the above-listed criteria

Some patients also manifest learning disabilities or language disorders. A careful examination and a detailed history of the patient’s symptoms help distinguish NF1 and NF2.

Clinical Characteristics of Neurofibromatosis 2

The NIH Consensus Development Conference also developed guidelines for the diagnosis of NF2. NF2 is distinguished by bilateral vestibular schwannomas with multiple meningiomas, cranial nerve tumors, optic gliomas, and spinal tumors. A definite diagnosis is made on the basis of the presence of bilateral vestibular schwannomas or developing a unilateral vestibular schwannoma by age 30 years and a first-degree blood relative with NF2, or the presence of a unilateral vestibular schwannoma and developing at least two of the following conditions known to be associated with NF2: meningioma, glioma, schwannoma, or juvenile posterior subcapsular lenticular opacity or juvenile cortical cataract ( Table 52.1 ).

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, such as small vestibular schwannomas manifesting in an older individual. At the other end of the spectrum, some children present with multiple intracranial tumors at a very young age. Despite the heterogeneity of the disease, the expression of NF2 tends to be very similar within a family. 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. ^, Individuals with the severe form present with early onset of the disease with multiple intracranial schwannomas and meningiomas that result in blindness, deafness, paralysis, and possible death by age 40. Despite the strong genotype-phenotype correlation seen in NF2, individual differences in tumor growth occur within subjects, making it difficult to predict how an individual’s tumors will change over time even when the genotype is known. The milder form of NF2 is less debilitating. Schwannomas may remain stable for many years, few meningiomas develop, and patients may not develop symptoms until later in life and often have fewer associated disabilities. The genetic basis of the mild form has not been well characterized. Many of these may be mosaic forms of the disease.

Prevalence and Incidence of Neurofibromatosis 2

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. 52.1 ). 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 25,000 live births and 1 in 87,410 live births.

Imaging Studies for Neurofibromatosis 2

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 no contralateral tumor on the opposite side. Patients diagnosed with NF2 should have a complete spine series to evaluate the spine. A full spine MRI series and a head MRI with thin cuts through the IAC allow the clinician to 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 morbidity 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 initially identified with NF2 should have a complete cranial MRI scan with cervical, thoracic, and lumbar spinal imaging. These MRI scans serve as baseline studies. 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 every 3 to 5 years given the risk of developing tumors in the future. Monitoring spinal tumors every 3 years is recommended when they are stable and asymptomatic. Intracranial imaging is performed yearly unless studies over several years indicate stability of the tumors.

Molecular Genetics of Neurofibromatosis 2

The NF2 gene was mapped to chromosome 22 q 12-2 in 1993. 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 the 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. ^{, ,} The mild type of NF2 may be associated with missense mutations, whereas associations between the other mutations and phenotypes are not as clear. 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. Unilateral vestibular schwannomas may exhibit the same type of genetic markers as does NF2. 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.

Family History of Neurofibromatosis 2

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 low. 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 patients with NF2 are found to have the disease. Siblings of a diagnosed patient with NF2 are at risk, especially if the parent also has NF2. The type and timing of screening depend on each NF2 center’s preference. Early screening is advocated so that tumors may be diagnosed before the patient is symptomatic. Screening may occur via MRI or genetic blood testing.

Screening for Neurofibromatosis 2

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 ophthalmological 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 NF2 before symptoms present. MRI is recommended for at-risk children when this test can be performed without sedation; this can usually be done when the child is 7 to 9 years old. A recommended first step for children younger than 7 years is an audiogram. Any child with an NF2-associated symptom, such as hearing loss or facial weakness, should be screened without regard to the need for sedation or age; MRI should be performed as soon as possible after the symptoms become apparent. 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. The best molecular testing is performed on fresh vestibular schwannoma tissue or other NF2 tumor tissue. Any patient with a planned vestibular schwannoma removal should be offered the opportunity to have his or her tumor tissue tested for the genetic mutation. This is the most sensitive test, and it allows identification of the genetic mutation in most cases. The results of this test can then be used to screen relatives for NF2. There are currently two clinical laboratories that perform this test (Massachusetts General and University of Alabama), and there are many research laboratories associated with NF centers that may perform the test on recently resected tissue. The tissue must be kept frozen, and testing should be coordinated with the laboratories before surgical resection.

Schwannoma Tumor Types

Bilateral vestibular schwannomas (acoustic neuromas) are benign neoplasms of the acoustic or eighth cranial nerve ( Fig. 52.2 ). The tumors are thought to arise at the glial-Schwann 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. Despite the strong genetic effect in NF2, there is enormous variability in the number of tumor types, rate of progression, and disabilities experienced. This enormous variability is also found in patient presentation ( Table 52.2 ). Some patients may be asymptomatic. Patients who have no symptoms when diagnosed have generally been identified on the basis of genetic analysis conducted because a blood relative has NF2 or presymptomatic screening.

Although the NIH criteria for NF2 require the presence of bilateral vestibular schwannomas for diagnosis, patients may first develop unilateral schwannomas as a young child with no other tumors, or adult patients may present with multiple meningiomas (cranial and spinal) and no vestibular schwannomas. ^, Although the NIH criteria for NF2 imply that all NF2 patients develop bilateral vestibular schwannomas, some researchers are not convinced of this. Evans et al. based their conclusion on the observation of a possible variant form of NF2 manifesting with skin and spinal tumors in the absence of vestibular schwannomas. Nonetheless, the phenotype is generally reflective of the underlying disorder. The natural history study of vestibular schwannomas in NF2 study conducted at the House Ear Institute showed that 10 of 80 (12.5%) enrolled subjects had no symptoms at diagnosis, and 23 (28.8%) had cranial meningiomas and spinal meningiomas in addition to bilateral vestibular schwannomas. Nearly half (47.5%) had one vestibular schwannoma removed before enrollment. Generally, the tumor resected before enrollment was removed 1.5 years after discovery and was an average of 2.1 cm in diameter at removal. Few patients in the natural history study had spinal tumors or meningiomas removed before enrollment. The preliminary data would indicate that, for this sample of NF2 subjects, the most salient medical issue is the growth of the vestibular schwannomas.

Hearing Changes in Patients with Vestibular Schwannomas

Hearing loss is well documented as the most common presenting symptom in patients who have vestibular schwannomas. Auditory changes over time in vestibular schwannoma patients are less well known. Direct compression or invasion of the cochlear nerve by the growing tumor is one of the most commonly cited mechanisms. Rosenberg studied the natural history of 80 patients with non-NF2 unilateral vestibular schwannomas for an average of 4.4 years, finding a positive correlation between tumor growth and worsening pure-tone average. There was no statistically significant correlation, however, between positive tumor growth and speech discrimination, change in ABR, and bithermal caloric electronystagmography test result over time.

Lalwani et al. reported that pure-tone pattern speech receptive thresholds and word recognition scores were significantly poorer in NF2 patients who had a mild form of NF2 and large tumors compared with patients with mild NF2 with small tumors. The loss of acoustic reflexes and prolonged wave III and V were also associated with larger tumors. In contrast, patients with severe NF2 showed no relationship among tumor size and pure-tone levels, speech discrimination thresholds, or word recognition scores. The lack of association may have been due to complete loss of hearing in patients with severe NF2 at the time of the assessment. The larger tumors were also associated with prolonged ABR waves III and V latencies. No data across time were reported. Generally, hearing is progressively impaired with increasing growth of vestibular schwannomas necessitating the need for surgical intervention or medical treatments in NF2 patients. Another hearing loss mechanism that has been suggested is cochlear end organ damage. Asthagiri et al. reported MRI findings in 84 patients with NF2 and found abnormalities on fluid attenuated inversion recovery (FLAIR) sequences indicative of increased intralabyrinthine protein levels and cochlear aperture obstruction in ears with hearing loss. These abnormalities had a sensitivity of 94% and a negative predictive value of 91% in predicting hearing loss.

The natural history study evaluated hearing changes prospectively in 63 patients newly diagnosed with NF2 and found that hearing was stable after diagnosis. During the first 2 years after diagnosis, 27% of patients had a significant change in their hearing, and 73% had very stable hearing during the 2-year period. Patients with a family history of NF2 had more stable hearing after an initial diagnosis compared with patients without a family history. Patients with a family history are usually diagnosed at a younger age; the stability of hearing in this group may represent the younger age group. The better the hearing in the newly diagnosed patients, the more stable the hearing. Hearing changes did not vary between ears, with each ear acting independently.