The Neurofibromatoses

What are the neurofibromatoses?
The neurofibromatoses are a group of three genetically distinct but related disorders of the nervous system that cause tumors to grow around the nerves. Tumors begin in the cells that make up the myelin sheath, a thin membrane that envelops and protects nerve fibers, and often spread into adjacent areas. The type of tumor that develops depends on its location in the body and the kind of cells involved. The most common tumors are neurofibromas, which develop in the tissue surrounding peripheral nerves. Most tumors are non-cancerous, although occasionally they become cancerous over time.

Why these tumors occur still isn’t completely known, but it appears to be mainly related to mutations in genes that play key roles in suppressing tumor growth in the nervous system. These mutations keep the genes – identified as NF1 and NF2 – from making specific proteins that control cell production. Without these proteins, cells multiply out of control and form tumors.

An estimated 100,000 Americans have a neurofibromatosis (the singular form of neurofibromatoses) disorder, which occurs in both sexes and in all races and ethnic groups. Scientists have classified the disorders as neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and a type that was once considered to be a variation of NF2 but is now called schwannomatosis.

What is NF1?
NF1 is the most common neurofibromatosis, occurring in 1 in 3,000 to 4,000 individuals in the United States. Although many affected people inherit the disorder, between 30 to 50 percent of new cases occur because of a spontaneous genetic mutation from unknown causes. Once this mutation has taken place, the mutant gene can be passed on to succeeding generations.

What are the signs and symptoms of NF1?
To diagnose NF1, a doctor looks for two or more of the following:

• six or more light brown spots on the skin (often called "cafe-au-lait" spots), measuring more than 5 millimeters in diameter in children, or more than 15 millimeters across in adolescents and adults;
• two or more neurofibromas, or one plexiform neurofibroma (a neurofibroma that involves many nerves);
• freckling in the area of the armpit or the groin;
• two or more growths on the iris of the eye (known as Lisch nodules or iris hamartomas);
• a tumor on the optic nerve (optic glioma);
• abnormal development of the spine (scoliosis), the temple (sphenoid) bone of the skull, or the tibia (one of the long bones of the shin);
• a first degree relative (parent, sibling, or child) with NF1.

What other symptoms or conditions are associated with NF1?
Many children with NF1 have larger than normal head circumference and are shorter than average. Hydrocephalus, the abnormal buildup of fluid in the brain, is a possible complication of the disorder. Headache and epilepsy are also more likely in individuals with NF1 than in the normal population. Cardiovascular complications are associated with NF1, including congenital heart defects, high blood pressure (hypertension), and constricted, blocked, or damaged blood vessels (vasculopathy). Children with NF1 may have poor linguistic and visual-spatial skills, and perform less well on academic achievement tests, including those that measure reading, spelling, and math skills. Learning disabilities, such as attention deficit hyperactivity disorder (ADHD), are common in children with NF1.

When do symptoms appear?
Symptoms, particularly the most common skin abnormalities -- café-au-lait spots, neurofibromas, Lisch nodules, and freckling in the armpit and groin -- are often evident at birth or shortly afterwards, and almost always by the time a child is 10 years old. Because many features of these disorders are age dependent, a definitive diagnosis may take several years.

What is the prognosis for someone with NF1?
NF1 is a progressive disorder, which means most symptoms will worsen over time, although a small number of people may have symptoms that stay the same and never get any worse. It isn’t possible to predict the course of any individual’s disorder. In general, most people with NF1 will develop mild to moderate symptoms, and if complications arise they will not be life-threatening. Most people with NF1 have a normal life expectancy.

How is NF1 treated?
Since doctors don’t know how to prevent or stop neurofibromas from growing, surgery is often recommended to remove them. Several surgical options exist, but there is no general agreement among doctors about when surgery should be performed or which surgical option is best. Individuals considering surgery should carefully weigh the risks and benefits of all their options to determine which surgical treatment is right for them. There are also surgical and chemical techniques that can reduce the size of eye tumors (optic gliomas) when vision is threatened. In addition, some bone malformations, such as scoliosis, can be surgically corrected. In the rare instances when tumors become malignant (3 to 5 percent of all cases), treatment may include surgery, radiation, or chemotherapy.

Treatments for other conditions associated with NF1 are aimed at controlling or relieving symptoms. Headache and epileptic seizures are treated with medications. Since there is a higher than average risk for learning disabilities, children with NF1 should undergo a detailed neurological exam before they enter school. Once these children enter school, if teachers or parents suspect there is evidence of a learning disability (or disabilities), they should request an evaluation that includes an IQ test and the standard range of tests to evaluate verbal and spatial skills. Children with learning disabilities are eligible for special education services under the provisions of the Individuals with Disabilities Education Act (IDEA).

What is NF2?
This rare disorder affects about 1 in 40,000 people. NF2 is characterized by slow-growing tumors on the eighth cranial nerve. This nerve has two branches: the acoustic branch helps people hear by transmitting sound sensations to the brain; the vestibular branch helps people maintain their balance. The tumors of NF2, called vestibular schwannomas because of their location and the types of cells that compose them (Schwann cells, which form the myelin sheath around nerves), press against and sometimes even damage the nerves they surround. In some cases they will also damage nearby vital structures such as other cranial nerves and the brainstem, leading to a potentially life-threatening situation.

Individuals with NF2 are at risk for developing other types of nervous system tumors such as spinal schwannomas, which grow within the spinal cord and between the vertebrae, and meningiomas, which are tumors that grow along the membranes covering the brain and spinal cord.

What are the signs and symptoms of NF2?
To diagnose NF2, a doctor looks for the following:

• bilateral vestibular schwannomas, or
• a family history of NF2 (parent, sibling, or child) plus a unilateral vestibular schwannoma before age 30

or any two of the following:

• glioma,
• meningioma,
• schwannoma,
• juvenile posterior subcapsular lenticular opacity (juvenile cortical cataract).

When do symptoms appear?
Signs of NF2 may be present in childhood but are so subtle that they can be overlooked, especially in children who don’t have a family history of the disorder. Typically, symptoms of NF2 are noticed between 18 and 22 years of age. The most frequent first symptom is hearing loss or ringing in the ears (tinnitus). Less often, the first visit to a doctor will be because of disturbances in balance, vision impairment (such as vision loss from cataracts), weakness in an arm or leg, seizures, or skin tumors.

What is the prognosis for someone with NF2?
Because NF2 is so rare, few studies have been done to look at the natural progression of the disorder. The course of NF2 varies greatly among individuals, although inherited NF2 appears to run a similar course among affected family members. Generally, vestibular schwannomas grow slowly, and balance and hearing deteriorate over a period of years. A recent study suggests that an earlier age of onset is associated with faster tumor growth and a greater mortality risk.

How is NF2 treated?
NF2 is best managed at a specialty clinic with an initial screening and annual follow-up evaluations. Improved diagnostic technologies, such as MRI (magnetic resonance imaging), can reveal tumors as small as a few millimeters in diameter, which allows for early treatment. Vestibular schwannomas grow slowly, but they can grow large enough to completely engulf the eighth cranial nerve. Early surgery, to completely remove the tumor while it’s still small, might be advisable to preserve hearing and balance. There are several surgical options, depending on tumor size and the extent of hearing loss. Some techniques preserve the auditory nerve and enable individuals to retain some hearing; other techniques may involve removing the nerve and replacing it with an electronic auditory implant in the brainstem to restore hearing.

Surgery is available to correct cataracts and retinal abnormalities. A strategy of watchful waiting might be more appropriate for slowly growing brain and spinal tumors, which have higher risks of surgical complications.

What is schwannomatosis?
Schwannomatosis is a newly recognized neurofibromatosis that is genetically and clinically distinct from NF1 and NF2. Like NF2 it occurs rarely. Inherited forms of the disorder account for only 15 percent of all cases. Researchers still don’t fully understand what causes the tumors and the intense pain that are characteristics of the disorder.

What are the signs and symptoms of schwannomatosis?
The distinguishing feature of schwannomatosis is the development of multiple schwannomas everywhere in the body except on the vestibular nerve. The dominant symptom is excruciatingly intense pain, which develops when a schwannoma enlarges, compresses nerves, or presses on adjacent tissue. Some people experience additional neurological symptoms, such as numbness, tingling, or weakness in the fingers and toes. Patients with schwannomatosis never have neurofibromas.

About one-third of those with schwannomatosis have tumors limited to a single part of the body, such as an arm, a leg, or a segment of the spine. Some people develop many schwannomas; others develop only a few.

What is the prognosis for someone with schwannomatosis?
Anyone with schwannomatosis experiences some degree of pain, but the intensity varies. A small number of people have such mild pain that they are never diagnosed with the disorder. Most people have significant pain, which can be managed with medications or surgery. In some extreme cases, pain will be so severe and disabling it will keep people from working or leaving the house.

How is schwannomatosis treated?
There is no currently accepted medical treatment or drug for schwannomatosis, but surgical management is often effective. When tumors are completely removed pain usually subsides, although it may recur if new tumors form. When surgery isn’t possible, ongoing monitoring and management of pain in a multidisciplinary pain clinic is advisable.

Are there prenatal tests for the neurofibromatoses?
Clinical genetic testing can confirm the presence of a mutation in the NF1 gene with an accuracy of 95 percent. Some families and doctors may choose to use a genetic test to confirm an uncertain diagnosis when there is no family history of the disorder and when waiting for additional symptoms to appear would put an unnecessary emotional burden on the family. Prenatal testing for the NF1 mutation is also possible using amniocentesis or chorionic villus sampling procedures. Genetic testing for the NF2 mutation is sometimes available but is accurate in only 65 percent of those tested. Genetic counselors can provide information about these procedures and help families cope with the results.

Where can I get more information?
For more information on neurological disorders or research programs funded by the National Institute of Neurological Disorders and Stroke, contact the Institute's Brain Resources and Information Network (BRAIN) at:

BRAIN
P.O. Box 5801
Bethesda, MD 20824
(800) 352-9424
http://www.ninds.nih.gov

Information also is available from the following organizations:

Source: National Institutes of Health; National Institute of Neurological Disorders and Stroke

This information is provided by the Cleveland Clinic and is not intended to replace the medical advice of your doctor or health care provider. Please consult your health care provider for advice about a specific medical condition. For additional written health information, please contact the Health Information Center at the Cleveland Clinic (216) 444-3771 or toll-free (800) 223-2273 extension 43771 or visit www.clevelandclinic.org/health/.

index#6060