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| {{Infobox medical condition (new) | | {{Tuberous Sclerosis}} |
| | name = Tuberous sclerosis
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| | 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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| '''Tuberous sclerosis complex''' ('''TSC'''), is a rare autosomal dominant congenital disorder that affects multiple organ systems and is characterized by an abnormal growth of ectodermal and mesodermal cells that causes [[benign tumor|non-cancerous tumours]] 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]] <ref>Henske, Elizabeth P., et al. "Tuberous sclerosis complex." ''Nature reviews Disease primers'' 2.1 (2016): 1-18.</ref>
| | {{CMG}}; {{AE}} Person 1, Person 2, Your Name |
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| 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="TSFactSheet">{{cite web|url=https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Tuberous-Sclerosis-Fact-Sheet|title=Tuberous Sclerosis Fact Sheet|publisher=National Institute of Neurological Disorders and Stroke|accessdate=16 December 2018|date=2018-07-06}}</ref>
| | ==[[Tuberous sclerosis overview|Overview]]== |
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| The disease presents with a myriad of symptoms, having been described by multiple doctors throughtout the 19th century and called by many different names, but it is now called '''tuberous sclerosis complex''', and the relationship between benign brain tumors and the symptoms of the disease was [[timeline of tuberous sclerosis|first described]] by [[Désiré-Magloire Bourneville]] in 1880. <ref name=":0">Morgan, J. Elizabeth, and Francis Wolfort. "The early history of tuberous sclerosis." Archives of dermatology 115.11 (1979): 1317-1319.</ref>
| | ==[[[Tuberous sclerosis historical perspective|Historical Perspective]]== |
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| | ==[[[Tuberous sclerosis classification|Classification]]== |
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| Tuberous Sclerosis was described as a specific disease in the 19th century, being initially referred to adenoma sebaceum, epiloia, Pringle's disease or Bourneville's disease. Rayer, a French dermatologist, was the one to first describe the disease and the fibrovascular papules that characterize it, making illustrations of it. He described two cases of tuberous sclerosis in patients who had the nasolabial papular eruption with telangiectasias at the base. In 1850 the first written report of tuberous sclerosis appeared in "Vitiligoidea", published by Addison and Gull. It was not recognized as a distinct disease but was classified as "vitiligoidea tuberosa". In 1862, von Recklinghausen reported a tumor of the heart found in a newborn during autopsy, and by that he is credited to be the first that described the microscopic appearance of tuberous sclerosis. Bourneville in 1880, a French neurologist, described the case of a girl who presented at the age of 3 with facial eruption and died at 15 years of age due to epilepsy, which complicated with pneumonia and inanition. He found brain and kidney tumors on the autopsy which were correctly believed to be the cause of her seizures and mental retardation. In 1911, E. B. Sherlock, superintendent of Belmont Asylum of Idiots, London, coined the word "epiloia" that indicated a clinical triad of epilepsy, low intelligence and adenoma sebaceum.<ref name=":0" /> | | ==[[[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 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 |deadurl = yes |archiveurl = https://web.archive.org/web/20070315134445/http://www.tsdev.de/92001/Uploaded/hhehn%7Cgeschichte_der_tsc2005.pdf |archivedate = 15 March 2007 |df = dmy-all}}</ref>
| | ==[[Tuberous sclerosis causes|Causes]]== |
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| == Signs and symptoms == | | ==[[[Tuberous sclerosis differential diagnosis|Differentiating Any Disease from other Diseases]]== |
| 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.
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| === Neurological=== | | ==[[[Tuberous sclerosis epidemiology and demographics|Epidemiology and Demographics]]== |
| [[File:Tuberoese Sklerose 1J T2 axial2.png|thumb|TSC in MRI]] | |
| Three types of brain tumours are be associated with TSC:
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| * 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 = Journal of Child Neurology | volume = 19 | issue = 9 | pages = 658–65 | date = September 2004 | pmid = 15563011 | doi = 10.1177/08830738040190090501 }}</ref>
| | ==[[[Tuberous sclerosis risk factors|Risk Factors]]== |
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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 screening|Screening]]== |
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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 natural history, complications and prognosis|Natural History, Complications and Prognosis]]== |
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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.
| | ==Diagnosis== |
| {{clear}}
| | [[[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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| === Neuropsychiatric === | | ==Treatment== |
| About 90% of people with TSC develop a range of neurodevelopmental, behavioural, psychiatric, and psychosocial difficulties. The "TSC‐associated neuropsychiatric disorders" are abbreviated TAND. These difficulties are less frequently identified and thus undertreated when compared with the neurological symptoms.<ref name="TAND">{{cite journal | vauthors = de Vries PJ, Wilde L, de Vries MC, Moavero R, Pearson DA, Curatolo P | title = A clinical update on tuberous sclerosis complex-associated neuropsychiatric disorders (TAND) | journal = American Journal of Medical Genetics. Part C, Seminars in Medical Genetics | volume = 178 | issue = 3 | pages = 309–320 | date = September 2018 | pmid = 30117265 | doi = 10.1002/ajmg.c.31637 }}</ref> Most problems are associated with more severe intellectual delay or associated with childhood and adolescence, and some (for example depressed mood) may be unreported if the person is unable to communicate. TAND can be investigated and considered at six levels: behavioural, psychiatric, intellectual, academic, neuropsychological and psychosocial.<ref name="TAND" />
| | [[[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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| Behavioural problems most commonly seen include overactivity, impulsivity and sleeping difficulties. Also common are anxiety, mood swings and severe aggression. Less common are depressed mood, self-injury and obsessional behaviours.<ref name="TAND" />
| | ==Case Studies== |
| | [[[Tuberous sclerosis case study one|Case #1]] |
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| People with TSC are frequently also diagnosed psychiatric disorders: [[autism spectrum disorder]] (ASD), [[attention deficit hyperactivity disorder]] (ADHD), [[anxiety disorder]] and [[depressive disorder]]. [[Schizophrenia]] (and symptoms like [[hallucinations]] or [[psychosis]]) are no more common in TSC than the general population. TSC is one of the most common genetic causes of autism spectrum disorder, which affects nearly half of people with TSC. ASD is more common in TSC2 than TSC1 and more common with earlier and more severe epilepsy, and with lower intellectual ability. ADHD is nearly as frequently seen in TSC as ASD (up to half of all people with TSC). Anxiety and depressive disorders, when they occur, are typically diagnosed in early adulthood and among those intellectually able to express their moods.<ref name="TAND" />
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| The intellectual ability of people with TSC varies enormously. About 40-50% have a normal IQ. A normal IQ is much more commonly seen in TSC1 than TSC2, and profound intellectual disability seen in 34% of TSC2 compared with 10% of TSC1 in one study. Many studies have examined whether early onset, type and severity of epilepsy associates with intellectual ability. Academic issues occur even in people with TSC who have normal intellectual ability. These are often specific learning disorders such as [[dyscalculia]] (understanding mathematics), but also include other aspects affecting school life such as anxiety, lack of social skills or low self-esteem.<ref name="TAND" />
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| About half of people with TSC, when assessed for neuropsychological skills, are in the bottom 5th percentile in some areas, which indicates a severe impairment. These include problems with [[attention]] (for example, being able to concentrate on two separate things like looking and listening), [[memory]] (particularly [[Recall (memory)|recall]], [[Verbal memory|verbal]] and [[Spatial working memory|spacial working]] memory) and [[executive function]] (for example, [[Planning (cognitive)|planning]], [[Self-monitoring|self-monitoring]], [[cognitive flexibility]]).<ref name="TAND" />
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| The [[psychosocial]] impacts of TSC include low [[self-esteem]] and [[self-efficacy]] in the individual, and a [[Caregiver burden|burden on the family]] copying with a complex and unpredictable disorder.<ref name="TAND" />
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| === Kidneys ===
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| [[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]]
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| 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]].
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| Very rare (< 1%) problems include [[renal cell carcinoma]] and [[oncocytoma]]s ([[benign adenomatous hamartoma]]).
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| === Lungs ===
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| Patients with TSC can develop progressive replacement of the lung parenchyma with multiple cysts, known as [[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 | date = December 2003 | pmid = 14566858 | doi = 10.1002/gcc.10252 }}</ref>
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| === Heart ===
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| Small tumours of the [[Cardiac muscle|heart muscle]], called cardiac [[rhabdomyomas]], are rare in the general population (perhaps 0.2% of children) but very common in people with TSC. Around 80% of children under two-years-old with TSC have at least one rhabdomyoma, and about 90% of those will have several. The vast majority of children with at least one rhabdomyoma, and nearly all children with multiple rhabdomyomas will be found to have TSC. Prenatal ultrasound, performed by an [[Obstetric ultrasonography|obstetric sonographer]] specializing in cardiology, can detect a rhabdomyoma after 20 weeks. Rhabdomyoma vary in size from a few millimetres to several centimetres, and are usually found in the lower chambers ([[Ventricle (heart)|ventricles]]) and less often in the upper chambers ([[Atrium (heart)|atria]]). They grow in size during the second half of pregnancy, but regress after birth, and are seen in only around 20% of children over two years old.<ref name="Cardiovascular" />
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| Most rhabdomyomas cause no problems but some may cause heart failure in the foetus or first year of life. Rhabdomyomas are believed to be responsible for the development of [[heart arrhythmia]] later in life, which is relatively common in TSC. Arrhythmia can be hard to spot in people with TSC, other than by performing routine ECG. For example, arrhythmia may cause [[Syncope (medicine)|fainting]] that is confused with [[Atonic seizure|drop seizures]], and symptoms of arrhythmia such as palpitations may not be reported in an individual with developmental delay.<ref name="Cardiovascular">{{cite journal | vauthors = Hinton RB, Prakash A, Romp RL, Krueger DA, Knilans TK | title = Cardiovascular manifestations of tuberous sclerosis complex and summary of the revised diagnostic criteria and surveillance and management recommendations from the International Tuberous Sclerosis Consensus Group | journal = Journal of the American Heart Association | volume = 3 | issue = 6 | pages = e001493 | date = November 2014 | pmid = 25424575 | pmc = 4338742 | doi = 10.1161/JAHA.114.001493 }}</ref>
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| === Skin ===
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| 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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| * Hypomelanic [[macules]] ("ash leaf spots") are present in about 90% of people with TSC.<ref name="TSCDiagnosis" /> These small white or lighter patches of skin 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. On the scalp, the effect may be a white patch of hair ([[poliosis]]). Patches smaller than 3mm are known as "confetti" skin lesions.<ref name="TSCDiagnosis" />
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| * Facial [[angiofibroma]]s are present in about 75% of people with TSC.<ref name="TSCDiagnosis" /> These are a rash of reddish spots or bumps on the nose and cheeks in a [[malar rash|butterfly distribution]], which consist of blood vessels and fibrous tissue. This potentially socially embarrassing rash starts to appear during childhood.
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| * Ungual fibromas: Also known as [[Koenen's tumor]]s, these are small fleshy tumors that grow around and under the toenails or fingernails. These are rare in childhood, but common by middle age.<ref name="pmid20301399">{{cite book | vauthors = Northrup H, Koenig MK, Pearson DA, Au KS | veditors = Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Stephens K, Amemiya A | title = GeneReviews | chapter = Tuberous Sclerosis Complex | location = Seattle (WA) | publisher = University of Washington | pmid = 20301399 | url = http://www.ncbi.nlm.nih.gov/books/NBK1220/ }}</ref> They are generally more common on toes than on fingers, develop at 15–29 years, and are more common in women than in men.
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| * Fibrous cephalic plaques are present in about 25% of people with TSC.<ref name="TSCDiagnosis" /> These are raised, discoloured areas usually found on the forehead, but sometimes on the face or elsewhere on the scalp.
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| * [[Shagreen patch]]es are present in about half of people with TSC, appearing in childhood.<ref name="TSCDiagnosis" /> They are 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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| * [[Tooth enamel|Dental enamel]] pits are found in almost all adults with TSC.<ref name="TSCDiagnosis" />
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| * Intraoral [[fibroma]]s are small surface-tumours found in the gums, inside the cheeks or tongue. Gum (gingival) fibromas are found in about 20-50% of people with TSC, more commonly in adults.<ref name="TSCDiagnosis" />
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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 | vauthors = Arva NC, Pappas JG, Bhatla T, Raetz EA, Macari M, Ginsburg HB, Hajdu CH | title = Well-differentiated pancreatic neuroendocrine carcinoma in tuberous sclerosis--case report and review of the literature | journal = The American Journal of Surgical Pathology | volume = 36 | issue = 1 | pages = 149–53 | date = January 2012 | pmid = 22173120 | doi = 10.1097/PAS.0b013e31823d0560 }}</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">{{cite book | veditors = Curatolo P | title = Tuberous Sclerosis Complex: From Basic Science to Clinical Phenotypes | year = 2003 | isbn = 978-1-898683-39-1 | oclc = 53124670 | chapter = Diagnostic Criteria | series = International review of child neurology | location = London | publisher = Mac Keith Press }}</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 [[penetrance]].<ref name="pmid20301399" /><ref>{{cite journal|vauthors=Baraitser M, Patton MA|date=February 1985|title=Reduced penetrance in tuberous sclerosis|journal=Journal of Medical Genetics|volume=22|issue=1|pages=29–31|doi=10.1136/jmg.22.1.29|pmc=1049373|pmid=3981577}}</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 | display-authors = 6 | title = Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34 | journal = Science | volume = 277 | issue = 5327 | pages = 805–808 | date = August 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 | date = December 1993 | pmid = 8269512 | doi = 10.1016/0092-8674(93)90618-Z }}</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 = Nature Genetics | volume = 8 | issue = 4 | pages = 328–32 | date = December 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 = American Journal of Human Genetics | volume = 68 | issue = 1 | pages = 64–80 | date = January 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 = Human Mutation | volume = 26 | issue = 4 | pages = 374–83 | date = October 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 =
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| | 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 angiofibroma, 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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| Tuberous sclerosis complex is diagnosed with clinical and [[Genetic testing|genetic tests]]. There are many different mutations in the TSC1 and TSC2 genes that have been identified in individuals with TSC. A pathogenic mutation in the gene prevents the proteins from being made or inactivates the proteins. If such a pathogenic mutation is found then this alone is sufficient to diagnose TSC. However, some mutations are less clear in their effect, and so not sufficient alone for diagnosis. Between 1 in 10 and 1 in 4 of individuals with TSC have no mutation that can be identified. Once a particular mutation is identified in someone with TSC, this mutation can used to make confident diagnoses in other family members.<ref name="TSCDiagnosis" />
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| For clinical diagnosis, there isn't one [[medical sign|sign]] that is unique ([[pathognomonic]]) to TSC, nor are all signs seen in all individuals. Therefore several signs are considered together, classed as either major or minor features. An individual with two major features, or one major feature and at least two minor features can be given a definite diagnosis of TSC. If only one major feature or at least two minor features are present, the diagnosis is only regarded as possibly TSC.<ref name="TSCDiagnosis" />
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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="TSCDiagnosis">{{cite journal | vauthors = Northrup H, Krueger DA | title = Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference | journal = Pediatric Neurology | volume = 49 | issue = 4 | pages = 243–54 | date = October 2013 | pmid = 24053982 | pmc = 4080684 | doi = 10.1016/j.pediatrneurol.2013.08.001 }}</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 | vauthors = Crino PB, Nathanson KL, Henske EP | title = The tuberous sclerosis complex | journal = The New England Journal of Medicine | volume = 355 | issue = 13 | pages = 1345–56 | date = September 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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| | 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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| ! 2
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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 angiofibromas
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| |-
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| ! 3
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| | Fingers and toes
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| | Ungual [[fibroma]]
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| | Adolescent – adult
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| | At least two
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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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| | Eyes
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| | Multiple [[retinal]] [[nodule (medicine)|nodular]] [[hamartomas]]
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| | Infant
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| |-
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| ! 6
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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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| ! 7
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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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| ! 8
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| | Brain
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| | [[Subependymal zone|Subependymal]] giant cell [[astrocytoma]]
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| | Child – adolescent
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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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| |-
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| ! 10
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| | Lungs
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| | [[Lymphangioleiomyomatosis]]
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| | Adolescent – adult
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| |-
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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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| | At least two. Together, '''10''' and '''11''' count as one major feature.
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| |-
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| ! colspan="5" width="100%" | Minor 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="44%" colspan="2" | Note
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| |-
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| ! 1
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| | Skin
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| | "Confetti" skin lesions
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| | colspan="2" |
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| |-
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| ! 2
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| | Teeth
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| | Dental enamel pits
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| | colspan="2" | At least three
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| |-
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| ! 3
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| | Gums
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| | Intraoral fibromas
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| | colspan="2" | At least two
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| |-
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| ! 4
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| | Eyes
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| | Retinal achromic patch
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| | colspan="2" |
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| |-
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| ! 5
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| | Kidneys
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| | Multiple [[renal cyst]]s
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| | colspan="2" |
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| |-
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| ! 6
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| | Liver, spleen and other organs
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| | Nonrenal [[hamartoma]]
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| | colspan="2" |
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| |}
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| TSC can be first diagnosed at any stage of life. Prenatal diagnosis is possible by chance if heart tumours are discovered during routine [[ultrasound]]. In infancy, epilepsy, particularly infantile spasms, or developmental delay may lead to neurological tests. The white patches on the skin may also first become noticed. In childhood, behavioural problems and [[autism spectrum disorder]] may provoke a diagnosis. During adolescence the skin problems appear. In adulthood, kidney and lung problems may develop. An individual may also be diagnosed at any time as a result of genetic testing of family members of another affected person.<ref name="NHSBirmingham">{{cite web|url=https://www.uhb.nhs.uk/tuberous-sclerosis-complex.htm|title=Tuberous Sclerosis Complex|accessdate=16 December 2018|publisher=University Hospitals Birmingham NHS Foundation Trust}}</ref>
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| == Management ==
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| Tuberous sclerosis complex affects multiple organ systems so a multidisciplinary team of medical professionals is required.
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| In suspected or newly diagnosed TSC, the following tests and procedures are recommended by 2012 International Tuberous Sclerosis Complex Consensus Conference.<ref name="TSCManagement">{{cite journal | vauthors = Krueger DA, Northrup H | 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 = 255–65 | date = October 2013 | pmid = 24053983 | pmc = 4058297 | doi = 10.1016/j.pediatrneurol.2013.08.002 }}</ref>
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| *Take a [[Medical history|personal]] and [[Family history (medicine)|family history]] covering three generations. [[Genetic counseling|Genetic counselling]] and tests determine if other individuals are at risk.
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| *A magnetic resonance imaging (MRI) of the brain to identify tubers, subependymal nodules (SEN) and sub-ependymal giant cell astrocytomas (SEGA).
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| *Children undergo a baseline electroencephalograph (EEG) and family educated to identify seizures if/when they occur.
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| *Assess children for behavioural issues, autism spectrum disorder, psychiatric disorders, developmental delay, and neuropsychological problems.
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| *Scan the abdomen for tumours in various organs, but most importantly angiomyolipomata in the kidneys. MRI is superior to CT or ultrasound. Take blood pressure and test renal function.
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| *In adult women, test pulmonary function and perform a [[High-resolution computed tomography|high-resolution computed tomography]] (HRCT) of the chest.
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| * Examine 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).
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| *In infants under three, perform an [[echocardiogram]] to spot rhabdomyomas, and [[electrocardiogram]] (ECG) for any [[arrhythmia]].
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| *Use a [[Fundoscopy|fundoscope]] to spot retinal hamartomas or achromic patches.
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| The various symptoms and complications from TSC may appear throughout life, requiring continued surveillance and adjustment to treatments. The following ongoing tests and procedures are recommended by 2012 International Tuberous Sclerosis Complex Consensus Conference.<ref name="TSCManagement" />
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| *In children and adults younger than 25 years, a magnetic resonance imaging (MRI) of the brain is performed every one to three years to monitor for subependymal giant cell astrocytoma (SEGA). If a SEGA is large, growing or interfering with ventricles, the MRI is performed more frequently. After 25 years, if there are no SEGAs then periodic scans may no longer be required. A SEGA causing acute symptoms are removed with surgery, otherwise either surgery or drug treatment with an mTOR inhibitor may be indicated.
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| *Repeat screening for TSC-associated neuropsychiatric disorders (TAND) at least annually. Sudden behavioural changes may indicate a new physical problem (for example with the kidneys, epilepsy or a SEGA).
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| *Routine EEG determined by clinical need.
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| *Infantile spasms are best treated with [[vigabatrin]] and [[adrenocorticotropic hormone]] used as a second-line therapy. Other seizure types have no TSC-specific recommendation, though epilepsy in TSC is typically difficult to treat (medically refractory).
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| *Repeat MRI of abdomen every one to three years throughout life. Check renal (kidney) function annually. Should angiomyolipoma bleed, this is best treated with [[embolisation]] and then corticosteroids. Removal of the kidney ([[nephrectomy]]) is strongly to be avoided. An asymptomatic angiomyolipoma that is growing larger than 3cm is best treated with an mTOR inhibitor drug. Other renal complications spotted by imaging include [[polycystic kidney disease]] and [[renal cell carcinoma]].
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| *Repeat chest HRCT in adult women every five to 10 years. Evidence of [[lymphangioleiomyomatosis]] (LAM) indicates more frequent testing. An mTOR inhibitor drug can help, though a lung transplant may be required.
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| *A 12-lead ECG should be performed every three to five years.
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| The mTOR inhibitor [[everolimus]] was approved in the US 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 | vauthors = French JA, Lawson JA, Yapici Z, Ikeda H, Polster T, Nabbout R, Curatolo P, de Vries PJ, Dlugos DJ, Berkowitz N, Voi M, Peyrard S, Pelov D, Franz DN | 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 | journal = Lancet | volume = 388 | issue = 10056 | pages = 2153–63 | date = October 2016 | pmid = 27613521 | doi = 10.1016/s0140-6736(16)31419-2 }}</ref><ref name="pmid27601910">{{cite journal | vauthors = Capal JK, Franz DN | title = Profile of everolimus in the treatment of tuberous sclerosis complex: an evidence-based review of its place in therapy | journal = Neuropsychiatric Disease and Treatment | volume = 12 | issue = | pages = 2165–72 | date = 2016 | pmid = 27601910 | pmc = 5003595 | doi = 10.2147/NDT.S91248 }}</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>
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| Neurosurgical intervention may reduce the severity and frequency of seizures in TSC patients.<ref name="Asano_2005">{{cite journal | vauthors = Asano E, Juhász C, Shah A, Muzik O, Chugani DC, Shah J, Sood S, Chugani HT | title = Origin and propagation of epileptic spasms delineated on electrocorticography | journal = Epilepsia | volume = 46 | issue = 7 | pages = 1086–97 | date = July 2005 | pmid = 16026561 | doi = 10.1111/j.1528-1167.2005.05205.x | pmc = 1360692 }}</ref> <ref name="Chugani_2013">{{cite journal | vauthors = Chugani HT, Luat AF, Kumar A, Govindan R, Pawlik K, Asano E | title = α-[11C]-Methyl-L-tryptophan--PET in 191 patients with tuberous sclerosis complex | journal = Neurology | volume = 81 | issue = 7 | pages = 674–80 | date = August 2013 | pmid = 23851963 | doi = 10.1212/WNL.0b013e3182a08f3f | pmc = 3775695 }}</ref> [[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 name="TSCManagement" />
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| 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 | vauthors = Hong AM, Turner Z, Hamdy RF, Kossoff EH | title = Infantile spasms treated with the ketogenic diet: prospective single-center experience in 104 consecutive infants | journal = Epilepsia | volume = 51 | issue = 8 | pages = 1403–407 | date = August 2010 | pmid = 20477843 | doi = 10.1111/j.1528-1167.2010.02586.x | url = http://onlinelibrary.wiley.com/doi/10.1111/j.1528-1167.2010.02586.x/abstract }}</ref> Facial angiofibromas can be reduced with [[laser medicine|laser treatment]] and the effectiveness of mTOR inhibitor topical treatment is being investigated. Laser therapy is painful, requires anaesthesia, and has risks of scarring and dyspigmentation.<ref name="DermUpdate">{{cite journal | vauthors = Jacks SK, Witman PM | title = Tuberous Sclerosis Complex: An Update for Dermatologists | journal = Pediatric Dermatology | volume = 32 | issue = 5 | pages = 563–70 | date = September-October 2015 | pmid = 25776100 | doi = 10.1111/pde.12567 }}</ref>
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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 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" />
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| 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 [<nowiki/>[[Autism-spectrum disorder|Autism Spectrum Disorders]]]. 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 = European Journal of Paediatric Neurology | volume = 15 | issue = 2 | pages = 131–37 | date = March 2011 | pmid = 20817577 | doi = 10.1016/j.ejpn.2010.07.010 }}</ref>
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| 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 Clinic Proceedings | volume = 66 | issue = 8 | pages = 792–96 | date = August 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 International | volume = 70 | issue = 10 | pages = 1777–82 | date = November 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.
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| 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.
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| == Epidemiology ==
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| 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<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 | date = May 1998 | pmid = 9605811 | doi = 10.1016/S0140-6736(05)78872-3 }}</ref> estimated total population prevalence between about 7 and 12 cases per 100,000, with more than half of these cases undetected. Prior to the invention of [[computed tomography|CT]] scanning to identify the nodules and tubers in the brain, the prevalence was thought to be much lower and the disease associated with those people diagnosed clinically with learning disability, seizures, and facial angiofibroma. Whilst still regarded as a [[rare disease]], TSC is common when compared to many other genetic diseases, with at least 1 million individuals worldwide.<ref name="TSC-diagnosis" />
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| == History ==
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| {{Main article|Timeline of tuberous sclerosis}}
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| [[File:Désiré-Magloire Bourneville.jpg|thumb|150 px|Désiré-Magloire Bourneville]]
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| <br />
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| {{clear}}
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| == References ==
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| {{Reflist|32em}}
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| *
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| == External links ==
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| {{Medical resources
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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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| {{Commons category}}
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| *{{GeneTests|tuberous-sclerosis}}
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| *[https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=tuberous-sclerosisa GeneReview/NCBI/NIH/UW entry on Tuberous Sclerosis Complex]
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| {{Diseases of the skin and appendages by morphology}}
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| {{Phakomatoses}}
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| {{Deficiencies of intracellular signaling peptides and proteins}}
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| {{Use dmy dates|date=January 2011}}
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| {{Authority control}}
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| {{DEFAULTSORT:Tuberous Sclerosis}}
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| [[Category:Autosomal dominant disorders]]
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| [[Category:Genodermatoses]]
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| [[Category:Rare diseases]]
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| [[Category:Biology of attention deficit hyperactivity disorder]]
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| [[Category:Autism]]
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| [[Category:Intellectual disability]]
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| [[Category:Biology of obsessive–compulsive disorder]]
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| [[Category:Disorders causing seizures]]
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