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| {{Distinguish|tuberculosis}}
| | __NOTOC__ |
| {{Infobox medical condition | | {{Tuberous sclerosis}} |
| |Name=Tuberous sclerosis complex
| | {{CMG}}; {{AE}} {{Jose}} |
| |Image=Patient with facial angiofibromas caused by tuberous sclerosis.jpg
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| |Caption=A case of tuberous sclerosis showing facial angiofibromas in characteristic butterfly pattern
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| |Synonyms=Tuberous sclerosis complex (TSC),<br/>Bourneville disease
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| |Field=[[neurology]], [[medical genetics]]
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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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| |OMIM=191100
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| |OMIM_mult = {{OMIM2|613254}}
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| |MedlinePlus=000787
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| |eMedicineSubj=neuro
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| |eMedicineTopic=386
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| |eMedicine_mult={{eMedicine2|derm|438}} {{eMedicine2|ped|2796}} {{eMedicine2|radio|723}}
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| |MeSH=D014402
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| |GeneReviewsName=Tuberous Sclerosis Complex
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| |GeneReviewsNBK=NBK1220
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| |Orphanet=805
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| }} | |
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| '''Tuberous sclerosis complex''' ('''TSC''') is a rare multisystem [[genetic disorder|genetic disease]] that causes [[benign tumor]]s to grow in the [[human brain|brain]] and on other vital organs such as the [[kidney]]s, [[human heart|heart]], [[human liver|liver]], [[human eye|eye]]s, [[human lung|lung]]s, and [[human skin|skin]]. A combination of symptoms may include [[seizure]]s, [[intellectual disability]], [[Specific developmental disorder|developmental delay]], behavioral problems, skin abnormalities, and lung and kidney disease. TSC is caused by a [[mutation]] of either of two [[gene]]s, ''[[TSC1]]'' and ''[[TSC2]]'', which code for the [[protein]]s [[hamartin]] and [[tuberin]], respectively. These proteins act as [[Tumor suppressor gene|tumor growth suppressors]], agents that regulate cell proliferation and differentiation.<ref name=NINDS>{{cite web|url=http://www.ninds.nih.gov/disorders/tuberous_sclerosis/detail_tuberous_sclerosis.htm|title=Tuberous Sclerosis Fact Sheet|accessdate=9 January 2007|date=11 April 2006|publisher=NINDS}} (Some text copied with permission.)</ref>
| | ==[[Tuberous sclerosis overview|Overview]]== |
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| 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 ''[[post mortem]]''. These tubers [[timeline of tuberous sclerosis|were first described]] by [[Désiré-Magloire Bourneville]] in 1880; the cortical manifestations may sometimes still be known by the [[list of eponymously named diseases|eponym]] '''Bourneville's disease''' ({{IPAc-en|lang|b|ɔər|n|ˈ|v|iː|l}}) or '''Bourneville–Pringle disease''' (after Bourneville and [[John James Pringle]]). The full name of "tuberous sclerosis complex" is preferred among medical professionals and researchers today because the disease has manifestations outside of the brain.<ref>{{Cite web|url=https://books.google.com/ngrams/graph?content=tuberous+sclerosis+complex&year_start=1945&year_end=2010&corpus=15&smoothing=3&share=&direct_url=t1;,tuberous%20sclerosis%20complex;,c0|title=Google Ngram Viewer|website=books.google.com|access-date=2017-02-03}}</ref> Furthermore, the name reduces confusion with tuberculosis, a more well-known disease.
| | ==[[Tuberous sclerosis historical perspective|Historical Perspective]]== |
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| == Signs and symptoms == | | ==[[Tuberous sclerosis classification|Classification]]== |
| {{See also|List of dental abnormalities associated with cutaneous conditions}}
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| The physical manifestations of TSC are due to the formation of [[Hamartia (medical term)|hamartia]] (malformed tissue such as the cortical tubers), [[hamartoma]]s (benign growths such as facial [[Fibroma#Other types of fibroma|angiofibroma]] and subependymal nodules), and very rarely, cancerous [[hamartoblastoma]]s. The effect of these on the brain leads to neurological symptoms such as seizures, intellectual disability, developmental delay, and behavioral problems. Symptoms also include trouble in school and concentration problems.
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| === Central nervous system === | | ==[[Tuberous sclerosis pathophysiology|Pathophysiology]]== |
| [[File:Tuberoese Sklerose 1J T2 axial2.png|thumb|TSC in MRI]] | |
| About 50% of people with TSC have [[learning disabilities|learning difficulties]] ranging from mild to significant,<ref name="memory-deficits">{{cite journal | vauthors = Ridler K, Suckling J, Higgins NJ, de Vries PJ, Stephenson CM, Bolton PF, Bullmore ET | title = Neuroanatomical correlates of memory deficits in tuberous sclerosis complex | journal = Cereb. Cortex | volume = 17 | issue = 2 | pages = 261–71 | year = 2007 | pmid = 16603714 | doi = 10.1093/cercor/bhj144 }}</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 | vauthors = Harrison JE, Bolton PF | title = Annotation: tuberous sclerosis | journal = J Child Psychol Psychiatry | volume = 38 | issue = 6 | pages = 603–14 | year = 1997 | pmid = 9315970 | doi = 10.1111/j.1469-7610.1997.tb01687.x }}</ref> A 2008 study reported [[self-injurious behavior]] in 10% of people with TSC.<ref>{{cite journal | vauthors = Staley BA, Montenegro MA, Major P, Muzykewicz DA, Halpern EF, Kopp CM, Newberry P, Thiele EA | title = Self-injurious behavior and tuberous sclerosis complex: frequency and possible associations in a population of 257 patients | journal = Epilepsy Behav | volume = 13 | issue = 4 | pages = 650–3 | year = 2008 | pmid = 18703161 | doi = 10.1016/j.yebeh.2008.07.010 }}</ref> Other behaviors and disabilities, such as [[ADHD]], aggression, behavioral outbursts, and [[OCD]] can also occur. Lower IQ is associated with more brain involvement on MRI.
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| Three types of brain tumours may be associated with TSC:
| | ==[[Tuberous sclerosis causes|Causes]]== |
| * Giant cell astrocytoma: (grows and blocks the [[cerebrospinal fluid]] <!-- (CSF) --> flow, leading to dilatation of ventricles causing headache and vomiting)
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| * Cortical tubers: after which the disease is named
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| * Subependymal nodules: form in the walls of ventricles
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| Classic intracranial manifestations of TSC include sub[[ependyma]]l nodules and cortical/subcortical tubers.<ref name="brain-mapping">{{cite journal | vauthors = Ridler K, Suckling J, Higgins N, Bolton P, Bullmore E | title = Standardized whole brain mapping of tubers and subependymal nodules in tuberous sclerosis complex | journal = J. Child Neurol. | volume = 19 | issue = 9 | pages = 658–65 | year = 2004 | pmid = 15563011 }}</ref>
| | ==[[Tuberous sclerosis differential diagnosis|Differentiating Any Disease from other Diseases]]== |
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| 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 [[MRI|magnetic resonance imaging]], TSC patients can exhibit other signs consistent with abnormal neuron migration such as radial white matter tracts hyperintense on T2WI and heterotopic gray matter.
| | ==[[Tuberous sclerosis epidemiology and demographics|Epidemiology and Demographics]]== |
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| Subependymal nodules are composed of abnormal, swollen glial cells and bizarre multinucleated cells which are indeterminate for glial or neuronal origin. Interposed neural tissue is not present. 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]], which typically develops in the region of the [[Interventricular foramina (neuroanatomy)|foramen of Monro]], in which case it is at risk of developing an obstructive [[hydrocephalus]].
| | ==[[Tuberous sclerosis risk factors|Risk Factors]]== |
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| A variable degree of ventricular enlargement is seen, either obstructive (e.g. by a subependymal nodule in the region of the foramen of Monro) or idiopathic in nature.
| | ==[[Tuberous sclerosis screening|Screening]]== |
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| === Kidneys === | | ==[[Tuberous sclerosis natural history, complications and prognosis|Natural History, Complications and Prognosis]]== |
| [[File:Angiomyolipome TubSklerose cor.jpg|thumb|right|Computed tomography showing multiple angiomyolipomas of the kidney in a patient with lung lymphangioleiomyomatosis on CT: suspected TSC]] | |
| Between 60 and 80% of TSC patients have benign tumors (once thought hamartomatous, but now considered true neoplasms) of the kidneys called [[angiomyolipoma]]s frequently causing [[hematuria]]. These tumors are composed of [[Blood vessel|vascular]] (''angio–''), [[smooth muscle]] (''–myo–''), and [[fat]] (''–lip-'') tissue. Although benign, an angiomyolipoma larger than 4 cm is at risk for a potentially catastrophic hemorrhage either spontaneously or with minimal trauma. Angiomyolipomas are found in about one in 300 people without TSC. However, those are usually solitary, whereas in TSC they are commonly multiple and bilateral.
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| About 20-30% of people with TSC have renal cysts, causing few problems. However, 2% may also have [[autosomal dominant]] [[polycystic kidney disease]].
| | ==Diagnosis== |
| | [[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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| Very rare (< 1%) problems include [[renal cell carcinoma]] and [[oncocytoma]]s ([[benign adenomatous hamartoma]]).
| | ==Treatment== |
| | [[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]] |
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| === Lungs === | | ==Case Studies== |
| 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 TSC-related lymphangioleiomyomatosis is monoclonal metastasis from a coexisting renal angiomyolipoma. Cases of TSC-related lymphangioleiomyomatosis recurring following lung transplant have been reported.<ref name="LAM in TBS">{{cite journal | vauthors = Henske EP | title = Metastasis of benign tumor cells in tuberous sclerosis complex | journal = Genes Chromosomes Cancer | volume = 38 | issue = 4 | pages = 376–81 | year = 2003 | pmid = 14566858 | doi = 10.1002/gcc.10252 }}</ref>
| | [[Tuberous sclerosis case study one|Case #1]] |
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| === Heart ===
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| [[Rhabdomyoma]]s are benign tumors of striated muscle. A cardiac rhabdomyoma can be discovered using [[echocardiography]] in around 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 disappear entirely; alternatively, the tumor size remains constant as the heart grows, which has much the same effect.
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| Problems due to rhabdomyomas include obstruction, [[Cardiac arrhythmia|arrhythmia]], and a [[Heart murmur|murmur]]. Such complications occur almost exclusively during pregnancy or within the child's first year. 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 a family history of TSC exists.
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| === Skin ===
| | {{WH}} |
| Some form of dermatological sign is 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:
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| * Facial [[angiofibroma]]s ("adenoma sebaceum"): A rash of reddish spots or bumps, which appears on the nose and cheeks in a [[malar rash|butterfly distribution]], they consist of blood vessels and fibrous tissue. This potentially socially embarrassing rash starts to appear during childhood and can be removed using [[dermabrasion]] or laser treatment.
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| * Periungual fibromas: Also known as [[Koenen's tumor]]s, these are 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. They are generally more common on toes than on fingers, develop at 15–29 years, and are more common in women than in men. They can be induced by nail-bed trauma.
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| * Hypomelanic [[macules]] ("ash leaf spots"): White or lighter patches of skin, these may appear anywhere on the body and are caused by a lack of [[melanin]]. They 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.
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| * Forehead plaques: Raised, discolored areas on the forehead
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| * [[Shagreen patch]]es: Areas of thick leathery skin that are dimpled like an orange peel, and pigmented, they are usually found on the lower back or nape of the neck, or scattered across the trunk or thighs. The frequency of these lesions rises with age.
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| * Other skin features are not unique to individuals with TSC, including [[acrochordon|molluscum fibrosum]] or skin tags, which typically occur across the back of the neck and shoulders, [[café au lait spot|''café 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 ===
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| Retinal lesions, called astrocytic hamartomas (or "phakomas"), which appear as a greyish or yellowish-white lesion in the back of the globe on the ophthalmic examination. Astrocytic hamartomas can calcify, and they are in the differential diagnosis of a calcified globe mass on a [[computed tomography|CT]] scan.
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| Nonretinal lesions associated with TSC include:
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| * [[Coloboma]]
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| * [[Angiofibroma]]s of the eyelids
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| * [[Papilledema]] (related to hydrocephalus)
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| === Pancreas ===
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| Pancreatic neuroendocrine tumours have been described in rare cases of TSC.<ref>{{Cite journal
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| | last = Arva
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| | first = Nicoleta C.
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| | last2 = Pappas
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| | first2 = John G.
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| | last3 = Bhatla
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| | first3 = Teena
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| | last4 = Raetz
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| | first4 = Elizabeth A.
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| | last5 = Macari
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| | first5 = Michael
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| | last6 = Ginsburg
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| | first6 = Howard B.
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| | last7 = Hajdu
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| | first7 = Cristina H.
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| | date = 2012-01-01
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| | title = Well-differentiated pancreatic neuroendocrine carcinoma in tuberous sclerosis--case report and review of the literature
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| | journal = The American Journal of Surgical Pathology
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| | volume = 36
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| | issue = 1
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| | pages = 149–153
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| | doi = 10.1097/PAS.0b013e31823d0560
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| | pmid = 22173120
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| }}</ref>
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| === Variability ===
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| Individuals with TSC 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 TSC.{{clear}}
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| [[File:TSC-Frequency-Signs-Childhood.png|550px|thumb|left|The frequency of signs in children with TSC, grouped by age<ref name="TSC-diagnosis">Curatolo (2003), chapter: "Diagnostic Criteria".</ref>]]{{clear}}
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| == Genetics ==
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| [[File:Autosomal dominant - en.svg|thumb|right|TSC is inherited in an [[autosomal dominant]] fashion.]]
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| TSC is a genetic disorder with an [[autosomal dominant]] pattern of inheritance, variable expressivity, and incomplete <ref>{{Cite journal|last=Baraitser|first=M|last2=Patton|first2=M A|date=February 1985|title=Reduced penetrance in tuberous sclerosis.|journal=Journal of Medical Genetics|volume=22|issue=1|pages=29–31|issn=0022-2593|pmc=1049373|pmid=3981577}}</ref>[[penetrance]].<ref name="pmid20301399">{{cite journal | vauthors = Pagon RA, Adam MP, Ardinger HH, Bird TD, Dolan CR, Fong CT, Smith RJ, Stephens K, Northrup H, Koenig MK, Au KS | title = Tuberous Sclerosis Complex | journal = GeneReviews [Internet] | volume = | issue = | pages = | year = | pmid = 20301399 | doi = }}</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 roughly 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 | vauthors = 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 | title = Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34 | journal = Science | volume = 277 | issue = 5327 | pages = 805–8 | year = 1997 | pmid = 9242607 | doi = 10.1126/science.277.5327.805 }}</ref> ''TSC2'' encodes for the protein tuberin, is located on [[chromosome 16]] p13.3, and was discovered in 1993.<ref name=ECh16TSC>{{cite journal |author = European Chromosome 16 Tuberous Sclerosis Consortium | title = Identification and characterization of the tuberous sclerosis gene on chromosome 16 | journal = Cell | volume = 75 | issue = 7 | pages = 1305–15 | year = 1993 | pmid = 8269512 | doi = 10.1016/0092-8674(93)90618-Z | name-list-format = }}</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 polycystic kidney disease in childhood.<ref name="TCS2PKD1">{{cite journal | vauthors = Brook-Carter PT, Peral B, Ward CJ, Thompson P, Hughes J, Maheshwar MM, Nellist M, Gamble V, Harris PC, Sampson JR | title = Deletion of the TSC2 and PKD1 genes associated with severe infantile polycystic kidney disease--a contiguous gene syndrome | journal = Nat. Genet. | volume = 8 | issue = 4 | pages = 328–32 | year = 1994 | pmid = 7894481 | doi = 10.1038/ng1294-328 }}</ref> ''TSC2'' has been associated with a more severe form of TSC.<ref name="TSC2-severe">{{cite journal | vauthors = 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 | title = Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs | journal = Am. J. Hum. Genet. | volume = 68 | issue = 1 | pages = 64–80 | year = 2001 | pmid = 11112665 | pmc = 1234935 | doi = 10.1086/316951 }}</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 90%.<ref name="TSC-proportion">{{cite journal | vauthors = Rendtorff ND, Bjerregaard B, Frödin M, Kjaergaard S, Hove H, Skovby F, Brøndum-Nielsen K, Schwartz M | 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 | journal = Hum. Mutat. | volume = 26 | issue = 4 | pages = 374–83 | year = 2005 | pmid = 16114042 | doi = 10.1002/humu.20227 }}</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 high [[penetrance]], TSC has wide [[expressivity (genetics)|expressivity]].
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| {{columns
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| |col1=
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| {{infobox protein|align=left
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| | Name = [[TSC1|Hamartin]]
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| | caption =
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| | image =
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| | width =
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| | 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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| }}
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| |col2=
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| {{infobox protein|align=left
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| | Name = [[TSC2|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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| }}
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| }}
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| == Pathophysiology ==
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| Hamartin and tuberin function as a complex which is involved in the control of cell growth and cell division. The complex appears to interact with [[RHEB]] [[GTPase]], thus sequestering it from activating [[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. TSC affects tissues from different germ layers. Cutaneous and visceral lesions may occur, including adenoma sebaceum, cardiac rhabdomyomas, and renal angiomyolipomas. The central nervous system <!-- (CNS) --> lesions seen in this disorder include hamartomas of the cortex, hamartomas of the ventricular walls, and subependymal giant cell tumors, which typically develop in the vicinity of the [[Interventricular foramina (neural anatomy)|foramina of Monro]].
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| Molecular genetic studies have defined at least two loci for TSC. In ''TSC1'', the abnormality is localized on chromosome 9q34, but the nature of the gene protein, called hamartin, remains unclear. No missense mutations occur in ''TSC1''. In ''TSC2'', the gene abnormalities are on chromosome 16p13. This gene encodes tuberin, a guanosine triphosphatase–activating protein. The specific function of this protein is unknown. In ''TSC2'', all types of mutations have been reported; new mutations occur frequently. Few differences have yet been observed in the clinical phenotypes of patients with mutation of one gene or the other.
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| == Diagnosis ==
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| No [[pathognomonic]] clinical [[medical sign|signs]] for TSC complex are seen. Many signs are present in individuals who are healthy (although rarely), or who have another disease. In order to meet diagnostic criteria for TSC complex, an individual must either have: 1) Two or more major criteria; or 2) One major criterion along with two or more minor criteria.
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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="PMID24053982">{{cite journal | vauthors = Northrup H, Krueger DA, ((International Tuberous Sclerosis Complex Consensus Group)) | title = Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. | journal = Pediatr Neurol.| volume = 49 | issue = 4 | pages = 243–54 | year = 2013 | pmid = 24053982 | doi=10.1016/j.pediatrneurol.2013.08.001 | pmc=4080684}}</ref>
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| ! colspan="5" width="100%" | Major Criteria
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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 | vauthors = Crino PB, Nathanson KL, Henske EP | title = The tuberous sclerosis complex | journal = N. Engl. J. Med. | volume = 355 | issue = 13 | pages = 1345–56 | year = 2006 | pmid = 17005952 | doi = 10.1056/NEJMra055323 }}</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 fibrous cephalic plaque
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| | Infant – adult
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| | At least three
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| |-
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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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| | At least two
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| |-
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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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| | At least three, at least 5 mm in diameter.
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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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| |-
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| ! 5
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| | Brain
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| | [[cortex (anatomy)|Cortical]] dysplasias (includes tubers and cerebral white matter radial migration lines)
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| | Fetus
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| |-
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| ! 6
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| | Brain
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| | [[Subependymal zone|Subependymal]] [[nodule (medicine)|nodule]]
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| | Child – adolescent
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| |-
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| ! 7
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| | Brain
| |
| | [[Subependymal zone|Subependymal]] giant cell [[astrocytoma]]
| |
| | Child – adolescent
| |
| |
| |
| |-
| |
| ! 8
| |
| | Eyes
| |
| | Multiple [[retinal]] [[nodule (medicine)|nodular]] [[hamartomas]]
| |
| | Infant
| |
| |
| |
| |-
| |
| ! 9
| |
| | Heart
| |
| | Cardiac [[rhabdomyoma]]
| |
| | Fetus
| |
| | Single or multiple.
| |
| |-
| |
| ! 10
| |
| | Lungs
| |
| | [[Lymphangioleiomyomatosis]]
| |
| | Adolescent – adult
| |
| |
| |
| |-
| |
| ! 11
| |
| | Kidneys
| |
| | Renal [[angiomyolipoma]]
| |
| | Child – adult
| |
| | At least two. Together, '''10''' and '''11''' count as one major feature.
| |
| |-
| |
| ! colspan="5" width="100%" | Minor Criteria
| |
| |-
| |
| ! width="2%" |
| |
| ! width="12%" | Location
| |
| ! width="42%" | Sign
| |
| ! width="44%" colspan="2" | Note
| |
| |-
| |
| ! 12
| |
| | Teeth
| |
| | At least three randomly distributed pits in dental enamel
| |
| | colspan="2" |
| |
| |-
| |
| ! 13
| |
| | Skin
| |
| | "Confetti" skin lesions, 1–2 mm hypomelanotic papules
| |
| | colspan="2" |
| |
| |-
| |
| ! 14
| |
| | Gums
| |
| | Intraoral fibromas
| |
| | colspan="2" |
| |
| |-
| |
| ! 15
| |
| | Liver, spleen and other organs
| |
| | Nonrenal [[hamartoma]]
| |
| | colspan="2" | Histologic confirmation is suggested.
| |
| |-
| |
| ! 16
| |
| | Eyes
| |
| | Retinal achromic patch
| |
| | colspan="2" |
| |
| |-
| |
| ! 17
| |
| | Kidneys
| |
| | Multiple [[renal cyst]]s
| |
| | colspan="2" | Histologic confirmation is suggested.
| |
| <ref>{{cite journal | vauthors = Maruyama H, Seyama K, Sobajima J, Kitamura K, Sobajima T, Fukuda T, Hamada K, Tsutsumi M, Hino O, Konishi Y | title = Multifocal micronodular pneumocyte hyperplasia and lymphangioleiomyomatosis in tuberous sclerosis with a TSC2 gene | journal = Mod. Pathol. | volume = 14 | issue = 6 | pages = 609–14 | year = 2001 | pmid = 11406664 | doi = 10.1038/modpathol.3880359 }}</ref>
| |
| |
| |
| |}
| |
| | |
| In infants, the first clue is often the presence of seizures, delayed development, or white patches on the skin. A full clinical diagnosis involves:<ref name="TSFactSheet">{{cite web
| |
| | url = http://www.ninds.nih.gov/disorders/tuberous_sclerosis/detail_tuberous_sclerosis.htm
| |
| | title = Tuberous Sclerosis Fact Sheet
| |
| | accessdate = 3 October 2006
| |
| | date = 11 April 2006
| |
| | publisher = National Institute of Neurological Disorders and Stroke
| |
| }}</ref><ref name="TSAclinicalGuidelines">{{cite web
| |
| | url = http://www.tuberous-sclerosis.org/publications/clinicalguidelinessummary.pdf
| |
| |format=PDF| title = Summary of Clinical guidelines for the care of patients with Tuberous Sclerosis Complex
| |
| | accessdate = 3 October 2006
| |
| |date=April 2002
| |
| | publisher = Tuberous Sclerosis Association
| |
| }}</ref>
| |
| * Taking a [[Medical history|personal]] and [[Family history (medicine)|family history]]
| |
| * Examining the skin under a Wood's lamp (hypomelanotic macules), the fingers and toes (ungual fibroma), the face (angiofibromas), and the mouth (dental pits and gingival fibromas)
| |
| * Cranial imaging with nonenhanced CT or, preferably, [[MRI]] (cortical tubers and subependymal nodules)
| |
| * Renal [[ultrasound]] (angiomyolipoma or cysts)
| |
| * An [[echocardiogram]] in infants (rhabdomyoma)
| |
| * [[Fundoscopy]] (retinal nodular hamartomas or achromic patch)
| |
| The various signs are then marked against the diagnostic criteria to produce a level of diagnostic certainty:
| |
| * '''Definite''' – either two major features or one major feature plus two minor features
| |
| * '''Probable''' – one major plus one minor feature
| |
| * '''Suspect''' – either one major feature or two or more minor features
| |
| | |
| Due to the wide variety of mutations leading to TSC, no simple [[Genetic testing|genetic tests]] are available to identify new cases, nor are any [[Biomarker (medicine)|biochemical markers]] known for the gene defects.<ref name="TSC-diagnosis"/> 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 (biology)|somatic]] [[mosaic (genetics)|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.
| |
| | |
| == Management ==
| |
| TSC typically affects multiple organ systems and manifests differently in each patient and in different stages of the life course. Drug therapy, surgery, and other interventions can be effective in managing some of the manifestations and symptoms of TSC.
| |
| | |
| In the United States, the Food and Drug Administration has approved several drugs for managing some of the major manifestations of TSC. The antiepileptic medication [[vigabatrin]] was approved in 2009 for treatment of [[infantile spasms]] and was recommended as first-line therapy for infantile spasms in children with TSC by the 2012 International TSC Consensus Conference.<ref>{{Cite web|url=http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm179855.htm|title=Press Announcements - Sabril Approved by FDA to Treat Spasms in Infants and Epileptic Seizures|website=www.fda.gov|language=en|access-date=2017-02-08}}</ref><ref name=":0">{{Cite journal|last=Krueger|first=Darcy A.|last2=Northrup|first2=Hope|last3=International Tuberous Sclerosis Complex Consensus Group|date=2013-10-01|title=Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference|journal=Pediatric Neurology|volume=49|issue=4|pages=255–265|doi=10.1016/j.pediatrneurol.2013.08.002|pmc=4058297|pmid=24053983}}</ref> Adrenocorticotropic hormone was approved in 2010 to treat infantile spasms.<ref>{{Cite web|url=http://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022432Orig1s000Approv.pdf|title=Approval Package for H.P. Acthar Gel|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref> [[Everolimus]] was approved for treatment of TSC-related tumors in the brain ([[subependymal giant cell astrocytoma]]) in 2010 and in the kidneys (renal [[angiomyolipoma]]) in 2012.<ref>{{Cite web|url=http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm302048.htm|title=Press Announcements - FDA approves Afinitor for non-cancerous kidney tumors caused by rare genetic disease|website=www.fda.gov|language=en|access-date=2017-02-08}}</ref><ref>{{Cite web|url=https://www.cancer.gov/about-cancer/treatment/drugs/fda-everolimus|title=FDA Approval for Everolimus|website=National Cancer Institute|language=en|access-date=2017-02-08}}</ref> Everolimus also showed evidence of effectiveness at treating epilepsy in some people with TSC.<ref>{{Cite journal|last=French|first=Jacqueline A|last2=Lawson|first2=John A|last3=Yapici|first3=Zuhal|last4=Ikeda|first4=Hiroko|last5=Polster|first5=Tilman|last6=Nabbout|first6=Rima|last7=Curatolo|first7=Paolo|last8=Vries|first8=Petrus J de|last9=Dlugos|first9=Dennis J|title=Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study|url=https://dx.doi.org/10.1016/S0140-6736(16)31419-2|journal=The Lancet|volume=388|issue=10056|pages=2153–2163|doi=10.1016/s0140-6736(16)31419-2}}</ref> In 2017, the European Commission approved everolimus for treatment of refractory partial-onset seizures associated with TSC.<ref>{{Cite news|url=https://globenewswire.com/news-release/2017/01/31/912212/0/en/Novartis-drug-Votubia-receives-EU-approval-to-treat-refractory-partial-onset-seizures-in-patients-with-TSC.html|title=Novartis drug Votubia® receives EU approval to treat refractory partial-onset seizures in patients with TSC|last=AG|first=Novartis International|newspaper=GlobeNewswire News Room|access-date=2017-02-08|language=en-US}}</ref>
| |
| | |
| Neurosurgical intervention may reduce the severity and frequency of seizures in TSC patients. [[Embolization]] and other surgical interventions can be used to treat renal angiomyolipoma with acute hemorrhage. Surgical treatments for symptoms of [[lymphangioleiomyomatosis]] (LAM) in adult TSC patients include pleurodesis to prevent [[pneumothorax]] and [[lung transplantation]] in the case of irreversible lung failure.<ref>{{Cite journal|last=Krueger|first=Darcy A.|last2=Northrup|first2=Hope|last3=Northrup|first3=Hope|last4=Roberds|first4=Steven|last5=Smith|first5=Katie|last6=Sampson|first6=Julian|last7=Korf|first7=Bruce|last8=Kwiatkowski|first8=David J.|last9=Mowat|first9=David|title=Tuberous Sclerosis Complex Surveillance and Management: Recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference|url=https://dx.doi.org/10.1016/j.pediatrneurol.2013.08.002|journal=Pediatric Neurology|volume=49|issue=4|pages=255–265|doi=10.1016/j.pediatrneurol.2013.08.002|pmc=4058297|pmid=24053983}}</ref>
| |
| | |
| Other treatments that have been used to treat TSC manifestations and symptoms include a [[ketogenic diet]] for intractable epilepsy and pulmonary rehabilitation for LAM.<ref>{{Cite journal|last=Hong|first=Amanda M.|last2=Turner|first2=Zahava|last3=Hamdy|first3=Rana F.|last4=Kossoff|first4=Eric H.|date=2010-08-01|title=Infantile spasms treated with the ketogenic diet: Prospective single-center experience in 104 consecutive infants|url=http://onlinelibrary.wiley.com/doi/10.1111/j.1528-1167.2010.02586.x/abstract|journal=Epilepsia|language=en|volume=51|issue=8|pages=1403–1407|doi=10.1111/j.1528-1167.2010.02586.x}}</ref><ref name=":0" />
| |
| | |
| == Prognosis ==
| |
| 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 intellectual disability, uncontrollable seizures, and kidney failure. Those individuals with mild symptoms generally do well and live long, productive lives, while individuals with the more severe form may have serious disabilities. However, with appropriate medical care, most individuals with the disorder can look forward to normal life expectancy.<ref name="TSFactSheet"/>
| |
| | |
| A study of 30 TSC patients in Egypt found, "...earlier age of seizures commencement (<6 months) is associated with poor seizure outcome and poor intellectual capabilities. Infantile spasms and severely epileptogenic EEG patterns are related to the poor seizure outcome, poor intellectual capabilities and autistic behavior. Higher tubers numbers is associated with poor seizure outcome and autistic behavior. Left-sided tuber burden is associated with poor intellect, while frontal location is more encountered in ASD. So, close follow up for the mental development and early control of seizures are recommended in a trial to reduce the risk factors of poor outcome. Also early diagnosis of autism will allow for earlier treatment and the potential for better outcome for children with TSC."<ref name="pmid20817577">{{cite journal | vauthors = Samir H, Ghaffar HA, Nasr M | title = Seizures and intellectual outcome: clinico-radiological study of 30 Egyptian cases of tuberous sclerosis complex | journal = Eur. J. Paediatr. Neurol. | volume = 15 | issue = 2 | pages = 131–7 | date = March 2011 | pmid = 20817577 | doi = 10.1016/j.ejpn.2010.07.010 }}</ref>
| |
| | |
| Leading causes of death include renal disease, brain tumour, [[lymphangioleiomyomatosis]] of the lung, and status epilepticus or bronchopneumonia in those with severe mental handicap.<ref name="shepherd1991">{{cite journal | vauthors = Shepherd CW, Gomez MR, Lie JT, Crowson CS | title = Causes of death in patients with tuberous sclerosis | journal = Mayo Clin. Proc. | volume = 66 | issue = 8 | pages = 792–6 | year = 1991 | pmid = 1861550 | doi = 10.1016/s0025-6196(12)61196-3 }}</ref> Cardiac failure due to rhabdomyomas is a risk in the fetus or neonate, but is rarely a problem subsequently. Kidney complications such as [[angiomyolipoma]] 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 angiomyolipomas.<ref name="Rakowski2006">{{cite journal | vauthors = Rakowski SK, Winterkorn EB, Paul E, Steele DJ, Halpern EF, Thiele EA | title = Renal manifestations of tuberous sclerosis complex: Incidence, prognosis, and predictive factors | journal = Kidney Int. | volume = 70 | issue = 10 | pages = 1777–82 | year = 2006 | pmid = 17003820 | doi = 10.1038/sj.ki.5001853 }}</ref> In the brain, the subependymal nodules occasionally degenerate to subependymal giant cell astrocytomas. These may block the circulation of cerebrospinal fluid around the brain, leading to hydrocephalus.
| |
| | |
| Detection of the disease should be followed by genetic counselling. It is also important to realise that though the disease does not have a cure, symptoms can be treated symptomatically. Hence, awareness regarding different organ manifestations of TSC is important.
| |
| | |
| == Epidemiology ==
| |
| TSC occurs in all races and ethnic groups, and in both genders. The [[Live birth (human)|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 | vauthors = O'Callaghan FJ, Shiell AW, Osborne JP, Martyn CN | title = Prevalence of tuberous sclerosis estimated by capture-recapture analysis | journal = Lancet | volume = 351 | issue = 9114 | pages = 1490 | year = 1998 | pmid = 9605811 | doi = 10.1016/S0140-6736(05)78872-3 }}</ref> These estimates are significantly higher than those produced by older studies, when TSC was regarded as an extremely rare disease. This is due to the invention of CT and [[Medical ultrasonography|ultrasound]] scanning having enabled the diagnosis of many nonsymptomatic cases. Prior to this, the diagnosis of TSC was largely restricted to severely affected individuals with Vogt's triad of learning disability, seizures, and facial angiofibroma. The total population prevalence estimates 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]], TSC is common when compared to many other genetic diseases.<ref name="TSC-diagnosis"/>
| |
| | |
| == History ==
| |
| {{Main article|Timeline of tuberous sclerosis}}
| |
| [[File:Désiré-Magloire Bourneville.jpg|thumb|Désiré-Magloire Bourneville]]
| |
| TSC 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 who 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>
| |
| | |
| 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.
| |
| | |
| <!-- repeat of above 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. -->
| |
| 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 TSC.<ref name="Rott2005">{{cite web
| |
| | url = http://www.tsdev.de/92001/Uploaded/hhehn%7Cgeschichte_der_tsc2005.pdf
| |
| |format=PDF| title = Zur Geschichte der Tuberösen Sklerose (The History of Tuberous Sclerosis)
| |
| | accessdate = 8 January 2007
| |
| |vauthors=Rott HD, Mayer K, Walther B, Wienecke R |date=March 2005
| |
| | publisher = Tuberöse Sklerose Deutschland e.V
| |
| | language = German
| |
| }}</ref>
| |
| | |
| == References ==
| |
| {{Reflist|30em}}
| |
| | |
| == External links ==
| |
| {{Commons category}}
| |
| | |
| *{{GeneTests|tuberous-sclerosis}}
| |
| *[https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=tuberous-sclerosisa GeneReview/NCBI/NIH/UW entry on Tuberous Sclerosis Complex]
| |
| *The [http://www.tsalliance.org/ Tuberous Sclerosis Alliance] in the United States offers a comprehensive Web site, online discussion groups, and free publications.
| |
| *The [[Human Genome Organisation|HUGO]] Gene Nomenclature Committee web pages for [http://www.gene.ucl.ac.uk/nomenclature/data/get_data.php?hgnc_id=HGNC:12362 ''TSC1''] and [http://www.gene.ucl.ac.uk/nomenclature/data/get_data.php?hgnc_id=HGNC:12363 ''TSC2''] provide a selection of links for further genetic research.
| |
| *The [http://www.childhooddiseases.org/ Rothberg Institute For Childhood Diseases] have a [[distributed computing]] project called [[CommunityTSC]]
| |
| *[http://dermatlas.med.jhmi.edu/derm/result.cfm?Diagnosis=189 Dermatlas: Images of Tuberous sclerosis]
| |
| *Mass General Hospital's [http://www.massgeneral.org/livingwithtsc/ Living with TSC]
| |
| *The [http://www.tuberous-sclerosis.org/ Tuberous Sclerosis Association] in the UK and [http://www.tsa.org.au Tuberous Sclerosis Australia] both have comprehensive web sites
| |
| * [http://www.tscinternational.org/ Tuberous Sclerosis Complex International] lists all TSC organisations around the world
| |
| * [http://www.cancer.net/cancer-types/tuberous-sclerosis-syndrome Cancer.Net: Tuberous Sclerosis Syndrome]
| |
| *[http://www.cincinnatichildrens.org/health/t/tuberous-sclerosis/ Tuberous sclerosis] symptoms, diagnosis, treatment and prognosis
| |
| | |
| {{Diseases of the skin and appendages by morphology}}
| |
| {{Phakomatoses}}
| |
| {{Deficiencies of intracellular signaling peptides and proteins}}
| |
| {{Use dmy dates|date=January 2011}}
| |
| | |
| {{Authority control}}
| |
| | |
| {{DEFAULTSORT:Tuberous Sclerosis}}
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| [[Category:Autosomal dominant disorders]]
| |
| [[Category:Genodermatoses]]
| |
| [[Category:Rare diseases]]
| |
| [[Category:Biology of attention deficit hyperactivity disorder]]
| |
| [[Category:Autism]]
| |
| [[Category:Intellectual disability]]
| |
| [[Category:Biology of obsessive–compulsive disorder]]
| |
| [[Category:Disorders causing seizures]]
| |