An update on the central nervous system manifestations of neurofibromatosis type 1

Abstract

Neurofibromatosis 1 (NF1) is an autosomal dominant genetic disorder that presents with variable phenotypes as a result of mutations in the neurofibromatosis type 1 (NF1) gene and subsequently, abnormal function of the protein product, neurofibromin. Patients with NF1 are at increased risk for central nervous system (CNS) manifestations including structural, functional, and neoplastic disease. The mechanisms underlying the varied manifestations of NF1 are incompletely understood, but the loss of functional neurofibromin, resulting in sustained activation of the oncoprotein RAS, is responsible for tumorigenesis throughout the body, including the CNS. Much of our understanding of NF1-related CNS manifestations is from a combination of data from animal models and natural history studies of people with NF1 and CNS disease. Data from animal models suggest the importance of both Nf1 mutations and somatic genetic alterations, such as Tp53 loss, for development of neoplasms, as well as the role of the timing of the acquisition of such alterations on the variability of CNS manifestations. A variety of non-neoplastic structural (macrocephaly, hydrocephalus, aqueductal stenosis, and vasculopathy) and functional (epilepsy, impaired cognition, attention deficits, and autism spectrum disorder) abnormalities occur with variable frequency in individuals with NF1. In addition, there is increasing evidence that similar appearing CNS neoplasms in people with and without the NF1 syndrome are due to distinct oncogenic pathways. Gliomas in people with NF1 show alterations in the RAS/MAPK pathway, generally in the absence of BRAF alterations (common to sporadic pilocytic astrocytomas) or IDH or histone H3 mutations (common to diffuse gliomas subsets). A subset of low-grade astrocytomas in these patients remain difficult to classify using standard criteria, and occasionally demonstrate morphologic features resembling subependymal giant cell astrocytomas that afflict patients with tuberous sclerosis complex (“SEGA-like astrocytomas”). There is also emerging evidence that NF1-associated high-grade astrocytomas have frequent co-existing alterations such as ATRX mutations and an alternative lengthening of telomeres (ALT) phenotype responsible for unique biologic properties. Ongoing efforts are seeking to improve diagnostic accuracy for CNS neoplasms in the setting of NF1 versus sporadic tumors. In addition, MEK inhibitors, which act on the RAS/MAPK pathway, continue to be studied as rational targets for the treatment of NF1-associated tumors, including CNS tumors.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

References

  1. 1.

    Anastasaki C, Gutmann DH (2014) Neuronal NF1/RAS regulation of cyclic AMP requires atypical PKC activation. Hum Mol Genet 23:6712–6721. https://doi.org/10.1093/hmg/ddu389

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Appin CL, Brat DJ (2014) Molecular genetics of gliomas. Cancer J 20:66–72. https://doi.org/10.1097/ppo.0000000000000020

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Avery RA, Hwang EI, Ishikawa H, Acosta MT, Hutcheson KA, Santos D et al (2014) Handheld optical coherence tomography during sedation in young children with optic pathway gliomas. JAMA Ophthalmol 132:265–271. https://doi.org/10.1001/jamaophthalmol.2013.7649

    Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Bajaj A, Li QF, Zheng Q, Pumiglia K (2012) Loss of NF1 expression in human endothelial cells promotes autonomous proliferation and altered vascular morphogenesis. PLoS One 7:e49222. https://doi.org/10.1371/journal.pone.0049222

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Bajenaru ML, Donahoe J, Corral T, Reilly KM, Brophy S, Pellicer A et al (2001) Neurofibromatosis 1 (NF1) heterozygosity results in a cell-autonomous growth advantage for astrocytes. Glia 33:314–323. https://doi.org/10.1002/1098-1136(20010315)33:4%3c314:AID-GLIA1030%3e3.0.CO;2-Q

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Bajenaru ML, Hernandez MR, Perry A, Zhu Y, Parada LF, Garbow JR et al (2003) Optic nerve glioma in mice requires astrocyte Nf1 gene inactivation and Nf1 brain heterozygosity. Cancer Res 63:8573

    CAS  PubMed  Google Scholar 

  7. 7.

    Banerjee A, Jakacki RI, Onar-Thomas A, Wu S, Nicolaides T, Young Poussaint T et al (2017) A phase I trial of the MEK inhibitor selumetinib (AZD6244) in pediatric patients with recurrent or refractory low-grade glioma: a Pediatric Brain Tumor Consortium (PBTC) study. Neuro Oncol 19:1135–1144. https://doi.org/10.1093/neuonc/now282

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Barba C, Jacques T, Kahane P, Polster T, Isnard J, Leijten FSS et al (2013) Epilepsy surgery in neurofibromatosis type 1. Epilepsy Res 105:384–395. https://doi.org/10.1016/j.eplepsyres.2013.02.021

    Article  PubMed  Google Scholar 

  9. 9.

    Bennett MR, Rizvi TA, Karyala S, McKinnon RD, Ratner N (2003) Aberrant growth and differentiation of oligodendrocyte progenitors in neurofibromatosis type 1 mutants. J Neurosci 23:7207

    CAS  Article  Google Scholar 

  10. 10.

    Bessler WK, Kim G, Hudson FZ, Mund JA, Mali R, Menon K et al (2016) Nf1+/- monocytes/macrophages induce neointima formation via CCR2 activation. Hum Mol Genet 25:1129–1139. https://doi.org/10.1093/hmg/ddv635

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Blakeley JO, Plotkin SR (2016) Therapeutic advances for the tumors associated with neurofibromatosis type 1, type 2, and schwannomatosis. Neuro Oncol 18:624–638. https://doi.org/10.1093/neuonc/nov200

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Brown JA, Diggs-Andrews KA, Gianino SM, Gutmann DH (2012) Neurofibromatosis-1 heterozygosity impairs CNS neuronal morphology in a cAMP/PKA/ROCK-dependent manner. Mol Cell Neurosci 49:13–22. https://doi.org/10.1016/j.mcn.2011.08.008

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Brown JA, Diggs-Andrews KA, Gianino SM, Gutmann DH (2012) Neurofibromatosis-1 heterozygosity impairs CNS neuronal morphology in a cAMP/PKA/ROCK-dependent manner. Mol Cell Neurosci 49:13–22. https://doi.org/10.1016/j.mcn.2011.08.008

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Brown JA, Xu J, Diggs-Andrews KA, Wozniak DF, Mach RH, Gutmann DH (2011) PET imaging for attention deficit preclinical drug testing in neurofibromatosis-1 mice. Exp Neurol 232:333–338. https://doi.org/10.1016/j.expneurol.2011.09.005

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Buchanan ME, Davis RL (2010) A distinct set of drosophila brain neurons required for NF1-dependent learning and memory. J Neurosci 30:10135–10143. https://doi.org/10.1523/JNEUROSCI.0283-10.2010

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Byrne S, Connor S, Lascelles K, Siddiqui A, Hargrave D, Ferner RE (2017) Clinical presentation and prognostic indicators in 100 adults and children with neurofibromatosis 1 associated non-optic pathway brain gliomas. J Neurooncol 133:609–614. https://doi.org/10.1007/s11060-017-2475-z

    Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Cairns AG, North KN (2008) Cerebrovascular dysplasia in neurofibromatosis type 1. J Neurol Neurosurg Psychiatry 79:1165. https://doi.org/10.1136/jnnp.2007.136457

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Campian J, Gutmann DH (2017) CNS tumors in neurofibromatosis. J Clin Oncol 35:2378–2385. https://doi.org/10.1200/JCO.2016.71.7199

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Cichowski K, Shih TS, Schmitt E, Santiago S, Reilly K, McLaughlin ME et al (1999) Mouse models of tumor development in neurofibromatosis type 1. Science 286:2172

    CAS  Article  Google Scholar 

  20. 20.

    Collins VP, Jones DTW, Giannini C (2015) Pilocytic astrocytoma: pathology, molecular mechanisms and markers. Acta Neuropathol 129:775–788. https://doi.org/10.1007/s00401-015-1410-7

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Costa RM, Federov NB, Kogan JH, Murphy GG, Stern J, Ohno M et al (2002) Mechanism for the learning deficits in a mouse model of neurofibromatosis type 1. Nature 415:526. https://doi.org/10.1038/nature711

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    D’Angelo F, Ceccarelli M, Tala, Garofano L, Zhang J, Frattini V et al (2019) The molecular landscape of glioma in patients with Neurofibromatosis 1. Nat Med 25:176–187. https://doi.org/10.1038/s41591-018-0263-8

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Dasgupta B, Yi Y, Chen DY, Weber JD, Gutmann DH (2005) Proteomic analysis reveals hyperactivation of the mammalian target of rapamycin pathway in neurofibromatosis 1–associated human and mouse brain tumors. Cancer Res 65:2755

    CAS  Article  Google Scholar 

  24. 24.

    DeClue JE, Papageorge AG, Fletcher JA, Diehl SR, Ratner N, Vass WC et al (1992) Abnormal regulation of mammalian p21ras contributes to malignant tumor growth in von Recklinghausen (type 1) neurofibromatosis. Cell 69:265–273. https://doi.org/10.1016/0092-8674(92)90407-4

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Diggs-Andrews KA, Brown JA, Gianino SM, Rubin JB, Wozniak DF, Gutmann DH (2014) Sex is a major determinant of neuronal dysfunction in Neurofibromatosis Type 1. Ann Neurol 75:309–316. https://doi.org/10.1002/ana.24093

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Diggs-Andrews KA, Tokuda K, Izumi Y, Zorumski CF, Wozniak DF, Gutmann DH (2013) Dopamine deficiency underlies learning deficits in Neurofibromatosis-1 mice. Ann Neurol 73:309–315. https://doi.org/10.1002/ana.23793

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    DiPaolo DP, Zimmerman RA, Rorke LB, Zackai EH, Bilaniuk LT, Yachnis AT (1995) Neurofibromatosis type 1: pathologic substrate of high-signal-intensity foci in the brain. Radiology 195:721–724. https://doi.org/10.1148/radiology.195.3.7754001

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Dombi E, Baldwin A, Marcus LJ, Fisher MJ, Weiss B, Kim A et al (2016) Activity of selumetinib in neurofibromatosis type 1-related plexiform neurofibromas. N Engl J Med 375:2550–2560. https://doi.org/10.1056/NEJMoa1605943

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Donovan S, Shannon KM, Bollag G (2002) GTPase activating proteins: critical regulators of intracellular signaling. Biochim Biophys Acta 1602:23–45. https://doi.org/10.1016/S0304-419X(01)00041-5

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Downward J (2003) Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer 3:11. https://doi.org/10.1038/nrc969

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    Evans DGR, Salvador H, Chang VY, Erez A, Voss SD, Schneider KW et al (2017) Cancer and central nervous system tumor surveillance in pediatric neurofibromatosis 1. Clin Cancer Res 23:e46

    Article  Google Scholar 

  32. 32.

    Fangusaro JR, Onar-Thomas A, Young-Poussaint T, Wu S, Ligon AH, Lindeman NI et al (2017) A phase II prospective study of selumetinib in children with recurrent or refractory low-grade glioma (LGG): a Pediatric Brain Tumor Consortium (PBTC) study. J Clin Oncol 35:10504–10504. https://doi.org/10.1200/JCO.2017.35.15_suppl.10504

    Article  Google Scholar 

  33. 33.

    Fisher MJ, Avery RA, Allen JC, Ardern-Holmes SL, Bilaniuk LT, Ferner RE et al (2013) Functional outcome measures for NF1-associated optic pathway glioma clinical trials. Neurology 81:S15

    CAS  Article  Google Scholar 

  34. 34.

    Freret ME, Gutmann DH (2007) Understanding vision loss from optic pathway glioma in neurofibromatosis type 1. Ann Neurol 61:189–198. https://doi.org/10.1002/ana.21107

    CAS  Article  PubMed Central  Google Scholar 

  35. 35.

    Friedman JM, Arbiser J, Epstein JA, Gutmann DH, Huot SJ, Lin AE et al (2002) Cardiovascular disease in neurofibromatosis 1: report of the NF1 Cardiovascular Task Force. Genet Med 4:105. https://doi.org/10.1097/00125817-200205000-00002

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Gales J, Prayson RA (2017) Hippocampal sclerosis and associated focal cortical dysplasia-related epilepsy in neurofibromatosis type I. J Clin Neurosci 37:15–19. https://doi.org/10.1016/j.jocn.2016.10.048

    Article  PubMed  Google Scholar 

  37. 37.

    Garg S, Green J, Leadbitter K, Emsley R, Lehtonen A, Evans DG et al (2013) Neurofibromatosis type 1 and autism spectrum disorder. Pediatrics 132:e1642–1648. https://doi.org/10.1542/peds.2013-1868

    Article  PubMed  Google Scholar 

  38. 38.

    Grill J, Couanet D, Cappelli C, Habrand JL, Rodriguez D, Sainte-Rose C et al (2001) Radiation-induced cerebral vasculopathy in children with neurofibromatosis and optic pathway glioma. Ann Neurol 45:393–396. https://doi.org/10.1002/1531-8249(199903)45:3%3c393:AID-ANA17%3e3.0.CO;2-B

    Article  Google Scholar 

  39. 39.

    Guillamo JS, Créange A, Kalifa C, Grill J, Rodriguez D, Barbarot S, for the Réseau NFF et al (2003) Prognostic factors of CNS tumours in Neurofibromatosis 1 (NF1)A retrospective study of 104 patients. Brain 126:152–160. https://doi.org/10.1093/brain/awg016

    Article  PubMed  Google Scholar 

  40. 40.

    Gutmann DH (2002) Review article: neurofibromin in the brain. J Child Neurol 17:592–601. https://doi.org/10.1177/088307380201700809

    Article  PubMed  Google Scholar 

  41. 41.

    Gutmann DH, Ferner RE, Listernick RH, Korf BR, Wolters PL, Johnson KJ (2017) Neurofibromatosis type 1. Nat Rev Dis Primers 3:17004. https://doi.org/10.1038/nrdp.2017.4

    Article  PubMed  Google Scholar 

  42. 42.

    Gutmann DH, Giovannini M (2002) Mouse Models of Neurofibromatosis 1 and 2. Neoplasia 4:279–290. https://doi.org/10.1038/sj.neo.7900249

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Gutmann DH, Loehr A, Zhang Y, Kim J, Henkemeyer M, Cashen A (1999) Haploinsufficiency for the neurofibromatosis 1 (NF1) tumor suppressor results in increased astrocyte proliferation. Oncogene 18:4450. https://doi.org/10.1038/sj.onc.1202829

    CAS  Article  PubMed  Google Scholar 

  44. 44.

    Gutmann DH, Rasmussen SA, Wolkenstein P, MacCollin MM, Guha A, Inskip PD et al (2002) Gliomas presenting after age 10 in individuals with neurofibromatosis type 1 (NF1). Neurology 59:759

    CAS  Article  Google Scholar 

  45. 45.

    Hamilton SJ, Friedman JM (2001) Insights into the pathogenesis of neurofibromatosis 1 vasculopathy. Clin Genet 58:341–344. https://doi.org/10.1034/j.1399-0004.2000.580501.x

    Article  Google Scholar 

  46. 46.

    Hegedus B, Dasgupta B, Shin JE, Emnett RJ, Hart-Mahon EK, Elghazi L et al (2007) 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. https://doi.org/10.1016/j.stem.2007.07.008

    CAS  Article  PubMed  Google Scholar 

  47. 47.

    Helfferich J, Nijmeijer R, Brouwer OF, Boon M, Fock A, Hoving EW et al (2016) Neurofibromatosis type 1 associated low grade gliomas: a comparison with sporadic low grade gliomas. Crit Rev Oncol Hematol 104:30–41. https://doi.org/10.1016/j.critrevonc.2016.05.008

    Article  PubMed  Google Scholar 

  48. 48.

    Helfferich J, Nijmeijer R, Brouwer OF, Boon M, Fock A, Hoving EW et al (2016) Neurofibromatosis type 1 associated low grade gliomas: a comparison with sporadic low grade gliomas. Crit Rev Oncol Hematol 104:30–41. https://doi.org/10.1016/j.critrevonc.2016.05.008

    Article  PubMed  Google Scholar 

  49. 49.

    Ho IS, Hannan F, Guo H-F, Hakker I, Zhong Y (2007) Distinct functional domains of neurofibromatosis type 1 regulate immediate versus long-term memory formation. J Neurosci 27:6852

    CAS  Article  Google Scholar 

  50. 50.

    Hsieh H-Y, Fung H-C, Wang C-J, Chin S-C, Wu T (2011) Epileptic seizures in neurofibromatosis type 1 are related to intracranial tumors but not to neurofibromatosis bright objects. Seizure 20:606–611. https://doi.org/10.1016/j.seizure.2011.04.016

    Article  PubMed  Google Scholar 

  51. 51.

    Hyman SL, Shores A, North KN (2005) The nature and frequency of cognitive deficits in children with neurofibromatosis type 1. Neurology 65:1037

    Article  Google Scholar 

  52. 52.

    Jacks T, Shih TS, Schmitt EM, Bronson RT, Bernards A, Weinberg RA (1994) Tumour predisposition in mice heterozygous for a targeted mutation in Nf1. Nature Genet 7:353. https://doi.org/10.1038/ng0794-353

    CAS  Article  PubMed  Google Scholar 

  53. 53.

    Jessen WJ, Miller SJ, Jousma E, Wu J, Rizvi TA, Brundage ME et al (2013) MEK inhibition exhibits efficacy in human and mouse neurofibromatosis tumors. J Clin Invest 123:340–347. https://doi.org/10.1172/JCI60578

    CAS  Article  PubMed  Google Scholar 

  54. 54.

    Jones DTW, Gronych J, Lichter P, Witt O, Pfister SM (2012) MAPK pathway activation in pilocytic astrocytoma. Cell Mol Life Sci 69:1799–1811. https://doi.org/10.1007/s00018-011-0898-9

    CAS  Article  PubMed  Google Scholar 

  55. 55.

    Karlsgodt KH, Rosser T, Lutkenhoff ES, Cannon TD, Silva A, Bearden CE (2012) Alterations in white matter microstructure in neurofibromatosis-1. PLoS One 7:e47854. https://doi.org/10.1371/journal.pone.0047854

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Karmakar S, Reilly KM (2017) The role of the immune system in neurofibromatosis type 1-associated nervous system tumors. CNS Oncol 6:45–60. https://doi.org/10.2217/cns-2016-0024

    CAS  Article  PubMed  Google Scholar 

  57. 57.

    Kemp S, Achan A, Ng T, Dexter MAJ (2012) Rosette-forming glioneuronal tumour of the lateral ventricle in a patient with neurofibromatosis 1. J Clin Neurosci 19:1180–1181. https://doi.org/10.1016/j.jocn.2011.12.013

    CAS  Article  PubMed  Google Scholar 

  58. 58.

    Korf BR, Schneider G, Poussaint TY (1999) Structural anomalies revealed by neuroimaging studies in the brains of patients with neurofibromatosis type 1 and large deletions. Genet Med 1:136–140. https://doi.org/10.1097/00125817-199905000-00004

    CAS  Article  PubMed  Google Scholar 

  59. 59.

    Kulkantrakorn K, Geller TJ (1998) Seizures in neurofibromatosis 1. Pediatr Neurol 19:347–350. https://doi.org/10.1016/S0887-8994(98)00075-7

    CAS  Article  PubMed  Google Scholar 

  60. 60.

    Kurtelius A, Kallionpää RA, Huttunen J, Huttunen TJ, Helin K, Koivisto T, Frösen J, von Und Zu et al (2017) Neurofibromatosis type 1 is not associated with subarachnoid haemorrhage. PLoS ONE 12:e0178711–e0178711. https://doi.org/10.1371/journal.pone.0178711

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Lau N, Feldkamp MM, Roncari L, Loehr AH, Shannon P, Gutmann DH et al (2000) Loss of neurofibromin is associated with activation of RAS/MAPK and PI3-K/AKT signaling in a neurofibromatosis 1 astrocytoma. J Neuropathol Exp Neurol 59:759–767. https://doi.org/10.1093/jnen/59.9.759

    CAS  Article  PubMed  Google Scholar 

  62. 62.

    Lee J-S, Padmanabhan A, Shin J, Zhu S, Guo F, Kanki JP et al (2010) Oligodendrocyte progenitor cell numbers and migration are regulated by the zebrafish orthologs of the NF1 tumor suppressor gene. Hum Mol Genet 19:4643–4653. https://doi.org/10.1093/hmg/ddq395

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Lee JC, Villanueva-Meyer JE, Ferris SP, Sloan EA, Hofmann JW, Hattab EM et al (2019) Primary intracranial sarcomas with DICER1 mutation often contain prominent eosinophilic cytoplasmic globules and can occur in the setting of neurofibromatosis type 1. Acta Neuropathol 137:521–525. https://doi.org/10.1007/s00401-019-01960-x

    Article  PubMed  PubMed Central  Google Scholar 

  64. 64.

    Lellouch-Tubiana A, Bourgeois M, Vekemans M, Robain O (1995) Dysembryoplastic neuroepithelial tumors in two children with neurofibromatosis type 1. Acta Neuropathol 90:319–322. https://doi.org/10.1007/BF00296517

    CAS  Article  PubMed  Google Scholar 

  65. 65.

    Li F, Munchhof AM, White HA, Mead LE, Krier TR, Fenoglio A, Chen S, Wu X et al (2006) Neurofibromin is a novel regulator of RAS-induced signals in primary vascular smooth muscle cells. Hum Mol Genet 15:1921–1930. https://doi.org/10.1093/hmg/ddl114

    CAS  Article  PubMed  Google Scholar 

  66. 66.

    Lion-Francois L, Gueyffier F, Mercier C, Gerard D, Herbillon V, Kemlin I et al (2014) The effect of methylphenidate on neurofibromatosis type 1: a randomised, double-blind, placebo-controlled, crossover trial. Orphanet J Rare Dis 9:142. https://doi.org/10.1186/s13023-014-0142-4

    Article  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Listernick R, Ferner RE, Piersall L, Sharif S, Gutmann DH, Charrow J (2004) Late-onset optic pathway tumors in children with neurofibromatosis 1. Neurology 63:1944–1946

    CAS  Article  Google Scholar 

  68. 68.

    Lummus S, Breeze R, Lucia MS, Kleinschmidt-DeMasters BK (2014) Histopathologic features of intracranial vascular involvement in fibromuscular dysplasia, ehlers-danlos type IV, and neurofibromatosis I. J Neuropathol Exp Neurol 73:916–932. https://doi.org/10.1097/NEN.0000000000000113

    Article  PubMed  Google Scholar 

  69. 69.

    Maloney SE, Chandler KC, Anastasaki C, Rieger MA, Gutmann DH, Dougherty JD (2018) Characterization of early communicative behavior in mouse models of neurofibromatosis type 1. Autism Res 11:44–58. https://doi.org/10.1002/aur.1853

    Article  PubMed  Google Scholar 

  70. 70.

    Mendoza MC, Er EE, Blenis J (2011) The Ras-ERK and PI3 K-mTOR pathways: cross-talk and compensation. Trends Biochem Sci 36:320–328. https://doi.org/10.1016/j.tibs.2011.03.006

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Milewicz DM, Kwartler CS, Papke CL, Regalado ES, Cao J, Reid AJ (2010) Genetic variants promoting smooth muscle cell proliferation can result in diffuse and diverse vascular diseases: evidence for a hyperplastic vasculomyopathy. Genet Med 12:196–203. https://doi.org/10.1097/GIM.0b013e3181cdd687

    CAS  Article  PubMed  Google Scholar 

  72. 72.

    Moutal A, Dustrude ET, Khanna R (2017) Sensitization of ion channels contributes to central and peripheral dysfunction in neurofibromatosis type 1. Mol Neurobiol 54:3342–3349. https://doi.org/10.1007/s12035-016-9907-1

    CAS  Article  PubMed  Google Scholar 

  73. 73.

    Neurofibromatosis. Conference statement. National Institutes of Health Consensus Development Conference (1988) Arch Neurol 45:575-578

  74. 74.

    Oderich GS, Sullivan TM, Bower TC, Gloviczki P, Miller DV, Babovic-Vuksanovic D et al (2007) Vascular abnormalities in patients with neurofibromatosis syndrome type I: clinical spectrum, management, and results. J Vasc Surg 46:475–484.e471. https://doi.org/10.1016/j.jvs.2007.03.055

    Article  PubMed  Google Scholar 

  75. 75.

    Otero JJ, Rowitch D, Vandenberg S (2011) OLIG2 is differentially expressed in pediatric astrocytic and in ependymal neoplasms. J Neurooncol 104:423–438. https://doi.org/10.1007/s11060-010-0509-x

    Article  PubMed  Google Scholar 

  76. 76.

    Palsgrove DN, Brosnan-Cashman JA, Giannini C, Raghunathan A, Jentoft M, Bettegowda C et al (2018) Subependymal giant cell astrocytoma-like astrocytoma: a neoplasm with a distinct phenotype and frequent neurofibromatosis type-1-association. Mod Pathol 31:1787–1800. https://doi.org/10.1038/s41379-018-0103-x

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Pecoraro A, Arehart E, Gallentine W, Radtke R, Smith E, Pizoli C, Kansagra S et al (2017) Epilepsy in neurofibromatosis type 1. Epilepsy Behav 73:137–141. https://doi.org/10.1016/j.yebeh.2017.05.011

    Article  PubMed  Google Scholar 

  78. 78.

    Pemov A, Li H, Patidar R, Hansen NF, Sindiri S, Hartley SW et al (2017) The primacy of NF1 loss as the driver of tumorigenesis in neurofibromatosis type 1-associated plexiform neurofibromas. Oncogene 36:3168. https://doi.org/10.1038/onc.2016.464

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Phillips HS, Kharbanda S, Chen R, Forrest WF, Soriano RH, Wu TD et al (2006) Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell 9:157–173. https://doi.org/10.1016/j.ccr.2006.02.019

    CAS  Article  PubMed  Google Scholar 

  80. 80.

    Philpott C, Tovell H, Frayling IM, Cooper DN, Upadhyaya M (2017) The NF1 somatic mutational landscape in sporadic human cancers. Hum Genomics 11:13–13. https://doi.org/10.1186/s40246-017-0109-3

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  81. 81.

    Pong WW, Higer SB, Gianino SM, Emnett RJ, Gutmann DH (2013) Reduced microglial CX3CR1 expression delays neurofibromatosis-1 glioma formation. Ann Neurol 73:303–308. https://doi.org/10.1002/ana.23813

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  82. 82.

    Pride NA, Barton B, Hutchins P, Coghill DR, Korgaonkar MS, Hearps SJC et al (2018) Effects of methylphenidate on cognition and behaviour in children with neurofibromatosis type 1: a study protocol for a randomised placebo-controlled crossover trial. BMJ Open 8:e021800. https://doi.org/10.1136/bmjopen-2018-021800

    Article  PubMed  PubMed Central  Google Scholar 

  83. 83.

    Reinhardt A, Stichel D, Schrimpf D, Sahm F, Korshunov A, Reuss DE et al (2018) Anaplastic astrocytoma with piloid features, a novel molecular class of IDH wildtype glioma with recurrent MAPK pathway, CDKN2A/B and ATRX alterations. Acta Neuropathol 136:273–291. https://doi.org/10.1007/s00401-018-1837-8

    CAS  Article  PubMed  Google Scholar 

  84. 84.

    Reis GF, Bloomer MM, Perry A, Phillips JJ, Grenert JP, Karnezis AN et al (2013) Pilocytic astrocytomas of the optic nerve and their relation to pilocytic astrocytomas elsewhere in the central nervous system. Mod Pathol 26:1279. https://doi.org/10.1038/modpathol.2013.79

    CAS  Article  PubMed  Google Scholar 

  85. 85.

    Rodriguez EF, Scheithauer BW, Giannini C, Rynearson A, Cen L, Hoesley B et al (2011) PI3 K/AKT pathway alterations are associated with clinically aggressive and histologically anaplastic subsets of pilocytic astrocytoma. Acta Neuropathol 121:407–420. https://doi.org/10.1007/s00401-010-0784-9

    CAS  Article  PubMed  Google Scholar 

  86. 86.

    Rodriguez FJ, Brosnan-Cashman JA, Allen SJ, Vizcaino MA, Giannini C, Camelo-Piragua S et al (2019) Alternative lengthening of telomeres, ATRX loss and H3-K27 M mutations in histologically defined pilocytic astrocytoma with anaplasia. Brain Pathol 21:126–140. https://doi.org/10.1111/bpa.12646

    CAS  Article  Google Scholar 

  87. 87.

    Rodriguez FJ, Ligon AH, Horkayne-Szakaly I, Rushing EJ, Ligon KL, Vena N et al (2012) BRAF duplications and MAPK pathway activation are frequent in gliomas of the optic nerve proper. J Neuropathol Exp Neurol 71:789–794. https://doi.org/10.1097/NEN.0b013e3182656ef8

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  88. 88.

    Rodriguez FJ, Perry A, Gutmann DH, O’Neill BP, Leonard J, Bryant S et al (2008) Gliomas in neurofibromatosis type 1: a clinicopathologic study of 100 patients. J Neuropathol Exp Neurol 67:240–249. https://doi.org/10.1097/NEN.0b013e318165eb75

    Article  PubMed  PubMed Central  Google Scholar 

  89. 89.

    Rodriguez FJ, Vizcaino MA, Blakeley J, Heaphy CM (2016) Frequent alternative lengthening of telomeres and ATRX loss in adult NF1-associated diffuse and high-grade astrocytomas. Acta Neuropathol 132:761–763. https://doi.org/10.1007/s00401-016-1619-0

    Article  PubMed  Google Scholar 

  90. 90.

    Rosser TL, Vezina G, Packer RJ (2005) Cerebrovascular abnormalities in a population of children with neurofibromatosis type 1. Neurology 64:553. https://doi.org/10.1212/01.WNL.0000150544.00016.69

    Article  PubMed  Google Scholar 

  91. 91.

    Ryu HH, Jung TY, Lee GJ, Lee KH, Jung SH, Jung S et al (2015) Differences in the clinical courses of pediatric and adult pilocytic astrocytomas with progression: a single-institution study. Childs Nerv Syst 31:2063–2069. https://doi.org/10.1007/s00381-015-2887-z

    Article  PubMed  Google Scholar 

  92. 92.

    Sabbagh A, Pasmant E, Imbard A, Luscan A, Soares M, Blanché H et al (2013) NF1 molecular characterization and neurofibromatosis type I genotype-phenotype correlation: the French Experience. Hum Mutat 34:1510–1518. https://doi.org/10.1002/humu.22392

    CAS  Article  PubMed  Google Scholar 

  93. 93.

    Salyer WR, Salyer DC (1974) The vascular lesions of neurofibromatosis. Angiology 25:510–519. https://doi.org/10.1177/000331977402500803

    CAS  Article  PubMed  Google Scholar 

  94. 94.

    See WL, Tan IL, Mukherjee J, Nicolaides T, Pieper RO (2012) Sensitivity of glioblastomas to clinically available MEK inhibitors is defined by neurofibromin 1 deficiency. Cancer Res 72:3350–3359. https://doi.org/10.1158/0008-5472.CAN-12-0334

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  95. 95.

    Shibahara I, Sonoda Y, Suzuki H, Mayama A, Kanamori M, Saito R et al (2018) Glioblastoma in neurofibromatosis 1 patients without IDH1, BRAF V600E, and TERT promoter mutations. Brain Tumor Pathol 35:10–18. https://doi.org/10.1007/s10014-017-0302-z

    CAS  Article  PubMed  Google Scholar 

  96. 96.

    Shilyansky C, Karlsgodt KH, Cummings DM, Sidiropoulou K, Hardt M, James AS et al (2010) Neurofibromin regulates corticostriatal inhibitory networks during working memory performance. Proc Natl Acad Sci USA 107:13141–13146. https://doi.org/10.1073/pnas.1004829107

    Article  PubMed  Google Scholar 

  97. 97.

    Shin J, Padmanabhan A, de Groh ED, Lee J-S, Haidar S, Dahlberg S et al (2012) Zebrafish neurofibromatosis type 1 genes have redundant functions in tumorigenesis and embryonic development. Dis Model Mech 5:881–894. https://doi.org/10.1242/dmm.009779

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  98. 98.

    Sieg EP, Payne R, Langan S, Specht CS (2016) Case report: a rosette-forming glioneuronal tumor in the tectal plate in a patient with neurofibromatosis type I. Cureus 8:e857. https://doi.org/10.7759/cureus.857

    Article  PubMed  PubMed Central  Google Scholar 

  99. 99.

    Simmons GW, Pong WW, Emnett RJ, White CR, Gianino SM, Rodriguez FJ et al (2011) 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. https://doi.org/10.1097/NEN.0b013e3182032d37

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  100. 100.

    Solga AC, Toonen JA, Pan Y, Cimino PJ, Ma Y, Castillon GA et al (2017) The cell of origin dictates the temporal course of neurofibromatosis-1 (Nf1) low-grade glioma formation. Oncotarget 8:47206–47215. https://doi.org/10.18632/oncotarget.17589

    Article  PubMed  PubMed Central  Google Scholar 

  101. 101.

    Stafstrom CE, Staedtke V, Comi AM (2017) Epilepsy mechanisms in neurocutaneous disorders: tuberous sclerosis complex, neurofibromatosis type 1, and Sturge-Weber syndrome. Front Neurol 8:87. https://doi.org/10.3389/fneur.2017.00087

    Article  PubMed  PubMed Central  Google Scholar 

  102. 102.

    Stansfield BK, Bessler WK, Mali R, Mund JA, Downing BD, Kapur R et al (2014) Ras-Mek-Erk signaling regulates Nf1 heterozygous neointima formation. Am J Pathol 184:79–85. https://doi.org/10.1016/j.ajpath.2013.09.022

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  103. 103.

    Stansfield BK, Bessler WK, Mali R, Mund JA, Downing BD, Kapur R et al (2014) Ras-Mek-Erk signaling regulates Nf1 heterozygous neointima formation. Am J Pathol 184:79–85. https://doi.org/10.1016/j.ajpath.2013.09.022

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  104. 104.

    Strowd RE 3rd, Rodriguez FJ, McLendon RE, Vredenburgh JJ, Chance AB, Jallo G et al (2016) Histologically benign, clinically aggressive: progressive non-optic pathway pilocytic astrocytomas in adults with NF1. Am J Med Genet A 170:1455–1461. https://doi.org/10.1002/ajmg.a.37622

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  105. 105.

    Takei H, Rouah E, Bhattacharjee MB (2015) Cerebellar pleomorphic xanthoastrocytoma in a patient with neurofibromatosis type 1: a case report and literature review. Int J Clin Exp Pathol 8:7570–7574

    CAS  PubMed  PubMed Central  Google Scholar 

  106. 106.

    Talman LS, Bisker ER, Sackel DJ, Long DA Jr, Galetta KM, Ratchford JN et al (2010) Longitudinal study of vision and retinal nerve fiber layer thickness in multiple sclerosis. Ann Neurol 67:749–760. https://doi.org/10.1002/ana.22005

    Article  PubMed  PubMed Central  Google Scholar 

  107. 107.

    Terry Anna R, Jordan Justin T, Schwamm L, Plotkin Scott R (2016) Increased risk of cerebrovascular disease among patients with neurofibromatosis type 1. Stroke 47:60–65. https://doi.org/10.1161/STROKEAHA.115.011406

    CAS  Article  PubMed  Google Scholar 

  108. 108.

    Thara K, Sharma R, Thiagarajan G, Ramdas A, Varghese RG (2017) Anaplastic pleomorphic xanthoastrocytoma in a case of neurofibromatosis type 1: a case report. J Clin Diagn Res JCDR 11:ED23–ED24. https://doi.org/10.7860/jcdr/2017/26685.9713

    CAS  Article  PubMed  Google Scholar 

  109. 109.

    Toelle SP, Poretti A, Weber P, Seute T, Bromberg JE, Scheer I et al (2015) Cerebellar hypoplasia and dysmorphia in neurofibromatosis type 1. Cerebellum 14:642–649. https://doi.org/10.1007/s12311-015-0658-8

    CAS  Article  PubMed  Google Scholar 

  110. 110.

    Tognini G, Ferrozzi F, Garlaschi G, Piazza P, Patti A, Virdis R et al (2005) Brain apparent diffusion coefficient evaluation in pediatric patients with neurofibromatosis type 1. J Comput Assist Tomogr 29:298–304

    Article  Google Scholar 

  111. 111.

    Toonen JA, Anastasaki C, Smithson LJ, Gianino SM, Li K, Kesterson RA et al (2016) NF1 germline mutation differentially dictates optic glioma formation and growth in neurofibromatosis-1. Hum Mol Genet 25:1703–1713. https://doi.org/10.1093/hmg/ddw039

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  112. 112.

    Toonen JA, Solga AC, Ma Y, Gutmann DH (2017) Estrogen activation of microglia underlies the sexually dimorphic differences in Nf1 optic glioma–induced retinal pathology. J Exp Med 214:17–25. https://doi.org/10.1084/jem.20160447

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  113. 113.

    Tsipi M, Poulou M, Fylaktou E, Kosma K, Tsoutsou E, Pons M-R et al (2018) Phenotypic expression of a spectrum of Neurofibromatosis Type 1 (NF1) mutations identified through NGS and MLPA. J Neurol Sci 395:95–105. https://doi.org/10.1016/j.jns.2018.10.006

    CAS  Article  PubMed  Google Scholar 

  114. 114.

    Ullrich NJ, Robertson R, Kinnamon DD, Scott RM, Kieran MW, Turner CD et al (2007) Moyamoya following cranial irradiation for primary brain tumors in children. Neurology 68:932. https://doi.org/10.1212/01.wnl.0000257095.33125.48

    CAS  Article  PubMed  Google Scholar 

  115. 115.

    Uusitalo E, Leppävirta J, Koffert A, Suominen S, Vahtera J, Vahlberg T et al (2015) Incidence and mortality of neurofibromatosis: a total population study in Finland. J Invest Dermatol 135:904–906. https://doi.org/10.1038/jid.2014.465

    CAS  Article  PubMed  Google Scholar 

  116. 116.

    Van Es S, North KN, McHugh K, De Silva M (1996) MRI findings in children with neurofibromatosis type 1: a prospective study. Pediatr Radiol 26:478–487

    Article  Google Scholar 

  117. 117.

    Verhaak RGW, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD et al (2010) An integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR and NF1. Cancer Cell 17:98. https://doi.org/10.1016/j.ccr.2009.12.020

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  118. 118.

    Viola F, Villani E, Natacci F, Selicorni A, Melloni G, Vezzola D et al (2012) Choroidal abnormalities detected by near-infrared reflectance imaging as a new diagnostic criterion for neurofibromatosis 1. Ophthalmology 119:369–375. https://doi.org/10.1016/j.ophtha.2011.07.046

    Article  PubMed  Google Scholar 

  119. 119.

    Vizcaíno MA, Shah S, Eberhart CG, Rodriguez FJ (2015) Clinicopathologic implications of NF1 gene alterations in diffuse gliomas(). Hum Pathol 46:1323–1330. https://doi.org/10.1016/j.humpath.2015.05.014

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  120. 120.

    Walsh KS, Janusz J, Wolters PL, Martin S, Klein-Tasman BP, Toledo-Tamula MA et al (2016) Neurocognitive outcomes in neurofibromatosis clinical trials: recommendations for the domain of attention. Neurology 87:S21–S30. https://doi.org/10.1212/WNL.0000000000002928

    Article  PubMed  PubMed Central  Google Scholar 

  121. 121.

    Walsh KS, Velez JI, Kardel PG, Imas DM, Muenke M, Packer RJ et al (2013) Symptomatology of autism spectrum disorder in a population with neurofibromatosis type 1. Dev Med Child Neurol 55:131–138. https://doi.org/10.1111/dmcn.12038

    Article  PubMed  Google Scholar 

  122. 122.

    Warrington NM, Gianino SM, Jackson E, Goldhoff P, Garbow JR, Piwnica-Worms D et al (2010) Cyclic AMP suppression is sufficient to induce gliomagenesis in a mouse model of neurofibromatosis-1. Cancer Res 70:5717

    CAS  Article  Google Scholar 

  123. 123.

    Watters JJ, Schartner JM, Badie B (2005) Microglia function in brain tumors. J Neurosci Res 81:447–455. https://doi.org/10.1002/jnr.20485

    CAS  Article  PubMed  Google Scholar 

  124. 124.

    White KA, Swier VJ, Cain JT, Kohlmeyer JL, Meyerholz DK, Tanas MR et al (2018) A porcine model of neurofibromatosis type 1 that mimics the human disease. JCI Insight 3:e120402. https://doi.org/10.1172/jci.insight.120402

    Article  PubMed Central  Google Scholar 

  125. 125.

    Wimmer K, Rosenbaum T, Messiaen L (2016) Connections between constitutional mismatch repair deficiency syndrome and neurofibromatosis type 1. Clin Genet 91:507–519. https://doi.org/10.1111/cge.12904

    CAS  Article  Google Scholar 

  126. 126.

    Wolman MA, de Groh ED, McBride SM, Jongens TA, Granato M, Epstein JA (2014) Modulation of cAMP and ras signaling pathways improves distinct behavioral deficits in a zebrafish model of neurofibromatosis type 1. Cell reports 8:1265–1270. https://doi.org/10.1016/j.celrep.2014.07.054

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  127. 127.

    Wood MD, Mukherjee J, Pieper RO (2018) Neurofibromin knockdown in glioma cell lines is associated with changes in cytokine and chemokine secretion in vitro. Sci Rep 8:5805. https://doi.org/10.1038/s41598-018-24046-2

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  128. 128.

    Zhu Y, Guignard F, Zhao D, Liu L, Burns DK, Mason RP et al (2005) Early inactivation of p53 tumor suppressor gene cooperating with NF1 loss induces malignant astrocytoma. Cancer Cell 8:119–130. https://doi.org/10.1016/j.ccr.2005.07.004

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  129. 129.

    Zhu Y, Harada T, Liu L, Lush ME, Guignard F, Harada C et al (2005) Inactivation of NF1 in CNS causes increased glial progenitor proliferation and optic glioma formation. Development 132:5577

    CAS  Article  Google Scholar 

  130. 130.

    Zhu Y, Romero MI, Ghosh P, Ye Z, Charnay P, Rushing EJ et al (2001) Ablation of NF1 function in neurons induces abnormal development of cerebral cortex and reactive gliosis in the brain. Genes Dev 15:859–876. https://doi.org/10.1101/gad.862101

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors would like to thank contributors to several figures Drs. Doris Lin (Fig. 2), Bette Kleinschmidt-Demasters (Fig. 2), Christopher Heaphy (Figs. 4 and 6) and Liam Chen (Fig. 7).

Funding

The work was funded in part by This work was supported in part by Pilocytic/Pilomyxoid Fund, including Lauren’s First and Goal, and the Stick it to Brain Tumors Annual Women’s Ice Hockey Tournament (F.J.R.), Department of Defense Grant W81XWH-18-1-0496 and NIH Grant P30 CA006973 to the Sidney Kimmel Comprehensive Cancer Center (PI: W. Nelson).

Author information

Affiliations

Authors

Contributions

All authors participated in the writing, reviewed, and approved the manuscript.

Corresponding author

Correspondence to Fausto J. Rodriguez.

Ethics declarations

Conflict of interest

The authors have no conflict of interest to report.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Nix, J.S., Blakeley, J. & Rodriguez, F.J. An update on the central nervous system manifestations of neurofibromatosis type 1. Acta Neuropathol 139, 625–641 (2020). https://doi.org/10.1007/s00401-019-02002-2

Download citation

Keywords

  • Neurofibromatosis
  • Neurofibromin
  • Glioma
  • Brain tumor
  • Vasculopathy
  • Hydrocephalus
  • Seizure