# Tuberous Sclerosis Complex

## What is tuberous sclerosis complex?

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.

Common neurological symptoms of TSC include:

Brain tumors—The three types of brain lesions seen in TSC are:
              - 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 (SEN), which form in the walls of the ventricles (fluid-filled cavities of the brain)  
              - 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.

## Who is more likely to get tuberous sclerosis complex?

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. 

## How is tuberous sclerosis complex diagnosed and treated?

**Diagnosing TSC**

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.

**Treating TSC**

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.

## What are the latest updates on tuberous sclerosis complex? 

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.

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## How can I or my loved one help improve care for people with tuberous sclerosis complex?

Consider participating in a clinical trial so clinicians and scientists can learn more about TSC. Clinical research uses human volunteers to help researchers learn more about a disorder and perhaps find better ways to safely detect, treat, or prevent disease. 

All types of volunteers are needed—those who are healthy or may have an illness or disease—of all different ages, sexes, races, and ethnicities to ensure that study results apply to as many people as possible, and that treatments will be safe and effective for everyone who will use them. 

For information about participating in clinical research visit NIH Clinical Research Trials and You. Learn about clinical trials currently looking for people with TSC at Clinicaltrials.gov, a database of current and past clinical studies, some of which have research results.
> Where can I find more information about tuberous sclerosis complex?
Information may be available from the following resources: 

Epilepsy FoundationPhone: 866-748-8008

Genetic and Rare Diseases (GARD) Information Center

National Organization for Rare Disorders (NORD)Phone: 800-999-6673

Tuberous Sclerosis AlliancePhone: 301-562-9800

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