Approach Considerations
Genetic analysis for disease-causing mutations of neurofibromatosis type 2 (NF2) is clinicially available. Detection rates for molecular-based testing approaches 72% in simplex cases; therefore, such testing has some inherent limitations when trying to confirm a diagnosis of NF2. However, for a patient with suspected NF2 who is still young, has a negative family history, and may eventually develop additional criteria, the identification of a specific mutation may be very helpful.
In light of the high rate of somatic mosaicism in sporadic cases of NF2 (perhaps as many as 25%), molecular testing of tumor tissue may augment traditional molecular studies when analysis of deoxyribonucleic acid (DNA) obtained from blood lymphocytes is nondiagnostic.
The UK NF2 Genetic Severity Score (GSS) provides useful genetic-phenotype correlations with potential for further clinical use: [24, 25]
-
Type 1: Mild: mosaic for mutations only found in tumor, not blood
-
Type 2a: Mild: missense variants, exon 1 and 13/14 truncating, splicing 7-15, mosaic for variants except in 2b in blood
-
Type 2b: Moderately severe: large deletions, splicing variants exons 1-6, mosaic for truncating variants (exon 2-13) in blood
-
Type 3: Severe: truncating mutations exons 2-13
Type 3 is the most severe gradation, with early childhood onset, a high frequency of meningiomas, and early mortality. [24, 25] In addition, a higher growth rate of vestibular schwannomas is associated with higher gradation. [26]
Imaging studies and auditory, ophthalmic, and histologic examinations are also important in the diagnosis and management of NF2.
Genetic Studies
Attempts to increase the detection rate of NF2 mutations have met with some success by using a variety of technologies. Denaturing high-performance liquid chromatography has shown promise in identifying more point mutations in affected individuals, and, when used in conjunction with multiplex ligation-dependent probe amplification, may uncover NF2 gene rearrangements. The addition of a third technique, high-resolution melting analysis, rounds out the new molecular armamentarium, which enables exons to be more efficiently scanned, thereby further improving the detection rate by uncovering additional point mutations. [27]
For families with asymptomatic, at-risk members, the application of molecular testing is viewed from a slightly different perspective. Once the clinical diagnosis has been established unequivocally in a given individual, he or she could be offered direct molecular analysis to see if a mutation can be identified. If a mutation were found, then other asymptomatic family members might benefit from presymptomatic testing to see who would and who would not develop neurofibromatosis type 2 (NF2). Screening and surveillance recommendations would then be based on the results of this testing and, if a sibling or child of an affected person were found not to carry the mutation, he or she would need not be concerned about developing NF2 in the future.
For families in which no mutation can be identified in a known affected individual, linkage analysis or indirect genetic testing methods may be utilized. However, this requires cooperation on the part of the family, as well as DNA samples from multiple affected and unaffected individuals. Even utilizing the best technology available, diagnostic uncertainty may remain, depending on the geographical relationship between the genetic markers and the disease-causing gene. On the other hand, with advances that have taken place in genetic mapping and the likelihood of finding informative markers close to or within the gene itself, linkage analysis remains an excellent choice for determining risk from a molecular standpoint.
For a parent who has NF2, prenatal testing can be done on amniocytes or chorionic villi, either through direct gene mutation analysis when such a change has been identified or through linkage analysis. Prenatal testing may not be possible if the affected parent is the first affected person in the family and a mutation cannot be found. For an affected parent with a known mutation, preimplantation genetic diagnosis may be possible if the couple is willing to undergo in vitro fertilization with transfer of unaffected embryos.
One note of caution must be made in light of advances in molecular genetic technology. Presymptomatic testing of at-risk family members requires a vigorous informed consent process and might best be done during a genetic counseling session at a cancer, genetic, or neurofibromatosis center that specializes in such matters. This is of even greater concern when considering testing of minors, in whom the potential harm must be weighed against medical benefit.
Since aggressive medical surveillance can still be implemented in the absence of a definitive diagnosis and no preventive or curative measures are currently available, the decision to undergo presymptomatic testing for this adult-onset disease is a personal one that must be made after a frank and complete discussion with health professionals.
Imaging Studies
Radiography
Plain films of the spine may be helpful in evaluating scoliosis but are of limited value in looking for spinal cord tumors that may occur in NF2.
Magnetic resonance imaging
Magnetic resonance imaging (MRI) remains the mainstay for diagnosis and screening of CNS, cranial nerve, and spinal cord tumors (see the images below). At-risk individuals may be monitored for CNS tumors beginning in their teens, with annual MRI scans of the head performed through their late 50s. Clear molecular diagnosis may help to modify risks for family members and prevent unnecessary testing for asymptomatic individuals who are found not to carry a gene mutation.
Multiple meningiomas (on the left) on the surface of the brain in a patient with neurofibromatosis type 2.
Bilateral acoustic neuromas and a left-sided meningioma in a patient with neurofibromatosis type 2.
MRI using 3-dimensional (3D) volumetrics is now the preferred method for following vestibular schwannoma growth over time. [2]
MRI of the spine is indicated diagnostically when an individual presents with motor or sensory changes suggestive of a spinal cord lesion or lesions. The key point here is early detection, which may result in prompt action and provide a better outcome. However, routine MRI imaging of the spinal cord probably is not indicated for asymptomatic affected or at-risk individuals.
Although whole body MRI is often utilized within clinical trials, its use within clinical practice is still being defined. Short-tau inversion recovery (STIR) sequences have been particularly useful for the detection of whole body tumor burden. [28]
Auditory Evaluation
Hearing evaluations, including brainstem auditory-evoked response (BAER), are important in the identification of early hearing loss and may demonstrate latency abnormalities before a mass is detectable on MRI. In light of this, auditory screening on an annual basis may be quite useful in asymptomatic or presymptomatic individuals.
Once a vestibular schwannoma is identified, full audiometry testing, including acoustic reflex testing as well as BAER, is useful as a means of monitoring disease progression. Clinical experience clearly indicates that the size of the vestibular tumor often does not correlate with the degree of hearing loss. The Response Evaluation in Neurofibromatosis and Schwannomatosis International Collaboration (REiNS) found the Self-Assessment of Communication adult and adolescent forms for the assessment of patient-reported hearing function and quailty of life to be the most useful and recommends them for use in NF2 clinical trials. [29]
Ophthalmic Examination
Dilated eye examinations are an important part of the care of affected individuals because they are at a risk for developing visually significant cataracts or retinal lesions. As a diagnostic test, an eye examination for lens opacities, retinal hamartomas, or epiretinal membranes may be quite useful even in a child at risk for neurofibromatosis type 2 (NF2). In fact, juvenile cataracts, as the name implies, frequently occur in children and may be seen long before there is any evidence of vestibular schwannomas.
For children and adults with NF2, annual eye examinations are recommended, since unrecognized visual impairment can further interfere with activities of daily living, especially in an individual with concomitant hearing loss.
Histologic Findings
Unlike the tumors associated with neurofibromatosis type 1 (NF1), those found in neurofibromatosis type 2 (NF2) are usually made up of 1 of 3 cell types—Schwann cells, glial cells, or meningeal cells. Although the tumors in NF2 can be locally invasive and cause significant morbidity as a result of their growth properties, they rarely, if ever, undergo malignant transformation. This is somewhat different than in NF1, in which plexiform neurofibromas occasionally develop into neurosarcomas.
However, vestibular schwannomas and meningiomas in NF2 tend to be more aggressive than they are in cases of sporadic tumors (ie, those not related to NF2), with a tendency for more extensive local invasion and with histologic evidence of increased mitoses.
-
Subcutaneous and cutaneous lesions in a young man with neurofibromatosis type 2; note paucity of cafe-au-lait spots.
-
Right neck mass in a patient with neurofibromatosis type 2.
-
Facial asymmetry, OS proptosis, and exotropia, as well as several subcutaneous lesions on the forehead and face, in a 20-year-old man with neurofibromatosis type 2.
-
Posterior cervical scar from cord lesion resection, thoracic scoliosis, and subcutaneous masses in a young adult with neurofibromatosis type 2.
-
Meningioma to the left of midline in a patient with neurofibromatosis type 2.
-
Multiple meningiomas (on the left) on the surface of the brain in a patient with neurofibromatosis type 2.
-
Bilateral acoustic neuromas in a patient with neurofibromatosis type 2.
-
Bilateral acoustic neuromas and a left-sided meningioma in a patient with neurofibromatosis type 2.
-
Small ependymoma in a patient with neurofibromatosis type 2.
-
Multiple meningiomas in a patient with neurofibromatosis type 2.
