von Recklinghausen's neurofibromatosis

Definition

Von Recklinghausen's neurofibromatosis is also called von Recklinghausen disease or simply neurofibromatosis (NF). It is an automsomal dominant hereditary disorder. NF is the most common neurological disorder caused by a single gene. Patients develop multiple soft tumors (neurofibromas) and very often skin spots (freckling AND café au lait). The tumors occur under the skin and throughout the nervous system.

Description

There are three types of neurofibromatosis. The two main types of neurofibromatosis are Neurofibromatosis 1 (NF1) and Neurofibromatosis 2 (NF2). NF1 is more common than NF2. NF1 affects approximately 1 in 2, 000 to 1 in 5, 000 births worldwide. NF2 affects 1 in 35, 000 to 1 in 40, 000 births worldwide. Recently, schwannomatosis has been recognized as a rare form of NF. Since NF is the most common neurological disorder, NF is more prevalent than the number of people affected by cystic fibrosis, hereditary muscular dystrophy, Huntington's disease, and Tay Sachs combined. In addition to skin and nervous system tumors and skin freckling, NF can lead to disfigurement, blindness, deafness, skeletal abnormalities, loss of limbs, malignancies, and learning disabilities. The degree a person is affected with a form of neurofibromatosis may vary greatly between patients.

Causes and symptoms

A defective gene causes NF1 and NF2. NF1 is due to a defect on chromosome 17. NF2 results from a defect on chromosome 22. Both neurofibromatosis disorders are inherited in an autosomal dominant fashion. In an autosomal dominant disease, one copy of a defective gene will cause the disease. However, family pattern of NF is only evident for about 50% to 70% of all NF cases. The remaining cases of NF are due to a spontaneous mutation (a change in a person's gene rather than a mutation inherited from a parent). As with an inherited mutated gene, a person with a spontaneously mutated gene has a 50% chance of passing the spontaneously mutated gene to any offspring.

NF1 has a number of possible symptoms:

• Five or more light brown skin spots (café au lait spots, a French term meaning "coffee with milk"). The skin spots measure more than 0.2 inches (5 millimeters) in diameter in patients under the age of puberty or more than 0.6 inches (15 millimeters) in diameter across in adults and children over the age of puberty. Nearly all NF1 patients display café au lait spots.
• Multiple freckles in the armpit or groin area.
• Ninety percent of patients with NF1 have tiny tumors in the iris (colored area of the eye) called Lisch nodules (iris nevi).
• Two or more Neurofibromas. Neurofibromas are soft tumors and are the hallmark of NF1. Neurofibromas 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, which cause vision disturbance in about 20% of patients.
• The presence of NF1 in a patient's parent, child, or sibling.

There are very high rates of speech impairment, learning disabilities, and attention deficit disorder in children with NF1. 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 patients with NF1. 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 ). Symptoms are often visible at birth or during infancy, and almost always by the time a child is about 10 years old.

In contrast to patients with NF1, patients with NF2 have few, if any, café au lait spots or tumors under the skin. Patients with NF2 most commonly have tumors (schwannomas) on the eighth cranial nerve (one of 12 pairs of nerves that enter or emerge from the brain), and occasionally on other nerves. The location of the schwann cell derived tumors determines the effect on the body. The characteristic symptoms of NF2 include dysfunction in hearing, ringing in the ears (tinnitus), and body balance. The common characteristic symptoms of NF2 are due to tumors along the acoustic and vestibular branches of the eighth cranial nerve. Tumors that occur on neighboring nervous system structures may cause weakness of the muscles of the face, headache, dizziness, numbness, and weakness in an arm or leg. Cloudy areas on the lens of the eye (called cataracts) frequently develop at an early age. As in NF1, the chance of brain tumors developing is unusually high. Symptoms of NF2 may not begin until after puberty.

Multiple schwannomas on cranial, spinal, and peripheral nerves characterize schwannomatosis. People with schwannomatosis usually have greater problems with pain than with neurological disability. The first symptom of schwannomatosis is usually pain in any part of the body without any source. It can be several years before a tumor is found. About 1/3 of patients with schwannomatosis have tumors in a single part of the body, such as an arm, leg or segment of spine. People with schwannomatosis do not develop vestibular tumors, any other kinds of tumors (such as meningiomas, ependymomas, or astrocytomas), do not go deaf, and do not have learning disabilities.

Diagnosis

Diagnosis of a form of neurofibromatosis is based on the symptoms outlined above. Although a visual inspection may be sufficient for inspection of tumors for a clinical diagnosis of neurofibromatosis, magnetic resonance imaging (MRI) may be useful for early diagnosis of tumors. Diagnosis of NF1 requires that at least two of the above listed symptoms are present. A slit lamp is used to visualize the presence of any Lisch nodules in a person's eye. A person with a parent, sibling, or child with NF1 is another tool used to diagnose a person with NF1.

NF2 can be diagnosed three different ways and with symptoms different from NF1 symptoms:

• The presence of bilateral cranial eighth nerve tumors.
• A person who has a parent, sibling, or child with NF2 and a unilateral eighth nerve tumor (vestibular schwannoma or acoustic neuroma).
• A person who has a parent, sibling, or child with NF2 and any two of the following: glioma, meningioma , neurofibroma, schwannoma, or an early age cataract.

The presence of multiple schwannomas may be a symptom of NF2 or schwannomatosis. An older person with multiple schwannomas and no hearing loss probably does not have NF2. A high-quality MRI scan should be used to detect any possible vestibular tumors to differentiate between NF2 and schwannomatosis in a younger person with multiple schwannomas or any person with hearing loss and multiple schwannomas.

In prepubertal children a yearly assessment including blood pressure measurement, eye examination, development screening, and neurologic examination is recommended.

Monitoring the progression of neurofibromatosis involves careful testing of vision and hearing (audiometry). X-ray studies of the bones are frequently done to watch 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 involvement of the acoustic nerve, and EEG (electroencephalogram, a record of electrical currents in the brain) may be needed for patients with suspected seizures.

Treatment

There are no cures for any form of neurofibromatosis. To some extent, the symptoms of NF1 and NF2 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 , including gamma knife 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 types of tumors which an individual 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.

Clinical Trials

As of 2001, there were two clinical trials taking place involving people affected with NF (<http://clinicaltrials.gov>). Patients can contact the House Ear Institute for more information about the clinical trial, "Natural History of Vestibular Schwannomas in Neurofibromatosis 2." By the end of 2001, The House Ear Institute expected to expand the clinical trial to include people with whole body NF2. More information about the clinical trial "Diagnosis of Pheochromocytoma" can be obtained from the National Institute of Child Health and Human Development (NICHHD).

The use of an auditory brainstem implant (ABI) as part of hearing rehabilitation in patients with NF2 has been tested in Europe and the United States.

Prevention

There is no known way to prevent the cases of NF that are due to a spontaneous change in the genes (mutation). Since genetic tests for NF1 and NF2 are available, 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, and the specific genetic defect causing the parent's disease has been identified, prenatal tests can be performed on the fetus during pregnancy. Amniocentesis and chorionic villus sampling are two techniques that 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. Genetic testing may also be useful for evaluating individuals with a family history of neurofibromatosis, who do not yet show symptoms.

Resources

BOOKS

Jones, Kenneth Lyons. "Neurofibromatosis Syndrome." InSmith's Recognizable Patterns of Human Malformation.Philadelphia: W.B. Saunders Co., 1997, pp. 508-9.

PERIODICALS

Bance, M., and R.T. Ramsden. "Management of Neurofibromatosis Type 2." Ear Nose & Throat Journal 78, no. 2 (1999): 91-4.

Evans, D.G. "Neurofibromatosis Type 2: Genetic and Clinical Features." Ear Nose & Throat Journal 78, no. 2 (1999):97-100.

Gillespie, J.E. "Imaging in Neurofibromatosis Type 2: Screening Using Magnetic Resonance Imaging." Ear Nose & Throat Journal 78, no. 2 (1999): 102-9.

Huson, S.M. "What Level of Care for the Neurofibromatoses?"Lancet 353, no. 9159 (1999): 1114-6.

Laszig, R., et al. "Central Electrical Stimulation of the Auditory Pathway in Neurofibromatosis Type 2." Ear Nose & Throat Journal 78, no. 2 (1999): 110-7.

MacCollin, M., and V.F. Mautner. "The Diagnosis and Management of Neurofibromatosis 2 in Childhood." Seminars in Pediatric Neurology 5, no. 4 (1998): 243-52.

North, K.N. "Neurofibromatosis 1 in Childhood." Seminars in Pediatric Neurology 5, no. 4 (1998): 231-42.

Rasmussen, S.A., and J.M. Friedman. "NF1 Gene and Neurofibromatosis." American Journal of Epidemiology 151, no.1 (2000): 33-40.

ORGANIZATIONS

Acoustic Neuroma Association. 600 Peachtree Parkway, Suite108, Cumming, GA, 30041-6899. (770) 205-8211. <http://www.anausa.org>.

March of Dimes Birth Defects Foundation. National Office, 1275 Mamaroneck Ave., White Plains, NY 10605. <http://www.modimes.org>.

Massachusetts General Hospital Neurofibromatosis Clinic. Harvard Medical School, Massachusetts General Hospital, Boston, MA 02114. (617) 724-7856. <http://neurosurgery.mgh.harvard.edu/NFclinic.htm>.

National Cancer Institute. Information Office, Building 31, Room 10A03, 9000 Rockville Pike, Bethesda, MD, 20892-2580. (800) 4-CANCER. <http://cancernet.nci.nih.gov>.

National Institute of Child Health and Human Development. Building 31, Room 2A32, MSC 2425, 31 Center Dr., Bethesda, MD, 20892. (800) 370-2943. <http://www.nichd.nih.gov>.

National Institute of Neurological Disorders and Stroke. Officeof Communications and Public Liaison, PO Box 5801, Bethesda, MD, 20824. (800) 352-9424. <http://www.ninds.nih.gov>. National Organization focused on neurological biomedical research.

The National Neurofibromatosis Foundation, Inc.(NNF). 95Pine St., 16th Floor, New York, NY 10005. (800) 323-7938. <http://www.nf.org>.

Neurofibromatosis Association (NFA). 82 London Road, Kingston upon Thames, Surrey KT2 6PX. 0208 547 1636.e-mail: nfa@zetnet.co.uk. <http://www.nfa.zetnet.co.uk>.

Neurofibromatosis, Inc. 8855 Annapolis Rd., #110, Lanham, MD 20706-2924. (800) 942-6825. <http://www.nfinc.org>.

Rosalyn S. Carson-DeWitt

Laura Ruth, Ph.D.

KEY TERMS

Audiometry

—Testing a person's hearing by exposing ear to sounds in a soundproof room.

Autosomal dominant

—Genetic information on a single non-sex chromosome that is expressed with only one copy of a gene. Child of an affected parent has a 50% chance of inheriting an autosomal dominant gene.

Cancer

—Abnormal and uncontrolled growth of cells that can invade surrounding tissues and other parts of the body. Although some cancers are treatable, recurrence and death from cancer can occur.

Cataract

—Lens of eye loses transparency and becomes cloudy. Cloudiness blocks light rays entering the eye that may lead to blindness.

Chromosome

—A structure within the nucleus of every cell, that contains genetic information governing the organism's development. There are 22 non-sex chromosomes and one sex chromosome.

Ependymoma

—Tumor that grows from cells that line the cavities of brain ventricles and spinal cord.

Gamma knife

—A type of highly focused radiation therapy.

Gene

—Piece of information contained on a chromosome. A chromosome is made of many genes.

Magnetic resonance imaging

—Magnetic Resonance imaging (MRI) measures the response of tissues to magnetic fields to produce detailed pictures of the body, including the brain.

Meningioma

—Tumor that grows from the protective brain and spinal cord membrane cells (meninges).

Mutation

—A permanent change to the genetic code of an organism. Once established, a mutation can be passed on to offspring.

Neurofibroma

—A soft tumor usually located on a nerve.

Radiation therapy

—Exposing tumor cells to controlled doses of x-ray irradiation for treatment. Although tumor cells are susceptible to irradiation, surrounding tissues will also be damaged. Radiation therapy alone rarely cures a tumor, but can be useful when used in conjunction with other forms of therapy or when a patient cannot tolerate other forms of therapy.

Schwannoma

—Tumor that grows from the cells that line the nerves of the body (Schwann cells).

Tinnitus

—Noises in the ear that can include ringing, whistling or booming.

Tumor

—An abnormally multiplying mass of cells. Tumors that invade surrounding tissues and other parts of the body are malignant and considered a cancer. Non-malignant tumors do not invade surrounding tissues and other parts of the body. Malignant and non-malignant tumors can cause severe symptoms and death.

QUESTIONS TO ASK THE DOCTOR

• How can I tell if I have neurofibromatosis?
• Which type of neurofibromatosis do I have?
• Will I develop tumors? Will they be cancerous?
• Is my neurofibromatosis genetic?
• What medical tests are important?
• What treatments are available for neurofibromatosis?
• Will I die from neurofibromatosis?