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Tuberous sclerosis (meaning "hard swellings") is a rare genetic disorder primarily characterized by a triad of seizures, mental retardation, and skin lesions (called facial angiofibroma or 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.
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 syndrome.
Tuberous sclerosis (TSC) is a genetic disorder caused by mutations on either of two genes TSC1 and TSC2. It has an autosomal dominant pattern of inheritance and penetrance is 100%. The incidence is between 1/6,000 and 1/10,000. One third of cases are inherited; the rest are new mutations.
TSC1 is located on chromosome 9q34 and encodes for the protein hamartin. It was discovered in 1997. TSC2 is located on chromosome 16p13.3 and encodes for the protein tuberin. It was discovered in 1993. TSC2 is contiguous with PKD1 (which causes one form of polycystic kidney disease). Gross deletions affecting both genes may account for the 2% of individuals with TSC who develop PKD in childhood.
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 the wide expressivity of the disease. Of the two, TSC2 has been associated with a more severe form of TSC. However, the difference is subtle and statistical and cannot be used to identify the mutation clinically. Estimates of the proportion of TSC caused by TSC2 ranges from 55% to 80-90%. Current genetic tests have difficulty locating the mutation in approximately 20% of individuals.
Hamartin/tuberin function as a complex, whose biological activity appears to be a Rheb GTPase. They function within the growth factor (insulin) signalling pathway and are involved in suppressing mTOR signalling.
Diagnosis of tuberous sclerosis is initially clinical based on the diagnostic criteria of major/minor features:
- Definite tuberous sclerosis complex - Either two major features or one major feature plus two minor features
- Probable tuberous sclerosis complex - One major plus one minor feature
- Possible tuberous sclerosis complex - Either one major feature or two or more minor features
- Facial angiofibromas or forehead plaque
- Nontraumatic ungual or periungual fibrom
- Hypomelatonic macules (three or more)
- Shagreen patch (connective-tissue nevus)
- Multiple retinal nodular hamartomas
- Cortical tubera
- Subependymal nodule
- Subependymal giant-cell astrocytoma
- Cardiac rhabdomyoma, single or multiple
- Renal angiomyolipoma
- Multiple, randomly distributed pits in dental enamel
- Hamarromatous rectal polyps
- Bone cysts
- Cerebral white matter radial migration lines
- Gingival fibromas
- Nonrenal hamartoma
- Retinal achromic patch
- 'Confetti' skin lesions
- Multiple renal cysts
Major and minor criteria: Roach ES, Gomez MR, Northrup H. (1998). Tuberous sclerosis consensus conference: revised clinical diagnostic criteria. J Child Neurol 13: 624-8. PMID 9881533.
Genetic testing may then be performed along with screening of other family members if a particular mutation is found.
Cognitive and behavioural featuresEdit
About 50% of people with TSC have learning difficulties ranging from mild to profound and studies have reported that between 25% and 61% of affected individuals meet the diagnostic criteria for autism with an even higher proportion showing features of a broader pervasive developmental disorder. Other conditions, such as ADHD, aggression, behavioral outbursts and OCD can also occur. Lower IQ is associated with more brain involvement on MRI.
Neuroradiographic featuresEditClassic 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.
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 manifestationsEditBetween 60 and 80% of TSC patients have benign tumors (hamartomas) of the kidneys called angiomyolipomas (AML). These tumors are composed of vascular tissue (angio), smooth muscle (myo), and fat (lipoma). Although benign, an AML larger than 4 cm is at risk for a potentially catastrophic hemorrhage either spontaneously or with minimal trauma. AMLs are found in about 1 in 300 people without TSC. However those are usually solitary, whereas in TSC they are commonly multiple and bilateral.
Very rare (< 1%) problems include renal cell carcinoma and oncocytomas (benign adenomatous hamartoma).
Pulmonary manifestationsEditPatients 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 metastasis from a coexisting renal angiomyolipoma. There have been cases of TSC-related LAM recurring following lung transplant. (Henske EP. Metastasis of benign tumor cells in tuberous sclerosis complex. Genes, Chromosomes & Cancer. Dec. 2003. 38(4):376-81)
Rhabdomyomas are benign tumors of striated heart muscle. A cardiac rhabdomyoma can be discovered using echocardiography in approximately 50% of people with TSC. However the incidence in the newborn may be as high as 90% and in adults as low as 20%. These tumors grow during the second half of pregnancy and regress after birth. Many will disappear entirely. Alternatively, the tumor size remains constant as the heart grows, which has much the same effect.
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.
Some form of dermatological sign will be present in 96% of individuals with TSC. Most cause no problems but are helpful in diagnosis. Some cases may cause disfigurement, necessitating treatment. The most common skin abnormalities include:
- Hypomelanic macules ("ash leaf spots"): White or lighter patches of skin that may appear anywhere on the body and are caused by a lack of melanin. These are usually the only visible sign of TSC at birth. In fair-skinned individuals a Wood's lamp (ultraviolet light) may be required to see them.
- Facial angiofibromas: A rash of reddish spots or bumps, which appear on the nose and cheeks in a butterfly distribution. They consist of blood vessels and fibrous tissue. This socially embarrassing rash starts to appear during childhood and can be removed using dermabrasion or laser treatment.
- Forehead plaques: Raised, discolored areas on the forehead.
- Shagreen patches: Areas of thick leathery skin that are dimpled like an orange peel, usually found on the lower back or nape of the neck.
- Ungual or subungual fibromas: Small fleshy tumors that grow around and under the toenails or fingernails and may need to be surgically removed if they enlarge or cause bleeding. These are very rare in childhood but common by middle age.
- Other skin features that are not unique to individuals with TSC, including molluscum fibrosum or skin tags, which typically occur across the back of the neck and shoulders, cafe-au-lait spots or flat brown marks, and poliosis, a tuft or patch of white hair that may appear on the scalp or eyelids.
Retinal lesions, called astrocytic hamartomas, which appear as a greyish or yellowish-white lesion in the back of the globe on the ophthalmic 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
Older literature may use the following terms:
- Adenoma sebaceum. This misnomer is sometimes used to refer to TSC. There is no involvement of the sebaceous glands and the term angiofibromatosis is now used.
- Bourneville disease. Bourneville first described the disease "sclerose tubereuse" from which the name Tuberous Sclerosis is derived and is now exclusively used in medical literature.
- Vogt triad. Prior to genetics, the presence of seizures, mental retardation, and skin lesions altogether was used to diagnose the condition.
Community TSC is a distributed computing project to find drugs to treat TSC. Volunteers are welcome.
- Manuel Rodriguez Gomez (Editor), Julian R. Sampson (Editor), Vicky Holets Whittemore (Editor) (1999). Tuberous Sclerosis Complex (Developmental Perspectives in Psychiatry) 3rd edition, Oxford University Press. ISBN 0195122100.
- Paolo Curatolo (Editor) (2003). Tuberous Sclerosis Complex : From Basic Science to Clinical Phenotypes, MacKeith Press. ISBN 1898683395.
- ^ van Slegtenhorst M, de Hoogt R, Hermans C, Nellist M, Janssen B, Verhoef S, Lindhout D, van den Ouweland A, Halley D, Young J, Burley M, Jeremiah S, Woodward K, Nahmias J, Fox M, Ekong R, Osborne J, Wolfe J, Povey S, Snell RG, Cheadle JP, Jones AC, Tachataki M, Ravine D, Sampson JR, Reeve MP, Richardson P, Wilmer F, Munro C, Hawkins TL, Sepp T, Ali JB, Ward S, Green AJ, Yates JR, Kwiatkowska J, Henske EP, Short MP, Haines JH, Jozwiak S, Kwiatkowski DJ (1997). Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science 277 (5327): 805-8. PMID 9242607.
- ^ (1993) Identification and characterization of the tuberous sclerosis gene on chromosome 16. The European Chromosome 16 Tuberous Sclerosis Consortium. Cell 75 (7): 1305-15. PMID 8269512.
- ^ Brook-Carter PT, Peral B, Ward CJ, Thompson P, Hughes J, Maheshwar MM, Nellist M, Gamble V, Harris PC, Sampson JR (1994). Deletion of the TSC2 and PKD1 genes associated with severe infantile polycystic kidney disease--a contiguous gene syndrome. Nat Genet 8 (4): 328-32. PMID 7894481.
- ^ Dabora SL, Jozwiak S, Franz DN, Roberts PS, Nieto A, Chung J, Choy YS, Reeve MP, Thiele E, Egelhoff JC, Kasprzyk-Obara J, Domanska-Pakiela D, Kwiatkowski DJ (2001). Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs. Am J Hum Genet 68 (1): 64-80. PMID 11112665.
- ^ Rendtorff ND, Bjerregaard B, Frodin M, Kjaergaard S, Hove H, Skovby F, Brondum-Nielsen K, Schwartz M (2005). Analysis of 65 tuberous sclerosis complex (TSC) patients by TSC2 DGGE, TSC1/TSC2 MLPA, and TSC1 long-range PCR sequencing, and report of 28 novel mutations. Hum Mutat 26 (4): 374-83. PMID 16114042.
- ^ Harrison JE, Bolton, PF (1997). Annotation: Tuberous sclerosis. Journal of Child Psychology and Psychiatry 38: 603-614. PMID 9315970.
- NINDS Tuberous Sclerosis Information Page
- GeneReviews: Tuberous Sclerosis Complex
- The HUGO Gene Nomenclature Committee web pages for TSC1 and TSC2 provide a selection of links for further genetic research.
- United Kingdom: The Tuberous Sclerosis Association. Awareness month is October.
- United States: Tuberous Sclerosis Alliance. Awareness month is May.
- Canada: Tuberous Sclerosis Canada. Awareness month is May.
- Australasia: Australasian Tuberous Sclerosis Society.
- The Rothberg Institute For Childhood Diseases have a distributed computing project called CommunityTSC.
- Brazil: Associação Brasileira de Escolerose Tuberosa (Brazilian Tuberous Sclerosis Association)de:Tuberöse Sklerose
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