Neurofibromatosis 2
Summary
Clinical characteristics.
Neurofibromatosis 2 (NF2) is characterized by bilateral vestibular schwannomas with associated symptoms of tinnitus, hearing loss, and balance dysfunction. The average age of onset is 18 to 24 years. Almost all affected individuals develop bilateral vestibular schwannomas by age 30 years. Affected individuals may also develop schwannomas of other cranial and peripheral nerves, meningiomas, ependymomas, and, very rarely, astrocytomas. Because NF2 is considered an adult-onset disease, it may be underrecognized in children, in whom skin tumors and ocular findings (retinal hamartoma, thickened optic nerves, cortical wedge cataracts, third cranial nerve palsy) may be the first manifestations. Mononeuropathy that occurs in childhood is an increasingly recognized finding; it frequently presents as a persistent facial palsy or hand/foot drop.
Diagnosis/testing.
The diagnosis of NF2 is established in a proband with clinical findings that meet the consensus diagnostic criteria and/or by identification of a heterozygous pathogenic variant in NF2 on molecular genetic testing.
Management.
Treatment of manifestations: Treatment of vestibular schwannoma is primarily surgical; stereotactic radiosurgery, most commonly with the gamma knife, may be an alternative to surgery. Individuals with vestibular tumors need to be aware of insidious problems with balance and underwater disorientation, which can result in drowning. Treatment for hearing loss includes referral to an audiologist, lip-reading and sign language instruction, and possibly hearing aids and/or cochlear or brain stem implants.
Surveillance: For affected or at-risk individuals: annual MRI beginning at approximately age ten to 12 years and continuing until at least the fourth decade of life; hearing evaluation, including BAER testing; annual complete eye examination.
Agents/circumstances to avoid: Radiation therapy of NF2-associated tumors, especially in childhood, when malignancy risks are likely to be substantially larger.
Evaluation of relatives at risk: Early identification of relatives who have inherited the family-specific NF2 pathogenic variant allows for appropriate surveillance, resulting in earlier detection and treatment of disease manifestations.
Genetic counseling.
NF2 is inherited in an autosomal dominant manner. Approximately 50% of individuals with NF2 have an affected parent, and 50% have NF2 as the result of a de novo pathogenic variant. However, 25% to 30% of simplex cases (i.e., single occurrence in a family) are mosaic for an NF2 pathogenic variant. If the proband has other affected family members, each child of the proband has a 50% chance of inheriting the pathogenic variant. Once the NF2 pathogenic variant has been identified in the family, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.
Diagnosis
Suggestive Findings
Neurofibromatosis type 2 (NF2) should be suspected in individuals with the following findings:
In children (two or more of these findings)
- A schwannoma at any location including intradermal
- Skin plaques present at birth or in early childhood (often plexiform schwannoma on histology)
- A meningioma, particularly non-meningothelial (non-arachnoidal) cell in origin
- A cortical wedge cataract
- A retinal hamartoma
- A mononeuropathy, particularly causing a facial nerve palsy, foot or wrist drop, or third nerve palsy
In adults
- Bilateral vestibular schwannomas
- Unilateral vestibular schwannoma accompanied by ANY TWO of the following: meningioma, schwannoma, glioma, neurofibroma, cataract in the form of subcapsular lenticular opacities or cortical wedge cataract
- Multiple meningiomas accompanied by EITHER of the following:
- Unilateral vestibular schwannoma
- ANY TWO of the following: schwannoma, glioma, neurofibroma, cataract in the form of subcapsular lenticular opacities or cortical wedge cataract
For individuals of all ages with any of these clinical findings, having a first-degree relative with NF2 increases the likelihood of the disorder being present.
Establishing the Diagnosis
The diagnosis of NF2 is established in a proband with clinical findings that meet the consensus diagnostic criteria and/or by identification of a heterozygous pathogenic variant in NF2 on molecular genetic testing (see Table 1).
Clinical Findings
By the modified NIH consensus diagnostic criteria [Baser et al 2002], NF2 is diagnosed in individuals with ONE of the following:
- Bilateral vestibular schwannomas
- A first-degree relative with NF2 AND
- Unilateral vestibular schwannoma OR
- ANY TWO of the following: meningioma, schwannoma, glioma, neurofibroma, cataract in the form of posterior subcapsular lenticular opacities or cortical wedge cataract
- Unilateral vestibular schwannoma AND ANY TWO of the following: meningioma, schwannoma, glioma, neurofibroma, cataract in the form of posterior subcapsular lenticular opacities or cortical wedge cataract
- Multiple meningiomas AND
- Unilateral vestibular schwannoma OR
- ANY TWO of the following: schwannoma, glioma, neurofibroma, cataract in the form of posterior subcapsular lenticular opacities or cortical wedge cataract
Note: Those with suspicious findings should have molecular genetic testing.
Molecular Genetic Testing
Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (chromosomal microarray analysis, exome sequencing, exome array, genome sequencing) depending on the phenotype.
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of NF2 is broad, individuals with the distinctive findings described in Suggestive Findings and adults who meet the consensus diagnostic criteria described in Establishing the Diagnosis are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of NF2 has not been considered (especially in children) or those who do not fulfill the consensus diagnostic criteria are more likely to be diagnosed using genomic testing (see Option 2).
Option 1. When the phenotypic and laboratory findings suggest the diagnosis of NF2, molecular genetic testing approaches can include single-gene testing, chromosomal microarray analysis (CMA), or use of a multigene panel:
- Single-gene testing. Sequence analysis of NF2 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected.Perform sequence analysis first. If no pathogenic variant is found perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
- Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including NF2) that cannot be detected by sequence analysis.
- A multigene panel that includes NF2 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2. When the diagnosis of NF2 is not considered because an individual has atypical phenotypic features (features in a child may not immediately suggest NF2) or does not meet the clinical consensus diagnostic criteria as an adult, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is the most commonly used genomic testing method; genome sequencing is also possible. Exome array (when clinically available) may be considered if exome sequencing is not diagnostic, to evaluate for a large deletion/duplication type of variant in NF2.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in Neurofibromatosis Type 2 (NF2)
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| NF2 | Sequence analysis 3 | 75% 4 |
| Gene-targeted deletion/duplication analysis 5, 6 or CMA 7 | 20% 8 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
Halliday et al [2017]
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 6.
Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes may not be detected by these methods.
- 7.
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including NF2) that cannot be detected by sequence analysis. The ability to determine the size of the deletion/duplication depends on the type of microarray used and the density of probes in the 22q12.2 region. CMA designs in current clinical use target the 22q12.2 region.
- 8.
Smith et al [2016]
Testing for somatic mosaicism. Somatic mosaicism is frequent in NF2. As many as 25% to 33% of individuals with a de novo pathogenic NF2 variant have somatic mosaicism for the variant [Kluwe et al 2003, Mohyuddin et al 2003, Evans et al 2007b, Evans et al 2013].
Such individuals may have normal molecular genetic testing of NF2 in unaffected tissue, such as lymphocytes; thus, molecular genetic testing of tumor tissue may be necessary to establish the presence of somatic mosaicism [Mohyuddin et al 2002, Evans et al 2007b].
When tumor DNA is tested, pathogenic variants in both NF2 alleles must be identified:
- This may mean testing for loss (or inactivation) of one NF2 allele by assessing for loss of heterozygosity.
- Once both variant NF2 alleles are identified in the tumor, leukocyte DNA can be tested to determine which of the pathogenic variants is constitutional and which is somatic (i.e., present in the tumor only).
Clinical Characteristics
Clinical Description
The average age of onset of findings in individuals with neurofibromatosis 2 (NF2) is 18 to 24 years (onset range: birth to 70 years). Almost all affected individuals develop bilateral vestibular schwannomas by age 30 years. In addition to vestibular schwannoma, individuals with NF2 develop schwannomas of other cranial and peripheral nerves, meningiomas, ependymomas, and (very rarely) astrocytomas.
Variable expressivity of NF2 among individuals results in varying size, location, and number of tumors. Although these tumors are not malignant, their anatomic location and multiplicity lead to great morbidity and early mortality. The average age of death is 36 years. Actuarial survival from the time of establishing the correct diagnosis is 15 years. Survival is improving with earlier diagnosis and better treatment in specialty centers [Baser et al 2002, Evans et al 2005a, Hexter et al 2015].
Because NF2 is considered an adult-onset disease, it may be underrecognized in children, in whom skin tumors and ocular findings may be the first manifestations [Evans et al 1999, Ruggieri et al 2005, Ruggieri et al 2016].
The presenting symptoms of 120 individuals with NF2 studied by Evans et al [1992] in Great Britain are listed in Table 2. Although individuals in this study were mostly adults, some children were included. The study did not include as a first symptom skin tumors or cataracts, either of which may be the earliest finding in children.
Table 2.
Presenting Symptoms of 120 Individuals with NF2
| Symptom | % of Affected Individuals |
|---|---|
| Unilateral hearing loss | 35% |
| Focal weakness 1 | 12% |
| Tinnitus | 10% |
| Bilateral hearing loss | 9% |
| Balance dysfunction | 8% |
| Seizure | 8% |
| Focal sensory loss | 6% |
| Blindness | 1% |
| No symptom, but detected on screening because a parent was affected | 11% |
Adapted from Evans et al [1992]
- 1.
Can result from spinal tumors, mononeuropathy, or polyneuropathy
Presenting Features of NF2 in Childhood
Skin findings include intradermal plaque-like tumors that often have excess hair and skin pigmentation.
Ocular findings include [Evans et al 2005a, Feucht et al 2008, Ruggieri et al 2016]:
- Retinal hamartoma
- Thickened optic nerves
- Cortical wedge cataracts that may be congenital and associated with amblyopia
- Third cranial nerve palsy
Other
- A mononeuropathy (e.g., a facial nerve palsy, foot or wrist drop) with no obvious tumor cause
- An isolated meningioma, or a schwannoma at any site [Evans et al 1999, Perry et al 2001, Pathmanaban et al 2017]
Details of Typical Clinical Findings in NF2
Vestibular schwannoma. Initial symptoms include tinnitus, hearing loss, and balance dysfunction. Onset of disability is usually insidious, although occasionally hearing loss may occur suddenly, presumably as a result of vascular compromise by the tumor. Affected individuals often report difficulty in using the telephone in one ear or unsteadiness when walking at night or on uneven ground.
With time, vestibular tumors extend medially into the cerebellar pontine angle and, if left untreated, cause compression of the brain stem and hydrocephalus. Significant facial palsy is rare even in large tumors.
Schwannomas may also develop on other cranial and peripheral nerves, with sensory nerves more frequently affected than motor nerves.
Children and young adults with an apparently isolated vestibular or other cranial nerve schwannoma should be considered at risk for de novo and often mosaic NF2 [Pathmanaban et al 2017].
Spinal tumors. At least two thirds of individuals with NF2 develop spinal tumors, which are often the most devastating and difficult to manage [Dow et al 2005]. The most common spinal tumors are schwannomas, which usually originate within the intravertebral canal on the dorsal root and extend both medially and laterally, taking the shape of a "dumbbell." Intramedullary tumors of the spinal cord, such as astrocytoma and ependymoma, occur in 5% to 33% of individuals with NF2. Most persons with spinal cord involvement have multiple tumors. Although multiple tumors are often present on imaging studies, they remain asymptomatic in many individuals.
Meningioma. Approximately half of individuals with NF2 have meningiomas in cross-sectional studies [Goutagny & Kalamarides 2010]; however, lifetime risk may approach 80% [Smith et al 2011]. Most are intracranial, although spinal meningiomas occur. NF2 meningiomas tend to occur less frequently in the skull base than supratentorially and are usually of the fibroblastic variety [Evans et al 2000, Kros et al 2001]. Meningiomas in the orbit may compress the optic nerve and result in visual loss. Those at the skull base may cause cranial neuropathy, brain stem compression, and hydrocephalus.
See Genotype-Phenotype Correlations.
Ocular involvement. One third of individuals with NF2 have decreased visual acuity in one or both eyes. Posterior subcapsular lens opacity – rarely progressing to a visually significant cataract – is the most common ocular finding. Lens opacities may appear prior to the onset of symptoms from vestibular schwannoma and can be seen in children.
Retinal hamartoma and epiretinal membrane are seen in up to one third of individuals. Rarely, other ocular manifestations may occur: persistent hyperplastic primary vitreous has been reported in a father and son [Nguyen et al 2005]. In adulthood, particular problems with the cornea can occur especially after surgery, resulting in the loss of facial, trigeminal, and intermedius nerve function.
Intracranial and intraorbital tumors may result in decreased visual acuity and diplopia.
Mono-/polyneuropathy. A recognized feature of NF2 is a mononeuropathy occurring particularly in childhood [Evans et al 1999] and frequently presenting as a facial palsy that usually only partially recovers, a squint (3rd nerve palsy), or a foot or hand drop. The foot drop may mimic polio.
A progressive polyneuropathy of adulthood not directly related to tumor masses is also recognized [Sperfeld et al 2002].
Further evidence for the mononeuropathy of childhood and the polyneuropathy of adulthood has come from sural nerve biopsies [Hagel et al 2002].
Other. Renal vascular disease similar to that occurring in neurofibromatosis type 1 (NF1) has been reported once [Cordeiro et al 2006], but may be coincidental as it has not been reported again.
Somatic mosaicism for pathogenic variants in NF2. Mosaicism has been suspected in individuals with unilateral vestibular schwannoma and multiple other, often ipsilateral, tumors [Mohyuddin et al 2003, Evans et al 2008]. This has now been confirmed for most cases in which DNA from multiple tumors has been analyzed [Mohyuddin et al 2003, Wallace et al 2004, Aghi et al 2006, Evans et al 2008].
Histopathology. The tumors of NF2 are derived from Schwann cells, meningeal cells, and glial cells. They are uniformly benign. Approximately 40% of NF2 vestibular tumors have a lobular pattern that is uncommon in tumors from individuals without a diagnosis of NF2.
- NF2-associated vestibular schwannomas tend to be more invasive and to have a higher degree of dividing cells than non-NF2 tumors.
- NF2-associated meningiomas have a higher degree of dividing cells than non-NF2 meningiomas. NF2 meningiomas are usually of the fibroblastic variety.
- No histologic differences have been observed between glial tumors in individuals with NF2 and individuals who do not have NF2.
Genotype-Phenotype Correlations
Intrafamilial variability is much lower than interfamilial variability, suggesting a strong effect of the underlying genotype on the resulting phenotype.
Unlike neurofibromatosis type 1 (NF1), large deletions of NF2 have been associated with a mild phenotype [Baser et al 2004]; even if quite large, these deletions are not associated with intellectual disability.
The type of NF2 germline pathogenic variant is an important determinant of the number of NF2-associated intracranial meningiomas, spinal tumors, and peripheral nerve tumors [Baser et al 2004]:
- Nonsense and frame-shifting variants have been associated with severe disease regardless of their position within the gene [Baser et al 2004].
- Splice site variants have been associated with both mild and severe disease [Kluwe et al 1998, Baser et al 2005] and may be milder if occurring in the 3' half of the gene [Baser et al 2005].
- Missense variants are usually associated with a mild phenotype, often causing the mildest form of NF2 [Evans et al 1998a, Baser et al 2002].
- Truncating variants are associated with earlier onset and greater number of NF2-associated intracranial meningiomas, spinal tumors, and peripheral nerve tumors. In general, truncating variants (frameshift and nonsense) are associated with greater disease-related mortality than missense and splice site variants or deletions [Baser et al 2002, Baser et al 2005]. Truncating variants are also associated with increased prevalence of spinal tumors [Patronas et al 2001, Dow et al 2005]. Although most of these pathogenic variants would be predicted to result in nonsense-mediated decay, and thus no protein product, the apparent dominant-negative effect of these variants requires further investigation.
- Pathogenic variants in the 3' half of NF2 (especially those in exons 14-16) are associated with lower risk of meningioma than pathogenic variants in the 5' half of the gene [Smith et al 2011] (see Figure 1).
Figure 1.
The position of pathogenic variants in NF2 affects the likelihood of developing a meningioma. A. The Kaplan-Meier plot shows the risk of meningioma within each functional domain. Gene regions are divided into exons 1-3, 4-6, 7-9, 10-13, and 14-15.
Somatic mosaicism (even when detected in lymphocyte DNA) for typical pathogenic truncating variants that would normally cause severe NF2 may result in a milder phenotype [Evans et al 1998a, Evans et al 2007b, Evans et al 2013].
Penetrance
Penetrance is close to 100%. Virtually all individuals who have a germline pathogenic variant develop the disease in an average lifetime.
Age at onset can vary with variant type; see Genotype-Phenotype Correlations.
Nomenclature
The term "neurofibromatosis" is a misnomer because the primary tumor types in NF2 are schwannoma and meningioma. Vestibular schwannoma (previously termed "acoustic neuroma") was initially considered part of von Recklinghausen neurofibromatosis type 1, leading to multiple instances in which individuals with NF2 were included in series of individuals with NF1.
Since 1987, the great majority of reports have correctly distinguished between NF1 and NF2, with NF2 described as "bilateral acoustic" or "central" neurofibromatosis.
Prevalence
The estimated prevalence of NF2 is 1:60,000 [Evans et al 2010], with a birth incidence of 1:33,000.
NF2 has no ethnic or racial predilections.
Differential Diagnosis
Table 3.
Disorders to Consider in the Differential Diagnosis of NF2
| Disorder | Gene(s) | MOI | Clinical Features of This Disorder | |
|---|---|---|---|---|
| Overlapping w/NF2 | Distinguishing from NF2 | |||
| Neurofibromatosis type 1 | NF1 | AD | Dumbbell configuration of spinal tumors |
|
| Schwannomatosis 1 | SMARCB1 | AD | Multiple schwannomas | No vestibular schwannomas |
| Schwannomatosis 2 | LZTR1 1 | AD | Unilateral vestibular schwanomma & other schwannomas | No intradermal schwannoma plaques, cataract, or ependymoma |
| Unilateral vestibular schwannoma 2 | N/A | N/A | Vestibular schwannoma |
|
| Meningioma 3 | Typically N/A; rarely SMARCB1 4 | Rarely AD | Multiple meningiomas | No vestibular schwannomas |
AD = autosomal dominant; MOI = mode of inheritance; N/A = not applicable
- 1.
Smith et al [2017] found that for individuals with a unilateral vestibular schwannoma and additional non-intradermal schwannomas, a constitutional LZTR1 pathogenic variant is a significant possibility.
- 2.
The risk that a unilateral tumor is the first manifestation of NF2 is closely related to the age of the affected individual. Individuals younger than age 30 years with a symptomatic unilateral vestibular schwannoma are at high risk of developing a contralateral tumor and NF2 and should be monitored closely, while individuals older than age 30 years who have a unilateral vestibular schwannoma are at very low risk of developing NF2 [Evans et al 2007a].
- 3.
Multiple meningiomas typically occur in older adults; thus, the finding of a single meningioma in an individual younger than age 25 years should prompt evaluation for an underlying genetic condition [Evans et al 2005b].
- 4.
A pathogenic variant in SMARCB1 was found to be responsible for schwannomatosis in several members of one family [Christiaans et al 2011]; however, the great majority of individuals with multiple meningiomas do not harbor a SMARCB1 pathogenic variant [Hadfield et al 2010].
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with neurofibromatosis 2 (NF2), the following are recommended if they have not already been completed:
- Head MRI
- Hearing evaluation, including brain stem auditory evoked response (BAER)
- Ophthalmologic evaluation
- Cutaneous examination
- Consultation with a clinical geneticist and/or genetic counselor
Note: Evaluation and treatment of individuals with neurofibromatosis 2 (NF2) are best undertaken in an NF2 center experienced in managing the multiple complications of the disease [Baser et al 2002, Evans et al 2005a].
- For NF specialists see www.ctf.org.
- For NF2 service centers in the UK see www.nfauk.org.
Treatment of Manifestations
Vestibular schwannoma. Untreated tumors may be slow growing and not require active intervention in the short term [Masuda et al 2004, Slattery et al 2004]. Therapy remains primarily surgical.
- Small vestibular tumors (<1.5 mm) that are completely intercanalicular can often be completely resected, with preservation of both hearing and facial nerve function.
- Larger tumors are probably best managed expectantly, with debulking or decompression carried out only when brain stem compression, deterioration of hearing, and/or facial nerve dysfunction occur [Evans et al 2005a]. However, balancing between early surgery and preservation of facial function and later surgery when an affected individual is still hearing is difficult [Evans et al 2005a].
Stereotactic radiosurgery, most commonly with the gamma knife, has been offered as an alternative to surgery in select individuals with vestibular schwannoma. However, the outcomes from radiation treatment in individuals with NF2 are not as good as for individuals with sporadic unilateral vestibular schwannoma, with only approximately 60% long-term tumor control [Rowe et al 2003, Chung et al 2018].
Malignant transformation is a possible (though probably not common) sequela [Baser et al 2000]; however, it should be noted that tumor development following radiation may take 15 years [Evans et al 2006]. This may involve development of a malignancy within the treated lesion or a new malignancy (e.g., glioblastoma) in the radiation field [Balasubramaniam et al 2007, Halliday et al 2018].
More recently, treatment with the VEGF antibody bevacizumab has shown promise in the treatment of rapidly growing vestibular schwannomas, with some individuals regaining hearing [Plotkin et al 2009, Morris et al 2016, Halliday et al 2018]. Response to treatment occurs in about 60%-70% of individuals; treatment can be sustained over years but with some concerns over renal toxicity [Slusarz et al 2014, Morris et al 2016, Halliday et al 2018].
Management of individuals with vestibular tumors should include counseling for insidious problems with balance and underwater disorientation, which can result in drowning.
Other tumors. Other intracranial, cranial nerve, or spinal nerve tumors are very slow growing, and surgical intervention for a tumor producing little impairment may cause disability years before it would occur naturally.
Although ependymoma in individuals without NF2 is optimally treated with complete resection, and occasionally with radiotherapy and chemotherapy, it is unclear whether ependymoma in individuals with NF2 warrants aggressive management. However, bevacizumab has shown some clinical benefit in some individuals [Farschtschi et al 2016, Morris et al 2017].
Use of radiation therapy for NF2-associated tumors should be carefully considered because radiation exposure may induce, accelerate, or transform tumors in an individual (especially a child) with an inactive tumor suppressor gene [Baser et al 2000, Evans et al 2006].
Hearing. Hearing preservation and augmentation are important in the management of individuals with NF2. All affected individuals and their families should be referred to an audiologist to receive training in optimization of hearing and speech production.
- Lip-reading skills may be enhanced by instruction.
- Sign language may often be more effectively acquired before the individual loses hearing.
- Hearing aids may be helpful early in the course of the disease [Evans et al 2005a].
- Auditory rehabilitation with a cochlear or brain stem implant should be discussed with those who have lost hearing [Evans et al 2005a]. Rarely, individuals who have had vascular insult to the cochlea, but otherwise are without nerve damage, may benefit from a cochlear implant. Implants can also be used in stable tumors where hearing has been lost but there is evidence of cochlear nerve function [North et al 2016]
Ocular involvement. Early recognition and management of visual impairment from other manifestations of NF2 are extremely important. Most NF2-associated cataracts do not require removal, but particular attention should be paid to cataracts in infancy that may affect vision by causing amblyopia. These may require removal and patching of the unaffected eye.
Cutaneous involvement. While removal of cutaneous schwannomas is not required, it may be indicated if the schwannomas are causing disfigurement or pain. Removal may also help diagnostically.
Prevention of Secondary Complications
Treatment concentrates on prevention of secondary complications. Prevention of substantial handicap from the disease can be achieved by appropriate expert treatment of tumors:
- A cervical spinal scan should be performed before cranial surgery to prevent complications from manipulation under anesthesia [Evans et al 2005a].
- Spinal tumors may make epidural analgesia difficult; therefore, lumbosacral imaging should be performed before regional analgesia is given [Sakai et al 2005, Spiegel et al 2005].
Surveillance
For at-risk individuals (1) in whom the known pathogenic variant in the family has been identified or (2) whose genetic status cannot be clarified by molecular genetic testing:
- MRI is usually begun between ages ten and 12 years but can be delayed in families in which the onset is known to be later [Evans et al 2005a]. MRI should be continued on an annual basis until at least the fourth decade of life. It is not clear if earlier surveillance (i.e., cranial MRI before age 10 years) is beneficial, and it is not known at what age monitoring can be safely stopped. Although some individuals with NF2 do not have symptoms until they are in their fifties, it is likely that "silent" tumors would be detected on an MRI performed at a younger age.
- Hearing evaluation, including BAER testing, may be useful in detecting changes in auditory nerve function before changes can be visualized by MRI.
- Complete eye examinations should be part of the care of all individuals with NF2 and ideally should be conducted annually.
Agents/Circumstances to Avoid
Radiotherapy for NF2 should be avoided in childhood, when malignancy risks are likely to be substantially larger [Evans et al 2006].
Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger sibs of a proband and other at-risk relatives in order to identify as early as possible those who would benefit from prompt initiation of appropriate screening (see Surveillance), thus resulting in earlier detection of disease manifestations and improved final outcomes [Evans et al 2005a].
Note: Tumor testing can identify both mutational hits in the majority of cases of isolated NF2 and allow exclusion testing in sibs and other at-risk relatives.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Pregnancy Management
Although there is no convincing evidence that schwannomas increase in size during pregnancy, hormonal effects on meningiomas are possible; therefore, assessment of the potential risk of increased intracranial pressure is important for women considering pregnancy.
Therapies Under Investigation
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions.