Tuberous sclerosis complex
Tuberous sclerosis complex (TSC) is a genetic condition that affects many organ systems including the brain, skin, heart, kidneys, eyes, and lungs. Benign (non-cancerous) growths or tumors called hamartomas form in various parts of the body, disrupting their normal functions.
The term tuberous sclerosis refers to the small, knoblike growths in the brain of patients with TSC that were found in patients upon autopsy and, today, can be viewed using computed tomography (also called a CT scan). The condition is also referred to as tuberose sclerosis or simply tuberous sclerosis. The designation tuberous sclerosis complex is used to distinguish this condition from another genetic condition called Tourette syndrome that is abbreviated TS.
Persons with TSC have a variety of symptoms ranging from very mild to severe. Affected individuals may experience no serious health problems and, in the absence of a thorough clinical examination, may go through life without knowing that they are affected. Conversely, patients with TSC may have problems with behavioral, mental, and emotional functions as well as with their kidneys, heart, and eyes. In addition, specific skin abnormalities, often medically insignificant, are among the most common symptoms of TSC.
TSC is an autosomal dominant genetic disorder caused by a single change or alteration in a gene called a mutation in either the TSC1 gene, located on chromosome 9, or the TSC2 gene, located on chromosome 16. Approximately two-thirds (66%) of patients with TSC have it as the result of a new change in one of the TSC genes; that is, it was not inherited from one of their parents. When a new change occurs, it most commonly occurs in the TSC2 gene. An individual must have a mutation in one of these two copies of a TSC-causing gene in order to develop the condition. In addition, a person who has been diagnosed with TSC and who, therefore, has a genetic mutation in one of the TSC genes, has a 50% chance of passing on the genetic mutation to his or her offspring. Laboratory testing for changes in the TSC genes is not currently available.
TSC is a condition that can be caused by a change in either one of two separate genes. In addition, people who have the same change in the same gene may have very different medical problems and symptoms.
TSC1 is responsible for producing the protein hamartin and TSC2, tuberin. Both genes are known as tumor suppressor genes meaning that their normal function is to prevent the growth of tumors. Conversely, when gene function is altered, tumor growth results. Research on how the disruption of either protein results in the clinical condition of TSC is ongoing.
It is currently believed that every person who inherits or develops a mutation in either the TSC1 or TSC2 gene will develop some form of TSC. However, the severity of the disease, with its wide range of symptoms and complications, cannot accurately be predicted by identifying the specific gene mutation.
Germline mosaicism can explain the rare occurrence of unaffected parents having more than one child with TSC. Germline refers to the gonadal cells (sperm in males and eggs in females) and mosaicism refers to the presence of different cell lines in any given individual. A person with germline mosaicism for either the TSC1 or TSC2 gene is not affected with TSC but may have an affected child. Unaffected parents of a child with TSC are quoted a 2-3% chance of having additional affected children. Typical genetic testing methods are performed on somatic (non-germline) tissues such as blood or skin and, therefore, will not detect germline mosaicism.
Although tuberous sclerosis complex is considered to be a rare condition, estimates of the prevalence of the disorder have increased as clinical testing methods have improved. In the United States, as many as one child in 6,000 born is affected with TSC and about 50,000 people are currently living in the U.S. with the disease. TSC is seen in all ethnic groups and populations and, worldwide, there are between one and two million cases.
Signs and symptoms
The basic underlying cause for illness and, less often, death due to tuberous sclerosis complex is the development of growths called hamartomas throughout the body. Hamartoma is a general term used to describe tumor-like growths that are not cancerous and are composed of cells usually found in that site but poorly developed. While these growths are typically benign (i.e., not cancerous), their presence often disrupts the normal functions of a particular organ system. The various hamartomas found in TSC patients can be further distinguished and classified by their location and their histological
While the organs affected vary from person to person, most people with TSC have some type of skin irregularities called lesions. Some of the most commonly seen skin lesions are hypomelanotic macules—white or light patches sometimes in an ash-leaf shape and called Ash-leaf spots. Many people in the general population have one or two light areas of skin. However, the presence of three or more such macules in any one individual is considered a major diagnostic finding of TSC. A second major diagnostic feature of the condition is the appearance of small, red bumps called fibromas, either on the face (facial angiofibromas) or around or under the finger- or toenails (ungual fibromas). In addition, rough patches of skin termed Shagreen patches are highly specific to a diagnosis of TSC. Finally, groups of small light circles called Confetti spots are considered a minor feature of the disorder.
In contrast to skin lesions, brain lesions tend to be serious and are responsible for the neurological symptoms and cognitive impairment seen in severely affected individuals. There are four primary abnormalities that can be detected by magnetic resonance imaging (MRI) or computer tomography (CT) scanning, the first of which are cortical tubers—nodular growths found in the cortex of the brain—and give tuberous sclerosis (literally "hard growths") its name. Subependymal nodules are growths found underneath the lining of the ventricles in the brain and may cause no problems for the patient unless they grow or begin to block the flow of the cerebral spinal
About 85% of affected individuals will develop epileptic seizures at some point in their lifetime, most beginning by the first year of life. Research suggests that early control of epilepsy by medication will decrease the chance of a child developing serious mental complications. People with TSC have a range of mental abilities from normal to mild or moderate developmental delays and learning disabilities, to severe mental retardation. Autism, attention deficit hyperactivity disorder (ADHD), and other behavioral problems are seen in affected individuals.
Fatty kidney tumors, known as renal angiomyolipomas, are one of the most common findings in TSC patients, affecting 70-80% of older children and adults, and often cause serious renal malfunction. In addition, the presence of multiple renal cysts (fluid filled areas within the kidneys) is suggestive of the condition. In addition to these benign growths, malignant kidney tumors may also develop.
The most common cardiac symptom is one or more tumors (cardiac rhabdomyomas) in the heart. These tumors are almost exclusively seen in infants and young children and usually spontaneously disappear by late childhood, thereby avoiding the need for surgery. About 47-67% of infants and children with TSC have heart tumors and some females develop the rhabdomyomas when they reach puberty.
Tuberous sclerosis complex affects the eyes in the form of retinal nodular hamartomas—multiple growths on the retina. A discoloration on the retina (retinal achromic patch) is also considered a minor feature of the condition.
In addition to the above, symptoms of TSC may include dental pits in the teeth, growths in the rectum (hamartomatous rectal polyps), bone cysts, growths on the gums (gingival fibromas) and other non-specific growths (nonrenal hamartomas). Women with TSC may develop lymphangiomyomatosis, a serious lung disease. Furthermore, all individuals with TSC are at a higher risk over the general population for developing specific cancers, with 2% of patients developing a malignant tumor in one of the affected body tissues such as kidney or brain.
When a person exhibits signs of TSC or has a family history of the condition, an evaluation by a medical geneticist, neurologist, or other qualified professional is recommended to confirm (or rule out) the diagnosis and to recommend screening and management options for the individual. In addition, speaking with a genetic counselor may help families understand the genetics behind the disorder, their recurrence risks (chances for having another affected family member) and the practical and psychosocial implications of the disease on their personal situation.
Detection of hypomelanotic macules (light patches on the skin) can be performed quickly and easily using a special ultraviolet lamp called a Wood's lamp. This light emphasizes the lightened areas on the skin that may otherwise be difficult to see using normal light. Other skin lesions called fibromas are easily visible and identifiable due to their characteristic smooth form, red color, and their even distribution on the face and/or their protrusions among the nails on the fingers and toes. Radiographic imaging using ultrasound, MRI, or CT technology can detect growths present in the brain, kidneys, heart, and eyes.
As basic understanding of and testing methods for tuberous sclerosis complex have improved, criteria used for confirming a diagnosis of tuberous sclerosis complex have been revised. The National Institutes of Health
- Facial angiofibromas or forehead plaque
- Nontraumatic ungual or periungual fibroma
- Hypomelanotic macules (more than three)
- Shagreen patch
- Multiple retinal hamartomas
- Cortical tuber
- Subependymal nodule
- Subependymal giant cell astrocytoma
- Cardiac rhabdomyoma (one or more)
- Renal angiomyolipoma
- Multiple randomly distributed dental pits
- Hamartomatous rectal polyps
- Bone cysts
- Cerebral white matter migration lines
- Gingival fibromas
- Nonrenal hamartoma
- Retinal achromic patch
- Confetti skin lesions
- Multiple renal cysts
A confirmed diagnosis of TSC requires that a patient display either two major features or one major and two minor features, a suspected diagnosis one major and one minor feature, and a possible diagnosis one major or two minor features in any one individual.
Treatment and management
Optimal treatment for TSC is dependent upon proper disease management. The following should be performed on all patients with TSC at the time of diagnosis to confirm a diagnosis of the disease as well as obtain baseline medical data for future evaluations:
- dermatologic (skin) examination
- fundoscopic (eye) examination
- renal (kidney) imaging study
- cardiac electrocardiogram (ECG) and echocardiogram (ECHO)
- brain magnetic resonance imaging (MRI)
Since the characteristic feature of tuberous sclerosis complex is the growth of benign tumors, treatments are often focused on appropriate surgical interventions to arrest tumor growth or remove tumors whose growth has resulted in or may lead to medical complications especially in the kidney or brain. Regular brain MRI studies should be performed in children and adults with previous findings as clinically indicated and every one to three years in children and, less frequently, in adults without symptoms. In addition, periodic brain electroencephalogram (EEG) studies are recommended for both children and adult patients when clinically indicated.
Children without previous kidney findings should be offered renal imaging studies using ultrasound, MRI, or CT scanning every three years until they reach adolescence and then, every one to three years as adults. Likewise, asymptomatic adults should have imaging of their kidneys every one to three years. Both children and adults who have kidney symptoms should be monitored using imaging studies every six months to one year until the tumor growth stabilizes or decreases.
Any child with cardiac rhabdomyomas should be monitored every six months to one year until the tumor stabilizes or regresses completely. Adults with previous findings of cardiac tumors should be monitored as clinically recommended by their treating physician. While monitoring is important, cardiac rhabdomyomas, as well as retinal lesions and gingival fibromas, usually do not require treatment. In contrast to these benign tumors, cancerous tumors that develop in patients with TSC should be treated by an oncologist as appropriate.
Facial angiofibromas and peri- and subungual fibromas on the nails are common symptoms in TSC patients. While they are generally not medically significant, they can cause skin irritations or be a cosmetic concern to the individual. Special techniques involving dermabrasion or laser therapy can be performed by a dermatologist or plastic surgeon to remove such growths.
Patients with seizure disorders are prescribed specific medications to control seizures. As of 2001, a new anti-epileptic drug (vigabatrin) has been shown to be an effective medication in infants with seizures and has been shown to improve long-term outcomes in behavioral and intellectual areas. In addition to controlling seizures, early intervention programs that include special education, behavior modification, physical and occupational therapies, and speech therapy is often recommended for individuals with learning disabilities, developmental delays, mental retardation, autism, and other mental and emotional disorders.
Neurodevelopmental testing is appropriate at the time of diagnosis for all children and should be performed every three years until adolescence and for any adult diagnosed with TSC who displays signs of impairment. Subsequent evaluations should be done on both children and adults with previous findings of developmental delays or problems.
While present in only 1% of patients with TSC, almost exclusively in females, lung complications can be serious and even fatal. Symptoms may include spontaneous pneumothorax (air in the chest cavity), dyspnea (difficult breathing), cough, hemoptysis (spitting of blood), and pulmonary failure. Therefore, a computed tomography (CT) scan of the lungs is recommended for any TSC patient who has symptoms of lung disease or complications and for all female TSC patients at the age of 18. Clinical trials involving Tamoxifen and progesterone treatments have shown positive results in some patients with lung disease.
The lifespan of individuals with TSC varies with the severity of the condition in any one person. Many affected people have normal life expectancies and a high quality of life, relatively free of symptoms or complication of the disease. Conversely, severely affected or disabled individuals may experience a shortened lifespan and a high rate of illness and medical complications. Therefore, proper disease management, diagnostic monitoring, and follow-up are critical to achieving and maintaining optimal health in patients with TSC.
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Tuberous Sclerosis Alliance. 801 Roeder Rd., Suite 750, Silver Spring, MD 20910. (800) 225-6872. <http://www.tsalliance.org>.
Australasian Tuberous Sclerosis Society. <http://www.netspace.net.au/~atss/>.
The Global Tuberous Sclerosis Information Link. <http://members.aol.com/gtsil/ts/index.htm>.
Tuberous Sclerosis Alliance. <http://www.tsalliance.org>.
The Tuberous Sclerosis Association. <http://www.tuberous-sclerosis.org/>.
Pamela E. Cohen, MS, CGC