Overview
The Disease Pattern
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by a pathogenic loss of function variant in TSC1 or TSC2 .
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by a pathogenic loss-of-function variant in TSC1 or TSC2. These genes encode hamartin and tuberin, which normally restrain the mechanistic target of rapamycin (mTOR) pathway. When that brake is lost, mTOR signalling remains active, promoting abnormal cell growth and the formation of hamartomas in multiple organs. The lesions are usually non-malignant, but their location determines the danger. A cortical lesion can generate seizures; a subependymal giant cell astrocytoma (SEGA) can obstruct cerebrospinal fluid at the foramen of Monro; and a renal angiomyolipoma can bleed. The disease therefore requires surveillance even when the person appears well. Approximately two-thirds of cases result from a de novo variant, so the absence of a family history does not exclude TSC. In an affected individual, each pregnancy carries a 50% chance of inheriting the pathogenic variant, although the clinical severity can differ substantially between relatives. The clinical pattern is multisystem: - Brain: cortical tubers and radial migration lines, subependymal nodules, SEGA, epilepsy, and neurodevelopmental or behavioural difficulties. - Skin: hypomelanotic macules, often the earliest visible...