Tuberous sclerosis complex (TSC) is an inherited neurocutaneous disorder caused by mutations in either the TSC1 or TSC2 gene, resulting in the growth of benign tumors (hamartomas) in multiple organs. Major features include facial angiofibromas, hypomelanotic macules, shagreen patches, retinal nodular hamartomas, cortical tubers, subependymal nodules, and cardiac rhabdomyomas. Common manifestations are seizures (80-90%), cognitive deficits (44-65%), renal angiomyolipomas (40-70%), and retinal hamartomas. Everolimus has been approved to treat renal angiomyolipomas and subependymal

2. INTRODUCTION
Skin
Eyes
Brain
Heart
Lung
Kidney
Liver
Tuberous Sclerosis Complex (TSC)
inherited neuro-cutaneous disorder
multiple benign hamartomas:

3. GENETICS
 Autosomal dominant
 Incidence 1 : 5000 livebirths
 Mutation in
 TSC-1 (Hamartin) or
 TSC-2 (Tuberin)
 +ve family history in 7 – 37%

4. Cell Proliferation
complex
hamartin
TSC1
tuberin
TSC2
Hamartin-Tuberin complex
Central regulator of cell cycle
TSC: loss of
inhibition
to cell cycle

5. Diagnostic criteria
Major Features
 Facial angiofibromas
or forehead plaque
 Non-traumatic
ungual or periungual
fibroma
 Hypomelanotic
macules
 Shagreen patch
 Multiple retinal
nodular hamartomas
 Cortical tuber
 Subependymal
nodule
 Subependymal giant
cell astrocytoma
 Cardiac
rhabdomyoma
 Lymphangio-
myomatosis
 Renal
angiomyolipoma

6. Minor Features
Multiple pits in dental
enamel
Hamartomatous rectal
polyps
Bone cysts
Cerebral white matter
migration lines
Gingival fibromas
Non-renal hamartoma
Retinal achromic
patch
"Confetti" skin lesions
Multiple renal cysts

7. Diagnosis
Possible TSC
1 major 2 or more minor
Probable TSC
1 major plus 1 minor
Definite TSC
2 major 1 major + 2 minor

8. DERMATOLOGICAL
LESIONS:
81-95%

9. Angiofibromas

10. Fibrous plaque

11. Ash leaf spots

12. Periungual & subangual
fibromas

13. BRAIN LESIONS
90%

14. Glioneuronal hamartomas

15. Subependymal nodules

16. Subependymal Giant Cell tumor

17. Clinically:
 Epilepsy affecting 80 – 90%
 infantile spasms
 simple or complex partial seizures
 EEG +ve in 75 % of patients
 Cognitive deficits 44 – 65%
 Autism and behavioral problems

18. Diagnostic
features
associated
with increase
morbidity
New
symptoms
or
papilledema
Hydrocephalus
Serial
imaging
showing
growth of
lesions

19. RENAL
MANIFESTATIONS

20. Renal Angiomyolipomas (AML)
Frequency in TSC patients: ~ 40 – 70 %

21. Renal Angiomyolipomas (AML)
 Asymptomatic in most cases
 Symptoms
 bleeding
 mass effect
 2 histological types:
 Classic
 Epithelioid
 Diagnosis : demonstration of FAT in
the Tumor

22. Renal Angiomyolipomas (AML)
AML contain
fat
Peri-renal fat

23. Treatment of AML
Prophylactic surgery?
 Size ≥4cm to prevent bleeding
 High vascularity and/or
aneurysm ≥ 5mm
 High suspicion of malignancy

24. Treatment of AML
Therapeutic interventions
 Nephron sparing surgery
 Selective renal artery embolization
 Radiofrequency ablation
 Radical nephrectomy

25. Potential issues in women
 Female sex hormones promote
growth of renal AMLs and their
hemorrhagic complications during
pregnancy
 Frequency of U/S surveillance
should increase

26. Renal cystic disease
 The 2nd most common renal
manifestation in TSC
 3 types :
 Singe or multiple renal cysts
 TSC2/PKD1 contiguous gene
syndrome
 Glomerulocytic kidney disease

27. Chronic kidney disease
In absence of large AML, patients
may develop:
 CKD
 subnephrotic proteinuria
 hypertension
 ESRD
Renal biopsy often reveals FSGS

28. OPHTHALMIC
MANIFESTATIONS

29. Retinal hamartoma
Calcified
hamartoma

30. CARDIOPULMONARY

31. Cardiac Rhabdomyoma
 detected on prenatal US
 Benign tumor usually
undergo spontaneous
regression
Pulmonary (LAM)
 Lymphangio-
leiomyomatosis
 Manifestations are
similar to those with
interstitial lung
disease

32. Management
Everolimus
Pulmonary
Cosmetic
Renal AML
Seizure control

33. EVEROLIMUS
 FDA approved mTOR after ExIST-2 trail
 50% reduction in AML volume in 3 month
 Dose : 10 mg od for 38 weeks
 Candidates :
 patients with renal AML plus other organ
affected
 Rapidly growing AMLs
 Patients who underwent nephrectomy or
embolization

34. Cell Proliferation
complex
hamartin
TSC1
tuberin
TSC2
Hamartin-Tuberin complex
Central regulator of cell cycle
TSC: loss of
inhibition
to cell cycle
EVEROLIMUS

35. Prognosis
 TSC is progressive
 Cause of death:
 status epilepticus
 renal disease
 Surveillance : every 2 years
 mental, physical examination
 MRI brain
 U/S abdomen
 ECHO

36. THANK YOU