Tuberous Sclerosis Complex (TSC) is a genetic disorder causing non-cancerous tumors to form in organs like the brain, skin, kidneys, heart, and lungs. The effects of the condition vary significantly, with some individuals experiencing mild symptoms while others face more substantial health challenges. The expression of the disorder is so variable that even affected members of the same family can have vastly different outcomes. Because its signs can be subtle and develop over time, a diagnosis may not occur until later in life.
Genetic Origins of TSC
Tuberous Sclerosis Complex arises from mutations in one of two genes: TSC1 or TSC2. These genes provide instructions for making hamartin and tuberin, proteins that work together to regulate cell growth by inhibiting a protein called mTOR. This function effectively prevents cells from dividing in an uncontrolled manner.
A mutation in either gene disrupts this regulation, leaving the mTOR pathway constantly active. This signals cells to grow and multiply continuously, resulting in the formation of benign tumors called hamartomas. The specific gene affected can influence the condition’s severity, with TSC2 mutations generally associated with a more significant clinical presentation.
About one-third of cases are inherited from a parent with the disorder. The remaining two-thirds result from a new, spontaneous mutation in the TSC1 or TSC2 gene. These instances are known as sporadic cases and are the more common origin of TSC, occurring in individuals with no prior family history.
Physical Manifestations
The signs and symptoms of Tuberous Sclerosis Complex depend on where growths develop and how large they become.
Brain
Neurological involvement is common in TSC, with three main types of brain lesions observed. Cortical tubers are areas on the brain’s surface that can disrupt normal activity and are a primary cause of seizures. Subependymal nodules (SENs) are small growths lining the brain’s ventricles. Some SENs can develop into larger tumors called subependymal giant cell astrocytomas (SEGAs), which may block cerebrospinal fluid flow and increase pressure inside the skull.
These brain abnormalities are linked to common TSC symptoms. Seizures affect about 85% of individuals with the condition and can begin in infancy. Many people with TSC also experience developmental and behavioral challenges, grouped under the term TSC-Associated Neuropsychiatric Disorders (TAND), which can include intellectual disabilities and features of autism spectrum disorder.
Skin
Nearly all individuals with TSC develop skin abnormalities, which are often one of the first clues for diagnosis. Common signs include hypomelanotic macules, or “ash-leaf spots,” which are patches of light-colored skin. Another characteristic finding is facial angiofibromas, which are reddish bumps that typically appear on the nose and cheeks during childhood.
Other skin manifestations include shagreen patches, which are areas of thick, pebbled skin usually found on the lower back. Small, fleshy growths called fibromas can also form around or under the fingernails and toenails. While most skin lesions do not cause significant medical problems, they can be a cosmetic concern.
Kidneys
Kidney problems are frequent in people with TSC and tend to develop over time. The most common growths are angiomyolipomas (AMLs), benign tumors of blood vessels, muscle, and fat. While not cancerous, these tumors can grow large enough to cause pain, impair kidney function, or rupture and cause serious internal bleeding. Multiple cysts can also form in the kidneys.
Heart
Benign tumors known as cardiac rhabdomyomas can develop in the heart and are common in infants with TSC, often detected on prenatal ultrasounds. In many cases, these heart tumors cause no symptoms and shrink or disappear as the child gets older. However, they can occasionally cause arrhythmias or obstruct blood flow in very young infants.
Lungs
Lung involvement in TSC primarily occurs as lymphangioleiomyomatosis (LAM), a condition where smooth muscle-like cells grow abnormally in the lungs. LAM almost exclusively affects women, usually becoming apparent during their childbearing years or later. This cell overgrowth can lead to cysts, causing shortness of breath, coughing, and sometimes lung collapse.
The Diagnostic Process
Diagnosing Tuberous Sclerosis Complex requires a comprehensive evaluation, as the disorder can affect many body systems. The first signs that lead to a suspicion of TSC are often the presence of seizures or specific skin lesions.
A clinical examination is performed to look for signs based on established diagnostic criteria, which are categorized into major and minor features. Major features include specific skin findings, brain lesions like cortical tubers, and tumors in the heart or kidneys. Minor features include multiple kidney cysts and pits in tooth enamel. A definitive diagnosis can be made based on the combination of these features.
Imaging studies are used to confirm tumors in internal organs. A brain MRI can identify tubers, subependymal nodules, and SEGAs. A kidney ultrasound detects angiomyolipomas and cysts, and a heart echocardiogram can identify cardiac rhabdomyomas. For adult women, a high-resolution CT scan of the chest may be recommended to screen for LAM.
Genetic testing can also provide a definitive diagnosis. A blood test analyzes the TSC1 and TSC2 genes for a pathogenic mutation, which is sufficient for diagnosis even without many clinical signs. In about 10-15% of individuals who meet the clinical criteria, a mutation cannot be found with current methods, so the diagnosis is based on clinical and imaging findings.
Management and Monitoring
Since there is no cure for Tuberous Sclerosis Complex, lifelong management focuses on monitoring tumor growth, preventing complications, and treating symptoms. This requires a multidisciplinary team of specialists to manage issues across different organ systems.
Regular surveillance involves routine imaging to track existing lesions and screen for new ones. Patients receive periodic brain MRIs until at least age 25 to monitor for SEGAs. Regular kidney imaging is performed throughout life to track the size of angiomyolipomas. Other check-ups include electrocardiograms (ECGs), eye exams, and lung function tests for those at risk.
A major advancement in treatment is the use of mTOR inhibitors, such as everolimus and sirolimus. These medications work by targeting the overactive mTOR pathway. These drugs can shrink or slow the growth of certain tumors, including SEGAs in the brain and angiomyolipomas (AMLs) in the kidneys. Topical forms of mTOR inhibitors have also been approved to treat facial angiofibromas.
Treatment is also tailored to specific symptoms. Epilepsy is often managed with anti-seizure medications, with surgery as an option for difficult-to-control seizures. Symptomatic or high-risk tumors, such as large AMLs, may be treated with surgery or embolization. Educational, behavioral, and psychiatric therapies are used to support individuals with related neuropsychiatric disorders.