Tuberous sclerosis-also called tuberous sclerosis complex (TSC)1
- is a rare, multi-system genetic disease that causes benign tumors to
grow in the brain and on other vital organs such as the kidneys, heart,
eyes, lungs, and skin. It commonly affects the central nervous system and
results in a combination of symptoms including seizures, developmental
delay, behavioral problems, skin abnormalities, and kidney disease.
The disorder affects as many as 25,000 to 40,000 individuals in the
United States and about 1 to 2 million individuals worldwide, with an
estimated prevalence of one in 6,000 newborns. TSC occurs in all races and
ethnic groups, and in both genders.
The name tuberous sclerosis comes from the characteristic
tuber or root-like growths in the brain, which
calcify with age and become hard or sclerotic.
The disorder-once known as epiloia or
Bourneville's disease-was first identified by a
French physician more than 100 years ago.
TSC may be present at birth, but signs of the disorder can be subtle
and full symptoms may take some time to develop. As a result, TSC is
frequently unrecognized and misdiagnosed for years.
TSC is caused by defects, or mutations, on two genes-TSC1 and TSC2.
Only one of the genes needs to be affected for TSC to be present. The TSC1
gene, discovered in 1997, is on chromosome 9 and produces a protein called
hamartin. The TSC2 gene, discovered in 1993, is
on chromosome 16 and produces the protein
tuberin. Scientists believe these proteins act
as tumor growth suppressors, agents that regulate cell proliferation and
differentiation-the processes in which nerve cells divide to form new
generations of cells and acquire individual characteristics.
Although some individuals may inherit the disorder from a parent with
TSC, most cases occur as spontaneous mutations. In these situations,
neither parent has the disorder or the faulty gene(s). Instead, a faulty
gene first occurs in the affected individual.
In other cases, TSC is an autosomal dominant disorder, which means that
the disease is carried by a dominant gene. In those cases where it is
passed from parent to child, only one parent needs to have the gene in
order to produce the disease in a child. If a parent has the TSC gene,
each offspring has a 50 percent chance of developing the disorder.
Children who inherit TSC may not have the same symptoms as their parent
and they may have either a milder or a more severe form of the disorder.
Some individuals acquire TSC through a process called
gonadal mosaicism. These patients have parents
with no apparent defects in the two genes that cause the disorder. Yet
these parents can have a child with TSC because a portion of one of the
parent's reproductive cells (sperm or eggs) can contain the genetic
mutation without the other cells of the body being involved. In cases of
gonadal mosaicism, genetic testing of a blood sample might not reveal the
potential for passing the disease to offspring.
TSC can affect any or all systems of the body, causing a variety of
signs and symptoms. Signs of the disorder vary depending on which system
and which organs are involved. The natural course of TSC varies from
individual to individual, with symptoms ranging from very mild to quite
severe. In addition to the benign tumors that frequently occur in TSC,
other common symptoms include seizures, mental retardation, behavior
problems, and skin abnormalities. Tumors can grow on any organ, but they
most commonly occur on the brain, kidneys, heart, lungs, and skin.
Malignant tumors are rare in TSC. Those that do occur primarily affect the
kidneys.
Kidney problems such as
cysts and
angiomyolipomas occur in an estimated 40 to 80
percent of individuals with TSC, usually occurring between ages 20 and 30.
Cysts are usually small, appear in limited
numbers, and cause no serious problems. Approximately 2 percent of
individuals with TSC develop large numbers of cysts in a pattern similar
to polycystic kidney disease2
during childhood. In these cases, kidney function is compromised and
kidney failure occurs. In rare instances, the cysts may bleed, leading to
blood loss and anemia.
Angiomyolipomas - benign growths consisting
of fatty tissue and muscle cells-are the most common kidney lesions in
TSC. These growths, which are not rare or unique to TSC, are found in
about 1 in 300 people without TSC. Angiomyolipomas caused by TSC are
usually found in both kidneys and in most cases they produce no symptoms.
However, they can sometimes grow so large that they cause pain or kidney
failure. Bleeding from angiomyolipomas may also occur, causing both pain
and weakness. If severe bleeding does not stop naturally, there may severe
blood loss, resulting in profound anemia and a life-threatening drop in
blood pressure, warranting urgent medical attention.
Other rare kidney problems include renal cell carcinoma, developing
from an angiomyolipoma, and oncocytomas, benign tumors unique to
individuals with TSC.
Three types of brain tumors are associated with TSC:
cortical tubers, for which the disease is named,
generally form on the surface of the brain, but may also appear in the
deep areas of the brain; subependymal nodules,
which form in the walls of the ventricles-the fluid-filled cavities of the
brain; and giant-cell astrocytomas, a type of
tumor that can grow and block the flow of fluids within the brain, causing
a buildup of fluid and pressure and leading to headaches and blurred
vision.
Tumors called cardiac rhabdomyomas sometimes are found
in the hearts of infants and young children with TSC. If the tumors are
large or there are multiple tumors, they can block circulation and cause
death. However, if they do not cause problems at birth-when in most cases
they are at their largest size-they usually do not grow and probably will
not affect the individual in later life.
Benign tumors called phakomas are sometimes found in
the eyes of individuals with TSC, appearing as white patches on the
retina. Generally they do not cause vision loss or other vision problems,
but they can be used to help diagnose the disease.
Additional tumors and cysts may be found in other areas of the body,
including the liver, lung, and pancreas. Bone cysts, rectal polyps, gum
fibromas, and dental pits may also occur.
A wide variety of skin abnormalities may occur in
individuals with TSC. Most cause no problems but are helpful in diagnosis.
Some cases may cause disfigurement, necessitating treatment. The most
common skin abnormalities include:
- Hypomelanic macules ("ash leaf spots"), which are
white or lighter patches of skin that may appear anywhere on the body
and are caused by a lack of skin pigment or melanin-the substance that
gives skin its color.
- Reddish spots or bumps called facial
angiofibromas (also called adenoma
sebaceum), which appear on the face (sometimes resembling
acne) and consist of blood vessels and fibrous tissue.
- Raised, discolored areas on the forehead called forehead
plaques, which are common and unique to TSC and may help
doctors diagnose the disorder.
- Areas of thick leathery, pebbly skin called shagreen
patches, usually found on the lower back or nape of the
neck.
- Small fleshy tumors called ungual or subungual
fibromas that grow around and under the toenails or
fingernails and may need to be surgically removed if they enlarge or
cause bleeding.
- Other skin features that are not unique to individuals with TSC,
including molluscum fibrosum or skin tags,
which typically occur across the back of the neck and shoulders,
café au lait spots or flat brown marks, and
poliosis, a tuft or patch of white hair that
may appear on the scalp or eyelids.
TSC can cause seizures and varying degrees of mental disability.
Seizures of all types may occur, including infantile spasms; tonic-clonic
seizures (also known as grand mal seizures); or tonic, akinetic, atypical
absence, myoclonic, complex partial, or generalized seizures.
Approximately one-half to two-thirds of individuals with TSC have
mental disabilities ranging from mild learning disabilities to severe
mental retardation. Behavior problems, including aggression, sudden rage,
attention deficit hyperactivity disorder, acting out, obsessive-compulsive
disorder, and repetitive, destructive, or self-harming behavior, may occur
in children with TSC. Some individuals with TSC may also have a
developmental disorder called autism.
In most cases the first clue to recognizing TSC is the presence of
seizures or delayed development. In other cases, the first sign may be
white patches on the skin (hypomelanotic macules).
Diagnosis of the disorder is based on a careful clinical exam in
combination with computed tomography (CT) or magnetic resonance imaging
(MRI) of the brain, which may show tubers in the brain, and an ultrasound
of the heart, liver, and kidneys, which may show tumors in those organs.
Doctors should carefully examine the skin for the wide variety of skin
features, the fingernails and toenails for ungual fibromas, the teeth and
gums for dental pits and/or gum fibromas, and the eyes for dilated pupils.
A Wood's lamp or ultraviolet light may be used to locate the hypomelantic
macules which are sometimes hard to see on infants and individuals with
pale or fair skin.
In infants TSC may be suspected if the child has cardiac rhabdomyomas
or seizures (infantile spasms) at birth. With a careful examination of the
skin and brain, it may be possible to diagnose TSC in a very young infant.
However, most children are not diagnosed until later in life when their
seizures begin and other symptoms such as facial angiofibromas
appear.
There is no cure for TSC, although treatment is available for a number
of the symptoms. Antiepileptic drugs may be used to control seizures, and
medications may be prescribed for behavior problems. Intervention programs
including special schooling and occupational therapy may benefit
individuals with special needs and developmental issues. Surgery including
dermabrasion and laser treatment may be useful for treatment of skin
lesions. Because TSC is a lifelong condition, individuals need to be
regularly monitored by a doctor to make sure they are receiving the best
possible treatments. Due to the many varied symptoms of TSC, care by a
clinician experienced with the disorder is recommended.
The prognosis for individuals with TSC depends on the severity of
symptoms, which range from mild skin abnormalities to varying degrees of
learning disabilities and epilepsy to severe mental retardation,
uncontrollable seizures, and kidney failure. Those individuals with mild
symptoms generally do well and live long productive lives, while
individuals with the more severe form may have serious disabilities.
In rare cases, seizures, infections, or tumors in vital organs may
cause complications in some organs such as the kidneys and brain that can
lead to severe difficulties and even death. However, with appropriate
medical care, most individuals with the disorder can look forward to
normal life expectancy.
Within the Federal Government, the leading supporter of research on TSC
is the National Institute of Neurological Disorders and Stroke (NINDS).
The NINDS, part of the National Institutes of Health (NIH), is responsible
for supporting and conducting research on the brain and the central
nervous system. NINDS conducts research in its laboratories at NIH and
also supports studies through grants to major medical institutions across
the country. The National Heart, Lung, and Blood Institute and the
National Cancer Institute, also components of the NIH, support and conduct
research on TSC.
Scientists who study TSC seek to increase our understanding of the
disorder by learning more about the TSC1 and TSC2 genes that can cause the
disorder and the function of the proteins-tuberin and hamartin-produced by
these genes. Scientists hope knowledge gained from their current research
will improve the genetic test for TSC and lead to new avenues of
treatment, methods of prevention, and, ultimately, a cure for this
disorder.
In one study researchers defined the mutations in the TSC1 and TSC2
genes in a large (more than 300) group of individuals with TSC in an
effort to find correlations between types of mutations and clinical
features of the disorder. Mechanisms of mutation occurrence and the
effects of other genes on clinical severity are also being studied. These
same scientists are also developing mouse models of TSC, which will
provide a unique opportunity to examine how the disease develops, discover
the critical cell types that are affected in TSC, and provide the
opportunity for therapeutic intervention.
Another study focuses on two major brain disorders-autism and
epilepsy-that occur in children with TSC. Information from this study
could lead to a better understanding of all three disorders, as well as to
the development of new drug treatments.
Other scientists are trying to determine what causes skin tumors to
develop in individuals with TSC and to find the molecular basis of these
tumors. Findings from this study could shed new light on the genetics of
TSC.
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Tuberous Sclerosis Alliance
801 Roeder
Road
Suite 750
Silver Spring, MD 20910
(301) 562-9890
(800)
225-NTSA (-6872)
http://www.tsalliance.org/
Epilepsy
Foundation
4351 Garden City Drive
Suite 406
Landover,
MD 20785-2267
(301) 459-3700
(800) EFA-1000 (332-1000)
http://www.epilepsyfoundation.org/
National
Organization for Rare Disorders (NORD)
55 Kenosia
Avenue
P.O. Box 1968
Danbury, CT 06813-1968
(203)
744-0100
(800) 999-6673 (voicemail only)
Fax: (203) 798-2291
http://www.rarediseases.org/
BRAIN
P.O. Box 5801
Bethesda, MD
20824
(301) 496-5751
(800) 352-9424
http://www.ninds.nih.gov/
1Tuberous sclerosis is often referred to as
tuberous sclerosis complex (TSC) in medical literature to help distinguish
it from Tourette's syndrome, an unrelated neurological disorder.
2Polycystic kidney disease is a genetic
disorder characterized by the growth of numerous fluid-filled cysts in the
kidneys.
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