Tuberous Sclerosis Complex

Epidemiology and Etiology:

• AD
• TSC1 (20%) and TSC2 (60%) mutations

Common sites:

• brain
• hamartomas (cortical tubers, subependymal hamartomas)
• retinal glial hamartomas
• subependymal giant cell astrocytoma
• kidney
• angiomyolipoma
• cysts
• lungs
• leiomyomatosis
• heart
• rhabdomyoma
• liver
• cysts
• pancreas
• cysts
• skin
• angiofibroma
• shagreen patches – leathery thickenings
• hypopigmented areas (ash-leaf patches)
• subungual fibromas

Gross features:

• cortical hamartoma:
• firm
• potatoe-like

Histologic features:

• cortical hamartoma:
• haphazardly arranged neurons
• lack normal cortical architecture
• some large intermediate cells – express both GFAP and neurofilament
• large neuron-like vesicular nuclei with nucleoli
• abundant eosinophilic cytoplasm like gemistocytic astrocytes

Immunophenotype:

Marker:

Sensitivity:

Specificity:

Molecular features:

• 2 genes at which mutations can cause TS
• TSC1 (9q34) – encodes for Hamartin
• Mostly small deletions, insertions, nonsense mutations detectable by sequencing
• Interacts with ERM family of actin binding proteins
• Interacts with CDK to regulate cell cycle
• Regulates growth of neurites, synapse formation, and axon development
• TSC2 (16p13.3) – encodes for Tuberin
• Also include significant numbers of large deletions and rearrangements not detectable by sequencing
• homology to GTPase-activating protein
• downstream effects on growth and cell proliferation
• Hamartin and Tuberin form heterodimers
• May act in concert to regulate cell proliferation
• Participate in multiple signaling pathways – AKT, MAPK, AMPK, b-catenin, calmodulin, MTOR, CDK, cell cycle
• Large number of mutations, both are large genes
• High rate of somatic mosaicism (10-25%)

Other features:

• seizures

References:

• Robbins & Cotran Pathologic Basis of Disease (2005)
• NCBI Gene Reviews (2009)