The name, composed of the Latin tuber (swelling) and the Greek skleros (hard), refers to the pathological finding of thick, firm and pale gyri, called "tubers", in the brains of patients postmortem. These tubers were first described by Désiré-Magloire Bourneville in 1880; the cortical manifestations may sometimes still be known by the eponym Bourneville's disease.
Three type of brain tumours may be associated with TSC: i. Giant cell astrocytoma: (grows and blocks the CSF flow leading to dilatation of ventricles causing headache and vomiting. ii. Cortical tubers: after which the disease is named. iii. Sub-ependymal nodules: form in the walls of ventricles.
Classic intracranial manifestations of tuberous sclerosis include subependymal nodules and cortical/subcortical tubers.
The tubers are typically triangular in configuration, with the apex pointed towards the ventricles, and are thought to represent foci of abnormal neuronal migration. The T2 signal abnormalities may subside in adulthood, but will still be visible on histopathological analysis. On magnetic resonance imaging, TSC patients can exhibit other signs consistent with abnormal neuron migration (radial white matter tracts hyperintense on T2WI, heterotopic gray matter).
Subependymal nodules are composed of abnormal, swollen glial cells and bizarre multinucleated cells which are indeterminate for glial or neuronal origin. There is no interposed neural tissue. These nodules have a tendency to calcify as the patient ages. A nodule that markedly enhances and enlarges over time should be considered suspicious for transformation into a subependymal giant cell astrocytoma (SEGA). A SEGA typically develops in the region of the foramen of Monro, in which case it is at risk of developing an obstructive hydrocephalus.
A variable degree of ventricular enlargement, either obstructive (e.g. by a subependymal nodule in the region of the foramen of Monroe) or idiopathic in nature.
Prenatal ultrasound, performed by an obstetric sonographer specializing in cardiology, can detect a rhabdomyoma after 20 weeks. This rare tumour is a strong indicator of TSC in the child, especially if there is a family history of TSC.
Non-retinal lesions associated with TSC include
Tuberous sclerosis is a genetic disorder with an autosomal dominant pattern of inheritance, and penetrance is 100%. Two thirds of TSC cases result from sporadic genetic mutations, not inheritance, but their offspring may inherit it from them. Current genetic tests have difficulty locating the mutation in approximately 20% of individuals diagnosed with the disease. So far it has been mapped to two genetic loci, TSC1 and TSC2.
TSC1 encodes for the protein hamartin, is located on chromosome 9 q34 and was discovered in 1997. TSC2 encodes for the protein tuberin, is located on chromosome 16 p13.3 and was discovered in 1993. TSC2 is contiguous with PKD1, the gene involved in one form of polycystic kidney disease (PKD). Gross deletions affecting both genes may account for the 2% of individuals with TSC who also develop PKD in childhood. TSC2 has been associated with a more severe form of TSC. However, the difference is subtle and cannot be used to identify the mutation clinically. Estimates of the proportion of TSC caused by TSC2 range from 55% to 80-90%.
TSC1 and TSC2 are both tumor suppressor genes that function according to Knudson's "two hit" hypothesis. That is, a second random mutation must occur before a tumor can develop. This explains why, despite its 100 percent penetrance, TSC has wide expressivity.
Hamartin and tuberin function as a complex which is involved in the control of cell growth and cell division. (The complex appears to be a Rheb GTPase which suppresses mTOR signalling, part of the growth factor (insulin) signalling pathway.) Thus, mutations at the TSC1 and TSC2 loci result in a loss of control of cell growth and cell division, and therefore a predisposition to forming tumors.
|1||Head||Facial angiofibromas or forehead plaque||Infant – adult|
|2||Fingers and toes||Nontraumatic ungual or periungual fibroma||Adolescent – adult|
|3||Skin||Hypomelanotic macules||Infant – child||More than three.|
|4||Skin||Shagreen patch (connective tissue nevus)||Child|
|6||Brain||Subependymal nodule||Child – adolescent|
|7||Brain||Subependymal giant cell astrocytoma||Child – adolescent|
|8||Eyes||Multiple retinal nodular hamartomas||Infant|
|9||Heart||Cardiac rhabdomyoma||Fetus||Single or multiple.|
|10||Lungs||Lymphangiomyomatosis||Adolescent – adult|
|11||Kidneys||Renal angiomyolipoma||Child – adult||10 and 11 together count as one major feature.|
|12||Teeth||Multiple randomly distributed pits in dental enamel|
|13||Rectum||Hamartomatous rectal polyps||Histologic confirmation is suggested.|
|15||Brain||Cerebral white-matter "migration tracts"||Radiographic confirmation is sufficient. 5 and 15 together count as one major feature.|
|17||Liver, spleen and other organs||Nonrenal hamartoma||Histologic confirmation is suggested.|
|18||Eyes||Retinal achromic patch|
|19||Skin||"Confetti" skin lesions|
|20||Kidneys||Multiple renal cysts||Histologic confirmation is suggested.|
In infants, the first clue is often the presence of seizures, delayed development or white patches on the skin. A full clinical diagnosis involves
The various signs are then marked against the diagnostic criteria to produce a level of diagnostic certainty:
Due to the wide variety of mutations leading to TSC, there are no simple genetic tests available to identify new cases. Nor are there any biochemical markers for the gene defects. However, once a person has been clinically diagnosed, the genetic mutation can usually be found. The search is time-consuming and has a 15% failure rate, which is thought to be due to somatic mosaicism. If successful, this information can be used to identify affected family members, including prenatal diagnosis. As of 2006, preimplantation diagnosis is not widely available.
Leading causes of death include renal disease, brain tumour, lymphangiomyomatosis of the lung, and status epilepticus or bronchopneumonia in those with severe mental handicap. Cardiac failure due to rhabdomyomas is a risk in the fetus or neonate, but is rarely a problem subsequently. Kidney complications such as angiomyolipoma (AML) and cysts are common, and more frequent in females than males and in TSC2 than TSC1. Renal cell carcinoma is uncommon. Lymphangioleiomyomatosis (LAM) is only a risk for females with AMLs. In the brain, the subependymal nodules occasionally degenerate to subependymal giant cell astrocytomas (SEGA). These may block the circulation of cerebrospinal fluid around the brain, leading to hydrocephalus.
Detection of the disease should prompt one for genetic counselling. It is also important to know that even though the disease does not have a cure, symptoms can be treated symptomatically. Hence, awareness regarding different organ manifestations of tuberous sclerosis is important.
Tuberous sclerosis first came to medical attention when dermatologists described the distinctive facial rash (1835 and 1850). A more complete case was presented by von Recklinghausen (1862) who identified heart and brain tumours in a newborn that had only briefly lived. However, Bourneville (1880) is credited with having first characterized the disease, coining the name tuberous sclerosis, thus earning the eponym Bourneville's disease. The neurologist Vogt (1908) established a diagnostic triad of epilepsy, idiocy, and adenoma sebaceum (an obsolete term for facial angiofibroma).
Symptoms were periodically added to the clinical picture. The disease as presently understood was first fully described by Gomez (1979). The invention of medical ultrasound, CT and MRI has allowed physicians to examine the internal organs of live patients and greatly improved diagnostic ability.
Two genetic loci associated with tuberous sclerosis, TSC1 and TSC2, were discovered in 1997 and 1992 respectively. This has enabled the use of genetic testing as a diagnostic tool. The proteins associated with TSC1 and TSC2, harmartin and tuberin, function as a complex in the mTOR signalling pathway that controls cell growth and cell division. The importance of this pathway in cancer therapy has stimulated further research into Tuberous Sclerosis.
In 2002, treatment with rapamycin was found to be effective at shrinking tumours in animals. This has led to human trials of rapamycin as a drug to treat several of the tumors associated with Tuberous Sclerosis.
Conservative management of pulmonary lymphangioleiomyomatosis and tuberous sclerosis complicated by renal angiomyolipomas in pregnancy
Feb 01, 2004; Both pulmonary lymphangioleiomyomatosis and tuberous sclerosis are rare diseases. The optimal management in pregnancy is unclear....
Kidneys Sometimes Removed Needlessly in Patients with Rare Genetic Disorder; Tuberous Sclerosis Causes Benign Growths to Form on Organs That Doctors Can Mistake for Cancer
Jan 10, 2013; Byline: Lisa Esposito, HealthDay Reporter THURSDAY, Jan. 10 (HealthDay News) -- Too often, patients with a relatively rare...