Skip to main content
SpringerLink
Log in

Neurofibromatoses

  • Chapter
Neurodegenerative Diseases

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 724))

Abstract

The studies of familial tumor predisposition syndromes have contributed immensely to our understanding of oncogenesis. Neurofibromatosis 1, neurofibromatosis 2 and schwannomatosis are inherited autosomal dominant neurocutaneous disorders with complete penetrance. They are clinically and genetically distinct and considerable knowledge has been gathered about their pathogenesis. In this chapter, the genetics, molecular mechanism of disease, as well as clinical features, diagnosis and treatment are discussed.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Wishart JH. Case of tumours in the skull, dura mater and brain. Edinburgh Med Surg J 1822; 18:393–397.

    Google Scholar 

  2. von Recklinghausen F. Uber die multiplen Fibrome der Haut und ihre Beziehung zu multiplen Neuromen. Berlin, Germany: August Hirschwald; 1882.

    Google Scholar 

  3. Crump T. Translation of case reports in Ueber die multiplen Fibrome der Haut und ihre Beziehung zu den multiplen Neuromen by F. v. Recklinghausen. Adv Neurol 1981; 29:259–275.

    PubMed  CAS  Google Scholar 

  4. Friedman JM, Gutmann DH, MacCollin M et al. Neurofibromatosis: Phenotype, Natural History and Pathogenesis, 3rd edition, Baltimore, Johns Hopkins Press; 1999.

    Google Scholar 

  5. Evans DG, Huson SM, Donnai D et al. A clinical study of type 2 neurofibromatosis. Q J Med 1992; 304:603–618.

    Google Scholar 

  6. Antinheimo J, Sankila R, Carpen O et al. Population-based analysis of sporadic and type 2 neurofibromatosis-associated meningiomas and schwannomas. Neurology 2000; 54:71–76.

    PubMed  CAS  Google Scholar 

  7. Niimura M. Neurofibromatosis. Rinsho Derma 1973; 15:653–663.

    Google Scholar 

  8. MacCollin M, Willett C, Heinrich B et al. Familial schwannomatosis: exclusion of the NF2 locus as the germline event. Neurology 2003; 60(12):1968–1974.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  Google Scholar 

  10. Riccardi VM. Neurofibromatosis: past, present and future. N Engl J Med 1991; 324(18):1283–1285.

    Article  PubMed  CAS  Google Scholar 

  11. Evans DG, Howard E, Giblin C et al. Birth incidence and prevalence of tumour prone syndromes: estimates from a UK genetic family register service. Am J Med Genet A 2010; 152A:327–332.

    Article  PubMed  CAS  Google Scholar 

  12. 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; 19:5–12.

    Article  PubMed  CAS  Google Scholar 

  13. Ferner RE. Neurofibromatosis 1 and neurofibromatosis 2: a twenty first century perspective. Lancet Neurol 2007; 6:340–351.

    Article  PubMed  Google Scholar 

  14. Mautner VF, Baser ME, Thakkar SD et al. Vestibular schwannoma growth in patients with neurofibromatosis type 2: a longitudinal study. J Neurosurg 2002; 96:223–228.

    Article  PubMed  Google Scholar 

  15. Huang JH, Simon SL, Nagpal S et al. Management of patients with schwannomatosis: report of six cases and review of the literature. Surg Neurol 2004; 62:353–361.

    Article  PubMed  Google Scholar 

  16. MacCollin M, Woodfin W, Kronn D et al. Schwannomatosis-a clinical and pathologic study. Neurology 1996; 46:1072–1079.

    PubMed  CAS  Google Scholar 

  17. Wolkenstein P, Benchikhi H, Zeller J et al. Schwannomatosis: a clinical entity distinct from neurofibromatosis type 2. Dermatology 1997; 195:228–231.

    Article  PubMed  CAS  Google Scholar 

  18. Baser ME, Kuramoto L, Joe H et al. Genotype-phenotype correlations for nervous system tumors in neurofibromatosis 2: a population-based study. Am J Hum Genet 2004; 75(2):231–239.

    Article  PubMed  CAS  Google Scholar 

  19. Marchuk DA, Saulino AM, Tavakkol R et al. cDNA cloning of the type 1 neurofibromatosis gene: complete sequence of the NF1 gene product. Genomics 1991; 4:931–940.

    Article  Google Scholar 

  20. Rouleau GA, Merel P, Lutchman M et al. Alteration in a new gene encoding a putative membrane-organizing protein causes neuro-fibromatosis type 2. Nature 1993; 363(6429):515–521.

    Article  PubMed  CAS  Google Scholar 

  21. Xie YG, Han FY, Peyrard M et al. Cloning of a novel, anonymous gene from a megabase-range YAC and cosmid contig in the neurofibromatosis type 2/meningioma region on human chromosome 22q12. Hum Mol Genet 1993; 2(9):1361–1368.

    Article  PubMed  CAS  Google Scholar 

  22. Trofatter JA, MacCollin MM, Rutter JL et al. A novel moesin-, ezrin-, radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor. Cell 1993; 72:791–800.

    Article  PubMed  CAS  Google Scholar 

  23. Knudson AG. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 1971; 68:820–823.

    Article  PubMed  Google Scholar 

  24. Biegel JA, Zhou JY, Rorke LB et al. Germ-line and acquired mutations of INI1 in atypical teratoid and rhabdoid tumors. Cancer Res 1999; 59:74–79.

    PubMed  CAS  Google Scholar 

  25. Sevenet N, Sheridan E, Amram D et al. Constitutional mutations of the hSNF5/INI1 gene predispose to a variety of cancers. Am J Hum Genet 1999a; 65:1342–1348.

    Article  PubMed  CAS  Google Scholar 

  26. Fujisawa H, Takabatake Y, Fukusato T et al. Molecular analysis of the rhabdoid predisposition syndrome in a child: a novel germline hSNF5/INI1 mutation and absence of c-myc amplification. J Neurooncol 2003; 63:257–262.

    Article  PubMed  Google Scholar 

  27. Kaufman DL, Heinrich BS, Willett C et al. Somatic instability of the NF2 gene in schwannomatosis. Arch Neurol 2003; 60:1317–1320.

    Article  PubMed  Google Scholar 

  28. Cawthon RM, Weiss R, Xu GF et al. A major segment of the neurofibromatosis type 1 gene: cDNA sequence, genomic structure and point mutations. Cell 1990; 62(1):193–201.

    Article  PubMed  CAS  Google Scholar 

  29. Viskochil D, Buchberg AM, Xu G et al. Deletions and a translocation interrupt a cloned gene at the neurofibromatosis type 1 locus. Cell 1990; 62(1):187–192.

    Article  PubMed  CAS  Google Scholar 

  30. Wallace MR, Marchuk DA, Andersen LB et al. Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients. Science 1990; 249(4965):181–186.

    Article  PubMed  CAS  Google Scholar 

  31. Bollag G, McCormick F. Ras regulation. NF is enough of GAP. Nature 1992; 356:663–664.

    Article  PubMed  CAS  Google Scholar 

  32. Kluwe L, Friedrich R, Mautner VF. Loss of NF1 allele in Schwann cells but not in fibroblasts derived from an NF1-associated neurofibroma. Genes Chromosomes Cancer 1999; 24:283–285.

    Article  PubMed  CAS  Google Scholar 

  33. Rutkowski JL, Wu K, Gutmann DH et al. Genetic and cellular defects contributing to benign tumor formation in neurofibromatosis type 1. Hum Mol Genet 2000; 9:1059–1066.

    Article  PubMed  CAS  Google Scholar 

  34. Legius E, Marchuk DA, Collins FS et al. Somatic deletion of the neurofibromatosis type 1 gene in a neurofibrosarcoma supports a tumour suppressor gene hypothesis. Nat Genet 1993; 3:122–126.

    Article  PubMed  CAS  Google Scholar 

  35. Brown JA, Gianino SM, Gutmann DH. Defective cAMP generation underlies the sensitivity of CNS neurons to neurofibromatosis-1 heterozygosity. J Neurosci 2010; 30(16):5579–5589.

    Article  PubMed  CAS  Google Scholar 

  36. Warrington NM, Gianino SM, Jackson E et al. Cyclic AMP suppression is sufficient to induce gliomagenesis in a mouse model of neurofibromatosis-1. Cancer Res 2010; 70(14):5717–5727.

    Article  PubMed  CAS  Google Scholar 

  37. Hegedus B, Dasgupta B, Shin JE et al. Neurofibromatosis-1 regulates neuronal and glial cell differentiation from neuroglial progenitors in vivo by both cAMP-and Ras-dependent mechanisms. Cell Stem Cell 2007; 1(4):443–457.

    Article  PubMed  CAS  Google Scholar 

  38. Lee DY, Yeh TH, Emnett RJ et al. Neurofibromatosis-1 regulates neuroglial progenitor proliferation and glial differentiation in a brain region-specific manner. Genes Dev 2010; 24(20):2317–2329.

    Article  CAS  Google Scholar 

  39. Lee JS, Padmanabhan A, Shin J et al. Oligodendrocyte progenitor cell numbers and migration are regulated by the zebrafish orthologs of the NF1 tumor suppressor gene. Hum Mol Genet 2010; 19(23):4643–4653.

    Article  PubMed  CAS  Google Scholar 

  40. Staser K, Yang FC, Clapp DW. Plexiform neurofibroma genesis: questions of Nf1 gene dose and hyperactive mast cells. Curr Opin Hematol 2010; 17(4):287–293.

    Article  PubMed  Google Scholar 

  41. Chai G, Liu N, Ma J et al. MicroRNA-10b regulates tumorigenesis in neurofibromatosis type 1. Cancer Sci 2010.

    Google Scholar 

  42. Sun CX, Haipek C, Scoles DR et al. Functional analysis of the relationship between the neurofibromatosis 2 tumor suppressor and its binding partner, hepatocyte growth factor-regulated tyrosine kinase substrate. Hum Mol Genet 2002; 11(25):3167–3178.

    Article  PubMed  CAS  Google Scholar 

  43. Ramesh V. Merlin and the ERM proteins in Schwann cells, neurons and growth cones. Nat Rev Neurosci 2004; 5(6):462–470.

    Article  PubMed  CAS  Google Scholar 

  44. Lutchman M, Rouleau GA. The neurofibromatosis type 2 gene product, schwannomin, suppresses growth of NIH 3T3 cells. Cancer Res 1995; 55(11):2270–2274.

    PubMed  CAS  Google Scholar 

  45. McClatchey AI, Saotome I, Ramesh V et al. Genes Dev 1997; 11(10):1253–1265. The Nf2 tumor suppressor gene product is essential for extraembryonic development immediately prior to gastrulation. Genes Dev 1997; 11(10):1253–1265.

    Article  PubMed  CAS  Google Scholar 

  46. Sherman L, Xu HM, Geist RT et al. Interdomain binding mediates tumor growth suppression by the NF2 gene product. Oncogene 1997; 15(20):2505–2509.

    Article  PubMed  CAS  Google Scholar 

  47. Ikeda K, Saeki Y, Gonzalez-Agosti C et al. Inhibition of NF2-negative and NF2-positive primary human meningioma cell proliferation by overexpression of merlin due to vector-mediated gene transfer. J Neurosurg 1999; 91(1):85–92.

    Article  PubMed  CAS  Google Scholar 

  48. Fraenzer JT, Pan H, Minimo L Jr et al. Overexpression of the NF2 gene inhibits schwannoma cell proliferation through promoting PDGFR degradation. Int J Oncol 2003; 23(6):1493–1500.

    PubMed  CAS  Google Scholar 

  49. Xiao GH, Gallagher R, Shetler J et al. The NF2 tumor suppressor gene product, merlin, inhibits cell proliferation and cell cycle progression by repressing cyclin D1 expression. Mol Cell Biol 2005; 25(6):2384–2394.

    Article  PubMed  CAS  Google Scholar 

  50. Shaw RJ, Paez JG, Curto M et al. The Nf2 tumor suppressor, merlin, functions in Rac-dependent signaling. Dev Cell 2001; 1(1):63–72.

    Article  PubMed  CAS  Google Scholar 

  51. Kissil JL, Wilker EW, Johnson KC et al. Merlin, the product of the Nf2 tumor suppressor gene, is an inhibitor of the p21-activated kinase, Pak1. Mol Cell 2003; 12:841–849.

    Article  PubMed  CAS  Google Scholar 

  52. Chadee DN, Xu D, Hung G et al. Mixed-lineage kinase 3 regulates B-Raf through maintenance of the B-Raf/Raf-1 complex and inhibition by the NF2 tumor suppressor protein. Proc Natl Acad Sci USA 2006; 103(12):4463–4468.

    Article  PubMed  CAS  Google Scholar 

  53. Morrison H, Sperka T, Manent J et al. Merlin/neurofibromatosis type 2 suppresses growth by inhibiting the activation of Ras and Rac. Cancer Res 2007; 67(2):520–527.

    Article  PubMed  CAS  Google Scholar 

  54. Z Zender L, Spector MS, Xue W et al. Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach. Cell 2006; 125(7):1253–1267.

    Article  PubMed  CAS  Google Scholar 

  55. Dong J, Feldmann G, Huang J et al. Elucidation of a universal size-control mechanism in Drosophila and mammals. Cell 2007; 130(6):1120–1133.

    Article  PubMed  CAS  Google Scholar 

  56. Zhou D, Conrad C, Xia F et al. Mst1 and Mst2 maintain hepatocyte quiescence and suppress hepatocellular carcinoma development through inactivation of the Yap1 oncogene. Cancer Cell 2009; 16(5):425–438.

    Article  PubMed  CAS  Google Scholar 

  57. Zhang N, Bai H, David KK et al. The Merlin/NF2 tumor suppressor functions through the YAP oncoprotein to regulate tissue homeostasis in mammals. Dev Cell 2010; 19(1):27–38.

    Article  PubMed  CAS  Google Scholar 

  58. Lu L, Li Y, Kim SM et al. Hippo signaling is a potent in vivo growth and tumor suppressor pathway in the mammalian liver. Proc Natl Acad Sci USA 2010;107(4):1437–1442.

    Article  PubMed  CAS  Google Scholar 

  59. Song H, Mak KK, Topol L et al. Mammalian Mst1 and Mst2 kinases play essential roles in organ size control and tumor suppression. Proc Natl Acad Sci USA 2010; 107(4):1431–1436.

    Article  PubMed  CAS  Google Scholar 

  60. Zhan Y, Modi N, Stewart AM et al. Regulation of mixed lineage kinase 3 is required for Neurofibromatosis-2-mediated growth suppression in human cancer. Oncogene 2010.

    Google Scholar 

  61. Benhamouche S, Curto M, Saotome I et al. Nf2/Merlin controls progenitor homeostasis and tumorigenesis in the liver. Genes Dev 2010; 24(16):1718–1730.

    Article  PubMed  CAS  Google Scholar 

  62. Cole BK, Curto M, Chan AW et al. Localization to the cortical cytoskeleton is necessary for Nf2/ merlin-dependent epidermal growth factor receptor silencing. Mol Cell Biol 2008; 28(4):1274–1284.

    Article  PubMed  CAS  Google Scholar 

  63. James MF, Han S, Polizzano C et al. NF2/merlin is a novel negative regulator of mTOR complex 1 and activation of mTORC1 is associated with meningioma and schwannoma growth. Mol Cell Biol 2009; 29(15):4250–4261.

    Article  PubMed  CAS  Google Scholar 

  64. Li W, You L, Cooper J et al. Merlin/NF2 suppresses tumorigenesis by inhibiting the E3 ubiquitin ligase CRL4 (DCAF1) in the nucleus. Cell 2010; 140(4):477–490.

    Article  PubMed  CAS  Google Scholar 

  65. Hulsebos TJ, Plomp AS, Wolterman RA et al. Am J Hum Genet 2007; 80(4):805–810.

    Article  PubMed  CAS  Google Scholar 

  66. Zhang ZK, Davies KP, Allen J et al. Cell cycle arrest and repression of cyclin D1 transcription by INI1/hSNF5. Mol Cell Biol 2002; 22(16):5975–8859.

    Article  PubMed  CAS  Google Scholar 

  67. Tsikitis M, Zhang Z, Edelman W et al. Genetic ablation of Cyclin D1 abrogates genesis of rhabdoid tumors resulting from Ini1 loss. Proc Natl Acad Sci USA 2005; 102(34):12129–12134.

    Article  PubMed  CAS  Google Scholar 

  68. Fujisawa H, Misaki K, Takabatake Y et al. Cyclin D1 is overexpressed in atypical teratoid/rhabdoid tumor with hSNF5/INI1 gene inactivation. J Neurooncol 2005; 73(2):117–124.

    Article  PubMed  CAS  Google Scholar 

  69. Baser ME, Friedman JM, Wallace AJ et al. Evaluation of clinical diagnostic criteria for neurofibromatosis 2. Neurology 2002; 59(11):1759–1765.

    PubMed  CAS  Google Scholar 

  70. Baser ME, Friedman JM, Evans DG. Increasing the specificity of diagnostic criteria for schwannomatosis. Neurology 2006; 66(5):730–732.

    Article  PubMed  Google Scholar 

  71. MacCollin M, Chiocca EA, Evans DG et al. Diagnostic criteria for schwannomatosis. Neurology 2005; 64(11):1838–1845.

    Article  PubMed  CAS  Google Scholar 

  72. Harris GJ, Plotkin SR, Maccollin M et al. Three-dimensional volumetrics for tracking vestibular schwannoma growth in neurofibromatosis type II. Neurosurgery 2008; 62(6):1314–1319.

    Article  PubMed  Google Scholar 

  73. Colletti V. Auditory outcomes in tumor vs nontumor patients fitted with auditory brainstem implants. Adv Otorhinolaryngol 2006; 64:167–185.

    PubMed  Google Scholar 

  74. Plotkin SR, Stemmer-Rachamimov AO, Barker FG 2nd et al. Hearing improvement after bevacizumab in patients with neurofibromatosis type 2. N Engl J Med 2009; 361(4):358–367.

    Article  PubMed  CAS  Google Scholar 

  75. Baser ME, Friedman JM, Aeschliman D et al. Predictors of the risk of mortality in neurofibromatosis 2. Am J Hum Genet 2002; 71(4):715–723.

    Article  PubMed  Google Scholar 

  76. Messiaen LM, Callens T, Mortier G et al. Exhaustive mutation analysis of the NF1 gene allows identi-fication of 95% of mutations and reveals a high frequency of unusual splicing defects. Hum Mutat 2000; 15(6):541–555.

    Article  PubMed  CAS  Google Scholar 

  77. Spits C, De Rycke M, Van Ranst N et al. Preimplantation genetic diagnosis for neurofibromatosis type 1. Mol Hum Reprod 2005; 11(5):381–387.

    Article  PubMed  CAS  Google Scholar 

  78. Moyhuddin A, Baser ME, Watson C et al. Somatic mosaicism in neurofibromatosis 2: prevalence and risk of disease transmission to offspring. J Med Genet 2003; 40(6):459–463.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Stephen E. and Catherine Pappas Center for Neuro-Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA

    Erik J. Uhlmann & Scott R. Plotkin

Authors
  1. Erik J. Uhlmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Scott R. Plotkin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Scott R. Plotkin .

Editor information

Editors and Affiliations

  1. School of Science and Technology, Nottingham Trent University, Nottingham, UK

    Shamim I. Ahmad BSc, MSc, PhD

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Landes Bioscience and Springer Science+Business Media

About this chapter

Cite this chapter

Uhlmann, E.J., Plotkin, S.R. (2012). Neurofibromatoses. In: Ahmad, S.I. (eds) Neurodegenerative Diseases. Advances in Experimental Medicine and Biology, vol 724. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-0653-2_20

Download citation

Publish with us

Policies and ethics

Search

Navigation