Clinical meaning
Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disorder caused by loss-of-function mutations in either TSC1 (chromosome 9q34, encoding hamartin) or TSC2 (chromosome 16p13, encoding tuberin). The hamartin-tuberin complex normally acts as a tumor suppressor by inhibiting the mechanistic target of rapamycin (mTOR) signaling pathway, which regulates cell growth, proliferation, protein synthesis, and metabolism. When either hamartin or tuberin is dysfunctional, constitutive activation of mTOR leads to unregulated cell growth and formation of benign tumors (hamartomas) in multiple organ systems. Two-thirds of cases arise from de novo mutations. The clinical manifestations affect virtually every organ: CNS (cortical tubers causing seizures and intellectual disability, subependymal nodules, subependymal giant cell astrocytomas that can obstruct CSF flow at foramen of Monro causing hydrocephalus), skin (hypomelanotic macules or ash-leaf spots often the earliest sign visible under Wood lamp, facial angiofibromas or adenoma sebaceum appearing age 3-5 which are pathognomonic, shagreen patches, periungual fibromas or Koenen tumors which are pathognomonic), kidneys (angiomyolipomas containing fat, smooth muscle, and abnormal vessels with risk of hemorrhage present in 80%), lungs (lymphangioleiomyomatosis or LAM with progressive cystic lung disease predominantly in women), heart (cardiac rhabdomyomas which are the most common cardiac tumor in infants and often regress spontaneously), and eyes (retinal hamartomas). Seizures occur in 85% of patients and are often the presenting symptom in infancy, with infantile spasms (West syndrome) being a characteristic early seizure type.