Skip to main content
SpringerLink
Log in

Neurofibromatose Typ 2

Klinik und Genetik

Neurofibromatosis type 2

Clinical features and genetic profile

  • Übersichten
  • Published:
medizinische genetik

Zusammenfassung

Neurofibromatose Typ 2 (NF2) ist eine genetische Erkrankung, die autosomal-dominant vererbt wird und durch multiple Tumoren des Nervensystems gekennzeichnet ist. Bilaterale vestibuläre Schwannome, bekannt als Akustikusneurinome, sind das Hauptmerkmal der Erkrankung und treten bei etwa 90% der Betroffenen auf. Sie beeinträchtigen das Hörvermögen der Patienten und führen nicht selten zur Ertaubung. Ebenso häufig (>90%) treten bei NF2 spinale Tumoren (Schwannome, Meningiome und Ependymome) auf, die in etwa 1/3 der Fälle zu neurologischen Defiziten führen. Daneben finden sich zerebrale Schwannome und Meningiome als typische NF2-assoziierte Tumormanifestationen. Ferner kennzeichnen Polyneuropathie und okuläre Abnormalitäten das Krankheitsbild. Die genetische Ursache der NF2 ist eine heterozygote Inaktivierung des NF2-Tumorsuppressorgens, welches auf Chromosom 22q lokalisiert ist. Die Inzidenz der NF2 beträgt etwa 1:25.000 Geburten, wobei 50–80% der Patienten keine familiäre Belastung aufweisen. Bei Patienten mit Neumutationen (de novo) wurde eine Mosaikbildung mit überraschend hoher Frequenz (25–30%) nachgewiesen. Der vorliegende Beitrag beschreibt Klinik und Genetik der NF2 sowie aktuelle Entwicklungen in der medikamentösen Therapie.

Abstract

Neurofibromatosis type 2 (NF2) is a genetic autosomal-dominant disorder characterized by multiple benign tumors of the nervous system. Bilateral vestibular schwannomas, known as acoustic neuromas, are the hallmark of NF2 and can be found in more than 90% of patients, causing progressive hearing loss and not infrequently leading to deafness. Spinal tumors (schwannoma, meningioma and ependymoma) develop with similarly high frequency among NF2 patients, while approximately only 1/3 of these lead to neurological symptoms. Cranial non-vestibular schwannomas and meningiomas are also frequent in NF2 patients. The clinical spectrum of NF2 further includes ophthalmological lesions and polyneuropathy. With a birth incidence of around 1 in 25,000, the genetic cause for NF2 is the heterozygous inactivation of the NF2 tumor suppressor gene on 22q. More than half (50%–80%) of NF2 patients are found to bear de novo mutations which are frequently present in a mosaic fashion (25%–30%). This review presents clinical and genetic aspects of NF2, as well as recent developments in its pharmacological treatment.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Abb. 1
Abb. 2
Abb. 3
Abb. 4

Literatur

  1. Ahronowitz I, Xin W, Kiely R et al (2007) Mutational spectrum of the NF2 gene: a meta-analysis of 12 years of research and diagnostic laboratory findings. Hum Mutat 28:1–12

    Article  CAS  PubMed  Google Scholar 

  2. Asthagiri AR, Parry DM, Butman JA et al (2009) Neurofibromatosis type 2. Lancet 373:1974–1986

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  4. Baser ME, Kuramoto L, Woods R et al (2005) The location of constitutional neurofibromatosis 2 (NF2) splice site mutations is associated with the severity of NF2. J Med Genet 42(7):540–546

    Article  CAS  PubMed  Google Scholar 

  5. Bianchi AB, Hara T, Ramesh V et al (1994) Mutations in transcript isoforms of the neurofibromatosis 2 gene in multiple human tumour types. Nat Genet 6:185–192

    Article  CAS  PubMed  Google Scholar 

  6. Bosch MM, Boltshauser E, Harpes P, Landau K (2006) Ophthalmologic findings and long-term course in patients with neurofibromatosis type 2. Am J Ophthalmol 141(6):1068–1077

    Article  PubMed  Google Scholar 

  7. Curto M, McClatchey AI (2008) Nf2/Merlin: a coordinator of receptor signalling and intercellular contact. Br J Cancer 98(2):256–262

    Article  CAS  PubMed  Google Scholar 

  8. Evans DGR (2009) Neurofibromatosis type 2 (NF2): A clinical and molecular review. Orphanet J Rare Dis 19(4):16

    Article  Google Scholar 

  9. Evans DGR, Huson S, Donnai D et al (1992) A clinical study of type 2 neurofibromatosis. Q J Med 84:603–618

    CAS  PubMed  Google Scholar 

  10. Evans DGR, Ramsden R, Huson SM et al (1993) Type 2 neurofibromatosis: the need for supraregional care? J Laryngol Otol 107:401–406

    CAS  PubMed  Google Scholar 

  11. Evans DG, Trueman L, Wallace A et al (1998) Genotype/phenotype correlations in type 2 neurofibromatosis (NF2): evidence for more severe disease associated with truncating mutations. J Med Genet 35:450–455

    Article  CAS  PubMed  Google Scholar 

  12. Evans DG, Wallace AJ, Wu CL et al (1998) Somatic mosaicism: a common cause of classic disease in tumor-prone syndromes? Lessons from type 2 neurofibromatosis. Am J Hum Genet 63:727–736

    CAS  PubMed  Google Scholar 

  13. Evans DGR, Birch JM, Ramsdem RT (1999) Paediatric presentation of type 2 neurofibromatosis. Arch Dis Child 81:496–499

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  15. Evans DG, Birch JM, Ramsden RT et al (2006) Malignant transformation and new primary tumours after therapeutic radiation for benign disease: substantial risks in certain tumour prone syndromes. J Med Genet 43(4):289–294

    Article  CAS  PubMed  Google Scholar 

  16. Fisher LM, Doherty JK, Lev MH, Slattery WH (2009) Concordance of bilateral vestibular schwannoma growth and hearing changes in neurofibromatosis 2: neurofibromatosis 2 natural history consortium. Otol Neurotol 30:835–841

    Article  PubMed  Google Scholar 

  17. Hagel C, Lindenau M, Lamszus K et al (2002) Polyneuropathy in neurofibromatosis 2: clinical findings, molecular genetics and neuropathological alterations in sural nerve biopsy specimens. Acta Neuropathol 104(2):179–187

    Article  CAS  PubMed  Google Scholar 

  18. Hanemann CO (2008) Magic but treatable? Tumours due to loss of merlin. Brain 131:606–615

    Article  CAS  PubMed  Google Scholar 

  19. Kluwe L (2003) Method for the determination of data for the preparation of the diagnosis of phacomatosis. US patent 6,660,477

  20. Kluwe L, Mautner VF (1998) Mosaicism in sporadic neurofibromatosis 2 patients. Hum Mol Genet 7:2051–2055

    Article  CAS  PubMed  Google Scholar 

  21. Kluwe L, Bayer S, Baser ME et al (1996) Identification of NF2 germ-line mutations and comparison with neurofibromatosis 2 phenotypes. Hum Genet 98:534–538

    Article  CAS  PubMed  Google Scholar 

  22. Kluwe L, MacCollin M, Tatagiba M et al (1998) Phenotypic variability associated with 14 splice-site mutations in the NF2 gene. Am J Med Genet 77(3):228–233

    Article  CAS  PubMed  Google Scholar 

  23. Kluwe L, Friedrich RE, Tatagiba M, Mautner VF (2002) Presymptomatic diagnosis for children of sporadic neurofibromatosis 2 patients: a method based on tumor analysis. Genet Med 4(1):27–30

    Article  PubMed  Google Scholar 

  24. Kluwe L, Mautner V, Heinrich B et al (2003) Molecular study of frequency of mosaicism in neurofibromatosis 2 patients with bilateral vestibular schwannomas. J Med Genet 40(2):109–114

    Article  CAS  PubMed  Google Scholar 

  25. Kluwe L, Nygren AO, Errami A et al (2005) Screening for large mutations of the NF2 gene. Genes Chromosomes Cancer 42(4):384–391

    Article  CAS  PubMed  Google Scholar 

  26. MacCollin M, Mautner VF (1998) The diagnosis and management of neurofibromatosis 2 in childhood. Semin Pediatr Neurol 5(4):243–252

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  28. Mathieu D, Kondziolka D, Flickinger JC et al (2007) Stereotactic radiosurgery for vestibular schwannomas in patients with neurofibromatosis type 2: an analysis of tumor control, complications, and hearing preservation rates. Neurosurgery 60:468–470

    Google Scholar 

  29. Mautner VF, Tatagiba M, Guthoff R et al (1993) Neurofibromatosis 2 in the pediatric age group. Neurosurgery 33(1):92–96

    Article  CAS  PubMed  Google Scholar 

  30. Mautner VF, Tatagiba M, Lindenau M et al (1995) Spinal tumors in patients with neurofibromatosis type 2: MR imaging study of frequency, multiplicity, and variety. AJR Am J Roentgenol 165(4):951–955

    CAS  PubMed  Google Scholar 

  31. Mautner VF, Lindenau M, Baser ME et al (1996) The neuroimaging and clinical spectrum of neurofibromatosis 2. Neurosurgery 38(5):880–886

    Article  CAS  PubMed  Google Scholar 

  32. Mautner VF, Lindenau M, Baser ME et al (1997) Skin abnormalities in neurofibromatosis 2. Arch Dermatol 133(12):1539–1543

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  34. Mautner VF, Nguyen R, Kutta H et al (2009) Bevacizumab induces regression of vestibular schwannomas leading to improved hearing in patients with neurofibromatosis type 2. J Neurooncol in press

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

    Article  CAS  PubMed  Google Scholar 

  36. Parry DM, Eldridge R, Kaiser-Kupfer MI et al (1994) Neurofibromatosis 2 (NF2): clinical characteristics of 63 affected individuals and clinical evidence for heterogeneity. Am J Med Genet 52:450–461

    Article  CAS  PubMed  Google Scholar 

  37. Parry DM, MacCollin MM, Kaiser-Kupfer MI et al (1996) Germ-line mutations in the neurofibromatosis 2 gene: correlations with disease severity and retinal abnormalities. Am J Hum Genet 59:529–539

    CAS  PubMed  Google Scholar 

  38. Plotkin SR, Singh MA, O’Donnell CC et al (2008) Audiologic and radiographic response of NF2-related vestibular schwannoma to erlotinib therapy. Nat Clin Pract Oncol 5:487–491

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  41. Rowe J, Radatz M, Kemeny A (2008) Radiosurgery for type II neurofibromatosis. Prog Neurol Surg 21:176–182

    Article  PubMed  Google Scholar 

  42. Ruttledge MH, Andermann AA, Phelan CM et al (1996) Type of mutation in the neurofibromatosis type 2 gene (NF2) frequently determines severity of disease. Am J Hum Genet 59(2):331–342

    CAS  PubMed  Google Scholar 

  43. Samii M, Gerganov V, Samii A (2008) Microsurgery management of vestibular schwannomas in neurofibromatosis type 2: indications and results. Prog Neurol Surg 21:169–175

    Article  CAS  PubMed  Google Scholar 

  44. Sperfeld AD, Hein C, Schroder JM et al (2002) Occurrence and characterization of peripheral nerve involvement in neurofibromatosis type 2. Brain 125(Pt 5):996–1004

    Article  CAS  PubMed  Google Scholar 

  45. Trofatter JA, MacCollin MM, Rutter J et al (1993) A novel moesin-, ezrin-, radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor. Cell 72(5):791–800, erratum 75(4):826

    Google Scholar 

  46. Tsilchorozidou T, Menko FH, Lalloo F et al (2004) Constitutional rearrangements of chromosome 22 as a cause of neurofibromatosis 2. J Med Genet 41(7):529–534

    Article  CAS  PubMed  Google Scholar 

  47. Wellenreuther R, Kraus JA, Lenartz D et al (1995) Analysis of the neurofibromatosis 2 gene reveals molecular variants of meningioma. Am J Pathol 146:827–832

    CAS  PubMed  Google Scholar 

  48. Wentworth S, Pinn M, Bourland JD et al (2009) Clinical experience with radiation therapy in the management of neurofibromatosis-associated central nervous system tumors. Int J Radiat Oncol Biol Phys 73:208–213

    PubMed  Google Scholar 

Download references

Interessenkonflikt

Der korrespondierende Autor gibt an, dass kein Interessenkonflikt besteht.

Author information

Authors and Affiliations

  1. Sektion Phakomatosen, Klinik der Mund-, Kiefer- und Gesichtschirurgie, Universitätsklinikum Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Deutschland

    L. Kluwe & V.-F. Mautner

Authors
  1. L. Kluwe
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. V.-F. Mautner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to L. Kluwe.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kluwe, L., Mautner, VF. Neurofibromatose Typ 2. medgen 21, 532–538 (2009). https://doi.org/10.1007/s11825-009-0204-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11825-009-0204-5

Schlüsselwörter

Keywords

Search

Navigation