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.

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 (or likely pathogenic) variant in NF2 on molecular genetic testing (see Table 1).

Note: Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants.

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.

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.

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 regarding 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.

Mode of Inheritance

Neurofibromatosis 2 (NF2) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Approximately 50% of individuals diagnosed with NF2 have an affected parent. While there is a strong genotype-phenotype correlation, significant variability within families and even between identical twins can be seen.
• Approximately 50% of individuals diagnosed with NF2 have the disorder as the result of a de novo NF2 pathogenic variant.
  25% to 33% of individuals who are simplex cases (i.e., individuals with no family history of NF2) are mosaic for an NF2 pathogenic variant [Kluwe et al 2003, Mohyuddin et al 2003, Evans et al 2007b, Evans et al 2013].
• Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant.
• If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent. The incidence of pure germline mosaicism in NF2 is extremely low as thus far all parents having more than one affected child have had a detectable pathogenic variant in NF2 in blood DNA and have been clinically affected [Evans et al 2013]. There is one historical case of two affected children born to apparently unaffected parents before NF2 testing was available [Parry et al 1996].
• The family history of some individuals diagnosed with NF2 may appear to be negative because of failure to recognize the disorder in family members or early death of the parent before the onset of symptoms. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband.
• The possibility that a parent has NF2 can be excluded if the parent's offspring is shown to be mosaic, but absence of a pathogenic variant does not eliminate the possibility of mosaicism in the parent. Because the age of onset of symptoms is consistent within families, it is usually not necessary to offer surveillance to asymptomatic parents.
• If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected.

Sibs of a proband

• The risk to the sibs of the proband depends on the genetic status of the parents.
• If a parent of the proband is affected, the risk to the sibs is 50%.
• If the parents have been tested for the NF2 pathogenic variant identified in the proband and:
  • One parent of the proband has the NF2 pathogenic variant, the risk to the sibs of inheriting the variant is 50%. The age of onset of symptoms within a family is relatively consistent.
  • The NF2 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism. A single case of germline mosaicism in a clinically normal parent has been reported [Parry et al 1994].
• If the parents have not been tested for the NF2 pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. The sibs of a proband with clinically unaffected parents are still at increased risk for NF2 because of the possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with NF2 has up to a 50% chance of inheriting the pathogenic variant:

• If the proband has other affected family members, each child of the proband has a 50% chance of inheriting the pathogenic variant.
• If the proband is the only affected individual in the family, two possibilities exist:
  • The proband may have somatic mosaicism for the pathogenic variant. Offspring of an individual who is mosaic may have a less than 50% risk of inheriting the pathogenic variant.
    Persons with somatic mosaicism and bilateral vestibular tumors have a less than 50% chance of having an affected child [Evans et al 1998b]. If the pathogenic variant is detected in DNA from multiple tumors, but not in DNA from leukocytes, the risk to offspring is probably less than 5% [Evans et al 2009].
  • The proband may have a de novo germline pathogenic variant (i.e., present in the egg or sperm at the time of conception). Each offspring of an individual with a de novo germline pathogenic variant has a 50% chance of inheriting the variant.

Other family members. The risk to other family members depends on the genetic status of the proband's parents: if a parent is affected, the parent's family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Testing of at-risk asymptomatic family members. Consideration of molecular genetic testing of at-risk family members during childhood is appropriate for surveillance (see Surveillance).

Because early detection of at-risk individuals affects medical management, testing of at-risk asymptomatic individuals younger than age 18 years is beneficial. Parents often want to know the genetic status of their children prior to initiating screening in order to avoid unnecessary procedures for a child who has not inherited the pathogenic variant. Special consideration should be given to education of the children and their parents prior to genetic testing. A plan should be established for the manner in which results are to be given to the parents and children.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).

Prenatal Testing and Preimplantation Genetic Testing

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.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

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Author History

D Gareth Evans, MD, FRCP (2004-present)
Mia MacCollin, MD; Harvard Medical School (1998-2004)

Revision History

• 15 March 2018 (ha) Comprehensive update posted live
• 18 August 2011 (me) Comprehensive update posted live
• 19 May 2009 (me) Comprehensive update posted live
• 6 June 2006 (me) Comprehensive update posted live
• 6 April 2004 (me) Comprehensive update posted live
• 29 October 2001 (me) Comprehensive update posted live
• 14 October 1998 (pb) Review posted live
• 5 August 1998 (mm) Original submission