Tuberous Sclerosis Complex

Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disorder with an incidence of about 1 in 6,000 to 10,000, caused by pathogenic variants in TSC1 (hamartin, 9q34) or TSC2 (tuberin, 16p13.3). Two thirds of cases are de novo.

TSC2 variants cause more severe disease than TSC1 (earlier seizures, greater intellectual disability, more renal disease), and large TSC2 deletions extending into PKD1 cause early severe polycystic kidney disease. The hamartin tuberin complex inhibits mTORC1; loss of function leads to unrestrained mTOR signalling, cell growth and hamartoma formation in many organs. Around 10 to 15% have no mutation identified (mosaicism or deep intronic variants).

• Skin (over 90%): hypomelanotic macules (3 or more, at least 5 mm; ash leaf spots, best seen under Wood lamp), facial angiofibromas (3 or more), ungual fibromas (2 or more), shagreen patch, and forehead fibrous plaque
• Brain: cortical tubers, subependymal nodules, and subependymal giant cell astrocytomas (SEGA, about 5 to 15%; risk of hydrocephalus)
• Epilepsy (80 to 90%): infantile spasms (about 30 to 40%, usually with hypsarrhythmia), focal seizures, and Lennox-Gastaut-type syndromes; high risk of drug resistant epilepsy
• TSC-associated neuropsychiatric disorders (TAND): autism (40 to 50%), intellectual disability (about 50%), ADHD, anxiety, and aggression
• Cardiac: rhabdomyomas (about 80% of infants, often detected prenatally, regress spontaneously, may cause outflow obstruction or arrhythmia) and Wolff-Parkinson-White
• Renal: angiomyolipomas (up to 70-80%; risk of haemorrhage when above 3 to 4 cm or with aneurysms above 5 mm), renal cysts, and renal cell carcinoma (2 to 3%)
• Lung: lymphangioleiomyomatosis (LAM; about 30 to 40% of adult women; progressive dyspnoea, pneumothorax, chylous effusion), and multifocal micronodular pneumocyte hyperplasia
• Eye: retinal hamartomas; dental enamel pits (over 90% of adults), gingival fibromas, and sclerotic bone lesions

• Clinical criteria: definite diagnosis with 2 major features or 1 major with 2 or more minor; possible diagnosis with 1 major or 2 or more minor. Genetic criterion: a pathogenic TSC1 or TSC2 variant is sufficient for definite diagnosis. Investigation at diagnosis: brain MRI with and without gadolinium (and every 1 to 3 years until age 25 for SEGA screening), EEG, echocardiography and ECG, renal ultrasound or MRI, chest CT in women from age 18 (baseline), neuropsychiatric (TAND) assessment, dental and eye examination, and genetic testing of TSC1 and TSC2.

• Infantile spasms: vigabatrin 100 to 150 mg/kg/day in 2 divided doses (first line; monitor visual fields or retinal toxicity), alongside ACTH or prednisolone if refractory. Pre-emptive vigabatrin on EEG abnormality is under study.
• Other seizures: standard antiepileptics, ketogenic diet, everolimus (adjunctive 5 mg/m2/day, titrated to trough 5 to 15 ng/mL), cannabidiol (10 to 25 mg/kg/day), and epilepsy surgery (tuberectomy or lobectomy) or vagus nerve stimulation for refractory seizures.
• mTOR inhibitors: everolimus 4.5 mg/m2/day (titrated to trough 5 to 15 ng/mL) for SEGA that is growing but not requiring urgent surgery, and for renal angiomyolipoma over 3 cm (10 mg daily in adults); sirolimus is an alternative (topical sirolimus 0.2% gel for angiofibromas). Side effects: stomatitis, infections, hyperlipidaemia, and proteinuria.
• SEGA: surgical resection for acute hydrocephalus or symptomatic tumour.
• Angiomyolipoma: selective embolisation or nephron sparing surgery for acute haemorrhage; avoid nephrectomy.
• LAM: sirolimus 2 mg/day (trough 5 to 15 ng/mL) for declining lung function; avoid oestrogen; lung transplantation for end stage disease.
• Cardiac rhabdomyoma: observation, with medical treatment of arrhythmias or outflow obstruction.
• Skin: laser, topical sirolimus.
• TAND: early developmental interventions, SSRIs, and stimulants as needed.
• Surveillance: MRI brain every 1 to 3 years, renal imaging every 1 to 3 years, annual blood pressure and renal function, and echocardiography as indicated.
• Genetic counselling: 50% risk to offspring of an affected parent; examine parents and siblings.