Type 1 neurofibromatosis

The etiology of NF1 is a mutation involving the NF1 gene leading to either its functional disruption or its loss. Pathogenic variants involving this locus are common in humans (1 in 10,000).[7]Gitler AD, Kong Y, Choi JK, et al. Tie2-Cre-induced inactivation of a conditional mutant Nf1 allele in mouse results in a myeloproliferative disorder that models juvenile myelomonocytic leukemia. Pediatr Res. 2004 Apr;55(4):581-4. https://www.nature.com/articles/pr200491 http://www.ncbi.nlm.nih.gov/pubmed/14739366?tool=bestpractice.com The NF1 gene is very large and is a major target for all types of genetic mutation, both in eggs and in sperm, to cause the inherited condition, and in somatic cells to cause tumor and other features. The inheritance of NF1 is autosomal dominant, but tumors are caused by loss of both functioning copies. Links between the clinical phenotype have been difficult to establish, but large deletions of the gene cause a severe phenotype, and changes affecting a single amino acid cause a milder phenotype.[4]Upadhyaya M, Huson SM, Davies M, et al. An absence of cutaneous neurofibromas associated with a 3-bp in-frame deletion in exon 17 of the Nf1 gene (c.2970-2972 delAAT): evidence of a clinically significant NF1 genotype-phenotype correlation. Am J Hum Genet. 2007 Jan;80(1):140-51. http://www.cell.com/ajhg/fulltext/S0002-9297(07)60928-8 http://www.ncbi.nlm.nih.gov/pubmed/17160901?tool=bestpractice.com Mutations in the early part of the gene have been linked to an increased risk of optic pathway glioma.[10]Sharif S, Upadhyaya M, Ferner R, et al. A molecular analysis of individuals with neurofibromatosis type 1 (NF1) and optic pathway gliomas (OPGs), and an assessment of genotype-phenotype correlations. J Med Genet. 2011 Apr;48(4):256-60. http://www.ncbi.nlm.nih.gov/pubmed/21278392?tool=bestpractice.com

The consequence of the mutations is reduction of the NF1 gene product neurofibromin, which results in the disruption of multiple Ras oncogene-mediated signaling pathways in Schwann cells, glia, melanocytes, mast cells, vascular cells (endothelial and smooth muscle), osteocytes, chromaffin cells, gastrointestinal stromal cells, and likely other cell types. These disruptions lead to tissue-specific dysplasias and neoplasias, the net effect of which is the clinical condition NF1. Many of the cell types involved (e.g., Schwann cells, melanocytes, chromaffin cells, cephalic osteocytes) are derived from the neural crest, hence the early reference to NF1 as a neurocristopathy. Loss of heterozygosity (i.e., somatic cell loss of the normal NF1 allele) occurs in some benign lesions, including some neurofibromas (or portions thereof), café au lait spots, and at least two associated malignancies: malignant peripheral nerve sheath tumor and juvenile chronic myelogenous leukemia.

Neurofibromatosis (NIH consensus development conference statement)[2]National Institutes of Health consensus development conference statement. Bethesda, MD, July 13-15, 1987. Neurofibromatosis. 1988;1(3):172-8. http://consensus.nih.gov/1987/1987Neurofibramatosis064html.htm http://www.ncbi.nlm.nih.gov/pubmed/3152465?tool=bestpractice.com [3]Mulvihill JJ, Parry DM, Sherman JL, et al. Neurofibromatosis 1 (Recklinghausen disease) and neurofibromatosis 2 (bilateral acoustic neurofibromatosis): an update. Ann Intern Med. 1990 Jul 1;113(1):39-52. http://www.ncbi.nlm.nih.gov/pubmed/2112353?tool=bestpractice.com

NF1 is distinguished from neurofibromatosis type 2 (NF2), the latter being characterized by bilateral vestibular schwannomas (acoustic neuromas), central nervous system meningiomas, subcapsular cataracts, pigmentary retinopathy, and cutaneous schwannomas. The gene loci for NF1 and NF2 are on the long arms of chromosome 17 and chromosome 22, respectively.