What is TSC?

Tuberous sclerosis complex (TSC) is a genetic disorder that causes non-malignant tumors to form in many different organs, primarily in the brain, eyes, heart, kidney, skin and lungs.

The aspects of TSC that most strongly impact quality of life are generally associated with the brain: seizures, developmental delay, intellectual disability and autism. However, many people with TSC are living independent, healthy lives and enjoying challenging professions such as doctors, lawyers, educators and researchers.  The incidence and severity of the various aspects of TSC vary widely between individuals—even between identical twins. Seizures remain one of the most common neurological features of TSC, occurring in 85% of individuals with TSC; therefore, the early diagnosis and treatment of these seizures are critically important.

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How Many People Have TSC?

At least two children born each day will have tuberous sclerosis complex. Current estimates place tuberous sclerosis complex-affected births at one in 6,000. Nearly 1 million people worldwide are estimated to have TSC. Many cases may remain undiagnosed for years or decades due to the relative obscurity of the disease and the mild form symptoms may take in some people.

How Does a Person Develop TSC?

Tuberous sclerosis complex is a genetic disease that can be inherited from one parent with TSC or can result from a spontaneous genetic mutation. Children have a 50 percent chance of inheriting TSC if one of their parents has this condition. At this point, only one-third of TSC cases are known to be inherited. The other two-thirds result from a spontaneous and unpredictable mutation occurring during conception or very early development of the human embryo.

How is TSC Diagnosed?

Because TSC can manifest in so many different ways, diagnosis is generally made when physicians identify any two major features of TSC in one individual.  One major feature is cardiac rhabdomyoma, an abnormal growth in the heart muscle generally found in young children and sometimes found by ultrasound examination during pregnancy.  Other major features include specific abnormal skin growths or skin pigmentation, specific non-malignant tumors or growths such as subependymal nodules or subependymal giant cell astrocytomas (SEGAs) in the brain, lymphangioleiomyomatosis (LAM) in the lungs, angiomyolipomas in the kidney(s), and tubers in the brain or hamartomas in the eye.  Also, there are other minor features of TSC that might be diagnostic if found with a major feature in the same person.  TSC can also be diagnosed by genetic testing described below.

What Genes are Responsible for TSC?

Two genes have been identified that can cause tuberous sclerosis complex. Only one of the genes needs to be affected for TSC to be present. The TSC1 gene is located on chromosome 9 and is called the hamartin gene. The other gene, TSC2, is located on chromosome 16 and is called the tuberin gene. Laboratory research on the function of these genes over the past decade has led to a new drug therapy for two types of tumors in TSC.

How Can So Many Different Organs Be Affected by TSC?

Both the TSC1 and TSC2 genes suppress tumor growth in the body by carefully regulating cell growth through inhibition of a protein called mammalian target of rapamycin, or mTOR for short. When either the TSC1 or TSC2 gene is defective, cell growth is not adequately supressed and tuberous sclerosis complex results. Hamartin, tuberin, and mTOR are expressed in many different organs throughout the body, which explains why so many organs can be affected by TSC.  However, researchers are still working diligently to figure out why TSC is manifested so differently between different people.

Are the Tumors Cancerous?

The growth of tumors resulting from tuberous sclerosis complex is not as severely unregulated as in cancer, but these tumors may still cause serious problems. Tumors that grow in the brain can block the flow of cerebral spinal fluid in the spaces (ventricles) in the brain. This can lead to behavioral changes, nausea, headaches or a number of other symptoms. In the heart, the tumors are usually at their largest at birth and then decrease in size as the individual gets older. These heart tumors, called cardiac rhabdomyomas, can cause problems at birth if they are blocking the flow of blood or causing severe arrhythmia. The tumors in the eyes are not as common, but can present problems if they grow and block too much of the retina. The tumors in the kidney (renal angiomyolipomas) can become so large they eventually disrupt normal kidney function or begin to bleed internally. In the past, kidney failure was almost inevitable. Today, doctors can use drug therapy to shrink angiomyolipomas or can destroy individual tumors by embolization before they get too large and compromise healthy kidney tissue. In cases of severe pain or bleeding, angiomyolipomas can be removed by surgery.  Renal cell carcinoma is very rare in TSC.

What Is the Normal Life Expectancy of an Individual with TSC?

Most people with TSC will live a normal life span. There can be complications in some organs such as the kidneys and brain that can lead to severe difficulties and even death if left untreated. To reduce these dangers, people with TSC should be monitored throughout their life by their physician for potential complications. Thanks to research findings and improved medical therapies, people with tuberous sclerosis complex are experiencing better health care than ever before.  But more research is needed until we find a cure.

Since There Is No Cure, What Can Be Done?

Early diagnosis and intervention can help overcome developmental delays. Data show that early seizure control in children can improve learning as compared to children without good seizure control.  Advancements in research continue to bring new and improved therapeutic options. Some anti-seizure drugs can be effective in individuals with TSC.  When drug treatment fails to adequately control seizures, technology can help identify the exact portions of the brain stimulating seizures and creating new therapies to help control seizures.

For tumors in the brain, surgery is sometimes used to permanently remove tumors that are relatively few in number and easily accessible by the surgeon.  In other cases, drug treatment may be used to shrink brain tumors.  In the fall of 2010, the FDA approved the first drug with an indication specifically for TSC to treat a type of brain tumor known as subependymal giant cell astrocytomas (SEGAs). In 2012, the same drug was approved to treat growing angiomyolipomas, a type of kidney tumor in TSC.

Major advancements in treatments such as these require clinical studies to test the effectiveness of experimental drugs, surgery, or other interventions in people with TSC.  Because the TSC community is in vital need of new treatments, individuals with TSC frequently volunteer to participate in cutting-edge clinical studies.  Some ongoing clinical studies in TSC include testing the effects of drug treatment on neurocognitive function, testing a new combination drug treatment for LAM, finding biomarkers to identify infants at high risk of developing autism or infantile spasms, and testing a topical drug treatment of facial angiofibromas.  Thanks to volunteers in these and other studies, every new day brings us one step closer to finding improved treatments for TSC.

Diagnostic Criteria and Surveillance Recommendations

In July 2021, the International TSC Diagnostic Criteria and Surveillance and Management Recommendations were updated to reflect advances in knowledge and approval of new therapies.

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Diagnostic Criteria

In 2012, the International Tuberous Sclerosis Complex Consensus Conference reviewed prevalence and specificity of TSC-associated clinical manifestations and updated the TSC diagnostic criteria from 1998.   Clinical features of TSC continue to be a principal means of diagnosis but include additional clarification and simplification.  In addition, TSC may now be diagnosed via genetic testing.  The new clinical and genetic diagnostic criteria of 2012 are summarized below.

Surveillance Recommendations in TSC

At the time of diagnosis, many medical tests are performed. Individuals and parents should also be aware of routine testing that needs to be performed.  The following tables show suggested surveillance screening for TSC: