|
|
| (5 intermediate revisions by the same user not shown) |
| Line 1: |
Line 1: |
| __NOTOC__ | | __NOTOC__ |
| {{Tuberous sclerosis}} | | {{Tuberous sclerosis}} |
| {{CMG}} | | {{CMG}} {{AE}} {{Jose}} |
|
| |
|
| ==Overview== | | ==Overview== |
| Hamartin and tuberin, which are encoded by TSC1 and TSC2 genes respectively, function as a complex which is involved in the control of cell growth and cell division. (The complex appears to be a [[Rheb]] [[GTPase]] which suppresses [[Mammalian target of rapamycin|mTOR]] signaling, part of the [[growth factor]] ([[insulin]]) signaling 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. | | [[Hamartin]] and [[tuberin]], which are encoded by [[TSC1]] and [[TSC2]] [[genes]] respectively, function as a complex which is involved in the control of [[cell growth]] and [[cell division]]. 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]]. |
|
| |
|
| == Pathophysiology == | | == Pathophysiology == |
|
| |
|
| === Genetics === | | === Genetics === |
| [[Image:autodominant.jpg|thumb|left|Tuberous sclerosis is inherited in an [[autosomal dominant]] fashion.]]
| |
|
| |
|
| Tuberous sclerosis is a genetic disorder with an [[autosomal dominant]] pattern of inheritance, and [[penetrance]] is 100%.<ref>{{cite web
| | * Patients with tuberous sclerosis have loss-of-function germline [[mutations]] in one of the [[alleles]] of the following [[tumor suppressor genes]]: TSC1 or TSC2. |
| | url = http://www.geneclinics.org/profiles/tuberous-sclerosis/details.html
| | * One third of the [[mutations]] is inherited, two thirds are de novo [[mutations]]. The mutations causes the loss of one [[allele]], but as long as the second one remains intact, the cell won't present any metabolic change. |
| | title = Tuberous Sclerosis Complex
| | * When there is a second [[TSC1 (gene)|TSC1]] or [[TSC2]] mutation, which typically occurs in multiple cells over a person's lifetime, then the disease starts to manifest (fitting the "two-hit" tumor-suppressor gene model, with the germline mutation inactivating one gene and then a somatic event inactivating the remaining other one). |
| | accessdate = 2007-09-02
| | *[[TSC1 (gene)|TSC1]] codes for a protein called [[hamartin]], and [[TSC2]] codes for a protein called [[tuberin]]. |
| | author = Northrup H, Au K
| | *[[Tuberin]] and [[Hamartin]] belong to a protein complex that inhibits the [[mammalian target of rapamycin]] ([[MTORC1|mTOR]]) complex 1 via [[RAS]] homologue enriched in brain ([[RHEB]]) which regulates cell growth. |
| | date = [[5 December]] [[2005]]
| | * In a normal patient, [[RHEB]] activates [[mTORC1]] when bound to [[GTP-binding protein|GTP]], but in TSC there is a [[hyperactivation]] of [[RHEB]] and consequently of [[mTORC1]]. [[mTOR]] regulates [[cellular proliferation]], [[autophagy]], growth and protein and [[lipid synthesis]] and it enhances [[protein translation]] when activated, reprograming the [[cell metabolism]], which increases cell proliferation but also may make it vulnerable to death in nutrient-restricted media. |
| | work = GeneReviews
| | * Besides the [[TSC]]-[[RHEB]]-[[mTORC1]] pathway, there is evidence of alternate pathways also having a role in the disease that are [[mTORC1]] independent, but they are currently under investigation.<ref>{{Cite web|url=https://ghr.nlm.nih.gov/condition/tuberous-sclerosis-complex#genes|title=NIH - Tuberous Sclerosis|last=|first=|date=07/20/2020|website=NIH|archive-url=|archive-date=|dead-url=|access-date=}}</ref><ref name="pmid27226234">{{cite journal| author=Henske EP, Jóźwiak S, Kingswood JC, Sampson JR, Thiele EA| title=Tuberous sclerosis complex. | journal=Nat Rev Dis Primers | year= 2016 | volume= 2 | issue= | pages= 16035 | pmid=27226234 | doi=10.1038/nrdp.2016.35 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27226234 }}</ref> |
| }}</ref> Two thirds of TSC cases result from sporadic genetic mutations, not inheritance, but their offspring may inherit it from them. Current genetic tests have difficulty locating the mutation in approximately 20% of individuals diagnosed with the disease. So far it has been mapped to two genetic loci, TSC1 and TSC2.
| |
| | |
| TSC1 encodes for the protein '''hamartin''', is located on [[chromosome 9]] q34 and was discovered in 1997.<ref name=vanSlegtenhorst1997>{{cite journal
| |
| | author = van Slegtenhorst M, de Hoogt R, Hermans C, ''et al''
| |
| | title = Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34
| |
| | journal = Science
| |
| | volume = 277
| |
| | issue = 5327
| |
| | pages = 805-8
| |
| | year = 1997
| |
| | pmid = 9242607
| |
| }}</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
| |
| }}</ref> TSC2 is contiguous with PKD1, the gene involved in one form of [[polycystic kidney disease]] (PKD). Gross [[Genetic deletion|deletions]] affecting both genes may account for the 2% of individuals with TSC who also develop PKD in childhood.<ref name="TCS2PKD1">{{cite journal
| |
| | author=Brook-Carter PT, ''et al''
| |
| | title=Deletion of the TSC2 and PKD1 genes associated with severe infantile polycystic kidney disease--a contiguous gene syndrome
| |
| | journal = Nature Genetics | |
| | year = 1994
| |
| | pages = 328-32
| |
| | volume = 8
| |
| | issue = 4
| |
| | id = PMID 7894481}}</ref> TSC2 has been associated with a more severe form of TSC.<ref name="TSC2-severe">{{cite journal
| |
| | author=Dabora SL, ''et al''
| |
| | 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
| |
| | year = 2001
| |
| | pages = 64-80
| |
| | volume = 68
| |
| | issue = 1
| |
| | url = http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1234935&blobtype=pdf
| |
| | id = PMID 11112665}}</ref> However, the difference is subtle and cannot be used to identify the mutation clinically. Estimates of the proportion of TSC caused by TSC2 range from 55% to 80-90%.<ref name="TSC-proportion">{{cite journal
| |
| | author = Rendtorff ND, ''et al''
| |
| | 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
| |
| | year = 2005
| |
| | pages = 374-83
| |
| | volume = 26
| |
| | issue = 4
| |
| | id = PMID 16114042}}</ref>
| |
| | |
| TSC1 and TSC2 are both [[tumor suppressor gene]]s that function according to [[Knudson hypothesis|Knudson's "two hit" hypothesis]]. That is, a second random mutation must occur before a tumor can develop. This explains why, despite its 100 percent [[penetrance]], TSC has wide [[expressivity]].
| |
| <table><tr><td>{{protein
| |
| | Name = Hamartin
| |
| | caption =
| |
| | image =
| |
| | width =
| |
| | HGNCid = 12362
| |
| | Symbol = TSC1
| |
| | AltSymbols =
| |
| | EntrezGene = 7248
| |
| | OMIM = 605284
| |
| | RefSeq = NM_000368
| |
| | UniProt = Q92574
| |
| | PDB =
| |
| | ECnumber =
| |
| | Chromosome = 9
| |
| | Arm = q
| |
| | Band = 34
| |
| | LocusSupplementaryData =
| |
| }}</td><td>
| |
| {{protein
| |
| | Name = Tuberin
| |
| | caption =
| |
| | image =
| |
| | width =
| |
| | HGNCid = 12363
| |
| | Symbol = TSC2
| |
| | AltSymbols =
| |
| | EntrezGene = 7249
| |
| | OMIM = 191092
| |
| | RefSeq = NM_000548
| |
| | UniProt = P49815
| |
| | PDB =
| |
| | ECnumber =
| |
| | Chromosome = 16
| |
| | Arm = p
| |
| | Band = 13.3
| |
| | LocusSupplementaryData =
| |
| }}</td></tr></table>
| |
| | |
| == Pathology ==
| |
| ==== Skin ====
| |
| Some form of '''dermatological sign''' will be present in 96% of individuals with TSC. The most common skin abnormalities include:
| |
| * '''Facial angiofibromas''': A rash of reddish spots or bumps, which appear on the nose and cheeks in a [[malar rash|butterfly distribution]]. They consist of blood vessels and fibrous tissue. It starts to appear during childhood.
| |
| * '''Ungual''' or '''subungual fibromas''': Small fleshy tumors that grow around and under the toenails or fingernailsThese are very rare in childhood but common by middle age.
| |
| * '''Hypomelanic [[macules]]''' ("ash leaf spots"): White or lighter patches of skin that may appear anywhere on the body and are caused by a lack of [[melanin]]. These are usually the only visible sign of TSC at birth.
| |
| * '''Forehead plaques''': Raised, discolored areas on the forehead. | |
| * '''Shagreen patches''': Areas of thick leathery skin that are dimpled like an orange peel, usually found on the lower back or nape of the neck.
| |
| * Other skin features are not unique to individuals with TSC, including '''molluscum fibrosum''' or skin tags, which typically occur across the back of the neck and shoulders, '''[[cafe-au-lait spots]]''' or flat brown marks, and '''poliosis''', a tuft or patch of white hair on the scalp or eyelids.
| |
| | |
| ==== Eyes ====
| |
| Retinal lesions, called astrocytic hamartomas, which appear as a greyish or yellowish-white lesion in the back of the globe on the ophthalmic examination. Astrocytic hamartomas can calcify, and is in the differential diagnosis of a calcified globe mass on a [[computed tomography|CT]] scan.
| |
| | |
| Non-retinal lesions associated with TSC include:
| |
| * [[Coloboma]]
| |
| * Angiofibromas of the eyelids
| |
| * [[Papilledema]] (related to hydrocephalus)
| |
| | |
| ==== Heart ====
| |
| [[Rhabdomyoma]]s are benign tumors of striated muscle. Most commonly they arise from the ventricular myocardium. Other sites of involvement include atria and pericardium. Their range from 1 mm to 10 cm in size. Problems due to rhabdomyomas include obstruction, [[Cardiac arrhythmia|arrhythmia]] and a [[Heart murmur|murmur]]. | |
| | |
| ==== Lung ====
| |
| Patients with TSC can develop progressive replacement of the lung parenchyma with multiple cysts. This process is identical to another disease called [[lymphangioleiomyomatosis]] (LAM). Recent genetic analysis has shown that the proliferative bronchiolar smooth muscle in tuberous sclerosis-related LAM is monoclonal '''metastasis''' from a coexisting renal angiomyolipoma. There have been cases of TSC-related LAM recurring following lung transplant. <ref name="LAM in TBS">{{ cite journal
| |
| | author = Henske EP.
| |
| | title = Metastasis of benign tumor cells in tuberous sclerosis complex
| |
| | journal = Genes, Chromosomes & Cancer
| |
| | year = 2003
| |
| | volume = 38
| |
| | issue = 4
| |
| | pages = 376-381
| |
| | id = PMID 14566858}}</ref>
| |
| | |
| ==== Kidneys ====
| |
| Between 60 and 80% of TSC patients have benign tumors (hamartomas) of the kidneys called [[angiomyolipoma]]s (AML). These tumors are composed of [[Blood vessel|vascular]] tissue (''angio–''), [[smooth muscle]] (''–myo–''), and [[fat]](''–[[lipoma]]''). Although benign, an AML larger than 4 cm is at risk for a potentially catastrophic hemorrhage either spontaneously or with minimal trauma. AMLs are found in about 1 in 300 people without TSC. However those are usually solitary, whereas in TSC they are commonly multiple and bilateral.
| |
| | |
| ====Neurologic====
| |
| Classic intracranial manifestations of tuberous sclerosis include subependymal nodules and cortical/subcortical tubers.<ref name="brain-mapping">{{ cite journal
| |
| | author = Ridler K, ''et al'' | |
| | title = Standardized whole brain mapping of tubers and subependymal nodules in tuberous sclerosis complex | |
| | journal = Journal of Child Neurology | |
| | year = 2004 | |
| | volume = 19 | |
| | issue = 9 | |
| | pages = 658-665 | |
| | id = PMID 15563011}}</ref> | |
| | |
| Subependymal nodules are composed of abnormal, swollen glial cells and bizarre multinucleated cells which are indeterminate for glial or neuronal origin. There is no interposed neural tissue. These nodules have a tendency to calcify as the patient ages. A nodule that markedly enhances and enlarges over time should be considered suspicious for transformation into a subependymal giant cell astrocytoma (SEGA). A SEGA typically develops in the region of the [[interventricular foramina|foramen of Monroe]], in which case it is at risk of developing an obstructive [[hydrocephalus]].<ref name="pmid20924998">{{cite journal |author=Grajkowska W, Kotulska K, Jurkiewicz E, Matyja E |title=Brain lesions in tuberous sclerosis complex. Review |journal=Folia Neuropathol |volume=48 |issue=3 |pages=139–49 |year=2010 |pmid=20924998 |doi= |url=}}</ref>
| |
| | |
| A variable degree of ventricular enlargement, either obstructive (e.g. by a subependymal nodule in the region of the foramen of Monroe) or idiopathic in nature.
| |
|
| |
|
| ==References== | | ==References== |