TSC genetics & renal pathology
Genetics
- Autosomal dominant
- TSC1 (hamartin, chromosome 9) — milder phenotype
- TSC2 (tuberin, chromosome 16) — more severe; contiguous with PKD1
- Two-thirds of cases are de novo (no family history)
- Mosaicism in 10–25% — may need deep sequencing
- NHS National Genomic Test Directory R231
Kidney Manifestations
1. ANGIOMYOLIPOMAS (AMLs):
- Benign mixed mesenchymal tumours (vessels, smooth muscle, fat)
- 80% of TSC adults; usually bilateral, multifocal
- Grow at 0.2–1.4 cm/year on average
- Risk of spontaneous haemorrhage rises with size (≥ 3 cm) and aneurysmal vasculature (≥ 5 mm)
- Wunderlich syndrome: spontaneous retroperitoneal bleed
2. Cysts / Tsc2-pkd1 Contiguous Gene Syndrome
- 1–2% of TSC patients have deletions affecting both genes
- Presents as severe polycystic kidney disease in infancy/childhood
- Aggressive ADPKD-like phenotype + TSC features
- Genetic testing essential — alters family counselling
3. Renal Cell Carcinoma
- Lifetime risk ~3% (vs ~1% general population)
- Often multifocal, early-onset (median ~35 years)
- Variable histology — clear cell, papillary, hybrid oncocytic/chromophobe
- Distinguishing fat-poor AML from RCC on imaging is challenging — biopsy often required
4. Other
- Lymphangioleiomyomatosis (LAM) of the kidney rare; LAM lung disease in women is much more common
Surveillance & imaging
Baseline At Diagnosis
- MRI kidneys (preferred; avoids CT radiation and contrast risk)
- BP, eGFR, urinalysis
- Genetic confirmation (TSC1, TSC2 sequencing + deletion/duplication)
Ongoing
- MRI kidneys every 1–3 years (more often if AML > 3 cm or growing rapidly)
- Annual BP
- Annual eGFR, urine ACR
- Family screening
MULTI-SYSTEM SURVEILLANCE (TSC clinic):
- Brain MRI — SEGAs, tubers (childhood; less often as adults)
- Cardiac echo / ECG — rhabdomyomas
- Skin review — angiofibromas, ash-leaf macules
- Lung HRCT for women aged 18+ (LAM screen) — repeat every 5–10 years
- Eye examination — retinal hamartomas
- Neuropsychiatric screen — TAND (TSC-associated neuropsychiatric disorders)
Aml Characterisation On Imaging
- Fat density on CT or MRI = classic AML, usually no biopsy needed
- Fat-poor AML can mimic RCC — needs biopsy or close follow-up
- Aneurysm > 5 mm on MRA = higher bleed risk regardless of total size
Management of AML and TSC kidney disease
ASYMPTOMATIC AML < 3 cm:
- Surveillance only — MRI every 1–3 years
- BP and proteinuria control
- Genetic and family counselling
ASYMPTOMATIC AML ≥ 3 cm OR ANEURYSM ≥ 5 mm:
- EVEROLIMUS (Votubia) — NICE TA309
- 10 mg/day orally (adjust for hepatic impairment)
- Durable AML shrinkage (~50% reduction by 12 months in EXIST-2 trial)
- Reduces seizure burden (SEGA), facial angiofibromas, LAM lung function decline
- Side effects: mucositis, acne, hyperlipidaemia, hyperglycaemia, proteinuria, infection risk, rarely pneumonitis
- Monitor mouth, lipids, glucose, FBC, U&E, urine ACR
- Stopping → AML regrowth, so long-term continuous use is standard
- SIROLIMUS — alternative where everolimus not tolerated
- SELECTIVE EMBOLISATION — for rapid growth, refractory bleeding risk, or when mTOR not suitable
- PARTIAL NEPHRECTOMY — reserved for diagnostic uncertainty (RCC suspected) or complex bleeding
ACUTE HAEMORRHAGE (Wunderlich):
- Resuscitation: ABCDE, IV access, group & save / crossmatch
- Urgent CT angiography
- Selective embolisation = first-line
- Nephrectomy only if embolisation fails — preserve nephrons aggressively
- Restart / start everolimus to prevent re-bleed once stable
Advanced CKD / Transplantation
- Transplant outcomes are good; mTOR inhibitor immunosuppression can serve dual purpose
- Native nephrectomy occasionally needed before transplant for bulky AML
- Living donation must avoid affected first-degree relatives without genetic exclusion
Family / Genetic Counselling
- 50% transmission risk for affected parent
- De novo cases: parental testing offered for recurrence risk
- Pre-implantation genetic diagnosis available
- TSC-PKD contiguous gene families need ADPKD-style screening of children
UK PATHWAY: care is best delivered in specialist multi-disciplinary TSC clinics (renal + neurology + dermatology + respiratory + genetics) — refer through the Tuberous Sclerosis Association (TSA) or local rare-disease pathways.
