Tuberous Sclerosis Complex
Tuberous sclerosis complex is a rare genetic disease that causes non-cancerous tumors to develop in multiple organs throughout the body, particularly in the brain, kidneys, heart, skin, and lungs. While some people live with few symptoms, others may experience seizures, developmental delays, and serious organ complications that require lifelong monitoring and care.
Table of contents
- What is tuberous sclerosis complex?
- What causes this condition?
- Who is affected by tuberous sclerosis complex?
- Signs and symptoms
- How is tuberous sclerosis complex diagnosed?
- Treatment and management
- Living with tuberous sclerosis complex
What is tuberous sclerosis complex?
Tuberous sclerosis complex (TSC) is a rare genetic disorder that causes non-cancerous tumors, also called benign tumors, to grow in many parts of the body[1]. These tumors are actually overgrowths of cells and tissue that form in unexpected places[2]. The disease gets its name from the tuber-like growths that can develop in the brain and sometimes other organs[15].
TSC can affect different parts of the body to varying degrees of severity. The tumors most commonly grow in the brain, kidneys, heart, skin, lungs, and eyes[1]. Although these tumors are not cancerous, they can still cause serious health problems depending on where they grow and how large they become[3].
The condition affects approximately 50,000 people in the United States and about 1 million people worldwide[3]. TSC occurs in about 1 in 6,000 to 10,000 people[1]. At least two babies born each day in the United States will have it[4].
What causes this condition?
TSC is caused by changes, called variants or mutations, in one of two genes: TSC1 or TSC2[1]. These genes provide instructions for making two important proteins called hamartin and tuberin, which help regulate how cells grow and divide[1].
Normally, hamartin and tuberin work together to help stop cells from growing too quickly. They do this by controlling another protein called mTOR, which plays a key role in cell growth[1]. When mTOR is not regulated properly because of mutations in the TSC1 or TSC2 genes, cells can grow and divide in an uncontrolled way, leading to the formation of tumors[1].
In about two-thirds of cases, there is no family history of the condition, and the genetic change happens randomly in an individual during development[15]. However, TSC can also be inherited. A person with TSC has a 50 percent chance of passing it on to each of their children[9][15].
Who is affected by tuberous sclerosis complex?
TSC is a condition you have when you’re born[3]. Healthcare providers diagnose about half of all cases by the time a child reaches 7 months old[3]. The symptoms of TSC usually appear before a child is 6 months old[5].
However, not all cases are diagnosed early. Sometimes tuberous sclerosis can have such mild symptoms that the condition isn’t diagnosed until adulthood, or it’s not diagnosed at all[2]. Milder cases may go unnoticed for years, and people diagnosed with TSC as children can also have other symptoms diagnosed after they become adults[3].
This condition is equally likely to happen in everyone, with no differences due to sex, race, or ethnicity[3]. TSC affects individuals differently, so even siblings and identical twins can have different experiences with the disease[4].
Signs and symptoms
The symptoms of TSC vary greatly from one person to the next, depending on what parts of the body are affected and how severe the condition is[1][5]. For many people with TSC, symptoms begin in infancy or childhood, but for others, symptoms may take years to develop[1].
Brain-related symptoms
Brain tumors and lesions are common in TSC. Three types of brain growths are typically seen: cortical tubers, which are clusters of cells on the outer surface of the brain; subependymal nodules (SEN), which are small collections of cells along the walls of fluid-filled spaces in the brain; and subependymal giant cell astrocytomas (SEGA), which develop from SEN and can grow large enough to block the flow of fluid in the brain[1].
Seizures are one of the most common symptoms, affecting about 85 percent of people with TSC[5]. These can include infantile spasms, which involve brief, repetitive muscle contractions in babies, as well as different types of seizures in older children and adults[1][5]. More than half of those who have epilepsy have seizures that do not respond well to standard medication[5].
Developmental delays and intellectual disabilities are also common[1]. Many people with TSC experience what’s called TSC-associated neuropsychiatric disorders (TAND), which refers to a range of cognitive, behavioral, and psychiatric conditions such as aggression, anxiety, attention deficit hyperactivity disorder, learning difficulties, obsessive-compulsive disorder, and autism spectrum disorder[1].
Skin changes
Skin differences are one of the earliest signs of TSC and appear in virtually all affected people[1][9]. These can include white or lighter patches of skin called ash leaf spots or hypomelanotic macules, which are sometimes present at birth[1][5].
Other skin changes include raised red or darker spots or bumps on the face called angiofibromas, which start in childhood and can look like acne[1][5]. Areas of thick, pebbled skin called shagreen patches usually appear on the lower back or neck[1]. Small growths under the nails, called ungual or subungual fibromas, may also develop[1].
Kidney problems
Over 80 percent of people with TSC have some type of kidney lesion[5]. The most common are kidney cysts, which are small fluid-filled bubbles, and renal angiomyolipomas, which are benign tumors made of fatty tissue and muscle cells[1][5].
While these rarely cause symptoms, angiomyolipomas can grow so large that they cause pain or lead to internal bleeding or kidney failure[1]. About 50 percent of people with TSC have kidney cysts, which can lead to increased blood pressure and, rarely, kidney failure[5].
Heart tumors
About 50 percent of people with TSC have non-cancerous tumors in the heart called rhabdomyomas[5]. These are often detected before birth on fetal ultrasound and are largest at birth[5]. Most rhabdomyomas do not grow and either get smaller or stay the same size over time[5]. However, they can sometimes block blood flow in the heart or cause irregular heartbeat[5].
Lung problems
Some people with TSC develop lymphangioleiomyomatosis (LAM), a rare lung disorder that mostly affects women of childbearing age or older[1]. Many people with TSC have no symptoms of LAM, while others suffer with breathlessness, which can get worse over time and be severe[1].
How is tuberous sclerosis complex diagnosed?
Diagnosing TSC requires a careful approach that integrates clinical assessments, imaging studies, and genetic testing[7]. Some manifestations, such as heart tumors or brain tubers, may be detected prenatally on routine ultrasound during pregnancy[5][13]. Other signs become apparent in infancy or childhood when symptoms like seizures or skin changes develop.
The healthcare provider will do a physical exam and talk with you about symptoms and family history[10]. The provider looks for tumors and skin changes that are commonly caused by tuberous sclerosis[10].
Several tests may be ordered to diagnose TSC and identify related problems[10]. An electroencephalogram (EEG) records electrical activity in the brain and can help determine what’s causing seizures[10]. Imaging tests like MRI (magnetic resonance imaging) and CT (computed tomography) scans create detailed images of the brain or other parts of the body to detect tumors[10]. Ultrasound uses high-frequency sound waves to create images of organs like the heart and kidneys[10].
Heart evaluation typically includes an echocardiogram, which uses sound waves to produce images of the heart, and an electrocardiogram (ECG or EKG), which records the electrical activity of the heart[10]. Eye exams using a light and magnifying lens check for abnormal growths in the retina[6].
Genetic testing can check for mutations in the TSC1 and TSC2 genes[6]. About 70 to 85 percent of individuals who have a definitive diagnosis of TSC have an identifiable mutation in one of these two genes[13]. Genetic counseling can also determine if tuberous sclerosis affects other members of your family[6].
Treatment and management
There is no cure for tuberous sclerosis complex, and the course of the disorder cannot be predicted[2]. However, treatments are available to manage symptoms and improve quality of life[2]. Treatment focuses on early identification and monitoring of potentially progressive lesions to prevent complications[12].
Medications
Antiepileptic drugs are the mainstay of therapy for patients with TSC who experience seizures[12]. Vigabatrin is the drug of first choice for children with TSC and infantile spasms[12][14]. When given preventatively, vigabatrin has been shown to reduce the risk and severity of epilepsy[14]. Other medications used include topiramate, lamotrigine, valproate, and cannabidiol, which was approved in 2020 for seizures associated with TSC in children aged 1 year or older[12].
mTOR inhibitors are a newer class of drugs that target the underlying problem in TSC. Everolimus is an mTOR inhibitor approved for treating subependymal giant cell astrocytomas (SEGA) in adults and children 1 year and older, renal angiomyolipoma in adults, and TSC-associated seizures in adults and children 2 years and older[12]. Studies have shown that everolimus significantly reduces seizure frequency compared with placebo, with improvements sustained after 2 years of treatment[14].
Topical sirolimus, another mTOR inhibitor, has approval for treating facial angiofibroma in patients with TSC aged 6 years and older[12].
Surgical treatments
Surgery may be needed to remove tumors that affect vital organs or cause serious complications[6]. This can include surgery to treat skin growths or remove brain tumors that cannot be managed with medication[6]. In some cases, surgery to remove specific areas of the brain causing seizures may be an option for patients with intractable epilepsy[12].
Vagus nerve stimulation is a minimally invasive surgical alternative that can help reduce seizures[6].
Supportive therapies
Educational and occupational therapy can help maximize the ability to perform everyday tasks[6]. Early intervention services like physical, occupational, and speech therapies can help children experiencing developmental delays learn the skills they need to thrive[22].
Behavioral interventions may be needed for cognitive or psychiatric symptoms associated with TAND[12]. Mental health support is important for addressing anxiety, depression, and other psychiatric conditions that may develop[1].
Ongoing monitoring
Because TSC is a lifelong condition that may progress slowly, people with this condition need to see a healthcare provider regularly throughout their life to monitor the condition[3]. Routine diagnostic imaging such as MRIs, CT scans, and ultrasounds help doctors track tumor growth and overall health[22].
Management typically requires care from multiple specialists, including neurologists, nephrologists (kidney specialists), cardiologists (heart specialists), dermatologists (skin specialists), and others as needed[10][21].
Living with tuberous sclerosis complex
The severity of TSC can vary widely from one person to another. Some people live with few symptoms while others need continual support[4][17]. Many people with TSC live independent, healthy lives and enjoy challenging professions such as medicine, law, education, and research[4]. Most people with TSC will live a normal life span[4][17].
People with less severe cases may see very few effects and have a normal lifespan, while severe cases can lead to serious complications[3]. Although there is no cure, there is hope. Research has proven that early diagnosis and intervention are key for optimizing long-term outcomes[4].
For those diagnosed as children, a continuum of care will be needed as they transition from pediatric to adult health services[13]. Coordination of care among different specialists is important to ensure comprehensive management across the lifespan[21].
Support is available through specialist TSC clinics, support navigators, community support networks, and patient organizations that can provide information, resources, and connections to others living with the condition[17].
