CommentaryOpen Access

Neurofibromatosis type 1-associated brain tumors

Emily Cockey and Nicole J Ullrich*

Department of Neurology, Boston Children’s Hospital, Boston, MA 02115, USA

Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder that predisposes patients to develop benign and malignant neoplasms, most often due to a loss of function mutation in the neurofibromatosis type 1 (NF1) gene. Neurofibromin, the protein product of NF1, regulates the inactivation of the Ras pathway, and thus acts as a tumor suppressor. Located in neurons, Schwann cells, and melanocytes, a decrease in neurofibromin predisposes patients with NF1 to tumors in both the central and peripheral nervous systems. Interestingly, brain tumors associated with NF1 often follow a more benign course than their sporadic counterparts and are often found in different locations. Thus, these tumors are often observed without tumor-directed therapy, unless clinical progression is noted, and then they are treated with surgery, chemotherapy or radiation. Current treatment trials seek to create more targeted therapies for specific tumor types associated with NF1 in order to increase efficacy and decrease treatment-related morbidity. This review will examine the most common types of brain tumors associated with NF1, including pilocytic astrocytomas, optic pathway gliomas, brainstem gliomas and glioblastomas, and will provide an overview of the clinical implications, current treatments, and ongoing clinical trials for these tumors.


 

Neurofibromatosis type 1 (NF1) is the most common heritable brain tumor predisposition disorder, affecting an estimated 1 in 3,500 people worldwide.1,2 This neurocutaneous disorder is autosomal dominant with approximately 50% of cases classified as sporadic and 50% as familial.3 Although NF1 has 100% penetrance, the disease phenotype varies greatly within and between families and even within an individual, based on age and presumed genetic mosaicism.4-6 Diagnostic standards for NF1 have been established by consensus criteria ( Table 1).7 Individuals with NF1 may also experience cognitive impairment, visual challenges, vascular abnormalities, and skeletal changes.4,8,9,10,11.

In more than 95% of cases, NF1 is associated with a heterozygous loss of function mutation in the neurofibromatosis type 1(NF1) gene, located at 17q11.2.2,4,12 Over 800 different mutations in this gene or its protein product, neurofibromin, have been associated with NF1, with point mutations occurring in approximately 90% of cases and larger 1-1.5MB deletions occurring in approximately 10% of cases.24,11.

Neurofibromin is expressed in both neurons and non-neuronal tissue, especially oligodendrocytes, Schwann cells, and developing melanocytes.2,13 This protein product functions as a tumor suppressor by negatively regulating the p21-RAS proto-oncogene, and thus, by regulating cell proliferation.14 Neurofibromin accomplishes this task by speeding the transformation of active GTP-bound Ras to inactive GDP-bound Ras.15,16 This transformation down-regulates Ras-driven signal transduction pathways, including those that target mTOR, ras, raf, PI3K, AKT, MAPK, PKB and cyclic A1MP.1,2 In addition, heterozygous loss of NF1 has been shown to affect proper actin cytoskeleton motility, leading to cells with irregular shapes, adhesion capabilities, and increased invasive cell motility.17.

Complete loss of NF1 gene function is thought to be causative in tumorigenesis.18 Since NF1 patients posses a heterozygous loss of NF1, they need only acquire one additional mutation to NF1 for tumorigenesis to occur.2,18 Due to the widespread expression of neurofibromin, NF1 patients may develop brain tumors, neurofibromas, malignant peripheral nerve sheath tumors (MPNSTs), carcinoid tumors, pheochromocytomas, leukemias and breast carcinomas, among others.19,20 This review will focus on NF1-associated brain tumors.

Optic pathway gliomas (OPGs) affect 15-20% of individuals with NF1 and are therefore the single most common type of brain tumor associated with the disorder.9,10,21,22,23 Due to their location in the optic pathway, OPGs are not usually biopsied, and thus researchers and physicians are limited in their ability to classify OPGs and to determine which molecular pathways have been disrupted in the tumorous tissue. However, with the limited pathologic data available, the majority of OPGs are classified as pilocytic astrocytomas, and fewer as diffuse astrocytoma, NOS per the updated WHO classification schema, or glioblastomas.24,25.

Pilocytic astrocytomas in NF1 are WHO grade 1 gliomas characterized by biphasic architecture, Rosenthal fibers, and eosinophilic granular bodies.11,21,24 NF1-associated pilocytic astrocytomas are characterized by a complete lack of NF1 gene expression, and thus by increased GTP-bound p21-Ras.18,2618,26 Pilocytic astrocytomas that occur sporadically do not have a loss of NF1 expression, suggesting a distinct mechanism of tumorigenesis.18,27.

OPGs are more common in children with NF1 than in the general population.19,26,28 NF1- associated OPGs are often benign and are most often diagnosed and progressive in children between the ages of 2 and 6.10,29 Approximately 33% of NF1 patients with OPGs will develop symptoms, however, there is no way to predict which tumors will cause clinical impairment, expressed as a decline in visual acuity or visual function.9,10 According to the Optic Pathway Glioma Task Force, given the frequency of OPGs in children with NF1 and the much smaller proportion of individuals with clinical symptoms, “serial ophthalmological examinations, particularly in young children with NF1, are very important” however, “screening neuroimaging of asymptomatic children with NF1 for the detection of optic pathway gliomas has not been shown to improve clinical outcome”.30

While OPGs are more common in the NF1 population, they are also typically less aggressive than in the non-NF1 population.21,31OPGs are more often found in the intraorbital optic nerve, or bilaterally in the optic nerves in patients with NF1 than they are in patients without NF1, who are more likely to have OPGs with optic tract involvement.28,31,32 In addition, individuals with NF1 are more likely to have symptoms of proptosis, precocious puberty, or visual acuity loss, while sporadic OPGs are more likely to be associated with hydrocephalus and nystagmus.31 Figure 1 demonstrates an optic pathway glioma found in a 10 year old girl who underwent neuroimaging for headaches. Visual acuity and visual fields were and remained stable without tumor directed therapy.

Treatment of OPGs is typically initiated when visual decline is noted, and then standard low grade glioma chemotherapy is the up-front treatment of choice. If there is an atypical appearance, surgery is considered.2,9 Following chemotherapy, 72% of NF1/OPG patients experience improvement and/or stabilization of visual acuity.10 The need for and response to second or third line treatments has not been assessed in this patient population; review of retrospective data is in process and a prospective, multicenter study is planned to collect these data.

Brainstem gliomas are the second most common type of brain tumor associated with NF1 and affect approximately 4% of patients.2,33 These tumors can be distinguished on imaging from the typical T2 hyperintense NF1- associated hamartomas or “NF spots”, because they cause focal or diffuse brainstem enlargement, exert mass effect and demonstrate variable contrast enhancement.23,34 Similar to OPGs, brainstem gliomas are rarely biopsied to prevent iatrogenic brainstem dysfunction, limiting the amount of tissue available to medical personnel for tumor classification and molecular research. Many of the tumors, however, are also classified as pilocytic astrocytomas.22

NF1-associated brainstem gliomas are often benign and progress clinically in only one-third, or less, of cases.35 Children with NF1 and known brainstem gliomas are monitored clinically for development of symptoms referable to the location, such as headache, hydrocephal1us, or cranial neuropathies.33 Similar to OPGs, NF1-associated brainstem gliomas are more indolent than those not associated with NF1 and most often do not require clinical intervention.2,36 Figure 2 demonstrates an expansive lesion in the cervico-medullary region that was detected on surveillance neuroimaging on a 4 year old boy with NF1, which on follow up imaging after 26 months had regressed significantly without any tumor-directed therapy. By contrast, brainstem gliomas in the non-NF1 population often cause death within 18 months of diagnosis.33 Because many brainstem gliomas do not progress, physicians recommend consistent neurologic exams and imaging to detect progression, which would then suggest the need for treatment.33

The typical location of NF1-associated brainstem gliomas also differs from the non-NF1 population. In NF1 patients, brainstem tumors are most often found in the lower medulla, followed by the pons, and finally in the midbrain, whereas in non-NF1 patients they are most prevalent in the pons and are typically more diffuse in nature and have a more aggressive clinical course.23,33,34

Glioblastomas are high grade (WHO grade IV) gliomas that are more common in adults than in children and are thought to cause approximately 2% of gliomas in NF1 patients.21,27,36,37 Although these high grade gliomas are thus rare in NF1, the risk of developing a glioblastoma is five times greater in patients with NF1 than in the general population.37

NF1-associated glioblastomas are most often found in supratentorial brain regions.38 Similar to the low-grade astrocytomas associated with NF1, glioblastomas have a better clinical course and overall survival than those not associated w1ith NF1.21However, even with a treatment series including surgery, radiation, and chemotherapy, NF1-associated glioblastomas have a 2-year survival rate of under 60%.21 Figure 3 demonstrates a right frontal glioblastoma in a 10 year old boy with history of NF1, which was treated with cranial irradiation and antiangiogenic therapy using bevacizumab.

NF1-associated low grade gliomas are most commonly located in the optic system or brainstem, but they can also occur in the cerebellum and cerebral hemispheres.2,22 These low grade gliomas reside in locations more amenable to biopsy, so although they occur less frequently, there is more tissue available for investigation.

While pilocytic astrocytomas are the most common NF1-associated tumor class, other types of gliomas do occur, which are similarly left untreated unless clinical symptoms arise.2 The second most common NF1- associated tumors are low-grade subtype intermediate (LGSI) tumors, followed by diffusely infiltrating astrocytomas.2424 Diffusely infiltrating astrocytomas are most often fibrillary astrocytomas, and tend to be less indolent than pilocytic astrocytomas and LGSIs.24 Rare cases of glioneuronal tumors (WHO grade 1), desmoplastic gangliomas, pilomyxoid astrocytomas (WHO grade II) and medulloblastomas (WHO grade IV) have also been reported in association with NF1.24,39

Common among many of the NF1-associated tumors is the fact that they have a more favorable course than their sporadic counterparts. The reasons behind this are not yet fully elucidated, but NF1-associated and non-NF1-associated tumors are thought to have distinct patterns of tumorigenesis; NF1-assocated tumors develop following complete loss of function of NF1 whereas sporadic tumors do not.40 Approximately 66% of sporadic tumors have a tandem duplication in BRAF which leads to a fusion between KIAA1549 and BRAF.41 KIAA1549:BRAF leads to hyperactivation of MAPK, a downstream product of Ras, and thus to aberrant cell proliferation.22,41 In fewer, typically higher grade II-IV gliomas, there is a mutation in BRAF that causes increased activation of MEK, another downstream element of the Ras pathway.22,42,43 Additionally, sporadic glioblastomas are associated with loss of TP53, amplified epidermal growth factor receptor (EGFR), loss of CDKN2A/p16, q10 deletions, and polysomy 7.40 Differences in outcomes for NF1-related and sporadic tumors may also be explained by the fact that NF1-associated tumors often have concurrent mutations in other genes such as p53.38

The majority of NF1-associated brain tumors can be approached conservatively and often tumor-directed treatment is not necessary.2,10 This course of action is taken for three reasons: 1) NF1-associated tumors are often benign, 2) it is difficult to predict which tumors will result in clinical symptoms, and 3) current therapies, especially radiation, may increase the risk of secondary tumors or malignant transformation of benign tumors.9,11,44 Surgery and/or chemotherapy are the typical treatments when clinical intervention does become necessary, due to the potentially deleterious side-effects noted after radiotherapy.2,9,10,11

Radiotherapy may increase the chance of moyamoya syndrome, malignant transformation of tumors, and secondary tumor formation, most often leading to sarcomas and breast cancers.11,44,45,46 Individuals with NF1 also represent an at risk-population with high risk of cognitive deficits after radiation.2

Targeted clinical trials which take advantage of the known molecular underpinnings of NF1 are underway, first using drugs that target the Ras pathway, which is often up-regulated in these neoplasms.47 Promising clinical studies are investigating the efficacy of mTOR inhibitors, MEK inhibitors and tyrosine kinase inhibitors (Table 2). Such inhibitors have shown anti-tumor properties in murine models or are currently used to treat other, non-NF1 related tumors.47,48,49 If successful, these drugs will greatly advance the treatment of NF1-associated tumors.

In summary, individuals with NF1 are predisposed to a variety of brain tumors such as optic pathway gliomas, brainstem gliomas, and glioblastomas that tend to act more indolently than their sporadic counterparts. The majority of these tumors will not progress to cause clinical deficits and unfortunately, it is currently difficult to predict which tumors will progress. Due to these facts and given the toxicities associated with current chemotherapy, radiology, and surgery treatments, NF1-related tumors are often observed without intervention until clinical symptoms appear. Many promising trials are underway to create therapies that are more specifically targeted to NF1-related tumors, but future studies are still needed to better predict which tumors will remain benign and which will progress to cause clinical losses in order to start treatment as early as possible.

  1. Pong WW, Gutmann DH. The ecology of brain tumors: lessons learned from neurofibromatosis-1. Oncogene. 2011 Mar 10;30(10):1135-46.
  2. Ullrich NJ. Neurocutaneous Syndromes and Brain Tumors. J Child Neurol. 2015 Oct 12.
  3. Friedman JM. Neurofibromatosis 1. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, et al, editors. GeneReviews(R). Seattle (WA): University of Washington, Seattle; 1993.
  4. Boyd KP, Korf BR, Theos A. Neurofibromatosis type 1. J Am Acad Dermatol. 2009 Jul;61(1):1,14; quiz 15-6.
  5. Riccardi VM, Lewis RA. Penetrance of von Recklinghausen neurofibromatosis: a distinction between predecessors and descendants. Am J Hum Genet. 1988 Feb;42(2):284-9.
  6. Jett K, Friedman JM. Clinical and genetic aspects of neurofibromatosis 1. Genet Med. 2010 Jan;12(1):1-11.
  7. National Institutes of Health Consensus Development Conference Statement: neurofibromatosis. Bethesda, Md., USA, July 13-15, 1987. Neurofibromatosis. 1988;1(3):172-8.
  8. Avery RA, Mansoor A, Idrees R, Biggs E, Alsharid MA, Packer RJ, et al. Quantitative MRI criteria for optic pathway enlargement in neurofibromatosis type 1. Neurology. 2016 May 11.
  9. Fisher MJ, Avery RA, Allen JC, Ardern-Holmes SL, Bilaniuk LT, Ferner RE, et al. Functional outcome measures for NF1-associated optic pathway glioma clinical trials. Neurology. 2013 Nov 19;81(21 Suppl 1):S15-24.
  10. Fisher MJ, Loguidice M, Gutmann DH, Listernick R, Ferner RE, Ullrich NJ, et al. Visual outcomes in children with neurofibromatosis type 1-associated optic pathway glioma following chemotherapy: a multicenter retrospective analysis. Neuro Oncol. 2012 Jun;14(6):790-7.
  11. Johansson G, Andersson U, Melin B. Recent developments in brain tumor predisposing syndromes. Acta Oncol. 2016 Apr;55(4):401-11.
  12. Messiaen LM, Callens T, Mortier G, Beysen D, Vandenbroucke I, Van Roy N, 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. 2000;15(6):541-55.
  13. Stocker KM, Baizer L, Coston T, Sherman L, Ciment G. Regulated expression of neurofibromin in migrating neural crest cells of avian embryos. J Neurobiol. 1995 Aug;27(4):535-52.
  14. Martin GA, Viskochil D, Bollag G, McCabe PC, Crosier WJ, Haubruck H, et al. The GAP-related domain of the neurofibromatosis type 1 gene product interacts with ras p21. Cell. 1990 Nov 16;63(4):843-9.
  15. Shen MH, Harper PS, Upadhyaya M. Molecular genetics of neurofibromatosis type 1 (NF1). J Med Genet. 1996 Jan;33(1):2-17.
  16. Weiss B, Bollag G, Shannon K. Hyperactive Ras as a therapeutic target in neurofibromatosis type 1. Am J Med Genet. 1999 Mar 26;89(1):14-22.
  17. Ozawa T, Araki N, Yunoue S, Tokuo H, Feng L, Patrakitkomjorn S, et al. The neurofibromatosis type 1 gene product neurofibromin enhances cell motility by regulating actin filament dynamics via the Rho-ROCK-LIMK2-cofilin pathway. J Biol Chem. 2005 Nov 25;280(47):39524-33.
  18. Gutmann DH, Donahoe J, Brown T, James CD, Perry A. Loss of neurofibromatosis 1 (NF1) gene expression in NF1-associated pilocytic astrocytomas. Neuropathol Appl Neurobiol. 2000 Aug;26(4):361-7.
  19. Patil S, Chamberlain RS. Neoplasms associated with germline and somatic NF1 gene mutations. Oncologist. 2012;17(1):101-16. 20. Endo M, Yamamoto H, Setsu N, Kohashi K, Takahashi Y, Ishii T, et al. Prognostic significance of AKT/mTOR and MAPK pathways and antitumor effect of mTOR inhibitor in NF1-related and sporadic malignant peripheral nerve sheath tumors. Clin Cancer Res. 2013 Jan 15;19(2):450-61.
  20. Huttner AJ, Kieran MW, Yao X, Cruz L, Ladner J, Quayle K, et al. Clinicopathologic study of glioblastoma in children with neurofibromatosis type 1. Pediatr Blood Cancer. 2010 Jul 1;54(7):890-6.
  21. Thangarajh M, Gutmann DH. Review: low-grade gliomas as neurodevelopmental disorders: insights from mouse models of neurofibromatosis-1. Neuropathol Appl Neurobiol. 2012 Jun;38(3):241-53.
  22. Ullrich NJ, Raja AI, Irons MB, Kieran MW, Goumnerova L. Brainstem lesions in neurofibromatosis type 1. Neurosurgery. 2007 Oct;61(4):762,6; discussion 766-7.
  23. Rodriguez FJ, Perry A, Gutmann DH, O'Neill BP, Leonard J, Bryant S, et al. Gliomas in neurofibromatosis type 1: a clinicopathologic study of 100 patients. J Neuropathol Exp Neurol. 2008 Mar;67(3):240-9.
  24. Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, et al. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol. 2016 Jun;131(6):803-20.
  25. Guha A, Feldkamp MM, Lau N, Boss G, Pawson A. Proliferation of human malignant astrocytomas is dependent on Ras activation. Oncogene. 1997 Dec 4;15(23):2755-65.
  26. Sharma MK, Zehnbauer BA, Watson MA, Gutmann DH. RAS pathway activation and an oncogenic RAS mutation in sporadic pilocytic astrocytoma. Neurology. 2005 Oct 25;65(8):1335-6.
  27. Stern JMD, Ph.D., DiGiacinto GVMD, Housepian EMMD. Neurofibromatosis and Optic Glioma: Clinical and Morphological Correlations. Neurosurgery. 1979 June;4(6):524-8.
  28. Listernick R, Ferner RE, Piersall L, Sharif S, Gutmann DH, Charrow J. Late-onset optic pathway tumors in children with neurofibromatosis 1. Neurology. 2004 Nov 23;63(10):1944-6.
  29. Listernick R, Louis DN, Packer RJ, Gutmann DH. Optic pathway gliomas in children with neurofibromatosis 1: consensus statement from the NF1 Optic Pathway Glioma Task Force. Ann Neurol. 1997 Feb;41(2):143-9.
  30. 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. 1995 Nov;127(5):718-22.
  31. 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. 1994 Jul;125(1):63-6.
  32. Molloy PT, Bilaniuk LT, Vaughan SN, Needle MN, Liu GT, Zackai EH, et al. Brainstem tumors in patients with neurofibromatosis type 1: a distinct clinical entity. Neurology. 1995 Oct;45(10):1897-902.
  33. Bilaniuk LT, Molloy PT, Zimmerman RA, Phillips PC, Vaughan SN, Liu GT, et al. Neurofibromatosis type 1: brain stem tumours. Neuroradiology. 1997 Sep;39(9):642-53.
  34. Gutmann DH, Rasmussen SA, Wolkenstein P, MacCollin MM, Guha A, Inskip PD, et al. Gliomas presenting after age 10 in individuals with neurofibromatosis type 1 (NF1). Neurology. 2002 Sep 10;59(5):759-61.
  35. Theeler BJ, Ellezam B, Yust-Katz S, Slopis JM, Loghin ME, de Groot JF. Prolonged survival in adult neurofibromatosis type I patients with recurrent high-grade gliomas treated with bevacizumab. J Neurol. 2014 Aug;261(8):1559-64.
  36. Graf N. Glioblastoma in children with NF1: the need for basic research. Pediatr Blood Cancer. 2010 Jul 1;54(7):870-1.
  37. Broekman ML, Risselada R, Engelen-Lee J, Spliet WG, Verweij BH. Glioblastoma multiforme in the posterior cranial fossa in a patient with neurofibromatosis type I. Case Rep Med. 2009;2009:757898.
  38. Pascual-Castroviejo I, Pascual-Pascual SI, Viano J, Carceller F, Gutierrez-Molina M, Morales C, et al. Posterior fossa tumors in children with neurofibromatosis type 1 (NF1). Childs Nerv Syst. 2010 Nov;26(11):1599-603.
  39. Gutmann DH, James CD, Poyhonen M, Louis DN, Ferner R, Guha A, et al. Molecular analysis of astrocytomas presenting after age 10 in individuals with NF1. Neurology. 2003 Nov 25;61(10):1397-400.
  40. Jones DT, Kocialkowski S, Liu L, Pearson DM, Backlund LM, Ichimura K, et al. Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res. 2008 Nov 1;68(21):8673-7.
  41. Horbinski C. To BRAF or not to BRAF: is that even a question anymore? J Neuropathol Exp Neurol. 2013 Jan;72(1):2-7.
  42. Schiffman JD, Hodgson JG, VandenBerg SR, Flaherty P, Polley MY, Yu M, et al. Oncogenic BRAF mutation with CDKN2A inactivation is characteristic of a subset of pediatric malignant astrocytomas. Cancer Res. 2010 Jan 15;70(2):512-9.
  43. Sharif S, Ferner R, Birch JM, Gillespie JE, Gattamaneni HR, Baser ME, et al. Second primary tumors in neurofibromatosis 1 patients treated for optic glioma: substantial risks after radiotherapy. J Clin Oncol. 2006 Jun 1;24(16):2570-5.
  44. Chao RC, Pyzel U, Fridlyand J, Kuo YM, Teel L, Haaga J, et al. Therapy-induced malignant neoplasms in Nf1 mutant mice. Cancer Cell. 2005 Oct;8(4):337-48.
  45. Ullrich NJ, Robertson R, Kinnamon DD, Scott RM, Kieran MW, Turner CD, et al. Moyamoya following cranial irradiation for primary brain tumors in children. Neurology. 2007 Mar 20;68(12):932-8.
  46. Dilworth JT, Kraniak JM, Wojtkowiak JW, Gibbs RA, Borch RF, Tainsky MA, et al. Molecular targets for emerging anti-tumor therapies for neurofibromatosis type 1. Biochem Pharmacol. 2006 Nov 30;72(11):1485-92.
  47. Sehgal SN. Sirolimus: its discovery, biological properties, and mechanism of action. Transplant Proc. 2003 May;35(3 Suppl):7S-14S.
  48. Choueiri TK, Escudier B, Powles T, Tannir NM, Mainwaring PN, Rini BI, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2016 Jun 3.
 

Article Info

View/Download pdf

Article Notes

  • Published on: August 25, 2016

Keywords

  • Neurofibromatosis type 1
  • brain tumors
  • Neurofibromin
  • Optic pathway gliomas (OPGs)
  • Brainstem gliomas
  • Glioblastomas

*Correspondence:

 Nicole J Ullrich
Department of Neurology
Boston Children’s Hospital, Boston, MA 02115,
USA
Email: nicole.ullrich@childrens.harvard.edu

Copyright: ©2016 Ullrich NJ. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License.
Citation: Cockey E, Ullrich NJ. Neurofibromatosis type 1-associated brain tumors. J Rare Dis Res & Treatment. (2016) 1(2): 11-16