Tuberous sclerosis is a relatively common neurocutaneous syndrome (otherwise known as a phakomatosis, from the Greek "phako", meaning a lens or lentil-shaped object or spot) with an incidence reported in a wide range from 1 in 10,000 to 1 in 150,000. Hamartomatous tumors and malformations that occur in many organs, chiefly the brain, kidney, lung, skin, and heart, characterize the syndrome. It was originally described in 1862 by von Recklinghausen, although the term "tuberous sclerosis of the cerebral convolutions" was not coined until 1882 by Bourneville (hence the eponymous "Bourneville disease"). Years later, in 1908, Vogt noted the triad of seizures, mental deficiency, and skin lesions (commonly, though inaccurately, referred to as adenoma sebaceum) that is considered the classic clinical presentation of TS. Only 30% of patients manifest all 3 features of the triad, while less than 10% of patients have none of the triad's three classic features. The inheritance pattern is autosomal dominant; up to 50% of cases are reported as sporadic, from apparent new spontaneous mutations. The incidence of the disease is variously reported as 1/10,000 to 1/150,000. There are no gender or race predilections. Today, it is recognized that TS displays a spectrum of phenotypic expression, ranging from patients exhibiting the classic Vogt triad to those with only a single or few suspicious lesions (forme fruste or presumptive TS).
The diagnosis of TS is based on the discovery of one or more pathognomonic lesions (cortical tuber, multiple subependymal glial nodules, retinal hamartoma, multiple facial angiofibromas, subungual fibroma, multiple renal angiomyolipomas, or fibrous plaques on the forehead or scalp.) There is a presumptive diagnosis when 2 or more of the following are discovered: seizure, calcified intraventricular tumor, focal areas of increased attenuation in cerebral or cerebellar cortex, wedge-shaped calcified cortical-subcortical lesion, hypomelanotic cutaneous lesions, shagreen patches, multiple renal cysts, cardiac rhabdomyoma, pulmonary lymphangiomyomatosis, or an immediate relative with TS. If only 1 of the latter findings is present, the diagnosis of TS is considered possible, but is not presumed.
The brain is the most commonly involved organ in TS, and it is not surprising that seizure is the most common clinical sign of the disease, present in 80-100% of patients. Several forms of hamartomas are found in the brain of the TS patient; they vary with respect to location and tumor morphology. The 4 most common lesions are the cortical tuber, white matter abnormalities, subependymal nodule (SEN), and the subependymal giant cell astrocytoma (SEGCT). The first 3 are benign, true hamartomas; SEGCT is a low grade (World Health Organization Grade I) neoplasm. Although the different names for the brain hamartomas suggest that they are distinctly different entities, in fact the cortical tubers, white matter abnormalities, and SEN are virtually identical lesions composed of disordered neurons, glia, and giant cells resembling both astrocytes and neurons. The lesions vary only in their size (cortical tubers tend to be large, white matter lesions tend to be linear, radial, or wedge-shaped, and SENs tend to be small) and their location (cortical gyri, white matter, or subependyma, respectively). Their nearly identical composition and their radial distribution led to the hypothesis that these findings reflect a dysgenetic event at the germinal matrix (in the subependymal and periventricular regions of the brain), which gives rise to an aberrant giant cell that may subsequently develop neuronal or astrocytic features. These aberrant giant cells radially migrate (as do the normal cells) from the germinal matrix to the cortex. As the brain grows, the cells can no longer simply elongate, so glial cells develop from stem cells to bridge gaps. It is thought that the radial glial-neuronal unit, having begun its formation at the germinal matrix, is fundamentally abnormal in patients with TS. Therefore, from the germinal matrix to the cortex, the radial migratory path may show hamartomatous lesions. The finding of SEN, linear and wedge-shaped white matter lesions, and cortical tubers reflects this abnormal radial glial-neuronal unit.
Subependymal giant cell astrocytomas are neoplastic tumors (World Health Organization grade I), thought to originate in a pre-existing SEN. They occur in approximately 15% of TS patients. They are typically slowly growing, solitary, and benign-acting tumors. Their morbidity relates to obstruction of the foramen of Monro, as they grow into the ventricular lumen and not into the brain parenchyma itself. They do not seed the cerebrospinal fluid and are unlikely to recur after resection.