eMedicine Specialties > Neurology > Pediatric Neurology

Neurofibromatosis, Type 2: Differential Diagnoses & Workup

Author: Beth A Pletcher, MD, Associate Professor, Co-Director of The Neurofibromatosis Center of New Jersey, Department of Pediatrics, University of Medicine and Dentistry of New Jersey
Contributor Information and Disclosures

Updated: Dec 10, 2008

Differential Diagnoses

Brainstem Gliomas
Ependymoma
Meningioma
Neurofibromatosis, Type 1

Other Problems to Be Considered

Juvenile cataracts
Multiple meningiomas
Schwannomatosis

Workup

Laboratory Studies

• Now that the gene for neurofibromatosis type 2 (NF2) has been identified, analysis for disease-causing mutations can be offered in some clinical settings. Detection rates for molecular-based testing approaches 65%; 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 DNA obtained from blood lymphocytes is nondiagnostic.
• Recent attempts to increase the detection rate of NF2 mutations have met with some success by using a variety of newer 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.³
• 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 is found, then other asymptomatic family members may benefit from presymptomatic testing to see who will and who will not develop 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 was found not to carry the mutation, he or she 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 the recent advances in genetic mapping and 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 whether to undergo presymptomatic testing for this adult-onset disease is a personal one that must be made after a frank and complete discussion with knowledgeable 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.
  • In general, MRI is the preferred technique for monitoring individuals with NF2 who have symptoms of spinal cord lesions.
• MRI
  • MRI remains the mainstay for diagnosis and screening of CNS, cranial nerve, and spinal cord tumors (see Media files 5-10). At-risk individuals may be monitored for CNS tumors beginning in their teens, with annual MRIs of the head done 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.
  • 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.

Other Tests

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.

Procedures

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 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 NF1, those found in NF2 are usually 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 NF1, in which plexiform neurofibromas can and occasionally do develop into neurosarcomas; however, both vestibular schwannomas and meningiomas in NF2 tend to be more aggressive than in cases of sporadic (ie, not related to NF2) tumors, with a tendency for more extensive local invasion and histologic evidence of increased mitoses.

• Search for CME/CE on This Topic »

• Neurofibromatosis (Orthopedic Surgery)
• Neurofibromatosis (Pediatrics: Genetics and Metabolic Disease)
• Neurofibromatosis Type 2 (Radiology)
• Neurofibromatosis (Dermatology)

• Bevacizumab May Improve Hearing in Neurofibromatosis Type 2
• Vascular Endothelial Cell Function Is Impaired in Neurofibromatosis 1 Patients
• Optimal Insulin Dosing Regimen for Type 2 Diabetes Identified

• Meningioma and Mobile Phone use - A Collaborative Case-Control Study in Five North European Countries
• Malignant Pleural Mesothelioma
• Management of Nerve Sheath Tumors Arising in the Sympathetic Chain

• Combination Therapy for Type 2 Diabetes
• Obesity
• Hypogonadism Resource Center