Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Primer
  • Published:

Neurofibromatosis type 1

Nature Reviews Disease Primers volume 3, Article number: 17004 (2017) Cite this article

Subjects

Abstract

Neurofibromatosis type 1 is a complex autosomal dominant disorder caused by germline mutations in the NF1 tumour suppressor gene. Nearly all individuals with neurofibromatosis type 1 develop pigmentary lesions (café-au-lait macules, skinfold freckling and Lisch nodules) and dermal neurofibromas. Some individuals develop skeletal abnormalities (scoliosis, tibial pseudarthrosis and orbital dysplasia), brain tumours (optic pathway gliomas and glioblastoma), peripheral nerve tumours (spinal neurofibromas, plexiform neurofibromas and malignant peripheral nerve sheath tumours), learning disabilities, attention deficits, and social and behavioural problems, which can negatively affect quality of life. With the identification of NF1 and the generation of accurate preclinical mouse strains that model some of these clinical features, therapies that target the underlying molecular and cellular pathophysiology for neurofibromatosis type 1 are becoming available. Although no single treatment exists, current clinical management strategies include early detection of disease phenotypes (risk assessment) and biologically targeted therapies. Similarly, new medical and behavioural interventions are emerging to improve the quality of life of patients. Although considerable progress has been made in understanding this condition, numerous challenges remain; a collaborative and interdisciplinary approach is required to manage individuals with neurofibromatosis type1 and to develop effective treatments.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Benign peripheral nerve sheath tumours.
Figure 2: Development of clinical features of neurofibromatosis type 1.
Figure 3: Neurofibromin signalling pathway.
Figure 4: Pigmentary features of neurofibromatosis type 1.
Figure 5: Pathogenesis of plexiform neurofibromas.
Figure 6: Pathogenesis of optic pathway gliomas.
Figure 7: Skeletal defects in neurofibromatosis type 1.
Figure 8: Central nervous system abnormalities.
Figure 9: Biopsychosocial factors affecting quality of life in neurofibromatosis type 1.

Similar content being viewed by others

References

  1. Gutmann, D. H., Wood, D. L. & Collins, F. S. Identification of the neurofibromatosis type 1 gene product. Proc. Natl Acad. Sci. USA 88, 9658–9662 (1991).

    Google Scholar 

  2. Uusitalo, E. et al. Incidence and mortality of neurofibromatosis: a total population study in Finland. J. Invest. Dermatol. 135, 904–906 (2015).

    Google Scholar 

  3. Risch, N., Reich, E. W., Wishnick, M. M. & McCarthy, J. G. Spontaneous mutation and parental age in humans. Am. J. Hum. Genet. 41, 218–248 (1987).

    Google Scholar 

  4. Liu, Q., Zoellner, N., Gutmann, D. H. & Johnson, K. J. Parental age and neurofibromatosis type 1: a report from the NF1 Patient Registry Initiative. Fam. Cancer 14, 317–324 (2014). This study highlights the value of patient-reported registries for epidemiological research.

    Google Scholar 

  5. Bunin, G. R., Needle, M. & Riccardi, V. M. Paternal age and sporadic neurofibromatosis 1: a case–control study and consideration of the methodologic issues. Genet. Epidemiol. 14, 507–516 (1997).

    Google Scholar 

  6. Snajderova, M. et al. The importance of advanced parental age in the origin of neurofibromatosis type 1. Am. J. Med. Genet. A 158A, 519–523 (2012).

    Google Scholar 

  7. Poyhonen, M., Kytola, S. & Leisti, J. Epidemiology of neurofibromatosis type 1 (NF1) in northern Finland. J. Med. Genet. 37, 632–636 (2000).

    Google Scholar 

  8. Sergeyev, A. S. On the mutation rate of neurofibromatosis. Humangenetik 28, 129–138 (1975).

    Google Scholar 

  9. Samuelsson, B. & Axelsson, R. Neurofibromatosis. A clinical and genetic study of 96 cases in Gothenburg, Sweden. Acta Derm. Venereol. Suppl. (Stockh.) 95, 67–71 (1981).

    Google Scholar 

  10. McKeever, K., Shepherd, C. W., Crawford, H. & Morrison, P. J. An epidemiological, clinical and genetic survey of neurofibromatosis type 1 in children under sixteen years of age. Ulster Med. J. 77, 160–163 (2008).

    Google Scholar 

  11. Sorensen, S. A., Mulvihill, J. J. & Nielsen, A. On the natural history of von Recklinghausen neurofibromatosis. Ann. NY Acad. Sci. 486, 30–37 (1986).

    Google Scholar 

  12. Evans, D. G. et al. 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, 1187–1191 (2011). This report describes a detailed analysis of patient survival in neurofibromatosis type 1.

    Google Scholar 

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

    Google Scholar 

  14. Masocco, M. et al. Mortality associated with neurofibromatosis type 1: a study based on Italian death certificates. Orphanet J. Rare Dis. 6, 11 (2011).

    Google Scholar 

  15. Zoller, M., Rembeck, B., Akesson, H. O. & Angervall, L. Life expectancy, mortality and prognostic factors in neurofibromatosis type 1. A twelve-year follow-up of an epidemiological study in Goteborg, Sweden. Acta Derm. Venereol. 75, 136–140 (1995).

    Google Scholar 

  16. Duong, T. A. et al. Mortality associated with neurofibromatosis 1: a cohort study of 1895 patients in 1980–2006 in France. Orphanet J. Rare Dis. 6, 18 (2011).

    Google Scholar 

  17. Messiaen, L. M. et al. Exhaustive mutation analysis of the NF1 gene allows identification of 95% of mutations and reveals a high frequency of unusual splicing defects. Hum. Mutat. 15, 541–555 (2000). This important study highlights how improvements in genetic testing facilitated the development of NF1 genetic testing.

    Google Scholar 

  18. Pasmant, E. et al. NF1 microdeletions in neurofibromatosis type 1: from genotype to phenotype. Hum. Mutat. 31, E1506–E1518 (2010).

    Google Scholar 

  19. Rojnueangnit, K. et al. High incidence of Noonan syndrome features including short stature and pulmonic stenosis in patients carrying NF1 missense mutations affecting p. Arg1809: genotype-phenotype correlation. Hum. Mutat. 36, 1052–1063 (2015).

    Google Scholar 

  20. Upadhyaya, 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. 80, 140–151 (2007).

    Google Scholar 

  21. Viskochil, D. et al. Deletions and a translocation interrupt a cloned gene at the neurofibromatosis type 1 locus. Cell 62, 187–192 (1990).

    Google Scholar 

  22. Wallace, M. R. et al. Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients. Science 249, 181–186 (1990).

    Google Scholar 

  23. DeClue, J. E., Cohen, B. D. & Lowy, D. R. Identification and characterization of the neurofibromatosis type 1 protein product. Proc. Natl Acad. Sci. USA 88, 9914–9918 (1991).

    Google Scholar 

  24. Basu, T. N. et al. Aberrant regulation of ras proteins in malignant tumour cells from type 1 neurofibromatosis patients. Nature 356, 713–715 (1992).

    Google Scholar 

  25. Dasgupta, B., Yi, Y., Chen, D. Y., Weber, J. D. & Gutmann, D. H. Proteomic analysis reveals hyperactivation of the mammalian target of rapamycin pathway in neurofibromatosis 1-associated human and mouse brain tumors. Cancer Res. 65, 2755–2760 (2005). This is the first report to demonstrate that neurofibromin negatively regulates mTOR signalling, which is relevant to neurofibromatosis type 1-associated tumour growth.

    Google Scholar 

  26. Johannessen, C. M. et al. The NF1 tumor suppressor critically regulates TSC2 and mTOR. Proc. Natl Acad. Sci. USA 102, 8573–8578 (2005).

    Google Scholar 

  27. Lin, A. L. & Gutmann, D. H. Advances in the treatment of neurofibromatosis-associated tumours. Nat. Rev. Clin. Oncol. 10, 616–624 (2013).

    Google Scholar 

  28. De Schepper, S. et al. Somatic mutation analysis in NF1 cafe au lait spots reveals two NF1 hits in the melanocytes. J. Invest. Dermatol. 128, 1050–1053 (2008).

    Google Scholar 

  29. Diwakar, G., Zhang, D., Jiang, S. & Hornyak, T. J. Neurofibromin as a regulator of melanocyte development and differentiation. J. Cell Sci. 121, 167–177 (2008).

    Google Scholar 

  30. Stevenson, D. A. et al. Double inactivation of NF1 in tibial pseudarthrosis. Am. J. Hum. Genet. 79, 143–148 (2006). This is the first report to demonstrate that biallelic NF1 loss occurs in non-tumour features of neurofibromatosis type 1.

    Google Scholar 

  31. Wang, W. et al. Mice lacking Nf1 in osteochondroprogenitor cells display skeletal dysplasia similar to patients with neurofibromatosis type I. Hum. Mol. Genet. 20, 3910–3924 (2011).

    Google Scholar 

  32. Sharma, R. et al. Hyperactive Ras/MAPK signaling is critical for tibial nonunion fracture in neurofibromin-deficient mice. Hum. Mol. Genet. 22, 4818–4828 (2013). This study demonstrates that hyperactive RAS underlies the skeletal defects that are observed in tibial fracture associated with neurofibromatosis type 1.

    Google Scholar 

  33. Yang, F. C. et al. Hyperactivation of p21ras and PI3K cooperate to alter murine and human neurofibromatosis type 1-haploinsufficient osteoclast functions. J. Clin. Invest. 116, 2880–2891 (2006).

    Google Scholar 

  34. He, Y. et al. c-Fms signaling mediates neurofibromatosis type-1 osteoclast gain-in-functions. PLoS ONE 7, e46900 (2012).

    Google Scholar 

  35. de la Croix Ndong, J. et al. Asfotase-alpha improves bone growth, mineralization and strength in mouse models of neurofibromatosis type-1. Nat. Med. 20, 904–910 (2014).

    Google Scholar 

  36. Elefteriou, F. et al. ATF4 mediation of NF1 functions in osteoblast reveals a nutritional basis for congenital skeletal dysplasiae. Cell Metab. 4, 441–451 (2006).

    Google Scholar 

  37. Costa, R. M. et al. Mechanism for the learning deficits in a mouse model of neurofibromatosis type 1. Nature 415, 526–530 (2002). This report reveals that neurofibromin controls mouse learning through RAS regulation of GABA signalling.

    Google Scholar 

  38. Li, W. et al. The HMG-CoA reductase inhibitor lovastatin reverses the learning and attention deficits in a mouse model of neurofibromatosis type 1. Curr. Biol. 15, 1961–1967 (2005).

    Google Scholar 

  39. Oyibo, H. K., Znamenskiy, P., Oviedo, H. V., Enquist, L. W. & Zador, A. M. Long-term Cre-mediated retrograde tagging of neurons using a novel recombinant pseudorabies virus. Front. Neuroanat. 8, 86 (2014).

    Google Scholar 

  40. Cui, Y. et al. Neurofibromin regulation of ERK signaling modulates GABA release and learning. Cell 135, 549–560 (2008).

    Google Scholar 

  41. Molosh, A. I. et al. Social learning and amygdala disruptions in Nf1 mice are rescued by blocking p21-activated kinase. Nat. Neurosci. 17, 1583–1590 (2014).

    Google Scholar 

  42. Chen, Y. H. et al. Mouse low-grade gliomas contain cancer stem cells with unique molecular and functional properties. Cell Rep. 10, 1899–1912 (2015).

    Google Scholar 

  43. Diggs-Andrews, K. A. et al. Dopamine deficiency underlies learning deficits in neurofibromatosis-1 mice. Ann. Neurol. 73, 309–315 (2013). This study demonstrates that neurofibromin controls mouse learning by increasing the levels of dopamine in the brain.

    Google Scholar 

  44. Brown, J. A. et al. Reduced striatal dopamine underlies the attention system dysfunction in neurofibromatosis-1 mutant mice. Hum. Mol. Genet. 19, 4515–4528 (2010).

    Google Scholar 

  45. Scheithauer, B. W., Erlandson, R. A. & Woodruff, J. M. Tumors of the Peripheral Nervous System (American Registry of Pathology, 1999).

    Google Scholar 

  46. Le, L. Q., Shipman, T., Burns, D. K. & Parada, L. F. Cell of origin and microenvironment contribution for NF1-associated dermal neurofibromas. Cell Stem Cell 4, 453–463 (2009).

    Google Scholar 

  47. Li, H. et al. Analysis of steroid hormone effects on xenografted human NF1 tumor Schwann cells. Cancer Biol. Ther. 10, 758–764 (2010).

    Google Scholar 

  48. Jouhilahti, E. M. et al. The development of cutaneous neurofibromas. Am. J. Pathol. 178, 500–505 (2011).

    Google Scholar 

  49. Wu, J. et al. Plexiform and dermal neurofibromas and pigmentation are caused by Nf1 loss in Desert Hedgehog-expressing cells. Cancer Cell 13, 105–116 (2008).

    Google Scholar 

  50. Le, L. Q. et al. Susceptible stages in Schwann cells for NF1-associated plexiform neurofibroma development. Cancer Res. 71, 4686–4695 (2011).

    Google Scholar 

  51. Mayes, D. A. et al. Perinatal or adult Nf1 inactivation using tamoxifen-inducible PlpCre each cause neurofibroma formation. Cancer Res. 71, 4675–4685 (2011).

    Google Scholar 

  52. Chen, Z. et al. Cells of origin in the embryonic nerve roots for NF1-associated plexiform neurofibroma. Cancer Cell 26, 695–706 (2014). This report reveals that Schwann cell precursors represent the likely cell of origin for plexiform neurofibromas in mice.

    Google Scholar 

  53. Joseph, N. M. et al. The loss of Nf1 transiently promotes self-renewal but not tumorigenesis by neural crest stem cells. Cancer Cell 13, 129–140 (2008).

    Google Scholar 

  54. Yang, F. C. et al. Nf1-dependent tumors require a microenvironment containing Nf1+/− and c-kit-dependent bone marrow. Cell 135, 437–448 (2008). This landmark study demonstrates that mast cells increase neoplastic Schwann cell growth through KIT ligand, which opens the door to imatinib as a potential therapy for plexiform neurofibromas.

    Google Scholar 

  55. Yang, F. C. et al. Neurofibromin-deficient Schwann cells secrete a potent migratory stimulus for Nf1+/− mast cells. J. Clin. Invest. 112, 1851–1861 (2003).

    Google Scholar 

  56. Yang, F. C. et al. Nf1+/− mast cells induce neurofibroma like phenotypes through secreted TGF-beta signaling. Hum. Mol. Genet. 15, 2421–2437 (2006).

    Google Scholar 

  57. Robertson, K. A. et al. Imatinib mesylate for plexiform neurofibromas in patients with neurofibromatosis type 1: a phase 2 trial. Lancet Oncol. 13, 1218–1224 (2012).

    Google Scholar 

  58. Prada, C. E. et al. Neurofibroma-associated macrophages play roles in tumor growth and response to pharmacological inhibition. Acta Neuropathol. 125, 159–168 (2013). This report suggests that macrophages also participate in the growth of plexiform neurofibromas in mice.

    Google Scholar 

  59. Wu, J. et al. Preclincial testing of sorafenib and RAD001 in the Nfflox/flox;DhhCre mouse model of plexiform neurofibroma using magnetic resonance imaging. Pediatr. Blood Cancer 58, 173–180 (2012).

    Google Scholar 

  60. Jessen, W. J. et al. MEK inhibition exhibits efficacy in human and mouse neurofibromatosis tumors. J. Clin. Invest. 123, 340–347 (2013).

    Google Scholar 

  61. Gregorian, C. et al. PTEN dosage is essential for neurofibroma development and malignant transformation. Proc. Natl Acad. Sci. USA 106, 19479–19484 (2009).

    Google Scholar 

  62. Keng, V. W. et al. PTEN and NF1 inactivation in Schwann cells produces a severe phenotype in the peripheral nervous system that promotes the development and malignant progression of peripheral nerve sheath tumors. Cancer Res. 72, 3405–3413 (2012).

    Google Scholar 

  63. Cichowski, K. et al. Mouse models of tumor development in neurofibromatosis type 1. Science 286, 2172–2176 (1999). This important study is the first to report the generation of mouse MPNSTs.

    Google Scholar 

  64. Lothe, R. A. et al. Biallelic inactivation of TP53 rarely contributes to the development of malignant peripheral nerve sheath tumors. Genes Chromosomes Cancer 30, 202–206 (2001).

    Google Scholar 

  65. Hirbe, A. C. et al. Spatially- and temporally-controlled postnatal p53 knockdown cooperates with embryonic Schwann cell precursor Nf1 gene loss to promote malignant peripheral nerve sheath tumor formation. Oncotarget 7, 7403–7414 (2016). This report describes the first mouse model of MPNST in which the timing and location of tumour development could be controlled.

    Google Scholar 

  66. DeClue, J. E. et al. Epidermal growth factor receptor expression in neurofibromatosis type 1-related tumors and NF1 animal models. J. Clin. Invest. 105, 1233–1241 (2000).

    Google Scholar 

  67. Mo, W. et al. CXCR4/CXCL12 mediate autocrine cell- cycle progression in NF1-associated malignant peripheral nerve sheath tumors. Cell 152, 1077–1090 (2013).

    Google Scholar 

  68. Lee, W. et al. PRC2 is recurrently inactivated through EED or SUZ12 loss in malignant peripheral nerve sheath tumors. Nat. Genet. 46, 1227–1232 (2014). This study reveals the importance of SUZ12 and PRC2 in the pathogenesis of MPNSTs.

    Google Scholar 

  69. De Raedt, T. et al. PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies. Nature 514, 247–251 (2014).

    Google Scholar 

  70. Bajenaru, M. L. et al. Optic nerve glioma in mice requires astrocyte Nf1 gene inactivation and Nf1 brain heterozygosity. Cancer Res. 63, 8573–8577 (2003). This is the first report of a mouse model for neurofibromatosis type 1-associated optic pathway glioma.

    Google Scholar 

  71. Gutmann, D. H. et al. Somatic neurofibromatosis type 1 (NF1) inactivation characterizes NF1-associated pilocytic astrocytoma. Genome Res. 23, 431–439 (2013).

    Google Scholar 

  72. Lee, D. Y., Yeh, T. H., Emnett, R. J., White, C. R. & Gutmann, D. H. Neurofibromatosis-1 regulates neuroglial progenitor proliferation and glial differentiation in a brain region-specific manner. Genes Dev. 24, 2317–2329 (2010).

    Google Scholar 

  73. Lee, D. Y., Gianino, S. M. & Gutmann, D. H. Innate neural stem cell heterogeneity determines the patterning of glioma formation in children. Cancer Cell 22, 131–138 (2012).

    Google Scholar 

  74. Hegedus, B. et al. Neurofibromatosis-1 regulates neuronal and glial cell differentiation from neuroglial progenitors in vivo by both cAMP- and Ras-dependent mechanisms. Cell Stem Cell 1, 443–457 (2007).

    Google Scholar 

  75. Pong, W. W., Higer, S. B., Gianino, S. M., Emnett, R. J. & Gutmann, D. H. Reduced microglial CX3CR1 expression delays neurofibromatosis-1 glioma formation. Ann. Neurol. 73, 303–308 (2013).

    Google Scholar 

  76. Daginakatte, G. C. & Gutmann, D. H. Neurofibromatosis-1 (Nf1) heterozygous brain microglia elaborate paracrine factors that promote Nf1-deficient astrocyte and glioma growth. Hum. Mol. Genet. 16, 1098–1112 (2007). This is the first study to demonstrate that microglia in the tumour microenvironment are important drivers of optic pathway glioma growth in mice.

    Google Scholar 

  77. Daginakatte, G. C., Gianino, S. M., Zhao, N. W., Parsadanian, A. S. & Gutmann, D. H. Increased c-Jun-NH2-kinase signaling in neurofibromatosis-1 heterozygous microglia drives microglia activation and promotes optic glioma proliferation. Cancer Res. 68, 10358–10366 (2008).

    Google Scholar 

  78. Simmons, G. W. et al. Neurofibromatosis-1 heterozygosity increases microglia in a spatially and temporally restricted pattern relevant to mouse optic glioma formation and growth. J. Neuropathol. Exp. Neurol. 70, 51–62 (2011).

    Google Scholar 

  79. Solga, A. C. et al. RNA sequencing of tumor-associated microglia reveals CCL5 as a stromal chemokine critical for neurofibromatosis-1 glioma growth. Neoplasia 17, 776–788 (2015).

    Google Scholar 

  80. Dasgupta, B., Li, W., Perry, A. & Gutmann, D. H. Glioma formation in neurofibromatosis 1 reflects preferential activation of K-RAS in astrocytes. Cancer Res. 65, 236–245 (2005).

    Google Scholar 

  81. Banerjee, S., Crouse, N. R., Emnett, R. J., Gianino, S. M. & Gutmann, D. H. Neurofibromatosis-1 regulates mTOR-mediated astrocyte growth and glioma formation in a TSC/Rheb-independent manner. Proc. Natl Acad. Sci. USA 108, 15996–16001 (2011).

    Google Scholar 

  82. Kaul, A., Toonen, J. A., Cimino, P. J., Gianino, S. M. & Gutmann, D. H. Akt- or MEK-mediated mTOR inhibition suppresses Nf1 optic glioma growth. Neuro Oncol. 17, 843–853 (2015).

    Google Scholar 

  83. Kaul, A., Toonen, J. A., Gianino, S. M. & Gutmann, D. H. The impact of coexisting genetic mutations on murine optic glioma biology. Neuro Oncol. 17, 670–677 (2015).

    Google Scholar 

  84. Hegedus, B. et al. Preclinical cancer therapy in a mouse model of neurofibromatosis-1 optic glioma. Cancer Res. 68, 1520–1528 (2008).

    Google Scholar 

  85. Hegedus, B. et al. Optic nerve dysfunction in a mouse model of neurofibromatosis-1 optic glioma. J. Neuropathol. Exp. Neurol. 68, 542–551 (2009).

    Google Scholar 

  86. Brown, J. A., Gianino, S. M. & Gutmann, D. H. Defective cAMP generation underlies the sensitivity of CNS neurons to neurofibromatosis-1 heterozygosity. J. Neurosci. 30, 5579–5589 (2010).

    Google Scholar 

  87. Diggs-Andrews, K. A. et al. Sex is a major determinant of neuronal dysfunction in neurofibromatosis type 1. Ann. Neurol. 75, 309–316 (2014). This report is the first to demonstrate that sex is a major determinant of vision loss in children and mice with neurofibromatosis type 1-associated optic pathway glioma.

    Google Scholar 

  88. Diggs-Andrews, K. A. et al. Reply: to PMID 24375753. Ann. Neurol. 75, 800–801 (2014).

    Google Scholar 

  89. Toonen, J. A., Solga, A. C., Ma, Y. & Gutmann, D. H. Estrogen activation of microglia underlies the sexually dimorphic differences in Nf1 optic glioma-induced retinal pathology. J. Exp. Med. 214, 17–25 (2017).

    Google Scholar 

  90. Toonen, J. A. et al. NF1 germline mutation differentially dictates optic glioma formation and growth in neurofibromatosis-1. Hum. Mol. Genet. 25, 1703–1713 (2016). This is the first study to show that the germline NF1 mutation could differentially dictate the formation of optic pathway gliomas in mice.

    Google Scholar 

  91. Anastasaki, C. & Gutmann, D. H. Neuronal NF1/RAS regulation of cyclic AMP requires atypical PKC activation. Hum. Mol. Genet. 23, 6712–6721 (2014).

    Google Scholar 

  92. Toonen, J. A., Ma, Y. & Gutmann, D. H. Defining the temporal course of murine neurofibromatosis-1 optic gliomagenesis reveals a therapeutic window to attenuate retinal dysfunction. Neuro Oncol. http://dx.doi.org/10.1093/neuonc/now267 (2016).

  93. [No authors listed.] Neurofibromatosis. Conference statement. National Institutes of Health Consensus Development Conference. Arch. Neurol. 45, 575–578 (1988).

  94. Evans, D. G. et al. Comprehensive RNA analysis of the NF1 gene in classically affected NF1 affected individuals meeting NIH criteria has high sensitivity and mutation negative testing is reassuring in isolated cases with pigmentary features only. EBioMedicine 7, 212–220 (2016).

    Google Scholar 

  95. Nunley, K. S., Gao, F., Albers, A. C., Bayliss, S. J. & Gutmann, D. H. Predictive value of cafe au lait macules at initial consultation in the diagnosis of neurofibromatosis type 1. Arch. Dermatol. 145, 883–887 (2009).

    Google Scholar 

  96. DeBella, K., Szudek, J. & Friedman, J. M. Use of the National Institutes of Health criteria for diagnosis of neurofibromatosis 1 in children. Pediatrics 105, 608–614 (2000).

    Google Scholar 

  97. Ruggieri, M. & Huson, S. M. The clinical and diagnostic implications of mosaicism in the neurofibromatoses. Neurology 56, 1433–1443 (2001).

    Google Scholar 

  98. Ruggieri, M. et al. The natural history of spinal neurofibromatosis: a critical review of clinical and genetic features. Clin. Genet. 87, 401–410 (2015).

    Google Scholar 

  99. Messiaen, L. et al. Clinical and mutational spectrum of neurofibromatosis type 1-like syndrome. JAMA 302, 2111–2118 (2009).

    Google Scholar 

  100. Trofatter, J. A. et al. A novel moesin-, ezrin-, radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor. Cell 72, 791–800 (1993).

    Google Scholar 

  101. Hulsebos, T. J. et al. Germline mutation of INI1/SMARCB1 in familial schwannomatosis. Am. J. Hum. Genet. 80, 805–810 (2007).

    Google Scholar 

  102. Smith, M. J. et al. Mutations in LZTR1 add to the complex heterogeneity of schwannomatosis. Neurology 84, 141–147 (2015).

    Google Scholar 

  103. Huson, S. M., Compston, D. A., Clark, P. & Harper, P. S. A genetic study of von Recklinghausen neurofibromatosis in south east Wales. I. Prevalence, fitness, mutation rate, and effect of parental transmission on severity. J. Med. Genet. 26, 704–711 (1989).

    Google Scholar 

  104. Verlinsky, Y. et al. Preimplantation diagnosis for neurofibromatosis. Reprod. Biomed. Online 4, 218–222 (2002).

    Google Scholar 

  105. De Raedt, T. et al. Elevated risk for MPNST in NF1 microdeletion patients. Am. J. Hum. Genet. 72, 1288–1292 (2003).

    Google Scholar 

  106. Listernick, R., Ferner, R. E., Liu, G. T. & Gutmann, D. H. Optic pathway gliomas in neurofibromatosis-1: controversies and recommendations. Ann. Neurol. 61, 189–198 (2007).

    Google Scholar 

  107. Listernick, R. et al. Late-onset optic pathway tumors in children with neurofibromatosis 1. Neurology 63, 1944–1946 (2004).

    Google Scholar 

  108. Listernick, R., Louis, D. N., Packer, R. J. & Gutmann, D. H. Optic pathway gliomas in children with neurofibromatosis 1: consensus statement from the NF1 Optic Pathway Glioma Task Force. Ann. Neurol. 41, 143–149 (1997). This is the first report from the Neurofibromatosis type 1 Optic Pathway Glioma Task Force, which outlines the recommended practices for the management of children with these tumours.

    Google Scholar 

  109. Fossali, E. et al. Renovascular disease and hypertension in children with neurofibromatosis. Pediatr. Nephrol. 14, 806–810 (2000).

    Google Scholar 

  110. Ferner, R. E. et al. Guidelines for the diagnosis and management of individuals with neurofibromatosis 1. J. Med. Genet. 44, 81–88 (2007).

    Google Scholar 

  111. Listernick, R., Charrow, J., Greenwald, M. & Mets, M. Natural history of optic pathway tumors in children with neurofibromatosis type 1: a longitudinal study. J. Pediatr. 125, 63–66 (1994).

    Google Scholar 

  112. King, A., Listernick, R., Charrow, J., Piersall, L. & Gutmann, D. H. Optic pathway gliomas in neurofibromatosis type 1: the effect of presenting symptoms on outcome. Am. J. Med. Genet. A 122A, 95–99 (2003).

    Google Scholar 

  113. Listernick, R., Charrow, J. & Greenwald, M. Emergence of optic pathway gliomas in children with neurofibromatosis type 1 after normal neuroimaging results. J. Pediatr. 121, 584–587 (1992).

    Google Scholar 

  114. Prada, C. E. et al. The use of magnetic resonance imaging screening for optic pathway gliomas in children with neurofibromatosis type 1. J. Pediatr. 167, 851–856.e1 (2015).

    Google Scholar 

  115. Fisher, M. J. et al. Visual outcomes in children with neurofibromatosis type 1-associated optic pathway glioma following chemotherapy: a multicenter retrospective analysis. Neuro Oncol. 14, 790–797 (2012). This is one of the first descriptions of risk factors that are important for vision loss in children with neurofibromatosis type 1-associated optic pathway glioma.

    Google Scholar 

  116. Mautner, V. F. et al. Assessment of benign tumor burden by whole-body MRI in patients with neurofibromatosis 1. Neuro Oncol. 10, 593–598 (2008).

    Google Scholar 

  117. Crawford, A. H. & Herrera-Soto, J. Scoliosis associated with neurofibromatosis. Orthop. Clin. North Am. 38, 553–562 (2007).

    Google Scholar 

  118. Heerva, E. et al. A controlled register-based study of 460 neurofibromatosis 1 patients: increased fracture risk in children and adults over 41 years of age. J. Bone Miner. Res. 27, 2333–2337 (2012).

    Google Scholar 

  119. Stevenson, D. A. et al. Approaches to treating NF1 tibial pseudarthrosis: consensus from the Children's Tumor Foundation NF1 Bone Abnormalities Consortium. J. Pediatr. Orthop. 33, 269–275 (2013). This consensus report describes the recommended management of tibial pseudarthrosis in children with neurofibromatosis type 1.

    Google Scholar 

  120. Hyman, S. L., Shores, A. & North, K. N. The nature and frequency of cognitive deficits in children with neurofibromatosis type 1. Neurology 65, 1037–1044 (2005).

    Google Scholar 

  121. Hyman, S. L., Arthur Shores, E. & North, K. N. Learning disabilities in children with neurofibromatosis type 1: subtypes, cognitive profile, and attention-deficit-hyperactivity disorder. Dev. Med. Child Neurol. 48, 973–977 (2006).

    Google Scholar 

  122. Mautner, V. F., Granstrom, S. & Leark, R. A. Impact of ADHD in adults with neurofibromatosis type 1: associated psychological and social problems. J. Atten. Disord. 19, 35–43 (2015).

    Google Scholar 

  123. Isenberg, J. C., Templer, A., Gao, F., Titus, J. B. & Gutmann, D. H. Attention skills in children with neurofibromatosis type 1. J. Child Neurol. 28, 45–49 (2013).

    Google Scholar 

  124. Lidzba, K., Granstrom, S., Lindenau, J. & Mautner, V. F. The adverse influence of attention-deficit disorder with or without hyperactivity on cognition in neurofibromatosis type 1. Dev. Med. Child Neurol. 54, 892–897 (2012).

    Google Scholar 

  125. Garg, S. et al. Neurofibromatosis type 1 and autism spectrum disorder. Pediatrics 132, e1642–e1648 (2013).

    Google Scholar 

  126. Morris, S. M. et al. Disease burden and symptom structure of autism in neurofibromatosis type 1: a study of the International NF1-ASD Consortium Team (INFACT). JAMA Psychiatry 73, 1276–1284 (2016). This international consortium study characterizes autism spectrum disorder in children with neurofibromatosis type 1.

    Google Scholar 

  127. Omrani, A. et al. HCN channels are a novel therapeutic target for cognitive dysfunction in neurofibromatosis type 1. Mol. Psychiatry 20, 1311–1321 (2015).

    Google Scholar 

  128. Bearden, C. E. et al. A randomized placebo-controlled lovastatin trial for neurobehavioral function in neurofibromatosis I. Ann. Clin. Transl Neurol. 3, 266–279 (2016).

    Google Scholar 

  129. van der Vaart, T. et al. Simvastatin for cognitive deficits and behavioural problems in patients with neurofibromatosis type 1 (NF1-SIMCODA): a randomised, placebo-controlled trial. Lancet Neurol. 12, 1076–1083 (2013).

    Google Scholar 

  130. Krab, L. C. et al. Effect of simvastatin on cognitive functioning in children with neurofibromatosis type 1: a randomized controlled trial. JAMA 300, 287–294 (2008). This is the first study to use a farnesyltransferase inhibitor to treat learning problems in children with neurofibromatosis type 1.

    Google Scholar 

  131. Payne, J. M. et al. A double-blind randomized placebo-controlled study of lovastatin for cognitive deficits in children with neurofibromatosis type 1. Neurology 87, 2575–2584 (2016).

    Google Scholar 

  132. Thomas, P. K. et al. Neurofibromatous neuropathy. Muscle Nerve 13, 93–101 (1990).

    Google Scholar 

  133. Stewart, D. R. et al. Diagnosis, management, and complications of glomus tumours of the digits in neurofibromatosis type 1. J. Med. Genet. 47, 525–532 (2010).

    Google Scholar 

  134. Leonard, J. R., Ferner, R. E., Thomas, N. & Gutmann, D. H. Cervical cord compression from plexiform neurofibromas in neurofibromatosis 1. J. Neurol. Neurosurg. Psychiatry 78, 1404–1406 (2007).

    Google Scholar 

  135. Tucker, T., Wolkenstein, P., Revuz, J., Zeller, J. & Friedman, J. M. Association between benign and malignant peripheral nerve sheath tumors in NF1. Neurology 65, 205–211 (2005).

    Google Scholar 

  136. Weiss, B. et al. Sirolimus for progressive neurofibromatosis type 1-associated plexiform neurofibromas: a neurofibromatosis Clinical Trials Consortium phase II study. Neuro Oncol. 17, 596–603 (2015).

    Google Scholar 

  137. Hirbe, A. C. & Gutmann, D. H. Neurofibromatosis type 1: a multidisciplinary approach to care. Lancet Neurol. 13, 834–843 (2014).

    Google Scholar 

  138. Dombi, E. et al. Activity of selumetinib in neurofibromatosis type 1-related plexiform neurofibromas. N. Engl. J. Med. 375, 2550–2560 (2017).

    Google Scholar 

  139. Ferner, R. E., Hughes, R. A., Hall, S. M., Upadhyaya, M. & Johnson, M. R. Neurofibromatous neuropathy in neurofibromatosis 1 (NF1). J. Med. Genet. 41, 837–841 (2004).

    Google Scholar 

  140. Drouet, A. et al. Neurofibromatosis 1-associated neuropathies: a reappraisal. Brain 127, 1993–2009 (2004).

    Google Scholar 

  141. Lin, B. T., Weiss, L. M. & Medeiros, L. J. Neurofibroma and cellular neurofibroma with atypia: a report of 14 tumors. Am. J. Surg. Pathol. 21, 1443–1449 (1997).

    Google Scholar 

  142. Beert, E. et al. Atypical neurofibromas in neurofibromatosis type 1 are premalignant tumors. Genes Chromosomes Cancer 50, 1021–1032 (2011).

    Google Scholar 

  143. Evans, D. G. et al. Malignant peripheral nerve sheath tumours in neurofibromatosis 1. J. Med. Genet. 39, 311–314 (2002).

    Google Scholar 

  144. Uusitalo, E. et al. Distinctive cancer associations in patients with neurofibromatosis type 1. J. Clin. Oncol. 34, 1978–1986 (2016).

    Google Scholar 

  145. Ferner, R. E. & Gutmann, D. H. International consensus statement on malignant peripheral nerve sheath tumors in neurofibromatosis. Cancer Res. 62, 1573–1577 (2002).

    Google Scholar 

  146. Warbey, V. S., Ferner, R. E., Dunn, J. T., Calonje, E. & O'Doherty, M. J. [18F]FDG PET/CT in the diagnosis of malignant peripheral nerve sheath tumours in neurofibromatosis type-1. Eur. J. Nucl. Med. Mol. Imaging 36, 751–757 (2009). This important study demonstrates the use of PET imaging for the diagnosis of MPNSTs associated with neurofibromatosis type 1.

    Google Scholar 

  147. Frustaci, S. et al. Adjuvant chemotherapy for adult soft tissue sarcomas of the extremities and girdles: results of the Italian randomized cooperative trial. J. Clin. Oncol. 19, 1238–1247 (2001).

    Google Scholar 

  148. Kroep, J. R. et al. First-line chemotherapy for malignant peripheral nerve sheath tumor (MPNST) versus other histological soft tissue sarcoma subtypes and as a prognostic factor for MPNST: an EORTC soft tissue and bone sarcoma group study. Ann. Oncol. 22, 207–214 (2011).

    Google Scholar 

  149. Carli, M. et al. Pediatric malignant peripheral nerve sheath tumor: the Italian and German soft tissue sarcoma cooperative group. J. Clin. Oncol. 23, 8422–8430 (2005).

    Google Scholar 

  150. Guillamo, J. S. et al. Prognostic factors of CNS tumours in neurofibromatosis 1 (NF1): a retrospective study of 104 patients. Brain 126, 152–160 (2003). This paper provides a detailed description of brain tumours arising in children with neurofibromatosis type 1.

    Google Scholar 

  151. DiPaolo, D. P. et al. Neurofibromatosis type 1: pathologic substrate of high-signal-intensity foci in the brain. Radiology 195, 721–724 (1995).

    Google Scholar 

  152. Fisher, M. J. et al. Gender as a disease modifier in neurofibromatosis type 1 optic pathway glioma. Ann. Neurol. 75, 799–800 (2014).

    Google Scholar 

  153. Habiby, R., Silverman, B., Listernick, R. & Charrow, J. Precocious puberty in children with neurofibromatosis type 1. J. Pediatr. 126, 364–367 (1995).

    Google Scholar 

  154. Listernick, R., Darling, C., Greenwald, M., Strauss, L. & Charrow, J. Optic pathway tumors in children: the effect of neurofibromatosis type 1 on clinical manifestations and natural history. J. Pediatr. 127, 718–722 (1995).

    Google Scholar 

  155. Packer, R. J. et al. Carboplatin and vincristine chemotherapy for children with newly diagnosed progressive low-grade gliomas. J. Neurosurg. 86, 747–754 (1997).

    Google Scholar 

  156. Grill, J. et al. Radiation-induced cerebral vasculopathy in children with neurofibromatosis and optic pathway glioma. Ann. Neurol. 45, 393–396 (1999).

    Google Scholar 

  157. Sharif, S. et al. Second primary tumors in neurofibromatosis 1 patients treated for optic glioma: substantial risks after radiotherapy. J. Clin. Oncol. 24, 2570–2575 (2006). This is the first study to demonstrate that radiation is associated with secondary malignancies in patients with neurofibromatosis type 1.

    Google Scholar 

  158. Mahdi, J. et al. A multi-institutional study of brainstem gliomas in children with neurofibromatosis type 1. Neurology (in the press).

  159. Ullrich, N. J., Raja, A. I., Irons, M. B., Kieran, M. W. & Goumnerova, L. Brainstem lesions in neurofibromatosis type 1. Neurosurgery 61, 762–766 (2007).

    Google Scholar 

  160. Opocher, G., Conton, P., Schiavi, F., Macino, B. & Mantero, F. Pheochromocytoma in von Hippel–Lindau disease and neurofibromatosis type 1. Fam.Cancer 4, 13–16 (2005).

    Google Scholar 

  161. Walther, M. M., Herring, J., Enquist, E., Keiser, H. R. & Linehan, W. M. von Recklinghausen's disease and pheochromocytomas. J. Urol. 162, 1582–1586 (1999).

    Google Scholar 

  162. Pappachan, J. M., Raskauskiene, D., Sriraman, R., Edavalath, M. & Hanna, F. W. Diagnosis and management of pheochromocytoma: a practical guide to clinicians. Curr. Hypertens. Rep. 16, 442 (2014).

    Google Scholar 

  163. Miles, D. K. et al. Patterns of hematopoietic lineage involvement in children with neurofibromatosis type 1 and malignant myeloid disorders. Blood 88, 4314–4320 (1996).

    Google Scholar 

  164. Andersson, J. et al. NF1-associated gastrointestinal stromal tumors have unique clinical, phenotypic, and genotypic characteristics. Am. J. Surg. Pathol. 29, 1170–1176 (2005).

    Google Scholar 

  165. Salvi, P. F. et al. Gastrointestinal stromal tumors associated with neurofibromatosis 1: a single centre experience and systematic review of the literature including 252 cases. Int. J. Surg. Oncol. 2013, 398570 (2013).

    Google Scholar 

  166. Joensuu, H., Hohenberger, P. & Corless, C. L. Gastrointestinal stromal tumour. Lancet 382, 973–983 (2013).

    Google Scholar 

  167. Cambiaghi, S., Restano, L. & Caputo, R. Juvenile xanthogranuloma associated with neurofibromatosis 1: 14 patients without evidence of hematologic malignancies. Pediatr. Dermatol. 21, 97–101 (2004).

    Google Scholar 

  168. Cham, E., Siegel, D. & Ruben, B. S. Cutaneous xanthogranulomas, hepatosplenomegaly, anemia, and thrombocytopenia as presenting signs of juvenile myelomonocytic leukemia. Am. J. Clin. Dermatol. 11, 67–71 (2010).

    Google Scholar 

  169. Han, M. & Criado, E. Renal artery stenosis and aneurysms associated with neurofibromatosis. J. Vascular Surg. 41, 539–543 (2005).

    Google Scholar 

  170. Terry, A. R., Jordan, J. T., Schwamm, L. & Plotkin, S. R. Increased risk of cerebrovascular disease among patients with neurofibromatosis type 1: population-based approach. Stroke 47, 60–65 (2016).

    Google Scholar 

  171. Farmakis, S. G., Han, M., White, F. & Khanna, G. Neurofibromatosis 1 vasculopathy manifesting as a peripheral aneurysm in an adolescent. Pediatr. Radiol. 44, 1328–1331 (2014).

    Google Scholar 

  172. Koss, M., Scott, R. M., Irons, M. B., Smith, E. R. & Ullrich, N. J. Moyamoya syndrome associated with neurofibromatosis type 1: perioperative and long-term outcome after surgical revascularization. J. Neurosurg. Pediatr. 11, 417–425 (2013).

    Google Scholar 

  173. Vranceanu, A. M., Merker, V. L., Park, E. R. & Plotkin, S. R. Quality of life among children and adolescents with neurofibromatosis 1: a systematic review of the literature. J. Neurooncol. 122, 219–228 (2015).

    Google Scholar 

  174. Vranceanu, A. M., Merker, V. L., Park, E. & Plotkin, S. R. Quality of life among adult patients with neurofibromatosis 1, neurofibromatosis 2 and schwannomatosis: a systematic review of the literature. J. Neurooncol. 114, 257–262 (2013).

    Google Scholar 

  175. Garwood, M. M. et al. Physical, cognitive, and psychosocial predictors of functional disability and health-related quality of life in adolescents with neurofibromatosis-1. Pain Res. Treat. 2012, 975364 (2012). This important study describes the predictors of QOL and functional disability in adolescents with neurofibromatosis type 1.

    Google Scholar 

  176. Graf, A., Landolt, M. A., Mori, A. C. & Boltshauser, E. Quality of life and psychological adjustment in children and adolescents with neurofibromatosis type 1. J. Pediatr. 149, 348–353 (2006).

    Google Scholar 

  177. Oostenbrink, R. et al. Parental reports of health-related quality of life in young children with neurofibromatosis type 1: influence of condition specific determinants. J. Pediatr. 151, 182–186.e2 (2007).

    Google Scholar 

  178. Krab, L. C. et al. Health-related quality of life in children with neurofibromatosis type 1: contribution of demographic factors, disease-related factors, and behavior. J. Pediatr. 154, 420–425.e1 (2009).

    Google Scholar 

  179. Wolkenstein, P. et al. Impact of neurofibromatosis 1 upon quality of life in childhood: a cross-sectional study of 79 cases. Br. J. Dermatol. 160, 844–848 (2009). This report describes the effect of neurofibromatosis type 1 on QOL in children with neurofibromatosis type 1.

    Google Scholar 

  180. Wolters, P. L. et al. Pain interference in youth with neurofibromatosis type 1 and plexiform neurofibromas and relation to disease severity, social-emotional functioning, and quality of life. Am. J. Med. Genet. A 167A, 2103–2113 (2015).

    Google Scholar 

  181. Martin, S. et al. Social–emotional functioning of children and adolescents with neurofibromatosis type 1 and plexiform neurofibromas: relationships with cognitive, disease, and environmental variables. J. Pediatr. Psychol. 37, 713–724 (2012).

    Google Scholar 

  182. Engel, G. L. The need for a new medical model: a challenge for biomedicine. Science 196, 129–136 (1977).

    Google Scholar 

  183. Page, P. Z. et al. Impact of neurofibromatosis 1 on quality of life: a cross-sectional study of 176 American cases. Am. J. Med. Genet. A 140A, 1893–1898 (2006).

    Google Scholar 

  184. Wolkenstein, P., Zeller, J., Revuz, J., Ecosse, E. & Leplege, A. Quality-of-life impairment in neurofibromatosis type 1: a cross-sectional study of 128 cases. Arch. Dermatol. 137, 1421–1425 (2001).

    Google Scholar 

  185. Nutakki, K., Hingtgen, C. M., Monahan, P., Varni, J. W. & Swigonski, N. L. Development of the adult PedsQL neurofibromatosis type 1 module: initial feasibility, reliability and validity. Health Qual. Life Outcomes 11, 21 (2013). The study describes the development of a QOL assessment tool for patients with neurofibromatosis type 1.

    Google Scholar 

  186. Afridi, S. K., Leschziner, G. D. & Ferner, R. E. Prevalence and clinical presentation of headache in a National Neurofibromatosis 1 Service and impact on quality of life. Am. J. Med. Genet. A 167A, 2282–2285 (2015).

    Google Scholar 

  187. Crawford, H. A. et al. The impact of neurofibromatosis type 1 on the health and wellbeing of Australian adults. J. Genet. Couns. 24, 931–944 (2015).

    Google Scholar 

  188. Merker, V. L. et al. Relationship between whole-body tumor burden, clinical phenotype, and quality of life in patients with neurofibromatosis. Am. J. Med. Genet. A 164A, 1431–1437 (2014).

    Google Scholar 

  189. Kodra, Y. et al. Health-related quality of life in patients with neurofibromatosis type 1. A survey of 129 Italian patients. Dermatology 218, 215–220 (2009).

    Google Scholar 

  190. Granstrom, S., Langenbruch, A., Augustin, M. & Mautner, V. F. Psychological burden in adult neurofibromatosis type 1 patients: impact of disease visibility on body image. Dermatology 224, 160–167 (2012).

    Google Scholar 

  191. Cohen, J. S., Levy, H. P., Sloan, J., Dariotis, J. & Biesecker, B. B. Depression among adults with neurofibromatosis type 1: prevalence and impact on quality of life. Clin. Genet. 88, 425–430 (2015).

    Google Scholar 

  192. Weiss, B. et al. Sirolimus for non-progressive NF1-associated plexiform neurofibromas: an NF clinical trials consortium phase II study. Pediatr. Blood Cancer 61, 982–986 (2014).

    Google Scholar 

  193. Widemann, B. C. et al. Phase 2 randomized, flexible crossover, double-blinded, placebo-controlled trial of the farnesyltransferase inhibitor tipifarnib in children and young adults with neurofibromatosis type 1 and progressive plexiform neurofibromas. Neuro Oncol. 16, 707–718 (2014).

    Google Scholar 

  194. Hua, C. et al. Sirolimus improves pain in NF1 patients with severe plexiform neurofibromas. Pediatrics 133, e1792–e1797 (2014).

    Google Scholar 

  195. Halloran, J. et al. Chronic inhibition of mammalian target of rapamycin by rapamycin modulates cognitive and non-cognitive components of behavior throughout lifespan in mice. Neuroscience 223, 102–113 (2012).

    Google Scholar 

  196. Martin, S. et al. Acceptance and commitment therapy in youth with neurofibromatosis type 1 (NF1) and chronic pain and their parents: a pilot study of feasibility and preliminary efficacy. Am. J. Med. Genet. A 170A, 1462–1470 (2016).

    Google Scholar 

  197. Vranceanu, A. M., Merker, V. L., Plotkin, S. R. & Park, E. R. The relaxation response resiliency program (3RP) in patients with neurofibromatosis 1, neurofibromatosis 2, and schwannomatosis: results from a pilot study. J. Neurooncol. 120, 103–109 (2014).

    Google Scholar 

  198. Wolters, P. L. et al. Patient-reported outcomes in neurofibromatosis and schwannomatosis clinical trials. Neurology 81, S6–S14 (2013).

    Google Scholar 

  199. Plotkin, S. R. et al. Achieving consensus for clinical trials: the REiNS International Collaboration. Neurology 81, S1–S5 (2013).

    Google Scholar 

  200. Gutmann, D. H., Blakeley, J. O., Korf, B. R. & Packer, R. J. Optimizing biologically targeted clinical trials for neurofibromatosis. Expert Opin. Investig. Drugs 22, 443–462 (2013).

    Google Scholar 

  201. Brossier, N. M. & Gutmann, D. H. Improving outcomes for neurofibromatosis 1-associated brain tumors. Expert Rev. Anticancer Ther. 15, 415–423 (2015).

    Google Scholar 

  202. Terzi, Y. K. et al. Reproductive decisions after prenatal diagnosis in neurofibromatosis type 1: importance of genetic counseling. Genet. Couns. 20, 195–202 (2009).

    Google Scholar 

  203. Hersh, J. H. & American Academy of Pediatrics Committee on Genetics. Health supervision for children with neurofibromatosis. Pediatrics 121, 633–642 (2008).

    Google Scholar 

  204. Walker, L. et al. A prospective study of neurofibromatosis type 1 cancer incidence in the UK. Br. J. Cancer 95, 233–238 (2006).

    Google Scholar 

  205. Gutmann, D. H. et al. Gliomas presenting after age 10 in individuals with neurofibromatosis type 1 (NF1). Neurology 59, 759–761 (2002).

    Google Scholar 

  206. Seminog, O. O. & Goldacre, M. J. Risk of benign tumours of nervous system, and of malignant neoplasms, in people with neurofibromatosis: population-based record-linkage study. Br. J. Cancer 108, 193–198 (2012).

    Google Scholar 

  207. Blanchard, G. et al. Systematic MRI in NF1 children under six years of age for the diagnosis of optic pathway gliomas. Study and outcome of a French cohort. Eur. J. Paediatr. Neurol. 20, 275–281 (2016).

    Google Scholar 

  208. Listernick, R., Charrow, J., Greenwald, M. J. & Esterly, N. B. Optic gliomas in children with neurofibromatosis type 1. J. Pediatr. 114, 788–792 (1989).

    Google Scholar 

  209. Sharif, S. et al. Women with neurofibromatosis 1 are at a moderately increased risk of developing breast cancer and should be considered for early screening. J. Med. Genet. 44, 481–484 (2007).

    Google Scholar 

  210. Madanikia, S. A., Bergner, A., Ye, X. & Blakeley, J. O. Increased risk of breast cancer in women with NF1. Am. J. Med. Genet. A 158A, 3056–3060 (2012).

    Google Scholar 

  211. Madubata, C. C., Olsen, M. A., Stwalley, D. L., Gutmann, D. H. & Johnson, K. J. Neurofibromatosis type 1 and chronic neurological conditions in the United States: an administrative claims analysis. Genet. Med. 17, 36–42 (2015).

    Google Scholar 

  212. Perini, P. & Gallo, P. The range of multiple sclerosis associated with neurofibromatosis type 1. J. Neurol. Neurosurg. Psychiatry 71, 679–681 (2001).

    Google Scholar 

  213. Ostendorf, A. P., Gutmann, D. H. & Weisenberg, J. L. Epilepsy in individuals with neurofibromatosis type 1. Epilepsia 54, 1810–1814 (2013).

    Google Scholar 

  214. Leschziner, G. D., Golding, J. F. & Ferner, R. E. Sleep disturbance as part of the neurofibromatosis type 1 phenotype in adults. Am. J. Med. Genet. A 161A, 1319–1322 (2013).

    Google Scholar 

  215. Licis, A. K. et al. Prevalence of sleep disturbances in children with neurofibromatosis type 1. J. Child Neurol. 28, 1400–1405 (2013).

    Google Scholar 

Download references

Acknowledgements

This work was partially funded by a grant from the US Department of Defense (W81XWH-12-1-0155 to B.R.K.).

Author information

Authors and Affiliations

  1. Department of Neurology, Washington University School of Medicine, Box 8111, 660 S. Euclid Avenue, St. Louis, 63110, Missouri, USA

    David H. Gutmann

  2. Department of Neurology, Guy's and St. Thomas' NHS Foundation Trust, London, UK

    Rosalie E. Ferner

  3. Department of Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College, London, London, UK

    Rosalie E. Ferner

  4. Department of Academic General Pediatrics and Primary Care, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA

    Robert H. Listernick

  5. Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA

    Robert H. Listernick

  6. Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA

    Bruce R. Korf

  7. Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA

    Pamela L. Wolters

  8. Master of Public Health Program, Brown School, St. Louis, Missouri, USA

    Kimberly J. Johnson

Authors
  1. David H. Gutmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rosalie E. Ferner
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Robert H. Listernick
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bruce R. Korf
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Pamela L. Wolters
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kimberly J. Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Introduction (B.R.K.); Epidemiology (K.J.J.); Mechanisms/pathophysiology (D.H.G.); Diagnosis, screening and prevention (R.E.F.); Management (R.H.L. and R.E.F.); Quality of life (P.L.W.); Outlook (B.R.K.); Overview of Primer (D.H.G.).

Corresponding author

Correspondence to David H. Gutmann.

Ethics declarations

Competing interests

The authors declare no competing interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gutmann, D., Ferner, R., Listernick, R. et al. Neurofibromatosis type 1. Nat Rev Dis Primers 3, 17004 (2017). https://doi.org/10.1038/nrdp.2017.4

Download citation

  • Published:

  • DOI: https://doi.org/10.1038/nrdp.2017.4

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing