Tuberous sclerosis is a rare genetic multisystem disorder that is typically apparent shortly after birth. The disorder may be characterized by episodes of uncontrolled electrical activity in the brain (seizures); mental retardation; distinctive skin abnormalities (lesions); and benign (noncancerous), tumor-like nodules (hamartomas) of the brain, certain regions of the eyes (e.g., retinas), the heart, the kidneys, the lungs, or other tissues or organs. In addition, many affected individuals may have cyst-like areas within certain skeletal regions, particularly bones of the fingers and toes (phalanges). Characteristic skin lesions include sharply defined areas of decreased skin coloration (hypopigmentation) that may develop during infancy and relatively small reddish nodules that may appear on the cheeks and nose beginning at approximately age four. These reddish lesions eventually enlarge, blend together (coalesce), and develop a wart-like appearance (sebaceous adenomas). Additional skin lesions may also develop, including flat, "coffee-colored" areas of increased skin pigmentation (cafe-au-lait spots); benign, fibrous nodules (fibromas) arising around or beneath the nails; or rough, elevated, "knobby" lesions (shagreen patches) on the lower back.
Tuberous sclerosis results from changes (mutations) in a gene or genes that may occur spontaneously (sporadically) for unknown reasons or be inherited as an autosomal dominant trait. Most cases represent new (sporadic) gene mutations, with no family history of the disease. Mutations of at least two different genes are known to cause tuberous sclerosis. One gene (TSC1) has been mapped to the long arm (q) of chromosome 9 (9q34). A second gene for the disease (TSC2) is located on the short arm (p) of chromosome 16 (16p13.3). It remains unclear whether some sporadic and familial cases of the disease may be caused by mutations of other, currently unidentified genes (genetic heterogeneity).
The symptoms associated with tuberous sclerosis and, consequently, the severity of the disorder varies greatly from case to case depending upon the specific organ systems involved. The first symptoms of tuberous sclerosis usually occur during infancy or early childhood, but some do not occur until the second or third decade (adult onset). Approximately 80 percent of individuals with tuberous sclerosis have seizures as their first symptom. These episodes of seizures may include muscle spasms (myoclonic jerks). Brain wave abnormalities can be detected with an electroencephalograph (hypsarrhythmia). Forty to fifty percent of individuals with tuberous sclerosis are mildly or severely mentally retarded.
Benign brain tumors may be detected with computerized tomography (CT scans), even in the developing fetus.
Between 60 and 90 percent of infants with tuberous sclerosis have white patches or spots (hypomelanotic macules) on their skin at birth. The characteristic tumors of this disorder (angiofibroma) appear between the ages of 3 and 5 years. The tumors generally become more numerous during puberty. Collagen (a white glistening protein) may accumulate in the skin of the back and front of the body. This may appear as elevated, yellowish-brown patches with the texture of an orange peel. Small benign tumors (fibromas) may develop around or under the fingernails and the nail beds (periungual or subungual). Brown spots (cafe-au-lait macules) and soft sac-like growths (cutaneous nodules) may appear on the skin. About 50 to 90 percent of patients develop tumors in the retina of the eyes (astrocytic hamartomas) and 80 to 90 percent develop benign tumor-like nodules in the brain that often become hard and calcify.
Delayed speech, slow motor development, and learning disabilities may be associated with tuberous sclerosis. Typical behavior patterns include symptoms resembling childhood autism, screaming, crying, or rage.
Some individuals with tuberous sclerosis develop lymphangioleiomyomatosis (LAM), a condition in which the spread and uncontrolled growth (proliferation) of specialized cells (smooth muscle cells) forms tumors in the lungs resulting in shortness of breath, coughing, and/or difficulty breathing (dyspnea), especially following periods of exercise or exertion. LAM mostly occurs in women of childbearing age.
Another form of tumor associated with tuberous sclerosis is angiomyolipoma, a benign tumor made up of fat, blood vessels and smooth muscle cells. These tumors affect the kidneys and may not cause symptoms (asymptomatic) or may cause kidney (renal) dysfunction. Angiomyolipomas are prone to bleeding (hemorrhaging).
In most individuals with tuberous sclerosis, the disorder results from spontaneous genetic changes (mutations) that occur for unknown reasons. According to investigators, at least 50 percent and possibly up to more than 80 percent of cases may represent new (sporadic) mutations in which the parents are unaffected.
In other affected individuals, tuberous sclerosis is inherited as an autosomal dominant trait. Genetic diseases are determined by two genes, one received from the father and one from the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.
Mutations of at least two different genes are known to result in tuberous sclerosis. One gene, known as TSC1, is located on the long arm (q) of chromosome 9 (9q34). A second gene, designated TSC2, has been mapped to the short arm (p) of chromosome 16 (16p13.3). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q.” Chromosome are further subdivided into bands that are numbered.
The TSC1 gene regulates (encodes for) production of a protein known as hamartin that is thought to function as a tumor suppressor. In addition, the TSC2 gene encodes for a different tumor suppressor protein known as tuberin.
Research is ongoing to determine whether some sporadic and familial cases of tuberous sclerosis may be caused by mutations of other, currently unidentified genes.
Tuberous sclerosis is a rare genetic disorder that affects 1 in 10,000 people in the United States. Some new estimates are as high as 1 in 5,000 to 6,000 live births. Approximately 40,000 to 80,000 people in the United States have tuberous sclerosis. Males and females are affected equally and it occurs in all races.
The treatment for tuberous sclerosis is supportive and symptomatic. Treatment may include the administration of anticonvulsant drugs to control seizures. Facial tumors (angiofibromas) may be removed using a skin scraping technique known as derabrasion or with laser treatments. Surgery may become necessary for certain rapidly growing tumors that might interfere with normal function. Special education and related services will be helpful for those children who are mentally retarded or have learning disabilities.
Conventional anticonvulsants drugs that may be administered include phenobarbital, phenytoin (Dilantin), clonazepam (Clonopin), valproic acid (Depakene), carbamazepine (Tegretol), ethosuximide (Zarontin), or acetazolemide (Diamox). All these anticonvulsants have potential side effects and require careful monitoring by a physician.
Sabril (vigabatrin) Oral Solution was approved in 2009 by the U.S. Food and Drug Administration to treat infantile spasms in children ages 1 month to 2 years. Treatment of children with tuberous sclerosis and infantile spasms with vigabatrin has been found to be very effective. Visual field loss is an important safety concern with the use of this medication.
Certain immunizations, such as DPT and rubella, can prompt seizures in children with tuberous sclerosis. “Infantile spasms” can be treated in some infants by the use of prednisone or ACTH (adreno-corticotrophic hormone). These medications are used cautiously because of their side effects.
The obstruction of cerebrospinal fluid (CSF) circulation inside the brain (intracranial hypertension) because of a benign tumor may require a shunting procedure to drain the liquid or the surgical removal of the tumor. A benign tumor inside the heart (rhabdomyoma) may not cause symptoms and not require treatment. Large cystic lesions of the kidneys may also require surgical decompression or removal, possibly leading to loss of a kidney. If large groups of enlarged blood vessels (angiolipomas) bleed in the lining of the abdominal cavity (peritoneum), emergency treatment for shock may be necessary.
Genetic counseling will be of benefit for patients and their families.
Novartis is conducting a clinical trial to determine if the investigational drug RAD001 is effective at shrinking or slowing the growth of subependymal giant cell astrocytoma (SEGA) lesions in patients with tuberous sclerosis. The goal of a second clinical research study is to learn if this investigational drug can shrink or slow the growth of kidney lesions, known as angiomyolipoma in patients with tuberous sclerosis or lymphangioleiomyomatosis. Additional information is available in the following links:
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, contact:
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