INTRODUCTION
Skin
Eyes
Brain
Heart
Lung
Kidney
Liver
Tuberous Sclerosis Complex (TSC)
inherited neuro-cutaneous di...
GENETICS
 Autosomal dominant
 Incidence 1 : 5000 livebirths
 Mutation in
 TSC-1 (Hamartin) or
 TSC-2 (Tuberin)
 +ve ...
Cell Proliferation
complex
hamartin
TSC1
tuberin
TSC2
Hamartin-Tuberin complex
Central regulator of cell cycle
TSC: loss o...
Diagnostic criteria
Major Features
 Facial angiofibromas
or forehead plaque
 Non-traumatic
ungual or periungual
fibroma
...
Minor Features
Multiple pits in dental
enamel
Hamartomatous rectal
polyps
Bone cysts
Cerebral white matter
migration l...
Diagnosis
Possible TSC
1 major 2 or more minor
Probable TSC
1 major plus 1 minor
Definite TSC
2 major 1 major + 2 minor
DERMATOLOGICAL
LESIONS:
81-95%
Angiofibromas
Fibrous plaque
Ash leaf spots
Periungual & subangual
fibromas
BRAIN LESIONS
90%
Glioneuronal hamartomas
Subependymal nodules
Subependymal Giant Cell tumor
Clinically:
 Epilepsy affecting 80 – 90%
 infantile spasms
 simple or complex partial seizures
 EEG +ve in 75 % of pat...
Diagnostic
features
associated
with increase
morbidity
New
symptoms
or
papilledema
Hydrocephalus
Serial
imaging
showing
gr...
RENAL
MANIFESTATIONS
Renal Angiomyolipomas (AML)
Frequency in TSC patients: ~ 40 – 70 %
Renal Angiomyolipomas (AML)
 Asymptomatic in most cases
 Symptoms
 bleeding
 mass effect
 2 histological types:
 Cla...
Renal Angiomyolipomas (AML)
AML contain
fat
Peri-renal fat
Treatment of AML
Prophylactic surgery?
 Size ≥4cm to prevent bleeding
 High vascularity and/or
aneurysm ≥ 5mm
 High sus...
Treatment of AML
Therapeutic interventions
 Nephron sparing surgery
 Selective renal artery embolization
 Radiofrequenc...
Potential issues in women
 Female sex hormones promote
growth of renal AMLs and their
hemorrhagic complications during
pr...
Renal cystic disease
 The 2nd most common renal
manifestation in TSC
 3 types :
 Singe or multiple renal cysts
 TSC2/P...
Chronic kidney disease
In absence of large AML, patients
may develop:
 CKD
 subnephrotic proteinuria
 hypertension
 E...
OPHTHALMIC
MANIFESTATIONS
Retinal hamartoma
Calcified
hamartoma
CARDIOPULMONARY
Cardiac Rhabdomyoma
 detected on prenatal US
 Benign tumor usually
undergo spontaneous
regression
Pulmonary (LAM)
 Lymp...
Management
Everolimus
Pulmonary
Cosmetic
Renal AML
Seizure control
EVEROLIMUS
 FDA approved mTOR after ExIST-2 trail
 50% reduction in AML volume in 3 month
 Dose : 10 mg od for 38 weeks...
Cell Proliferation
complex
hamartin
TSC1
tuberin
TSC2
Hamartin-Tuberin complex
Central regulator of cell cycle
TSC: loss o...
Prognosis
 TSC is progressive
 Cause of death:
 status epilepticus
 renal disease
 Surveillance : every 2 years
 men...
THANK YOU
Tuberous Sclerosis Complex With Renal AML 2
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Tuberous Sclerosis Complex With Renal AML 2

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  • Targets for mTOR regulation of translational initiation and elongation. AMPK = AMP-activated kinase. TSC1 and TSC2 = Tuberous sclerosis tumor suppressors 1 (hamartin) and 2 (tuberin); Rheb = Ras homolog enriched in brain; PKB/Akt = protein kinase B; 4EBP1 = eIF-4E binding protein; p70S6K = 70kDa ribosomal protein S6 kinase, also called S6K; eEF2K = eukaryotic elongation factor 2 kinase.
  • M tor : mailman target of rapamycin
  • Targets for mTOR regulation of translational initiation and elongation. AMPK = AMP-activated kinase. TSC1 and TSC2 = Tuberous sclerosis tumor suppressors 1 (hamartin) and 2 (tuberin); Rheb = Ras homolog enriched in brain; PKB/Akt = protein kinase B; 4EBP1 = eIF-4E binding protein; p70S6K = 70kDa ribosomal protein S6 kinase, also called S6K; eEF2K = eukaryotic elongation factor 2 kinase.
  • Tuberous Sclerosis Complex With Renal AML 2

    1. 1. INTRODUCTION Skin Eyes Brain Heart Lung Kidney Liver Tuberous Sclerosis Complex (TSC) inherited neuro-cutaneous disorder multiple benign hamartomas:
    2. 2. GENETICS  Autosomal dominant  Incidence 1 : 5000 livebirths  Mutation in  TSC-1 (Hamartin) or  TSC-2 (Tuberin)  +ve family history in 7 – 37%
    3. 3. Cell Proliferation complex hamartin TSC1 tuberin TSC2 Hamartin-Tuberin complex Central regulator of cell cycle TSC: loss of inhibition to cell cycle
    4. 4. 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
    5. 5. 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
    6. 6. Diagnosis Possible TSC 1 major 2 or more minor Probable TSC 1 major plus 1 minor Definite TSC 2 major 1 major + 2 minor
    7. 7. DERMATOLOGICAL LESIONS: 81-95%
    8. 8. Angiofibromas
    9. 9. Fibrous plaque
    10. 10. Ash leaf spots
    11. 11. Periungual & subangual fibromas
    12. 12. BRAIN LESIONS 90%
    13. 13. Glioneuronal hamartomas
    14. 14. Subependymal nodules
    15. 15. Subependymal Giant Cell tumor
    16. 16. 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
    17. 17. Diagnostic features associated with increase morbidity New symptoms or papilledema Hydrocephalus Serial imaging showing growth of lesions
    18. 18. RENAL MANIFESTATIONS
    19. 19. Renal Angiomyolipomas (AML) Frequency in TSC patients: ~ 40 – 70 %
    20. 20. Renal Angiomyolipomas (AML)  Asymptomatic in most cases  Symptoms  bleeding  mass effect  2 histological types:  Classic  Epithelioid  Diagnosis : demonstration of FAT in the Tumor
    21. 21. Renal Angiomyolipomas (AML) AML contain fat Peri-renal fat
    22. 22. Treatment of AML Prophylactic surgery?  Size ≥4cm to prevent bleeding  High vascularity and/or aneurysm ≥ 5mm  High suspicion of malignancy
    23. 23. Treatment of AML Therapeutic interventions  Nephron sparing surgery  Selective renal artery embolization  Radiofrequency ablation  Radical nephrectomy
    24. 24. 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
    25. 25. 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
    26. 26. Chronic kidney disease In absence of large AML, patients may develop:  CKD  subnephrotic proteinuria  hypertension  ESRD Renal biopsy often reveals FSGS
    27. 27. OPHTHALMIC MANIFESTATIONS
    28. 28. Retinal hamartoma Calcified hamartoma
    29. 29. CARDIOPULMONARY
    30. 30. 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
    31. 31. Management Everolimus Pulmonary Cosmetic Renal AML Seizure control
    32. 32. 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
    33. 33. Cell Proliferation complex hamartin TSC1 tuberin TSC2 Hamartin-Tuberin complex Central regulator of cell cycle TSC: loss of inhibition to cell cycle EVEROLIMUS
    34. 34. Prognosis  TSC is progressive  Cause of death:  status epilepticus  renal disease  Surveillance : every 2 years  mental, physical examination  MRI brain  U/S abdomen  ECHO
    35. 35. THANK YOU
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