Neurofibromatosis Type 1
What is neurofibromatosis type 1 (NF1)?
NF1 is a disorder characterized by the growth of noncancerous tumors called neurofibromas. Neurofibromas usually form on or just underneath the skin, as well as in the brain and peripheral nervous system. But they can also develop in other parts of the body, such as the eye.
The disorder is caused by a mutation in a gene on chromosome 17. The gene codes for a protein called neurofibromin. This protein regulates the activity of another protein, called ras, which promotes cell division. When the NF1 gene is mutated, it usually leads to a shortened version of the neurofibromin protein that cannot bind to ras or regulate its activity. As a result, the ras protein is more active. Cells are told to begin dividing and never told when to stop, causing them to form tumors.
How do people get NF1?
About half of the time, a person inherits the mutated gene from a parent. The disorder is inherited in an autosomal dominant pattern, which means that a child needs to inherit just one copy of the defective gene to get the disorder. Each child of a parent with NF1 has a 1 in 2 chance of getting the disorder.
In the other half of NF1 cases, there is no family history of the disease. The mutation is new and has likely occurred either in the child's parents during egg or sperm production, or early in embryonic development). Embryonic mutations will not be present in every cell of the body, just in some of them. But if it does happen to be in the germ cells (egg or sperm), the person can pass the defective copy to their children. New mutations in NF1 are relatively frequent because the gene is very large, making it more likely to accrue mutations.
What are the symptoms of NF1?
The severity and physical signs of NF1 can vary widely from patient to patient. Most people with this disorder have very distinctive café au lait spots (the color of coffee with milk), as well as freckles. The number of café au lait spots and freckles increases with age. People with NF1 also have many noncancerous tumors called neurofibromas throughout their body. Rarely, these tumors can progress into malignant cancers.
Others may also have high blood pressure, bone defects, scoliosis (curvature of the spine), learning disabilities, Lisch nodules (benign growths on the iris of the eye), and optic gliomas (benign tumors on the optic nerve that connects the eye to the brain).
Scientists don't know exactly why symptoms vary so much, even among people from the same family. But they predict that genetics has a lot to do with it. It is likely that each patient's unique genetic makeup influences the severity of his or her symptoms. That is, one or more additional genes other than NF1 might also play a role. Scientists call these "modifier genes," and they could be any of the thousands of genes in the human genome.
How do modifier genes work? Proteins encoded by modifier genes might work in the same biological pathways as neurofibromin, and therefore affect how well these pathways work. Variations in the DNA sequence of a modifier gene may alter its protein's function enough to influence the severity of NF1.
To date, scientists have not found any strong candidate NF1 modifier genes.
Other factors that may contribute to the variability observed among NF1 patients are environmental events and different mutations found in the NF1 gene itself. (Over 500 different mutations have been found, and all of them cause this disorder!)
How do doctors diagnose NF1?
Most of the time, the NF1 is fairly easy to diagnose by its physical symptoms (tumors or café au lait spots) or by a family history of the disorder. The café au lait spots usually appear within the first two years of a child's life.
NF1 can be diagnosed by sequencing a person's NF1 gene to identify mutations. But because of the gene's large size and the high number of possible mutations, genetic testing is usually impracticaland very expensive.
While doctors don't usually recommend genetic testing for NF1, the one exception is for people who have a family history of NF1. If another family member has been tested, and the mutation has been identified, then it becomes relatively easy to look for that same mutation in other family members. Finding the mutation would then confirm the diagnosis of NF1.
How is NF1 treated?
There is no cure or treatment for NF1, but surgery can remove tumors and correct malformed bones. In a very small percentage of cases, the tumors become cancerous. As in other cancers, these tumors are surgically removed and treated with chemotherapy or radiation (to kill cancer cells).
Interesting facts about NF1
People who have NF1 may have very few neurofibromas or they may have thousands of them.
Neurofibromatosis was first described in medical literature by Dr. Friedrich von Recklinghausen. NF was called Von Recklinghausen's disease for many years.