Neurofibromatosis (NF), or von Recklinghausen disease, is a disorder which causes development of multiple soft tumors (neurofibromas). These tumors occur under the skin and throughout the nervous system (cells which control body movement and sensation).
Description
Neural crest cells are primitive cells which exist during fetal development. These cells eventually turn into cells that form nerves throughout the brain, spinal cord, and body. Collectively, this system of nerve cells is called the nervous system, which coordinates movement and sensation. Some nerve cells carry impulses from the brain to muscles or other peripheral structures, hence the name peripheral nervous system. Another group of nerve cells called the central nervous system are capable of transmitting sensation back to the brain for interpretation (such as feeling cold or hot).
In neurofibromatosis, a genetic defect causes these neural crest cells to develop abnormally. This results in numerous tumors and malformations of the nerves, bones, and skin.
Genetic profile
Both forms of neurofibromatosis are caused by a defective gene. NF-1 is due to a defect on chromosome 17; NF-2 results from a defect on chromosome 22. Both of these disorders are inherited as a dominant trait. This means that anybody who receives just one defective gene will have the disease. However, a family pattern of NF is only evident for about half of all cases of NF. The other cases of NF occur due to a spontaneous mutation (a spontaneous and permanent change in the structure of a specific gene). Once a spontaneous mutation has been established in an individual it is then possible to be passed on to any offspring. The chance of a person with NF passing on the NF gene to their child is 50%. There are different pathologic alleles (variations of the mutant gene). The frequency of spontaneous (new) mutations is very high and causes for this are still unknown.
Demographics
Neurofibromatosis-I occurs in about one of every 4,000 births. Neurofibromatosis-I is one of the most common genetic disorders that is dominantly inherited. Two types of NF exist, NF-1 (90% of all cases), and NF-2 (10% of all cases).
Signs and symptoms
NF-1 has a number of possible signs and can be diagnosed if any two of the following are present:
The presence of café-au-lait (French for coffee-with-milk) spots. These are patches of tan or light brown skin, usually about five to 15 mm in diameter. Nearly all patients with NF-1 will display these spots.
Multiple freckles in the armpit or groin area.
Ninty percent of patients with NF-1 have tiny tumors called Lisch nodules in the iris (colored area) of the eye.
Neurofibromas. These soft tumors are the hallmark of NF-1. They occur under the skin, often located along nerves or within the gastrointestinal tract. Neurofibromas are small and rubbery, and the skin overlying them may be somewhat purple in color.
Tumors along the optic nerve (the nerve cells which transmit a visual stimulus to the back part of the brain called the occipital lobe, for intrepretation), which cause vision disturbance occurs in about 20% of patients.
The presence of NF-1 in a patient's parent, child, or sibling.
Hypertension, or elevated blood pressure.
There are very high rates of speech impairment, learning disabilities, and attention deficit disorder in children with NF-1. Other complications include the development of a seizure disorder (an abnormal firing of nerve cells in muscles, causing severe contractions, sometimes involving the whole body), or abnormal accumulation of fluid within the brain (a condition called hydrocephalus). A number of cancers are more common in patients with NF-1. These include a variety of types of malignant brain tumors, as well as leukemia, and cancerous tumors of certain muscles (rhabdomyosarcoma), the adrenal glands (pheochromocytoma), or the kidneys (Wilms' tumor).
Patients with NF-2 do not necessarily have the same characteristic skin symptoms (café-au-lait spots, freckling, and neurofibromas of the skin) that appear in NF-1. The characteristic symptoms of NF-2 are due to tumors along the acoustic nerve. Interfering with the function of this nerve results in the loss of hearing; and the tumor may spread to neighboring nervous system structures, causing weakness of the muscles of the face, headache, dizziness, poor balance, and uncoordinated walking. Cloudy areas on the lens of the eye (called cataracts) frequently develop at an unusually early age. As in NF-1, the chance of brain tumors developing is unusually high.
Diagnosis
Diagnosis is based on the broad spectrum of clinical signs previously described, which usually can be detected by careful physical examination, ophthalmologic evaluation (visualizing the structures in the eye) and audiogram (test to measure hearing ability). Diagnosis of NF-1 requires that at least two of the listed signs are present. Diagnosis of NF-2 requires the presence of either a mass on the acoustic nerve or another distinctive nervous system tumor. An important diagnostic clue for either NF-1 or NF-2 is the presence of the disorder in a patient's parent, child, or sibling. A test to detect a protein (the end-products of a gene) relevant to NF-1 mutagenesis has been created, but accuracy for this procedure has not been established.
Monitoring the progression of neurofibromatosis involves careful testing of vision and hearing. X ray studies of the bones are frequently indicated to detect for the development of deformities. CT scans and MRI scans are performed to track the development/progression of tumors in the brain and along the nerves. Auditory evoked potentials (the electric response evoked in the cerebral cortex by stimulation of the acoustic nerve) may be helpful to determine acoustic nerve involvement, and EEG (electroencephalogram, a record of electrical impulses in the brain) may be required for patients with suspected seizures. Regular blood pressure monitoring is also advised.
Treatment
There are no available treatments for the disorders which underlie either type of neurofibromatosis. To some extent, the symptoms of NF-1 and NF-2 can be treated individually. Skin tumors can be surgically removed. Some brain tumors, and tumors along the nerves, can be surgically removed, or treated with drugs (chemotherapy) or x-ray treatments (radiation therapy). Twisting or curving of the spine and bowed legs may require surgical treatment, or the wearing of a special brace.
Prognosis
Prognosis varies depending on the tumor type which develops. As tumors grow, they begin to destroy surrounding nerves and structures. Ultimately, this destruction can result in blindness, deafness, increasingly poor balance, and increasing difficulty with the coordination necessary for walking. Deformities of the bones and spine can also interfere with walking and movement. When cancers develop, prognosis worsens according to the specific type of cancer.
Prevention
There is no known way to prevent the approximately 50% of all NF cases that occur due to a spontaneous change in the genes (mutation). New cases of inherited NF can be prevented with careful genetic counseling. A person with NF can be made to understand that each of his or her offspring has a 50% chance of also having NF when a parent has NF. Special tests can be performed on the fetus (developing baby) during pregnancy to determine if the fetus will be born with this disorder. Amniocentesis (where a needle is passed through the mother's abdomen into the amniotic sac which contains the amniotic fluid and cushions the developing fetus) or chorionic villus sampling (a procedure involving extraction of a tissue sample from the placenta, the structure which connects the fetal blood with the mother, necessary for nutrient and waste exchange) are two techniques which allow small amounts of fetal DNA (deoxyribonucleic acid, the chemical which contains specific codes which determine genetic makeup of an individual) removed for analysis. The tissue can then be examined for the presence of the parent's genetic defect. Some families choose to use this information in order to prepare for the arrival of a child with a serious medical condition. Other families may choose not to continue the pregnancy.
BOOKS
Haslam, Robert H. A. "Neurocutaneous Syndromes." In Nelson Textbook of Pediatrics, edited by Richard Behrman. Philadelphia: W. B. Saunders Co., 1996.
PERIODICALS
"Health Supervision for Children with Neurofibromatosis." Pediatrics 96, 2 (August 1995): 368+.
Heim R. A., et al. "Distribution of 13 truncating mutations in the neurofibromatosis 1 gene." Human Molecular Genetics 4 (1995): 975-81.
Levy, Charles E. "Physiatry and Care of Patients with Neurofibromatosis." The Journal of the American Medical Association 278, 18 (November 12, 1997): 1493+.
Waller, Amy L., and James E. Baumgartner. "Current Concepts in the Management of Neurofibromatosis Type 1." Physician Assistant 21, 8 (August 1997): 103+.
ORGANIZATIONS
March of Dimes Birth Defects Foundation. National Office, 1275 Mamaroneck Ave., White Plains, NY 10605. (888) 663-4637. resourcecenter@modimes.org. <http://222.modimes.org>.
The National Neurofibromatosis Foundation, Inc. 95 Pine St., 16th Floor, New York, NY 10005. (800)323-7938. <http://nf.org>.
