Neurofibromatosis

Definition

Neurofibromatosis (NF) is a genetic disease in which multiple soft tumors (neurofibromas) develop under the skin and throughout the nervous system. Various sized tumors may grow on the nerves in or leading away from the brain and spinal cord (peripheral nerves) and in the vascular system (veins and arteries) and other organ systems. There are two types of NF: NF-1, also called vonRecklinghausen NF, and NF-2, also called acoustic NF (sometimes bilateral acoustic NF or BAN). NF-1 is more common, representing 90 percent of all cases, while NF-2 is diagnosed in 10 percent of NF cases.

Description

Neural crest cells are primitive cells that are present as part of the nervous system during fetal development. These cells eventually turn into the following:

• cells that form nerves throughout the brain, spinal cord, and body
• cells that serve as coverings around the nerves throughout the body
• pigment cells that provide color to body structures
• meninges, the thin, membranous coverings of the brain and spinal cord
• cells that ultimately develop into the bony structures of the head and neck

In both types of NF, a genetic defect causes these neural crest cells to develop abnormally, resulting in numerous tumors and malformations of the nerves, bones, and skin.

NF-1 affects nerves throughout the body, occurring as groups of soft, fibrous swellings that grow on nerves in the skin, brain, and spinal cord (central nervous system), muscles, and bone. Severe disfigurement can result from the development of these tumors as the disease progresses and bone deformities may occur as well.

NF-2 is a rare type of NF in which multiple tumors grow on the cranial (head) and spinal nerves and other growths can occur in the brain and spinal cord. Tumor growth (schwannoma) on the nerves to the ears (auditory nerves) is most characteristic of NF-2. Disfigurement does not occur although hearing and visual problems are typical.

Demographics

NF-1 is a common genetic disorder that occurs in about one of every 4,000 births worldwide. NF-2 is rare, occurring in one of every 40,000 births. Children with a family history of neurofibromatosis are at highest risk for having either form of the condition.

Causes and symptoms

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 in a dominant fashion, which means that anyone 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 permanent change in the structure of a specific gene). Once such a spontaneous mutation has been established in an individual, however, it can then be passed on to any offspring. The chance of a person with NF passing on the NF gene to a child is 50 percent.

NF-1 has a number of possible signs and can be diagnosed if any two of the following are present:

• The presence of coffee-colored spots. These are patches of tan or light brown skin, usually about 5 to 15 mm in diameter. Nearly all patients with NF-1 will display these spots.
• Multiple freckles in the armpit or groin area.
• Ninety percent of patients with NF-1 have tiny tumors called Lisch nodules in the iris (colored area) of the eye.
• Soft tumors (neurofibromas) 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.
• Skeletal deformities, such as a twisted spine ( scoliosis ), curved spine (humpback), or bowed legs.
• Tumors along the optic nerve, causing vision disturbances in about 20 percent of those affected.
• The presence of NF-1 in a child's parent or sibling.

Very high rates of speech impairment, learning disabilities, and attention deficit disorder occur in children with NF-1. Other complications include the development of a seizure disorder or the abnormal accumulation of fluid within the brain ( hydrocephalus ). A number of cancers are more common in individuals who have NF-1. These include various 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 that appear in NF-1. The characteristic symptoms of NF-2 are due to tumors along the acoustic nerve that result in nerve dysfunction and the loss of hearing. The tumor may also 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 (cataracts) frequently develop at an unusually early age. As in NF-1, the chance of brain tumors developing is unusually high.

When to call the doctor

A history of either form of NF in the child's parent or sibling is reason to consult a physician. The presence of any of the symptoms associated with NF-1 or NF-2 should be investigated by a physician as well, particularly spots on the skin or small movable lumps under the skin and visual disturbances, memory loss, or difficulty maintaining balance. Hearing loss may be the first sign of NF-2 but can also be due to other unrelated conditions.

Diagnosis

Diagnosis is based on characteristic symptoms and physical examination. Diagnosis of NF-1 requires that at least two of the characteristic signs are present. Diagnosis of NF-2 requires the presence of either a nodule or mass (tumor) on the acoustic nerve or another distinctive nervous system tumor, which may only be identifiable through imaging studies. An important diagnostic clue for either NF-1 or NF-2 is the known presence of the disorder in a child's parent or sibling. Gene studies may be done to detect abnormalities on chromosomes 17 and 22.

Diagnosis of NF-1 will be confirmed by manipulation of the skin to reveal moveable, small, solid lumps (nodules) and the presence of coffee-colored spots on the skin of the trunk and pelvis. The spots may appear in childhood and typically become more noticeable in young adults. Two or more nodules and six or more discolored spots are usually definitive for a diagnosis of NF-1. Curvature of the spin (scoliosis) may be present, elevated blood pressure, and abnormalities in height, weight, and head size may also be noticed on physical examination.

Diagnosis of NF-2 also relies on manipulation of the skin to indicate the presence of nodules and evaluation of hearing and vision to determine any impairment.

X rays, CT scans, and MRI scans are performed to track the development/progression of tumors in the brain and along the nerves. Auditory evoked potential testing (the electric response evoked in the cerebral cortex by stimulation of the acoustic nerve) may be helpful to determine involvement of the acoustic nerve, and EEG ( electroencephalogram , a record of electrical currents in the brain) may be needed for children who have possible seizures. As the disease progresses, hearing and vision are carefully monitored and imaging studies of the bones are frequently done to watch for the development of deformities.

Treatment

There is no standard treatment for 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 chemotherapeutic drugs or x-ray treatments (radiation therapy). Twisting or curving of the spine and bowed legs may be corrected to some degree by surgical treatment or the wearing of a special brace. Social adjustment problems are common among young children with physical deformities caused by the condition.

Prognosis

NF of either type is progressive, and the clinical outcome is not predictable. Prognosis varies depending on the types of tumors that develop. 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 other kinds of movement. When cancers develop as a result of NF, prognosis worsens according to the specific type of cancer . Successful surgical removal of neurofibromas has a survival rate of 50 to 90 percent.

Prevention

There is no known way to prevent NF cases that occur as a result of spontaneous change in the genes (mutation). New cases of inherited NF can be prevented with careful genetic counseling. Parents with NF can be encouraged to understand that each of his or her offspring has a 50 percent chance of also having NF. When a parent has NF, and the specific genetic defect causing the parent's disease has been identified, tests can be performed on the fetus (developing baby) during pregnancy. Procedures such as amniocentesis or chorionic villus sampling allow small amounts of the baby's cells to be removed for examination. 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 problem. Other families may choose not to continue the pregnancy.

Parental concerns

Parents may worried about the development of deformities associated with NF-1. Social workers and psychologists can be consulted about possible counseling for children with the disease, helping them to cope with changes in their bodies that may be hard to accept. Hearing loss and visual disturbances associated with NF-2 are usually not reversible and specialists can be consulted about possible therapies to improve functioning in existing sight or hearing senses. Surgery to remove tumors may require the provision of educational information for both parents and children so that the procedure and possible complications are understood ahead of time.

Resources

ORGANIZATIONS

March of Dimes Birth Defects Foundation. Resource Center, 1275 Mamaroneck Ave., White Plains, NY 10605. Web site: http://www.modimes.org.

National Neurofibromatosis Foundation Inc. 95 Pine St., 16th Floor, New York, NY 10005. Web site: http://nf.org.

WEB SITES

"Neurofibromatosis." MedlinePlus. Available online at http://www.nlm.nih.gov/medlineplus/neurofibromatosis.html (accessed October 12, 2004).

"Neurofibromatosis." fc Inc. Available online at http://www.rfinc.org/ (accessed October 12, 2004).

L. Lee Culvert Rosalyn Carson-DeWitt, MD