Tuberous sclerosis complex

Tuberous sclerosis complex (TSC), also known as Bourneville disease or Bourneville-Pringle disease, is a genetic multisystem disorder characterized by the growth of benign (noncancerous) tumors called hamartomas in multiple organs throughout the body. TSC is caused by pathogenic variants in either the TSC1 gene (encoding hamartin) or the TSC2 gene (encoding tuberin), both of which function as tumor suppressors through regulation of the mTOR (mechanistic target of rapamycin) signaling pathway. Loss of function of either protein leads to constitutive activation of mTOR, resulting in uncontrolled cell growth and proliferation. TSC affects virtually every organ system, but the brain, skin, kidneys, heart, lungs, and eyes are most commonly involved. Key neurological features include cortical tubers, subependymal nodules, and subependymal giant cell astrocytomas (SEGAs), which can lead to epilepsy (often presenting as infantile spasms), intellectual disability, and autism spectrum disorder. Collectively, the neuropsychiatric manifestations are referred to as TSC-associated neuropsychiatric disorders (TAND). Skin findings are among the earliest and most recognizable features and include hypomelanotic macules (ash-leaf spots), facial angiofibromas, shagreen patches, fibrous cephalic plaques, and ungual fibromas. Renal angiomyolipomas occur in the majority of patients and can cause life-threatening hemorrhage. Cardiac rhabdomyomas are frequently detected prenatally or in infancy and often regress spontaneously. Lymphangioleiomyomatosis (LAM) predominantly affects women and can lead to progressive lung destruction. The treatment landscape for TSC has been transformed by the availability of mTOR inhibitors, particularly everolimus, which is approved for the treatment of SEGAs, renal angiomyolipomas, and as adjunctive therapy for refractory epilepsy associated with TSC. Vigabatrin is considered first-line treatment for TSC-associated infantile spasms. Management requires a multidisciplinary approach with regular surveillance of affected organ systems according to established consensus guidelines. Surgical interventions may be necessary for refractory epilepsy, large renal tumors, or obstructive brain lesions. Early developmental and behavioral interventions are recommended for TAND.

Data sourced from FDA regulatory filings and ClinicalTrials.gov. Updated periodically.

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