NF1 (Neurofibromatosis type 1) – risk management

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 pathogenic variant in 2 or more genes that confer a predisposition to cancer should also be individualised.

• Known or obligate NF1 gene pathogenic variant 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 pathogenic variant.
• 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 pathogenic variant.

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

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 elsewhere^rr Review Checklist - NF1 Tumour related manifestations are listed below.  

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.

**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)

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Bibliography

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.

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Caen S, Cassiman C, Legius E, et al. 2015. "Proposal for a new screening algorithm." Eur J Paediatr Neurol. 19(4):415-22.

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PURPOSE: Efforts are made to unify the protocol concerning the ophthalmological screening, monitoring and treatment of Optic Pathway Gliomas (OPGs) in children with neurofibromatosis type 1 (NF1). The aim of this study is to compare the most recent recommendations published in 2007 with the screening strategies in NF1 centres. The integration of these data resulted into a recommendation for an improved screening strategy. METHODS: A literature search on PubMed between 1984 and 2013 was performed. A questionnaire on the ophthalmological screening in NF1 was sent to centres of expertise in the field of NF1. Literature and questionnaire data were analysed. Also, findings of a round table discussion on the ophthalmological screening of NF1 patients at the European Paediatric Ophthalmological Society (EPOS) meeting in 2013 were summarized. RESULTS: In most centres ophthalmological screening in NF1 patients is well organized, but is performed longer and at more regular intervals than is mentioned in the recommendations. Visual acuity testing, fundoscopy and pupillary reflexes are carried out unanimously. CONCLUSIONS: There is no uniformity of the ophthalmological screening in NF1 patients. The present recommendation advises to screen annually until the age of 8. Because OPGs are likely to develop before the age of 6 and children do not usually complain of visual problems, OPGs can be missed or detection can be delayed if screening is only yearly performed at this young age. Based on these arguments, about half of our responders screen more frequently and until a later age. Therefore, we suggest performing a six monthly screening until the age of 6 and a yearly examination from 6 years until adulthood. This examination should include visual acuity assessment, pupillary reflexes and a fundoscopy.

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

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OBJECTIVE: The National Institutes of Health (NIH) Diagnostic Criteria for neurofibromatosis 1 (NF1) are very useful clinically, but some individuals who are later shown to have NF1 cannot be diagnosed in early childhood using these criteria. The aim of this study is to determine the value of the NIH Diagnostic Criteria for NF1 in early childhood, to determine the age at which diagnosis can confidently be made, and to clarify the age at onset of the cardinal clinical features used in the NIH Diagnostic Criteria. METHODS: We studied 1893 NF1 patients under 21 years old from the National Neurofibromatosis Foundation International Database to determine the age at which the features included in the NIH Diagnostic Criteria appear. RESULTS: Approximately 46% of sporadic NF1 cases fail to meet the NIH Diagnostic Criteria by 1 year of age. Nearly all (97%; 95% confidence interval: 94-98) NF1 patients meet the criteria for diagnosis by 8 years old, and all do so by 20 years old. The usual order of appearance of the clinical features listed as NIH criteria is café-au-lait macules, axillary freckling, Lisch nodules, and neurofibromas. Symptomatic optic glioma is usually diagnosed by 3 years old, and characteristic osseous lesions are usually apparent within the first year of life. CONCLUSION: The diagnosis of NF1 cannot always be made in young children using the NIH Diagnostic Criteria. Modification of these criteria may be necessary for children under 8 years old.

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.

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Neurofibromatosis 1 (NF1) is a comparatively common autosomal dominant disorder. However, relatively few studies have assessed lifetime risk; and information about the effect of NF1 on mortality remains uncertain. NF1 patients were identified using The North West regional family Genetic Register, which covers the 4.1 million people living in North West England, including the regions of Greater Manchester, Cheshire and Cumbria. Data relating to tumours and malignancies were obtained from The North West Cancer Intelligence Service. Death data for the general North West population were obtained from the Office of National Statistics. We identified 1186 individuals with NF1, of whom 1023 lived within the strict regional boundaries (constituting a region of North West England bound by The Pennines to the east and Irish Sea to the west, but excluding the conurbation of Liverpool (Merseyside) and the Wirral peninsula) and 131 had died. MPNST and glioma were found to be the two most common causes of reduced life expectancy among NF1 patients. In Kaplan-Meier analyses the median survival for NF1 patients was shown to be 71.5 years, with women living approximately 7.4 years longer than men. On average both men and women lived approximately 8 years less than their counterparts in the general population. Reduction in life expectancy for NF1 patients was found to be much lower (8 years) than the previously estimated 15-year decrease. Limitations relating to the underreporting of NF1 on death certificates were once again highlighted and should be considered in future investigations.

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.

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Neurofibromatosis 1 (NF1) is a common neurocutaneous condition with an autosomal dominant pattern of inheritance. The complications are diverse and disease expression varies, even within families. Progress in molecular biology and neuroimaging and the development of mouse models have helped to elucidate the aetiology of NF1 and its clinical manifestations. Furthermore, these advances have raised the prospect of therapeutic intervention for this complex and distressing disease. Members of the United Kingdom Neurofibromatosis Association Clinical Advisory Board collaborated to produce a consensus statement on the current guidelines for diagnosis and management of NF1. The proposals are based on published clinical studies and on the pooled knowledge of experts in neurofibromatosis with experience of providing multidisciplinary clinical and molecular services for NF1 patients. The consensus statement discusses the diagnostic criteria, major differential diagnoses, clinical manifestations and the present strategies for monitoring and management of NF1 complications.

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

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

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Neurofibromatosis 1 is a multisystem disorder that primarily involves the skin and nervous system. Its population prevalence is 1 in 3500. The condition usually is recognized in early childhood, when cutaneous manifestations are apparent. Although neurofibromatosis 1 is associated with marked clinical variability, most affected children do well from the standpoint of their growth and development. Some features of neurofibromatosis 1 are present at birth, and others are age-related abnormalities of tissue proliferation, which necessitate periodic monitoring to address ongoing health and developmental needs and to minimize the risk of serious medical complications. This clinical report provides a review of the clinical criteria needed to establish a diagnosis, the inheritance pattern of neurofibromatosis 1, its major clinical and developmental manifestations, and guidelines for monitoring and providing intervention to maximize the growth, development, and health of an affected child.

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.

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A population-based study in south-east Wales (population 668,100) identified 135 patients with von Recklinghausen neurofibromatosis (prevalence 20/10(5]. In addition to multiple cafe-au-lait spots and/or dermal neurofibromas, freckling was present in the axilla (67%), groin (44%) or submammary areas (29% of adult females). Although not a criterion for diagnosis, Lisch nodules were almost invariably present in the iris (93% of patients overall; 96% of those aged greater than or equal to 20 yrs). The complications of von Recklinghausen neurofibromatosis in this cohort (n = 135 unless stated) were plexiform neurofibromas (40/125), severe mental retardation (1), epilepsy (6), optic glioma (2), spinal neurofibroma (2), aqueduct stenosis (2), meningioangiomatosis (1), scoliosis requiring surgery (6), pseudoarthrosis (3), delayed puberty (2), visceral and endocrine tumours (6), and congenital glaucoma (1). There were no cases of acoustic neuroma. Considering all living family members aged greater than or equal to 18 yrs, together with their deceased relatives, the frequency of CNS and malignant tumours related to the disease was 4.4-5.2%. Uncomplicated von Recklinghausen neurofibromatosis is disfiguring but not a major cause of morbidity. The management of the disease relates to its complications which can be divided into three categories: those which occur in childhood and cause lifelong morbidity (moderate-severe mental handicap, facial plexiform neurofibromas, orthopaedic), those which can occur at any time but are 'treatable' (benign disorders of the nervous system, visceral and endocrine tumours, renal artery stenosis), and malignant or CNS tumours. The combined frequency for each category based on this survey was 12%, 16% and 4.4-5.2%, respectively.

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.

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Children with neurofibromatosis type 1 (NF1) may present with optic pathway gliomas (OPG) that can progress to visual loss or other neurologic symptoms. These tumors may become evident either as a result of patient signs or symptoms or as an incidental finding on baseline neuroimaging studies. In an attempt to determine if there were differences between symptomatic and asymptomatic children with OPG, a retrospective cohort study of ninety children with NF1 and OPG was performed using data from two large NF1 referral centers. Age at diagnosis, presenting symptoms, tumor location, associated features, and clinical response were assessed for children who were initially symptomatic from their OPG (n = 51) and compared to similar data of asymptomatic children whose tumors were incidentally discovered by MRI (n = 39). There were no differences in age at presentation, tumor location, NF1-associated symptoms, or clinical response between the groups. Initially symptomatic children were much more likely to require treatment (OR: 14.8, 95% CI [1.9-116.7]) than those with incidentally discovered, asymptomatic OPG. Although 36% of OPG were diagnosed in children over the age of 6 years, none received prior neuroimaging and only two children had previously normal eye examinations, suggesting that the vast majority of OPG in this group were longstanding, undiagnosed tumors. Based on these findings, we do not advocate baseline MRI in children with NF1, but strongly recommend that all children of the age 10 years and younger with NF1 have complete annual ophthalmologic evaluations.

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.

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Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder associated with increased risk for neoplasms. Two studies in the United Kingdom have indicated that women with NF1 (particularly women under 50) may also be at increased risk of breast cancer. No such study has been done to date in the United States. Chart review for breast cancer diagnoses was undertaken for 126 women with NF1 followed at Johns Hopkins who were 20 years of age or older. Four of 126 women who met eligibility criteria were diagnosed with breast cancer (3.2% over 15 years). The unadjusted standardized incidence ratio (SIR) for breast cancer in the NF1 population between the ages of 20 and 49 was 2.68 (P = 0.076, 95% CI 0.68-7.29) based on incidence rates of breast cancer in the general population taken from the Surveillance Epidemiology and End Results (SEER) database. The unadjusted SIR for women with NF1 >/=50 was 0.81 (P = 0.84, 95% CI 0.041-4.01). When adjusted for race, the rate of NF1 in the general population and time of diagnosis, the SIR was 4.41 (P = 0.0049, 95% CI 1.12-12.00) for women <50 versus 0.94 (P = 0.95, 95% CI 0.047-4.65) for women >/=50. The trend of a higher-than-expected number of breast cancer cases in women <50 with NF1 agrees with the prior studies from the literature. Cumulatively, the data suggests an increased risk of breast cancer for women with NF1 < 50 years old, implying a need for closer surveillance and the establishment of screening guidelines for this patient population.

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.

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Although neurofibromatosis 1 (NF1) is a relatively common autosomal dominant condition, information about its effect on mortality is limited. We used Multiple-Cause Mortality Files, compiled from U.S. death certificates by the National Center for Health Statistics, for 1983 through 1997. We identified 3,770 cases of presumed NF1 among 32,722,122 deaths in the United States, a frequency of 1/8,700, which is one-third to one-half the estimated prevalence. Mean and median ages at death for persons with NF1 were 54.4 and 59 years, respectively, compared with 70.1 and 74 years in the general population. Results of proportionate mortality ratio (PMR) analyses showed that persons with NF1 were 34 times more likely (PMR=34.3, 95% confidence interval [CI] 30.8-38.0) to have a malignant connective or other soft-tissue neoplasm listed on their death certificates than were persons without NF1. Overall, persons with NF1 were 1.2 times more likely than expected (PMR=1.21, 95% CI 1.14-1.28) to have a malignant neoplasm listed on their death certificates, but the PMR was 6.07 (95% CI 4.88-7.45) for persons who died at 10-19 years of age and was 4.93 (95% CI 4.14-5.82) for those who died at 20-29 years of age. Similarly, vascular disease was recorded more often than expected on death certificates of persons with NF1 who died at <30 years of age (PMR=3.26, 95% CI 1.31-6.71 at age <10 years; PMR=2.68, 95% CI 1.38-4.68 at age 10-19 years; and PMR=2.25, 95% CI 1.46-3.32 at 20-29 years) but not in older persons. This study supports previous findings of decreased life expectancy for persons with NF1 and, within the limitations of death certificates, provides population-based data about NF1 morbidity and mortality that are useful to clinicians caring for patients with NF1.

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

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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.

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BACKGROUND: The risk of malignant myeloid disorders in young children with neurofibromatosis type 1 is 200 to 500 times the normal risk. The gene for neurofibromatosis type 1 (NF1) encodes neurofibromin, a protein that negatively regulates signals transduced by Ras proteins. Genetic and biochemical data support the hypothesis that NF1 functions as a tumor-suppressor gene in immature myeloid cells, but inactivation of both NF1 alleles has not been demonstrated in leukemic cells from patients with neurofibromatosis type 1. METHODS: Using an in vitro transcription and translation system, we screened bone marrow samples from 18 children with neurofibromatosis type 1 and myeloid disorders for NF1 mutations that cause a truncated protein. Mutations were confirmed by direct sequencing of genomic DNA from the patients, and from their affected parents, in cases of familial neurofibromatosis type 1. RESULTS: Specimens from 9 of the 18 children contained abnormal peptide fragments, and truncating mutations of the NF1 gene were found in specimens from 8 of these children. The normal NF1 allele was absent in bone marrow samples from five of the eight children. We detected the same mutation in DNA from the affected parent of each child with familial neurofibromatosis type 1. CONCLUSIONS: Both alleles of the NF1 gene are inactivated in leukemic cells in some patients with neurofibromatosis type 1. NF1 appears to function as a tumor-suppressor gene in immature myeloid cells.

Side LE, Emanuel PD,Taylor B, et al. 1998. "Mutations of the NF1 gene in children with juvenile myelomonocytic leukemia without clinicals evidence of neurofibromatosis, type 1." Blood. 92(1):267-72

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Juvenile myelomonocytic leukemia (JMML) is a pediatric myelodysplastic syndrome that is associated with neurofibromatosis, type 1 (NF1). The NF1 tumor suppressor gene encodes neurofibromin, which regulates the growth of immature myeloid cells by accelerating guanosine triphosphate hydrolysis on Ras proteins. The purpose of this study was to determine if the NF1 gene was involved in the pathogenesis of JMML in children without a clinical diagnosis of NF1. An in vitro transcription and translation system was used to screen JMML marrows from 20 children for NF1 mutations that resulted in a truncated protein. Single-stranded conformational polymorphism analysis was used to detect RAS point mutations in these samples. We confirmed mutations of NF1 in three leukemias, one of which also showed loss of the normal NF1 allele. An NF1 mutation was detected in normal tissue from the only patient tested and this suggests that JMML may be the presenting feature of NF1 in some children. Activating RAS mutations were found in four patients; as expected, none of these samples harbored NF1 mutations. Because 10% to 14% of children with JMML have a clinical diagnosis of NF1, these data are consistent with the existence of NF1 mutations in approximately 30% of JMML cases.

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.

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We identified all children enrolled in the Intergroup Rhabdomyosarcoma Study Group-IV with neurofibromatosis type I (NF1) and rhabdomyosarcoma. Among 1025 eligible patients, 5 (0.5 %) had NF1. Three children had relapses, two of whom died of progressive disease. Patients with NF1 and rhabdomyosarcoma should be treated with intensive contemporary therapy protocols.

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.

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Neurofibromatosis type 1 (NF1) is an autosomal dominant condition affecting around one in 3000 live births. The manifestations of this condition are extremely variable, even within families, and genetic counselling is consequently difficult with regard to prognosis. Individuals with NF1 are acknowledged to be at increased risk of malignancy. Several studies have previously attempted to quantify this risk, but have involved relatively small study populations. We present prospective data from 448 individuals with NF1 with a total of 5705 years of patient follow-up. These data have been collected via the UK NF1 association for patients. Demographic information on the affected individuals was cross-referenced with UK cancer registry data by the UK Office of National Statistics. The overall risk of cancer was 2.7 times higher in this cohort of NF1 patients than in the general population (95% confidence interval (CI) 1.9-3.7). The cumulative risk of a malignancy by age 50 years was 20% (95% CI 14-29%); beyond this age, the risk of cancer was not significantly elevated (P=0.27). The most frequent types of cancer were connective tissue (14% risk by age 70, 95% CI 7.8-24%) and brain tumours (7.9, 95% CI 3.9-16%). There was no statistically significant excess of cancers at other sites (P=0.22).

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.

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Neurofibromatosis type 1 (NF1) is one of the most common cancer predisposing syndromes with an incidence of 1 in 3,500 worldwide. Certain neoplasms or malignancies are over-represented in individuals with NF1; however, an increased risk of breast cancer has not been widely recognized or accepted. We identified 76 women with NF1 seen in the Henry Ford Health System (HFHS) from 1990 to 2009, and linked them to the Surveillance Epidemiology and End Results (SEER) registry covering the metropolitan Detroit area. Fifty-one women (67%) were under age 50 years at the time of data analysis. Six women developed invasive breast cancer before age 50, and three developed invasive breast cancer after age 50. Using standardized incidence ratios (SIRs) calculated based on the SEER age-adjusted invasive breast cancer incidence rates, our findings demonstrated a statistically significant increase of breast cancer incidence occurring in NF1 women (SIR = 5.2; 95% CI 2.4-9.8), and this relative increase was especially evident among those with breast cancer onset under age 50 (SIR = 8.8; 95% CI 3.2-19.2). These data are consistent with other reports suggesting an increase in breast cancer risk among females with NF1, which indicate that breast cancer screening guidelines should be evaluated for this potentially high-risk group.

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

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Neurofibromatosis type 1 (NF1) is an autosomal dominant condition with a worldwide incidence of approximately 1 per 2500 to 3000 individuals. Caused by a germ-line-inactivating mutation in the NF1 gene on chromosome 17, the disease is associated with increased morbidity and mortality. In the past several years, significant progress has been made in standardizing management of the major clinical features of neurofibromatosis type 1. Moreover, improved understanding of how the neurofibromatosis type 1 protein, neurofibromin, regulates cell growth recently provided insight into the pathogenesis of the disease and has led to the development of new therapies. In this review, we describe the clinical manifestations, recent molecular and genetic findings, and current and developing therapies for managing clinical problems associated with neurofibromatosis type 1.

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.

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BACKGROUND: The development of malignant and benign tumors in patient with neurofibromatosis type 1 (NF1) was investigated in a long term follow-up study of 70 adult NF1 patients living in Goteborg, Sweden, on January 1, 1978. Their mean age at that time was 44 years (range, 20-81 years). The 70 NF1 patients had previously been investigated in a population-based study. METHODS: The first part of this study involved a cancer registry study. The authors compared the number of tumors in the 70 NF1 patients reported to the Swedish Cancer Registry during the period 1978-1989 with the number of tumors expected in the general population by matching the incidence rates of the two populations specific to age, time of follow-up, and gender. The 95% confidence interval for the risk quotient between the risk to the patients and the risk to the general population was estimated. The second part of the study was a clinical pathologic follow-up study. All living patients were offered a clinical reexamination in 1990. All hospital records for all the NF1 patients were reviewed, and death certificates were also reviewed when available. RESULTS: Malignant tumors were reported to the Cancer Registry four times as often in the NF1 patient group as in the general population (95% confidence interval, 2.1-7.6) during the follow-up period 1978-1989. Before 1978, 5 of 70 patients (7%) had 6 malignant tumors; these patients were not included in the Cancer Registry study. Using all available clinical data on the 70 NF1 patients from their birth up to 1990, the authors found that 17 of 70 patients (24%) had developed a total of 19 malignant tumors, namely, 5 sarcomas (in 7% of patients), 13 carcinomas (in 16%), and 1 malignant melanoma (in 1%). Four pheochromocytomas (in 6% of patients), 2 adenomas, and 1 C-cell hyperplasia were diagnosed. Five gastrointestinal stromal tumors (in 7% of patients) were also diagnosed. CONCLUSIONS: Malignant tumors were reported to the Swedish Cancer Registry significantly more often in the NF1 patients than was expected in the general population matched for age, gender, and time of follow-up. The development of tumors is part of the NF1 disease process, and this deserves attention both in the clinical setting and in family counseling dealing with complications of NF1 in adulthood.

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