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Therapeutics for Childhood Neurofibromatosis Type 1 and Type 2

  • Pediatric Neurology (Harvey Singer, Section Editor)
  • Published:
Current Treatment Options in Neurology Aims and scope Submit manuscript

Opinion statement

Neurofibromatosis type 1 (NF1) and type 2 (NF2) are genetically and medically distinct neurocutaneous disorders that are both associated with tumors affecting the central and peripheral nervous systems. NF1 has a frequency of 1 in 3,000, compared with 1 in 30,000 for NF2. Careful surveillance is important for both conditions, to allow early identification and treatment of complications. The most common and important problems in NF1 are cognitive impairment, optic pathway gliomas, plexiform neurofibromas, and orthopaedic issues. Early intervention and tailored educational programs are indicated for learning difficulties. Attention deficit hyperactivity disorder may be amenable to treatment with stimulant medication. A clinical trial is under way to evaluate lovastatin in the treatment of cognitive problems in children with NF1. Chemotherapy with vincristine and carboplatin is the current standard of care for symptomatic optic pathway gliomas, but new agents with improved efficacy are needed. Plexiform neurofibromas may be treated with surgery, but often recur. To date, no medical therapy has proven effective in limiting plexiform neurofibroma growth, but several candidate medications are under consideration in clinical trials. Malignant peripheral nerve sheath tumors may arise in preexisting plexiform neurofibromas, so changes in tumor growth or an increase in pain or focal neurologic deficit should prompt further investigation and early treatment with wide surgical resection, with or without adjuvant chemotherapy or radiotherapy. Specialist surgical intervention may be needed for scoliosis and tibial pseudoarthrosis. In NF2, surgical treatment remains a cornerstone of management for symptomatic progressive vestibular schwannomas, meningiomas, and spinal tumors. Vascular endothelial growth factor inhibitors show promise for the treatment of vestibular schwannomas, with the aim of delaying surgery, and other targeted molecular therapies are becoming available as investigational options. Hearing aids and brainstem and cochlear implants have a role in optimizing functional hearing in some patients. Specialist ophthalmology input should be arranged to monitor for ophthalmologic complications. A coordinated effort is needed to enroll NF1 and NF2 patients in international multicenter clinical trials of promising new pharmacologic agents. Genetic testing is useful for prenatal diagnosis and may be important in understanding individual responses to novel medical therapies in the future. Effective transition to adult services is important, considering the likelihood of further complications in the adult years.

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References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: •Of importance ••Of major importance

  1. Cichowski K, Jacks T. NF1 tumor suppressor gene function: narrowing the GAP. Cell. 2001;104(4):593–604.

    Article  PubMed  CAS  Google Scholar 

  2. McClatchey AI. Neurofibromatosis. Annu Rev Pathol. 2007;2:191–216.

    Article  PubMed  CAS  Google Scholar 

  3. Shilyansky C, Karlsgodt KH, Cummings DM, et al. Neurofibromin regulates corticostriatal inhibitory networks during working memory performance. Proc Natl Acad Sci USA. 2010;107(29):13141–6.

    Article  PubMed  CAS  Google Scholar 

  4. • Ferner RE. The neurofibromatoses. Pract Neurol. 2010;10(2):82–93.

    Article  PubMed  Google Scholar 

  5. Williams VC, Lucas J, Babcock MA, et al. Neurofibromatosis type 1 revisited. Pediatrics. 2009;123(1):124–33.

    Article  PubMed  Google Scholar 

  6. Ferner RE, Huson SM, Thomas N, et al. Guidelines for the diagnosis and management of individuals with neurofibromatosis 1. J Med Genet. 2007;44(2):81–8.

    Article  PubMed  CAS  Google Scholar 

  7. Hyman SL, Shores A, North KN. The nature and frequency of cognitive deficits in children with neurofibromatosis type 1. Neurology. 2005;65(7):1037–44.

    Article  PubMed  Google Scholar 

  8. Mautner VF, Kluwe L, Thakker SD, et al. Treatment of ADHD in neurofibromatosis type 1. Dev Med Child Neurol. 2002;44(3):164–70.

    Article  PubMed  Google Scholar 

  9. Payne JM, Moharir MD, Webster R, et al. Brain structure and function in neurofibromatosis type 1: current concepts and future directions. J Neurol Neurosurg Psychiatr. 2010;81(3):304–9.

    Article  PubMed  Google Scholar 

  10. Dilts CV, Carey JC, Kircher JC, et al. Children and adolescents with neurofibromatosis 1: a behavioral phenotype. J Dev Behav Pediatr. 1996;17(4):229–39.

    Article  PubMed  CAS  Google Scholar 

  11. Thompson HL, Viskochil D, Stevenson DA, et al. Speech-language characteristics of children with neurofibromatosis type 1. Am J Med Genet A. 2010;152A(2):284–90.

    Article  PubMed  Google Scholar 

  12. Li W, Cui Y, Kushner SA, et al. The HMG-CoA reductase inhibitor lovastatin reverses the learning and attention deficits in a mouse model of neurofibromatosis type 1. Curr Biol. 2005;15(21):1961–7.

    Article  PubMed  CAS  Google Scholar 

  13. Listernick R, Ferner RE, Liu GT, et al. Optic pathway gliomas in neurofibromatosis-1: controversies and recommendations. Ann Neurol. 2007;61(3):189–98.

    Article  PubMed  CAS  Google Scholar 

  14. Thiagalingam S, Flaherty M, Billson F, et al. Neurofibromatosis type 1 and optic pathway gliomas: follow-up of 54 patients. Ophthalmology. 2004;111(3):568–77.

    Article  PubMed  Google Scholar 

  15. Chang L, El-Dairi MA, Frempong TA, et al. Optical coherence tomography in the evaluation of neurofibromatosis type-1 subjects with optic pathway gliomas. J AAPOS. 2010;14(6):511–7.

    Article  PubMed  Google Scholar 

  16. Fisher MJ, Balcer L, Gutmann DH, et al. Neurofibromatosis type 1 associated optic glioma visual outcomes following chemotherapy: an international multi-center retrospective analysis. Neurooncol. 2010;12(6):ii19–20.

    Google Scholar 

  17. Rosser T, Packer RJ. Intracranial neoplasms in children with neurofibromatosis 1. J Child Neurol. 2002;17(8):630–7.

    Article  PubMed  Google Scholar 

  18. Korf BR. Plexiform neurofibromas. Am J Med Genet. 1999;89(1):31–7.

    Article  PubMed  CAS  Google Scholar 

  19. Nguyen R, Kluwe L, Fuensterer C, et al. Plexiform neurofibromas in children with neurofibromatosis type 1: frequency and associated clinical deficits. J Pediatr. 2011 May 27 (Epub ahead of print).

  20. Dombi E, Solomon J, Gillespie AJ, et al. NF1 plexiform neurofibroma growth rate by volumetric MRI: relationship to age and body weight. Neurology. 2007;68(9):643–7.

    Article  PubMed  CAS  Google Scholar 

  21. Yang FC, Ingram DA, Chen S, et al. Nf1-dependent tumors require a microenvironment containing Nf1+/−− and c-kit-dependent bone marrow. Cell. 2008;135(3):437–48.

    Article  PubMed  CAS  Google Scholar 

  22. Evans DG, Baser ME, McGaughran J, et al. Malignant peripheral nerve sheath tumours in neurofibromatosis 1. J Med Genet. 2002;39(5):311–4.

    Article  PubMed  CAS  Google Scholar 

  23. Mautner VF, Friedrich RE, von Deimling A, et al. Malignant peripheral nerve sheath tumours in neurofibromatosis type 1: MRI supports the diagnosis of malignant plexiform neurofibroma. Neuroradiology. 2003;45(9):618–25.

    Article  PubMed  CAS  Google Scholar 

  24. Moharir M, London K, Howman-Giles R, et al. Utility of positron emission tomography for tumour surveillance in children with neurofibromatosis type 1. Eur J Nucl Med Mol Imag. 2010;37(7):1309–17.

    Article  Google Scholar 

  25. Friedrich RE, Hartmann M, Mautner VF. Malignant peripheral nerve sheath tumors (MPNST) in NF1-affected children. Anticancer Res. 2007;27(4A):1957–60.

    PubMed  CAS  Google Scholar 

  26. Cairns AG, North KN. Cerebrovascular dysplasia in neurofibromatosis type 1. J Neurol Neurosurg Psychiatr. 2008;79(10):1165–70.

    Article  PubMed  CAS  Google Scholar 

  27. Vivarelli R, Grosso S, Calabrese F, et al. Epilepsy in neurofibromatosis 1. J Child Neurol. 2003;18:338–42.

    Article  PubMed  Google Scholar 

  28. Ruggieri M, Iannetti P, Clementi M, et al. Neurofibromatosis type 1 and infantile spasms. Childs Nerv Syst. 2009;25(2):211–6.

    Article  PubMed  Google Scholar 

  29. Mautner VF, Kluwe L, Friedrich RE, et al. Clinical characterisation of 29 neurofibromatosis type-1 patients with molecularly ascertained 1.4 Mb type-1 NF1 deletions. J Med Genet. 2010;47(9):623–30.

    Article  PubMed  CAS  Google Scholar 

  30. Upadhyaya M, Huson SM, Davies M, et al. An absence of cutaneous neurofibromas associated with a 3-bp inframe deletion in exon 17 of the NF1 gene (c.2970-2972 delAAT): evidence of a clinically significant NF1 genotype-phenotype correlation. Am J Hum Genet. 2007;80(1):140–51.

    Article  PubMed  CAS  Google Scholar 

  31. Evans DG, Wallace A. An update on age related mosaic and offspring risk in neurofibromatosis 2 (NF2). J Med Genet. 2009;46(11):792.

    Article  PubMed  CAS  Google Scholar 

  32. Messiaen L, Yao S, Brems H, et al. Clinical and mutational spectrum of neurofibromatosis type 1-like syndrome. JAMA. 2009;302(19):2111–8.

    Article  PubMed  CAS  Google Scholar 

  33. Binning MJ, Liu JK, Kestle JR, et al. Optic pathway gliomas: a review. Neurosurg Focus. 2007;23(5):E2.

    Article  PubMed  Google Scholar 

  34. Ferner RE, Gutmann DH. International consensus statement on malignant peripheral nerve sheath tumors in neurofibromatosis. Cancer Res. 2002;62(5):1573–7.

    PubMed  CAS  Google Scholar 

  35. Koptan W, El Miligui Y. Surgical correction of severe dystrophic neurofibromatosis scoliosis: an experience of 32 cases. Eur Spine J. 2010;19(9):1569–75.

    Article  PubMed  Google Scholar 

  36. Baaj AA, Agazzi S, Sayed ZA, et al. Surgical management of moyamoya disease: a review. Neurosurg Focus. 2009;26(4):E7.

    Article  PubMed  Google Scholar 

  37. Grill J, Couanet D, Cappelli C, et al. Radiation-induced cerebral vasculopathy in children with neurofibromatosis and optic pathway glioma. Ann Neurol. 1999;45(3):393–6.

    Article  PubMed  CAS  Google Scholar 

  38. Merchant TE, Kun LE, Wu S, et al. Phase II trial of conformal radiation therapy for pediatric low-grade glioma. J Clin Oncol. 2009;27(22):3598–604.

    Article  PubMed  Google Scholar 

  39. Krab LC, de Goede-Bolder A, Aarsen FK, et al. Effect of simvastatin on cognitive functioning in children with neurofibromatosis type 1: a randomized controlled trial. JAMA. 2008;300(3):287–94.

    Article  PubMed  CAS  Google Scholar 

  40. Kim A, Gillespie A, Dombi E, et al. Characteristics of children enrolled in treatment trials for NF1-related plexiform neurofibromas. Neurology. 2009;73(16):1273–9.

    Article  PubMed  CAS  Google Scholar 

  41. Packer RJ, Gutmann DH, Rubenstein A, et al. Plexiform neurofibromas in NF1: toward biologic-based therapy. Neurology. 2002;58(10):1461–70.

    PubMed  CAS  Google Scholar 

  42. Babovic-Vuksanovic D, Ballman K, Michels V, et al. Phase II trial of pirfenidone in adults with neurofibromatosis type 1. Neurology. 2006;67(10):1860–2.

    Article  PubMed  CAS  Google Scholar 

  43. Widemann BC, Salzer WL, Arceci RJ, et al. Phase I trial and pharmacokinetic study of the farnesyltransferase inhibitor tipifarnib in children with refractory solid tumors or neurofibromatosis type I and plexiform neurofibromas. J Clin Oncol. 2006;24(3):507–16.

    Article  PubMed  CAS  Google Scholar 

  44. •• Kissil JL, Blakeley JO, Ferner RE, et al. What’s new in neurofibromatosis? Proceedings from the 2009 NF Conference: new frontiers. Am J Med Genet A. 2010;152A(2):269–83.

    Article  PubMed  Google Scholar 

  45. •• Huson SM, Acosta MT, Belzberg AJ, et al. Back to the future: proceedings from the 2010 NF Conference. Am J Med Genet A. 2011;155(2):307–21.

    Article  Google Scholar 

  46. Ullrich NJ, Zimmerman M, Smith E, et al. Association of rapidly progressive moyamoya syndrome with bevacizumab treatment for glioblastoma in a child with neurofibromatosis type 1. J Child Neurol. 2011;26(2):228–30.

    Article  PubMed  Google Scholar 

  47. Asthagiri AR, Parry DM, Butman JA, et al. Neurofibromatosis type 2. Lancet. 2009;373(9679):1974–86.

    Article  PubMed  CAS  Google Scholar 

  48. • Evans DG, Neurofibromatosis type 2 (NF2): a clinical and molecular review. Orphanet J Rare Dis. 2009;4:16.

    Article  PubMed  Google Scholar 

  49. Nunes F, MacCollin M. Neurofibromatosis 2 in the pediatric population. J Child Neurol. 2003;18(10):718–24.

    Article  PubMed  Google Scholar 

  50. Otsuka G, Saito K, Nagatani T, et al. Age at symptom onset and long-term survival in patients with neurofibromatosis Type 2. J Neurosurg. 2003;99(3):480–3.

    Article  PubMed  Google Scholar 

  51. Evans DG, Birch JM, Ramsden RT. Paediatric presentation of type 2 neurofibromatosis. Arch Dis Child. 1999;81(6):496–9.

    Article  PubMed  CAS  Google Scholar 

  52. MacCollin M, Mautner VF. The diagnosis and management of neurofibromatosis 2 in childhood. Semin Pediatr Neurol. 1998;5(4):243–52.

    Article  PubMed  CAS  Google Scholar 

  53. Mautner VF, Tatagiba M, Guthoff R, et al. Neurofibromatosis 2 in the pediatric age group. Neurosurgery. 1993;33(1):92–6.

    Article  PubMed  CAS  Google Scholar 

  54. Evans DG, Baser ME, O’Reilly B, et al. Management of the patient and family with neurofibromatosis 2: a consensus conference statement. Br J Neurosurg. 2005;19(1):5–12.

    Article  PubMed  CAS  Google Scholar 

  55. Harris GJ, Plotkin SR, Maccollin M, et al. Three-dimensional volumetrics for tracking vestibular schwannoma growth in neurofibromatosis type II. Neurosurgery. 2008;62(6):1314–9.

    Article  PubMed  Google Scholar 

  56. Brackmann DE, Fayad JN, Slattery III WH, et al. Early proactive management of vestibular schwannomas in neurofibromatosis type 2. Neurosurgery. 2001;49(2):274–80.

    PubMed  CAS  Google Scholar 

  57. Evans DG, Birch JM, Ramsden RT, et al. Malignant transformation and new primary tumours after therapeutic radiation for benign disease: substantial risks in certain tumour prone syndromes. J Med Genet. 2006;43(4):289–94.

    Article  PubMed  CAS  Google Scholar 

  58. Wentworth S, Pinn M, Bourland JD, et al. Clinical experience with radiation therapy in the management of neurofibromatosis-associated central nervous system tumors. Int J Radiat Oncol Biol Phys. 2009;73(1):208–13.

    Article  PubMed  Google Scholar 

  59. Plotkin SR, Stemmer-Rachamimov AO, Barker 2nd FG, et al. Hearing improvement after bevacizumab in patients with neurofibromatosis type 2. N Engl J Med. 2009;361(4):358–67.

    Article  PubMed  CAS  Google Scholar 

  60. Plotkin SR, Halpin C, McKenna MJ, et al. Erlotinib for progressive vestibular schwannoma in neurofibromatosis 2 patients. Otol Neurotol. 2010;31(7):1135–43.

    Article  PubMed  Google Scholar 

  61. Chamberlain MC, Glantz MJ, Fadul CE. Recurrent meningioma: salvage therapy with long-acting somatostatin analogue. Neurology. 2007;69(10):969–73.

    Article  PubMed  CAS  Google Scholar 

  62. Wen PY, Yung WK, Lamborn KR, et al. Phase II study of imatinib mesylate for recurrent meningiomas (North American Brain Tumor Consortium study 01–08). Neuro Oncol. 2009;11(6):853–60.

    Article  PubMed  CAS  Google Scholar 

  63. Neff BA, Wiet RM, Lasak JM, et al. Cochlear implantation in the neurofibromatosis type 2 patient: long-term follow-up. Laryngoscope. 2007;117(6):1069–72.

    Article  PubMed  Google Scholar 

  64. •• Evans DG, Kalamarides M, Hunter-Schaedle K, et al. Consensus recommendations to accelerate clinical trials for neurofibromatosis type 2. Clin Cancer Res. 2009;15(16):5032–9.

    Article  PubMed  Google Scholar 

  65. Plotkin SR, Halpin C, Blakeley JO, et al. Suggested response criteria for phase II antitumor drug studies for neurofibromatosis type 2 related vestibular schwannoma. J Neurooncol. 2009;93(1):61–77.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Institute for Neuroscience and Muscle Research, The Children’s Hospital at Westmead, Corner Hawkesbury Rd and Hainsworth Avenue, Westmead, NSW, 2145, Australia

    Kathryn N. North FRACP, MD

  2. TY Nelson Department of Neurology and Neurosurgery, The Children’s Hospital at Westmead, Corner Hawkesbury Rd and Hainsworth Avenue, Westmead, NSW, 2145, Australia

    Simone L. Ardern-Holmes MBChB, FRACP

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  1. Simone L. Ardern-Holmes MBChB, FRACP
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  2. Kathryn N. North FRACP, MD
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Correspondence to Kathryn N. North FRACP, MD.

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Ardern-Holmes, S.L., North, K.N. Therapeutics for Childhood Neurofibromatosis Type 1 and Type 2. Curr Treat Options Neurol 13, 529–543 (2011). https://doi.org/10.1007/s11940-011-0142-9

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  • DOI: https://doi.org/10.1007/s11940-011-0142-9

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