Adult Summary Report Secondary Findings in Adult Subjects Non-diagnostic, excludes newborn screening & prenatal testing/screening A Current Version Rule-Out Dashboard Release History Status (Adult): Passed (Consensus scoring is Complete)

Condition: Neurofibromatosis type 1
Narrative Description of Evidence
1. What is the nature of the threat to health for an individual carrying a deleterious allele?
Prevalence of the Genetic Disorder
Neurofibromatosis type 1 (NF1) occurs with a birth incidence of 1 in 2,500-3,000 and a prevalence of 1 in 3,500-5,000.
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Clinical Features
(Signs / symptoms)
Characteristics symptoms of NF1 include: multiple café-au-lait spots, axillary and inguinal freckling, multiple cutaneous neurofibromas (benign peripheral nerve sheath tumors), iris Lisch nodules (hamartomas), and characteristics bony dysplasia of the long bones and sphenoid wing. Most individuals have normal intelligence, but learning disabilities are present in at least 50%. Less common but potentially more serious manifestations can include: other forms of tumors (e.g., plexiform neurofibromas, malignant peripheral nerve sheath tumors), ocular (e.g., optic gliomas), cognitive (e.g. intellectual disability), neurologic (e.g., seizures, migraines), musculoskeletal (e.g., scoliosis), and vascular/cardiac (e.g., hypertension) findings.
Women with NF1 have a substantially increased risk of developing breast cancer before age 50 years with estimated risk at least three times greater than the general population. People with NF1 may also be at increased risk for many other common cancers.
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Natural History
(Important subgroups & survival / recovery)
Approximately 90% of individuals with NF1 will have two or more diagnostic criteria by age 6, 97% by age 8, and all do so by 20 years of age. The most common presenting feature is multiple café-au-lait spots. Many individuals with NF1 develop only cutaneous manifestations of the disease and Lisch nodules, but the frequency of more serious complications increases with age. Bony manifestations are congenital, and café-au-lait spots are present at birth and increase in number the first few years of life. Discrete cutaneous and subcutaneous neurofibromas are rare before late childhood. The total number of neurofibromas in adults vary from a few to thousands, with more developing throughout life, though the rate of appearance may vary from year to year. Many women experience a rapid increase in the number and size of neurofibromas during pregnancy. Plexiform neurofibromas generally grow slowly over years, but rapid growth can occur in benign lesions, especially in early childhood. Most are asymptomatic; however, when symptomatic, plexiform neurofibromas can cause disfigurement and may compromise function or even jeopardize life. Malignant peripheral nerve sheath tumors tend to occur at a much younger age in people with NF1, often in adolescence or early adulthood. Optic gliomas, which may lead to blindness, are generally present before age six with loss of visual acuity or proptosis, but may not become symptomatic until later in childhood or adulthood. Symptomatic optic gliomas progress slowly, and may even regress.
The significant risk of breast cancer appears to begin at age 30 and drop after age 50 where risk is not significantly different from that of the general population.
The median life expectancy of individuals with NF1 is approximately 8-15 years lower than the general population with early causes of death including malignancy and vasculopathy. In a study of US death certificates, mean and median ages of death were estimated as 54.4 and 59 years respectively. Cosmetic, medical, behavioral, and social features of the disease all may compromise the quality of life in people with NF1.
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2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
Patient Management
To establish the extend of disease and needs in an individual diagnosed with NF1, the following evaluations are recommended:
- Personal medical history with particular attention to the features of NF1
- Physical examination with particular attention to the skin, skeleton, cardiovascular system, and neurologic systems
- Ophthalmologic evaluation including slit lamp examination of the irides
- Other studies as indicated on the basis of clinically apparent signs or symptoms
- Medical genetics consultation (Tier 4)
There is no medical treatment that can prevent or reverse the characteristic lesions. The mainstay of management is age specific monitoring of disease manifestations and patient education to allow early detection of treatable complications (e.g., removal of malignant peripheral nerve sheath tumors) and prompt institution of therapy. Management is often performed under the aegis of a specialized "Neurofibromatosis Clinic", where considerable expertise representing multiple medical disciplines can be gathered. NF1 individuals need to be encouraged to seek review of any unusual symptoms and ask if they are related to NF1. Young adults aged 16-25 years are at a vulnerable stage of life and require education about NF1 and its possible complications. Counseling about disease inheritance and psychological support are advised, particularly as neurofibromas often start to develop in late adolescence. (Tier 2)
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If present, cognitive impairment remains stable in adulthood. Adults should be asked about their literacy and numeracy as impairment of these skills reduces clinic attendance and understanding of information about their condition. Referral to adult literacy classes might be appropriate in some instances. Clinic visits should be followed where possible by a telephone call to ascertain that the individual understands his/her care plan. (Tier 2)
When caring for pregnant women, close liaison between the obstetrician and neurofibromatosis clinician is important due to the potential for neurofibromas to grow in size and number. Hypertension requires care evaluation. (Tier 2)
Adults should be offered the opportunity of attending a specialist NF1 clinic, typically run by geneticists and neurologists, on an annual basis. Monitoring after the mid-twenties depends on patient preference and disease severity. Adults with mild disease have a much lower risk of complications. If they elect not to attend a specialist NF1 clinic, they should be fully conversant with the problems that they might encounter. The minimum requirement for an asymptomatic adult is to be aware of unusual symptoms, particularly the clinical features of malignant peripheral nerve sheath tumors and of spinal cord compression, and blood pressure measurement. Treatment of essential hypertension is the same as in the general population. (Tier 2)
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Women should be offered annual mammogram starting at age 30 and could consider breast MRI with contrast from ages 30-50 years. At this time there are no data to suggest an increase in breast cancer risk after age 50. A population based study in Finland of 1,404 patients with NF1 showed a significant association between NF1 and breast cancer risk (SIR: 3.04, 95% CI: 2.06-4.31; p<0.001). The highest excess incidence was noted in women under age 40 (SIR: 11.10, 95% CI: 5.56-19.50; p<0.001). Increased risk was also noted in England (SIR: 3.5, 95% CI: 1.9-5.9), with higher risks in women under 50 (SIR: 4.9, 95% CI: 2.4-8.8). The cumulative risk of developing breast cancer was estimated at 8.4% by age 50. Case-control analysis of women from England show that relative risk estimates are higher for women ages 30 to 39 (RR: 6.5, 95% CI: 2.6-13.5) and ages 40 to 49 (RR: 4.4, 95% CI: 2.5-7.0) but then drops for women ages 50 to 59 (RR: 2.6, 95% CI: 1.5-4.2) and continue to drop as age increases (RR: 1.9, 95% CI: 1.0-3.3 for ages 60 to 69; RR: 0.8, 95% CI: 0.2-2.2 for ages 70 to 79). There is no data regarding the benefit of risk-reducing mastectomy for women with NF1 mutations; therefore, risk reducing surgery is not recommended for these patients but may be considered based on family history. (Tier 2)
No studies on the effectiveness of screening for breast cancer in women with NF1 mutations were identified. One guideline summarizes that low quality evidence suggests a disease specific survival benefit with mammographic surveillance in women aged less than 50 years with a family history of breast cancer. First, an observational study indicated a decreased risk of death from breast cancer when diagnosed during mammographic surveillance (lead time adjusted HR 0.24 [95% CI 0.09 to 0.66]). Modeling data predicts a decrease in 10 year breast cancer mortality death in those undergoing screening RR 0.80 (95% CI 0.66 to 0.96). A retrospective study showed a decreased rate of all-cause mortality in BRCA1/2 carriers diagnosed with breast cancer during an intensive mammographic surveillance program (HR 0.44 [95% CI 0.25 to 0.77]). (Tier 1)
Circumstances to Avoid
Radiotherapy is contraindicated because of risk of malignancy. (Tier 2)
3. What is the chance that this threat will materialize?
Mode of Inheritance
Autosomal Dominant
Prevalence of Genetic Mutations
The mutation rate for NF1 (~1:10,000) is among the highest known for any gene in humans. Half of affected individuals have NF1 as a result of a de novo mutation. Given that all cases of NF1 are associated with mutations in NF1 it is expected that the prevalence of the mutation would be similar to the prevalence of the condition. (Tier 3)
(Include any high risk racial or ethnic subgroups)
Penetrance is virtually complete after childhood. (Tier 4)
Frequency of onset of major clinical manifestations:
- Cafe´-au-lait patches: >99%
- Skin-fold freckling: 85%
- Lisch nodules: 90–95%
- Cutaneous neurofibromas: >99%
- Plexiform neurofibromas: 30%(visible) – 50%(on imaging)
- Malignant peripheral nerve sheath tumor: 2–5% (8–13% lifetime risk)
- Scoliosis: 10%
- Pseudarthrosis of tibia: 2%
- Renal artery stenosis: 2%
- Pheochromocytoma: 2%
- Severe cognitive impairment (IQ <70): 4–8%
- Learning problems: 30–60%
- Epilepsy: 6–7%
- Optic pathway glioma: 15% (only 5% symptomatic)
- Cerebral gliomas: 2–3%
- Sphenoid wing dysplasia: <1
- Aqueduct stenosis: 1.5% (Tier 3)
The cumulative risk of developing breast cancer was estimated at 8.4% by age 50. (Tier 3)
Relative Risk
(Include any high risk racial or ethnic subgroups)
Among one cohort the relative risk of malignant neoplasms or benign central nervous system tumors was estimated at 4.0. A second cohort identified a relative risk of developing malignant peripheral nerve sheath tumors of 113. (Tier 3)
NF1 is characterized by extreme clinical variability, not only between unrelated individuals and among affected individuals within a single family but even within a single person with NF1 at different times in life. (Tier 4)
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4. What is the Nature of the Intervention?
Nature of Intervention
Recommendations for management of individuals with NF1 include increased pregnancy monitoring, measurement of hypertension, and enhanced breast cancer surveillance.
5. Would the underlying risk or condition escape detection prior to harm in the settting of recommended care?
Chance to Escape Clinical Detection
Clinical management of persons with NF is complicated by a wide range of variability of expression, often impeding accurate diagnosis. (Tier 3)
Approximately 90% of individuals with NF1 will have two or more diagnostic criteria by age 6, 97% by age 8, and all do so by 20 years of age. (Tier 4)
Occasionally, a parent of an affected individual has been found to have a segmental/mosaic form of NF1 with few health problems. (Tier 4)

Final Consensus Scores
Outcome / Intervention Pair
Nature of the
Malignant peripheral nerve sheath tumors / Consultation with a provider experienced with NF1 for educational purposes
Breast Cancer / Surveillance
To see the scoring key, please go to:
Description of sources of evidence:
Tier 1: Evidence from a systematic review, or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.
Reference List
1. Prevention and control of neurofibromatosis: memorandum from a joint who/nnff meeting. Bull World Health Organ. (1992) 70(2):173-82.
2. Ferner RE, Huson SM, Thomas N, Moss C, Willshaw H, Evans DG, Upadhyaya M, Towers R, Gleeson M, Steiger C, Kirby A. Guidelines for the diagnosis and management of individuals with neurofibromatosis 1. J Med Genet. (2007) 44(2):81-8.
3. JM Friedman. Neurofibromatosis 1. 1998 Oct 02 [Updated 2014 Sep 04]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019. Available from:
4. Radtke HB, Sebold CD, Allison C, Haidle JL, Schneider G. Neurofibromatosis type 1 in genetic counseling practice: recommendations of the national society of genetic counselors. J Genet Couns. (2007) 16(4):387-407.
5. Genetic/familial high-risk assessment: breast and ovarian. Publisher: National Comprehensive Cancer Network. (2016) Accessed: 2017-04-26. Website:
6. Gutmann DH, Aylsworth A, Carey JC, Korf B, Marks J, Pyeritz RE, Rubenstein A, Viskochil D. The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. JAMA. (1997) 278(1):51-7.
7. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. Neurofibromatosis, type i; nf1. MIM: 162200: 2016 Nov 15. World Wide Web URL:
8. 2013 Jun.
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