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 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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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You can obtain further information on the neurofibromatoses, including
information about treatment centers and genetic counseling from the
following voluntary health organizations:
National Neurofibromatosis Foundation
95 Pine Street,
16th Floor
New York, NY 10005
212-344-NNFF
(6633)
800-323-7938
http://www.nf.org/
Neurofibromatosis, Inc.
8855 Annapolis Road
Suite 110
Lanham,
Maryland 20706-2924
410-577-8984
410-461-5213
(TDD)
800-942-6825
http://www.nfinc.org/
Acoustic Neuroma Association
600 Peachtree Parkway
Suite
108
Cumming, GA 30041
770-205-8211
http://www.anausa.org/
For more information on research in the neurofibromatoses, you may wish
to contact:
NIH Neurological Institute
Office of Communications and Public
Liaison
P.O. Box 5801
Bethesda, Maryland 20824
(301)
496-5751
(800) 352-9424
National Cancer Institute
Information Office
Building 31, Room
10A03
9000 Rockville Pike
Bethesda, Maryland 20892-2580
(301)
435-3848
800-4-CANCER (422-6237)
cancernet.nih.gov
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