Tuberous sclerosis

🧬 Tuberous Sclerosis Complex (TSC) is an autosomal-dominant, variably penetrant, multi-system disorder caused by pathogenic variants in TSC1 (hamartin) or TSC2 (tuberin). Loss of the hamartin–tuberin complex → unchecked mTOR signalling → hamartomas in brain, skin, kidneys, heart, lungs and eyes.

📌 Quick pearls

• “Adenoma sebaceum” is outdated → use facial angiofibromas (malar papules).
• 🏷️ Café-au-lait spots are classic for NF1; they can occur in TSC but are not typical or diagnostic.
• 👶 Infantile spasms are common and vigabatrin is first-line in TSC-related spasms.
• 💊 Many TSC tumours shrink with mTOR inhibitors (everolimus/sirolimus).

📈 Genetics & Pathophysiology

• TSC1 (chr 9q34) → hamartin; TSC2 (chr 16p13) → tuberin.
• mTOR over-activation drives cell growth, angiogenesis and hamartoma formation.
• ~2/3 are de novo; variable expressivity even within families.

🧩 Diagnostic Criteria (consensus)

Definite TSC = 2 major features, or 1 major + ≥2 minor; Possible TSC = 1 major or ≥2 minor.

• Major (examples): ≥3 hypomelanotic macules (≥5 mm), facial angiofibromas (≥3) or fibrous cephalic plaque, shagreen patch, ungual fibromas (≥2), cortical tubers/SEGAs/subependymal nodules, multiple retinal hamartomas, cardiac rhabdomyoma, lymphangioleiomyomatosis (LAM), renal angiomyolipomas (≥2).
• Minor (examples): “Confetti” skin lesions, dental enamel pits (>3), intraoral fibromas (≥2), retinal achromic patch, multiple renal cysts, non-renal hamartomas.

🩺 Clinical Features (by system)

• Skin: hypomelanotic “ash-leaf” macules (Wood’s lamp), facial angiofibromas, shagreen patch (lumbosacral), ungual fibromas.
• Neurological: epilepsy (often early; spasms ✔), cortical dysplasia/tubers, subependymal nodules; SEGA near foramen of Monro → hydrocephalus. TAND (TSC-associated neuropsychiatric disorders): autism, ADHD, anxiety, learning difficulties.
• Renal: multiple angiomyolipomas (AMLs) → haemorrhage risk; cysts; ↑ RCC risk.
• Cardiac: rhabdomyomas (antenatal/neonatal; often regress), arrhythmias/conduction defects.
• Pulmonary (esp. women): LAM → dyspnoea, pneumothorax, chylous effusions.
• Ophthalmic: retinal astrocytic hamartomas (usually asymptomatic).

🔎 Investigations

• Skin exam incl. Wood’s lamp for hypomelanotic macules.
• MRI brain (preferred to CT): cortical tubers, subependymal nodules, SEGA.
• Renal MRI/US: AML burden, cysts.
• ECG ± echo: rhabdomyomas (infancy), conduction disease.
• Chest HRCT/spirometry in adult females or if respiratory symptoms (LAM).
• Genetic testing (TSC1/TSC2) supports/confirm diagnosis; helpful for family counselling.

🗓️ Surveillance (practical schedule)

• 🧠 Brain MRI: every 1–3 yrs in childhood/adolescence to screen for SEGA; sooner if headache/vomiting or papilloedema.
• 🧪 Epilepsy/TAND: routine neurodevelopmental and mental-health screening each visit; EEG if clinical change.
• 🧂 Kidneys: BP, eGFR, urinalysis annually; renal MRI/US every 1–3 yrs lifelong.
• ❤️ Cardiac: echo in infancy until rhabdomyomas regress; ECG every 3–5 yrs lifelong.
• 🌬️ Lungs (females ≥18 yrs): baseline HRCT + periodic reassessment (interval per respiratory clinic); counsel on pneumothorax risk.
• 👁️ Eyes: baseline ophthalmology; follow-up if symptomatic/lesions near macula.
• 🩺 Dermatology/dental reviews as needed (angiofibromas, ungual fibromas, enamel pits, oral fibromas).

🛠️ Management

• Seizures: Vigabatrin first-line for infantile spasms; other ASMs per seizure type. Early control improves outcomes; consider ketogenic diet/epilepsy surgery in refractory cases.
• SEGA: Everolimus (mTOR inhibitor) can shrink lesions and defer/avoid surgery; neurosurgical CSF diversion if hydrocephalus.
• Renal AMLs:
  • Asymptomatic <3–4 cm: observe.
  • ≥3–4 cm, growth, pain or bleeding risk: mTOR inhibitor (everolimus) is first-line; selective arterial embolisation if bleeding; nephron-sparing surgery rarely.
• LAM: Sirolimus improves lung function/symptoms; manage pneumothorax per BTS guidance; avoid oestrogen therapy if possible.
• Cutaneous: topical sirolimus, laser for angiofibromas; excision/laser of ungual fibromas if symptomatic.
• Cardiac rhabdomyoma: usually regress; manage arrhythmias; rarely resection if obstruction.
• TAND: structured assessment, speech/occupational therapy, behavioural and psychological support; treat anxiety/ADHD/depression.
• Genetic counselling (50% transmission risk; prenatal options).

⚠️ Red flags (urgent action)

• Headache, vomiting, lethargy, visual change → possible SEGA/raised ICP → urgent MRI/neurosurgery.
• Acute flank pain, haematuria, hypotension → AML haemorrhage → resuscitate, urgent imaging, IR embolisation.
• Pleuritic chest pain, sudden dyspnoea → pneumothorax (LAM) → ED assessment.
• New infantile spasms (salaam attacks) → treat now with vigabatrin; expedite EEG/paeds neuro.

🧑‍⚕️ Case vignette (exam-style)

A 6-month-old infant with hypomelanotic “ash-leaf” patches (Wood’s lamp +) develops clusters of flexor spasms on waking. Echo shows a regressing cardiac rhabdomyoma. MRI brain reveals cortical tubers and subependymal nodules. ✅ Definite TSC. Start vigabatrin; arrange MRI surveillance for SEGA, renal US, ECG; discuss genetic testing and TAND screening with the family.

References

• Tuberous Sclerosis – NCBI Bookshelf
• TSC Alliance