Tuberous sclerosis
Classification & external resources

Earliest illustration, from Rayer's atlas of skin diseases, 1835.
ICD-10	Q85.1
ICD-9	759.5
OMIM	191100
DiseasesDB	13433
MedlinePlus	000787
eMedicine	neuro/386  derm/438 ped/2796 radio/723
MeSH	D014402

Tuberous sclerosis is a rare genetic disorder characterized by a triad of signs: seizures, mental retardation, and small benign facial skin tumors (angiofibromas). The name, composed of the Latin tuber (swelling) and the Greek skleros (hard), refers to the pathological finding of thick, firm and pale gyri, called "tubers", in the brains of patients postmortem. The acronym for Tuberous Sclerosis is TSC (Tuberous Sclerosis Complex), to avoid confusion with Tourette syndrome. Image File history File links Size of this preview: 552 × 600 pixel Image in higher resolution (2772 × 3012 pixel, file size: 1. ... Pierre Rayer (March 8, 1793 - September 10, 1867) was a French dermatologist whose career spanned over several fields. ... The International Statistical Classification of Diseases and Related Health Problems (commonly known by the abbreviation ICD) provides codes to classify diseases and a wide variety of signs, symptoms, abnormal findings, complaints, social circumstances and external causes of injury or disease. ... The following codes are used with International Statistical Classification of Diseases and Related Health Problems. ... // Q00-Q99 - Congenital malformations, deformations and chromosomal abnormalities (Q00-Q07) Congenital malformations of the nervous system (Q00) Anencephaly and similar malformations (Q01) Encephalocele (Q02) Microcephaly (Q03) Congenital hydrocephalus (Q04) Other congenital malformations of brain (Q05) Spina bifida (Q06) Other congenital malformations of spinal cord (Q07) Other congenital malformations of nervous... The International Statistical Classification of Diseases and Related Health Problems (commonly known by the abbreviation ICD) provides codes to classify diseases and a wide variety of signs, symptoms, abnormal findings, complaints, social circumstances and external causes of injury or disease. ... The following is a list of codes for International Statistical Classification of Diseases and Related Health Problems. ... The Mendelian Inheritance in Man project is a database that catalogues all the known diseases with a genetic component, and - when possible - links them to the relevant genes in the human genome. ... The Disease Bold textDatabase is a free website that provides information about the relationships between medical conditions, symptoms, and medications. ... MedlinePlus (medlineplus. ... eMedicine is an online clinical medical knowledge base that was founded in 1996. ... Medical Subject Headings (MeSH) is a huge controlled vocabulary (or metadata system) for the purpose of indexing journal articles and books in the life sciences. ... A genetic disorder, or genetic disease, is a condition caused by abnormal expression of one or more genes resulting in a clinical phenotype. ... This article is about the medical term, epileptic seizure, as distinct from psychogenic non-epileptic seizure. ... Mental retardation is a term for a pattern of persistently slow learning of basic motor and language skills (milestones) during childhood, and a significantly below-normal global intellectual capacity as an adult. ... Tumor (American English) or tumour (British English) originally means swelling, and is sometimes still used with that meaning. ... Soft Fibroma (fibroma molle). ... Pathology (in ancient Greek pathos = pain/pation and logos = word) is the study of diseases. ... Grays FIG. 726– Lateral surface of left cerebral hemisphere, viewed from the side. ... This page is a candidate to be moved to Wiktionary. ... For the Nirvana song, see tourettes (song). ...

The disease is caused by the proliferation of small benign tumors in the brain, as well as on the face and eyes, and in the kidneys, lungs, and other organs. Seizures and mental retardation are associated with the disturbance in brain function. Tumor (American English) or tumour (British English) originally means swelling, and is sometimes still used with that meaning. ...

Tuberous sclerosis was traditionally considered one of a family of disorders called neurocutaneous syndromes, or phakomatoses; however this nomenclature has lost support, since distinct genetic causes have been found for the various disorders. (Other disorders included in this family were Neurofibromatosis type I, Neurofibromatosis type II (a.k.a. MISME syndrome), Sturge-Weber, and Von Hippel-Lindau.) Phakomatoses (or neurocutaneous syndromes) are diseases that are caused by neurological disorders, and primarily result in lesions on the skin and the retina. ... Phakomatoses (or neurocutaneous syndromes) are diseases that are caused by neurological disorders, and primarily result in lesions on the skin and the retina. ... Neurofibromatosis type I (NF-1), also known as von Recklinghausen syndrome, comprises, along with neurofibromatosis type II (a. ... Neurofibromatosis Type II (or MISME Syndrome, for Multiple Inherited Schwannomas, Meningiomas, and Ependymomas) is an inherited disease. ... To meet Wikipedias quality standards, this article or section may require cleanup. ... Von Hippel-Lindau disease (VHL) is a rare inherited genetic condition involving the abnormal growth of tumors in parts of the body which are particularly rich in blood supply. ...

History

Main article: Timeline of tuberous sclerosis

Désiré-Magloire Bourneville

Tuberous sclerosis first came to medical attention when dermatologists described the distinctive facial tumors (1835 and 1850). A more complete case was presented by von Recklinghausen (1862) who identified heart and brain tumours in a newborn that had only briefly lived. However, Bourneville (1880) is generally credited with having first characterized the disease, and he coined the name tuberous sclerosis. The neurologist Vogt (1908) established a diagnostic triad of epilepsy, idiocy, and adenoma sebaceum (an obsolete term for facial angiofibroma).^[1] Désiré-Magloire Bourneville The timeline of tuberous sclerosis discovery and research stretches over less than 200 years. ... Image File history File links Size of this preview: 585 × 600 pixel Image in higher resolution (878 × 900 pixel, file size: 276 KB, MIME type: image/jpeg) العربية | Česky | Deutsch | English | Ελληνικά | Español | فارسی | Français | עברית | Indonesian | Italiano | 日本語 | 한국어 | Magyar | Nederlands | Polski | Português | Românǎ | Русский | Slovenščina | Српски | Sunda | 简体中文 | 正體中文 | Türkçe | Русский | Українська +/- File... Image File history File links Size of this preview: 585 × 600 pixel Image in higher resolution (878 × 900 pixel, file size: 276 KB, MIME type: image/jpeg) العربية | Česky | Deutsch | English | Ελληνικά | Español | فارسی | Français | עברית | Indonesian | Italiano | 日本語 | 한국어 | Magyar | Nederlands | Polski | Português | Românǎ | Русский | Slovenščina | Српски | Sunda | 简体中文 | 正體中文 | Türkçe | Русский | Українська +/- File... In 1882 Frederich Daniel von Recklinghausen released a monograph which reviewed previous literature and characterized the tumors of Neurofibromatosis 1 or NF-1 as neurofibromas, consisting of an intense commingling of nerve cells and fibrous tissue ... Désiré-Magloire Bourneville Désiré-Magloire Bourneville (October 20, 1840 - May 28, 1909), was a French neurologist. ... Heinrich Vogt (1875-04-23, Regensburg – 1936, Bad Pyrmont) was a German neurologist. ...

Symptoms were periodically added to the clinical picture. The disease as presently understood was first fully described by Gomez (1979). The invention of medical ultrasound, CT and MRI has allowed physicians to examine the internal organs of live patients and greatly improved diagnostic ability. Manuel Rodríguez Gómez (1928-07-04 – 2006-01-21) was an American neurologist most noted for his work on tuberous sclerosis, a rare genetic disorder. ... Medical ultrasonography (sonography) is an ultrasound-based diagnostic imaging technique used to visualize muscles and internal organs, their size, structures and possible pathologies or lesions. ... This article does not cite its references or sources. ... For the scientific journal entitled Magnetic Resonance Imaging, see Magnetic Resonance Imaging (journal). ...

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.^[1] The proteins associated with TSC1 and TSC2, Harmartin and Tuberin, function as a complex in the signalling pathway that regulates cell division (see below). 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 Tuberous Sclerosis.^[2] Sirolimus is a relatively new immunosuppressant drug used to prevent rejection in organ transplantation, and is especially useful in kidney transplants. ...

Pathophysiology

Tuberous sclerosis is inherited in an autosomal dominant fashion.

Small benign tumors grow on the face and eyes, as well as in the brain, kidneys, lungs and other organs. One third of all cases are inherited; they show an autosomal dominant pattern of inheritance, and penetrance is 100%. Based on this inheritance, the disease has been mapped to two genetic loci, TSC1 and TSC2. However, current genetic tests have difficulty locating the mutation in approximately 20% of individuals diagnosed with the disease. Image File history File links Autodominant. ... Image File history File links Autodominant. ... It has been suggested that this article or section be merged into Dominance relationship. ... It has been suggested that this article or section be merged into Dominance relationship. ... Penetrance is a term used in genetics that describes the extent to which the properties controlled by a gene, its phenotype, will be expressed. ...

Of the two loci, TSC2 has been associated with a more severe form of TSC.^[3] 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%.^[4]

TSC2 is located on chromosome 16 p13.3 and encodes for the protein Tuberin. It was discovered in 1993.^[5] TSC1 is located on chromosome 9 q34 and encodes for the protein Hamartin. It was discovered in 1997.^[6] Chromosome 16 is one of the 23 pairs of chromosomes in humans. ... Chromosome 9 is one of the 23 pairs of chromosomes in humans. ...

Hamartin and Tuberin function as a complex which is involved in the control of cell division. (The complex appears to be a Rheb GTPase which suppresses 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 division, and therefore a predisposition to forming tumors. The characteristic facial tumors usually have a butterfly distribution, which suggests that exposure to sunlight may be the precipitating factor in skin tumor formation. Rheb is a recently discovered member of the Ras superfamily that may be involved in neural plasticity. ... GTPases are a large family of enzymes that can bind and hydrolyze GTP. The GTP binding and hydrolysis takes place in the highly conserved G domain common to all GTPases. ... The mammalian target of rapamycin is commonly known as mTOR. It is a serine/threonine kinase that regulates translation and cell division. ... Growth factor is a protein that acts as a signaling molecule between cells (like cytokines and hormones) that attaches to specific receptors on the surface of a target cell and promotes differentiation and maturation of these cells. ... Insulin (from Latin insula, island, as it is produced in the Islets of Langerhans in the pancreas) is a polypeptide hormone that regulates carbohydrate metabolism. ... Malar rash is also called as the butterfly rash. ...

TSC1 and TSC2 are both tumor suppressor genes that function according to Knudson's "two hit" hypothesis. That is, a second random mutation must occur before a tumor can develop. This explains the wide expressivity of the disease. A tumor suppressor gene is a gene that reduces the probability that a cell in a multicellular organism will turn into a tumor cell. ... The Knudson hypothesis is the hypothesis that cancer is the result of accumulated mutations to a cells DNA. It was first proposed by Carl O. Nordling in 1953, [1][2] and later formulated by Alfred G. Knudson in 1971. ... Expressivity refers to variations of a phenotype in genetics. ...

TSC2 is contiguous with PKD1, the gene involved in one form of polycystic kidney disease (PKD). Gross deletions affecting both genes may account for the 2% of individuals with TSC who also develop PKD in childhood.^[7] Polycystic kidney disease (PKD) is a progressive, genetic disorder of the kidneys. ... A genetic deletion is a genetic aberration in which part of a chromosome is missing. ...

Hugo is a masculine name. ... The Entrez logo The Entrez Global Query Cross-Database Search System allows access to databases at the National Center for Biotechnology Information (NCBI) website. ... The Mendelian Inheritance in Man project is a database that catalogues all the known diseases with a genetic component, and - when possible - links them to the relevant genes in the human genome. ... The National Center for Biotechnology Information (NCBI) is part of the US National Library of Medicine (NLM), which is a branch of the US National Institutes of Health. ... Swiss-Prot is a curated biological database of protein sequences created in 1986 by Amos Bairoch during his PhD and developed by the Swiss Institute of Bioinformatics and the European Bioinformatics Institute. ... Short and long arms Chromosome. ... Chromosome 9 is one of the 23 pairs of chromosomes in humans. ... Hugo is a masculine name. ... The Entrez logo The Entrez Global Query Cross-Database Search System allows access to databases at the National Center for Biotechnology Information (NCBI) website. ... The Mendelian Inheritance in Man project is a database that catalogues all the known diseases with a genetic component, and - when possible - links them to the relevant genes in the human genome. ... The National Center for Biotechnology Information (NCBI) is part of the US National Library of Medicine (NLM), which is a branch of the US National Institutes of Health. ... Swiss-Prot is a curated biological database of protein sequences created in 1986 by Amos Bairoch during his PhD and developed by the Swiss Institute of Bioinformatics and the European Bioinformatics Institute. ... Short and long arms Chromosome. ... Chromosome 16 is one of the 23 pairs of chromosomes in humans. ...

Epidemiology

Tuberous sclerosis occurs in all races and ethnic groups, and in both genders. The incidence is estimated to be between 0.1 and 0.16 cases per 1000 live births; total population prevalence is 8 to 9 cases per 100,000. These estimates are significantly higher than those produced by older studies, when tuberous sclerosis was regarded as an extremely rare disease. The reason is that the invention of CT and ultrasound scanning have enabled the diagnosis of many non-symptomatic cases. Prior to this, the diagnosis of tuberous sclerosis was largely restricted to severely affected individuals with Vogt's triad of learning disability, seizures and facial angiofribroma. The prevalence figures have steadily increased from 1:150,000 in 1956, to 1:100,000 in 1968, to 1:70,000 in 1971, to 1:34,200 in 1984, to the present figure of 1:12,500 in 1998. Whilst still regarded as a rare disease, it is common when compared to many other genetic diseases.^[8][9] In optics one considers angles of incidence. ... A live birth of a human being occurs when a fetus is expelled and separated from the mothers body and subsequently shows some sign of life, such as voluntary movement, heartbeat, or pulsation of the umbilical cord, but for however brief thistime. ... In epidemiology, the prevalence of a disease in a statistical population is defined as the ratio of the number of cases of a disease present in a statistical population at a specified time and the number of individuals in the population at that specified time. ... CAT apparatus in a hospital Computed axial tomography (CAT), computer-assisted tomography, computed tomography, CT, or body section roentgenography is the process of using digital processing to generate a three-dimensional image of the internals of an object from a large series of two-dimensional X-ray images taken around... Medical ultrasonography (sonography) is an ultrasound-based diagnostic imaging technique used to visualize muscles and internal organs, their size, structures and possible pathologies or lesions. ... A rare disease (sometimes known as an orphan disease) has such a low prevalence in a population that a doctor in a busy general practice would not expect to see more than one case a year. ...

Clinical presentation

Since the advent of CT and ultrasound diagnosis, the "classic" Vogt triad of signs is now present in only 30–50% of cases. Up to 30% of people diagnosed with TSC reportedly have normal mentation. Seizures, when present, usually begin in the first year of life. Many symptoms appear in late childhood or adulthood. A given individual diagnosed with the disease may have a variable number of the symptoms, and may experience them with varying degrees of severity. CAT apparatus in a hospital Computed axial tomography (CAT), computer-assisted tomography, computed tomography, CT, or body section roentgenography is the process of using digital processing to generate a three-dimensional image of the internals of an object from a large series of two-dimensional X-ray images taken around... Medical ultrasonography (sonography) is an ultrasound-based diagnostic imaging technique used to visualize muscles and internal organs, their size, structures and possible pathologies or lesions. ... To meet Wikipedias quality standards, this article may require cleanup. ...

Central nervous system

About 50% of people with TSC have learning difficulties ranging from mild to profound,^[10] 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.^[11] Other conditions, such as ADHD, aggression, behavioral outbursts and OCD can also occur. Lower IQ is associated with more brain involvement on MRI. The term learning disability is used to refer to socio-biological conditions that affect a persons communicative capacities and potential to learn. ... // semi-protect. ... DISCLAIMER Please remember that Wikipedia is offered for informational use only. ... For other things named OCD, see OCD (disambiguation). ...

This is a set of images from an MRI of the brain in a patient with TSC.

Classic intracranial manifestations of tuberous sclerosis include subependymal nodules and cortical/subcortical tubers.^[12] Image File history File links Please see the file description page for further information. ... Image File history File links Please see the file description page for further information. ... The mri are a fictional alien species in the Faded Sun Trilogy of C.J. Cherryh. ...

The tubers are typically triangular in configuration, with the apex pointed towards the ventricles, and are thought to represent foci of abnormal neuronal migration. The T2 signal abnormalities may subside in adulthood, but will still be visible on histopathological analysis. On magnetic resonance imaging, TSC patients can exhibit other signs consistent with abnormal neuron migration (radial white matter tracts hyperintense on T2WI, heterotopic gray matter). In ordinary English, Mr is a written abbreviation for Mister. MR can also stand for: Magnetic resonance imaging, properly abbreviated MRI Magyar Rádió, a Hungarian radio station Master of the Rolls, the presiding officer of the Civil Division of the Court of Appeal in the UK legal system Mathematical...

Subependymal nodules are composed of abnormal, swollen glial cells and bizarre multinucleated cells which are indeterminate for glial or neuronal origin. There is no interposed neural tissue. These nodules have a tendency to calcify as the patient ages. A nodule that markedly enhances and enlarges over time should be considered suspicious for transformation into a subependymal giant cell astrocytoma (SEGA). A SEGA typically develops in the region of the foramen of Monroe, in which case it is at risk of developing an obstructive hydrocephalus. The interventricular foramen (aka the foramen of Monro) joins the lateral ventricles of the brain with the anterior third ventricle. ...

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.

Kidneys

This is an image from a contrast-enhanced CT of the abdomen in another patient with TSC.

Between 60 and 80% of TSC patients have benign tumors (hamartomas) of the kidneys called angiomyolipomas (AML). These tumors are composed of vascular tissue (angio), smooth muscle (myo), and fat (lipoma). Although benign, an AML larger than 4 cm is at risk for a potentially catastrophic hemorrhage either spontaneously or with minimal trauma. AMLs are found in about 1 in 300 people without TSC. However those are usually solitary, whereas in TSC they are commonly multiple and bilateral. Image File history File links Please see the file description page for further information. ... Image File history File links Please see the file description page for further information. ... Angiomyolipoma is a benign renal lesion. ... Vascular is an adjective for the word vessel and refers to tube-like structures. ... Cultured Smooth muscle of the aorta. ... For other uses, see Fat (disambiguation). ... A lipoma is a common, benign tumor composed of fatty tissue. ...

Approximately 20-30% of people with TSC will have renal cysts, causing few problems. However, 2% may also have autosomal dominant polycystic kidney disease. It has been suggested that this article or section be merged into Dominance relationship. ... Polycystic kidney disease (PKD) is a progressive, genetic disorder of the kidneys. ...

Very rare (< 1%) problems include renal cell carcinoma and oncocytomas (benign adenomatous hamartoma).
Renal cell carcinoma, also known by a gurnistical tumor, is the most common form of kidney cancer arising from the renal tubule. ...

Lungs

This computed tomography image shows randomly arranged cysts in both lungs. The patient had TSC and a renal AML.

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. (Henske EP. Metastasis of benign tumor cells in tuberous sclerosis complex. Genes, Chromosomes & Cancer. Dec. 2003. 38(4):376-81) Image File history File links Please see the file description page for further information. ... Image File history File links Please see the file description page for further information. ... This article does not cite its references or sources. ... Lymphangioleiomyomatosis (LAM) is the result of disorderly smooth muscle proliferation throughout the bronchioles, alveolar septa, perivascular spaces, and lymphatics, resulting in the obstruction of small airways (leading to pulmonary cyst formation and pneumothorax) and lymphatics (leading to chylous pleural effusion). ...

Heart

Rhabdomyomas are benign tumors of striated heart muscle. A cardiac rhabdomyoma can be discovered using echocardiography in approximately 50% of people with TSC. However the incidence in the newborn may be as high as 90% and in adults as low as 20%. These tumors grow during the second half of pregnancy and regress after birth. Many will disappear entirely. Alternatively, the tumor size remains constant as the heart grows, which has much the same effect. A rhabdomyoma is a benign tumor of muscle. ... An echocardiogram. ...

Problems due to rhabdomyomas include obstruction, arrhythmia and a murmur. Such complications occur almost exclusively during pregnancy or within the child's first year. Cardiac arrhythmia is a group of conditions in which the muscle contraction of the heart is irregular or is faster or slower than normal. ... Murmurs are abnormal heart sounds that are produced as a result of turbulent blood flow, which is sufficient to produce audible noise. ...

Prenatal ultrasound, performed by an obstetric sonographer specializing in cardiology, can detect a rhabdomyoma after 20 weeks. This rare tumour is a strong indicator of TSC in the child, especially if there is a family history of TSC. Obstetric ultrasonograph of a fetus at 16 weeks. ...

Skin

Some form of dermatological sign (pictures) will be present in 96% of individuals with TSC. Most cause no problems but are helpful in diagnosis. Some cases may cause disfigurement, necessitating treatment. The most common skin abnormalities include:

• Facial angiofibromas: A rash of reddish spots or bumps, which appear on the nose and cheeks in a butterfly distribution.[1] They consist of blood vessels and fibrous tissue. This socially embarrassing rash starts to appear during childhood and can be removed using dermabrasion or laser treatment.
• Ungual or subungual fibromas: Small fleshy tumors that grow around and under the toenails or fingernails and may need to be surgically removed if they enlarge or cause bleeding. These are very rare in childhood but common by middle age.
• Hypomelanic macules ("ash leaf spots"): White or lighter patches of skin that may appear anywhere on the body and are caused by a lack of melanin. These are usually the only visible sign of TSC at birth. In fair-skinned individuals a Wood's lamp (ultraviolet light) may be required to see them.
• 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.

Dermabrasion involves the removal of the surface of the skin with specialist equipment and usually involves a general anaesthetic. ... The macule is the simplest dermatological lesion. ... Broadly, melanin is any of the polyacetylene, polyaniline, and polypyrrole blacks and browns or their mixed copolymers. ... A Woods lamp is a diagnostic tool used in dermatology by which ultraviolet light is shone (at a wavelength of approximately 365 nanometers) onto the skin of the patient; a technician then observes any subsequent fluorescence. ... UV redirects here. ... Cafe-au-lait spots are pigmented birthmarks. ...

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 in is in the differential diagnosis of a calcified globe mass on a CT scan. This article does not cite its references or sources. ...

Non-retinal lesions associated with TSC include

• Coloboma
• Angiofibromas of the eyelids
• Papilledema (related to hydrocephalus)

A coloboma (also part of the rare Cat Eye syndrome) is the term used to describe a hole in one of the structures of the eye, such as the lens, eyelid, iris, retina, choroid or optic disc. ... Papilledema is optic disc swelling that is caused by increased intracranial pressure. ...

Variability

Individuals with tuberous sclerosis may experience none or all of the clinical signs discussed above. The following table shows the prevalence of some of the clinical signs in individuals diagnosed with tuberous sclerosis.

The frequency of clinical signs in children with tuberous sclerosis, grouped by age^[8]

Image File history File links Size of this preview: 800 × 540 pixel Image in higher resolution (1208 × 815 pixel, file size: 32 KB, MIME type: image/png) I, the creator of this work, hereby release it into the public domain. ... Image File history File links Size of this preview: 800 × 540 pixel Image in higher resolution (1208 × 815 pixel, file size: 32 KB, MIME type: image/png) I, the creator of this work, hereby release it into the public domain. ...

Diagnosis

There are no pathognomonic clinical signs for tuberous sclerosis. Many signs are present in individuals who are healthy (although rarely), or who have another disease. A combination of signs, classified as major or minor, is required in order to establish a clinical diagnosis. Pathognomonic is a word, often used in medicine, which means characteristic or diagnostic for a particular disease. ... In medicine, a sign is a feature of disease as detected by the doctor during physical examination of a patient. ...

In infants, the first clue is often the presence of seizures, delayed development or white patches on the skin. A full clinical diagnosis involves^[15][16] A thin section of lung tissue stained with hematoxylin and eosin. ... A radiograph of a right elbow-joint Radiography is the use of certain types of electromagnetic radiation—usually ionizing—to view objects. ...

• Taking a personal and 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 non enhanced 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: The medical history of a patient (sometimes called anamnesis [1][2] ) is information gained by a physician by asking specific questions, either of the patient or of other people who know the person and can give suitable information (in this case, it is sometimes called heteroanamnesis). ... In medicine, a family history consists of information about disorders that a patients direct blood relatives have suffered from. ... A Woods lamp is a diagnostic tool used in dermatology by which ultraviolet light is shone (at a wavelength of approximately 365 nanometers) onto the skin of the patient; a technician then observes any subsequent fluorescence. ... This article does not cite its references or sources. ... The mri are a fictional alien species in the Faded Sun Trilogy of C.J. Cherryh. ... A fetus in its mothers womb, viewed in a sonogram (brightness scan) A fetus, aged 29 weeks, in a 3D ultrasound Ultrasound is sound with a frequency greater than the upper limit of human hearing, this limit being approximately 20 kilohertz (20,000 hertz). ... The echocardiogram is an ultrasound of the heart. ... The ophthalmoscope, invented by Hermann von Helmholtz, is an instrument used to examine the eye. ...

• 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, there are no simple genetic tests available to identify new cases. Nor are there any biochemical markers for the gene defects.^[8] 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 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.^[13] Genetic testing allows the genetic diagnosis of vulnerabilities to inherited diseases, and can also be used to determine a persons ancestry. ... In medicine, a biomarker is an indicator of a particular disease state or a particular state of an organism. ... The term somatic refers to the body, as distinct from some other entity, such as the mind. ... In medicine (genetics), a mosaic or mosaicism denotes the presence of two populations of cells with different genotypes in one patient, where usually one of the two is affected by a genetic disorder. ... Prenatal diagnosis is the diagnosis of disease or condition in a fetus or embryo before it is born. ... 2006 is a common year starting on Sunday of the Gregorian calendar. ... Preimplantation diagnosis is the act of checking an ovum, zygote, or blastocyst for defects or diseases by cytogenetics before implanting into a womb. ...

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 mental retardation, 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.^[15]

Leading causes of death include renal disease, brain tumour, lymphangiomyomatosis of the lung, and status epilepticus or bronchopneumonia in those with severe mental handicap.^[17] Cardiac failure due to rhabdomyomas is a risk in the fetus or neonate, but is rarely a problem subsequently. Kidney complications such as angiomyolipoma (AML) 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 AMLs.^[18] In the brain, the subependymal nodules occasionally degenerate to subependymal giant cell astrocytomas (SEGA). These may block the circulation of cerebrospinal fluid around the brain, leading to hydrocephalus.

Management

Drug therapy for some of the manifestations of TSC is currently in the developmental stage.^[19] Community TSC is a distributed computing project to find drugs to treat TSC. Volunteers are welcome. CommunityTSC Drug Design Optimization Lab (D2OL)â„¢ is a distributed computing project developed by the Rothberg Institute For Childhood Diseases to test drug candidates interaction with a target molecule that is essential to the spread of the disease under scrutiny. ...

References

1. ^ ^{a b} Curatolo (2003), chapter: "Hisorical Background".
2. ^ Rott HD, Mayer K, Walther B, Wienecke R (03 2005). Zur Geschichte der Tuberösen Sklerose (The History of Tuberous Sclerosis) (German). Tuberöse Sklerose Deutschland e.V. Retrieved on 2007-01-08.
3. ^ Dabora SL, et al (2001). "Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs". American Journal of Human Genetics 68 (1): 64-80. PMID 11112665. 
4. ^ Rendtorff ND, et al (2005). "Analysis of 65 tuberous sclerosis complex (TSC) patients by TSC2 DGGE, TSC1/TSC2 MLPA, and TSC1 long-range PCR sequencing, and report of 28 novel mutations". Human Mutation 26 (4): 374-83. PMID 16114042. 
5. ^ (1993) "Identification and characterization of the tuberous sclerosis gene on chromosome 16. The European Chromosome 16 Tuberous Sclerosis Consortium". Cell 75 (7): 1305-15. PMID 8269512. 
6. ^ van Slegtenhorst M, et al (1997). "Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34". Science 277 (5327): 805-8. PMID 9242607. 
7. ^ Brook-Carter PT, et al (1994). "Deletion of the TSC2 and PKD1 genes associated with severe infantile polycystic kidney disease--a contiguous gene syndrome". Nature Genetics 8 (4): 328-32. PMID 7894481. 
8. ^ ^{a b c} Curatolo (2003), chapter: "Diagnostic Criteria".
9. ^ O'Callaghan F (1999). "Tuberous sclerosis.". BMJ 318 (7190): 1019-20. PMID 10205080. 
10. ^ Ridler K, et al (2006). "Neuroanatomical Correlates of Memory Deficits in Tuberous Sclerosis Complex". Cerebral Cortex. PMID 16603714. 
11. ^ Harrison JE, Bolton, PF (1997). "Annotation: Tuberous sclerosis". Journal of Child Psychology and Psychiatry 38: 603-614. PMID 9315970. 
12. ^ Ridler K, et al (2004). "Standardized whole brain mapping of tubers and subependymal nodules in tuberous sclerosis complex". Journal of Child Neurology 19 (9): 658-665. PMID 15563011. 
13. ^ ^{a b} Roach E, Sparagana S (2004). "Diagnosis of tuberous sclerosis complex.". Journal of Child Neurology 19 (9): 643-9. PMID 15563009. 
14. ^ Crino P, Nathanson K, Henske E (2006). "The Tuberous Sclerosis Complex.". New England Journal of Medicine 355 (13): 1345-56. PMID 17005952. 
15. ^ ^{a b} Tuberous Sclerosis Fact Sheet. National Institute of Neurological Disorders and Stroke (2006-04-11). Retrieved on 2006-10-03.
16. ^ Summary of Clinical guidelines for the care of patients with Tuberous Sclerosis Complex. Tuberous Sclerosis Association (April 2002). Retrieved on 2006-10-03.
17. ^ Shepherd C, Gomez M, Lie J, Crowson C (1991). "Causes of death in patients with tuberous sclerosis.". Mayo Clin Proc 66 (8): 792-6. PMID 1861550. 
18. ^ Rakowski SK, Winterkorn EB, Paul E, Steele DJ, Halpern EF, Thiele EA. (2006). "Renal manifestations of tuberous sclerosis complex: Incidence, prognosis, and predictive factors.". Kidney International. PMID 17003820. 
19. ^ Yates JR. Tuberous sclerosis. Eur J Hum Genet. 2006 Jul 26; PMID 16868562

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Further reading

• Paolo Curatolo (Editor) (2003). Tuberous Sclerosis Complex : From Basic Science to Clinical Phenotypes. MacKeith Press. ISBN 1-898683-39-5. 
• NINDS Tuberous Sclerosis Information Page
• GeneReviews: Tuberous Sclerosis Complex

The National Institute of Neurological Disorders and Stroke is a part of the U.S. National Institutes of Health. ...

External links

• The HUGO Gene Nomenclature Committee web pages for TSC1 and TSC2 provide a selection of links for further genetic research.
• The Rothberg Institute For Childhood Diseases have a distributed computing project called CommunityTSC.
• The story of a mother who gave birth to a baby with tuberous sclerosis

The Human Genome Organisation (HUGO) is an organization involved in the Human Genome Project, a project about mapping the human genome. ... Distributed computing is a method of computer processing in which different parts of a program run simultaneously on two or more computers that are communicating with each other over a network. ...

Pictures

• Gross pathological hallmarks
• Adenoma sebaceum, characteristic facial rash
• Dermatlas: Images of Tuberous sclerosis

Support groups

• United Kingdom: The Tuberous Sclerosis Association. Awareness month is October.
• United States: Tuberous Sclerosis Alliance. Awareness month is May.
• Canada: Tuberous Sclerosis Canada. Awareness month is May.
• Australasia: Australasian Tuberous Sclerosis Society.
• Brazil: Associação Brasileira de Esclerose Tuberosa (Brazilian Tuberous Sclerosis Association) (Portuguese)