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Stephanie Carapetian Randle, MD, MS, is an Assistant Professor of Pediatric Neurology and Epilepsy, University of Washington and Seattle Children's Hospital.
Disclosure: The author has no relevant financial relationships to disclose.
Tuberous sclerosis complex (TSC) is a multisystem neurocutaneous genetic disorder with an incidence of 1 per 6,000 to 10,000 live births. 1,2 TSC was first identified by Friedrich Daniel von Recklinghausen in 1862 in a baby with cardiac "myomatas" and areas of sclerotic brain tissue. 2 In 1880, Bourneville better explained the neurologic features, and observed associated dermatologic abnormalities, and subsequently, the term tuberous sclerosis was used to describe this disorder. 2 Since that time, TSC is known to have a variable presentation that classically involves the brain, skin, kidneys, heart, eyes, and lungs, but can affect any organ system. The hallmark of the disease is tumors consisting of glial-neuronal and retinal hamartomas, subependymal giant cell tumors, cardiac rhabdomyomas, renal and extra-renal angiomyolipomas (AML), and pulmonary lymphangioleiomyomatosis (LAM). Despite the typically benign pathology of these tumors, they may lead to secondary outflow abnormalities due to mass effect (ie, hydrocephalus, renal, and cardiac dysfunction) or interruption of the function of the normal tissue (ie, seizures and arrhythmia).
Pathophysiology and Genetics
The clinical manifestations of TSC are a result of dysfunction in cell differentiation, proliferation, and migration during early fetal development. TSC is known to be caused by a mutation in either the TSC1 or TSC2 gene. 3-6 TSC1 is found on chromosome 9q34 and encodes the protein hamartin, and TSC2 is found on chromosome 16p13 and encodes the protein tuberin. 2,5-8 Both hamartin and tuberin are widely expressed throughout normal tissue and together these proteins are involved in the mammalian target of rapamycin (mTOR) pathway. This pathway functions to regulate cell growth, size, and proliferation. Deregulation of the mTOR signaling pathway can result in tissue overgrowth as the TSC2 : TSC1 complex stops mTOR activation. 8
Approximately 30% of TSC cases are inherited in an autosomal dominant manner, and around 70% of cases are secondary to spontaneous mutations. 3,4 A mutation in TSC2 is 4 times more common in de novo cases; however, in familial cases of TSC, the incidence of a mutation in TSC1 is about equal to a mutation in TSC2 . 4...