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Neurofibromatosis 1 (NF1) is one of the most common tumors involving
nerves and pigment cells in the body. Also called von Recklinghausen
or Peripheral neurofibromatos, the disease is characterized by multiple
cafe-au-lait spots (evenly pigmented macules from pigmentation defects
in skin melanocytes) and neurofibromas (peripheral nerve tumors) on
or under the skin. Although Neurofibromas typically affect the peripheral
nerves, these tumors may affect virtually any organ in the body. The
tumors are composed of a mixture of cell types: Schwann cells, axons,
fibroblasts, mast cells, endothelial cells, and perineurial cells. (Hall,
159)
NF1 - a genetic disorder - is also characterized by enlargement and deformation of bones, incorrect curvature of the spine (scoliosis), and development of tumors on the brain, cranial nerves, or spinal cord. Neurofibromatosis is caused by gene mutations of the NF1 gene, which
occur once in approximately every three thousand live births via autosomal
dominant inheritance, leaving 75,000 affected individuals in the US
alone. Many (30-40%) of the cases represent new mutations. The disease was first discovered in 1882 by a German pathologist, Friedrich
Daniel von Recklinghausen. Von Recklinghausen provided a clinical description
of individuals with the disorder, and implied its connection with the
nervous system. He associated the syndrome with plexiform neurofibromas
- which can cause disfigurement; optic gliomas - which may lead to blindness;
scoliosis, vertebral dysplasia, overgrowth, and pseudoarthrosis - bone
complications. (http://www.nf.org)
Modern genetic studies have determined that this genetic disorder is extremely common. The NF1 gene of neurofibromatosis has one of the highest mutation rates of any human gene - recorded at 1/10,000 alleles per generation, a rate many times higher than the usual rate of gene mutations. Single locus mutations on the long arm of chromosome 17 in band q11.2 produce the majority of cases. The normal NF1 gene codes for a protein called neurofibromin. The NF1 gene is ubiquitously expressed in the early embryonic development of mammals, but its expression becomes limited to neural tissues and in the adrenal medulla later on in development. Although the function of neurofibromin is unknown, a portion may act as GTPase activator involved in controlling cellular proliferation. The NF1 gene also seems to act as a tumor suppressor - somatic loss of the gene occurs during the development of some malignant neoplasms. It has also been noted that cells with a NF1 gene mutation display abnormal tyrosine and tryptophan metabolism. When neural crest cells display NF1 mutations, the neurofibromin protein is not produced, and the cells take on tumor cell properties. (Lakkis, 2) Although neural crest cells are principally involved in neurofibromatosis,
there is a secondary involvement of mesodermal derivatives and there
are associated cardiac malformations. Although this involvement is not
fully understood, it is possible that a mutation of the same gene plays
a role in the nonneural crest tissue. A more likely possibility for
this secondary involvement is due to a displaced migration that causes
neural crest cells to differentiate into a
non-neural crest derivative. (Rutkowski,
3) Joseph Merrick (1862-1890) is responsible for much of the publicity surrounding von Recklinghausen's neurofibromatosis. Merrick was the 'Elephant Man', and he displayed grossly abnormal skin and severe skeletal defects. In his severe case, skeletal defects were likely caused by bone-matrix stimulating factors produced by the neurofibromas. (http://www.nf.org) |
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