Tuberous sclerosis complex
TSC; tuberous sclerosis; Bourneville disease (older eponym); Bourneville-Pringle disease (older — combining the original neurological and dermatological descriptions)
Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem hamartoma syndrome caused by germline loss-of-function mutations of TSC1 (encoding hamartin) on chromosome 9q34 or TSC2 (encoding tuberin) on chromosome 16p13.3. Both proteins form a complex that negatively regulates the mTOR signalling pathway, and loss of function results in mTOR hyperactivation that drives the formation of benign-appearing but functionally disabling hamartomas across multiple organ systems. Cutaneous manifestations are universal and frequently the diagnostic clue: hypomelanotic macules ("ash-leaf spots"), facial angiofibromas (formerly "adenoma sebaceum"), shagreen patches, ungual / periungual fibromas (Koenen tumours), confetti-like macules and forehead plaques. CNS involvement (cortical tubers, subependymal nodules, subependymal giant-cell astrocytoma — SEGA), renal angiomyolipomas and lymphangioleiomyomatosis (LAM) drive morbidity and mortality. The dermatologist often makes the initial diagnosis through the cutaneous triad and is critical for life-saving surveillance and access to mTOR-inhibitor therapy (sirolimus, everolimus — both topical for facial angiofibromas and systemic for SEGA, renal AML and LAM).
Genetics
- Germline loss-of-function mutations of TSC1 (hamartin) on 9q34 or TSC2 (tuberin) on 16p13.3.
- The two proteins form a complex that negatively regulates mTOR signalling; loss of function → mTOR hyperactivation → hamartomatous proliferation.
- TSC2 mutations more common (~75%); TSC2 disease tends to be more severe than TSC1.
- Autosomal dominant; ~70% sporadic (de novo), ~30% inherited.
- Mosaicism is common — >1 in 5 sporadic cases; cascade testing of relatives important.
- Confirm by clinical Tuberous Sclerosis Diagnostic Criteria (2021 revision) or germline TSC1 / TSC2 testing.
Cutaneous features
- Hypomelanotic macules ("ash-leaf spots") — present at birth or develop in infancy in >90%; 1–3 cm white macules best seen with Wood's lamp; trunk and extremities; often the first diagnostic clue.
- Facial angiofibromas (formerly "adenoma sebaceum") — multiple 1–4 mm pink-red vascular papules concentrated on the centrofacial skin (nasolabial folds, cheeks, chin); develop from age 3–4; cosmetically disfiguring.
- Shagreen patch — connective-tissue naevus; thickened, peau d'orange textured plaque on the lower back (lumbosacral); develops in childhood.
- Ungual / periungual fibromas (Koenen tumours) — small flesh-coloured fibromas around the nail folds, usually toes; develop in adolescence onwards.
- Confetti-like skin macules — multiple 1–2 mm hypopigmented "confetti" macules on the trunk and limbs.
- Forehead plaque / fibrous cephalic plaque — yellow-brown plaque on the forehead or scalp; congenital.
- Café-au-lait macules in some patients.
Extracutaneous features
- Central nervous system — cortical tubers, subependymal nodules, subependymal giant-cell astrocytoma (SEGA — periventricular tumour causing obstructive hydrocephalus); seizures (drug-resistant in many), intellectual disability, autism, "TSC-associated neuropsychiatric disorders" (TAND).
- Renal — angiomyolipomas (multiple, bilateral, fatty hamartomas; lifetime risk >75%; risk of haemorrhage when >4 cm); renal cysts; rarely renal cell carcinoma.
- Pulmonary — lymphangioleiomyomatosis (LAM) in adult women (~30%); progressive cystic lung disease, pneumothorax, chylothorax.
- Cardiac — rhabdomyomas (often present at birth, regress spontaneously through childhood); arrhythmia.
- Ophthalmic — retinal hamartomas; rarely vision-threatening.
- Endocrine — rare parathyroid adenomas and pancreatic neuroendocrine tumours have been reported in TSC; there is no recognised MEN-1-like phenotype.
- Modest increase in malignancy risk overall — not historically considered a major cancer-predisposition syndrome but emerging data.
Diagnosis (2021 TSC Diagnostic Criteria)
- Definite diagnosis — two major features, OR one major + ≥ 2 minor features, OR a pathogenic TSC1 / TSC2 variant.
- Possible diagnosis — one major feature, OR ≥ 2 minor features.
- Major criteria — hypomelanotic macules ≥3 (≥5 mm), angiofibromas ≥3 or fibrous cephalic plaque, ungual fibromas ≥2, shagreen patch, multiple retinal hamartomas, multiple cortical dysplasias, subependymal nodules, SEGA, cardiac rhabdomyoma, LAM, angiomyolipomas ≥2.
- Minor criteria — confetti skin lesions, dental enamel pits, intraoral fibromas ≥2, retinal achromic patch, multiple renal cysts, non-renal hamartomas.
Management & surveillance
- Multidisciplinary care through a TSC Clinic — neurology, neurosurgery, nephrology, respiratory, cardiology, dermatology, ophthalmology, clinical genetics, neuropsychiatry.
- Annual surveillance — full skin / dental examination; ophthalmology; blood pressure; renal MRI 1–3 yearly; brain MRI 1–3 yearly in childhood / adolescence; EEG if seizures; lung function and HRCT in adult women.
- Cutaneous management:
- Topical sirolimus 0.1–1% ointment — first-line for facial angiofibromas; sustained suppression with continued use; UK availability via specialist services. NICE TA972 for topical sirolimus in facial angiofibroma was terminated without a recommendation, so use local specialist commissioning / formulary routes.
- Pulsed dye laser, CO₂ laser, electrocautery for individual angiofibromas.
- Surgical excision of disfiguring or symptomatic lesions.
- Hypomelanotic macules — cosmetic camouflage; tacrolimus ineffective.
- SEGA — everolimus — first-line for non-resectable SEGA; alternative to surgery, usually accessed through specialist TSC neurology / neurosurgical commissioning pathways rather than a simple NICE TA code.
- Renal angiomyolipoma — everolimus for inoperable or disease >3 cm; selective embolisation for haemorrhage; nephron-sparing surgery for very large lesions. Confirm current specialised commissioning / formulary route through nephrology.
- Pulmonary LAM — sirolimus.
- Drug-resistant epilepsy — vigabatrin (especially infantile spasms), other anticonvulsants, ketogenic diet, epilepsy surgery, vagus nerve stimulation; cannabidiol (Epidyolex) for TSC-associated seizures is recommended by NICE TA873.
- TAND — multidisciplinary neuropsychiatric assessment and management.
- Genetic counselling and cascade testing.
References
- Northrup H et al. Updated international Tuberous Sclerosis Complex diagnostic criteria and surveillance and management recommendations. Pediatr Neurol; 2021.
- Wataya-Kaneda M et al. Topical sirolimus therapy for facial angiofibromas. JAMA Dermatol; 2018.
- NICE TA873. Cannabidiol for treating seizures caused by tuberous sclerosis complex. London: NICE; 2023.
- NICE TA972. Sirolimus for treating facial angiofibroma caused by tuberous sclerosis complex in people 6 years and over. London: NICE; 2024 (terminated appraisal; last updated 27 January 2026; no NICE recommendation).
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