Tuberous sclerosis complex is a genetic disorder characterized by the growth of numerous noncancerous (benign) tumors in many parts of the body. These tumors can occur in the brain, kidneys, heart, skin, and other organs, in some cases leading to significant health problems. Tuberous sclerosis complex also causes developmental problems, and the signs and symptoms of the condition vary from person to person.

Tuberous sclerosis complex often affects the brain, with some affected individuals having benign growths in the outer surface of the brain (cerebral cortex) known as cortical tubers. Individuals with tuberous sclerosis complex often develop a pattern of behaviors called TSC-associated neuropsychiatric disorders (TAND). These disorders include hyperactivity, aggression, psychiatric conditions, intellectual disability, and problems with communication and social interaction (autism spectrum disorder). Additionally, individuals with tuberous sclerosis complex may have attention-deficit/hyperactivity disorder (ADHD) or seizures.

Kidney tumors are common in people with tuberous sclerosis complex; these growths can cause severe problems with kidney function and may be life-threatening in some cases. Additionally, tumors can develop in the heart (cardiac rhabdomyoma) and the light-sensitive tissue at the back of the eye (the retina). Some women with tuberous sclerosis complex develop lymphangioleiomyomatosis (LAM), which is a lung disease characterized by the abnormal overgrowth of smooth muscle-like tissue in the lungs that causes coughing, shortness of breath, chest pain, and lung collapse.

Virtually all affected people have skin abnormalities, including patches of unusually light-colored skin, areas of raised and thickened skin, and growths under the nails. Tumors on the face called facial angiofibromas are also common beginning in childhood. Sometimes, affected individuals have areas of bone or dental damage.

Tuberous sclerosis complex (TSC), also known as tuberous sclerosis, is a rare genetic disease that causes non-cancerous (benign) tumors to grow in the brain and several areas of the body, including the spinal cord, nerves, eyes, lung, heart, kidneys, and skin. The name tuberous sclerosis comes from the characteristic tuber or potato-like nodules in the brain, which are affected by calcium with age and become hard or sclerotic.

TSC is a lifelong condition. Currently there is no cure for TSC, but some symptoms can be treated. The prognosis for individuals with TSC is highly variable and depends on the severity of symptoms. Some people with TSC are able to lead independent, productive lives, while others have symptoms that can affect everyday life and even be life-threatening.

Many people with TSC show signs of the disorder as early as the first year of life, while the signs and symptoms may take years to develop in others. All individuals with TSC are at risk for life-threatening conditions related to the brain tumors, kidney lesions, or lung lesions.

Tuberous sclerosis complex affects 1 in 6,000 to 10,000 people.

TSC occurs in all races and, ethnic groups, and in males and females. In the U.S., an estimated one in 6,000 children are born each year with this disorder.

If a parent has TSC, each child has a 50 percent chance of developing the disorder. Children who inherit TSC may not have the same symptoms as their parent and may have either a more mild or severe form of the disorder.

TSC is caused by genetic mutations on either the TSC1 or TSC2 gene. Only one of the genes needs to be affected for TSC to be present. A mutation of either one of these genes leads to abnormal development and exponential growth of cells within the body.

The TSC1 gene produces a protein called hamartin. The TSC2 gene produces the protein tuberin. Scientists believe these proteins act as growth suppressors by silencing or interfering with the activation of a protein called mTOR. Loss of regulation of mTOR occurs in cells lacking either hamartin or tuberin, and this leads to abnormal cell changes and development, and to the generation of enlarged cells, as are seen in TSC brain lesions.

Although some cases of TSC are inherited from a parent, most cases are sporadic (developing on their own) due to new, spontaneous mutations in TSC1 or TSC2—meaning neither parent has the disorder or the genetic mutation(s).

In rare instances, people may acquire TSC through a process called gonadal mosaicism. These individuals have parents with no apparent mutations in the TSC1 or TSC2 gene. 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.

Normal Function

The TSC1 gene provides instructions for producing a protein called hamartin. Within cells, hamartin interacts with a protein called tuberin, which is produced from the TSC2 gene. These two proteins help control cell growth and division (proliferation) and cell size. Proteins that normally prevent cells from growing and dividing too fast or in an uncontrolled way are known as tumor suppressors. Hamartin and tuberin carry out their tumor suppressor function by interacting with and regulating a wide variety of other proteins.

Health Conditions Related to Genetic Changes

Lymphangioleiomyomatosis

TSC1 gene variants (also known as mutations) can cause a disorder called lymphangioleiomyomatosis (LAM), although variants in the TSC2 gene appear to be responsible for most cases of this disorder. This destructive lung disease is caused by the abnormal overgrowth of smooth muscle-like tissue in the lungs. It occurs almost exclusively in women, causing coughing, shortness of breath, chest pain, and lung collapse.

LAM can occur alone (isolated or sporadic LAM) or in combination with a condition called tuberous sclerosis complex (described below). Researchers suggest that sporadic LAM can be caused by a random variant in the TSC1 gene that occurs very early in development. As a result, some of the body's cells have a normal version of the gene, while others have the altered version. This situation is called mosaicism. When a variant occurs in the other copy of the TSC1 gene in certain cells during a woman's lifetime (a somatic variant), she may develop LAM.

Tuberous sclerosis complex

Hundreds of variants in the TSC1 gene have been identified in individuals with tuberous sclerosis complex, a condition characterized by developmental problems and the growth of noncancerous (benign) tumors in many parts of the body. Most of these variants involve either small deletions or insertions of DNA in the TSC1 gene. Some variants create a premature stop signal in the instructions for making hamartin.

People with TSC1-related tuberous sclerosis complex are born with one altered copy of the TSC1 gene in each cell. A TSC1 gene change prevents the cell from making functional hamartin from that copy of the gene. Enough hamartin is usually produced from the other, normal copy of the TSC1 gene to regulate cell growth effectively. For some types of tumors to develop, a second variant involving the other copy of the gene must occur in certain cells during a person's lifetime.

When both copies of the TSC1 gene are altered in a particular cell, that cell cannot produce any functional hamartin. The loss of this protein allows the cell to grow and divide in an uncontrolled way to form a tumor. A shortage of hamartin also interferes with the normal development of certain cells. In people with TSC1-related tuberous sclerosis complex, a second TSC1 gene variant typically occurs in multiple cells over an affected person's lifetime. The loss of hamartin in different types of cells disrupts normal development and leads to the growth of tumors in many different organs and tissues, leading to the signs and symptoms of tuberous sclerosis complex.

Cholangiocarcinoma

MedlinePlus Genetics provides information about Cholangiocarcinoma

Other disorders

Inherited variants in the TSC1 gene can cause a disorder known as focal cortical dysplasia of Taylor balloon cell type. This disorder involves malformations of the cerebrum, the large, frontal part of the brain that is responsible for thinking and learning. Focal cortical dysplasia causes severe recurrent seizures (epilepsy) in affected individuals.

Other Names for This Gene

• hamartin
• KIAA0243
• TSC1_HUMAN
• tuberous sclerosis 1

Genomic Location

Normal Function

The TSC2 gene provides instructions for producing a protein called tuberin. Within cells, tuberin interacts with a protein called hamartin, which is produced from the TSC1 gene. These two proteins help control cell growth and division (proliferation) and cell size. Proteins that normally prevent cells from growing and dividing too fast or in an uncontrolled way are known as tumor suppressors. Hamartin and tuberin carry out their tumor suppressor function by interacting with and regulating a wide variety of other proteins.

Health Conditions Related to Genetic Changes

Lymphangioleiomyomatosis

TSC2 gene variants (also known as mutations) cause most cases of a disorder called lymphangioleiomyomatosis (LAM). This destructive lung disease is characterized by the abnormal overgrowth of smooth muscle-like tissue in the lungs. It occurs almost exclusively in women, causing coughing, shortness of breath, chest pain, and lung collapse.

LAM can occur alone (isolated or sporadic LAM) or in combination with a condition called tuberous sclerosis complex (described below). Researchers suggest that sporadic LAM is caused by a random variant in the TSC2 gene that occurs very early in development. As a result, some of the body's cells have a normal version of the gene, while others have the altered version. This situation is called mosaicism. When a variant occurs in the other copy of the TSC2 gene in certain cells during a woman's lifetime (a somatic variant), she may develop LAM.

Tuberous sclerosis complex

More than a thousand variants in the TSC2 gene have been identified in individuals with tuberous sclerosis complex, a condition characterized by developmental problems and the growth of noncancerous tumors in many parts of the body. Most of these variants insert or delete a small number of DNA building blocks (base pairs) in the TSC2 gene. Other variants change a single base pair in the TSC2 gene or create a premature stop signal in the instructions for making tuberin.

People with TSC2-related tuberous sclerosis complex are born with one altered copy of the TSC2 gene in each cell. A TSC2 gene variant prevents the cell from making functional tuberin from that copy of the gene. Enough tuberin is usually produced from the other, normal copy of the TSC2 gene to regulate cell growth effectively. For some types of tumors to develop, a second variant involving the other copy of the gene must occur in certain cells during a person's lifetime.

When both copies of the TSC2 gene are altered in a particular cell, that cell cannot produce any functional tuberin. The loss of this protein allows the cell to grow and divide in an uncontrolled way to form a tumor. A shortage of tuberin also interferes with the normal development of certain cells. In people with TSC2-related tuberous sclerosis complex, a second TSC2 gene variant typically occurs in multiple cells over an affected person's lifetime. The loss of tuberin in different types of cells disrupts normal development and leads to the growth of tumors in many different organs and tissues, leading to the signs and symptoms of tuberous sclerosis complex.

Other Names for This Gene

• PPP1R160
• TSC2_HUMAN
• tuberin
• tuberous sclerosis 2

Genomic Location

Tuberous sclerosis complex has an autosomal dominant pattern of inheritance, which means one copy of the altered gene in each cell is sufficient to increase the risk of developing tumors and other problems with development. In about one-third of cases, an affected person inherits an altered TSC1 or TSC2 gene from a parent who has the disorder. The remaining two-thirds of people with tuberous sclerosis complex are born with new variants in the TSC1 or TSC2 gene. These cases, which are described as sporadic, occur in people with no history of tuberous sclerosis complex in their family. TSC1 gene variants appear to be more common in familial cases of tuberous sclerosis complex, while variants in the TSC2 gene occur more frequently in sporadic cases.

Rarely, individuals with tuberous sclerosis complex do not have an identified variant in the TSC1 or TSC2 gene. Research suggests that in these cases the condition may be caused by a random variant in the TSC1 or TSC2 gene that occurs very early in development. As a result, some of the body's cells have a normal version of the gene, while others have the altered version. This situation is called mosaicism.

Common neurological symptoms of TSC include:

Brain tumors—The three types of brain lesions seen in TSC are:

1. 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
2. Subependymal nodules (SEN), which form in the walls of the ventricles (fluid-filled cavities of the brain)
3. Subependymal giant-cell astrocytomas (SEGA), which develop from SEN and grow to potentially block the flow of fluid within the brain, which causes a buildup of fluid and pressure that can lead to headaches and blurred vision

Other types of tumors can form in the hearts of infants and young children with TSC (called rhabdomyomas) and in the eyes (called phakomas). Other tumors and cysts may be found in other areas of the body, including the liver, lung, and pancreas.

Seizures—Most people with TSC are affected by seizures at some time in their life. While some kinds of seizures caused by TSC result in obvious convulsive movements, others alter awareness, behavior, or postural tone without convulsions.

Cognitive difficulties—Developmental delay occurs in about one-half to two-thirds of people with TSC. Delays range from mild learning disabilities to severe impairment of cognitive abilities.

Behavior problems—Aggressive behavior, sudden rage, attention deficit hyperactivity disorder, acting out, obsessive-compulsive disorder, and repetitive, destructive, or self-harming behavior occur in children with TSC and can be difficult to manage.

Autism Spectrum Disorder—There is a strong relationship between autism spectrum disorder and TSC. Many children with TSC develop autism spectrum disorder.

Other symptoms include:

Skin abnormalities vary widely in individuals with TSC. Some cases may cause disfigurement and may need to be treated. 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.
• Facial angiofibromas (also known as adenoma sebaceum) are reddish spots or bumps which appear on the face (sometimes resembling acne) and consist of blood vessels and fibrous tissue.
• Forehead plaques are raised, discolored areas on the forehead which are common and unique to TSC and may help doctors diagnose the disorder.
• Shagreen patches are areas of thick leathery, pebbly skin, usually found on the lower back or nape of the neck.
• Ungual or subungual fibromas are small fleshy tumors that grow around and under the toenails or fingernails and may need to be surgically removed if they enlarge or cause bleeding. These usually appear later in life, ages 20-50.
• 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.

Kidney problems—Cysts and angiomyolipomas (benign growths of fatty tissue and muscle cells) occur in an estimated 70 to 80 percent of individuals with TSC. They usually occur between ages 15 and 30.

• Cysts are usually small, appear in limited numbers, and most often cause no serious problems. A very small percent of individuals with TSC develop large numbers of cysts during childhood, which may lead to bleeding, anemia, and kidney failure.
• Angiomyolipomas are the most common kidney lesions in TSC and can be found in people without TSC. Angiomyolipomas caused by TSC are usually found in both kidneys and in most cases do not produce 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 and, in some instances, 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.

Lung lesions—Legions are present in about one-third of adult women with TSC and are much less commonly seen in men. Lung lesions include lymphangioleiomyomatosis (LAM) and multinodular multifocal pneumocyte hyperplasia (MMPH).

• LAM is a tumor-like disorder in which cells increase in the lungs, and there is lung destruction with cyst formation. A range of symptoms can occur with LAM, with many TSC individuals having no symptoms, while others suffer with breathlessness, which can progress and be severe.
• MMPH is a more benign tumor that occurs in men and women equally.

Diagnosing TSC is based upon clinical criteria which includes identifying signs and symptoms, looking at family history, and diagnostic imaging including CT scans or MRI, (particularly in the brain) and ultrasound of the heart, liver, and kidneys. Seizures and delayed development may be the first clues of having TSC. An examination of the skin, fingernails, toenails, teeth, gums, and eyes will also help doctors diagnose the disorder.

In infants, TSC may be suspected if the child has cardiac rhabdomyomas at birth or seizures (especially the kind called infantile spasms) in the first six months of life. With a careful examination of the skin and brain, it may be possible to diagnose TSC in a very young infant. However, many children are not diagnosed until later in life when their seizures begin and other symptoms appear.

Currently there is no cure for TSC, but treatment is available for a number of symptoms. Treatment is symptomatic and supportive, such as early developmental interventions to reduce the risk of developmental delays. Interventions may include physical, occupational, speech, and behavioral therapy. Since TSC is unique to each person, an individualized treatment plan will provide the best possible disorder management.

Antiepileptic drugs may be used to control seizures. Vigabatrin is a particularly useful medication in TSC and has been approved by the U.S. Food and Drug Administration (FDA) for treatment of infantile spasms in TSC, although it has significant side effects. The FDA has approved the drug everolimus (Afinitor®) to treat certain brain and kidney tumors, in addition to intractable seizures (seizures not controlled well by medicine). Special medications may be prescribed for behavioral problems. Surgery may be needed to remove tumors from affected organs if they are not properly functioning. If lung lesions are severe enough, they can be treated with supplemental oxygen therapy or lung transplantation.

Basic laboratory studies have revealed insight into the function of the TSC genes and have led to use of rapamycin (mTOR) inhibitors and related drugs for treating some of the manifestations of TSC.

The National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health (NIH), supports and conducts 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. Scientists hope knowledge gained from this research may improve diagnostic and genetic testing for TSC, and lead to new avenues of treatment, methods of prevention, and, ultimately, a cure.

The National Heart, Lung, and Blood Institute (NHLBI) and the National Cancer Institute (NCI), also support and conduct research on TSC.

NINDS-funded scientists are using animal or cell-based models to understand:

• The role of TSC1/TSC2 and the mTOR pathway in neurodevelopment
• How TSC mutations contribute to cognitive dysfunction and intellectual disability

• Shared mechanisms with related neurodevelopmental disorders
• The mechanisms that lead to epilepsy and autism in TSC

In one NINDS-supported clinical trial, researchers are studying the effectiveness of early intervention with vigabatrin, an antiseizure medication, and how it might prevent seizures and improve neurocognitive outcomes in infants with TSC.

NIH's Rare Diseases Clinical Research Network (RDCRN) furthers medical research on rare diseases by providing support for clinical studies and facilitating collaboration, study enrollment, and data sharing. RDCRN includes the Developmental Synaptopathies Consortium which supports natural history, imaging, and biomarker identification for TSC and related neurodevelopmental disorders.