What is Tuberous Sclerosis Complex?
What is Tuberous Sclerosis (TSC)?
The Patient Advocacy Organization, Tuberous Sclerosis Alliance, has an excellent website with information for individuals/families, healthcare professionals and researchers which can be found here: tscalliance.org
Tuberous Sclerosis Complex (also commonly referred to as tuberous sclerosis or TS) is a genetic condition that affects many organs and can cause tumors in the skin, kidney, brain, heart, eyes, lungs, and other organs. The severity of TSC can range from mild, such as skin abnormalities, to severe, such as seizures, intellectual disability or renal failure. TSC affects approximately 50,000 people in the United States and one million worldwide, with an estimated incidence of 1 in 6,000 live births.
What are the symptoms?
The most common symptoms of TSC are seizures and developmental delay as well as benign tumors and lesions which can affect virtually every organ system of the body including the brain, kidneys, heart, lungs, eyes, skin, and other organs. In many instances, symptoms of TSC will be apparent in the first six months of life.
Brain and Neurological Function:
In 95% of individuals with TSC, the brain is somehow affected. This usually takes the form of cortical tubers, subependymal nodules (SEN) and subependymal giant cell astrocytomas (SEGA), which can be detected by brain imaging.
Epilepsy is by far the most common medical condition in TSC, occurring in 80-90% of individuals, with up to 75% of affected individuals developing seizures prior to age two. Caregivers should be educated to recognize seizures, especially when they are not present at the time of diagnosis. Epilepsy may start out as infantile spasms, with peak onset occurring at about 4-6 months of age. Early recognition and control of seizures is highly correlated with improved developmental and neurological outcomes.
Individuals with TSC have an increased risk of having neurodevelopmental and behavioral impairment. Although approximately 50% of individuals with TSC do not have intellectual disability, developmental delay and learning disabilities are commonly found in children with TSC. Additionally, up to 60% of individuals with TSC can develop autism.
Skin:
Skin lesions, including those found on the face, body and nails, are found in almost all individuals with TSC. The earliest sign may be white skin patches (hypomelanotic macules), which are best seen under ultraviolet light. As a child grows older, a characteristic facial rash across the nose and cheeks may appear, known as angiofibromas.
Heart:
Cardiac (heart) involvement is common in TSC and is found in up to two thirds of individuals. Benign heart tumors (cardiac rhabdomyomas) are often an early sign of TSC. Fortunately, these tumors often regress spontaneously, shrinking or completely disappearing with time. It is estimated that 90-95% of infants with a prenatal diagnosis of two or more cardiac rhabdomyomas will have TSC.
Kidney:
Kidney lesions occur in over half of all children at the time of initial evaluation. Benign renal lesions, which account for 75% of abnormalities, are made up of vascular tissue, smooth muscle, and fat. They usually grow very slowly and may not be problematic until young adulthood. Larger kidney lesions can cause symptoms and may require intervention.
What causes TSC?
TSC is caused by a pathogenic genetic variant (disease-causing sequence change) in one of two genes: TSC1 or TSC2. Typically, these genes function to slow cell growth in various parts of our body. If one copy of TSC1 or TSC2 is not working properly, we are at greater risk of developing overgrowths, or benign tumors, in different organs.
At this time, genetic testing for TSC is able to detect pathogenic variants in the TSC1 or TSC2 genes in approximately 85% of individuals. For the other 15% of individuals without an identifiable sequence change, researchers are studying ways to accurately find variants in these two known genes and look for additional genes that may be involved. It is also possible for individuals to be mosaic for a variant in TSC1 or TSC2, where the sequence change is present in some tissues in the body (ex. skin or brain cells), but not others.
To learn more about the genetics of TSC and mosaicism, please visit this webpage from the Tuberous Sclerosis Association.
How is TSC inherited?
In general, one third of individuals with TSC inherit the genetic condition from a parent. Two thirds of all cases are sporadic, or occur for the first time in a family.
TSC is inherited as an autosomal dominant genetic condition. This means that a TSC1 or TSC2 variant in only one copy of the gene causes the condition. Individuals with TSC have a 50% chance of passing their condition to each of their children.
How is TSC diagnosed?
A diagnosis of TSC can be made based on a set of clinical criteria or a genetic test result showing a pathogenic sequence change in TSC1 or TSC2.
A clinical diagnosis of TSC is based on a careful physician exam in combination with imaging of the brain, heart and kidneys. The physician will carefully examine the skin for the wide variety of skin lesions, often using an ultraviolet light called a Wood’s lamp which may be useful for finding skin features that can be hard to see on infants or individuals with pale skin.
There is no single clinical feature absolutely specific to the condition. In addition, many features of TSC, such as seizures and developmental delay, are seen in individuals without TSC. Therefore, a constellation of features is necessary for the diagnosis, and an increasing number of features make the clinical suspicion of TSC more likely.
Additionally, a positive genetic test that finds a pathogenic TSC1 or TSC2 variant is considered diagnostic, regardless of the clinical features identified to date.
What is the prognosis of TSC?
The prognosis of individuals with TSC varies from individual to individual. The severity of the complications determines the long term outlook, and symptoms can range from mild to severe. Even individuals with the same TSC1 or TSC2 variant in the same family may experience widely different symptoms and severity. Most individuals who are mildly affected with TSC and are under an experienced physician’s care can expect to live active and productive lives with normal life expectancy.
What is the treatment of TSC?
Effective treatments are available for a variety of TSC symptoms. Drugs to prevent seizures are accessible to individuals and surgery can often correct skin abnormalities. Surgery to remove tumors can help to preserve the function of affected organs. For other symptoms of TSC, such as developmental delay, services such as early intervention, special education and other therapies are often effective in moderating symptoms.