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| __NOTOC__ | | __NOTOC__ |
| {{Infobox_Disease | | | {{Tuberous sclerosis}} |
| Name = Tuberous sclerosis|
| | {{CMG}}; {{AE}} {{Jose}} |
| Image = TuberousSclerosis-Rayer.jpg|
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| Caption = Earliest illustration, from [[Pierre François Olive Rayer|Rayer]]'s atlas of skin diseases, 1835.|
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| DiseasesDB = 13433|
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| ICD10 = {{ICD10|Q|85|1|q|80}} |
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| ICD9 = {{ICD9|759.5}} |
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| ICDO = |
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| OMIM = 191100|
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| MedlinePlus = 000787|
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| eMedicineSubj = |
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| eMedicineTopic = |
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| eMedicine_mult = |
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| MeshID = D014402|
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| }} | |
| {{CMG}} {{AE}} {{RT}} | |
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| {{SK}} Tuberous sclerosis complex, TSC, Bourneville disease, Bourneville-Pringle syndrome, Epiloia
| | ==[[Tuberous sclerosis overview|Overview]]== |
| == Overview ==
| |
| [[Tuberous sclerosis]] or '''tuberous sclerosis complex''' ('''TSC''') is a rare, multi-system [[genetic disorder|genetic disease]] that causes benign tumours to grow in the [[brain]] and on other vital organs such as the [[kidney]]s, [[heart]], [[eye]]s, [[lung]]s, and [[skin]]. <ref name=NINDS>{{cite web | |
| | url = http://www.ninds.nih.gov/disorders/tuberous_sclerosis/detail_tuberous_sclerosis.htm
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| | title = Tuberous Sclerosis Fact Sheet
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| | accessdate = 2007-01-09
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| | date = 2006-04-11
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| | publisher = NINDS
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| }} (Some text copied with permission.)</ref>
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| ==Historical Perspective== | | ==[[Tuberous sclerosis historical perspective|Historical Perspective]]== |
| The name, composed of the Latin ''tuber'' (swelling) and the Greek ''skleros'' (hard), refers to the [[pathological]] finding of thick, firm and pale [[gyrus|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.
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| [[Image:Désiré-Magloire Bourneville.jpg|thumb|left|Désiré-Magloire Bourneville]]
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| Tuberous sclerosis first came to medical attention when dermatologists described the distinctive facial rash (1835 and 1850). A more complete case was presented by [[Friedrich Daniel von Recklinghausen|von Recklinghausen]] (1862) who identified heart and brain tumours in a newborn that had only briefly lived. However, [[Désiré-Magloire Bourneville|Bourneville]] (1880) is credited with having first characterized the disease, coining the name ''tuberous sclerosis'', thus earning the [[eponym]] Bourneville's disease. The neurologist [[Heinrich Vogt|Vogt]] (1908) established a diagnostic triad of epilepsy, idiocy, and adenoma sebaceum (an obsolete term for facial angiofibroma).<ref name="TSC-history">Curatolo (2003), chapter: "Historical Background".</ref> | |
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| Symptoms were periodically added to the clinical picture. The disease as presently understood was first fully described by [[Manuel Rodríguez Gómez|Gomez]] (1979). The invention of [[Medical ultrasonography|medical ultrasound]], [[computed tomography|CT]] and [[magnetic resonance imaging|MRI]] has allowed physicians to examine the internal organs of live patients and greatly improved diagnostic ability.
| | ==[[Tuberous sclerosis classification|Classification]]== |
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| 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.<ref name="TSC-history"/> The proteins associated with TSC1 and TSC2, harmartin and tuberin, function as a complex in the [[Mammalian target of rapamycin|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.
| | ==[[Tuberous sclerosis pathophysiology|Pathophysiology]]== |
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| 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.<ref name="Rott2005>{{cite web
| | ==[[Tuberous sclerosis causes|Causes]]== |
| | url = http://www.tsdev.de/92001/Uploaded/hhehn%7Cgeschichte_der_tsc2005.pdf
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| | title = Zur Geschichte der Tuberösen Sklerose (The History of Tuberous Sclerosis)
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| | accessdate = 2007-01-08
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| | author = Rott HD, Mayer K, Walther B, Wienecke R
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| | year = 2005
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| | month = 03
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| | publisher = Tuberöse Sklerose Deutschland e.V
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| | language = German
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| }}</ref>
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| ==Pathophysiology== | | ==[[Tuberous sclerosis differential diagnosis|Differentiating Any Disease from other Diseases]]== |
| Hamartin and tuberin, which are encoded by TSC1 and TSC2 genes respectively, 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 [[Mammalian target of rapamycin|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.
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| ===Genetics=== | | ==[[Tuberous sclerosis epidemiology and demographics|Epidemiology and Demographics]]== |
| [[Image:autodominant.jpg|thumb|left|Tuberous sclerosis is inherited in an [[autosomal dominant]] fashion.]] | |
| Tuberous sclerosis is a genetic disorder with an [[autosomal dominant]] pattern of inheritance, and [[penetrance]] is 100%.<ref>{{cite web
| |
| | url = http://www.geneclinics.org/profiles/tuberous-sclerosis/details.html
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| | title = Tuberous Sclerosis Complex
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| | accessdate = 2007-09-02
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| | author = Northrup H, Au K
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| | date = [[5 December]] [[2005]]
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| | work = GeneReviews
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| }}</ref> 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.
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| TSC1 encodes for the protein '''hamartin''', is located on [[chromosome 9]] q34 and was discovered in 1997.<ref name=vanSlegtenhorst1997>{{cite journal
| | ==[[Tuberous sclerosis risk factors|Risk Factors]]== |
| | author = van Slegtenhorst M, de Hoogt R, Hermans C, ''et al''
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| | title = Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34
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| | journal = Science
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| | volume = 277
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| | issue = 5327
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| | pages = 805-8
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| | year = 1997
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| | pmid = 9242607
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| }}</ref> TSC2 encodes for the protein '''tuberin''', is located on [[chromosome 16]] p13.3 and was discovered in 1993.<ref name=ECh16TSC>{{cite journal
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| | author = European Chromosome 16 Tuberous Sclerosis Consortium
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| | title = Identification and characterization of the tuberous sclerosis gene on chromosome 16
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| | journal = Cell
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| | volume = 75
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| | issue = 7
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| | pages = 1305-15
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| | year = 1993
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| | pmid = 8269512
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| }}</ref> TSC2 is contiguous with PKD1, the gene involved in one form of [[polycystic kidney disease]] (PKD). Gross [[Genetic deletion|deletions]] affecting both genes may account for the 2% of individuals with TSC who also develop PKD in childhood.<ref name="TCS2PKD1">{{cite journal
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| | author=Brook-Carter PT, ''et al''
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| | title=Deletion of the TSC2 and PKD1 genes associated with severe infantile polycystic kidney disease--a contiguous gene syndrome
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| | journal = Nature Genetics
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| | year = 1994
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| | pages = 328-32
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| | volume = 8
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| | issue = 4
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| | id = PMID 7894481}}</ref> TSC2 has been associated with a more severe form of TSC.<ref name="TSC2-severe">{{cite journal
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| | author=Dabora SL, ''et al''
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| | title=Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs
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| | journal = American Journal of Human Genetics
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| | year = 2001
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| | pages = 64-80
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| | volume = 68
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| | issue = 1
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| | url = http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1234935&blobtype=pdf
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| | id = PMID 11112665}}</ref> 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%.<ref name="TSC-proportion">{{cite journal
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| | author = Rendtorff ND, ''et al''
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| | title = 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
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| | journal = Human Mutation
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| | year = 2005
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| | pages = 374-83
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| | volume = 26
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| | issue = 4
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| | id = PMID 16114042}}</ref>
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| TSC1 and TSC2 are both [[tumor suppressor gene]]s that function according to [[Knudson hypothesis|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]].
| | ==[[Tuberous sclerosis screening|Screening]]== |
| <table><tr><td>{{protein
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| | Name = Hamartin
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| | caption =
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| | image =
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| | width =
| |
| | HGNCid = 12362
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| | Symbol = TSC1
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| | AltSymbols =
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| | EntrezGene = 7248
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| | OMIM = 605284
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| | RefSeq = NM_000368
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| | UniProt = Q92574
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| | PDB =
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| | ECnumber =
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| | Chromosome = 9
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| | Arm = q
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| | Band = 34
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| | LocusSupplementaryData =
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| }}</td><td>
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| {{protein
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| | Name = Tuberin
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| | caption =
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| | image =
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| | width =
| |
| | HGNCid = 12363
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| | Symbol = TSC2
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| | AltSymbols =
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| | EntrezGene = 7249
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| | OMIM = 191092
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| | RefSeq = NM_000548
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| | UniProt = P49815
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| | PDB =
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| | ECnumber =
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| | Chromosome = 16
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| | Arm = p
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| | Band = 13.3
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| | LocusSupplementaryData =
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| }}</td></tr></table><br style="clear:both;">
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| ===Pathology=== | | ==[[Tuberous sclerosis natural history, complications and prognosis|Natural History, Complications and Prognosis]]== |
| ====Skin====
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| Some form of '''dermatological sign''' will be present in 96% of individuals with TSC. The most common skin abnormalities include:
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| ** '''Facial angiofibromas''': A rash of reddish spots or bumps, which appear on the nose and cheeks in a [[malar rash|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.
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| ** '''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.
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| ** '''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.
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| ** '''Forehead plaques''': Raised, discolored areas on the forehead.
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| ** '''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.
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| ** Other skin features 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 on the scalp or eyelids.
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| ====Eyes==== | | ==Diagnosis== |
| 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 is in the differential diagnosis of a calcified globe mass on a[[computed tomography|CT]] scan.
| | [[Tuberous sclerosis history and symptoms|History and Symptoms]] | [[Tuberous sclerosis physical examination|Physical Examination]] | [[Tuberous sclerosis laboratory findings|Laboratory Findings]] | [[Tuberous sclerosis electrocardiogram|Electrocardiogram]] | [[Tuberous sclerosis chest x ray|Chest X Ray]] | [[Tuberous sclerosis CT|CT]] | [[Tuberous sclerosis MRI|MRI]] | [[Tuberous sclerosis echocardiography or ultrasound|Echocardiography or Ultrasound]] | [[Tuberous sclerosis other imaging findings|Other Imaging Findings]] | [[Tuberous sclerosis other diagnostic studies|Other Diagnostic Studies]] |
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| Non-retinal lesions associated with TSC include
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| * [[Coloboma]]
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| * Angiofibromas of the eyelids
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| * [[Papilledema]] (related to hydrocephalus)
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| ====Lung====
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| 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 '''metastasis''' from a coexisting renal angiomyolipoma. There have been cases of TSC-related LAM recurring following lung transplant. <ref name="LAM in TBS">{{ cite journal
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| | author = Henske EP.
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| | title = Metastasis of benign tumor cells in tuberous sclerosis complex
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| | journal = Genes, Chromosomes & Cancer
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| | year = 2003
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| | volume = 38
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| | issue = 4
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| | pages = 376-381
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| | id = PMID 14566858}}</ref>
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| ==Epidemiology and Demographics==
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| * Tuberous sclerosis occurs in all races and ethnic groups, and in both genders.
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| * The [[live birth|live-birth]] [[prevalence]] is estimated to be between 10 and 16 cases per 100,000. A 1998 study estimated total population prevalence between about 7 and 12 cases per 100,000, with more than half of these cases undetected.<ref name="TSC-prevalence">{{cite journal
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| | author = O'Callaghan FJK, Shiell AW, Osborne JP, Martyn CN
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| | title = Prevalence of tuberous sclerosis estimated by capture-recapture analysis
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| | journal = Lancet
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| | volume = 351
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| | issue = 9114
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| | year = 1998
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| | pages = 1490
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| | doi = 10.1016/S0140-6736(05)78872-3}}</ref> These estimates are significantly higher than those produced by older studies, when tuberous sclerosis was regarded as an extremely rare disease. The reason is that the invention of [[CT scan|CT]] and [[Medical ultrasonography|ultrasound]] scanning have enabled the diagnosis of many non-symptomatic cases. Prior to this, the diagnosis of tuberous sclerosis was largely restricted to severely affected individuals with Vogt's triad of learning disability, [[seizures]] and facial [[angiofibroma]]. The total population prevalence figures have steadily increased from 1:150,000 in 1956, to 1:100,000 in 1968, to 1:70,000 in 1971, to 1:34,200 in 1984, to the present figure of 1:12,500 in 1998. Whilst still regarded as a [[rare disease]], it is common when compared to many other genetic diseases.<ref name="TSC-diagnosis"/>
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| * The incidence of [[rhabdomyomas]] 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.
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| ==Natural History, Complications and Prognosis==
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| ===Natural History===
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| * Those individuals with mild symptoms generally do well and live long productive lives, while individuals with the more severe form may have serious disabilities.
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| * However, with appropriate medical care, most individuals with the disorder can look forward to normal life expectancy.<ref name="TSFactSheet"/>
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| ===Complications===
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| * [[Cardiac failure]] due to [[rhabdomyomas]]
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| * [[Bronchopneumonia]]
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| * [[Lymphangiomyomatosis]] of the lung is only a risk for females with AMLs.<ref name="Rakowski2006">{{cite journal
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| | author = Rakowski SK, Winterkorn EB, Paul E, Steele DJ, Halpern EF, Thiele EA.
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| | title = Renal manifestations of tuberous sclerosis complex: Incidence, prognosis, and predictive factors.
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| | journal = Kidney International | |
| | volume =
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| | issue =
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| | pages =
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| | year = 2006
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| | id = PMID 17003820
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| }}</ref>
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| * [[Renal failure]]
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| * [[Autosomal dominant]] [[Polycystic kidney disease]] in 2 % patients.
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| * [[Angiomyolipoma]] (AML) and cysts in [[kidneys]] are common, and more frequent in females than males and in TSC2 than TSC1.<ref name="shepherd1991">{{cite journal
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| | author = Shepherd C, Gomez M, Lie J, Crowson C
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| | title = Causes of death in patients with tuberous sclerosis.
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| | journal = Mayo Clin Proc
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| | volume = 66
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| | issue = 8 | |
| | pages = 792-6
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| | year = 1991
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| | id = PMID 1861550
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| }}</ref>
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| * [[Renal cell carcinoma]] is uncommon.
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| * [[Brain tumor]]
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| * [[Status epilepticus]]
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| * 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]].
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| ===Prognosis===
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| * The prognosis for individuals with TSC depends on the severity of symptoms, which range from mild skin abnormalities to varying degrees of learning disabilities and epilepsy to severe mental retardation, uncontrollable seizures, and [[kidney failure]].
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| == Diagnosis ==
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| There are no [[pathognomonic]] clinical [[medical sign|signs]] for [[tuberous sclerosis]]. Many signs are present in individuals who are healthy (although rarely), or who have another disease. A combination of signs, classified as major or minor, is required in order to establish a clinical diagnosis.
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| | |
| {| class=wikitable width="75%" style="margin: 1em auto 1em auto"
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| |+ Diagnostic Criteria for Tuberous Sclerosis Complex<ref name="PMID15563009">{{cite journal
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| | author = Roach E, Sparagana S
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| | title = Diagnosis of tuberous sclerosis complex.
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| | journal = Journal of Child Neurology
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| | volume = 19
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| | issue = 9
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| | pages = 643-9
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| | year = 2004
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| | id = PMID 15563009
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| | url = http://www.medscape.com/viewarticle/495642
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| }}</ref>
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| ! colspan="5" width="100%" | Major Features
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| |-
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| ! width="2%" |
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| ! width="12%" | Location
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| ! width="42%" | Sign
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| ! width="22%" | Onset<ref name="PMID17005952">{{cite journal
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| | author = Crino P, Nathanson K, Henske E
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| | title = The Tuberous Sclerosis Complex.
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| | journal = New England Journal of Medicine
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| | volume = 355
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| | issue = 13
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| | pages = 1345-56
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| | year = 2006
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| | id = PMID 17005952
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| }}</ref>
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| ! width="22%" | Note
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| |-
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| ! 1
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| | Head
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| | Facial angiofibromas or forehead plaque
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| | Infant – adult
| |
| |
| |
| |-
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| ! 2
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| | Fingers and toes
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| | Nontraumatic ungual or periungual fibroma
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| | Adolescent – adult
| |
| |
| |
| |-
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| ! 3
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| | Skin
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| | Hypomelanotic macules
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| | Infant – child
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| | More than three.
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| |-
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| ! 4
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| | Skin
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| | Shagreen patch (connective tissue nevus)
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| | Child
| |
| |
| |
| |-
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| ! 5
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| | Brain
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| | Cortical tuber
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| | Fetus
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| |
| |
| |-
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| ! 6
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| | Brain
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| | Subependymal nodule
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| | Child – adolescent
| |
| |
| |
| |-
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| ! 7
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| | Brain
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| | Subependymal giant cell astrocytoma
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| | Child – adolescent
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| |
| |
| |-
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| ! 8
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| | Eyes
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| | Multiple retinal nodular hamartomas
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| | Infant
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| |
| |
| |-
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| ! 9
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| | Heart
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| | Cardiac rhabdomyoma
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| | Fetus
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| | Single or multiple.
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| |-
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| ! 10
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| | Lungs
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| | Lymphangiomyomatosis
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| | Adolescent – adult
| |
| |
| |
| |-
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| ! 11
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| | Kidneys
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| | Renal angiomyolipoma
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| | Child – adult
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| | '''10''' and '''11''' together count as one major feature.
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| |-
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| ! colspan="5" width="100%" | Minor Features
| |
| |-
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| ! width="2%" |
| |
| ! width="12%" | Location
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| ! width="42%" | Sign
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| ! width="44%" colspan="2" | Note
| |
| |-
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| ! 12
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| | Teeth
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| | Multiple randomly distributed pits in dental enamel
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| | colspan="2" |
| |
| |-
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| ! 13
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| | Rectum
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| | Hamartomatous rectal polyps
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| | colspan="2" | [[Histology|Histologic]] confirmation is suggested.
| |
| |-
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| ! 14
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| | Bones
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| | Bone cysts
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| | colspan="2" |
| |
| |-
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| ! 15
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| | Brain
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| | Cerebral white-matter "migration tracts"
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| | colspan="2" | [[Radiography|Radiographic]] confirmation is sufficient. '''5''' and '''15''' together count as one major feature.
| |
| |-
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| ! 16
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| | Gums
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| | Gingival fibromas
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| | colspan="2" |
| |
| |-
| |
| ! 17
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| | Liver, spleen and other organs
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| | Nonrenal hamartoma
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| | colspan="2" | Histologic confirmation is suggested.
| |
| |-
| |
| ! 18
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| | Eyes
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| | Retinal achromic patch
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| | colspan="2" |
| |
| |-
| |
| ! 19
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| | Skin
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| | "Confetti" skin lesions
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| | colspan="2" |
| |
| |-
| |
| ! 20
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| | Kidneys
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| | Multiple renal cysts
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| | colspan="2" | Histologic confirmation is suggested.
| |
| |}
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| ===Variability===
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| Individuals with tuberous sclerosis may experience none or all of the clinical signs discussed above. The following table shows the prevalence of some of the clinical signs in individuals diagnosed with tuberous sclerosis.<br style="clear:both;">
| |
| [[Image:TSC-Frequency-Signs-Childhood.png|550px|thumb|left|The frequency of clinical signs in children with tuberous sclerosis, grouped by age<ref name="TSC-diagnosis">Curatolo (2003), chapter: "Diagnostic Criteria".</ref>]]<br style="clear:both;">
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| The various signs are then marked against the diagnostic criteria to produce a level of diagnostic certainty:
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| *'''Definite''' – Either two major features or one major feature plus two minor features.
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| *'''Probable''' – One major plus one minor feature.
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| *'''Suspect''' – Either one major feature or two or more minor features.
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| | |
| ===Symptoms===
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| * Skin problems, such as light patches and thickened skin
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| * [[Seizures]]
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| * [[Behavior problems]]
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| * Learning disabilities - seen in 50% patients ranging from mild to profound,<ref name="memory-deficits">{{cite journal
| |
| | author = Ridler K, ''et al'' | |
| | title = Neuroanatomical Correlates of Memory Deficits in Tuberous Sclerosis Complex
| |
| | journal = Cerebral Cortex
| |
| | year = 2006
| |
| | id = PMID 16603714 }}</ref> 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]].<ref name="autism-prevalence">{{cite journal
| |
| | author = Harrison JE, Bolton, PF
| |
| | title = Annotation: Tuberous sclerosis
| |
| | journal = Journal of Child Psychology and Psychiatry | |
| | year = 1997
| |
| | pages = 603-614
| |
| | volume = 38
| |
| | id = PMID 9315970}}</ref>
| |
| * [[Mental retardation]]
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| * Kidney problems
| |
| | |
| Most of the neurologic manifestations of tuberous sclerosis are due to the effects of hamartia (malformed tissue such as the cortical tubers),[[hamartoma]]s (benign growths such as facial [[angiofibroma]] and subependymal nodules) and, very rarely, cancerous hamartoblastomas on the brain tissue.
| |
| | |
| In infants, the first clue is often the presence of [[seizures]], [[delayed development]] or white patches on the skin. A full clinical diagnostic workup should be undertaken in such situations.<ref name="TSFactSheet">{{cite web
| |
| | url = http://www.ninds.nih.gov/disorders/tuberous_sclerosis/detail_tuberous_sclerosis.htm
| |
| | title = Tuberous Sclerosis Fact Sheet
| |
| | accessdate = 2006-10-03
| |
| | date = [[2006-04-11]]
| |
| | publisher = National Institute of Neurological Disorders and Stroke
| |
| }}</ref><ref name="TSAclinicalGuidelines">{{cite web
| |
| | url = http://www.tuberous-sclerosis.org/publications/clinicalguidelinessummary.pdf
| |
| | title = Summary of Clinical guidelines for the care of patients with Tuberous Sclerosis Complex | |
| | accessdate = 2006-10-03
| |
| | year = 2002
| |
| | month = April
| |
| | publisher = Tuberous Sclerosis Association
| |
| }}</ref>
| |
| | |
| ===Physical Examination ===
| |
| ====Skin====
| |
| [[Image:Adenoma_sebaceum.jpg|thumb|left|Adenoma sebaceum.<ref>http://picasaweb.google.com/mcmumbi/USMLEIIImages</ref>]]
| |
| The skin is examined under a [[Wood's lamp]]. The most common skin abnormalities include:
| |
| | |
| * Facial angiofibromas
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| * Ungual or subungual fibromas
| |
| * Hypomelanic [[macules]] ("ash leaf spots")
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| * Forehead plaques
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| * Shagreen patches
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| * Molluscum fibrosum or skin tags, [[cafe-au-lait spots]] or flat brown marks, and poliosis,
| |
| | |
| ====Eyes====
| |
| * Retinal lesions - astrocytic hamartomas
| |
| * Non-retinal lesions associated with TSC include
| |
| ** [[Coloboma]]
| |
| ** Angiofibromas of the eyelids
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| ** [[Papilledema]] (related to hydrocephalus)
| |
| | |
| ====Heart====
| |
| * A heart murmur can be heard due to the obstruction of blood flow by [[rhabdomyomas]].
| |
| | |
| ====Lungs====
| |
| * Coarse rales are heard when lung parenchyma is involved.
| |
| * Bronchial breathing and bronchophony are heard on auscultation when multiple cysts occur in the lungs.
| |
| | |
| ====Kidneys====
| |
| Between 60 and 80% of TSC patients have benign tumors (hamartomas) of the kidneys called [[angiomyolipoma]]s (AML). These tumors are composed of [[Blood vessel|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.
| |
| | |
| ====Neurologic====
| |
| * Lower IQ is associated with more brain involvement on MRI.
| |
| | |
| Classic intracranial manifestations of tuberous sclerosis include subependymal nodules and cortical/subcortical tubers.<ref name="brain-mapping">{{ cite journal
| |
| | author = Ridler K, ''et al'' | |
| | title = Standardized whole brain mapping of tubers and subependymal nodules in tuberous sclerosis complex
| |
| | journal = Journal of Child Neurology
| |
| | year = 2004
| |
| | volume = 19
| |
| | issue = 9
| |
| | pages = 658-665
| |
| | id = PMID 15563011}}</ref>
| |
| | |
| 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 [[interventricular foramina|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.
| |
| | |
| ===Imaging===
| |
| ====CT====
| |
| {| align="center"
| |
| |+ '''Tuberous sclerosis'''
| |
| !
| |
| |-valign="top" | |
| | [[Image:TS-LAM.png|thumb|This CT image shows randomly arranged cysts in both lungs. The patient had TSC and a renal AML.]]
| |
| | [[Image:bilateralrenalAML.jpg|thumb|140px|This is an image from a contrast-enhanced [[computed tomography]] (CT) scan of the abdomen in another patient with TSC.]] | |
| |}
| |
| | |
| ====MRI====
| |
| 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 [[MR|magnetic resonance imaging]], TSC patients can exhibit other signs consistent with abnormal neuron migration (radial white matter tracts hyperintense on T2WI, heterotopic gray matter).
| |
| | |
| [[Image:tuberoussclerosisbrainFLAIR.png|thumb|center|300px|[[MRI]] of the brain in a patient with TSC.]]
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| | |
| ====Echocardiography====
| |
| * A cardiac rhabdomyoma can be discovered using [[echocardiography]] in approximately 50% of people with TSC.
| |
| | |
| ====Ultrasoud====
| |
| | |
| * Ultrasound abdomen is used to visualize kidney [[angiomyolipomas]] and cysts
| |
| * Prenatal ultrasound, performed by an [[Obstetric ultrasonography|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.
| |
|
| |
|
| ==Treatment== | | ==Treatment== |
| Drug therapy for some of the manifestations of TSC is currently in the developmental stage.<ref>{{cite journal | pmid = 16868562 | doi=10.1038/sj.ejhg.5201625 | volume=14 | issue=10 | title=Tuberous sclerosis | year=2006 | month=October | author=Yates JR | journal=Eur. J. Hum. Genet. | pages=1065–73}}</ref> For example, a 2008 study found that treatment with [[rapamycin]] rescued learning and memory deficits in a mouse model of tuberous sclerosis.<ref>{{cite journal |journal= Nat Med |year=2008 |title= Reversal of learning deficits in a Tsc2+/− mouse model of tuberous sclerosis |author= Ehninger D, Han S, Shilyansky C ''et al.'' |doi=10.1038/nm1788 |pmid=18568033 |laysummary=http://www.sciencedaily.com/releases/2008/06/080622224428.htm |laysource= Science News |laydate=23 June 2008 |volume= 14 |pages= 843–8 |issue= 8 |pmc= 2664098}}</ref> [[Community TSC]] is a distributed computing project to find drugs to treat TSC.{{Citation needed|date=June 2008|laysummary=http://www.childhooddiseases.org/community_tsc.html}}
| | [[Tuberous sclerosis medical therapy|Medical Therapy]] | [[Tuberous sclerosis surgery|Surgery]] | [[Tuberous sclerosis primary prevention|Primary Prevention]] | [[Tuberous sclerosis secondary prevention|Secondary Prevention]] | [[Tuberous sclerosis cost-effectiveness of therapy|Cost-Effectiveness of Therapy]] | [[Tuberous sclerosis future or investigational therapies|Future or Investigational Therapies]] |
| The patients usually have relapse of symptoms in the clinical course. Unless any vital function is affected, life expectancy is good. Majority of patients will require some medications to control symptoms, e.g., anti-epileptics to control seizures.
| |
| In 2010 [[everolimus]] was approved for the treatment of [[subependymal giant cell astrocytoma]].
| |
| | |
| Other drugs used include:
| |
| * [[Vigabatrin]]<ref name="pmid19557123">{{cite journal |author=Tsao CY |title=Current trends in the treatment of infantile spasms |journal=Neuropsychiatr Dis Treat |volume=5 |issue= |pages=289–99 |year=2009 |pmid=19557123 |pmc=2695218 |doi= |url=http://www.dovepress.com/articles.php?article_id=3150}}</ref>
| |
| * [[ACTH]]<ref name="Shorvon2010">{{cite book|author=Simon D. Shorvon|title=Handbook of Epilepsy Treatment|url=http://books.google.com/books?id=ce1YGxllLsgC&pg=PA93|accessdate=11 October 2010|year=2010|publisher=John Wiley and Sons|isbn=978-1-4051-9818-9|pages=93–}}</ref>
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| | |
| ==References==
| |
| {{Reflist|2}}
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| | |
| ====Support Groups====
| |
| * United Kingdom: [http://www.tuberous-sclerosis.org/ The Tuberous Sclerosis Association]. Awareness month is October.
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| * United States: [http://www.tsalliance.org/ Tuberous Sclerosis Alliance]. Awareness month is May.
| |
| * Canada: [http://www.tscst.org/ Tuberous Sclerosis Canada]. Awareness month is May.
| |
| * Australasia: [http://www.atss.org.au/ Australasian Tuberous Sclerosis Society].
| |
| * Brazil: [http://www.abet.org.br/entrada.htm Associação Brasileira de Esclerose Tuberosa (''Brazilian Tuberous Sclerosis Association'')] {{pt icon}}
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| * Taiwan: [http://www.ttsc.org.tw Taiwan Tuberous Sclerosis Complex]
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|
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|
| {{Phakomatoses and other congenital malformations not elsewhere classified}}
| | ==Case Studies== |
| | [[Tuberous sclerosis case study one|Case #1]] |
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