The Neurofibromatoses

  • Karen Stephens


Neurofibromatosis type 1 and neurofibromatosis type 2 are two distinct genetic disorders that predispose to the development of tumors primarily of the nervous system (Table 21-1).1 A recently recognized third form of neurofibromatosis, known as schwannomatosis,2 is not included in this review, as molecular genetic testing is not available for this disorder.


Malignant Peripheral Nerve Sheath Tumor Vestibular Schwannoma Somatic Mosaicism Denature High Performance Liquid Chromatography Preimplantation Diagnosis 
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  1. 1.
    Friedman JM, Butmann DH, MacCollin M, Riccardi VM, eds. Neurofibromatosis: Phenotype, Natural History, and Pathogenesis. 3rd ed. Baltimore: Johns Hopkins University Press; 1999.Google Scholar
  2. 2.
    MacCollin M, Chiocca EA, Evans DG, et al. Diagnostic criteria for schwannomatosis. Neurology. 2005;64:1838–1845.PubMedCrossRefGoogle Scholar
  3. 3.
    Friedman JM. Neurofibromatosis 1: clinical manifestations and diagnostic criteria. J Child Neurol. 2002;17:548–554.PubMedGoogle Scholar
  4. 4.
    Friedman JM. Neurofibromatosis 1. In: GeneReviews at GeneTests: Medical Genetics Information Resource [database online]. Seattle: University of Washington; 1997–2005. Available at: Accessed October 20, 2005. Updated October 5, 2004.Google Scholar
  5. 5.
    DeBella K, Szudek J, Friedman JM. Use of the national institutes of health criteria for diagnosis of neurofibromatosis 1 in children. Pediatrics. 2000;105 (pt 1):608–614.PubMedCrossRefGoogle Scholar
  6. 6.
    Evans DG, Baser ME, McGaughran J, Sharif S, Howard E, Moran A. Malignant peripheral nerve sheath tumours in neurofibromatosis 1. J Med Genet. 2002;39:311–314.PubMedCrossRefGoogle Scholar
  7. 7.
    Stephens K. Neurofibromatosis 1. In: Lupski JR, Stankiewicz P, eds. Genomic Disorders: The Genomic Basis of Genetic Disease. Trenton, NJ: Humana Press; 2006, pp. 207–219.Google Scholar
  8. 8.
    Dasgupta B, Gutmann DH. Neurofibromatosis 1: closing the GAP between mice and men. Curr Opin Genet Dev. 2003;13:20–27.PubMedCrossRefGoogle Scholar
  9. 9.
    De Raedt T, Brems H, Wolkenstein P, et al. Elevated risk for MPNST in NF1 microdeletion patients. Am J Hum Genet. 2003;72:1288–1292.PubMedCrossRefGoogle Scholar
  10. 10.
    Spiegel M, Oexle K, Horn D, et al. Childhood overgrowth in patients with common NF1 microdeletions. Eur J Hum Genet. 2005;13:883–888.PubMedCrossRefGoogle Scholar
  11. 11.
    Dorschner MO, Sybert VP, weaver M, Pletcher BA, Stephens K. NF1 microdeletion breakpoints are clustered at flanking repetitive sequences. Hum Mol Genet. 2000;9:35–46.PubMedCrossRefGoogle Scholar
  12. 12.
    Gutmann DH, James CD, Poyhonen M, et al. Molecular analysis of astrocytomas presenting after age 10 in individuals with NF1. Neurology. 2003;61:1397–1400.PubMedGoogle Scholar
  13. 13.
    Venturin M, Guarnieri P, natacci F, et al. Mental retardation and cardiovascular malformations in NF1 microdeleted patients point to candidate genes in 17q11.2. J Med Genet. 2004;41:35–41.PubMedCrossRefGoogle Scholar
  14. 14.
    Kehrer-Sawatzki H, Kluwe L, Funsterer C, Mautner VF. Extensively high load of internal tumors determined by whole body MRI scanning in a patient with neurofibromatosis type 1 and a non-LCRmediated 2-Mb deletion in 17q11.2. Hum Genet. 2005;116:466–475.PubMedCrossRefGoogle Scholar
  15. 15.
    L’Azaro C, Gaona A, Lynch M, Kruyer H, Ravella A, Estivill X. molecular characterization of the breakpoints of a 12-kb deletion in the NF1 gene in a family showing germ-line mosaicism. Am J Hum Genet. 1995;57:1044–1049.Google Scholar
  16. 16.
    Kehrer-Sawatzki H, Kluwe L, Sandig C, et al. High frequency of mosaicism among patients with neurofibromatosis type 1 (NF1) with microdeletions caused by somatic recombination of the JJAZ1 gene. Am J Hum Genet. 2004;75:410–423.PubMedCrossRefGoogle Scholar
  17. 17.
    Ruggieri M, Huson SM. The clinical and diagnostic implications of mosaicism in the neurofibromatoses. Neurology. 2001;56:1433–1443.PubMedGoogle Scholar
  18. 18.
    Leppig KA, Viskochil D, Neil S, et al. The detection of contiguous gene deletions at the neurofibromatosis 1 locus with fluorescence in situ hybridization. Cytogenet Cell Genet. 1996;72:95–98.PubMedCrossRefGoogle Scholar
  19. 19.
    Lopez-Correa C, Dorschner M, Brems H, et al. Recombination hotspot in NF1 microdeletion patients. Hum Mol Genet. 2001;10:1387–1392.PubMedCrossRefGoogle Scholar
  20. 20.
    Mantripragada KK, Thuresson AC, Piotrowski A, et al. Identification of novel deletion breakpoints bordered by segmental duplications in the NF1 locus using high-resolution array-CGH. J Med Genet. 2006;43:28–38.PubMedCrossRefGoogle Scholar
  21. 21.
    Messiaen LM, Callens T, Mortier G, 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;15:541–555.PubMedCrossRefGoogle Scholar
  22. 22.
    Fahsold R, Hoffmeyer S, Mischung C, et al. Minor lesion mutational spectrum of the entire NF1 gene does not explain its high mutability but points to a functional domain upstream of the GAP-related domain. Am J Hum Genet. 2000;66:790–818.PubMedCrossRefGoogle Scholar
  23. 23.
    Mattocks C, Baralle D, Tarpey P, Ffrench-Constant C, Bobrow M, Whittaker J. Automated comparative sequence analysis identifies mutations in 89% of NF1 patients and confirms a mutation cluster in exons 11-17 distinct from the GAP related domain. J Med Genet. 2004;41:e48.PubMedCrossRefGoogle Scholar
  24. 24.
    Han SS, Cooper DN, Upadhyaya MN. Evaluation of denaturing high performance liquid chromatography (DHPLC) for the mutational analysis of the neurofibromatosis type 1 ( NF1) gene. Hum Genet. 2001;109:487–497.PubMedCrossRefGoogle Scholar
  25. 25.
    De Luca A, Buccino A, Gianni D, et al. NF1 gene analysis based on DHPLC. Hum Mutat. 2003;21:171–172.PubMedCrossRefGoogle Scholar
  26. 26.
    Gite S, Lim M, Carlson R, Olejnik J, Zehnbauer B, Rothschild K. A high-throughput nonisotopic protein truncation test. Nat Biotechnol. 2003;21:194–197.PubMedCrossRefGoogle Scholar
  27. 27.
    Klose A, Peters H, Hoffmeyer S, et al. Two independent mutations in a family with neurofibromatosis type 1 (NF1). Am J Med Genet. 1999;83:6–12.PubMedCrossRefGoogle Scholar
  28. 28.
    Wimmer K, Eckart M, Rehder H, Fonatsch C. Illegitimate splicing of the NF1 gene in healthy individuals mimics mutation-induced splicing alterations in NF1 patients. Hum Genet. 2000;106:311–313.PubMedCrossRefGoogle Scholar
  29. 29.
    Ars E, Serra E, de la Luna S, Estivill X, Lazaro C. Cold shock induces the insertion of a cryptic exon in the neurofibromatosis type 1 (NF1) mRNA. Nucleic Acids Res. 2000;28:1307–1312.PubMedCrossRefGoogle Scholar
  30. 30.
    Li Y, O’Connell P, Breidenbach HH, et al. Genomic organization of the neurofibromatosis 1 gene (NF1). Genomics. 1995;25:9–18.PubMedCrossRefGoogle Scholar
  31. 31.
    Gervasini C, Bentivegna A, Venturin M, Corrado L, Larizza L, Riva P. Tandem duplication of the NF1 gene detected by high-resolution FISH in the 17q11.2 region. Hum Genet. 2002;110:314–321.PubMedCrossRefGoogle Scholar
  32. 32.
    Kehrer-Sawatzki H, Messiaen L. Interphase FISH, the structure of reciprocal translocation chromosomes and physical mapping studies rule out the duplication of the NF1 gene at 17q11.2. A reply. Hum Genet. 2003;113:188–190.PubMedGoogle Scholar
  33. 33.
    Yu H, Zhao X, Su B, et al. Expression of NF1 pseudogenes. Hum Mutat. 2005;26:487–488.PubMedCrossRefGoogle Scholar
  34. 34.
    Thomson SA, Fishbein L, Wallace MR. NF1 mutations and molecular testing. J Child Neurol. 2002;17:555–561; discussion 71–72, 646–651.PubMedGoogle Scholar
  35. 35.
    Ruggieri M, Iannetti P, Polizzi A, et al. Earliest clinical manifestations and natural history of neurofibromatosis type 2 (NF2) in childhood: a study of 24 patients. Neuropediatrics. 2005;36:21–34.PubMedCrossRefGoogle Scholar
  36. 36.
    Baser ME, Evans R, Gareth D, Gutmann DH. Neurofibromatosis 2. Curr Opin Neurol. 2003;16:27–33.PubMedCrossRefGoogle Scholar
  37. 37.
    Evans DG, Sainio M, Baser ME. Neurofibromatosis type 2. J Med Genet. 2000;37:897–904.PubMedCrossRefGoogle Scholar
  38. 38.
    Evans DG. Neurofibromatosis 2. In: GeneReviews at GeneTests: Medical Genetics Information Resource [database online]. Seattle: University of Washington, 1997–2005. Available at: Accessed October 20, 2005. Updated April 6, 2004.Google Scholar
  39. 39.
    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;75:231–239.PubMedCrossRefGoogle Scholar
  40. 40.
    Baser ME, Friedman JM, Wallace AJ, Ramsden RT, Joe H, Evans DG. Evaluation of clinical diagnostic criteria for neurofibromatosis 2. Neurology. 2002;59:1759–1765.PubMedCrossRefGoogle Scholar
  41. 41.
    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.PubMedCrossRefGoogle Scholar
  42. 42.
    McClatchey AI, Giovannini M. Membrane organization and tumorigenesis— the NF2 tumor suppressor, merlin. Genes Dev. 2005;19:2265–2277.PubMedCrossRefGoogle Scholar
  43. 43.
    Kluwe L, Mautner V, Heinrich B, et al. Molecular study of frequency of mosaicism in neurofibromatosis 2 patients with bilateral vestibular schwannomas. J Med Genet. 2003;40:109–114.PubMedCrossRefGoogle Scholar
  44. 44.
    Abou-Sleiman PM, Apessos A, Harper JC, Serhal P, Winston RM, Delhanty JD. First application of preimplantation genetic diagnosis to neurofibromatosis type 2 (NF2). Prenat Diagn. 2002;22:519–524.PubMedCrossRefGoogle Scholar
  45. 45.
    Baser ME, Kuramoto L, Woods R, et al. The location of constitutional neurofibromatosis 2 (NF2) splice site mutations is associated with the severity of NF2. J Med Genet. 2005;42:540–546.PubMedCrossRefGoogle Scholar
  46. 46.
    Parry DM, MacCollin MM, Kaiser-Kupfer MI, et al. Germ-line mutations in the neurofibromatosis 2 gene: correlations with disease severity and retinal abnormalities. Am J Hum Genet. 1996;59:529–539.PubMedGoogle Scholar
  47. 47.
    Evans DG, Trueman L, Wallace A, Collins S, Strachan T. Genotype/ phenotype correlations in type 2 neurofibromatosis (NF2): evidence for more severe disease associated with truncating mutations. J Med Genet. 1998;35:450–455.PubMedGoogle Scholar
  48. 48.
    Kluwe L, MacCollin M, Tatagiba M, et al. Phenotypic variability associated with 14 splice-site mutations in the NF2 gene. Am J MedGenet. 1998;77:228–233.CrossRefGoogle Scholar
  49. 49.
    Sestini R, Vivarelli R, Balestri P, Ammannati F, Montali E, Papi L. Neurofibromatosis type 2 attributable to gonosomal mosaicism in a clinically normal mother, and identification of seven novel mutations in the NF2 gene. Hum Genet. 2000;107:366–371.PubMedCrossRefGoogle Scholar
  50. 50.
    Wallace AJ, Watson CJ, Oward E, Evans DG, Elles RG. Mutation scanning of the NF2 gene: an improved service based on meta-PCR/sequencing, dosage analysis, and loss of heterozygosity analysis. Genet Test. 2004;8:368–380.PubMedCrossRefGoogle Scholar
  51. 51.
    Kluwe L, Mautner VF. Mosaicism in sporadic neurofibromatosis 2 patients. Hum Mol Genet. 1998;7:2051–2055.PubMedCrossRefGoogle Scholar
  52. 52.
    Evans DG, Wallace AJ, Wu CL, Trueman L, Ramsden RT, Strachan T. Somatic mosaicism: a common cause of classic disease in tumorprone syndromes? Lessons from type 2 neurofibromatosis. Am J Hum Genet. 1998;63:727–736.PubMedCrossRefGoogle Scholar
  53. 53.
    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;40:459–463.PubMedCrossRefGoogle Scholar
  54. 54.
    Kluwe L, Friedrich RE, Tatagiba M, Mautner VF. Presymptomatic diagnosis for children of sporadic neurofibromatosis 2 patients: a method based on tumor analysis. Genet Med. 2002;4:27–30.PubMedCrossRefGoogle Scholar
  55. 55.
    Kluwe L, Nygren AO, Errami A, et al. Screening for large mutations of the NF2 gene. Genes Chromosomes Cancer. 2005;42:384–391.PubMedCrossRefGoogle Scholar
  56. 56.
    Diebold R, Bartelt-Kirbach B, Evans DG, Kaufmann D, Hanemann CO. Sensitive detection of deletions of one or more exons in the neurofibromatosis type 2 (NF2) gene by multiplexed gene dosage polymerase chain reaction. J Mol Diagn. 2005;7:97–104.PubMedGoogle Scholar
  57. 57.
    Buckley PG, Mantripragada KK, Benetkiewicz M, et al. A fullcoverage, high-resolution human chromosome 22 genomic microarray for clinical and research applications. Hum Mol Genet. 2002;11:3221–3229.PubMedCrossRefGoogle Scholar
  58. 58.
    Stokowski RP, Cox DR. Functional analysis of the neurofibromatosis type 2 protein by means of disease-causing point mutations. Am J Hum Genet. 2000;66:873–891.PubMedCrossRefGoogle Scholar
  59. 59.
    Gutmann DH, Hirbe AC, Haipek CA. Functional analysis of neurofibromatosis 2 (NF2) missense mutations. Hum Mol Genet. 2001;10:1519–1529.PubMedCrossRefGoogle Scholar
  60. 60.
    Ryu CH, Kim SW, Lee KH, et al. The merlin tumor suppressor interacts with Ral guanine nucleotide dissociation stimulator and inhibits its activity. Oncogene. 2005;24:5355–5364.PubMedCrossRefGoogle Scholar
  61. 61.
    Bijlsma EK, Wallace AJ, Evans DG. Misleading linkage results in an NF2 presymptomatic test owing to mosaicism. J MedGenet. 1997;34:934–936.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Karen Stephens
    • 1
    • 2
  1. 1.Department of Medicine and of Laboratory MedicineUSA
  2. 2.Genetics LaboratoryUniversity of Washington, Medical GeneticsSeattleUSA

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