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Evaluation of genotype-phenotype correlations in neurofibromatosis type 1
  1. B Castle1,
  2. M E Baser2,
  3. S M Huson3,
  4. D N Cooper1,
  5. M Upadhyaya1
  1. 1Institute of Medical Genetics, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, UK
  2. 22257 Fox Hills Drive, Los Angeles, CA 90064, USA
  3. 3Department of Clinical Genetics, Oxford Radcliffe Hospitals NHS Trust, Oxford OX3 7LJ, UK
  1. Correspondence to:
 Dr M Upadhyaya
 Institute of Medical Genetics, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, UK; upadhyayacardiff.ac.uk

https://doi.org/10.1136/jmg.40.10.e109

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    Neurofibromatosis type 1 (NF1) is an autosomal dominant disease with complete penetrance and extremely variable expression, and an incidence of approximately 1 in 4000 live births. Despite the high incidence of NF1, neither the natural history nor the genetic epidemiology of the disorder are well understood. People with NF1 have reduced reproductive fitness and life expectancy,1 but the cause of the high mutation rate at the NF1 locus is unknown.

    The most prominent clinical hallmarks of NF1 are café-au-lait (CAL) macules, neurofibromas, Lisch nodules of the iris, and axillary freckling.2 Other clinical manifestations are abnormalities of the cardiovascular, gastrointestinal, renal, and endocrine systems, facial and body disfigurement, cognitive deficit, and malignancies of the peripheral nerve sheath and central nervous system. About 25% of people with NF1 develop one or more of these clinical complications, which together cause significant morbidity and mortality.3 The tumours that occur in NF1 are dermal and plexiform neurofibromas, optic gliomas, malignant peripheral nerve sheath tumours (MPNSTs), pheochromocytomas, and rhabdomyosarcomas.1 Children with NF1 have an increased risk of developing myeloid disease, particularly juvenile chronic myeloid leukaemia. Some 30–40% of NF1 patients develop plexiform neurofibromas2–4 that become MPNSTs in 5–10% of cases,5–7 often in pre-existing plexiform neurofibromas.

    The NF1 gene on chromosome 17q11.2 spans more than 350 kb of genomic DNA and contains 60 exons.8 The 8457 bp open reading frame predicts a protein of 2818 amino acids with an estimated mass of 327 kDa.9,10 The NF1 gene product, neurofibromin, contains a 360 amino acid region with homology to the catalytic domain of the mammalian guanosine triphosphatase activating protein. Neurofibromin is a GTPase activating protein for members of the p21ras (Ras) protein family. Loss of neurofibromin function leads to downstream cell growth activation because neurofibromin negatively regulates …

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