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NF1 (Neurofibromatosis type 1) – risk management

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Neurofibromatosis type 1 (NF1) is an autosomal dominant benign and malignant tumour pre-disposition condition, characterised by the development of benign peripheral nerve sheath tumours (neurofibromas). Approximately 50% of cases are de novo, and of these, a small proportion is mosaic, often with milder, asymmetrical or segmental disease.r

This risk management guideline has been developed for individuals who have NOT been diagnosed with a relevant cancer. The care of affected individuals should be individualised based on their clinical situation, and the monitoring they need as part of their treatment and post-treatment follow up.

The risk management of an individual with a mutation in 2 or more genes that confer a predisposition to cancer should also be individualised.

  • Known or obligate NF1 gene mutation carrier.
  • Individual meeting clinical criteria for NF1, but for whom genetic testing is uninformative or has not been performed.
  • Individual at 50% risk of inheriting a NF1 gene mutation.
  • Individual with a first degree relative who meets clinical criteria for NF1, but where genetic testing is uninformative or has not been performed.
  • Children under age 5 where clinical or molecular diagnosis is uncertain (for example a child with >6 café au lait patches who does not otherwise fulfil the criteria for diagnosis of NF1*).

Exclusion criteria

  • Individual who has a first degree relative who meets clinical criteria for NF1, but does not have any clinical signs of NF1 after age 20 years.*
  • Individual with a SPRED1 mutation.

*Caution should be taken in excluding the diagnosis of NF1 based on clinical criteria due to the possibility of minimally manifesting mutation carriers.r

Cancer Risk for NF1 carriers General population
by age 85 yrs*
Cancer (both sexes) 25.1% by 30 yrsr
38.8% by 50 yrsr
59.6% by 85 yrsr		 46%
Cancer (female) 30.6% by 30 yrsr
45.2% by 50 yrsr		 40%
Cancer (male) 20.8% by 30 yrsr
32.0% by 50 yrsr		 52%
Malignant peripheral nerve sheath tumours 8.5% by 30 yrsr
12.3% by 50 yrsr
15.8% by 85 yrsr		 <1%
Optic nerve pathway glioma 15%r Not available 
Brain/spinal cord glioma Up to 3%r Not available
Breast cancer (female)

30–39 yrs: 2–5.5%rr
                    6.5 (2.6–13.5) fold riskrrr

40-49 yrs: 3.9–7.8%rrr
                   4.4 (2.5–7.0) fold risk

50–59 yrs: 5.8%rr
                     2.1–2.6 fold riskrr

60–69 yrs: 4.1%rr
                     1.8–1.9 fold riskrr

70–79 yrs: 3.9%rr
                     0.8 fold riskrr

Lifetime: 18%r
                 SIR 1.8–3.5rrr

30–39 yrs: 0.44%

40–49 yrs: 1.68%

50–59 yrs: 2.50%

Lifetime: 13.05%
Phaeochromocytoma Up to 2% (12% are malignant)r <1%
Gastrointestinal stromal tumour (GIST) 6%r <1%

The published literature is biased towards NF1 families with higher tumour incidence. The published data expresses some cancer risk estimates as observed/expected rather than age related penetrance. 

*Australian Institute of Health and Welfare (AIHW) 2018. Australian Cancer Incidence and Mortality (ACIM) books. 2015 data

There are a broad spectrum of additional health problems associated with NF1, and these are summarised elsewhererr Review Checklist - NF1 Tumour related manifestations are listed below.  

Manifestationrr Risk for NF1 carriersrr General population to age 85 yrs
Cutaneous neurofibromas >99% Not available

Plexiform neurofibromas

- Disfiguring facial plexiform neurofibromas

50–60%

3–5%

 Not available
Extra-adrenal paraganglioma <5% Not available
Dysembryoplastic neuroepithelial tumour <5% Not available
Carcinoid 1.5% Not available
Xanthogranuloma 0.7% Not available

All children with NF1 should be managed by local specialists (e.g. paediatricians and/or a multidisciplinary team). Adults with NF1 could be managed by their general practitioner with referral to specialised services as necessary. More complex cases could be referred to a NF1 clinic or multidisciplinary team who have extensive experience with the condition.

Individuals with mosaic or segmental NF1 may require less intensive review depending on their clinical presentation.

Tumour type Recommendations**
Optic nerve pathway glioma
Surveillance		 Age to begin Strategy and frequency

From infancy
  • 6 monthly examination by ophthalmologist.r
  • Routine screening neuroimaging is not recommended.r

From age 4 to 16 

Annual examination by ophthalmologist.r

From age 16

3–5 yearly examination by ophthalmologist if no tumour has arisen during childhood.
Breast cancer (female only) Surveillance

All ages

Breast awareness with prompt reporting to general practitioner of persistent or unusual changes.

From age 35 to 50
  • In families with breast cancer diagnosed under age 35 yrs, individualised screening recommendations may apply.
  • 35–40 yrs - annual MRI, +/- US
  • 40–50 yrs - annual MRI, +/- MMG, +/- US
  • >50 yrs - 2 yearly MMG, +/- US
  • Pregnant - no MRI or MMG, consider US.
Phaeochromocytoma Surveillance

From age 10
Malignant peripheral nerve sheath tumour Surveillance

From age 10
  • Annual clinical review with physical examination
  • Encourage early reporting of symptoms (Link to HELP card)
  • Consider referral to specialised sarcoma centre.

**The impact of lifestyle on cancer risk should be discussed e.g. exercise regularly, maintain healthy weight, have a healthy diet, limit alcohol intake, do not smoke and avoid excessive sun exposure.

Management of other NF1 associated manifestations is summarised by the NF1 review checklist

Acknowledgements: This document is adapted and reproduced with permission of the Neurofibromatosis Service, Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK. 

The evidence supporting these management guidelines is provided by expert consensus opinion.

Cancer (all)

Some types of cancer in NF1 are associated with poorer survival when compared with general population controls, particularly in those diagnosed at age <40 years.r Therefore, concerning symptoms should be investigated promptly.

The type, timing and degree of intervention/ surgery, chemotherapy or radiotherapy treatment of NF1 patients (if any) should be carefully made by a multidisciplinary team with experience in managing NF1.rr Radiotherapy should be avoided where possible due to increased risk of secondary tumours.r

Other possible NF1 associated cancers include juvenile myelomonocytic leukaemia, thyroid cancer, malignant fibrous histiocytomas and rhabdomyosarcoma.rr

Optic nerve pathway gliomas

Most optic nerve gliomas occur between 3–5 years of age, and do not require intervention.rr

Breast cancer

Women with NF1 have poorer breast cancer survival rates, compared with women in the general population (67.9% vs 87.8% 5 year survival).r

Breast surveillance

Breast screening guidelines are based on expert consensus rather than solid evidence. Breast screening is recommended from 35 years given the increased risk of early breast cancer. Breast MRI is recommended due to the high sensitivity of MRI compared with MMG and ultrasound in young women. MRI detects tumours which are smaller and more likely to be node-negative than mammography. MRI is also preferred over MMG in young women with NF1, if available, to reduce ionizing radiation exposure. MRI has a recall rate (requiring further investigation and/or biopsy) of 15% for initial screening, which decreases with subsequent rounds of screening to <10%. The effectiveness of breast cancer screening in women with NF1 is still unclear and data about the utility of screening programs is mostly extrapolated from cancer screening studies in other groups at increased risk of breast cancer.

Breast surgical

There is no evidence regarding the benefit of risk reducing mastectomy in women with NF1. The lifetime risk of breast cancer is considered to be in the moderate risk range, therefore risk reducing mastectomy is not recommended in this group.

Malignant peripheral nerve sheath tumour (MPNST)

MPNSTs are aggressive sarcomas that often arise in plexiform neurofibroma and are associated with a poor survival. The median age of diagnosis for MPNST is 30–34 years.r Individuals with deep, truncal location of plexiform neurofibroma, previous radiation and an NF1 microdeletion have an increased risk of MPNSTs.r

First degree blood relatives (parents/brothers/sisters/children) may be at up to 50% risk of having the condition. First degree relatives should be referred to a clinical team with expertise in NF1 such as a Clinical Genetics or familial cancer service. 

Link to information sheet on Informing family members about hereditary cancer.

Centre for Genetics Education NSW Health
Genetic Alliance Australia  
Children's Tumour Foundation (NF Australia)

Further references

For further references used to develop this protocol please see the history section.

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Version 7

Date Summary of changes
16/06/2011 New protocol taken to cancer genetics reference committee meeting.
17/08/2011 Approved and published on eviQ.
07/09/2012 Additional reference added to reference list Huson, S. 2008. "Neurofibromatosis: emerging phenotypes, mechanisms and management." Clin Med 8(6):611-617.
09/04/2013

Discussed at March 6, 2013 reference committee meeting and the following changes made:

  • First sentence updated.
  • Target group - added- children under age 5 where clinical or molecular diagnosis is uncertain (for example a child with >6 café au lait patches but does not otherwise fulfil criteria for diagnosis of NF1).
  • Exclusion criteria - added-  individual with a SPRED1 mutation.
  • Lifetime risk of cancer table updated and juvenile myelomoncytic leukaemia added. 
  • Cancer risk management guidelines - table updated.
    - optic nerve pathway glioma -surveillance changed from annual surveillance by ophthalmologist until age 10 to annual surveillance by ophthalmologist until age 8 years then 2nd yearly until 18 years added routine screening neuroimaging is not recommended.
    - breast cancer - surveillance changed from annual mammography from 40 yrs to annual mammography between 40-50 yrs then 2nd yearly. 
  • Support and information - paragraph updated.
  • References -  reviewed and updated.
13/10/2015

Discussed at 7 May, 2015 reference committee meeting and the following changes made:

  • Target group changed to known or obligate carrier of NF1 mutation/clinical diagnosis of NF1.
  • Link updated - Genetic Alliance Australia.
07/01/2016 Sentence added to Risk Management template: "The impact of lifestyle of cancer risk should be discussed".
14/04/2016 Sentence added to Risk Management template: "This risk management guideline has been developed for individuals who have NOT been diagnosed with a relevant cancer/tumour.  The care of affected individuals should be individualised based on their clinical situation, and the monitoring they need as part of their treatment and post-treatment follow up".
20/02/2017

Discussed at 20 October 2016 cancer genetics reference committee meeting and the following changes made:

  • target group - amended
  • exclusion criteria - amended
  • lifetime risk of cancer - amended
  • lifetime risk of non-cancer related manifestations - added
  • cancer risk management guidelines - amended
  • management of associated health problems and side effects - amended
  • evidence for cancer risk management guidelines - evidence for cancer (all), optic nerve pathway gliomas and breast cancer added
  • references - updated
  • changed to version 4 
  • next review in 2 years.
31/05/2017 Transferred to new eviQ website. Version number changed to V.5.
22/03/2019

Protocol reviewed and presented at the November 2018 eviQ RC meeting. Discussion continued over email and document approved for publication with the following changes: 

Summary: Sentence from updated template added.

Lifetime risk of cancer section: Statistics updated, including breast cancer further stratified by age. 

Lifetime risk of non-cancer manifestations section: Statistics updated.

Cancer risk management guidelines section:

  • Breast cancer surveillance age to begin and recommended screening methods updated.
  • Malignant peripheral nerve sheath tumour surveillance added.
  • Table caption 'the impact of lifestyle...' updated to reflect new template wording.

Management of associated health problems section: 

  • NF1 review checklist updated.

Evidence for risk management guidelines section:

  • Sentence removed on 'lifelong implications of the condition'.
  • Breast cancer section updated to include subsections on surveillance and surgical.
  • Section added on malignant peripheral nerve sheath tumours.

Version changed to V.6.
05/04/2019 Management of associated health problems: The following line removed "For permission to use in another setting, please contact susan.huson@cmft.nhs.uk" as Susan Huson has now retired, and the original NF1 review checklist has been adapted by RNSH.
23/04/2019 Cancer risk management guidelines: Link to ID 3558 - Risk management for SDH related paraganglioma-phaeochromocytoma predisposition syndromes added in as 3558 now published.
12/06/2019 Review date moved back from 2 yearly review, to yearly in light of potential new evidence being published. Review now due 22 March 2020.
09/07/2019 Cancer risk management guidelines: Breast cancer - surveillance - 'annual MMG, +/- US' changed back to '2 yearly MMG, +/- US', as per authors and consensus at May 2019 RCM.
28/08/2019 Protocol title changed from 'Risk management for neurofibromatosis type 1 (NF1)' to 'NF1 (Neurofibromatosis type 1) – risk management' in accordance with Cancer Genetics Reference Committees' consensus. Version number increased to V.7.
 

Further references used to develop this protocol:

Madanikia, S. A., A. Bergner, X. Ye, et al. 2012. "Increased risk of breast cancer in women with NF1." Am J Med Genet A 158A(12):3056-3060.

Wang, X., A. M. Levin, S. E. Smolinski, et al. 2012. "Breast cancer and other neoplasms in women with neurofibromatosis type 1: a retrospective review of cases in the Detroit metropolitan area." Am J Med Genet A 158A(12):3061-3064.

Riccardi, V. M. 1981. "Von Recklinghausen neurofibromatosis." N Engl J Med 305(27):1617-1627.

Bausch, B., W. Borozdin and H. P. Neumann. 2006. "Clinical and genetic characteristics of patients with neurofibromatosis type 1 and pheochromocytoma." N Engl J Med 354(25):2729-2731.

Ghrist, T. D. 1963. "Gastrointestinal Involvement in Neurofibromatosis." Arch Intern Med 112:357-362.

Side, L., B. Taylor, M. Cayouette, et al. 1997. "Homozygous inactivation of the NF1 gene in bone marrow cells from children with neurofibromatosis type 1 and malignant myeloid disorders." N Engl J Med 336(24):1713-1720.

Walker, L., D. Thompson, D. Easton, et al. 2006. "A prospective study of neurofibromatosis type 1 cancer incidence in the UK." Br J Cancer 95(2):233-238

Evans, D. G., C. O'Hara, A. Wilding, et al. 2011. "Mortality in neurofibromatosis 1: in North West England: an assessment of actuarial survival in a region of the UK since 1989." Eur J Hum Genet 19(11):1187-1191.

Rasmussen, S. A., Q. Yang and J. M. Friedman. 2001. "Mortality in neurofibromatosis 1: an analysis using U.S. death certificates." Am J Hum Genet 68(5):1110-1118.

Ferner, R. E., S. M. Huson, N. Thomas, et al. 2007. "Guidelines for the diagnosis and management of individuals with neurofibromatosis 1." J Med Genet 44(2):81-88.

Huson, S. M., P. S. Harper and D. A. Compston. 1988. "Von Recklinghausen neurofibromatosis. A clinical and population study in south-east Wales." Brain 111 ( Pt 6):1355-1381

Hersh, J. H. 2008. "Health supervision for children with neurofibromatosis." Pediatrics 121(3):633-642.

Williams, V. C., J. Lucas, M. A. Babcock, et al. 2009. "Neurofibromatosis type 1 revisited." Pediatrics 123(1):124-133.

King, A., R. Listernick, J. Charrow, et al. 2003. "Optic pathway gliomas in neurofibromatosis type 1: the effect of presenting symptoms on outcome." Am J Med Genet A 122A(2):95-99

Sung, L., J. R. Anderson, C. Arndt, et al. 2004. "Neurofibromatosis in children with Rhabdomyosarcoma: a report from the Intergroup Rhabdomyosarcoma study IV." J Pediatr 144(5):666-668

Zoller, M. E., B. Rembeck, A. Oden, et al. 1997. "Malignant and benign tumors in patients with neurofibromatosis type 1 in a defined Swedish population." Cancer 79(11):2125-2131.

DeBella K, Szudek J, Friedman JM. Use of the national institutes of health criteria for diagnosis of neurofibromatosis 1 in children. Pediatrics. 2000;105(3 Pt 1):608-14

Side LE, Emanuel PD,Taylor B, Franklin J, Thompson P, Castleberry RP, Shannon KM. Mutations of the NF1 gene in children with juvenile myelomonocytic leukemia without clinicals evidence of neurofibromatosis, type 1. Blood. 1998;92(1):267-72

Caen S, Cassiman C, Legius E, Casteels I. Comparative study of the ophthalmological examinations in neurofibromatosis type 1. Proposal for a new screening algorithm. Eur J Paediatr Neurol. 2015;19(4):415-22

The information contained in this document is based on the highest level of available evidence and consensus of the eviQ reference committee regarding their views of currently accepted approaches to care or treatment. Any clinician seeking to apply or consult this document is expected to use independent clinical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au

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15 Oct 2019