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Neurofibromatosis type 1 (NF1)

Written2006-02Katharina Wimmer
Medizinische Universitüt Wien, Institut für Humangenetik, Klinischen Instituts für Medizinische und Chemische Labordiagnostik (KIMCL), Wühringerstrasse 10, 1090 Wien, è_sterreich, Austria
This article is an update of :
1997-09Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France

(Note : for Links provided by Atlas : click)


Other namesVon Recklinghausen neurofibromatosis
Peripheral neurofibromatosis
Atlas_Id 10006
Genes implicated inNF1  
Inheritance autosomal dominant with almost complete penetrance; frequency is 30/105 newborns (and 1 of 200 mentally handicapped persons): one of the most frequent genetically inheritable disease; neomutation in 50%, mostly from the paternal allele; highly variable expressivity, from very mild to very severe; expressivity is also age-related


Note NF1 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; the embryonic origin of dysgenetic tissues involved in NF1 is ectoblastic.
Phenotype and clinics Diagnosis is made on the ground of at least 2 of the following:
  • café-au-lait spots (6 or more over 0. 5 cm of diameter (in pre-puberty))
  • 2 or more neurofibromas or 1 plexiform neurofibromas (mainly cutaneous)
  • 2 or more Lisch nodules (melanocytic hamartomas of the iris)
  • freckling in the axillary/inguinal region (Crowe's sign)
  • glioma of the optic nerve
  • distintive bone anomalies (scoliosis, pseudoarthroses, bony defects (orbital wall) ...)
  • positive family history

    Other features:

  • macrocephaly
  • epilepsy
  • mental retardation in 10 %; learning diabilities in half patients
  • sexual precocity and other endocrine anomalies
  • hypertension (renal artery stenosis)
  • Neoplastic risk
  • 5% of NF1 patients experience a malignant neoplasm
  • neurofibromas, especially the plexiform variety; polyclonal (benign) proliferation; may be present at birth or appear later, may be a few or thousands, small or enormous, occur in the skin and in various tissus and organs; neurofibromas localized to the spine are extremely difficult to manage.
  • neurofibrosarcomatous transformation (malignant) of these in 5-10 %
  • optic nerve gliomas
  • childhood MDS (myelodysplasia) and ANLL, often with monosomy 7 (monosomy 7 syndrome, 'juvenile myelomonocytic leukaemia'): risk, increased by X 200 to 500, is still low, as JMML is rare ; M>F; most often before the age of 5 yrs; no increased risk of leukaemia in the adult.
  • pheochromocytomas
  • various other neoplasias, of which are rhabdomyosarcomas
  • Treatment early diagnosis, lifetime monitoring and surgery are essential


    Inborn conditions no special feature
    Cytogenetics of cancer according to the cancer type in most cases
    JMML : monosomy 7

    Genes involved and Proteins

    Gene NameNF1 (neurofibromin 1)
    Location 17q11.2
    Description the protein has been called neurofibromin; GTPase activating protein (GAP) ; tumour suppressor.
    Germinal mainly nucleotide substitutions (splicing defects, nonsense mutations, missense mutations) and frameshift alterations, microdeletions (5-10%), some intragenic copy number changes on one allele
    Somatic the second allele is often lost in the neoplatic cell owing to copy number loss and mitotic recombination events, but also minor lesion mutations are found


    Elevated risk for MPNST in NF1 microdeletion patients.
    De Raedt T, Brems H, Wolkenstein P, Vidaud D, Pilotti S, Perrone F, Mautner V, Frahm S, Sciot R, Legius E
    American journal of human genetics. 2003 ; 72 (5) : 1288-1292.
    PMID 12660952
    The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2.
    Gutmann DH, Aylsworth A, Carey JC, Korf B, Marks J, Pyeritz RE, Rubenstein A, Viskochil D
    JAMA : the journal of the American Medical Association. 1997 ; 278 (1) : 51-57.
    PMID 9207339
    A genetic study of von Recklinghausen neurofibromatosis in south east Wales. I. Prevalence, fitness, mutation rate, and effect of parental transmission on severity.
    Huson SM, Compston DA, Clark P, Harper PS
    Journal of medical genetics. 1989 ; 26 (11) : 704-711.
    PMID 2511318
    Chromosome pattern in juvenile chronic myelogenous leukemia, myelodysplastic syndrome, and acute leukemia associated with neurofibromatosis.
    Kaneko Y, Maseki N, Sakurai M, Shibuya A, Shinohara T, Fujimoto T, Kanno H, Nishikawa A
    Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1989 ; 3 (1) : 36-41.
    PMID 2491896
    Genetic and epigenetic mechanisms in the pathogenesis of neurofibromatosis type I.
    Metheny LJ, Cappione AJ, Skuse GR
    Journal of neuropathology and experimental neurology. 1995 ; 54 (6) : 753-760.
    PMID 7595647


    This paper should be referenced as such :
    Wimmer, K
    Neurofibromatosis type 1 (NF1)
    Atlas Genet Cytogenet Oncol Haematol. 2006;10(3):206-207.
    Free journal version : [ pdf ]   [ DOI ]
    On line version :
    History of this paper:
    Huret, JL. Neurofibromatosis type 1 (NF1). Atlas Genet Cytogenet Oncol Haematol. 1997;1(1):36-37.

    Other genes implicated (Data extracted from papers in the Atlas) [ 9 ]


    External links

    OrphanetNeurofibromatosis type 1
    Other databaseNeurofibromatosis type 1 (GARD)
    Other databaseNeurofibromatosis Type 1 - GeneClinics
    Genes implicated inNF1   [ Atlas ]   [ Entrez ]  [ LOVD ]  [ GeneReviews ]  

    REVIEW articlesautomatic search in PubMed
    Last year articlesautomatic search in PubMed

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