Neurofibromatosis 2

[Bilateral Acoustic Neurofibromatosis, Central Neurofibromatosis, NF2, Neurofibromatosis Type II]

Clinical Diagnosis

Modifications to NIH consensus diagnostic criteria for neurofibromatosis 2 (NF2) have been suggested to enable earlier diagnosis of a founder (i.e., the individual in the first generation of a family known to be affected). These clinical diagnostic criteria for NF2 have been found to improve sensitivity substantially without affecting specificity [Baser et al 2002]. According to the modified criteria, 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: meningioma, schwannoma, glioma, neurofibroma, posterior subcapsular lenticular opacities *

• Unilateral vestibular schwannoma AND any two of: meningioma, schwannoma, glioma, neurofibroma, posterior subcapsular lenticular opacities *

• Multiple meningiomas AND

  • Unilateral vestibular schwannoma OR

  • Any two of: schwannoma, glioma, neurofibroma, cataract *

* Any two of = two individual tumors or cataract

Testing

Chromosome analysis. A variety of chromosome abnormalities can be associated with NF2; however, gross chromosomal changes detectable on normal cytogenetic analysis are fairly uncommon.

• Cytogenetically visible deletions encompassing the NF2 gene may cause mental retardation and can cause congenital abnormalities [Barbi et al 2002].

• Ring chromosome 22 can also cause multiple meningiomas and vestibular schwannomas fulfilling NF2 diagnostic criteria [Tsilchorozidou et al 2004]. The NF2 locus itself is usually present within the ring, but the ring itself is frequently lost as a result of instability.

• Apparently balanced chromosomal translocations that disrupt the NF2 gene have also been described as causing NF2 [Tsilchorozidou et al 2004].

Fluorescence in situ hybridization (FISH) analysis. Smaller deletions that remove multiple exons of the NF2 gene or the whole gene can also be identified by FISH analysis [Tsilchorozidou et al 2004].

Molecular Genetic Testing

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.

Gene. NF2 is the only gene known to be associated with neurofibromatosis 2.

Clinical testing

Sequence analysis/mutation scanning. The mutation detection rate in leukocyte DNA depends on which generation in a family is tested and whether the family history is positive or negative, i.e., the individual being tested represents a simplex case (i.e., a single occurrence in a family).

• In 79/108 (73%) families with NF2, sequence analysis identified a mutation in a member of the second generation [Evans et al 2007a; Author, unpublished data].

• In simplex cases, the mutation detection rate is approximately 60% [Evans et al 2007a].
  
  Note: Approximately 25% to 33% of mutations are not detected as a result of somatic mosaicism [Kluwe et al 2003, Moyhuddin et al 2003]. Mutations with mosaicism levels greater than 10% can be detected in lymphocyte DNA [Evans et al 2007a]. Identification of the remainder of mosaic mutations usually requires testing of tumor material [Evans et al 2007a].

Note: The detection rate of disease-causing mutations using mutation scanning is comparable to that of sequence analysis in up to two-thirds of cases.

Deletion/duplication analysis that systematically detects whole-exon deletions and duplications suggests that at least 10% to 15% of NF2 constitutional aberrations are deletions ranging in size from 10 to 600 kb [Zucman-Rossi et al 1998, Wallace et al 2004, Kluwe et al 2005]. However, in inherited cases they make up approximately 20%, boosting sensitivity of the combination of sequence analysis and deletion/duplication testing to 93% (101/108).

Note: Most large deletions and, less commonly, duplications of single exons or multiple exons can be detected by MLPA [Kluwe et al 2005, Evans et al 2007a].

Linkage analysis. Linkage analysis can be considered in families in whom no disease-causing mutation is identified and at least two family members of different generations are affected. Linkage studies are based on an accurate clinical diagnosis of NF2 in the affected family members and accurate understanding of genetic relationships in the family. Linkage analysis depends on the availability and willingness of family members to be tested. The markers used for linkage analysis of NF2 are highly informative and very tightly linked to the NF2 gene; thus, they can be used in more than 95% of families with NF2 with greater than 99% accuracy. Linkage testing is not usually available to families with a single affected individual, a situation that often occurs when an individual has a de novo gene mutation and no affected offspring; however, modified linkage analysis using both constitutional and tumor DNA can exclude NF2 in those children of a simplex case who have not inherited the allele lost in the tumor [Kluwe et al 2005, Evans et al 2007a].

Table 1 summarizes molecular genetic testing for this disorder.

Table 1. Molecular Genetic Testing Used in Neurofibromatosis 2

Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
NF2	Sequence analysis	Sequence variants	75%	Clinical
	Mutation scanning		~65% 2
	Deletion/duplication testing 3	Partial- and whole-gene deletions	10%-15% 2
	Linkage analysis	NA	NA

1. Mutation detection rates are lower in simplex cases and in the person in the first generation of a family to have NF2 because they are more likely to have somatic mosaicism (see Interpretation of test results).

2. When mutation scanning is combined with deletion/duplication analysis of single exons, the mutation detection rate approaches 72% in simplex cases and exceeds 92% for familial cases [Wallace et al 2004, Kluwe et al 2005, Evans et al 2007a]. Other studies have reported lower mutation detection rates, which may reflect the inclusion of some more mildly affected individuals with somatic mosaicism (see Interpretation of test results).

3. Testing that detects deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, real-time PCR, multiplex ligation dependent probe amplification (MLPA), or array CGH may be used.

Interpretation of test results

• For issues to consider in interpretation of sequence analysis results, click here.

• Research has shown that as many as 25% to 33% of individuals with NF2 caused by a de novo mutation have somatic mosaicism for the mutation [Kluwe et al 2003, Moyhuddin et al 2003, Evans et al 2007a]. Recognition of individuals who have somatic mosaicism for an NF2 disease-causing mutation can be problematic because these individuals:

  • May not have bilateral vestibular schwannomas [Evans et al 2008]

  • May have normal molecular genetic testing of the NF2 gene 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 2007a].

• A parent can be excluded as having NF2 if his/her offspring is shown to have somatic mosaicism for an NF2 mutation. Absence of an NF2 mutation in an offspring does not eliminate the possibility of somatic mosaicism for an NF2 mutation in the offspring or parent.

Testing Strategy

Confirmatory diagnostic testing in a proband

One of two sample types is used:

• Leukocyte DNA from an individual who has an affected parent

• Tumor DNA from an individual who is a simplex case

Molecular genetic testing is performed in the following order:

• 1

  Testing for large deletions using a technique such as MLPA which is simpler and cheaper than sequence analysis

• 2

  Sequence analysis of exons 1-15 (Mutations have never been described in exons 16-17.)

When tumor DNA is tested, mutations 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 (LOH).

• Once both NF2 mutant alleles are identified in the tumor, leukocyte DNA can be tested to determine which one of the mutations is constitutional and which is somatic (present in the tumor only).

Predictive testing

• At-risk relatives whose genetic status is unknown can be tested for presence of the NF2 mutation (either constitutional or somatic mosaic) identified in an affected relative (e.g., the proband).

• In the rare instance in which an NF2 mutation cannot be identified, linkage analysis can be used in families with at least two affected family members of different generations or tumor DNA can be used to clarify the genetic status of children of a simplex case.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Genetically Related (Allelic) Disorders

No other phenotypes are known to be associated with mutations in the NF2 gene.

Natural History

The average age of onset of findings in individuals with neurofibromatosis 2 (NF2) is 18 to 24 years. The age of onset ranges from 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 anatomical 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].

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.

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 develop meningiomas. Most are intracranial; however, 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. Meningioma may be the presenting feature of NF2, particularly in childhood [Evans et al 1999, Perry et al 2001].

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. Intracranial and intra-orbital tumors may result in decreased visual acuity and diplopia. Rarely, other ocular manifestations may occur; persistent hyperplastic primary vitreous (PHPV) has been reported in a father and son [Nguyen et al 2005].

Intracranial and intraorbital tumors may result in decreased visual acuity and diplopia.

Cataracts can be present at birth and amblyopia is common in the formative years [Feucht et al 2008]. In adulthood particular problems with the cornea can occur, especially after surgery that results in the loss of facial, trigeminal, and intermedius nerve function.

Mono-/polyneuropathy. An increasingly 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 (third 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 being increasingly 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 [Cordiero et al 2006].

Somatic mosaicism for disease-causing mutations in the NF2 gene. Mosaicism has been suspected in individuals with unilateral vestibular schwannoma and multiple other, often ipsilateral, tumors [Moyhuddin et al 2003, Evans et al 2008]. This has now been confirmed for most cases in which DNA from multiple tumors has been analyzed [Moyhuddin 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 who have no known family history 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 the NF2 gene have been associated with a mild phenotype [Baser et al 2004]. At least 10% to 15% of NF2 constitutional aberrations are deletions ranging in size from 10 to 600 kb [Zucman-Rossi et al 1998, Wallace et al 2004, Kluwe et al 2005]; nonetheless, these deletions are not associated with mental retardation, even if quite large.

The type of NF2 constitutional mutation 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 mutations have been associated with severe disease regardless of their positions within the gene [Baser et al 2004].

• Splice site mutations 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 mutations are usually mild, often causing the mildest form of NF2 [Evans et al 1998a, Baser et al 2002].

• Truncating mutations are associated with earlier onset and greater number of NF2-associated intracranial meningiomas, spinal tumors, and peripheral nerve tumors. In general, truncating mutations (frameshift and nonsense) are associated with greater disease-related mortality than missense and splice site mutations or deletions [Baser et al 2002, Baser et al 2005]. Truncating mutations are also associated with increased prevalence of spinal tumors [Patronas et al 2001, Dow et al 2005]. Although most of these mutations would be predicted to result in nonsense-mediated decay and, thus, no protein product, the apparent dominant negative affect of these mutations requires further investigation.

Somatic mosaicism (even when detected in lymphocyte DNA) for typical truncating mutations that would normally cause severe NF2 may result in a milder phenotype [Evans et al 1998a, Evans et al 2007a].

Penetrance

Penetrance is 100%. All individuals who have a pathogenic mutation develop the disease in an average lifetime. Age at onset can vary with mutation type, as described in Genotype-Phenotype Correlations.

Anticipation

Although some reports suggested anticipation in NF2, it is likely that these were instances of milder disease associated with mosaicism for an NF2 mutation in the first generation and more severe disease associated with an NF2 germline (i.e., constitutional) mutation in the second and subsequent generations.

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 incidence of NF2 was initially reported as 1:33,000-40,000 individuals. Disease prevalence is somewhat lower at 1:200,000. However, a recent update suggests that the incidence may be as high as 1:25,000; and the prevalence is now be higher than 1:80,000 [Evans et al 2005b].

NF2 has no ethnic or racial predilections.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with neurofibromatosis 2 (NF2), the following evaluations are recommended:

• Head MRI

• Hearing evaluation, including BAER

• Ophthalmologic evaluation

• Cutaneous examination

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].

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].

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].

Malignant transformation is a possible, though probably not common, sequelum [Baser et al 2000]; however, it should be noted that tumor development following radiation may take 15 years [Evans et al 2006].

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.

Radiation therapy of NF2-associated tumors should be carefully considered because radiation exposure may induce, accelerate, or transform tumors in an individual with an inactive tumor suppressor gene, especially a child [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.

Ocular involvement. Early recognition and management of visual impairment from other manifestations of NF2 are extremely important.

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 who have either tested positive for the known disease-causing mutation in their families or 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.

Routine complete eye examinations should be part of the care of all individuals with NF2.

Agents/Circumstances to Avoid

Radiotherapy should be avoided in children with NF2 [Evans et al 2006].

Testing of Relatives at Risk

Consideration of molecular genetic testing of at-risk family members (see Genetic Counseling) during childhood is appropriate for surveillance:

• Early identification of relatives who have inherited the family-specific NF2 mutation allows for appropriate screening using MRI for neuroimaging and brain stem auditory evoked response (BAER) testing for audiologic evaluation, thus resulting in earlier detection of disease manifestations and improved final outcomes [Evans et al 2005a].

• Early identification of those who have not inherited the family-specific NF2 mutation eliminates the need for costly screening with MRI and BAER testing.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

The search for an effective medical treatment for NF2-related tumors continues. One of the first group of agents suggested were PAK1-blocking drugs [Hirokawa et al 2004]. Targeting the ERK1/, AKT, integrin/focal adhesion kinase/Src/Ras signaling cascades, PDGFRbeta, phosphatidylinositol 3-kinase/protein kinase C/Src/c-Raf pathway, VEG-F and other pathways [Hanemann 2008; Evans et al, in press], drugs such as avastin, elotinib [Plotkin et al 2008], lapatinib, and sorafenib [Ammoun et al 2008] may well be effective treatments for NF2. These agents could be tried on the Nf2 mouse model; the first human clinical trials in North America and the UK are also commencing.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

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 with NF2 have an affected parent, and 50% have NF2 as the result of a de novo mutation. However, 25% to 33% of individuals who are simplex cases (i.e., individuals with no family history of NF2) are mosaic for an NF2 mutation [Kluwe et al 2003, Moyhuddin et al 2003, Evans et al 2007a].

• Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include a clinical history and, if any suspicion of NF2 exists, an MRI scan. A parent can be excluded as having NF2 if his/her offspring is shown to be mosaic, but absence of a mutation detected in the child 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.

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 neither parent of an individual with NF2 is symptomatic, the risk to the sibs of the affected individual is low because the age of onset of symptoms is relatively uniform within families. However, a single case of germline mosaicism in a clinically normal parent has been reported. In addition, somatic mosaicism (which may include germline mosaicism) is found in 25%-33% of individuals with NF2 who are simplex cases.

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

• If the proband has other affected family members, each child of the proband has a 50% chance of inheriting the mutation.

• If the proband is the only affected individual in the family, two possibilities exist:

  • The proband may have somatic mosaicism for the disease-causing mutation. Offspring of an individual who is mosaic may have less than a 50% risk of inheriting the disease-causing mutation.

  • The proband may have a de novo germline mutation (i.e., present in the egg or sperm at the time of conception). Each offspring of an individual with a de novo germline mutation has a 50% chance of inheriting the mutation.

• Persons with somatic mosaicism and bilateral vestibular tumors have less than a 50% chance of having an affected child [Evans et al 1998b]. If the mutation is detected in DNA from multiple tumors, but not in DNA from leukocytes, the risk to offspring is probably less than 5%.

Other family members of a proband. The risk to other family members depends on the genetic status of the proband's parents. If a parent is affected, his or her family members may be at risk, depending on the family structure.

Related Genetic Counseling Issues

See the Testing of Relatives at Risk section for information on testing at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made 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.

Considerations in families with an apparent de novo mutation. When the parents of a proband with an autosomal dominant condition are unaffected, possible non-medical explanations include alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption.

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). Molecular genetic testing used in early identification of at-risk family members may be either mutation analysis or linkage analysis. Mutation analysis can only be used for testing of at-risk relatives if a disease-causing mutation has been identified in an affected family member. Linkage analysis is the preferred method of testing in families with more than one affected family member.

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 altered gene. 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.

DNA banking. DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant when the sensitivity of currently available testing is less than 100% or when linkage analysis is utilized. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis of pregnancies at 50% risk for NF2 is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15-18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. The disease-causing allele of an affected family member must be identified or linkage established in the family before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

Literature Cited

Published Statements and Policies Regarding Genetic Testing

No specific guidelines regarding genetic testing for this disorder have been developed.

Suggested Reading

Author History

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

Revision History

• 19 May 2009 (me) Comprehensive update posted live

• 6 June 2006 (me) Comprehensive update posted to live Web site

• 6 April 2004 (me) Comprehensive update posted to live Web site

• 29 October 2001 (me) Comprehensive update posted to live Web site

• 14 October 1998 (pb) Review posted to live Web site

• 5 August 1998 (mm) Original submission