Neurofibromatosis type 1 (NF1)

2006-02-01   Katharina Wimmer 

Medizinische Universitüt Wien, Institut für Humangenetik, Klinischen Instituts für Medizinische und Chemische Labordiagnostik (KIMCL), Wühringerstrasse 10, 1090 Wien, è_sterreich, Austria



Neurofibromatosis type 1 (NF1)


Von Recklinghausen neurofibromatosis , Peripheral neurofibromatosis


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






636 Neurofibromatosis type 1





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 (Crowes 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 condition

    no special feature

    Cancer cytog

    according to the cancer type in most cases
    JMML : monosomy 7

    Genes involved and Proteins


    the protein has been called neurofibromin; GTPase activating protein (GAP) ; tumour suppressor.


    mainly nucleotide substitutions (splicing defects, nonsense mutations, missense mutations) and frameshift alterations, microdeletions (5-10%), some intragenic copy number changes on one allele


    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

    To be noted




    http:\/\/ Neurofibromatosis


    http:\/\/\/profiles\/nf1 Neurofibromatosis Type 1 - GeneClinics


    Pubmed IDLast YearTitleAuthors
    126609522003Elevated risk for MPNST in NF1 microdeletion patients.De Raedt T et al
    92073391997The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2.Gutmann DH et al
    25113181989A genetic study of von Recklinghausen neurofibromatosis in south east Wales. I. Prevalence, fitness, mutation rate, and effect of parental transmission on severity.Huson SM et al
    24918961989Chromosome pattern in juvenile chronic myelogenous leukemia, myelodysplastic syndrome, and acute leukemia associated with neurofibromatosis.Kaneko Y et al
    75956471995Genetic and epigenetic mechanisms in the pathogenesis of neurofibromatosis type I.Metheny LJ et al