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.
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References
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
Appin CL, Brat DJ (2014) Molecular genetics of gliomas. Cancer J 20:66–72. https://doi.org/10.1097/ppo.0000000000000020
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Campian J, Gutmann DH (2017) CNS tumors in neurofibromatosis. J Clin Oncol 35:2378–2385. https://doi.org/10.1200/JCO.2016.71.7199
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
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
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
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
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
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
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
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
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
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
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
Downward J (2003) Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer 3:11. https://doi.org/10.1038/nrc969
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
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
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
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
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
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
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
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
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
Gutmann DH (2002) Review article: neurofibromin in the brain. J Child Neurol 17:592–601. https://doi.org/10.1177/088307380201700809
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
Gutmann DH, Giovannini M (2002) Mouse Models of Neurofibromatosis 1 and 2. Neoplasia 4:279–290. https://doi.org/10.1038/sj.neo.7900249
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
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
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
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
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
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
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
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
Hyman SL, Shores A, North KN (2005) The nature and frequency of cognitive deficits in children with neurofibromatosis type 1. Neurology 65:1037
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
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
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
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
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
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
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
Kulkantrakorn K, Geller TJ (1998) Seizures in neurofibromatosis 1. Pediatr Neurol 19:347–350. https://doi.org/10.1016/S0887-8994(98)00075-7
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
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
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
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
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
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
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
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
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
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
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
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
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
Neurofibromatosis. Conference statement. National Institutes of Health Consensus Development Conference (1988) Arch Neurol 45:575-578
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Salyer WR, Salyer DC (1974) The vascular lesions of neurofibromatosis. Angiology 25:510–519. https://doi.org/10.1177/000331977402500803
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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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).
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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
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DOI: https://doi.org/10.1007/s00401-019-02002-2