Tuberous Sclerosis Complex

Introduction

Tuberous sclerosis complex (TSC) is a genetic disorder that affects multiple parts of the body, including the brain, skin, kidneys, heart, lungs and eyes. It can lead to the development of benign tumors (non-cancerous growths) and may cause a range of health issues depending on their location and size. While the severity and symptoms of TSC vary from person to person, early diagnosis and management can significantly improve quality of life.

Causes

TSC is caused by mutations in the TSC1 or TSC2 genes (responsible for encoding the protein Hamartin on chromosome 9q34 and Tuberin on chromosome 16p13.3 respectively). These genes produce proteins that regulate cell growth and division. Mutations of these genes cause overactivation of the mTOR (mammalian target of rapamycin) pathway with increased cell growth, leading to the formation of tumors.

Prevalence

TSC is considered a rare disease. The incidence of TSC is generally estimated at between 1:6,000 and 1:10,000 live births¹. From a local study, the overall prevalence of TSC patients in Hong Kong is about 3.87 in 100,000².

Mode of Inheritance

TSC follows an autosomal dominant inheritance pattern, meaning a single mutated gene inherited from one parent is sufficient to cause the condition. If one parent has TSC, each child (regardless of gender) has a 50% chance of inheriting the disorder.

However, many cases are due to "new mutations” in the TSC1 or TSC2 genes, meaning the condition can develop for the first time in the family. In these instances, the mutation occurs spontaneously (de novo condition) during the formation of the child’s genes rather than being passed down from a parent.

Signs and Symptoms

TSC is a progressive disorder and the signs and symptoms of TSC can vary widely. While some patients experience mild symptoms, others may face more serious complications. Seizure is often one of the first indicators of TSC, especially in infants and children. Epilepsy is commonly noted, with onset at any age, in 80-90% of TSC patients, and with higher risk in patients with cortical tubers and pathogenic TSC2 variants. Common presentations of TSC in infants include seizures, hypopigmented skin lesions and cardiac tumors called rhabdomyomas. Here are some common signs and symptoms:

• Skin abnormalities: These may include hypomelanotic macules (light-coloured patches appear as white spots), facial angiofibromas (small red bumps on the face), fibrous plagues on forehead, ungual fibroma over the nails, shagreen patches (connective tissue nevi) over lower back.
• Seizures: Many individuals experience seizures due to abnormal electrical activity in the brain. These seizures can range from mild (brief staring episodes) to severe (including uncontrolled shaking). Patients may present as infantile epileptic spasm syndrome (a severe type of seizure) or focal seizure especially during infancy period.
• Developmental delays: Children with TSC may present as delays in acquiring skills such as talking, walking, or problem solving. They may struggle with social interactions and making friends.
• TSC-associated neuropsychiatric disorders (TAND): May manifest as intellectual disability, autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), behavioral problems (overactivity, impulsivity, sleep difficulties, aggressive behavior, temper tantrums, repetitive / ritualistic behavior), speech / language delay, anxiety / mood changes.
• Organ tumors
  • Brain: Cortical tubers, subependymal nodules, migrational defect and subependymal giant cell astrocytoma (SEGA) which is a benign, slow-growing tumor that can cause headache, seizures, or increase intracranial pressure.
  • Kidney: Renal cysts or benign kidney tumors called angiomyolipomas may develop, and their growth can lead to complications, potentially causing pain or bleeding.
  • Heart: Some infants may develop cardiac rhabdomyomas, which can affect heart function.
• Lungs: A small number of adults (mostly women aged 18 or above) with TSC may develop lymphangioleiomyomatosis (LAM) which is a cystic lung disease that can affect lung function.
• Eyes: Retinal hamartomas and angiofibromas of eyelids can occur though less frequently.
• Oral and dental: Intraoral fibromas, gingival hyperplasia, dental enamel pits and deforming jaw bone cysts.

Diagnosis

The diagnosis of TSC can be based on clinical diagnostic criteria according to the updated international tuberous sclerosis complex diagnostic criteria published in 2021¹.

A definitive diagnosis of TSC typically requires genetic testing to identify mutations in the TSC1 or TSC2 genes. This testing can confirm the diagnosis and guide management strategies.

Additional tests may be conducted to assess the disease's extent, including:

• Echocardiography (ECG): Especially if younger than three years old to assess underlying conduction defects.
• Electroencephalogram (EEG): Obtain baseline EEG while awake and asleep to detect abnormal excessive electrical activity in the brain.
• Magnetic resonance imaging (MRI) of the brain: To detect brain tumors and assess brain function.
• Screening for hypertension, evaluation of renal functions and ultrasound / MRI of the abdomen to assess presence of angiomyolipomas and renal cysts.

Treatment and Management

General

While there is currently no cure for TSC, treatment focuses on managing symptoms and preventing complications. Once a diagnosis of TSC is made, there should be continuous surveillance and management of complications from various organs. Treatment approach depends on the severity of the condition and the specific symptoms present.

Common strategies include:

• Perform a detailed clinical dermatologic examination and document the dermatological features at diagnosis.
• Refer to the ophthalmologist for a complete ophthalmologic evaluation.
• Seizures: Educate parents to recognize infantile epileptic spasm syndrome and focal seizures, with EEG surveillance to look for abnormal excessive electrical activity in the brain during the first two years of life. Anti-seizure medications, such as vigabatrin will be prescribed for pre-symptomatic patients with abnormal excessive electrical activity or patients with infantile epileptic spasm syndrome / focal seizures during infancy period. The EPISTOP trial³ and PREVeNT trial⁴ showed that early pre-symptomatic treatment with vigabatrin reduced or delayed onset of epileptic spasms. Patients with poorly controlled epilepsy will be assessed by paedatric neurologists with drug titration and offered other options, such as ketogenic diet and epilepsy surgery (resective surgery or vagal nerve stimulation).
• Refer to the Child Assessment Centre for early assessment, education and training for emerging TAND manifestation.
• Refer to the child psychiatrist for early intervention of existing TAND manifestation.
• Targeted therapies such as everolimus / sirolimus (mTOR inhibitors) may be used to shrink tumors, or for drug resistant epilepsy cases.
• Surgery: If tumors cause significant issues, surgical removal may be necessary, particularly those affecting vital organs like the brain or kidneys.
• Rehabilitation therapy: Occupational, physical, and speech therapy can support development and improve quality of life.

Special management and follow-up available in HKCH

HKCH provides expert paediatric service to manage patients with TSC. We offer inpatient, day patient and outpatient assessment and follow-up for TSC patients.

In HKCH, paediatric oncologists and paediatric neurologists will provide assessment, counselling, diagnostic workup and treatment for children with TSC in neurocutaneous oncology clinic and neurocutaneous neurology clinic which run as parallel sessions on the same day to save patients’ travelling time for repeated hospital visits.

During hospital visits, you can expect a comprehensive evaluation, discussions about treatment plans, and support from a professional care team.

TSC patients have multiple body system involvement and often need a multidisciplinary team for assessment and management. TSC cases with complex medical and neurological problems especially those cases with drug resistant epilepsy would be followed by a multidisciplinary team consisting of paediatric neurologists, paediatric oncologists, neurosurgeons, paediatric radiologists, developmental paediatricians, other specialists, and rehabilitation teams including clinical psychologists, physiotherapists, occupational therapists, speech therapists, dietitians and medical social workers.

These cases would also be assigned to a case manager (a paediatric neurology nurse) to enhance communication with the multidisciplinary and provide support and advice on daily care and seizure management.

There are ongoing research studies on management of TSC patients and these may provide new hope to improve quality of life for TSC patients.

References

1. Northrup, Hope, et al. "Updated international tuberous sclerosis complex diagnostic criteria and surveillance and management recommendations." Pediatric Neurology 123 (2021): 50-66.
2. Chu, William Ching-Yuen, et al. "Prevalence, mortality and healthcare economic burden of tuberous sclerosis in Hong Kong: a population-based retrospective cohort study (1995– 2018)." Orphanet Journal of Rare Diseases 15.1 (2020): 1-9.
3. Kotulska, Katarzyna, et al . "Prevention of Epilepsy in Infants with Tuberous Sclerosis Complex in the EPISTOP Trial." Annals of Neurology 89 (2) (2021): 304–314.
4. Bebin EM , et al. "Early treatment with vigabatrin does not decrease focal seizures or improve cognition in tuberous sclerosisc complex: the PREVeNT trial." Annals of Neurology 2023 Aug 28: doi: 10.1002/ana.26778

References

Tuberous Sclerosis Complex Association of Hong Kong

Tuberous Sclerosis Alliance

Acknowledgement

Principal author: Dr Yeung Wai-lan on behalf of Neurology Team, HKCH

Initial posting: Nov 2025

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