Tuberous Sclerosis Complex (TSC)

What causes tuberous sclerosis complex?

TSC is caused by a disease-causing variant in one of two genes:

• TSC1, which makes the protein hamartin
• TSC2, which makes the protein tuberin

Together these proteins act as a brake on mTOR, a central switch for cell growth. When the brake fails, cells grow and divide too much in many tissues, forming hamartomas. TSC2 variants tend to cause more severe disease than TSC1.

Inheritance

TSC is autosomal dominant. About one-third of people inherit it from a parent, who has a 50% chance of passing it to each child. About two-thirds have a new (de novo) variant not found in either parent. Mildly affected parents are sometimes diagnosed only after their child is. Genetic counseling helps families understand recurrence risks and options such as prenatal testing.

Signs and symptoms by organ

Brain

• Cortical tubers: patches of abnormal brain tissue that can trigger seizures
• Subependymal nodules (SENs): small growths along the walls of the brain's fluid spaces
• Subependymal giant cell astrocytomas (SEGAs): slow-growing tumors in 5 to 15% of people, mostly in childhood and adolescence, that can block fluid flow and cause hydrocephalus

Seizures and epilepsy

Epilepsy affects most people with TSC, usually starting in the first year of life. Infantile spasms, clusters of sudden jerks or head drops, are common and need urgent treatment because early control improves development.

TSC-associated neuropsychiatric disorders (TAND)

• Autism spectrum disorder in roughly 40 to 50%
• Intellectual disability in about half, ranging from mild to profound; many have normal intelligence
• ADHD, anxiety, depression, sleep problems, aggressive or self-injurious behavior, and specific learning difficulties

Skin

Most people with TSC have skin findings, and pale patches are often the earliest visible sign. See white patches on skin for other causes.

Kidneys

• Angiomyolipomas (AMLs): benign tumors of blood vessels, muscle and fat, found in most adults with TSC. Large ones (over about 3 to 4 cm) can bleed
• Cysts, and with TSC2 gene deletions that also affect the neighboring PKD1 gene, severe polycystic kidney disease in childhood
• Kidney cancer, rarely

Kidney complications are a leading cause of illness and death in adults with TSC.

Heart

Cardiac rhabdomyomas are often the first sign, seen on prenatal ultrasound. They usually shrink and disappear on their own during childhood. Rarely they block blood flow or cause arrhythmias in newborns.

Lungs

Lymphangioleiomyomatosis (LAM), in which abnormal muscle-like cells form cysts in the lungs, affects a large share of adult women with TSC (and rarely men). It causes breathlessness, collapsed lung and declining lung function.

Eyes

Retinal hamartomas are common but rarely affect vision.

Diagnosis

The International TSC Consensus criteria define:

• Definite TSC: two major features, or one major plus two or more minor features, or a pathogenic TSC1 or TSC2 variant on genetic testing
• Possible TSC: one major feature, or two or more minor features

Major features include 3 or more hypomelanotic macules at least 5 mm across, 3 or more angiofibromas or a forehead plaque, 2 or more ungual fibromas, a shagreen patch, multiple retinal hamartomas, cortical tubers, SENs, SEGA, cardiac rhabdomyoma, LAM and 2 or more angiomyolipomas.

Minor features include confetti skin lesions, dental enamel pits, gum fibromas, kidney cysts and certain other findings.

Tests at diagnosis typically include brain MRI, EEG, kidney MRI or ultrasound, echocardiogram and ECG in children, eye exam, skin exam with a Wood's lamp, developmental and TAND assessment, and genetic testing.

Treatment

Seizures

• Vigabatrin is the first-line treatment for infantile spasms in TSC and is sometimes started preventively when EEG changes appear before seizures
• Standard antiseizure medicines for other seizure types
• Cannabidiol is approved for TSC-related seizures
• Everolimus reduces seizure frequency in drug-resistant epilepsy
• Epilepsy surgery, vagus nerve stimulation, or ketogenic diet in selected cases

mTOR inhibitors

These drugs correct the underlying overactive growth signal:

• Everolimus shrinks SEGAs and kidney angiomyolipomas
• Sirolimus stabilizes lung function in LAM
• Topical sirolimus gel improves facial angiofibromas

Other treatments

• Kidney AMLs: everolimus for growing tumors over about 3 cm, and embolization (blocking the blood supply) for bleeding
• SEGA: surgery or everolimus
• Skin: lasers or surgery for angiofibromas and ungual fibromas
• TAND: early intervention, behavioral and educational support, speech and occupational therapy, and medicines for ADHD, anxiety or sleep

Lifelong surveillance

Regular checks catch problems before symptoms appear:

• Brain MRI every 1 to 3 years until about age 25 to watch for SEGA
• Kidney MRI every 1 to 3 years for life, plus yearly blood pressure and kidney function tests
• Chest CT for women from age 18, and if symptoms develop
• Yearly skin and dental exams
• Yearly TAND screening using a checklist
• Echocardiograms in children with rhabdomyomas until they regress

Outlook

Life expectancy is near normal for many people with TSC, particularly with good seizure control and kidney monitoring. The main risks to health come from uncontrolled epilepsy (including sudden unexpected death in epilepsy), kidney bleeding or failure, LAM, and brain tumors causing blocked fluid flow. Quality of life depends greatly on the level of intellectual disability and behavioral needs, which is why early developmental support matters.

Frequently asked questions

What are the first signs of tuberous sclerosis?

The earliest signs are often heart tumors (rhabdomyomas) on a pregnancy scan, pale ash-leaf skin patches at birth, or seizures, especially infantile spasms, in the first year of life. Facial bumps (angiofibromas) usually appear later in childhood.

Is tuberous sclerosis inherited?

It can be. TSC is autosomal dominant, so an affected parent has a 50% chance of passing it to each child. However, about two-thirds of people have a new genetic change not inherited from either parent. Genetic testing of the child and parents clarifies the risk for future pregnancies.

Are the tumors in tuberous sclerosis cancerous?

Almost all are benign hamartomas, not cancer. They cause problems through their size and location, for example blocking brain fluid flow, bleeding in the kidneys or damaging lung tissue. A small increased risk of kidney cancer exists, which is part of why regular kidney imaging is recommended.

What is the life expectancy with tuberous sclerosis?

Many people with TSC have a near-normal life expectancy, especially with modern treatment and regular surveillance. Severe epilepsy, kidney complications, LAM and brain tumors are the main causes of reduced lifespan, and most can be prevented or managed when caught early.

Is there a cure for tuberous sclerosis complex?

No cure exists yet, but treatment has improved greatly. mTOR inhibitors such as everolimus and sirolimus shrink brain, kidney and skin growths and help seizures and lung disease. Combined with seizure control, developmental support and lifelong screening, they allow many people to live full lives.