Neurofibromatosis, Type 2

Synonyms and related keywords: bilateral acoustic neurofibromatosis, bilateral acoustic neuroma, central neurofibromatosis, NF2, spinal cord tumor, spinal cord schwannoma, vestibular schwannoma, meningioma, multiple meningiomas, glioma, juvenile cataracts

Author:Beth A Pletcher, MD, Director of Neurofibromatosis Center, Assistant Professor, Department of Pediatrics, University of Medicine and Dentistry of New Jersey

Beth A Pletcher, MD, is a member of the following medical societies: American Academy of Pediatrics, and American College of Medical Genetics

Editor(s): David Griesemer, MD, Chairman of Neurology, Associate Professor, Departments of Pediatrics and Neurology, Medical University of South Carolina; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, Pharmacy, eMedicine; Kenneth J Mack, MD, PhD, Senior Associate Consultant, Department of Child and Adolescent Neurology, Mayo Clinic; Matthew J Baker, MD, Consulting Staff, Collier Neurologic Specialists, Naples Community Hospital; and Nicholas Lorenzo, MD, eMedicine Chief Publishing Officer, Chief Editor, eMedicine Neurology; Consulting Staff, Neurology Specialists and Consultants

Background: Central neurofibromatosis or neurofibromatosis type 2 (NF2) is a multisystem genetic disorder associated with bilateral vestibular schwannomas, spinal cord schwannomas, meningiomas, gliomas, and juvenile cataracts with a paucity of cutaneous features, which are seen more consistently in neurofibromatosis type 1 (NF1). Although quite variable in its age of onset and severity of symptoms in affected individuals, NF2 is associated with significant morbidity and decreased life span. Furthermore, diagnosis in childhood is often difficult because of the absence of central nervous system involvement at a young age.

Pathophysiology: The manifestations of NF2 result from mutations in (or rarely deletion of) the NF2 gene located on the long arm of chromosome 22. The gene product known as merlin serves as a tumor suppressor; decreased function or production of this protein results in a predisposition to develop a variety of tumors of the central and peripheral nervous systems. Half of affected individuals have NF2 as a result of a new (de novo) gene mutation.

Frequency:

• Internationally: The estimated incidence of NF2 is 1 in 37,000 per year, with about half of affected individuals representing first cases in the family as a result of new dominant mutations.

Mortality/Morbidity:

• Vestibular schwannomas are the most common and well-recognized feature of NF2 leading to significant morbidity. Symptoms of tinnitus, gradual hearing loss, and even vestibular dysfunction are frequently the initial signs of NF2. Although unilateral hearing loss is the number one presenting symptom, eventually bilateral deafness would be expected in most affected individuals. Untreated vestibular schwannomas can extend locally and may result in brainstem compression, hydrocephalus, and occasionally facial nerve palsy.

• Dumbbell-shaped spinal cord schwannomas are quite common in NF2 and result in significant morbidity; they present a great therapeutic challenge. Spinal cord ependymomas, astrocytomas, and meningiomas also occur, but less frequently. Intracranial meningiomas, on the other hand, are a frequent finding and may cause a variety of symptoms and CNS deficits.

• Posterior subcapsular or so-called "juvenile cataracts" can predate CNS symptomatology. These cataracts may progress over time, leading to decreased visual acuity. A fair percentage of affected individuals are found to have retinal hamartomas or epiretinal membranes that may or may not be visually significant.

Race: All races and ethnic groups are affected equally with NF2.

Sex: Males and females are affected equally with this autosomal dominant inherited condition.

Age: Although the genetic change causing NF2 is present at conception, the clinical manifestations occur over many years. The typical age of onset of symptoms is in the late teens to early 20s, but the age range covers the entire life span. Some evidence indicates that age of onset of clinical symptoms is lower in maternally transmitted NF2. While NF2 is quite variable in severity from person to person, family studies have shown some intrafamilial consistency in age of onset.

History: Clinical diagnosis of NF2 requires that an individual present with at least 1 of the 3 situations described below. As approximately half of affected persons represent new gene changes, family history is often negative and makes diagnosis all the more difficult.

• Bilateral eighth nerve masses visualized on MRI using thin cuts, with and without gadolinium and on both axial and coronal views

• First-degree relative with documented NF2 and a unilateral eighth nerve mass imaged as already described

• First-degree relative with documented NF2 and at least 2 of the following additional findings:

• Meningioma

• Glioma

• Schwannoma

• Juvenile cataract

Physical: Unlike NF1, which frequently is associated with a number of cutaneous diagnostic clues, NF2 is accompanied by few external signs.

• Presenting symptoms include hearing loss, ringing in the ears, and balance problems associated with vestibular nerve lesions. Individuals at risk for NF2 should be screened carefully for early signs of hearing loss, motor or sensory changes, and visual deficits.

• Differentiating clinically between the relatively common NF1 and the rare NF2 is occasionally problematic. Patients with NF2 almost never have a large number of cafe-au-lait spots (although rarely 6 or more may be seen), whereas cafe-au-lait spots are numerous and ubiquitous in NF1. Neither axillary nor inguinal freckles are common occurrences in NF2.

• Malignant transformation of benign growths is almost unheard of in NF2, unlike NF1. However, individuals with either NF1 or NF2 can develop multiple subcutaneous lesions that may be clinically indistinguishable (see Images 1-4). In NF2 these lesions most often would be defined histologically as schwannomas or neurilemomas, while in NF1 these would be defined histologically as neurofibromas. Subcutaneous neurofibromas are occasional findings in NF2.

• Posterior subcapsular lenticular opacities, even in childhood, would be suggestive of NF2, whereas Lisch nodules would be diagnostic of NF1.

• Finally, although individuals with either NF1 or NF2 can develop dumbbell-shaped spinal cord tumors, schwannomas are common in NF2, whereas neurofibromas are seen primarily in NF1.

Causes:

• NF2 is an autosomal dominant inherited condition caused by decreased production of the protein merlin, which has a putative tumor suppressor function. Affected individuals need only 1 mutated or deleted NF2 gene to exhibit signs of the condition.

• The NF2 gene has been localized to the long arm of chromosome 22; numerous mutations in this gene have been identified, most of which are predicted to result in production of a truncated protein with loss of its usual function.

Brainstem Gliomas
Ependymoma

Meningioma

Neurofibromatosis, Type 1

Other Problems to be Considered:

Juvenile cataracts
Multiple meningiomas
Schwannomatosis

Continuing Education

Patient Education

Lab Studies:

• Now that the gene for NF2 has been identified, analysis for disease-causing mutations can be offered in some clinical settings. Detection rates for molecular-based testing are approximately 65%; therefore, such testing is of limited use in making the diagnosis of NF2. However, in 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 helpful.

• 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 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.

• 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:

• X-rays: 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 and spinal cord tumors (see Images 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 changes. 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 any evidence of vestibular schwannomas is noted. 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.

Medical Care:

• For individuals diagnosed with NF2, medical care consists of routine examinations focusing on some of the potential complications related to CNS or spinal cord lesions. Interval history should focus on subtle motor or sensory symptoms such as paresthesias, radiculopathies, weakness, or muscle atrophy. Unless clinical deterioration occurs, MRI of the head on an annual basis would be reasonable, as would annual eye examinations and auditory screening using BAERs.

• Annual neurologic assessment by a trained specialist is most useful in this clinical setting; the neurologist may detect subtle sensory or motor deficits even before the patient is aware of any difficulties.

• For patients with multiple medical problems associated with NF2, management by a team of specialists through a multidisciplinary clinic may provide the most comprehensive and cost-effective care over time. This is especially important with rapid advances in surgical management including such new tools as stereotactic radiosurgery and brainstem implants.

• For at-risk individuals who do not carry a diagnosis of NF2, such as siblings and offspring of affected persons, optimal screening recommendations are more difficult to establish. However, since early detection of tumors may improve long-term outcome, many reasons exist to consider a program of surveillance and routine screening. For families in which a specific mutation or linkage has been established, at-risk individuals may choose to know for sure whether they are at risk. Even when no diagnostic certainty is possible but an individual's chance of having NF2 is at least 50%, annual focused examinations, accompanied by annual head MRI and hearing evaluation with BAER, seem to be reasonable screening options.

• Although surgical resection of symptomatic tumors represents the most common approach to clinically significant lesions, in some rare instances, radiation and/or chemotherapy may be recommended to treat disabling ependymomas; however, concerns remain regarding additional risks of radiation therapy in a patient with a germline tumor suppressor gene mutation (ie, someone with NF2) as opposed to an individual with an isolated tumor.

Surgical Care:

• Surgical resection of tumors remains the mainstay of treatment in NF2, with recent advances in surgery permitting preservation of hearing for some affected individuals. For small vestibular schwannomas, both surgical resection and stereotactic radiosurgery have been employed and may preserve both hearing and facial nerve function in selected patients. Larger tumors also may require surgical resection despite irreversible hearing loss, especially when evidence is noted of brainstem compression, facial nerve palsy or, in extreme cases, early hydrocephalus. Larger tumors may be approached surgically if a patient has a significant decline in hearing, since a debulking procedure may result in preservation of hearing or, at the minimum, prolongation of auditory decompensation.

• Intracranial meningiomas, on the other hand, may be quite slow growing; surgical resection should be considered only when such lesions are causing serious, disabling symptoms.

• Resection of spinal cord tumors is often quite difficult and the risks and benefits of surgery must be considered on an individual basis. To maximize operative success, acting promptly is important when neurological symptoms appear, yet complete resection of a spinal cord tumor may not always be possible and in some cases serves primarily a palliative function.

• Surgical resection of cutaneous or subcutaneous growths can be accomplished by any competent surgeon, although plastic surgical consultation is advisable for areas of great cosmetic concern, such as the face.

Consultations:

• The neurologist and neurosurgeon work closely in the management of central and spinal cord lesions in NF2. The neurologist provides valuable information regarding any changes in neurological status over time, whereas the neurosurgeon provides insight into optimal timing and approach for surgical intervention.

• The otolaryngologist or otologist is an important consultant in the surgical management of vestibular schwannomas, especially if brainstem implants are being considered. Cochlear implants, on the other hand, have not been as effective in treatment of NF2 as originally hoped and generally are reserved for a small subset of patients with vascular compromise of the cochlea without substantial nerve involvement.

• The audiologist serves as an essential member of the management team for individuals with acoustic nerve lesions. After performing annual hearing evaluations by BAER to quantitate disease progression, he or she can provide advice regarding usefulness of amplification. For many patients, augmentation may permit good sound discrimination well into the course of the disease. The audiologist also may make suggestions regarding any additional services such as speech therapy or classes for lip reading or sign language that may be helpful as hearing deficits increase.

• The ophthalmologist is an important team member and can assist in both the diagnosis and care of the patient with NF2. Early detection of juvenile cataracts is quite helpful in making a diagnosis in an at-risk child with minimal symptomatology. Furthermore, annual follow-up for affected individuals permits early detection and possible intervention for visual loss secondary to lenticular lesions.

• Finally, the geneticist may provide both diagnostic and genetic information to affected and at-risk individuals. For family members who are considering molecular testing, an explanation of risks, benefits, and test reliability to all individuals is essential as part of the informed consent process. Issues of potential insurance discrimination, confidentiality, and privacy need to be discussed in addition to personal perspectives on undergoing such testing before an individual can provide consent. For couples considering prenatal diagnosis for NF2, genetic consultation is recommended.

Activity: Activity restriction is not necessary except as recommended by the neurologist or neurosurgeon on the basis of neurological deficits. However, patients with vestibular schwannomas need to be warned about potential balance problems, which may worsen in an underwater situation. Therefore, these individuals should be advised to never swim alone and to have someone with them at all times if they are diving or snorkeling. If disorientation occurs underwater as a result of the acoustic nerve involvement, such activities may need to be curtailed.

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