Information on the following diseases can be found in the Related Disorders section of this report:

• Sturge-Walker Syndrome
• Hypomelanosis of Ito
• Epidermal Nevus Syndrome

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.

Symptoms of the following disorders can be similar to those of tuberous sclerosis. Comparisons may be useful for a differential diagnosis:

Sturge-Walker syndrome is a rare disorder that is apparent at birth. This disorder is characterized by three major symptoms; excessive blood vessel growth within the membranes that surround the spinal cord (leptomenigal angiomas); seizures; and accumulation of excessive calcium within the brain. Generally there is a large birth mark (port wine stain or nevus flammeus) on one side of the face. The seizures that are common with this disorder generally increase in frequency as the patient gets older. Over half of the children with Sturge-Walker syndrome experience some degree of mental retardation. (For more information on this disorder, choose "Sturge-Walker" as your search term in the Rare Disease Database.)

Hypomelanosis of Ito is a rare disorder that is characterized by an unusual lack of skin color (hypopigmentation) affecting many areas of the body. Other symptoms may include mental retardation, seizures, inability to sweat in the areas that lack pigmentation, crossed eyes (strabismus), nearsightedness and a cleft along the edge of the eyeball (coloboma). (For more information on this disorder, choose "Hypomelanosis of Ito" as your search term in the Rare Disease Database.)

Epidermal nevus syndrome is a rare disorder characterized by distinctive birth marks (nevus) on the skin. Neurological and skeletal abnormalities may also occur. This disorder is usually apparent at birth and the skin lesions are most often seen in the midface from the forehead down into the nasal area. Epidermal nevus syndrome is often associated with seizures, mental deficiency, eye problems, bone malformations and atrophy of the brain. (For more information on this disorder, choose "Epidermal Nevus" as your search term in the Rare Disease Database.)

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.

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.

Information on current clinical trials and studies 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 website.

For information about clinical trials and studies being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

Adult patients (18-65) are currently being enrolled in a clinical trial to study the effectiveness of the drug rapamycin in the treatment of tuberous sclerosis and lymphangioleiomyomatosis. Specifically, in this trial the effect of rapamycin on the size of kidney tumors (angiomyolipomas) will be measured. This study will also look at the effects of the drug on tuberous sclerosis lesions of the brain, skin, and lungs. The trial is sponsored by the Cincinnati Children’s Hospital Medical Center. For additional information and enrollment criteria, contact:

Gail Chuck, Research Coordinator
Phone: (513) 636-8016
Email: gail.chuck@cchmc.org

The oral antiepileptic drug vigabatrin (Sabril) has been studied for use in the treatment of infantile spasm associated with tuberous sclerosis. Presently (2004), Vigabatrin has not gained FDA marketing approval in the U.S., but is being marketed in some other countries. On April 5, 2004, Ovation Pharmaceuticals located in Deerfield, Ill., announced that it has acquired North American rights to vigabatrin and is planning renewed efforts to obtain FDA approval. More study is needed to determine the long-term safety and effectiveness of this drug for the treatment of seizures of tuberous sclerosis. For information, contact:

Ovation Pharmaceuticals, Inc.
Four Parkway North
Deerfield, IL 60015
Tel: (847) 282-1000
Web: www.ovationpharma.com

Investigations into the cause and possible treatments for tuberous sclerosis are ongoing. Blood and skin cells of tuberous sclerosis patients have been banked at the Camden Cell Repository in New Jersey, at Massachusetts General Hospital and the Brain and Tissue Bank at the University of Miami School of Medicine and are available to researchers around the world. Scientists are trying to locate and study the two TS genes, and then the development of prenatal tests and diagnostic blood tests for tuberous sclerosis may be possible.

Tissue studies are being conducted at the Massachusetts General Hospital. For information, contact:

Kamala Martin, RN, Research Coordinator
Tel: (617) 726-5470
E-mail: kmartin3@partners.org

Online Mendelian Inheritance in Man, OMIM (TM). John Hopkins University, Baltimore, MD. MIM Number 191100; 1/5/00. Available at: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?191100.

Online Mendelian Inheritance in Man, OMIM (TM). John Hopkins University, Baltimore, MD. MIM Number 191092; 1/11/00. Available at: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?191092.

Online Mendelian Inheritance in Man, OMIM (TM). John Hopkins University, Baltimore, MD. MIM Number 191091; 7/16/98. Available at: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?191091.

Online Mendelian Inheritance in Man, OMIM (TM). John Hopkins University, Baltimore, MD. MIM Number 191090; 6/11/99. Available at: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?191090.

TEXTBOOKS
Kwiatkowski DJ. Tuberous Sclerosis. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:595-6.

Jones KL. Smith's Recognizable Patterns of Human Malformation. 5th ed. Philadelphia, PA; W.B. Saunders Company; 1997:506-507.

Buyse ML. Birth Defects Encyclopedia. Dover, MA; Blackwell Scientific Publications, Inc.; 1990:1712-1714.

Behrman RE, et al., eds. Nelson Textbook of Pediatrics. 15th ed. Philadelphia, PA; W.B. Saunders Company; 1996:1358, 1707, 1793-1794, 1848.

JOURNAL ARTICLES
Timotin L, et al., Tuberous sclerosis without mental impairment, diagnosed in adulthood. Rev Med Interne. 2005;26:511-3.

Curatolo P, et al., Intractable seizures in tuberous sclerosis complex: from molecular pathogenesis to the rationale for treatment. J Child Neurol. 2005;20:318-25.

Mayer K, et al. Mutation screening of the entire coding regions of the TSC1 and the TSC2 gene with the protein truncation test (PTT) identifies frequent splicing defects. Hum Mutat. 1999;14:401-411.

Kwiatkowska J, et al. Comprehensive mutational analysis of the TSC1 gene: observations on frequency of mutation, associated features, and nonpenetrance. Ann Hum Genet. 1998;62:277-285.

Au KS, et al. Germ-line mutational analysis of the TSC2 gene in 90 tuberous-sclerosis patients. Am J Hum Genet. 1998;62:286-294.

Beauchamp RL, et al. Exon scanning of the entire TSC2 gene for germline mutations in 40 unrelated patients with tuberous sclerosis. Hum Mutat. 1998;12:408-416.

Xiao GH, et al. The tuberous sclerosis 2 gene product, tuberin, functions as a Rab5 GTPase activating protein (GAP) in modulating endocytosis. J Biol Chem. 1997;272:6097-6100.

van Bakel I, et al. Mutations in the TSC2 gene: analysis of the complete coding sequence using the protein truncation test (PTT). Hum Molec Genet. 1997;6:1409-1414.

Jones AC, et al. Molecular genetic and phenotypic analysis reveals differences between TSC1 and TSC2 associated familial and sporadic tuberous sclerosis. Hum Molec Genet. 1997;6:2155-2161.

Povey S, et al. Two loci for tuberous sclerosis: one on 9q34 and one on 16p13. Ann Hum Genet. 1994;58:107-127.

Kandt RS, et al. Linkage of a major gene locus for tuberous sclerosis to a chromosome 16 marker for polycystic kidney disease. Am J Hum Genet. 1992;51(suppl.):A4.

Haines JL, et al. Localization of one gene for tuberous sclerosis within 9q32-9q34, and further evidence for heterogeneity. Am J Hum Genet. 1991;49:764-772.