sections include: NF1, NF2
Neurofibromatosis consists of two different genetic disorders: neurofibromatosis 1 (NF1) and neurofibromatosis 2 (NF2). Both forms cause tumors to grow along the nerves and also affect nonnervous tissues, such as the skin. Some NF2- associated tumors may be fatal; fatal tumors are less frequent in NF1 but can occur. There are other similarities between the two, but NF1 and NF2 are distinct entities caused by mutations of different genes.
NF1 affects about 1 in 3,000 people. It is caused by mutations of the neurofibromin gene (designated NF1) on chromosome 17. We do not completely understand the function of neurofibromin, but it is probably involved in regulating cell growth. The disease can be passed on from parent to child; each child of an affected person has a 50 percent risk of inheriting the disease. Half of NF1 cases arise as new mutations and, therefore, occur in individuals whose parents are unaffected. The other half of individuals with NF1 inherit the disease from an affected parent.
The first signs of NF1 are usually changes in the skin, which may include multiple café au lait spots (light brown, the color of coffee with cream) and freckling in skin folds as well as on areas exposed to sunlight. Most affected people develop neurofibromas, which are firm, noncancerous tumors of the nerve sheaths. These growths appear as lumps in or under the skin. Neurofibromas can range in diameter from three hundredths of an inch to more than half an inch and tend to increase in number and size as people age. Older adults may have hundreds or thousands of skin neurofibromas. Their impact is often only cosmetic, but they may cause pain or affect the function of adjacent structures.
In addition to café au lait spots and skin neurofibromas, the other most common features of NF1 are:
- mild shortness of stature
- learning disabilities (of varying severity, but usually with normal intelligence)
- macrocephaly, or an abnormally large head
- scoliosis, curvature of the spine
- large neurofibromas that can affect almost any part of the body.
In addition, about 15 percent of people with NF1 develop optic nerve tumors; these usually do not cause any symptoms and do not become progressively worse. Other central nervous system tumors may also appear. All the symptoms of NF1 and their severity can vary greatly, even within affected members of a single family.
About 5 percent to 10 percent of people with NF1 develop malignant, or cancerous, peripheral nerve sheath tumors. Brain tumors, seizures, long-bone pseudarthrosis (bending and fracturing of a long bone, usually in the leg), pheochromocytoma (a tumor of the adrenal gland), and vascular disease are less common but potentially serious complications. Many people with NF1 never develop any of these severe features, but it is hard to predict who will.
Doctors generally make a diagnosis of NF1 based on physical findings. The café au lait spot is the hallmark of the disorder and is often the only feature apparent in young children. Many people have one or two small spots of this sort, but adults with six or more café au lait spots greater than half an inch in diameter are likely to have NF1. (For children, doctors look for six or more spots one fifth of an inch in diameter.) Multiple café au lait spots can also occur in other conditions, so a confident diagnosis of NF1 requires the presence of at least one other characteristic feature as well.
Other signs of NF1 include freckling in the armpits (axillae) or in the groin; at least two neurofibromas of any type, or at least one large neurofibroma that involves a more extensive area than the typical skin tumor (a plexiform neurofibroma); a distinctive bony lesion that shows up on X rays; and two or more clumps of pigment on the iris (Lisch nodules). Thus, a doctor may take X-ray or magnetic resonance imaging (MRI) scans of an affected site, examine the eyes, order a biopsy of skin lesions, perform a black light test, and do other analyses.
Most symptoms of NF1 do not appear until people with the disorder are older, and doctors cannot make the diagnosis in some young children even though they may have the NF1 gene. A gene test has been developed, but it is not widely available and usually is not needed to establish the diagnosis.
Specialists who see people with NF1 include medical geneticists, neurologists, dermatologists, ophthalmologists, and orthopedic surgeons. Some major medical centers have neurofibromatosis clinics that bring together physicians from these many disciplines. Early diagnosis of NF1 permits increased vigilance in monitoring complications and allows patients and their families to consult genetic counselors about the possibility of children inheriting the disease.
No specific treatment for NF1 is available. We do not know how to prevent the onset or progression of particular symptoms. Treating serious symptoms by surgery or otherwise is often possible, however. Malignant tumors or tumors that cause pain or loss of function are removed on an individual basis. The life expectancy for people with NF1 is reduced by about 15 years from the norm, on average. Most of these deaths result from malignant tumors or vascular disease. NF1 is extremely variable in its manifestations, however, and the cause of this variability is unclear. One area of active research is the role of neurofibromin in the control of cell growth and tumor development.
NF2 affects about 1 in 40,000 people. It is caused by mutations in the merlin (sometimes called schwannomin, or NF2 gene on chromosome 22. The function of merlin is poorly understood, but it appears to be involved in regulating cell structure and growth. The NF2 protein has some structural similarities to a class of proteins known as erlins. “Merlin” is a play on the word erlin. The disease is transmitted genetically from parent to child, with a 50 percent risk that it will be passed on to any child. It can occur sporadically as a result of new mutations. Many people with NF2 inherit the disease from an affected parent, but it may also arise as a new mutation in an individual whose parents are unaffected.
For most people with NF2, the first symptom they notice is ringing in the ears or hearing loss as a result of schwannomas (benign tumors) of the vestibular nerves. Seeking medical help for the hearing problem can lead to diagnosis of a person’s NF2. Although vestibular schwannomas are not infrequent in older adults who do not have NF2, these tumors tend to occur at a much younger age, sometimes even in childhood, in people with NF2. The diagnostic feature, however, is that schwannomas usually involve both vestibular nerves in NF2, and this rarely, if ever, occurs in people who do not have the condition.
Most symptoms of NF2 are caused by compression of neural structures by schwannomas or other tumors of the cranial nerves, the spinal nerves, or the central nervous system. Meningiomas (tumors that grow on the membranes that enclose the brain and spinal cord) may also occur, often several at a time. A variety of neurological symptoms can result, depending on the structures affected by tumors. Localized weakness, loss of sensation, and seizures are the most common symptoms arising from tumors of nerves other than those of the ears.
NF2 is progressive, with worsening neurological problems as the tumors increase in size and number. The age at onset and rate of progression vary in different families, but the course tends to be similar in affected relatives. The average age when people are diagnosed is in the early 20s, and some individuals are much more severely and quickly affected than others.
Doctors usually diagnose NF2 using an MRI to confirm the presence of vestibular nerve tumors. Spotting the disease in people who do not have these tumors but have other symptoms is more difficult, and several sets of diagnostic criteria have been proposed. There is a gene test for NF2, but it is of limited value clinically. Its use is generally limited to presymptomatic diagnosis in the offspring of affected individuals. Neurologists, otolaryngologists (who diagnose and treat disorders of the ear, nose, throat and nearby parts of the head and neck), and medical geneticists are often involved in caring for people with NF2. Early diagnosis of the disorder permits doctors to watch carefully for tumor development and associated complications. Regular neurological assessment and hearing tests are important to determine whether the problems are getting worse and to permit early treatment of complications. Treatment options for vestibular schwannomas and other tumors include surgery and radiation therapy.
On average, people with NF2 die from their tumors at about 36 years of age, but this prognosis varies substantially from family to family. Researchers are seeking ways to improve treatments for NF2-related tumors, as well as to determine the role of merlin in tumor development.
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