Central European Journal of Medicine

, Volume 4, Issue 1, pp 11–16 | Cite as

The Neurofibromatosis type 1:A dominantly inherited tumors-predisposing disorder

  • Maria Scalzone
  • Paola Coccia
  • Antonio Ruggiero
  • Ilaria Lazzareschi
  • Stefano Mastrangelo
  • Riccardo Riccardi
Review Article


Neurofibromatosis type I (NF1) is a hereditary multisystem disease involving the skin and nervous system. It is the most common form of autosomal dominant phakomatoses with 100% penetrance but wide phenotypic variability. The NF1 gene is located on chromosome 17q11.2 and encodes for a tumour suppressor protein. Because affected individuals have an increased risk of tumor formation, this disorder is classified as inherited cancer syndrome. The risk of malignancies in NF1 affected patients is estimated to be 5–15% higher than in the general population. We reviewed clinical aspects and genetic mechanisms of tumorigenesis in NF1 affected patients.


Neurofibromatosis type I Tumor Pathogenesis Children 


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  1. [1]
    Friedman J.M., Riccardi V.M., Neurofibromatosis: phenotype, natural history and pathogenesis, 3rd ed., Baltimore, Johns Hopkins University Press, 1999Google Scholar
  2. [2]
    Riccardi V.M., Lewis R.A., Penetrance of von Recklinghausen neurofibromatosis: a distinction between predecessors and descendant, Am. J. Hum. Genet., 1988, 42, 284–289PubMedGoogle Scholar
  3. [3]
    Szudek J., Joe K., Friendman J.M., Analysis of Intrafamilial Phenotype Variation in Neurofibromatosis 1 (NF1), Genet. Epidem., 2002, 23, 150–164CrossRefGoogle Scholar
  4. [4]
    Wallace M.R., Marchuk D.A., Andersen L.B., Letcher R., Odeh H.M., Saulino A.M., et al., Type 1 neurofibromatosis gene: identification of a larger transcript disrupted in three NG1 patients, Science, 1990, 249, 181–186PubMedCrossRefGoogle Scholar
  5. [5]
    Xu G.F., O’Connell P., Viskochil D., Cawthon R., Robertson M., Culver M., et al., The neurofibromatosis type 1 gene encodes a protein related to GAP, Cell, 1990, 62, 599–608PubMedCrossRefGoogle Scholar
  6. [6]
    Walzer L., Thompson D., Ponder B.M., Frayling I., Baralle D., A prospective study of neurofibromatosis type I cancer incidence in the UK, Brit. J. Cancer, 2006, 95, 233–238CrossRefGoogle Scholar
  7. [7]
    Zoller M.E., Rembeck B., Oden A., Samuelsson M., Angervall L., Malignant and benign tumors in patients with neurofibromatosis type 1 in a defined Swedish population, Cancer, 1997, 79, 2125–2133PubMedCrossRefGoogle Scholar
  8. [8]
    National Institutes of Health Consensus Development Conference Statement, Neurofibromatosis, Arch. Neurol. (Chicago), 1988, 45, 575–578Google Scholar
  9. [9]
    Ward B.A., Gutmann D.H., Neurofibromatosis 1: from lab bench to clinic, Pediatr. Neurol., 2005, 32, 221–228PubMedCrossRefGoogle Scholar
  10. [10]
    Tonsgard J.H., Clinical manifestations and management of neurofibromatosis type 1, Semin. Pediatr. Neurol., 2006, 13, 2–7PubMedCrossRefGoogle Scholar
  11. [11]
    Messiaen L.M., 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, 541–555PubMedCrossRefGoogle Scholar
  12. [12]
    Jentarra G., Snyder S.L., Narayanan V., Genetic aspects of neurocutaneous disorders, Semin. Pediatr. Neurol., 2006, 13, 43–47PubMedCrossRefGoogle Scholar
  13. [13]
    Gutmann D.H., Wood D.L., Collins F.S., Identification of the neurofibromatosis type 1 gene product, Proc. Natl. Acad. Sci. USA, 1991, 88, 9658–9662PubMedCrossRefGoogle Scholar
  14. [14]
    Daston M.M., Scrable H., Nordlund M., Sturbaum AK., Nissen L.M., Ratner N., The protein product of the neurofibromatosis type 1 gene is expressed at highest abundance in neurons, Schwann cells, and oligodendrocytes, Neuron., 1992, 8, 415–428PubMedCrossRefGoogle Scholar
  15. [15]
    Castle B., Baser M.E., Huson S.M., Cooper D.N., Upadhyaya M., Evaluation of genotype-phenotype correlations in neurofibromatosis type 1, J. Med. Genet., 2003, 40, 109CrossRefGoogle Scholar
  16. [16]
    Trovo-Marqui A.B., Tajara E.H., Neurofibromin: a general outlook. Clin. Genet., 2006, 70, 1–13PubMedCrossRefGoogle Scholar
  17. [17]
    Weiss B., Bollag G., Shannon K., Hyperactive Ras as a therapeutic target in neurofibromatosis type 1, Am. J. Med. Genet., 1999, 89, 14–22PubMedGoogle Scholar
  18. [18]
    Rasmussen S.A., Overman J., Thomson S.A., Colman S.D., Abernathy C.R., Trimpert R.E., et al., Chromosome 17 loss of heterozygosity studies in benign and malignant tumors in neurofibromatosis type 1, Genes Chromosomes Cancer, 2000, 28, 425–31PubMedCrossRefGoogle Scholar
  19. [19]
    Sawada S., Florell S., Purandare S.M., Ota M., Stephens K., Viskochil D., Identification of NF1 mutations in both alleles of a dermal Neurofibroma, Nat. Genet., 1996, 14, 110–112PubMedCrossRefGoogle Scholar
  20. [20]
    Korf B., Malignancy in neurofibromatosis type 1, Oncologist, 2000, 5, 477–485PubMedCrossRefGoogle Scholar
  21. [21]
    Zhu Y., Parada L.F., The molecular and genetic basis of neurological tumours, Nat. Rev. Cancer, 2002, 2, 616–626PubMedCrossRefGoogle Scholar
  22. [22]
    Castle B., Baser M.E., Huson S.M., Cooper D.N., Upadhyaya M., Evaluation of genotype-phenotype correlations in neurofibromatosis type 1, J. Med. Genet., 2003, 40, 109CrossRefGoogle Scholar
  23. [23]
    Levy P., Vidaud D., Leroy K., Laurendeau I., Wechsler J., Bolasco G., et al., Molecular profiling of malignant peripheral nerve sheath tumors associated with neurofibromatosis type 1, based on large-scale real-time RT-PCR, Mol. Cancer, 2004, 3, 20PubMedCrossRefGoogle Scholar
  24. [24]
    Shearer P., Parham D., Kovnar E., Kun L., Rao B., Lobe T., et al., Neurofibromatosis type I and malignancy: review of 32 pediatric cases treated at a single institution, Med. Pediatr. Oncol., 1994, 22, 78–83PubMedCrossRefGoogle Scholar
  25. [25]
    Glover T.W., Stein C.K., Legius E., Andersen L.B., Brereton A., Johnson S., Molecular and cytogenetic analysis of tumors in von Recklinghausen neurofibromatosis, Genes Chromosomes Cancer, 1991, 3, 62–70PubMedCrossRefGoogle Scholar
  26. [26]
    Li Y., O’Connel P., Breidenbach H.H., Cawthon R., Stevens J., Xu G., et al., Genomic organization of the neurofibromatosis 1 gene (NF1), Genomics, 1995, 25, 918CrossRefGoogle Scholar
  27. [27]
    Korf B., Malignancy in neurofibromatosis type 1, Oncologist, 2000, 5, 477–485PubMedCrossRefGoogle Scholar
  28. [28]
    Kimura M., Kamata Y., Matsumoto K., Takaya H., Electron microscopical study on the tumour of von Recklinghausen’s neurofibromatosis. Acta. Pathol. Jpn., 1974, 24, 79–91PubMedGoogle Scholar
  29. [29]
    Tonsgard J.H., Kwak S.M., Short M.P., Dachman A.H., CT imaging in adults with neurofibromatosis-1: frequent asymptomatic plexiform lesions, Neurology, 1998, 50, 1755–1760PubMedGoogle Scholar
  30. [30]
    Lott I.T., Richardson E.P., Neuropathologic findingsand the biology of neurofibromatosis, Adv. Neuron., 1981, 29, 23–32Google Scholar
  31. [31]
    Ferner R.E., Neurofibromatosis 1, Eur. J. Hum. Genet., 2007, 15, 131–8PubMedCrossRefGoogle Scholar
  32. [32]
    DeBella K., Szudek J., Friedman J.M., Use of the national institutes of health criteria for diagnosis of neurofibromatosis 1 in children, Pediatrics, 2000, 105, 608–614PubMedCrossRefGoogle Scholar
  33. [33]
    Evans D.G., Baser M.E., Mc Gaughran J., Sharif S., Howard E., Moran A., Malignant peripheral nerve sheath tumours in neurofibromatosis 1, J. Med. Genet., 2002, 39, 311–314PubMedCrossRefGoogle Scholar
  34. [34]
    Carli M., Ferrari A., Mattke A., Zanetti I., Casanova M., Bisogno G., et al., Pediatric malignant peripheral nerve sheath tumor: the Italian and German Soft Tissue Sarcoma Cooperative Group, J. Clin. Oncol., 2005, 23, 8422–8430PubMedCrossRefGoogle Scholar
  35. [35]
    Lakkis M.M., Tennekoon G.I., Neurofibromatosis type1. I. General overview, J. Neurosci. Res., 2000, 62, 755–763PubMedCrossRefGoogle Scholar
  36. [36]
    Guha A., Lau N., Huvar I., Gutmann D., Provias J., Pawson T., et al., RAS-GTP levels are elevated in human peripheral nerve tumours, Oncogene, 1996, 12, 507–513PubMedGoogle Scholar
  37. [37]
    Wu R., Lopez-Correa C., Rutkowski J.L., Baumbach L.L., Glover T.W., Legius E., Germline mutations in NF1 patients with malignancies, Genes Chromosomes Cancer, 1999, 26, 376–380PubMedCrossRefGoogle Scholar
  38. [38]
    Birindelli A., Perrone F., Oggionni M., Lavarino C., Pasini B., Vergani B., et al. Pathway alterations in sporadic and NF1-related malignant peripheral nerve sheath tumours, Lab. Invest., 2001, 81, 833–844PubMedGoogle Scholar
  39. [39]
    De Raedt T., Brems H., Wolkenstein P, Vidaud D., Pilotti S., Perrone F., et al., Elevated risk for MPNST in NF1 microdeletion patient, Am. J. Hum. Genet., 2003, 72, 1288–1292PubMedCrossRefGoogle Scholar
  40. [40]
    Perrone F., Tabano S., Colombo F., Dagrada G., Birindelli S., Gronchi A., et al., p15INK4b, p14ARF and p16INK4a inactivation in sporadic and neurofibromatosis type 1-related malignant peripheral nerve sheath tumours, Clin. Cancer Res., 2003, 9, 4132–4138PubMedGoogle Scholar
  41. [41]
    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, 125, 63–66PubMedCrossRefGoogle Scholar
  42. [42]
    Listernick R., Louis D.N., Packer R.J., Gutmann D.H, Optic pathway gliomas in children with neurofibromatosis 1: consensus statement from the NF1 Optic Pathway Glioma Task Force, Ann. Neurol., 1997, 41, 143–149PubMedCrossRefGoogle Scholar
  43. [43]
    Arun D., Gutmann D.H., Recent advances in neurofibromatosis type 1, Curr. Opin. Neuro., 2004, 7, 101–105CrossRefGoogle Scholar
  44. [44]
    Singhal S., Birch J.M., Kerr B., Lashford L., Evans D.G., Neurofibromatosis type 1 and sporadic optic gliomas. Arch. Dis. Child., 2002, 87. 65–70PubMedCrossRefGoogle Scholar
  45. [45]
    Thiagalingam S., Flaherty M., Billson F., North K., Neurofibromatosis type 1 and optic pathway gliomas: follow-up of 54 patients, Ophthalmology, 2004, 111, 568–577PubMedCrossRefGoogle Scholar
  46. [46]
    Dasgupta B., Yi Y., Chen D.Y., Weber J.D., Gutmann D.H., Proteomic analysis reveals hyper-activation of the mammalian target of rapamycin pathway in neurofibromatosis 1-associated human and mouse brain tumours, Cancer Res., 2005, 1, 2755–2760CrossRefGoogle Scholar
  47. [47]
    Zhu Y., Harada T., Liu L., Lush M.E., Guignard F., Harada C., et al., Inactivation of NF1 in CNS causes increased glial progenitor proliferation and optic glioma formation, Development, 2005, 132, 5577–5588PubMedCrossRefGoogle Scholar
  48. [48]
    Sung L., Anderson J.R., Arndt C., Raney R.B., Meyer W.H., Pappo A.S., Neurofibromatosis in children with rhabdomyosarcoma: a report from the Intergroup Rhabdomyosarcoma Study IV, J. Pediatr., 2004, 144, 666–668PubMedCrossRefGoogle Scholar
  49. [49]
    Reich S., Overberg-Schmidt S.O., Leenen A., Henze G., Neurofibromatosis 1 associated with embryonal rhabdomyosarcoma of the urinary bladder, Pediatric. Hematol. Oncol., 1999, 16, 263–266CrossRefGoogle Scholar
  50. [50]
    Lampe A.K., Seymour G., Thompson P.W., Toutain A., Lynch S.A., Familial neurofibromatosis microdeletion syndrome complicated by rhabdomyosarcoma. Arch. Dis. Child., 2002, 87, 444–445PubMedCrossRefGoogle Scholar
  51. [51]
    Jang K.A., Choi J.H., Sung K.J., Moon K.C., Koh J.K., Im D.J., Juvenile chronic myelogenous leukemia, neurofibromatosis 1, and xanthoma, J. Dermatol., 1999, 26, 33–35PubMedGoogle Scholar
  52. [52]
    Benessahraoui M., Aubin F., Paratte F., et al., Juvenile myelomonocytic leukaemia, xanthoma, and neurofibromatosis type 1, Arch. Pediatr., 2003, 10, 891–894.PubMedCrossRefGoogle Scholar

Copyright information

© © Versita Warsaw and Springer-Verlag Berlin Heidelberg 2009

Authors and Affiliations

  • Maria Scalzone
    • 1
  • Paola Coccia
    • 1
  • Antonio Ruggiero
    • 1
  • Ilaria Lazzareschi
    • 1
  • Stefano Mastrangelo
    • 1
  • Riccardo Riccardi
    • 1
  1. 1.Department of Pediatrics, Division of Pediatric OncologyCatholic University, “A. Gemelli” HospitalRomaItaly

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