Tuberous sclerosis is an autosomal dominant syndrome characterized by the development of hamartomas and benign neoplasms involving the brain and other tissues. CNS hamartomas variously consist of cortical tubers and subependymal hamartomas, including a larger tumefactive form known as subependymal giant cell astrocytoma. Because of their proximity to the foramen of Monro, they often present acutely with obstructive hydrocephalus, which requires surgical intervention and/or therapy with an mTOR inhibitor (see later). Seizures are associated with cortical tubers and can be difficult to control with anti-epileptic drugs. Extracerebral lesions include renal angiomyolipomas, retinal glial hamartomas, pulmonary lymphangiomyomatosis, and cardiac rhabdomyomas. Cysts may be found at various sites, including the liver, kidneys, and pancreas. Cutaneous lesions include angiofibromas, leathery thickenings in localized patches (shagreen patches), hypopigmented areas (ash leaf patches), and subungual fibromas.
Tuberous sclerosis results from disruption of either TSC1, which encodes hamartin, or TSC2, which encodes tuberin. The two TSC proteins form a dimeric complex that negatively regulates mTOR, a kinase that “senses” the cell’s nutrient status and regulates cellular metabolism. Loss of either protein upregulates mTOR activity, which disrupts normal feedback mechanisms that restrict uptake of nutrients and leads to increased cell growth.
MORPHOLOGYCortical hamartomas arefirmerthannormalcortexandhavebeenlikenedinappearancetopotatoes—hencetheappellationtubers. Theyarecomposedofhaphazardlyarrangedlargeneuronsthatlackthenormalcorticallaminararchitecture.Thesecellsmayexhibitamixtureofglialandneuronalfeatures,havinglargevesicularnucleiwithnucleoli(likeneurons)andabundanteosinophiliccytoplasm.Similarabnormalcellsarepresentinsubependymal nodules, inwhichlargeastrocytelikecellsclusterbeneaththeventricularsurface.
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In this autosomal dominant disorder, affected individuals develop hemangioblastomas within the cerebellar hemispheres, retina, and, less commonly, the brain stem, spinal cord, and nerve roots. Patients also may have cysts involving the pancreas, liver, and kidneys and have an increased propensity to develop renal cell carcinoma. The disease frequency is 1 in 30,000 to 40,000. Therapy is directed at the symptomatic neoplasms, including surgical resection of cerebellar tumors and laser ablation of retinal tumors.
The affected gene, the tumor suppressor VHL, encodes a protein that is part of a ubiquitin-ligase complex that degrades the transcription factor hypoxia-inducible factor (HIF). Tumors arising in patients with von Hippel–Lindau disease generally have lost all VHL protein function. As a result, the tumors express high levels of HIF, which drives the expression of VEGF, various growth factors, and sometimes erythropoietin; the latter effect may produce a paraneoplastic form of polycythemia.