Neurofibromatosis type 2 (NF2)

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Written1997-09Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
Updated1998-03Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
Updated2001-02James F Gusella
Molecular Neurogenetics Unit, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA

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1. Identity

Other namesCentral neurofibromatosis
Bilateral acoustic neurofibromatosis
Bilateral acoustic neurinoma
Bilateral acoustic schwannomas
Atlas_Id 10007
Genes implicated inNF2 
Inheritance autosomal dominant with almost complete penetrance; frequency is 3/105 newborns; neomutation represent 50% of cases; variable expressivity from mild disease through life (Gardner type) to severe condition at young age (Wishart type: with more than 3 tumours)

2. Clinics

Note NF2 is an hamartoneoplastic syndrome; hamartomas are localized tissue proliferations with faulty differenciation and mixture of component tissues; they are heritable malformations that have a potential towards neoplasia
Phenotype and clinics
  • bilateral vestibular (8th cranial pair) schwannomas; other central or peripheral nerve schwannomas; meningiomas; ependymomas.
  • hearing loss (average age 20 yrs), tinnitus, imbalance, headache, cataract in 50%, facial paralysis.
  • café-au-lait spots and cutaneous and peripheral neurofibromas may be present, but far less extensively than in neurofibromatosis type 1
  • Neoplastic risk NF2 cases represent about 5 % of schwannomas and meningiomas (i.e. risk increased by 2000), appearing at the age of 20, while they are found in the general population at the age of 50 and over
    Prognosis these tumours are usually benign, but their location within the central nervous system gives them a grave prognosis; patients with the Wishart severe form usually do not survive past 50 yrs

    3. Cytogenetics

    Inborn conditions normal
    Cytogenetics of cancer chromosome 22 loss is very frequent both in sporadic and in NF2 schwannomas and meningiomas

    4. Genes involved and Proteins

    Gene NameNF2 (neurofibromatosis type 2)
    Location 22q12.2
    Description 17 exons (1-15, 17 constitutive, 16 alternatively spliced)
    Description Isoform 1 595 amino acids, isoform 2 590 amino acids (due to inclusion of exon 16 in transcript); contains a FERM domain and a large a helix domain
    Expression wide
    Function membrane-cytoskeleton anchor; tumour suppressor
    Homology band 4.1 family , ezrin, radixin, moesin
    Germinal germ-line mutations in NF2 patients lead to protein truncation; splice-site or missense mutations are also found; phenotype-genotype correlations are observed (i.e. that severe phenotype are found in cases with protein truncations rather than those with amino acid substitution)
    Somatic mutation and allele loss events in tumours in neurofibromatosis type 2 and in sporadic schwannomas and meningiomas are in accordance with the two-hit model for neoplasia

    5. Bibliography

    Impaired interaction of naturally occurring mutant NF2 protein with actin-based cytoskeleton and membrane.
    Deguen B, Mérel P, Goutebroze L, Giovannini M, Reggio H, Arpin M, Thomas G
    Human molecular genetics. 1998 ; 7 (2) : 217-226.
    PMID 9425229
    Diagnostic issues in a family with late onset type 2 neurofibromatosis.
    Evans DG, Bourn D, Wallace A, Ramsden RT, Mitchell JD, Strachan T
    Journal of medical genetics. 1995 ; 32 (6) : 470-474.
    PMID 7666400
    Conditional biallelic Nf2 mutation in the mouse promotes manifestations of human neurofibromatosis type 2.
    Giovannini M, Robanus-Maandag E, van der Valk M, Niwa-Kawakita M, Abramowski V, Goutebroze L, Woodruff JM, Berns A, Thomas G
    Genes & development. 2000 ; 14 (13) : 1617-1630.
    PMID 10887156
    Merlin: the neurofibromatosis 2 tumor suppressor.
    Gusella JF, Ramesh V, MacCollin M, Jacoby LB
    Biochimica et biophysica acta. 1999 ; 1423 (2) : M29-M36.
    PMID 10214350
    The parental origin of new mutations in neurofibromatosis 2.
    Kluwe L, Mautner V, Parry DM, Jacoby LB, Baser M, Gusella J, Davis K, Stavrou D, MacCollin M
    Neurogenetics. 2000 ; 3 (1) : 17-24.
    PMID 11085592
    Advances in neurofibromatosis 2 (NF2): a workshop report.
    Lim DJ, Rubenstein AE, Evans DG, Jacks T, Seizinger BG, Baser ME, Beebe D, Brackmann DE, Chiocca EA, Fehon RG, Giovannini M, Glazer R, Gusella JF, Gutmann DH, Korf B, Lieberman F, Martuza R, McClatchey AI, Parry DM, Pulst SM, Ramesh V, Ramsey WJ, Ratner N, Rutkowski JL, Ruttledge M, Weinstein DE
    Journal of neurogenetics. 2000 ; 14 (2) : 63-106.
    PMID 10992163
    The Nf2 tumor suppressor gene product is essential for extraembryonic development immediately prior to gastrulation.
    McClatchey AI, Saotome I, Ramesh V, Gusella JF, Jacks T
    Genes & development. 1997 ; 11 (10) : 1253-1265.
    PMID 9171370
    Neurofibromatosis 2 (NF2): clinical characteristics of 63 affected individuals and clinical evidence for heterogeneity.
    Parry DM, Eldridge R, Kaiser-Kupfer MI, Bouzas EA, Pikus A, Patronas N
    American journal of medical genetics. 1994 ; 52 (4) : 450-461.
    PMID 7747758
    Germ-line mutations in the neurofibromatosis 2 gene: correlations with disease severity and retinal abnormalities.
    Parry DM, MacCollin MM, Kaiser-Kupfer MI, Pulaski K, Nicholson HS, Bolesta M, Eldridge R, Gusella JF
    American journal of human genetics. 1996 ; 59 (3) : 529-539.
    PMID 8751853
    Alteration in a new gene encoding a putative membrane-organizing protein causes neuro-fibromatosis type 2.
    Rouleau GA, Merel P, Lutchman M, Sanson M, Zucman J, Marineau C, Hoang-Xuan K, Demczuk S, Desmaze C, Plougastel B
    Nature. 1993 ; 363 (6429) : 515-521.
    PMID 8379998
    Type of mutation in the neurofibromatosis type 2 gene (NF2) frequently determines severity of disease.
    Ruttledge MH, Andermann AA, Phelan CM, Claudio JO, Han FY, Chretien N, Rangaratnam S, MacCollin M, Short P, Parry D, Michels V, Riccardi VM, Weksberg R, Kitamura K, Bradburn JM, Hall BD, Propping P, Rouleau GA
    American journal of human genetics. 1996 ; 59 (2) : 331-342.
    PMID 8755919
    A novel moesin-, ezrin-, radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor.
    Trofatter JA, MacCollin MM, Rutter JL, Murrell JR, Duyao MP, Parry DM, Eldridge R, Kley N, Menon AG, Pulaski K
    Cell. 1993 ; 72 (5) : 791-800.
    PMID 8453669

    6. Citation

    This paper should be referenced as such :
    Gusella, JF
    Neurofibromatosis type 2 (NF2)
    Atlas Genet Cytogenet Oncol Haematol. 2001;5(2):150-151.
    Free journal version : [ pdf ]   [ DOI ]
    On line version :
    History of this paper:
    Huret, JL. Neurofibromatosis type 2 (NF2). Atlas Genet Cytogenet Oncol Haematol. 1997;1(1):38-39.
    Huret, JL. Neurofibromatosis type 2 (NF2). Atlas Genet Cytogenet Oncol Haematol. 1998;2(3):109-110.

    7. External links

    OrphanetNeurofibromatosis type 2
    MeSHD009464  D016518  
    MedGenD009464  D016518  
    UMLSC0027832  C0027859  
    Other databaseNeurofibromatosis Type 2 - GeneClinics
    REVIEW articlesautomatic search in PubMed
    Last year articlesautomatic search in PubMed

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