Overview
Type 1 neurofibromatosis is an autosomal dominant genetic condition caused by a mutation in, or a deletion of, the NF1 gene. Only 1 deleted or mutated NF1 gene is required to affect individuals.
The NF1 gene product, the protein neurofibromin, serves as a tumor suppressor. However, the precise role of neurofibromin is not yet fully elucidated, although neurofibromin deficiency causes multiple clinical effects, suggesting that this gene product has diverse functions in a variety of tissues. The genetic change that causes type 1 neurofibromatosis is present at conception, but the clinical manifestations may appear over many years.
The NF1 gene is located within the long arm of chromosome 17. More than 250 mutations that lead to protein truncation have been identified in affected individuals. The spontaneous mutation rate is 100 times greater than for many genes, and it is thought to contribute to approximately 30-50% of neurofibromatosis cases. A more severe phenotype occurs in a subset of patients who have a complete gene deletion.
The high mutation rate for the NF1 gene may reflect the huge size of its locus (estimated to be 350,000 base pairs). Most genes contain several tens of thousands of base pairs, and the largest known, the gene for Duchenne muscular dystrophy, encompasses 2.5 million base pairs.
The type 1 neurofibromatosis phenotype is highly penetrant (ie, almost all individuals with an NF1 gene mutation have some clinical manifestation of neurofibromatosis), but it has widely variable expressivity (ie, varying degrees of severity of the clinical manifestations, even within families).
Mutations in another gene, SPRED1, have been identified in a subset of patients described as having "mild neurofibromatosis."[1] Individuals with SPRED1 mutations may be incorrectly diagnosed with type 1 neurofibromatosis based on the presence of multiple café au lait spots and axillary and/or inguinal freckles. However, these patients do not develop neurofibromas or Lisch nodules, which are seen in most adults with true type 1 neurofibromatosis.
Prenatal testing is now possible in some families, but its use is minimal, because, in most patients, mutations have not been easy to identify. The manifestations of type 1 neurofibromatosis vary from one person to another; however, each individual who carries the gene eventually exhibits some clinical features of the disease. Cloning of the gene has allowed the creation of animal models that ultimately may be used to develop improved therapy against the disease.
NF Genes
Type 1 neurofibromatosis is linked to a large gene on band 17q11.2.[2] The NF1 gene has at least 59 exons and encodes the 327-kd protein known as neurofibromin. This protein has a guanosine triphosphatase (GTPase) region that binds to Ras and positively modulates conversion of guanosine triphosphate (GTP) to guanosine diphosphate (GDP). Neurofibromin has been shown to be essential for the negative regulation of Ras; this finding suggests that neurofibromin acts as a tumor suppressor. Several studies have confirmed this suggestion. Truncations in neurofibromin led to the mutations responsible for type 1 neurofibromatosis in most cases.
The gene for type 2 neurofibromatosis is on band 22q11.[3] Less is known about the action of the protein encoded at this location; however, loss of heterozygosity at this region has been reported in cases of acoustic neuromas, neurofibromas, and meningiomas. Thus, the NF2 gene is speculated to also encode a tumor suppressor.
Genetic Testing
Sequencing of the neurofibromin gene has a high detection rate and is the preferred molecular diagnostic study for individuals suspected of having type 1 neurofibromatosis. Detection rates using current sequencing methodologies is greater than 95% in clinically affected individuals.
Molecular testing is sometimes also useful in confirming the diagnosis in patients with a single clinical finding (eg, multiple café-au-lait spots) in the absence of a family history.
In a family with multiple affected members and no recognizable mutation, linkage analysis can be used to track the NF1 gene through the generations to determine which chromosome 17 region the fetus received. However, with advances in molecular diagnosis, family studies are rarely necessary.
For a parent with type 1 neurofibromatosis who is the only affected family member, sequencing can often identify a specific gene mutation. Once a mutation is identified in an affected parent, prenatal diagnosis using amniocentesis or chorionic villus sampling may be feasible.
When a parent has an identified gene mutation, preimplantation genetic diagnosis may also be possible, if the couple is willing and able to undergo in vitro fertilization followed by the transfer of unaffected embryos.
Spurlock G, Bennett E, Chuzhanova N, et al. SPRED1 mutations (Legius syndrome): another clinically useful genotype for dissecting the neurofibromatosis type 1 phenotype. J Med Genet. Jul 2009;46(7):431-7. [Medline].
Barker D, Wright E, Nguyen K, et al. Gene for von Recklinghausen neurofibromatosis is in the pericentromeric region of chromosome 17. Science. May 29 1987;236(4805):1100-2. [Medline].
Rouleau GA, Wertelecki W, Haines JL, et al. Genetic linkage of bilateral acoustic neurofibromatosis to a DNA marker on chromosome 22. Nature. Sep 17-23 1987;329(6136):246-8. [Medline].
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