Key Terms: Audiometry, Autosomal dominant, Cancer, Cataract, Chromosome, Ependymoma, Gamma knife, Gene, Magnetic resonance imaging, Meningioma, Mutation, Neurofibroma, Radiation therapy, Schwannoma, Tinnitus.
Definition
Von Recklinghausen's neurofibromatosis is also called von Recklinghausen disease, or simply neurofibromatosis (NF)1. 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 spots). The tumors occur under the skin and throughout the nervous system. The disease is named for Friedrich Daniel von Recklinghausen (1833–1910), a German pathologist, although cases of it have been described in European medical publications since the sixteenth century.
Description
There are three types of neurofibromatosis, although some researchers have proposed as many as eight categories. The two main types of neurofibromatosis are neurofibromatosis 1 (NF1), which affects about 85% of patients diagnosed with neurofibromatosis, and neurofibromatosis 2 (NF2), which accounts for another 10% of patients. 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 disease 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 17q. 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 distributed over the body.
- 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 visual disturbances 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) is the most useful type of imaging study for early diagnosis of tumors while CT scans are better for detecting skeletal abnormalities. 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. In general, however, patients with neurofibromatosis have a shortened life expectancy; the average age at death is 55–59 years, compared with 70–74 years for the general United States population. 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 2004 the National Cancer Institute (NCI) is sponsoring one clinical trial for children with neurofibromatosis type 1. The trial is an evaluation of tipifarnib (Zarnestra), a drug that inactivates certain proteins that encourage tumor growth. It is hoped that tipifarnib may prove to be an effective drug treatment for the disorder, as surgery is presently considered the only standard treatment.
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,
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?
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
Beers, Mark H., MD, and Robert Berkow, MD, editors. "Disorders of the Peripheral Nervous System." Section 14, Chapter 183 In The Merck Manual of Diagnosis and Therapy. Whitehouse Station, NJ: Merck Research Laboratories, 2002.
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.
Khan, Ali Nawaz, MBBS, and Ian Turnbull, MD. "Neurofibromatosis Type 1." eMedicine February 10, 2004.
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.
Lynch, H. T., T. G. Shaw, and J. F. Lynch. "Inherited Predisposition to Cancer: A Historical Overview." American Journal of Medical Genetics, Part C: Seminars in Medical Genetics 129 (August 15, 2004): 5–22.
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, Suite 108, Cumming, GA, 30041-6899. (770) 205-8211.
March of Dimes Birth Defects Foundation. National Office, 1275 Mamaroneck Ave., White Plains, NY 10605.
Massachusetts General Hospital Neurofibromatosis Clinic. Harvard Medical School, Massachusetts General Hospital, Boston, MA 02114. (617) 724-7856.
National Cancer Institute. Information Office, Building 31, Room 10A03, 9000 Rockville Pike, Bethesda, MD, 20892-2580. (800) 4-CANCER.
National Institute of Child Health and Human Development. Building 31, Room 2A32, MSC 2425, 31 Center Dr., Bethesda, MD, 20892. (800) 370-2943.
National Institute of Neurological Disorders and Stroke. Office of Communications and Public Liaison, PO Box 5801, Bethesda, MD, 20824. (800) 352-9424.
The National Neurofibromatosis Foundation, Inc.(NNF). 95 Pine St., 16th Floor, New York, NY 10005. (800) 323-7938.
Neurofibromatosis Association (NFA). 82 London Road, Kingston upon Thames, Surrey KT2 6PX. 0208 547 1636. e-mail: nfa@zetnet.co.uk.
Neurofibromatosis, Inc. 8855 Annapolis Rd., #110, Lanham, MD 20706-2924. (800) 942-6825.
