Neurofibromatosis Type 1 And Type 2: Causes, Symptoms, Treatment

Neurofibromatosis Type 1 And Type 2: Causes, Symptoms, Treatment


What are the neurofibromatoses?


The neurofibromatoses are genetic disorders of the nervous system that primarily affect the development and growth of neural (nerve) cell tissues. These disorders cause tumors to grow on nerves and produce other abnormalities such as skin changes and bone deformities. The neurofibromatoses occur in both sexes and in all races and ethnic groups. Scientists have classified the disorders as neurofibromatosis type 1 (NF1) and neurofibromatosis type 2 (NF2). Other or variant types of the neurofibromatoses may exist, but are not yet identified.

NF1, also called von Recklinghausen NF or peripheral NF, is characterized by multiple café au lait spots (patches of tan or light brown skin) and neurofibromas (soft, fleshy growths) on or under the skin. Enlargement and deformation of bones and curvature of the spine (scoliosis) may also occur. Occasionally, tumors may develop in the brain, on cranial nerves, or on the spinal cord. More than 50% of people with NF1 also have learning disabilities.

NF2, also called bilateral acoustic NF (BAN), is much less common than NF1 and is characterized by multiple tumors on the cranial and spinal nerves. Tumors that affect both of the auditory nerves and hearing loss beginning in the teens or early twenties are generally the first symptom of NF2.

What Causes Neurofibromatosis?


Neurofibromatosis is caused by genetic defects (mutations) that either are passed on by a parent or occur spontaneously at conception. Each form of neurofibromatosis is caused by mutations in different genes.

Neurofibromatosis 1 (NF1)


The NF1 gene is located on chromosome 17. Normally, this gene produces a protein called neurofibromin, which is abundant in nervous system tissue and helps regulate cell growth. A mutation of the NF1 gene causes a loss of neurofibromin, which allows cells to grow uncontrolled.

Neurofibromatosis 2 (NF2)


A similar problem occurs with NF2. The NF2 gene is located on chromosome 22, which produces a protein called merlin. A mutation of the NF2 gene causes loss of merlin, which also leads to uncontrolled cell growth.

Schwannomatosis


Schwannomatosis may be associated with a mutation of the SMARCB1 gene located on chromosome 22. Other gene mutations may be involved in schwannomatosis. The occurrence of schwannomatosis may be inherited or may be sporadic (spontaneous), but these are not known yet.

What is Neurofibromatosis Type 1?


NF1 is the more common type of the neurofibromatoses, occurring in about 1 in 4,000 individuals in the United States. Although many affected persons inherit the disorder, between 30 and 50 percent of new cases arise spontaneously through mutation (change) in an individual's genes. Once this change has taken place, the mutant gene can be passed on to succeeding generations.

Previously, NF1 was known as peripheral neurofibromatosis (or von Recklinghausen's neurofibromatosis) because some of the symptoms--skin spots and tumors--seemed to be limited to the outer nerves, or peripheral nervous system, of the affected person. This name is no longer technically accurate because central nervous system tumors are now known to occur in NF1.

What are the signs and symptoms of Neurofibromatosis Type 1?


In diagnosing NF1, a physician looks for two or more of the following:

  • five or more light brown skin spots (cafe-au-lait macules) measuring more than 5 millimeters in diameter in patients under the age of puberty or more than 15 millimeters across in adults and children over the age of puberty;
  • two or more neurofibromas (tumors that grow on a nerve or nerve tissue, under the skin) or one plexiform neurofibroma (involving many nerves);
  • freckling in the armpit or groin areas;
  • benign growths on the iris of the eye (known as Lisch nodules or iris hamartomas);
  • a tumor on the optic nerve (optic glioma);
  • severe scoliosis (curvature of the spine);
  • enlargement or deformation of certain bones other than the spine; and
  • a parent, sibling, or child with NF1.

When do symptoms appear?


Symptoms, particularly those on the skin, are often evident at birth or during infancy, and almost always by the time a child is about 10 years old. Neurofibromas become evident at around 10 to 15 years of age. In most cases, symptoms are mild and patients live normal and productive lives. In some cases, however, NF1 can be severely debilitating.

Symptoms and severity of the disorder may vary among members of affected families.

How is Neurofibromatosis Type 1 treated?


Treatments are presently aimed at controlling symptoms. Surgery can help some bone malformations. For scoliosis, bone surgery may be combined with back braces. Surgery can also remove painful or disfiguring tumors; however, there is a chance that the tumors may grow back and in greater numbers. In the rare instances when tumors become malignant (3 to 5 percent of all cases), treatment may include surgery, radiation, or chemotherapy.

What is Neurofibromatosis Type 2?


This less common of the neurofibromatoses affects about 1 in 40,000 persons. NF2 is characterized by bilateral (occurring on both sides of the body) tumors on the eighth cranial nerve. It was formerly called bilateral acoustic neurofibromatosis or central neurofibromatosis because the tumors, which cause progressive hearing loss, were thought to grow primarily on the auditory nerve, a branch of the eighth cranial nerve responsible for hearing. Scientists now know that the tumors typically occur on the vestibular nerve, another branch of the eighth cranial nerve near the auditory nerve. The tumors, called vestibular schwannomas for their location and for the type of cells in them, cause pressure damage to neighboring nerves. In some cases, the damage to nearby vital structures, such as other cranial nerves and the brainstem, can be life-threatening.

What are the signs and symptoms of Neurofibromatosis Type 2?


To determine if an individual has NF2, a physician looks for the following:

1. Bilateral eighth nerve tumors,

2. A parent, sibling, or child with NF2 and a unilateral eighth nerve tumor, or

3. A parent, sibling, or child with NF2 and any two of the following:

  • glioma,
  • meningioma,
  • neurofibroma,
  • schwannoma, or
  • cataract at an early age.

When do symptoms appear?


Affected individuals may notice hearing loss as early as the teen years. In addition to changes in hearing that may occur in one or both ears, other early symptoms may include tinnitus (ringing noise in the ear) and poor balance. Headache, facial pain, or facial numbness, caused by pressure from the tumors, may also occur.

How is Neurofibromatosis Type 2 treated?


Treatments for NF2 are aimed at controlling the symptoms. Improved diagnostic technologies, such as MRI (magnetic resonance imaging), can reveal tumors as small as a few millimeters in diameter, thus allowing early treatment. Surgery to remove tumors completely is one option, but may result in hearing loss. Other options include partial removal of tumors, radiation, and, if the tumors are not progressing rapidly, the conservative approach of watchful waiting.

Are there prenatal tests for the neurofibromatoses?


Genetic testing is available for families with documented cases of NF1 and NF2. Genetic analysis can be used to confirm clinical diagnosis if the disease is a result of familial inheritance. New (spontaneous) mutations cannot be confirmed genetically. Prenatal diagnosis of familial NF1 or NF2 is also possible utilizing amniocentesis or chorionic villus sampling procedures. Genetic counselors can provide information about these procedures and offer guidance in coping with the neurofibromatoses.

What do scientists know about the neurofibromatoses?


Formerly the neurofibromatoses were grouped as one disorder with at least two variations. Scientists now know that NF1 and NF2 are two distinct entities because the genes believed to be responsible for them are located on different chromosomes. The NF1 gene is on chromosome 17, while the gene for NF2 is on chromosome 22.

Humans have 23 pairs of chromosomes, receiving one set of 23 chromosomes from each parent. Chromosomes carry genes that determine an individual's characteristics, such as sex, stature, hair and eye color, and distinctive family traits. Genes produce proteins that control an individual's development and health. If an inherited gene is defective, or a gene becomes defective spontaneously before birth, a genetic disorder may result. The neurofibromatoses are inherited as dominant disorders, which means that if either parent has the defective gene, each child born to that parent has a 50 percent chance of inheriting the defective gene.

Caring for Your Child with Neurofibromatosis


The first noticeable sign of neurofibromatosis usually is the presence of multiple café-au-lait spots. If your child has several of these spots, ask your doctor to do a thorough examination; he or she may need to screen your child for other signs of NF.

If your child has already been diagnosed with NF and you notice that a growing tumor is beginning to cause a problem, tell your doctor immediately.

One of the most important things you can do is get early intervention if your child has learning disabilities. It also helps to seek out support groups that can provide your family with practical advice and encouragement.

Remember, most people (about 60%) diagnosed with NF1 have only relatively mild signs of the disorder, like café-au-lait spots and a few neurofibromas on the surface of the skin, which require little or no treatment.

Kids diagnosed with mild NF who remain fairly healthy into early adulthood are less likely to develop more serious complications later in life. Kids diagnosed with more serious forms often have correctable complications and with appropriate help and support can lead happy and productive lives.

What research is being done on the neurofibromatoses?


The National Institute of Neurological Disorders and Stroke (NINDS), a unit of the Federal Government's National Institutes of Health (NIH), has primary responsibility for conducting and supporting research on neurological disorders. The Institute sponsors basic studies aimed at understanding normal and abnormal development of the brain and nervous system, and clinical studies to improve diagnosis and treatment of neurological disorders. In conjunction with the NIH's National Cancer Institute, the NINDS encourages research specifically targeted on the neurofibromatoses.

Several years ago, research teams supported by the NINDS located the exact position of the NF1 gene on chromosome 17. The NF1 gene has been cloned and its structure analyzed. The product of the NF1 gene is a large and complex protein called neurofibromin. One portion of this protein is similar to a family of proteins called GAP (guanosine triphosphatase-activating protein). Scientists have demonstrated that GAP proteins play a significant role in tumor suppression in certain cancers. The proteins act as switches that regulate the complex chemical interactions and sequences of cell growth. The similarity of the NF1 protein to GAP proteins suggests that the NF1 protein may have a similar switching role in the development of neurofibromas. Scientists theorize that defects in the gene may lessen or inhibit the normal output of its protein and allow the irregular cell growth that may lead to tumor development.

In addition to the work on NF1, intensive efforts have led to the identification of the NF2 gene on chromosome 22. As in NF1, the NF2 gene product is a tumor suppressor protein (termed merlin or schwannomin). Basic studies in molecular genetics may lead one day to nonsurgical or pharmacologic treatments aimed at retarding or suppressing tumors associated with the neurofibromatoses.

The NINDS also encourages research aimed at developing improved methods of diagnosing the neurofibromatoses and at identifying factors that contribute to the wide variations of symptoms and severity of the disorders. Early diagnosis of the neurofibromatoses is essential so that affected individuals can obtain treatment, counseling, and referral to specialized facilities.

The Interinstitute Medical Genetics Research Program at the NIH Clinical Center conducts NF2 family history research, including a study involving individuals and families with NF2. With information from this study, investigators have confirmed the location of the NF2 gene on chromosome 22. Also, using specimens from some of the families, scientists have isolated and sequenced the NF2 gene, and have described two different patterns of clinical features in NF2 patients. Investigators are continuing to study these patterns to see if they correspond to specific types of gene mutations.