Neurofibromatosis

Definition

Neurofibromatosis (NF) is a genetic disease in which multiple soft tumors (neurofibromas) develop under the skin and throughout the nervous system. Various sized tumors may grow on the nerves in or leading away from the brain and spinal cord (peripheral nerves) and in the vascular system (veins and arteries) and other organ systems. There are two types of NF: NF-1, also called vonRecklinghausen NF, and NF-2, also called acoustic NF (sometimes bilateral acoustic NF or BAN). NF-1 is more common, representing 90 percent of all cases, while NF-2 is diagnosed in 10 percent of NF cases.

Description

Neural crest cells are primitive cells that are present as part of the nervous system during fetal development. These cells eventually turn into the following:

• cells that form nerves throughout the brain, spinal cord, and body
• cells that serve as coverings around the nerves throughout the body
• pigment cells that provide color to body structures
• meninges, the thin, membranous coverings of the brain and spinal cord
• cells that ultimately develop into the bony structures of the head and neck

In both types of NF, a genetic defect causes these neural crest cells to develop abnormally, resulting in numerous tumors and malformations of the nerves, bones, and skin.

NF-1 affects nerves throughout the body, occurring as groups of soft, fibrous swellings that grow on nerves in the skin, brain, and spinal cord (central nervous system), muscles, and bone. Severe disfigurement can result from the development of these tumors as the disease progresses and bone deformities may occur as well.

NF-2 is a rare type of NF in which multiple tumors grow on the cranial (head) and spinal nerves and other growths can occur in the brain and spinal cord. Tumor growth (schwannoma) on the nerves to the ears (auditory nerves) is most characteristic of NF-2. Disfigurement does not occur although hearing and visual problems are typical.

Demographics

NF-1 is a common genetic disorder that occurs in about one of every 4,000 births worldwide. NF-2 is rare, occurring in one of every 40,000 births. Children with a family history of neurofibromatosis are at highest risk for having either form of the condition.

Causes and symptoms

Both forms of neurofibromatosis are caused by a defective gene. NF-1 is due to a defect on chromosome 17; NF-2 results from a defect on chromosome 22. Both of these disorders are inherited in a dominant fashion, which means that anyone who receives just one defective gene will have the disease. However, a family pattern of NF is only evident for about half of all cases of NF. The other cases of NF occur due to a spontaneous mutation (a permanent change in the structure of a specific gene). Once such a spontaneous mutation has been established in an individual, however, it can then be passed on to any offspring. The chance of a person with NF passing on the NF gene to a child is 50 percent.

NF-1 has a number of possible signs and can be diagnosed if any two of the following are present:

• The presence of coffee-colored spots. These are patches of tan or light brown skin, usually about 5 to 15 mm in diameter. Nearly all patients with NF-1 will display these spots.
• Multiple freckles in the armpit or groin area.
• Ninety percent of patients with NF-1 have tiny tumors called Lisch nodules in the iris (colored area) of the eye.
• Soft tumors (neurofibromas) are the hallmark of NF-1. They 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, causing vision disturbances in about 20 percent of those affected.
• The presence of NF-1 in a child's parent or sibling.

Very high rates of speech impairment, learning disabilities, and attention deficit disorder occur in children with NF-1. 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 individuals who have NF-1. These include various 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 ).

Patients with NF-2 do not necessarily have the same characteristic skin symptoms that appear in NF-1. The characteristic symptoms of NF-2 are due to tumors along the acoustic nerve that result in nerve dysfunction and the loss of hearing. The tumor may also spread to neighboring nervous system structures, causing weakness of the muscles of the face, headache , dizziness , poor balance, and uncoordinated walking. Cloudy areas on the lens of the eye (cataracts) frequently develop at an unusually early age. As in NF-1, the chance of brain tumors developing is unusually high.

When to call the doctor

A history of either form of NF in the child's parent or sibling is reason to consult a physician. The presence of any of the symptoms associated with NF-1 or NF-2 should be investigated by a physician as well, particularly spots on the skin or small movable lumps under the skin and visual disturbances, memory loss, or difficulty maintaining balance. Hearing loss may be the first sign of NF-2 but can also be due to other unrelated conditions.

Diagnosis

Diagnosis is based on characteristic symptoms and physical examination. Diagnosis of NF-1 requires that at least two of the characteristic signs are present. Diagnosis of NF-2 requires the presence of either a nodule or mass (tumor) on the acoustic nerve or another distinctive nervous system tumor, which may only be identifiable through imaging studies. An important diagnostic clue for either NF-1 or NF-2 is the known presence of the disorder in a child's parent or sibling. Gene studies may be done to detect abnormalities on chromosomes 17 and 22.

Diagnosis of NF-1 will be confirmed by manipulation of the skin to reveal moveable, small, solid lumps (nodules) and the presence of coffee-colored spots on the skin of the trunk and pelvis. The spots may appear in childhood and typically become more noticeable in young adults. Two or more nodules and six or more discolored spots are usually definitive for a diagnosis of NF-1. Curvature of the spin (scoliosis) may be present, elevated blood pressure, and abnormalities in height, weight, and head size may also be noticed on physical examination.

Diagnosis of NF-2 also relies on manipulation of the skin to indicate the presence of nodules and evaluation of hearing and vision to determine any impairment.

X rays, CT scans, and MRI scans are performed to track the development/progression of tumors in the brain and along the nerves. Auditory evoked potential testing (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 children who have possible seizures. As the disease progresses, hearing and vision are carefully monitored and imaging studies of the bones are frequently done to watch for the development of deformities.

Treatment

There is no standard treatment for either type of neurofibromatosis. To some extent, the symptoms of NF-1 and NF-2 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 chemotherapeutic drugs or x-ray treatments (radiation therapy). Twisting or curving of the spine and bowed legs may be corrected to some degree by surgical treatment or the wearing of a special brace. Social adjustment problems are common among young children with physical deformities caused by the condition.

Prognosis

NF of either type is progressive, and the clinical outcome is not predictable. Prognosis varies depending on the types of tumors that develop. 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 other kinds of movement. When cancers develop as a result of NF, prognosis worsens according to the specific type of cancer . Successful surgical removal of neurofibromas has a survival rate of 50 to 90 percent.

KEY TERMS

Chromosome —A microscopic thread-like structure found within each cell of the human body and consisting of a complex of proteins and DNA. Humans have 46 chromosomes arranged into 23 pairs. Chromosomes contain the genetic information necessary to direct the development and functioning of all cells and systems in the body. They pass on hereditary traits from parents to child (like eye color) and determine whether the child will be male or female.

Mutation —A permanent change in the genetic material that may alter a trait or characteristic of an individual, or manifest as disease. This change can be transmitted to offspring.

Neurofibroma —A soft tumor usually located on a nerve.

Tumor —A growth of tissue resulting from the uncontrolled proliferation of cells.

Prevention

There is no known way to prevent NF cases that occur as a result of spontaneous change in the genes (mutation). New cases of inherited NF can be prevented with careful genetic counseling. Parents with NF can be encouraged to understand that each of his or her offspring has a 50 percent chance of also having NF. When a parent has NF, and the specific genetic defect causing the parent's disease has been identified, tests can be performed on the fetus (developing baby) during pregnancy. Procedures such as amniocentesis or chorionic villus sampling 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.

Parental concerns

Parents may worried about the development of deformities associated with NF-1. Social workers and psychologists can be consulted about possible counseling for children with the disease, helping them to cope with changes in their bodies that may be hard to accept. Hearing loss and visual disturbances associated with NF-2 are usually not reversible and specialists can be consulted about possible therapies to improve functioning in existing sight or hearing senses. Surgery to remove tumors may require the provision of educational information for both parents and children so that the procedure and possible complications are understood ahead of time.

Resources

ORGANIZATIONS

March of Dimes Birth Defects Foundation. Resource Center, 1275 Mamaroneck Ave., White Plains, NY 10605. Web site: <www.modimes.org>.

National Neurofibromatosis Foundation Inc. 95 Pine St., 16th Floor, New York, NY 10005. Web site: <nf.org>.

WEB SITES

"Neurofibromatosis." MedlinePlus. Available online at <www.nlm.nih.gov/medlineplus/neurofibromatosis.html> (accessed October 12, 2004).

"Neurofibromatosis."fc Inc. Available online at <www.rfinc.org/> (accessed October 12, 2004).

L. Lee Culvert Rosalyn Carson-DeWitt, MD

Neurofibromatosis

Definition

Neurofibromatosis (NF), or von Recklinghausen disease, is a genetic disease in which patients develop multiple soft tumors (neurofibromas). These tumors occur under the skin and throughout the nervous system.

Description

Neural crest cells are primitive cells which exist during fetal development. These cells eventually turn into:

• cells which form nerves throughout the brain, spinal cord, and body
• cells which serve as coverings around the nerves that course through the body
• pigment cells, which provide color to structures
• the meninges, the thin, membranous coverings of the brain and spinal cord
• cells which ultimately develop into the bony structures of the head and neck

In neurofibromatosis, a genetic defect causes these neural crest cells to develop abnormally. This results in numerous tumors and malformations of the nerves, bones, and skin.

Neurofibromatosis occurs in about one of every 4,000 births. Two types of NF exist, NF-1 (90% of all cases), and NF-2 (10% of all cases).

Causes and symptoms

Both forms of neurofibromatosis are caused by a defective gene. NF-1 is due to a defect on chromosome 17; NF-2 results from a defect on chromosome 22. Both of these disorders are inherited in a dominant fashion. This means that anybody who receives just one defective gene will have the disease. However, a family pattern of NF is only evident for about half of all cases of NF. The other cases of NF occur due to a spontaneous mutation (a permanent change in the structure of a specific gene). Once such a spontaneous mutation has been established in an individual, however, it is then possible to be passed on to any offspring. The chance of a person with NF passing on the NF gene to a child is 50%.

NF-1 has a number of possible signs and can be diagnosed if any two of the following are present:

• The presence of café-au-lait (French for coffee-with-milk) spots. These are patches of tan or light brown skin, usually about 5-15 mm in diameter. Nearly all patients with NF-1 will display these spots.
• Multiple freckles in the armpit or groin area.
• Ninty percent of patients with NF-1 have tiny tumors called Lisch nodules in the iris (colored area) of the eye.
• Neurofibromas. These soft tumors are the hallmark of NF-1. They 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 NF-1 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 NF-1. 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 NF-1. 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).

Patients with NF-2 do not necessarily have the same characteristic skin symptoms (café-au-lait spots, freckling, and neurofibromas of the skin) that appear in NF-1. The characteristic symptoms of NF-2 are due to tumors along the acoustic nerve. Interfering with the function of this nerve results in the loss of hearing; and the tumor may spread to neighboring nervous system structures, causing weakness of the muscles of the face, headache, dizziness, poor balance, and uncoordinated walking. Cloudy areas on the lens of the eye (called cataracts ) frequently develop at an unusually early age. As in NF-1, the chance of brain tumors developing is unusually high.

Diagnosis

Diagnosis is based on the symptoms outlined above. Diagnosis of NF-1 requires that at least two of the listed signs are present. Diagnosis of NF-2 requires the presence of either a mass on the acoustic nerve or another distinctive nervous system tumor. An important diagnostic clue for either NF-1 or NF-2 is the presence of the disorder in a patient's parent, child, or sibling.

Monitoring the progression of neurofibromatosis involves careful testing of vision and hearing. 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 available treatments for the disorders which underlie either type of neurofibromatosis. To some extent, the symptoms of NF-1 and NF-2 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 ). 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.

Prevention

There is no known way to prevent the approximately 50% of all NF cases which occur due to a spontaneous change in the genes (mutation). 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, tests can be performed on the fetus (developing baby) during pregnancy. Amniocentesis or chorionic villus sampling are two techniques which 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.

Resources

ORGANIZATIONS

March of Dimes Birth Defects Foundation. 1275 Mamaroneck Ave., White Plains, NY 10605. (914) 428-7100. resourcecenter@modimes.org. 〈http://www.modimes.org〉.

National Neurofibromatosis Foundation, Inc. 95 Pine St., 16th Floor, New York, NY 10005. (800) 323-7938. 〈http://nf.org〉.

Neurofibromatosis, Inc. 8855 Annapolis Rd., #110, Lanham, MD 20706-2924. (800) 942-6825.

KEY TERMS

Chromosome— A structure within the nucleus of every cell, which contains genetic information governing the organism's development.

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.

Tumor— An abnormally multiplying mass of cells.

Neurofibromatosis

Definition

Neurofibromatosis (NF), or von Recklinghausen disease, is a disorder which causes development of multiple soft tumors (neurofibromas). These tumors occur under the skin and throughout the nervous system (cells which control body movement and sensation).

Description

Neural crest cells are primitive cells which exist during fetal development. These cells eventually turn into cells that form nerves throughout the brain, spinal cord, and body. Collectively, this system of nerve cells is called the nervous system, which coordinates movement and sensation. Some nerve cells carry impulses from the brain to muscles or other peripheral structures, hence the name peripheral nervous system. Another group of nerve cells called the central nervous system are capable of transmitting sensation back to the brain for interpretation (such as feeling cold or hot).

In neurofibromatosis, a genetic defect causes these neural crest cells to develop abnormally. This results in numerous tumors and malformations of the nerves, bones, and skin.

Genetic profile

Both forms of neurofibromatosis are caused by a defective gene . NF-1 is due to a defect on chromosome 17; NF-2 results from a defect on chromosome 22. Both of these disorders are inherited as a dominant trait. This means that anybody who receives just one defective gene will have the disease. However, a family pattern of NF is only evident for about half of all cases of NF. The other cases of NF occur due to a spontaneous mutation (a spontaneous and permanent change in the structure of a specific gene). Once a spontaneous mutation has been established in an individual it is then possible to be passed on to any offspring. The chance of a person with NF passing on the NF gene to their child is 50%. There are different pathologic alleles (variations of the mutant gene). The frequency of spontaneous (new) mutations is very high and causes for this are still unknown.

Demographics

Neurofibromatosis-I occurs in about one of every 4,000 births. Neurofibromatosis-I is one of the most common genetic disorders that is dominantly inherited. Two types of NF exist, NF-1 (90% of all cases), and NF-2 (10% of all cases).

Signs and symptoms

NF-1 has a number of possible signs and can be diagnosed if any two of the following are present:

• The presence of café-au-lait (French for coffee-with-milk) spots. These are patches of tan or light brown skin, usually about five to 15 mm in diameter. Nearly all patients with NF-1 will display these spots.
• Multiple freckles in the armpit or groin area.
• Ninty percent of patients with NF-1 have tiny tumors called Lisch nodules in the iris (colored area) of the eye.
• Neurofibromas. These soft tumors are the hallmark of NF-1. They 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 (the nerve cells which transmit a visual stimulus to the back part of the brain called the occipital lobe, for intrepretation), which cause vision disturbance occurs in about 20% of patients.
• The presence of NF-1 in a patient's parent, child, or sibling.
• Hypertension, or elevated blood pressure.

There are very high rates of speech impairment, learning disabilities, and attention deficit disorder in children with NF-1. Other complications include the development of a seizure disorder (an abnormal firing of nerve cells in muscles, causing severe contractions, sometimes involving the whole body), or abnormal accumulation of fluid within the brain (a condition called hydrocephalus ). A number of cancers are more common in patients with NF-1. These include a variety of types of malignant brain tumors, as well as leukemia, and cancerous tumors of certain muscles (rhabdomyosar-coma), the adrenal glands (pheochromocytoma), or the kidneys (Wilms' tumor).

Patients with NF-2 do not necessarily have the same characteristic skin symptoms (café-au-lait spots, freckling, and neurofibromas of the skin) that appear in NF-1. The characteristic symptoms of NF-2 are due to tumors along the acoustic nerve. Interfering with the function of this nerve results in the loss of hearing; and the tumor may spread to neighboring nervous system structures, causing weakness of the muscles of the face, headache, dizziness, poor balance, and uncoordinated walking. Cloudy areas on the lens of the eye (called cataracts) frequently develop at an unusually early age. As in NF-1, the chance of brain tumors developing is unusually high.

Diagnosis

Diagnosis is based on the broad spectrum of clinical signs previously described, which usually can be detected by careful physical examination, ophthalmologic evaluation (visualizing the structures in the eye) and audiogram (test to measure hearing ability). Diagnosis of NF-1 requires that at least two of the listed signs are present. Diagnosis of NF-2 requires the presence of either a mass on the acoustic nerve or another distinctive nervous system tumor. An important diagnostic clue for either NF-1 or NF-2 is the presence of the disorder in a patient's parent, child, or sibling. A test to detect a protein (the end-products of a gene) relevant to NF-1 muta-genesis has been created, but accuracy for this procedure has not been established.

Monitoring the progression of neurofibromatosis involves careful testing of vision and hearing. X ray studies of the bones are frequently indicated to detect 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 acoustic nerve involvement, and EEG (electroencephalogram, a record of electrical impulses in the brain) may be required for patients with suspected seizures. Regular blood pressure monitoring is also advised.

Treatment and management

There are no available treatments for the disorders which underlie either type of neurofibromatosis. To some extent, the symptoms of NF-1 and NF-2 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). 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 tumor type which 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 .

Prevention

There is no known way to prevent the approximately 50% of all NF cases that occur due to a spontaneous change in the genes (mutation). 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. Special tests can be performed on the fetus (developing baby) during pregnancy to determine if the fetus will be born with this disorder. Amniocentesis (where a needle is passed through the mother's abdomen into the amniotic sac which contains the amniotic fluid and cushions the developing fetus) or chorionic villus sampling (a procedure involving extraction of a tissue sample from the placenta, the structure which connects the fetal blood with the mother, necessary for nutrient and waste exchange) are two techniques which allow small amounts of fetal DNA (deoxyribonucleic acid , the chemical which contains specific codes which determine genetic makeup of an individual) removed for analysis. 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 condition. Other families may choose not to continue the pregnancy.

Resources

BOOKS

Haslam, Robert H. A. "Neurocutaneous Syndromes." In Nelson Textbook of Pediatrics, edited by Richard Behrman. Philadelphia: W. B. Saunders Co., 1996.

PERIODICALS

"Health Supervision for Children with Neurofibromatosis." Pediatrics 96, 2 (August 1995): 368+.

Heim R. A., et al. "Distribution of 13 truncating mutations in the neurofibromatosis 1 gene." Human Molecular Genetics 4 (1995): 975-81.

Levy, Charles E. "Physiatry and Care of Patients with Neurofibromatosis." The Journal of the American Medical Association 278, 18 (November 12, 1997): 1493+.

Waller, Amy L., and James E. Baumgartner. "Current Concepts in the Management of Neurofibromatosis Type 1." Physician Assistant 21, 8 (August 1997): 103+.

ORGANIZATIONS

March of Dimes Birth Defects Foundation. National Office, 1275 Mamaroneck Ave., White Plains, NY 10605. (888) 663-4637. resourcecenter@modimes.org. <http://222.modimes.org>.

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

Neurofibromatosis, Inc. 8855 Annapolis Rd., #110, Lanham, MD 20706-2924. (800) 942-6825.

Laith Farid Gulli, MD

Neurofibromatosis

Definition

Neurofibromatosis (NF) is a genetic condition in which fleshy tumors called neurofibromas grow throughout the body. Neurofibromatosis was first written up in the medical literature in 1882 by a German physician, Dr. Friedrich Daniel von Recklinghausen.

Description

Neurofibromas are tumors that are composed of the fibrous substance that covers nerve cells. These neurofibromas grow along the nerves in the body (the peripheral nerves), and cause skin and bone abnormalities. Furthermore, while neurofibromas initially start out as benign (non-cancerous) growths, 3–5% of all neurofibromas are converted into malignant (cancerous) tumors. Neurofibromatosis patients are also at risk of developing other types of cancerous tumors of the nervous system.

Neurofibromatosis is divided into two types, NF1 and NF2. NF1, also called Von Recklinghausen disease or peripheral neurofibromatosis, is the most common. Visible skin signs of NF1 tend to be present at birth, or certainly by about age 10. NF1 causes predominantly skin and bone changes, as well as problems due to the growing neurofibromas exerting damaging pressure on peripheral nerves. NF2, also called central neurofibromatosis or bilateral acoustic neurofibromatosis, is less common. Its predominant problem involves neurofibromas growing on the eighth cranial nerve (also known as the acoustic or auditory nerve). These tumors interfere with the functioning of the cranial nerve VIII, causing serious hearing impairment or even profound deafness, as well as a variety of symptoms due to pressure on adjacent nerves that serve the head and neck areas.

Demographics

NF1 occurs in one out of 4,000 births; NF2 occurs in one out of 40,000 births. Males and females are equally affected. In the United States, about 100,000 people are identified as having either NF1 or NF2.

Causes and symptoms

Neurofibromatosis is a genetic disease that is inherited in an autosomal dominant fashion, meaning that only one parent with neurofibromatosis is required to pass on the disease to offspring. Half of all cases of neurofibromatosis is inherited from a parent with the disorder; the other half of cases of neurofibromatosis does not have a history of the disease in a parent. They are considered to have developed the disease due to a spontaneous mutation, which can then be passed on to the patient's own offspring. When one parent has neurofibromatosis, each child has a 50% chance of inheriting the condition.

Neurofibromatosis 1

Patients with NF1 are most often diagnosed in childhood or even infancy. The most common characteristics of NF1 include:

• cafe-au-lait macules (light brown, flat skin patches)
• freckles in the armpit and groin areas (axillary and inguinal freckling)
• neurofibromas on and under the skin, ranging from millimeters to inches (centimeters) in size (an individual may have anywhere from several to thousands of these soft, rubbery, flesh-colored tumors)
• Lisch nodules, tumors within the iris of the eye
• vision problems, probably due to gliomas (tumors made of cells called glial cells that serve a supportive function within the central nervous system ) located within or exerting pressure on the optic nerves
• learning problems or frank mental retardation
• scoliosis (side-to-side curvature of the spine)
• high blood pressure
• short adult height
• early (precocious) puberty
• increased risk of malignant brain and spinal cord tumors, kidney tumors (Wilms' tumor), adrenal tumors (pheochromocytoma), leukemia (cancer of blood cells), and tumors of the tendons, muscles, or connective tissue (rhabdomyosarcoma)

Neurofibromatosis 2

The most common characteristics of NF2 include:

• hearing problems due to neurofibromas in both acoustic nerves

• cataracts, the abnormal clouding of the lens of the eye
• headache , pain or numbness in the face
• problems with balance and coordination when walking, resulting in unsteadiness
• ringing in the ears (tinnitus)
• cafe-au-lait macules (many fewer than in NF1)
• neurofibromas on and under the skin (many fewer than in NF1)

Diagnosis

NF1 is diagnosed when the patient has at least two of the following criteria:

• six or more cafe-au-lait macules that measure more than 0.2 in (5 mm) in children before puberty, or that measure more than 0.6 in (15 mm) in patients after puberty
• demonstration of two or more neurofibromas
• axillary or inguinal freckling
• presence of optic glioma
• presence of two or more Lisch nodules, diagnosed through slit-lamp examination (a slit-lamp is a micro-scope with an extremely strong light that can be focused into a slit in order to examine the eye)
• bone abnormalities such as defects of the skull bone (sphenoid wing) or abnormal thinning of the usually dense outer layer of the long thigh, leg, or arm bones
• a parent, sibling, or child who has been diagnosed with NF1

NF2 is diagnosed when the patient has at least one of the following criteria:

• gadolinium-enhanced magnetic resonance imaging (MRI) scan or other appropriate imaging study that demonstrates tumors of the two cranial nerves VIII
• a parent, sibling, or child who has been diagnosed with NF2, and has either a diagnosed tumor on one cranial nerve VIII or at least two of the following: neurofibroma, meningioma (tumor of the membrane that covers the spinal cord and brain [meninges]), glioma (tumor composed of the supportive cells called glial cells), schwannoma (tumor composed of the schwann cells that normally wrap around nerves throughout the body, creating a sheath that both insulates the nerves and allows nerve conduction to occur more quickly), or a specific type of cataract called a juvenile posterior subcapsular lenticular opacity

Treatment team

Treatment of neurofibromatosis requires a multidisciplinary team approach, with neurologists, ophthalmologists, otolaryngologists (ENTs), neurosurgeons, general surgeons, plastic surgeons, orthopedic surgeons, and dermatologists all collaborating. Depending on the kinds of challenges that the specific patient faces, other team members may include speech and language specialists, learning specialists, occupational therapists, and physical therapists.

Treatment

There is no known cure for either NF1 or NF2. Regular examinations are important in order to catch new developments early, such as the advent of high blood pressure, malignant transformation of a neurofibroma, or development of cataracts.

Treatment is purely supportive and depends on the specific manifestations of the disease in a given patient. For example, a patient with scoliosis may require bracing; patients with cataracts may require surgery; patients with auditory nerve tumors may require traditional scalpel surgery or gamma-knife surgery (also called stereotactic radiosurgery, this is a technique that allows a very focused, very high dose of radiation to be delivered to a carefully designated tissue location). Optic gliomas may be treated with radiation therapy. Any tumors that are impinging on nerves and causing symptoms or tumors that have undergone malignant transformation may require surgical removal, while tumors that are purely problematic from a cosmetic standpoint may be left alone.

Clinical trials

A variety of clinical trials are underway, including studies of several types of drugs such as drug R115777, tipifarnib, pirfenidone, and combination methotrexate/vinblastine therapy, each of which may be useful in shrinking tumors associated with neurofibromatosis. Information about these trials are available through the National Cancer Institute.

Prognosis

Even within the same family, the manifestations and severity of neurofibromatosis can differ widely.

Special concerns

Genetic counseling is crucial for families with a history of neurofibromatosis to help ascertain the risk of future offspring being born with neurofibromatosis.

Resources

BOOKS

Barkovich, A. James, and Ruben I. Kuzniecky. "Neurocutaneous Syndromes." Cecil Textbook of Medicine, edited by Lee Goldman. Philadelphia: W. B. Saunders Company, 2003.

Berg, Bruce O. "Chromosomal Abnormalities and Neurocutaneous Disorders>" Textbook of Clinical Neurology, edited by Christopher G. Goetz. Philadelphia: W. B. Saunders Company, 2003.

Haslam, Robert H. A. "Neurocutaneous Syndromes." Nelson Textbook of Pediatrics, edited by Richard E. Behrman, et al. Philadelphia: W. B. Saunders Company, 2004.

WEBSITES

National Institute of Neurological Disorders and Stroke (NINDS). Neurofibromatosis Fact Sheet. (April 27, 2004). <http://www.ninds.nih.gov>.

ORGANIZATIONS

National Cancer Institute (NCI). 9000 Rockville Pike, Bethesda, MD 20892. gillesan@exchange.nih.gov or prpl@mail.cc.nih.gov.

The National Neurofibromatosis Foundation, Inc. 95 Pine Street, 16th Floor, New York, NY 10005. (212) 344-NNFF (6633) or (800) 323-7938. nnff@nf.org. <http://www.nf.org>.

Rosalyn Carson-DeWitt, MD

Neurofibromatosis

What Is Neurofibromatosis?

What Causes Neurofibromatosis?

What Are the Symptoms of Neurofibromatosis?

How Is Neurofibromatosis Treated?

Resource

Neurofibromatosis (noor-o-fy-bro-ma-TO-sis) is a genetic disorder that causes tumors to grow on nerves and is also characterized by skin changes and deformities in bone.

KEYWORDS

for searching the Internet and other reference sources

Inherited Genetic Disorders

Neurology

What Is Neurofibromatosis?

The most common form, called neurofibromatosis type 1 or NF-1, mainly affects nerves in the skin, producing soft nodules or bumps. Neurofibromatosis type 2 (NF-2) is a very rare disorder that affects the auditory nerves responsible for hearing and balance. Both types are caused by defective genes*.

*genes

are chemicals in the body that help determine a person’s characteristics, such as hair or eye color. They are inherited from a person’s parents and are contained in the chromosomes found in the cells of the body.

Neurofibromatosis also is called von Recklinghausen’s disease, after the German physician Friedrich von Recklinghausen (1833-1910), who described it in 1882. The tumors he noted, called neurofibromas (noor-o-fy-BRO-mas), arise from the cells that make up the covering sheaths of the nerves.

NF-1 and NF-2 neurofibromatoses occur in both sexes and in all racial and ethnic groups. In the United States, NF-1 occurs in about 1 of 4,000 persons. NF-2 is 10 times less common, occurring in about 1 in 40,000 people.

What Causes Neurofibromatosis?

Although many people who have neurofibromatosis inherited it from one of their parents, between 30 and 50 percent developed it spontaneously from a mutation (change) in their genes before birth.

Neurofibromatosis is inherited as an autosomal (non-sex-linked) dominant disorder. This means that each child born to a parent with neurofibromatosis has a 50 percent chance of inheriting the defective gene and developing the disease.

Genes produce proteins that determine a person’s body physical and metabolic characteristics, everything from the color of a person’s hair to how fast a person burns fat. Scientists recently have discovered that the neurofibromatosis genes, when normal, produce proteins that suppress tumors. This suggests that when the genes are defective, they may fail to produce enough of these proteins, thus allowing the growth of tumors. Further research is needed to confirm this theory, however.

What Are the Symptoms of Neurofibromatosis?

The signs and symptoms of neurofibromatosis vary greatly among individuals even in the same family. Many people do not know that they have NF-1 until it is diagnosed during a routine physical exam. The disease is usually mild.

The Elephant Man

Neurofibromatosis has long been associated with the “Elephant Man.” This was a name given to the Englishman Joseph Carey Merrick (1862-1890), who was exhibited in public as a medical freak because of his grotesque disfigurements. Merrick was, until recently, thought to have had a severe form of neurofibromatosis, but accumulating evidence now indicates that he was suffering from a much rarer disease called Proteus syndrome. Nonetheless, public awareness of neurofibromatosis was greatly increased after the production of a play in 1979 and a film in 1980 on the life of Merrick.

NF-1 produces many soft, bumpy or stalk-like tumors under the skin. Another common sign of this disorder is light-brown patches on the skin called cafe-au-lait spots. Although these spots may appear in people who do not have NF-1, people with NF-1 usually have six or more of them. Signs may also include freckles in the armpits or groin areas, growths in the eye or on the optic nerve, deformation of bones, and scoliosis, a side-to-side curvature of the spine.

These signs first appear in infancy or early childhood, and increase as a person grows older. Occasionally, tumors are massive or in rare cases become cancerous. They may also occur inside the body, squeezing or blocking internal organs.

The signs of NF-2 include tumors on the auditory (acoustic) nerves. These growths can cause loss of hearing and may damage nearby nerves and structures in the brain. Tinnitis (ti-NY-tus; a ringing in the ears), balance disturbances, or headache can also occur. People with NF-2 may first notice these symptoms in their teen or early adult years.

How Is Neurofibromatosis Treated?

The diagnosis of neurofibromatosis is made mainly by noting its outward signs. Internal viewing techniques, such as MRI (magnetic resonance imaging), are sometimes needed as well. Treatment is then based upon controlling symptoms.

Operations and braces may be needed to correct scoliosis. Surgery may also be performed to remove tumors that are exceptionally large, painful, or that press on organs. The tumors often grow back, however.

Various cancer treatments may be used in the rare instances that tumors become malignant*. Recent progress in biomedical research into the causes of neurofibromatosis has raised hopes that someday there will be treatment to slow or halt the growth of its tumors.

*malignant

(ma-LIG-nant) refers to cancerous tumors that spread to other places in the body, resulting in a condition that can lead to death.

Some cases of neurofibromatosis can be severely debilitating, and its complications can be fatal. In most instances, however, symptoms are mild, and the person with the disorder can lead a normal, productive life.

Genetic tests and counseling are available for people with neurofibromatosis. It can help them learn more about their condition or that of a family member, and can assist in making decisions about having children of their own.

See also

Genetic Diseases

Resource

Organization

The National Neurofibromatosis Foundation, 95 Pine Street, 16th Floor, New York, NY 10005. This organization provides information for patients and health professionals on neurofibromatosis.
Telephone 800-323-7938
http://www.nf.org