Tuberous sclerosis
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Tuberous sclerosis, (meaning "hard potatoes") is a rare genetic, disorder primarily characterized by a triad of seizures, mental retardation, and skin lesions (called adenoma sebaceum). This "classic" Vogt triad is present in 30-50% of cases; in particular, up to 30% of tuberous sclerosis reportedly have normal mentation. Tuberous sclerosis, along with Neurofibromatosis type I, Neurofibromatosis type II (a.k.a. MISME syndrome), Sturge-Weber, and Von Hippel-Lindau compromise the Phakomatoses or neurocutaneous syndromes, all of which have neurologic and dermatologic lesions. This grouping is an artifact of an earlier time in medicine, before the distinct genetic basis of each of these diseases was understood.
The neuropathologic findings of the cortical "tubers" (sclerose tubereuse) was first described by Bourneville in 1880.
Individuals with tuberous sclerosis may experience none or all of the symptoms with varying degrees of severity. Tuberous sclerosis is a multi-system disease that can affect the brain, kidneys, heart, eyes, lungs, and other organs. Small benign tumors may grow on the face and eyes, as well as in the brain, kidneys, and other organs. Neuroimaging studies may be able to confirm the diagnosis. Seizures most often begin in the first year of life.
Tuberous sclerosis' acronym is T.S.C. (Tuberous sclerosis complex) so as to avoid confusion with Tourette's Syndrome. May is designated National Tuberous Sclerosis Awareness month.
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Synonyms
Bournville disease
Genetics
Tuberous sclerosis (TSC) is transmitted by two genes, TS1 and TS2 which have an autosomal dominant pattern of inheritance: both function as tumor supressor genes. TS1 is present in 10-20% of TS patients and is located on 9q34, TS2 is present in 80-90% and is located on 16p13. The incidence is between 1/100,000 and 1/10,000.
Tsc1 encodes for the protein hamartin, and Tsc2 encodes for the protein tuberin. Hamartin/Tuberin function as a complex, whose biological activity apears to be a Rheb GTPase. The function within the insulin signaling pathway.
Neuroradiographic features of tuberous sclerosis
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 Monroe, in which case it is at risk of developing an obstructive hydrocephalus.
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This is a set of images from an MRI of the brain in a patient with TSC.
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.
Genitourinary manifestations of tuberous sclerosis
40-80% of TSC patients have benign tumors of the kidneys called angiomyolipomas (AML). These tumors are composed of fat, muscle, and blood vessels. Although benign, an AML larger than 4 cm is at risk for a potentially catastrophic hemorrhage either spontaneously or with minimal trauma.
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This is an image from a contrast-enhanced CT of the abdomen in another patient with TSC.
2-3% of TSC patients develop multiple, bilateral large renal cysts, eventually leading to renal failure. The TS2 gene is immediately adjacent to the PKD1 gene, which is one of the two genes responsible for autosomal dominant polycystic kidney disease, and TSC patients with cystic renal disease have the mutant TS2 gene. The presence of cystic disease in TSC signifies that the same genetic damage responsible for TSC extends onto the neighboring PKD1 gene.
Pulmonary manifestations of tuberous sclerosis
Patients with TSC can develop progressive replacement of the lung parenchyma with multiple cysts. This process is identical to another disease called lymphangioleiomyomatosis (LAM). Recent genetic analysis has shown that the proliferative bronchiolar smooth muscle in tuberous sclerosis-related LAM is monoclonal metastastases from a coexisting renal angiomyolipoma. There have been cases of TSC-related LAM reoccurring following lung transplant. (Henske EP. Metastasis of benign tumor cells in tuberous sclerosis complex. Genes, Chromosomes & Cancer. Dec. 2003. 38(4):376-81)
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This computed tomography image shows randomly arranged cysts in both lungs. The patient had TSC and a renal AML.
Cardiac manifestations of tuberous sclerosis
Rhabdomyomas are benign tumors of striated muscle. Cardiac rhabdomyomas can be diagnosed in 50-60% of patients with turberous sclerosis at some point. A cardiac rhabdomyoma is most commonly found within the left ventricle, where it may cause an asymptomatic murmer or possible a degree of congestive failure, or even sudden infant death. In utero, it may be a cause of hydrops foetalis.
The natural history of TSC-related cardiac rhabdomyomas is usually that of spontaneous regression, typically by the age of 4 years.
(references: Webb DW, Thomas RD, Osborne JP. Cardiac rhabdomyomas and their association with tuberous sclerosis. Archives of Disease in Childhood 1993 Mar;68(3):367–370)
Dermatologic manifestations of tuberous sclerosis
- Adenoma sebaceum (angiogibromatosis)
- Hypomelanotic nodules (also known as ash-leaf spots)
- Shagreen patches
Occular manifestations of tuberous sclerosis
Retinal lesions, called astrocytic hamartomas, which appear as a greyish or yellowish-white lesion in the back of the globe on the opthalmic examination. Astrocytic hamartomas can calcify, and in is in the differential diagnosis of a calcified globe mass on a CT scan.
Non-retinal lesions associated with TSC include
- Coloboma
- Angiofibromas of the eyelids
- Papilledema (related to hydrocephalus)
References
- NINDS Tuberous Sclerosis Information Page (http://www.ninds.nih.gov/health_and_medical/disorders/tuberous_sclerosis.htm#What_is_Tuberous_Sclerosis) (public domain)de:Tuberöse Sklerose