The Neurofibromatosis

NeurofibromatosisNeurofibromatoses (NF) are genetic disorders of the nervous system that result in the growth of noncancerous tumors along nerves. NF also can cause abnormalities of skin and bone.

There are two main forms of NF: NF1 (formerly called peripheral neurofibromatosis or von Recklinghausen’s disease) and NF2 (formerly called bilateral acoustic neurofibromatosis, central neurofibromatosis or vestibular schwannoma). In both forms of NF, severity of symptoms varies greatly.

In the past, it was believed that the deformities portrayed in a book, play and movie called “The Elephant Man” reflected an extreme case of NF1. Now, however, evidence indicates that the person portrayed had a different disorder called Proteus syndrome. Individuals with NF1 need not worry about becoming as disfigured as the Elephant Man.

How common is NF?
NF1 is one of the most common genetic disorders. About 1 baby in every 4,000 in the United States is born with NF1. NF2 is less common, occurring in about 1 in every 40,000 births. Both forms of NF are found in every racial and ethnic group throughout the world and affect both sexes equally.

What causes NF?
NF1 and NF2 are caused by two separate abnormal genes. The gene for NF1 is located on chromosome 17, and the gene for NF2 is on chromosome 22. The abnormal gene for either NF1 or NF2 can be inherited from one parent who has the disorder or can result from a new mutation (change) in the normal gene. This parent may be affected or have such a mild form that he/she may be unaware of having the disorder. Thus, NF1 or NF2 can occur in a person who has no family history of the condition. About half of NF1 and NF2 cases are caused by new mutations. The degree of disease is highly variable, even among affected members of a family. Thus, sometimes it is difficult to determine a family history. Having a family history of NF1 does not put a person at risk of having NF2, and vice versa.

Inheritance of the abnormal gene in each form of NF is “autosomal dominant,” so that any child of a parent with NF has a 50-50 chance of inheriting the NF gene and showing at least some signs of NF sooner or later.

What are the signs of NF1?
According to the National Institutes of Health, there are seven common signs of NF1. NF1 is diagnosed in individuals who have two or more of these signs:
Six or more tan spots on the skin, called “café-au-lait” (French for “coffee with milk”) spots, that are wider than 1/5 inch before puberty, or than 3/5 inch after puberty. These spots are usually present at birth or appear by 2 years of age. Café-au-lait spots may increase in size and number and darken with age.
Freckles that appear under the arms or in the groin, usually by 7 years of age.
Two or more benign (noncancerous) tumors (lumps), called neurofibromas, under the skin or deeper. (A person may have a single neurofibroma without having NF.) Neurofibromas grow on nerves and are made up of cells that surround nerves and of certain other cell types. These tumors usually develop at around 10 to 15 years of age, although they may develop at any age. An affected person may have any number of neurofibromas, from a few to hundreds. The tumors, which vary in size, may or may not be painful.
A tumor on the optic (eye) nerve, called an optic glioma, which can occasionally cause difficulties with sight. Most of these tumors, which are usually diagnosed by 10 years of age, cause no symptoms and require no treatment.
Two or more tiny tan or brown “Lisch nodules,” which are small clumps of pigment that appear in the iris (colored part of the eye). These usually appear at around 6 to 10 years of age and cause no vision problems.
A variety of bone defects, such as bowing of the legs below the knee, that usually are present at birth or develop during the first year of life.
A family history of NF1 in a parent, sibling or child.

How is NF1 diagnosed?
NF1 generally is diagnosed by physical examination by a doctor who is familiar with the disorder. The doctor may use a special lamp to examine the skin, so that very light colored café-au-lait spots can be seen. The doctor may recommend additional tests, including X-rays and other imaging tests (computerized tomography [CT scans] and magnetic resonance imaging [MRI]) and blood tests for defects in the NF1 gene to aid in diagnosis.

Some children under 8 years of age may have café-au-lait spots, but no other signs of NF1. These children should be monitored carefully to see if other signs of the disorder develop.

How does NF1 affect a person?
In most cases of NF1, symptoms are mild, and affected individuals live a normal life. Some characteristics of NF1 pose no risk to health, including café-au-lait spots, freckling and Lisch nodules. Some individuals have many skin neurofibromas on the face and body. While skin neurofibromas are mainly a cosmetic concern, they can sometimes cause psychological distress.

Neurofibromas also can grow inside the body and can affect many organ systems. These deep neurofibromas (plexiform neurofibromas) affect about 15 percent of individuals with NF1. They can result in serious symptoms, depending on the organ system involved. Neurofibromas may increase during puberty and pregnancy, apparently because of hormonal changes.

About half of children with NF1 have learning disabilities, speech problems and/or seizures, and may be hyperactive. Some affected children and adults have large heads, though this usually does not reflect a serious medical problem. Scoliosis (a progressive curvature of the spine) is common in NF1 and can begin at an early age. Individuals with NF1 may have short stature and high blood pressure. In about 1 percent of affected people, one or more fibromas become malignant and require treatment (surgery, chemotherapy and/or radiation). Eye tumors may cause bulging of the eye or visual difficulties. Individuals with NF1 appear to be at increased risk of leukemia and certain rare cancers, although these are uncommon.

How is NF1 treated?
There is no cure for NF1, but there are ways to treat some of its effects. Surgery can remove painful or disfiguring skin tumors. However, they often grow back. Optic gliomas (eye tumors) that affect vision can be treated with surgery and/or radiation. Scoliosis may be treated by surgery or a brace.

There are a number of multidisciplinary NF clinics throughout the United States that address specific medical concerns and routine NF-related health care issues.

What are the signs of NF2?
Almost all individuals with NF2 develop tumors that grow on the nerve from the ear to the brain, called the 8th cranial nerve (one of the 12 pairs of nerves that enter or emerge from the brain.) These tumors (called schwannomas because they come from Schwann cells, which support and protect nerve cells) often cause pressure on the acoustic (hearing) nerves, resulting in hearing loss. Many persons with NF2 also develop tumors on nerves elsewhere in the body, including the brain or spinal cord. They also may develop a special type of cataract (clouding of the eye’s lens) early in life. Persons with NF2 have few, if any, café-au-lait spots or neurofibromas, although they may have a small number of skin tumors (schwannomas).

How is NF2 diagnosed?
As with NF1, NF2 usually is diagnosed during an examination by a physician who is familiar with the disorder. The doctor may recommend a number of imaging tests, including MRI, to look at the brain and spinal cord. MRI can detect tiny tumors, allowing for early diagnosis. Genetic testing of blood can reveal damaging mutations in the NF2 gene. If NF2 is diagnosed, hearing tests (audiometry and brainstem auditory evoked response test) are recommended to determine how well the 8th cranial nerve is functioning.

How does NF2 affect a person?
Symptoms of NF2 usually appear in the teens or early twenties and include hearing loss, ringing in the ears, dizziness, facial numbness, balance problems and headaches.

Occasionally, spinal cord tumors may cause numbness or weakness of parts of the body, such as the legs. Some individuals also may have weakness in one arm or leg if tumors grow in nerves in the armpit or groin. Cataracts can result in vision loss.

How is NF2 treated?
Like NF1, there is no cure for NF2, but surgery and radiation treatment can help control symptoms. MRI scans can detect very small tumors, sometimes allowing for early treatment. However, surgery on the 8th cranial nerve can sometimes result in additional hearing loss, so individuals and families must carefully weigh the risks and benefits of surgery. Sometimes removing part of a tumor, followed by radiation treatment, or radiation treatment alone, can help relieve symptoms.

Is genetic testing available to help diagnose NF1 and NF2?
Yes. Genetic testing is available, and it can help confirm the diagnosis of NF1 and NF2. Genetic testing also can be conducted before birth and to help identify individuals with a family history of these disorders who do not yet show symptoms. However, there is not yet any way of predicting the degree of severity of either form of NF from genetic tests.

There are two main types of genetic testing. The first, called direct gene mutation analysis, seeks to identify a gene mutation that causes NF. This test is useful in about 70 percent of individuals suspected of having NF. If this test is not informative, the second test, called linkage analysis, may be recommended. Linkage analysis is useful only for families in which there are more than two affected members. Linkage analysis requires blood tests on multiple family members, and it tracks the chromosome segment that harbors the disease-causing gene through two or more generations. In general, linkage testing is more than 90 percent accurate in discerning if an individual has an NF gene mutation.

Individuals interested in genetic testing for NF1 and NF2 can contact the NF support organizations listed below for further information.

Genetic counseling may be helpful to people with NF who are considering have children. Genetic counselors can explain the risks to offspring and discuss prenatal testing. Genetic counselors can be found at many medical centers throughout the country.

Are there other forms of NF?
In rare instances, cases of NF occur that are not consistent with NF1 or NF2. Less is known about these rare conditions, including their genetic causes.

One recently identified, rare form of NF is called schwannomatosis. Affected individuals develop schwannomas, as do many people with NF2. However, the schwannomas do not develop on the 8th cranial nerves, so affected individuals do not develop hearing loss. The main symptom of schwannomatosis is pain, which can occur in any part of the body. Affected individuals also may have some other neurological problems, such as numbness, weakness or balance problems, but these usually are less severe than in NF1 or NF2. Schwannomas often can be surgically removed to relieve pain (although tumors sometimes grow back).