The neurofibromatoses are autosomal dominant genetic disorders associated with tumors of the peripheral and central nervous systems. There are 3 clinically and genetically distinct forms: neurofibromatosis (NF) type 1 (NF1), NF type 2 (NF2) and schwannomatosis. The potential benefit of genetic testing for NF is to confirm the diagnosis in an individual with suspected NF who does not fulfill diagnostic clinical criteria, or to determine future risk of NF in asymptomatic at-risk relatives.
The evidence for genetic testing in individuals who have suspected NF who do not fulfill diagnostic clinical criteria or who are asymptomatic, do not meet diagnostic clinical criteria but have close relative(s) with neurofibromatosis diagnosis, includes clinical validation studies of a multistep diagnostic protocol and genotype-phenotype correlation studies. Relevant outcomes are test accuracy and validity, symptoms, change in disease status, morbid events and functional outcomes. Published data on the analytic validity of genetic testing for NF is lacking. A multistep mutation testing protocol identifies more than 95% of pathogenic variants in NF1, and, for NF2, the mutation detection rate approaches 72% in simplex cases and exceeds 92% for familial cases. For individuals with a known pathogenic mutation in the family, testing of at-risk relatives will confirm or exclude the mutation with high certainty. Published evidence on the clinical utility of genetic testing for NF is lacking, but a definitive diagnosis can direct patient care according to established clinical management guidelines, including referrals to the proper specialists, treatment of manifestations and surveillance. Testing of at-risk relatives will lead to initiation or avoidance of management and/or surveillance. Early surveillance may be particularly important for patients with NF2, because early identification of internal lesions by imaging is expected to improve outcomes. The evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome.
There are 3 major clinically and genetically distinct forms of neurofibromatosis (NF): NF type 1 (NF1, also known as von Recklinghausen disease), NF type 2 (NF2) and schwannomatosis.
NF1 is one of the most common dominantly inherited genetic disorders, with an incidence at birth of 1 in 3,000 individuals.
The clinical manifestations of NF1 show extreme variability, between unrelated individuals, among affected individuals within a single family and within a single person at different times in life.
NF1 is characterized by multiple café-au-lait spots, axillary and inguinal freckling, multiple cutaneous neurofibromas and iris Lisch nodules. It is referred to as segmental NF1 when limited to 1 area of the body. Many individuals with NF1 only develop cutaneous manifestations of the disease and Lisch nodules.
Café-au-lait spots occur in nearly all affected individuals and intertriginous freckling occurs in almost 90%. Café-au-lait spots are common in the general population, but when more than 6 are present, NF1 should be suspected. Café-au-lait spots are often present at birth and increase in number during the first few years of life.
Neurofibromas are benign tumors of Schwann cells that affect virtually any nerve in the body and develop in most people with NF1. They are divided into cutaneous and plexiform types. Cutaneous neurofibromas, which develop in almost all people with NF1, are discrete, soft, sessile or pedunculated tumors. Discrete cutaneous and subcutaneous neurofibromas are rare before late childhood. They may vary from a few to hundreds or thousands, and the rate of development may vary greatly from year to year. Cutaneous neurofibromas do not carry a risk of malignant transformation, but may be a major cosmetic problem in adults.
Plexiform neurofibromas, which occur in about half of individuals with NF1, are more diffuse growths that may be locally invasive. They can be superficial or deep and, therefore, the extent cannot be determined by clinical examination alone; magnetic resonance imaging (MRI) is the method of choice for imaging plexiform neurofibromas.1 Plexiform neurofibromas represent a major cause of morbidity and disfigurement in individuals with NF1. They tend to develop and grow in childhood and adolescence and then stabilize throughout adulthood.1 Plexiform neurofibromas can compress the spinal cord or airway and can transform into malignant peripheral nerve sheath tumors (MPNST). MPNST occur in approximately 10% of affected individuals.1
Optic gliomas, which can lead to blindness, develop in the first 6 years of life. Symptomatic optic gliomas usually present before 6 years of age with loss of visual acuity or proptosis, but they may not become symptomatic until later in childhood or in adulthood.
Lisch nodules are innocuous hamartomas of the iris.
Other findings in NF1 include:
- Intellectual disability occurs at a frequency of about twice that in the general population, and features of autism spectrum disorder occur in up to 30% of children with NF1.
- Musculoskeletal features include dysplasia of the long bones, most often the tibia and fibula, which is almost always unilateral. Generalized osteopenia is more common in people with NF1 and osteoporosis is more common and occurs at a younger age than in the general population.1
- Cardiovascular involvement includes the common occurrence of hypertension. Vasculopathies may involve major arteries or arteries of the heart or brain and can have serious or fatal consequences. Cardiac issues include valvar pulmonic stenosis, and congenital heart defects and hypertrophic cardiomyopathy may be especially frequent in individuals with NF1 whole gene deletions.1 Adults may develop pulmonary hypertension, often in association with parenchymal lung disease.
Although the clinical manifestations of NF1 are extremely variable and some are age-dependent, the diagnosis can usually be made on clinical findings, and genetic testing is rarely needed for diagnosis.1
The clinical diagnosis of NF1 should be suspected in individuals with the diagnostic criteria for NF1 developed by the National Institutes of Health (NIH). The criteria are met when an individual has 2 or more of the following features:
- Six or more café-au-lait macules over 5 mm in greatest diameter in prepubertal individuals and over 15 mm in postpubertal individuals
- Two or more neurofibromas of any type or one plexiform neurofibroma
- Freckling in the axillary or inguinal regions
- Optic glioma
- Two or more Lisch nodules (raised, tan-colored hamartomas of the iris)
- A distinctive osseous lesion such as sphenoid dysplasia or tibial pseudarthrosis
- A first-degree relative with NF1 as defined by the above criteria
In adults, the clinical diagnostic criteria are highly specific and sensitive for a diagnosis of NF1.1
Approximately half of children with NF1 and no known family history of NF1 meet NIH criteria for the clinical diagnosis by age 1 year. Almost all do by 8 years of age because many features of NF1 increase in frequency with age. Children who have inherited NF1 from an affected parent can usually be diagnosed within the first year of life because the diagnosis requires 1 diagnostic clinical feature in addition to a family history of the disease. This feature is usually multiple café-au-lait spots, present in infancy in more than 95% of individuals with NF1.1
Young children with multiple café-au-lait spots and no other features of NF1 who do not have a parent with signs of NF1 should be suspected of having NF1, and followed clinically as if they do. A definitive diagnosis of NF1 can be made in most children by 4 years of age using NIH criteria.1
Molecular Genetic Testing
Molecular genetic testing is rarely needed to diagnose NF1.
Indications for testing in individuals may include those in whom NF1 is suspected but who do not fulfill NIH clinical diagnostic criteria (this is rarely necessary after early childhood), and in a young child with a serious tumor (e.g., optic glioma) in whom establishing a diagnosis of NF1 would affect immediate management.
NF1 is caused by mutations in the NF1 gene, which is a tumor suppressor gene located at chromosome 17q11.2. NF1 is inherited in an autosomal dominant manner, and half of affected individuals have it as a result of a de novo NF1 mutation. Penetrance is virtually complete after childhood; however, expressivity is highly variable.
The mutations responsible for NF1 are very heterogeneous, and include nonsense and missense single nucleotide changes, single base insertions/deletions, splicing mutations (30% of cases), whole gene deletions (5% of cases), intragenic copy number variants and other structural rearrangements. Several thousand pathogenic NF1 mutations have been identified; however, none is frequent.1
Patient management guidelines for NF1 have been developed by the American Academy of Pediatrics, the National Society of Genetic Counselors and other expert groups.1,2
After an initial diagnosis of NF1, the extent of the disease should be established, with personal medical history and physical examination and particular attention to features of NF1, ophthalmologic evaluation including slit lamp examination of the irides, developmental assessment in children and other studies as indicated on the basis of clinically apparent signs or symptoms.1
Surveillance recommendations for an individual with NF1 are for regular annual visits to include skin examination for new peripheral neurofibromas, signs of plexiform neurofibroma or progression of existing lesions, checks for hypertension, other studies (e.g., MRI) as indicated based on clinically apparent signs or symptoms and monitoring of abnormalities of the central nervous system, skeletal system or cardiovascular system by an appropriate specialist. In children, recommendations are for annual ophthalmologic examination in early childhood (less frequently in older children and adults) and regular developmental assessment.
Long-term care for individuals with NF1 aims at early detection and symptomatic treatment of complications.
It is recommended that radiotherapy be avoided, if possible, because radiotherapy in individuals with NF1 appears to be associated with a high risk of developing MPNST within the field of treatment.
NF2 (also known as bilateral acoustic neurofibromatosis and central neurofibromatosis) is estimated to occur in 1 in 33,000 individuals.
NF2 is characterized by bilateral vestibular schwannomas and associated symptoms of tinnitus, hearing loss and balance dysfunction.3 Average age of onset is 18 to 24 years, and almost all affected individuals develop bilateral vestibular schwannomas by age 30 years. Affected individuals may also develop schwannomas of other cranial and peripheral nerves, ependymomas, meningiomas and, rarely, astrocytomas. The most common ocular finding, which may be the first sign of NF2, is posterior subcapsular lens opacities; they rarely progress to visually significant cataracts.
Most patients with NF2 present with hearing loss, which is usually unilateral at onset. Hearing loss may be accompanied or preceded by tinnitus. Occasionally, features such as dizziness or imbalance are the first symptom.4 A significant proportion of cases (20%-30%) present with an intracranial meningioma, spinal or cutaneous tumor. The presentation in the pediatric population may differ from the adult population, in that, in children, vestibular schwannomas may account for as little as 15% to 30% of initial symptoms.4
The diagnosis of NF2 is usually made on clinical findings. Modified NIH diagnostic clinical criteria are one of the following:
- Bilateral vestibular schwannomas
- A first-degree relative with NF2 AND
- Unilateral vestibular schwannoma OR
- Any 2 of: meningioma, schwannoma, glioma, neurofibroma, posterior subcapsular lenticular opacities.
- Multiple meningiomas AND
- Unilateral vestibular schwannoma OR
- Any 2 of: schwannoma, glioma, neurofibroma, cataract.
NF2 is inherited in an autosomal dominant manner; approximately 50% of individuals have an affected parent and the other 50% have NF2 as a result of a de novo mutation.3
Between 25% and 33% of individuals with NF2 caused by a de novo mutation have somatic mosaicism. Mutation detection rates are lower in simplex cases and in an individual in the first generation of a family to have NF2 because they are more likely to have somatic mosaicism. Somatic mosaicism can make clinical recognition of NF2 difficult and results in lower mutation detection rates. Clinical recognition of NF2 in these patients may be more difficult because these individuals may not have bilateral vestibular schwannomas. Mutation detection rates may be lower because molecular genetic testing may be normal in unaffected tissue (e.g., lymphocytes), and molecular testing of tumor tissue may be necessary to establish the presence of somatic mosaicism.1
In an individual diagnosed with NF2, it is recommended that an initial evaluation establish the extent of the disease, typically using head MRI, hearing evaluation and ophthalmologic and cutaneous examinations.
Counseling is recommended for insidious problems with balance and underwater disorientation, which can result in drowning.
Hearing preservation and augmentation are part of the management of NF2, as is early recognition and management of visual impairment from other manifestations of NF2. Therefore, routine hearing and eye examination should be a part of care of individuals with NF2.
Surveillance measures for affected or at-risk individuals include annual MRI beginning at around age 10 and continuing until at least the fourth decade of life.
Treatment of manifestations includes surgical resection of small vestibular schwannomas, which may often be completely resected with preservation of hearing and facial nerve function. Larger tumors are often managed expectantly with debulking or decompression when brain stem compression, deterioration of hearing and/or facial nerve dysfunction occur.3
Radiotherapy should be avoided, because radiotherapy of NF2-associated tumors, especially in childhood, may induce, accelerate or transform tumors.3
Evaluation of At-Risk Relatives
Early identification of relatives who have inherited the family-specific NF2 mutation allows for appropriate screening using MRI for neuroimaging and audiologic evaluation, which result in earlier detection and improved outcomes.3 Identification of at-risk relatives who do not have the family-specific NF2 mutation eliminates the need for surveillance.
Schwannomatosis is a rare condition that is defined as multiple schwannomas without vestibular schwannomas that are diagnostic of NF2.3 Individuals with schwannomatosis may develop intracranial, spinal nerve root or peripheral nerve tumors. Familial cases are inherited in an autosomal dominant manner, with highly variable expressivity and incomplete penetrance. Clinically, schwannomatosis is distinct from NF1 and NF2, although some individuals eventually fulfill diagnostic criteria for NF2. SMARCB1 mutations have been shown to cause 30% to 60% of familial schwannomatosis but only a small number of simplex disease.
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests (LDTs) must meet the general regulatory standards of the Clinical Laboratory Improvement Act (CLIA). Lab tests for neurofibromatosis are available under the auspices of CLIA. Laboratories that offer LDTs must be licensed by CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.
Genetic counseling for genetic testing for neurofibromatosis is considered MEDICALLY NECESSARY.
Genetic testing for neurofibromatosis may be considered MEDICALLY NECESSARY when the diagnosis is clinically suspected due to signs of disease, but a definitive diagnosis cannot be made without genetic testing.
Genetic testing for neurofibromatosis in at-risk relatives with no signs of disease may be considered MEDICALLY NECESSARY when a definitive diagnosis cannot be made without genetic testing AND at least one of the following criteria is met:
- A close relative (i.e., first-, second- or third-degree relative) has a known NF mutation; or
- A close relative has been diagnosed with neurofibromatosis but whose genetic status is unavailable
Genetic testing for diagnosis of NF1 is considered MEDICALLY NECESSARY when at least two of the following signs are present:
- six or more light brown spots on the skin (often called "cafe-au-lait" spots), measuring more than 5 mm in diameter in children or more than 15 mm across in adolescents and adults;
- two or more neurofibromas, or one plexiform neurofibrom (a neurofibroma that involves many nerves);
- freckling in the area of the armpit or the groin;
- two or more growths on the iris of the eye (known as Lisch nodules or iris hamartomas);
- a tumor on the optic nerve (called an optic nerve glioma);
- abnormal development of the spine (scoliosis), the temple (sphenoid) bone of the skull or the tibia (one of the long bones of the shin);
- a parent, sibling or child with NF1.
Prenatal testing for diagnosis of NF1 is MEDICALLY NECESSARY only if the disease-causing allele of an affected family member has been identified before prenatal testing.
Genetic testing for diagnosis of NF2 is MEDICALLY NECESSARYwhen the diagnosis is clinically suspected due to signs of disease, but a definitive diagnosis cannot be made without genetic testing. The patient must meet one of the following criteria:
- Individuals with a first-degree relative with NF2 (i.e., affected parent, sibling or offspring)
- Multiple spinal tumors (schwannomas, meningiomas)
- Cutaneous schwannomas
- Apparently sporadic vestibular schwannoma less than 30 years of age, or spinal tumor or meningioma less than 20 years of age
- Unilateral vestibular schwannoma in those less than 20 years of age
Genetic testing for neurofibromatosis for all other situations not meeting the criteria outlined above is considered INVESTIGATIONAL.
Mutation scanning is a process by which a particular segment of DNA is screened to identify sequence variants. Variant gene regions are then further analyzed (e.g., by sequencing) to identify the sequence alteration. Mutation scanning allows for screening of large genes and novel sequence variants.
Schwann cells cover the nerve fibers in the peripheral nervous system and form the myelin sheath.
Simplex disease is a single occurrence of a disease in a family.
Somatic mosaicism is the occurrence of 2 genetically distinct populations of cells within an individual, derived from a postzygotic mutation. Unlike inherited mutations, somatic mosaic mutations may affect only a portion of the body and are not transmitted to progeny.
Genetic counseling is primarily aimed at patients who are at risk for inherited disorders, and experts recommend formal genetic counseling in most cases when genetic testing for an inherited condition is considered. The interpretation of the results of genetic tests and the understanding of risk factors can be very difficult and complex. Therefore, genetic counseling will assist individuals in understanding the possible benefits and harms of genetic testing, including the possible impact of the information on the individual’s family. Genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing. Genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.
CPT code 81405 includes the following test:
NF2 (neurofibromin 2 (merlin)) (e.g., neurofibromatosis, type), duplication/deletion analysis
CPT code 81406 includes the following test:
NF2 (neurofibromin 2 (merlin)) (e.g., neurofibromatosis, type), full gene sequence
CPT code 81408 includes the following test:
NF1 (neurofibromin 1) (e.g., neurofibromatosis, type 1), full gene sequence
BlueCard/National Account Issues
Some plans may have contract or benefit exclusions for genetic testing.
When possible, genetic testing for neurofibromatosis should be performed in an affected family member so that testing in at-risk family members with no signs of disease can be performed for the family-specific mutation found in the affected family member. However, coverage for testing of the affected index case (proband) depends on contract benefit language.
Specific contract language must be reviewed and considered when determining coverage for testing. In some cases, coverage for testing the index case may be available through the contract that covers the unaffected, at-risk individual who will benefit from knowing the results of genetic test.
This evidence review was created in January 2016, with a review of the literature through Nov. 12, 2015.
Schwannomatosis is rare and far less well-described than neurofibromatosis type 1 (NF1) and neurofibromatosis type 2 (NF2); therefore, this review will focus on NF1 and NF2.
Validation of the clinical use of any genetic test focuses on 3 main principles: (1) analytic validity, which refers to the technical accuracy of the test in detecting a mutation that is present or in excluding a mutation that is absent; (2) clinical validity, which refers to the diagnostic performance of the test (sensitivity, specificity, positive and negative predictive values) in detecting clinical disease; and (3) clinical utility, i.e., how the results of the diagnostic test will be used to change management of the patient and whether these changes in management lead to clinically important improvements in health outcomes.
Published evidence on the analytic validity of testing for NF1 is lacking.
According to 1 major laboratory’s website, the analytic validity of bidirectional sequencing of the entire NF1 coding region, intron-exon boundaries, multiplex ligation-dependent probe amplification (MLPA) to detect large NF1 locus and intragenic deletions/duplications is 99%.5
Published evidence on the analytic validity of testing for NF2 is lacking.
Detecting mutation in the NF1 gene is challenging because of the gene’s large size, the lack of mutation hotspots and the wide variety of possible lesions.
A multistep mutation testing protocol identifies more than 95% of NF1 pathogenic variants in individuals who fulfill the National Institutes of Health (NIH) diagnostic criteria.1 The protocol involves sequencing of both mRNA (cDNA) and genomic DNA, and testing for whole NF1 deletions (e.g., by MLPA) because whole gene deletions cannot be detected by sequencing. Due to the wide variety and rarity of individual pathogenic mutation variants in NF1, sequencing of cDNA increases the detection rate of mutations from approximately 61% with genomic DNA sequence analysis alone6 to greater than 95% with sequencing for both cDNA and genomic DNA and testing for whole gene deletions. This latter method is known as the multistep mutation detection protocol.
Sensitivity rates of more than 95% for detecting a mutation using the multistep protocol have been reported.7,8
Sabbagh et al. reported a comprehensive mutation analysis of constitutional NF1 mutations in unrelated, well-phenotyped index cases with typical clinical features of NF1 who enrolled in a French clinical research program.7 The 565 families for this study (N=1,697 individuals) were enrolled between 2002 and 2005; 1,083 fulfilled NIH diagnostic criteria for NF1. A comprehensive NF1 mutation screening (sequencing of both cDNA and genomic DNA, as well as large deletion testing by MLPA) was performed in 565 individuals, one from each family, who had a sporadic mutation or who represented the familial index case. An NF1 mutation was identified in 546, a mutation detection rate of 97%. A total of 507 alterations were identified at the cDNA and genomic DNA levels. Among these 507 alterations, 487 were identified using only the genomic DNA sequencing approach. Among these 507 alterations, 505 would have been identified if the single cDNA sequencing approach were used. MLPA detected 12 deletions/duplications that would not have been detected by sequencing. No mutation was detected in 19 patients (3.4%), 2 of whom had a SPRED1 mutation, which is frequently confused with NF; the remainder may have been due to an unknown mutation of the NF1 locus.
The authors then statistically evaluated the genotype-phenotype correlation in 439 of these patients harboring a truncating (n=368), in-frame splicing (n=36) or missense (n=35) NF1 mutation to assess the contribution of intragenic NF1 mutations (vs. large gene deletions) to the variable expressivity of NF1. Their findings suggested a tendency for truncating mutations to be associated with a greater incidence of Lisch nodules and a larger number of café-au-lait spots compared with missense mutations.
Valero et al. developed a method for detecting NF1 mutations by combining an RNA-based cDNA-polymerase chain reaction mutation detection method and denaturing high-performance liquid chromatography with MLPA.8 Their protocol was validated in a cohort of 56 patients with NF1 (46 sporadic cases, 10 familial cases) who fulfilled NIH diagnostic criteria. A mutation was identified in 53 cases (95% sensitivity), involving 47 different mutations, of which 23 were novel. After validation, the authors implemented the protocol as a routine test and subsequently reported the spectrum of NF1 mutations identified in 93 patients in a cohort of 105. The spectrum included a wide variety of mutations (nonsense, small deletions or insertions/duplications, splice defects, complete gene deletions, missense, single exon deletions and duplications and a multiexon deletion), confirming the heterogeneity of the NF1 gene mutations that can cause NF1.
NF1 is characterized by extreme clinical variability between unrelated individuals, among affected individuals within a single family and even within a single person with NF1 at different times in life. Only 2 clear correlations have been observed between certain NF1 alleles and consistent clinical phenotypes1:
- A deletion of the entire NF1 gene is associated with large numbers and early appearance of cutaneous neurofibromas, more frequent and severe cognitive abnormalities, somatic overgrowth, large hands and feet and dysmorphic facial features.1,9,10
- A 3-base pair inframe deletion of exon 17 is associated with typical pigmentary features of NF1, but no cutaneous or surface plexiform neurofibromas.11
Multigene Panel Testing
Multigene panel testing typically includes the NF1 gene and other genes associated within the differential diagnosis of NF1. The detection frequency of pathogenic variants in the NF1 gene on a panel performed by genomic DNA sequencing will be much lower than that obtained by using the multistep protocol described above.1
At least 200 different NF2 mutations have been described, most of which are point mutations. Large deletions of NF2 represent 10% to 15% of NF2 mutations. 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.3 Other studies have reported lower mutation detection rates, which likely reflects the inclusion of more mildly affected individuals with somatic mosaicism.3
Intrafamilial variability is much lower than interfamilial variability, and the phenotypic expression and natural history of the disease are similar within families with multiple members with NF2.12
Unlike NF1, large deletions of NF2 have been associated with a mild phenotype.
Frameshift or nonsense mutations cause truncated protein expression, which has been associated with more severe manifestations of NF2.12 Missense or inframe deletions have been associated with milder manifestations of the disease.12
Selvanathan et al. reported on genotype-phenotype correlations in 268 patients with an NF2 mutation.13 Mutations that resulted in a truncated protein were associated with statistically significantly younger age at diagnosis, higher prevalence and proportion of meningiomas, spinal tumors and tumors of cranial nerves other than VIII, vestibular schwannomas at a younger age and more cutaneous tumors. Mutations found in the later part of the gene, especially exons 14 and 15, were associated with milder disease and fewer meningiomas.
The clinical utility of genetic testing for NF depends on how the results can be used to improve patient management.
Clinical Utility for Individuals With Suspected NF
The clinical utility of genetic testing for NF1 in adults is limited because most cases of NF1 can be diagnosed clinically with the NIH diagnostic criteria, which are both highly sensitive and specific in all but the youngest of children. Rare cases in adults who do not fulfill the NIH diagnostic criteria may benefit from genetic testing to confirm the diagnosis and to direct clinical management according to accepted guideline recommendations.
The clinical utility of genetic testing for NF2 is higher than in NF1, in that affected individuals may have little in the way of external manifestations and the onset of symptoms may be due to tumors other than vestibular schwannomas, particularly in children. Early identification of patients with NF2 can lead to earlier intervention and improved outcomes, and direct clinical management according to accepted guideline recommendations.
Clinical Utility for At-Risk Relatives
Genetic testing in at-risk relatives of a patient with a diagnosis of NF1 is rarely necessary, in that one of the NIH criterion for diagnosis is having a first-degree relative with NF1 and, therefore, only 1 other clinical sign is necessary for diagnosis. Rare cases in at-risk relatives who do not fulfill the NIH diagnostic criteria may benefit from genetic testing to direct clinical management according to accepted guideline recommendations.
Testing for NF2 may be useful to identify at-risk relatives of patients with an established diagnosis of NF2, allowing for appropriate surveillance, earlier detection and treatment of disease manifestations, and avoiding unnecessary surveillance in an individual who does not have the family-specific mutation. Unlike NF1, the age of onset of symptoms of NF2 is relatively uniform within families. Therefore, it is usually not necessary to offer testing or surveillance to asymptomatic parents of a proband. However, testing of at-risk asymptomatic individuals younger than 18 years of age may be particularly useful, especially in children, to avoid unnecessary procedures in a child who has not inherited the mutation.3
Ongoing and Unpublished Clinical Trials
A search of ClinicalTrials.gov in December 2015 did not identify any ongoing or unpublished trials that would likely influence this review.
Summary of Evidence
The evidence for genetic testing in individuals who have suspected neurofibromatosis (NF) who do not fulfill diagnostic clinical criteria or who are asymptomatic, do not meet diagnostic clinical criteria but have close relative(s) with neurofibromatosis diagnosis, includes clinical validation studies of a multistep diagnostic protocol and genotype-phenotype correlation studies. Relevant outcomes are test accuracy and validity, symptoms, change in disease status, morbid events and functional outcomes. Published data on the analytic validity of genetic testing for NF is lacking. A multistep mutation testing protocol identifies more than 95% of pathogenic variants in NF type 1 (NF1) and, for NF type 2 (NF2), the mutation detection rate approaches 72% in simplex cases and exceeds 92% for familial cases. For individuals with a known pathogenic mutation in the family, testing of at-risk relatives will confirm or exclude the mutation with high certainty. Published evidence on the clinical utility of genetic testing for NF is lacking, but a definitive diagnosis can direct patient care according to established clinical management guidelines, including referrals to the proper specialists, treatment of manifestations and surveillance. Testing of at-risk relatives will lead to initiation or avoidance of management and/or surveillance. Early surveillance may be particularly important for patients with NF2, because early identification of internal lesions by imaging is expected to improve outcomes. The evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome.
Practice Guidelines and Position Statements
An expert panel and the Genetics Committee of the American Academy of Pediatrics have published diagnostic and health supervision guidelines for children with NF1.2
U.S. Preventive Services Task Force Recommendations
- Friedman JM. Neurofibromatosis 1. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews(R). Seattle (WA); 1993.
- Hersh JH. Health supervision for children with neurofibromatosis. Pediatrics. Mar 2008;121(3):633-642. PMID 18310216
- Evans DG. Neurofibromatosis 2. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews(R). Seattle (WA); 1993.
- Evans DG, Sainio M, Baser ME. Neurofibromatosis type 2. J Med Genet. Dec 2000;37(12):897-904. PMID 11106352
- ARUP Laboratories. Neurofibromatosis Type 1 (NF1) Sequencing and Deletion/Duplication. 2016; http://ltd.aruplab.com/Tests/Pub/2007154.
- van Minkelen R, van Bever Y, Kromosoeto JN, et al. A clinical and genetic overview of 18 years neurofibromatosis type 1 molecular diagnostics in the Netherlands. Clin Genet. Apr 2014;85(4):318-327. PMID 23656349
- Sabbagh A, Pasmant E, Imbard A, et al. NF1 molecular characterization and neurofibromatosis type I genotypephenotype correlation: the French experience. Hum Mutat. Nov 2013;34(11):1510-1518. PMID 23913538
- Valero MC, Martin Y, Hernandez-Imaz E, et al. A highly sensitive genetic protocol to detect NF1 mutations. J Mol Diagn. Mar 2011;13(2):113-122. PMID 21354044
- Pasmant E, Sabbagh A, Spurlock G, et al. NF1 microdeletions in neurofibromatosis type 1: from genotype to phenotype. Hum Mutat. Jun 2010;31(6):E1506-1518. PMID 20513137
- Mautner VF, Kluwe L, Friedrich RE, et al. Clinical characterisation of 29 neurofibromatosis type-1 patients with molecularly ascertained 1.4 Mb type-1 NF1 deletions. J Med Genet. Sep 2010;47(9):623-630. PMID 20543202
- Upadhyaya M, Huson SM, Davies M, et al. An absence of cutaneous neurofibromas associated with a 3-bp inframe deletion in exon 17 of the NF1 gene (c.2970-2972 delAAT): evidence of a clinically significant NF1 genotype-phenotype correlation. Am J Hum Genet. Jan 2007;80(1):140-151. PMID 17160901
- Evans DG. Neurofibromatosis type 2. In: UpToDate, ed. UpToDate. Waltham, MA; 2015.
- Selvanathan SK, Shenton A, Ferner R, et al. Further genotype--phenotype correlations in neurofibromatosis 2. Clin Genet. Feb 2010;77(2):163-170. PMID 19968670
See Policy Guidelines
Medical genetics and genetic counseling services, each 30 minutes face-to-face with patient/family
Neurofibromatosis (nonmalignant) code range
Not applicable. ICD-10-PCS codes are only used for inpatient services. There are no ICD procedure codes for laboratory tests.
Type of Service
Place of Service
Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.
This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross and Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.
"Current Procedural Terminology© American Medical Association. All Rights Reserved"
History From 2016 Forward
Annual review, medical necessity statement regarding genetic counseling added, no other changes made.
Annual review, adding medical necessity criteria for testing for NF2. No other changes to policy intent.
Updated category to Laboratory. No other changes
Interim review adding specificity to the medical necessity criteria. No other change to policy.