Tuberous sclerosis
Encyclopedia
Tuberous sclerosis or tuberous sclerosis complex (TSC) is a rare multi-system genetic disease
that causes non-malignant tumors to grow in the brain
and on other vital organs such as the kidney
s, heart
, eye
s, lung
s, and skin
. A combination of symptoms may include seizure
s, developmental delay
, behavioral problems, skin abnormalities, 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 growth suppressors
, agents that regulate cell proliferation and differentiation.
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. These tubers were first described by Désiré-Magloire Bourneville
in 1880; the cortical manifestations may sometimes still be known by the eponym
Bourneville's disease.
(malformed tissue such as the cortical tubers), hamartoma
s (benign growths such as facial angiofibroma and subependymal nodules) and, very rarely, cancerous hamartoblastomas. The effect of these on the brain leads to neurological symptoms such as seizure
s, developmental delay
and behavioral problems.
, 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
. A 2008 study reported self-injurious behavior in 10% of people with TSC. Other conditions, such as ADHD, aggression, behavioral outbursts and OCD can also occur. Lower IQ is associated with more brain involvement on MRI.
Three type of brain tumours may be associated with TSC:
i. Giant cell astrocytoma: (grows and blocks the CSF flow
leading to dilatation of ventricles causing headache
and vomiting)
ii. Cortical tubers: after which the disease is named.
iii. Sub-ependymal nodules: form in the walls of ventricles.
Classic intracranial manifestations of tuberous sclerosis include subependyma
l nodules and cortical/subcortical tubers.
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).
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 Monro
, in which case it is at risk of developing an obstructive hydrocephalus
.
A variable degree of ventricular enlargement, either obstructive (e.g. by a subependymal nodule in the region of the foramen of Monroe) or idiopathic in nature.
s (AML) frequently causing hematuria
. 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.
Approximately 20-30% of people with TSC will have renal cysts, causing few problems. However, 2% may also have autosomal dominant polycystic kidney disease
.
Very rare (< 1%) problems include renal cell carcinoma
and oncocytoma
s (benign adenomatous hamartoma).
(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.
s are benign tumors of striated 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.
Problems due to rhabdomyomas include obstruction, arrhythmia and a murmur
. Such complications occur almost exclusively during pregnancy or within the child's first year.
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.
scan.
Non-retinal lesions associated with TSC include
Tuberous sclerosis is a genetic disorder with an autosomal dominant pattern of inheritance, and penetrance
is variable. 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. TSC2 encodes for the protein Tuberin
, is located on chromosome 16 p13.3 and was discovered in 1993. 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. TSC2 has been associated with a more severe form of TSC. 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%.
TSC1 and TSC2 are both tumor suppressor gene
s that function according to 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
.
GTPase
, thus sequestering it from activating mTOR
signalling, part of the growth factor
(insulin
) signalling pathway.) Thus, mutations at the TSC1 and TSC2 loci result in a loss of control of cell growth and cell division, and therefore a predisposition to forming tumors.TSC affects tissues from different germ layers. Cutaneous and visceral lesions may occur, including adenoma sebaceum, cardiac rhabdomyomas, and renal angiomyolipomas. The central nervous system (CNS) lesions seen in this disorder include hamartomas of the cortex, hamartomas of the ventricular walls, and subependymal giant cell tumors, which typically develop in the vicinity of the foramina of Monro.
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.
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.
In infants, the first clue is often the presence of seizures, delayed development or white patches on the skin. A full clinical diagnosis involves
The various signs are then marked against the diagnostic criteria to produce a level of diagnostic certainty:
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. 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
. , preimplantation diagnosis is not widely available.
The patients usually have relapse of symptoms in the clinical course. Unless any vital function is affected, life expectancy is good. Majority of patients will require some medications to control symptoms, e.g., anti-epileptics to control seizures.
In 2010 everolimus
was approved for the treatment of subependymal giant cell astrocytoma.
Other drugs used include:
A study of 30 TSC patients in Egypt found that "...earlier age of seizures commencement (<6 months) is associated with poor seizure outcome and poor intellectual capabilities. Infantile spasms and severely epileptogenic EEG patterns are related to the poor seizure outcome, poor intellectual capabilities and autistic behavior. Higher tubers numbers is associated with poor seizure outcome and autistic behavior. Left sided tuber burden is associated with poor intellect, while frontal location is more encountered in ASD. So, close follow up for the mental development and early control of seizures are recommended in a trial to reduce the risk factors of poor outcome. Also early diagnosis of autism will allow for earlier treatment and the potential for better outcome for children with TSC."
Leading causes of death include renal disease, brain tumour, lymphangiomyomatosis of the lung, and status epilepticus or bronchopneumonia in those with severe mental handicap. 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. 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.
Detection of the disease should prompt one for genetic
counselling. It is also important to know that even though
the disease does not have a cure, symptoms can be treated
symptomatically. Hence, awareness regarding different
organ manifestations of tuberous sclerosis is important.
prevalence
is estimated to be between 10 and 16 cases per 100,000. A 1998 study estimated total population prevalence between about 7 and 12 cases per 100,000, with more than half of these cases undetected. 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 angiofibroma. The total population prevalence figures have steadily increased from 1:150,000 in 1956, to 1:100,000 in 1968, to 1:70,000 in 1971, to 1:34,200 in 1984, to the present figure of 1:12,500 in 1998. Whilst still regarded as a rare disease
, it is common when compared to many other genetic diseases.
Tuberous sclerosis first came to medical attention when dermatologists described the distinctive facial rash (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 credited with having first characterized the disease, coining the name tuberous sclerosis, thus earning the eponym
Bourneville's disease. The neurologist Vogt
(1908) established a diagnostic triad of epilepsy, idiocy, and adenoma sebaceum (an obsolete term for facial angiofibroma).
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.
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. The proteins associated with TSC1 and TSC2, harmartin and tuberin, function as a complex in the mTOR
signalling pathway that controls cell growth and cell division. The importance of this pathway in cancer therapy has stimulated further research into Tuberous Sclerosis.
In 2002, treatment with rapamycin was found to be effective at shrinking tumours in animals. This has led to human trials of rapamycin as a drug to treat several of the tumors associated with Tuberous Sclerosis.
Genetic disorder
A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....
that causes non-malignant tumors to grow in the brain
Human brain
The human brain has the same general structure as the brains of other mammals, but is over three times larger than the brain of a typical mammal with an equivalent body size. Estimates for the number of neurons in the human brain range from 80 to 120 billion...
and on other vital organs such as the kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
s, heart
Human heart
The human heart is a muscular organ that provides a continuous blood circulation through the cardiac cycle and is one of the most vital organs in the human body...
, eye
Human eye
The human eye is an organ which reacts to light for several purposes. As a conscious sense organ, the eye allows vision. Rod and cone cells in the retina allow conscious light perception and vision including color differentiation and the perception of depth...
s, lung
Human lung
The human lungs are the organs of respiration in humans. Humans have two lungs, with the left being divided into two lobes and the right into three lobes. Together, the lungs contain approximately of airways and 300 to 500 million alveoli, having a total surface area of about in...
s, and skin
Human skin
The human skin is the outer covering of the body. In humans, it is the largest organ of the integumentary system. The skin has multiple layers of ectodermal tissue and guards the underlying muscles, bones, ligaments and internal organs. Human skin is similar to that of most other mammals,...
. A combination of symptoms may include seizure
Seizure
An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...
s, developmental delay
Mental retardation
Mental retardation is a generalized disorder appearing before adulthood, characterized by significantly impaired cognitive functioning and deficits in two or more adaptive behaviors...
, behavioral problems, skin abnormalities, lung and kidney disease. TSC is caused by a mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
of either of two gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s, TSC1
TSC1
Tuberous sclerosis protein 1, also known as TSC1 or hamartin, is a human protein and gene.- Function :This peripheral membrane protein was implicated as a tumor suppressor...
and TSC2
TSC2
Tuberous sclerosis protein 2, also known as TSC2 and Tuberin, is a human protein and gene.-Interactions:TSC2 has been shown to interact with FOXO1, GSK3B, Peptidylglycine alpha-amidating monooxygenase, RAP1A, MAPK1, AKT1, AXIN1, TSC1, PTK2, Protein kinase, AMP-activated, alpha 1, YWHAZ, RPS6KA1,...
, which code for the protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s hamartin and tuberin respectively. These proteins act as tumor growth suppressors
Tumor suppressor gene
A tumor suppressor gene, or anti-oncogene, is a gene that protects a cell from one step on the path to cancer. When this gene is mutated to cause a loss or reduction in its function, the cell can progress to cancer, usually in combination with other genetic changes.-Two-hit hypothesis:Unlike...
, agents that regulate cell proliferation and differentiation.
The name, composed of the Latin tuber (swelling) and the Greek skleros (hard), refers to the pathological finding of thick, firm and pale gyri
Gyrus
A gyrus is a ridge on the cerebral cortex. It is generally surrounded by one or more sulci .-Notable gyri:* Superior frontal gyrus, lat. gyrus frontalis superior* Middle frontal gyrus, lat. gyrus frontalis medius...
, called "tubers," in the brains of patients postmortem. These tubers were first described by Désiré-Magloire Bourneville
Désiré-Magloire Bourneville
Désiré-Magloire Bourneville was a French neurologist born in Garencières. He studied medicine in Paris, and was an intern at the Salpêtrière and Bicêtre Hospitals....
in 1880; the cortical manifestations may sometimes still be known by the eponym
Eponym
An eponym is the name of a person or thing, whether real or fictitious, after which a particular place, tribe, era, discovery, or other item is named or thought to be named...
Bourneville's disease.
Signs and symptoms
The physical manifestations of tuberous sclerosis are due to the formation of hamartiaHamartia
Hamartia is a term developed by Aristotle in his work Poetics. The word hamartia is rooted in the notion of missing the mark and covers a broad spectrum that includes ignorant, mistaken, or accidental wrongdoing, as well as deliberate iniquity, error, or sin...
(malformed tissue such as the cortical tubers), hamartoma
Hamartoma
A hamartoma is a benign, focal malformation that resembles a neoplasm in the tissue of its origin. This is not a malignant tumor, and it grows at the same rate as the surrounding tissues. It is composed of tissue elements normally found at that site, but which are growing in a disorganized mass...
s (benign growths such as facial angiofibroma and subependymal nodules) and, very rarely, cancerous hamartoblastomas. The effect of these on the brain leads to neurological symptoms such as seizure
Seizure
An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...
s, developmental delay
Mental retardation
Mental retardation is a generalized disorder appearing before adulthood, characterized by significantly impaired cognitive functioning and deficits in two or more adaptive behaviors...
and behavioral problems.
Central nervous system
About 50% of people with TSC have learning difficulties ranging from mild to significant, and studies have reported that between 25% and 61% of affected individuals meet the diagnostic criteria for autism
Autism
Autism is a disorder of neural development characterized by impaired social interaction and communication, and by restricted and repetitive behavior. These signs all begin before a child is three years old. Autism affects information processing in the brain by altering how nerve cells and their...
, with an even higher proportion showing features of a broader pervasive developmental disorder
Pervasive developmental disorder
Pervasive developmental disorders is a diagnostic category refers to a group of disorders characterized by delays or impairments in communication, social behaviors, and cognitive development.Pervasive developmental disorders include Autism, Asperger's syndrome, Rett's syndrome, Childhood...
. A 2008 study reported self-injurious behavior in 10% of people with TSC. Other conditions, such as ADHD, aggression, behavioral outbursts and OCD can also occur. Lower IQ is associated with more brain involvement on MRI.
Three type of brain tumours may be associated with TSC:
i. Giant cell astrocytoma: (grows and blocks the CSF flow
leading to dilatation of ventricles causing headache
and vomiting)
ii. Cortical tubers: after which the disease is named.
iii. Sub-ependymal nodules: form in the walls of ventricles.
Classic intracranial manifestations of tuberous sclerosis include subependyma
Ependyma
Ependyma is the thin epithelial membrane lining the ventricular system of the brain and the spinal cord. Ependyma is one of the four types of neuroglia in the central nervous system. It is involved in the production of cerebrospinal fluid ....
l nodules and cortical/subcortical tubers.
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
MR
MR, Mr, mr, or mR may refer to:*Mr. an honorific title of menPlaces:* Morocco country code * Martinique country code...
, TSC patients can exhibit other signs consistent with abnormal neuron migration (radial white matter tracts hyperintense on T2WI, heterotopic gray matter).
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 Monro
Interventricular foramina
In the brain, the interventricular foramina are channels that connect the paired lateral ventricles with the third ventricle at the midline of the brain. As channels, they allow cerebrospinal fluid produced in the lateral ventricles to reach the third ventricle and then the rest of the brain's...
, in which case it is at risk of developing an obstructive hydrocephalus
Hydrocephalus
Hydrocephalus , also known as "water in the brain," is a medical condition in which there is an abnormal accumulation of cerebrospinal fluid in the ventricles, or cavities, of the brain. This may cause increased intracranial pressure inside the skull and progressive enlargement of the head,...
.
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
Between 60 and 80% of TSC patients have benign tumors (once thought hamartomatous, but now considered true neoplasms) of the kidneys called angiomyolipomaAngiomyolipoma
Angiomyolipoma are the most common benign tumour of the kidney and are composed of blood vessels, smooth muscle cells and fat cells. Angiomyolipoma are strongly associated with the genetic disease tuberous sclerosis, in which most individuals will have several angiomyolipoma affecting both kidneys...
s (AML) frequently causing hematuria
Hematuria
In medicine, hematuria, or haematuria, is the presence of red blood cells in the urine. It may be idiopathic and/or benign, or it can be a sign that there is a kidney stone or a tumor in the urinary tract , ranging from trivial to lethal...
. These tumors are composed of vascular
Blood vessel
The blood vessels are the part of the circulatory system that transports blood throughout the body. There are three major types of blood vessels: the arteries, which carry the blood away from the heart; the capillaries, which enable the actual exchange of water and chemicals between the blood and...
tissue (angio–), smooth muscle
Smooth muscle
Smooth muscle is an involuntary non-striated muscle. It is divided into two sub-groups; the single-unit and multiunit smooth muscle. Within single-unit smooth muscle tissues, the autonomic nervous system innervates a single cell within a sheet or bundle and the action potential is propagated by...
(–myo–), and fat
Fat
Fats consist of a wide group of compounds that are generally soluble in organic solvents and generally insoluble in water. Chemically, fats are triglycerides, triesters of glycerol and any of several fatty acids. Fats may be either solid or liquid at room temperature, depending on their structure...
(–lipoma
Lipoma
A lipoma is a benign tumor composed of adipose tissue. It is the most common form of soft tissue tumor. Lipomas are soft to the touch, usually movable, and are generally painless. Many lipomas are small but can enlarge to sizes greater than six centimeters. Lipomas are commonly found in adults...
). 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.
Approximately 20-30% of people with TSC will have renal cysts, causing few problems. However, 2% may also have autosomal dominant polycystic kidney disease
Polycystic kidney disease
Autosomal dominant polycystic kidney disease is an inherited systemic disorder that predominantly affects the kidneys, but may affect other organs including the liver, pancreas, brain, and arterial blood vessels...
.
Very rare (< 1%) problems include renal cell carcinoma
Renal cell carcinoma
Renal cell carcinoma is a kidney cancer that originates in the lining of the proximal convoluted tubule, the very small tubes in the kidney that filter the blood and remove waste products. RCC is the most common type of kidney cancer in adults, responsible for approximately 80% of cases...
and oncocytoma
Oncocytoma
An oncocytoma is a tumor made up of oncocytes, a special kind of cells. -Presentation:An oncocytoma is an epithelial tumor composed of oncocytes, large eosinophilic cells having small, round, benign-appearing nuclei with large nucleoli....
s (benign adenomatous hamartoma).
Lungs
Patients with TSC can develop progressive replacement of the lung parenchyma with multiple cysts. This process is identical to another disease called lymphangioleiomyomatosisLymphangioleiomyomatosis
Lymphangioleiomyomatosis is a rare lung disease that results in a proliferation of disorderly smooth muscle growth throughout the lungs, in the bronchioles, alveolar septa, perivascular spaces, and lymphatics, resulting in the obstruction of small airways and lymphatics...
(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.
Heart
RhabdomyomaRhabdomyoma
A rhabdomyoma is a benign tumor of striated muscle. Rhabdomyomas may be either "cardiac" or "extracardiac" . Extracardiac forms of rhabdomyoma are subclassified into three distinct types: Adult type, Fetal type, and Genital type.Cardiac rhabdomyomas are the most common primary tumor of the heart...
s are benign tumors of striated muscle. A cardiac rhabdomyoma can be discovered using echocardiography
Echocardiography
An echocardiogram, often referred to in the medical community as a cardiac ECHO or simply an ECHO, is a sonogram of the heart . Also known as a cardiac ultrasound, it uses standard ultrasound techniques to image two-dimensional slices of the heart...
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.
Problems due to rhabdomyomas include obstruction, arrhythmia and a murmur
Heart murmur
Murmurs are extra heart sounds that are produced as a result of turbulent blood flow that is sufficient to produce audible noise. Most murmurs can only be heard with the assistance of a stethoscope ....
. Such complications occur almost exclusively during pregnancy or within the child's first year.
Prenatal ultrasound, performed by an obstetric sonographer
Obstetric ultrasonography
Obstetric sonography is the application of medical ultrasonography to obstetrics, in which sonography is used to visualize the embryo or foetus in its mother's uterus...
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.
Skin
Some form of dermatological sign 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 ("adenoma sebaceum"): A rash of reddish spots or bumps, which appear on the nose and cheeks in a butterfly distributionMalar rashIn medicine, malar rash , also called butterfly rash, is a medical sign consisting of a characteristic form of facial rash. It is often seen in Lupus erythematosus but is not pathognomonic - it is also seen in other diseases such as Pellagra, dermatomyositis and Bloom Syndrome.The malar rash of...
. They consist of blood vessels and fibrous tissue. This socially embarrassing rash starts to appear during childhood and can be removed using dermabrasionDermabrasionDermabrasion is a surgical procedure that involves the controlled abrasion of the upper layers of the skin with sandpaper or other mechanical means. Nowadays it has become common to use CO2 or Erbium:YAG laser as well. The procedure requires a local anaesthetic...
or laser treatment. - Periungual fibromas: Also known as Koenen's tumorKoenen's tumorKoenen's tumor is a cutaneous condition that results in fifty percent of tuberous sclerosis cases....
s, these are small fleshy tumors that grow around and under the toenails or fingernails and may need to be surgically removed if they enlarge or cause bleeding. These are very rare in childhood but common by middle age. - 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 melaninMelaninMelanin is a pigment that is ubiquitous in nature, being found in most organisms . In animals melanin pigments are derivatives of the amino acid tyrosine. The most common form of biological melanin is eumelanin, a brown-black polymer of dihydroxyindole carboxylic acids, and their reduced forms...
. These are usually the only visible sign of TSC at birth. In fair-skinned individuals a Wood's lamp (ultravioletUltravioletUltraviolet light is electromagnetic radiation with a wavelength shorter than that of visible light, but longer than X-rays, in the range 10 nm to 400 nm, and energies from 3 eV to 124 eV...
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, café au lait spotsCafé au lait spotCafé au lait spots or Café au lait macules are pigmented birthmarks. The name café au lait is French for "milky coffee" and refers to their light-brown color...
or flat brown marks, and poliosis, a tuft or patch of white hair on the scalp or eyelids.
Eyes
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 CTComputed tomography
X-ray computed tomography or Computer tomography , is a medical imaging method employing tomography created by computer processing...
scan.
Non-retinal lesions associated with TSC include
- ColobomaColobomaA coloboma is a hole in one of the structures of the eye, such as the iris, retina, choroid or optic disc...
- Angiofibromas of the eyelids
- PapilledemaPapilledemaPapilledema is optic disc swelling that is caused by increased intracranial pressure. The swelling is usually bilateral and can occur over a period of hours to weeks. Unilateral presentation is extremely rare....
(related to hydrocephalus)
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.Genetics
Penetrance
Penetrance in genetics is the proportion of individuals carrying a particular variant of a gene that also express an associated trait . In medical genetics, the penetrance of a disease-causing mutation is the proportion of individuals with the mutation who exhibit clinical symptoms...
is variable. 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
TSC1
Tuberous sclerosis protein 1, also known as TSC1 or hamartin, is a human protein and gene.- Function :This peripheral membrane protein was implicated as a tumor suppressor...
and TSC2
TSC2
Tuberous sclerosis protein 2, also known as TSC2 and Tuberin, is a human protein and gene.-Interactions:TSC2 has been shown to interact with FOXO1, GSK3B, Peptidylglycine alpha-amidating monooxygenase, RAP1A, MAPK1, AKT1, AXIN1, TSC1, PTK2, Protein kinase, AMP-activated, alpha 1, YWHAZ, RPS6KA1,...
.
TSC1 encodes for the protein hamartin
TSC1
Tuberous sclerosis protein 1, also known as TSC1 or hamartin, is a human protein and gene.- Function :This peripheral membrane protein was implicated as a tumor suppressor...
, is located on chromosome 9 q34 and was discovered in 1997. TSC2 encodes for the protein Tuberin
TSC2
Tuberous sclerosis protein 2, also known as TSC2 and Tuberin, is a human protein and gene.-Interactions:TSC2 has been shown to interact with FOXO1, GSK3B, Peptidylglycine alpha-amidating monooxygenase, RAP1A, MAPK1, AKT1, AXIN1, TSC1, PTK2, Protein kinase, AMP-activated, alpha 1, YWHAZ, RPS6KA1,...
, is located on chromosome 16 p13.3 and was discovered in 1993. TSC2 is contiguous with PKD1, the gene involved in one form of polycystic kidney disease
Polycystic kidney disease
Autosomal dominant polycystic kidney disease is an inherited systemic disorder that predominantly affects the kidneys, but may affect other organs including the liver, pancreas, brain, and arterial blood vessels...
(PKD). Gross deletions
Genetic deletion
In genetics, a deletion is a mutation in which a part of a chromosome or a sequence of DNA is missing. Deletion is the loss of genetic material. Any number of nucleotides can be deleted, from a single base to an entire piece of chromosome...
affecting both genes may account for the 2% of individuals with TSC who also develop PKD in childhood. TSC2 has been associated with a more severe form of TSC. 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%.
TSC1 and TSC2 are both tumor suppressor gene
Tumor suppressor gene
A tumor suppressor gene, or anti-oncogene, is a gene that protects a cell from one step on the path to cancer. When this gene is mutated to cause a loss or reduction in its function, the cell can progress to cancer, usually in combination with other genetic changes.-Two-hit hypothesis:Unlike...
s that function according to Knudson's "two hit" hypothesis
Knudson hypothesis
The Knudson hypothesis is the hypothesis that cancer is the result of accumulated mutations to a cell's DNA. It was first proposed by Carl O. Nordling in 1953, and later formulated by Alfred G. Knudson in 1971. Knudson's work led indirectly to the identification of cancer-related genes...
. That is, a second random mutation must occur before a tumor can develop. This explains why, despite its 100 percent penetrance
Penetrance
Penetrance in genetics is the proportion of individuals carrying a particular variant of a gene that also express an associated trait . In medical genetics, the penetrance of a disease-causing mutation is the proportion of individuals with the mutation who exhibit clinical symptoms...
, TSC has wide expressivity
Expressivity
Expressivity is a term used in genetics to refer to variations in a phenotype among individuals carrying a particular genotype. The term can be used to characterize qualitatively or quantitatively the extent of phenotypic variation given a particular genotype. The term is analogous to the...
.
Pathophysiology
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 RhebRHEB
GTP-binding protein Rheb also known as Ras homolog enriched in brain is a protein that in humans is encoded by the RHEB gene.- Function :Rheb is a recently discovered member of the Ras superfamily that may be involved in neural plasticity...
GTPase
GTPase
GTPases are a large family of hydrolase enzymes that can bind and hydrolyze guanosine triphosphate . The GTP binding and hydrolysis takes place in the highly conserved G domain common to all GTPases.-Functions:...
, thus sequestering it from activating mTOR
Mammalian target of rapamycin
The mammalian target of rapamycin also known as mechanistic target of rapamycin or FK506 binding protein 12-rapamycin associated protein 1 is a protein which in humans is encoded by the FRAP1 gene...
signalling, part of the growth factor
Growth factor
A growth factor is a naturally occurring substance capable of stimulating cellular growth, proliferation and cellular differentiation. Usually it is a protein or a steroid hormone. Growth factors are important for regulating a variety of cellular processes....
(insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
) signalling pathway.) Thus, mutations at the TSC1 and TSC2 loci result in a loss of control of cell growth and cell division, and therefore a predisposition to forming tumors.TSC affects tissues from different germ layers. Cutaneous and visceral lesions may occur, including adenoma sebaceum, cardiac rhabdomyomas, and renal angiomyolipomas. The central nervous system (CNS) lesions seen in this disorder include hamartomas of the cortex, hamartomas of the ventricular walls, and subependymal giant cell tumors, which typically develop in the vicinity of the foramina of Monro.
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.
Diagnosis
There are no pathognomonicPathognomonic
Pathognomonic is a term, often used in medicine, that means characteristic for a particular disease. A pathognomonic sign is a particular sign whose presence means that a particular disease is present beyond any doubt...
clinical signs
Medical sign
A medical sign is an objective indication of some medical fact or characteristic that may be detected by a physician during a physical examination of a patient....
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.
| Major Features | ||||
|---|---|---|---|---|
| Location | Sign | Onset | Note | |
| 1 | Head | Facial angiofibromas or forehead plaque | Infant – adult | |
| 2 | Fingers and toes | Nontraumatic ungual or periungual fibroma Fibroma Fibromas are benign tumors that are composed of fibrous or connective tissue. They can grow in all organs, arising from mesenchyme tissue. The term "fibroblastic" or "fibromatous" is used to describe tumors of the fibrous connective tissue... |
Adolescent – adult | |
| 3 | Skin | Hypomelanotic macules | Infant – child | More than three. |
| 4 | Skin | Shagreen patch (connective tissue Connective tissue "Connective tissue" is a fibrous tissue. It is one of the four traditional classes of tissues . Connective Tissue is found throughout the body.In fact the whole framework of the skeleton and the different specialized connective tissues from the crown of the head to the toes determine the form of... nevus Nevus Nevus is the medical term for sharply-circumscribed and chronic lesions of the skin. These lesions are commonly named birthmarks and moles. Nevi are benign by definition... ) |
Child | |
| 5 | Brain | Cortical Cortex (anatomy) In anatomy and zoology the cortex is the outermost layer of an organ. Organs with well-defined cortical layers include kidneys, adrenal glands, ovaries, the thymus, and portions of the brain, including the cerebral cortex, the most well-known of all cortices.The cerebellar cortex is the thin gray... tuber |
Fetus | |
| 6 | Brain | Subependymal Subependymal zone The subependymal zone is a cell layer surrounding the lateral ventricles in the brain. This region contains adult neural stem cells which have the potential to generate new neurons and glial cells... nodule Nodule (medicine) For use of the term nodule in dermatology, see Nodule In medicine, a nodule refers to a relatively hard, roughly spherical abnormal structure.... |
Child – adolescent | |
| 7 | Brain | Subependymal Subependymal zone The subependymal zone is a cell layer surrounding the lateral ventricles in the brain. This region contains adult neural stem cells which have the potential to generate new neurons and glial cells... giant cell astrocytoma Astrocytoma Astrocytomas are a type of neoplasm of the brain. They originate in a particular kind of glial-cells, star-shaped brain cells in the cerebrum called astrocytes. This type of tumor does not usually spread outside the brain and spinal cord and it does not usually affect other organs... |
Child – adolescent | |
| 8 | Eyes | Multiple retinal Retinal Retinal, also called retinaldehyde or vitamin A aldehyde, is one of the many forms of vitamin A . Retinal is a polyene chromophore, and bound to proteins called opsins, is the chemical basis of animal vision... nodular Nodule (medicine) For use of the term nodule in dermatology, see Nodule In medicine, a nodule refers to a relatively hard, roughly spherical abnormal structure.... hamartomas |
Infant | |
| 9 | Heart | Cardiac rhabdomyoma Rhabdomyoma A rhabdomyoma is a benign tumor of striated muscle. Rhabdomyomas may be either "cardiac" or "extracardiac" . Extracardiac forms of rhabdomyoma are subclassified into three distinct types: Adult type, Fetal type, and Genital type.Cardiac rhabdomyomas are the most common primary tumor of the heart... |
Fetus | Single or multiple. |
| 10 | Lungs | Lymphangioleiomyomatosis Lymphangioleiomyomatosis Lymphangioleiomyomatosis is a rare lung disease that results in a proliferation of disorderly smooth muscle growth throughout the lungs, in the bronchioles, alveolar septa, perivascular spaces, and lymphatics, resulting in the obstruction of small airways and lymphatics... |
Adolescent – adult | |
| 11 | Kidneys | Renal angiomyolipoma Angiomyolipoma Angiomyolipoma are the most common benign tumour of the kidney and are composed of blood vessels, smooth muscle cells and fat cells. Angiomyolipoma are strongly associated with the genetic disease tuberous sclerosis, in which most individuals will have several angiomyolipoma affecting both kidneys... |
Child – adult | 10 and 11 together count as one major feature. |
| Minor Features | ||||
| Location | Sign | Note | ||
| 12 | Teeth | Multiple randomly distributed pits in dental enamel | ||
| 13 | Rectum | Hamartomatous rectal polyps | Histologic Histology Histology is the study of the microscopic anatomy of cells and tissues of plants and animals. It is performed by examining cells and tissues commonly by sectioning and staining; followed by examination under a light microscope or electron microscope... confirmation is suggested. |
|
| 14 | Bones | Bone cysts | ||
| 15 | Brain | Cerebral white-matter "migration tracts" | Radiographic Radiography Radiography is the use of X-rays to view a non-uniformly composed material such as the human body. By using the physical properties of the ray an image can be developed which displays areas of different density and composition.... confirmation is sufficient. 5 and 15 together count as one major feature. |
|
| 16 | Gums | Gingival fibromas | ||
| 17 | Liver, spleen and other organs | Nonrenal hamartoma | Histologic confirmation is suggested. | |
| 18 | Eyes | Retinal achromic patch | ||
| 19 | Skin | "Confetti" skin lesions | ||
| 20 | Kidneys | Multiple renal cysts | Histologic confirmation is suggested. | |
In infants, the first clue is often the presence of seizures, delayed development or white patches on the skin. A full clinical diagnosis involves
- Taking a personalMedical historyThe medical history or anamnesis of a patient 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 , with the aim of obtaining information useful in formulating a diagnosis and providing...
and family historyFamily history (medicine)In medicine, a family history consists of information about disorders from which the direct blood relatives of the patient have suffered. Genealogy typically includes very little of the medical history of the family, but the medical history could be considered a specific subset of the total 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 CTComputed tomographyX-ray computed tomography or Computer tomography , is a medical imaging method employing tomography created by computer processing...
or, preferably, MRI (cortical tubers and subependymal nodules). - Renal ultrasoundUltrasoundUltrasound is cyclic sound pressure with a frequency greater than the upper limit of human hearing. Ultrasound is thus not separated from "normal" sound based on differences in physical properties, only the fact that humans cannot hear it. Although this limit varies from person to person, it is...
(angiomyolipoma or cysts). - An echocardiogram in infants (rhabdomyoma).
- Fundoscopy (retinal nodular hamartomas or achromic patch).
The various signs are then marked against the diagnostic criteria to produce a level of diagnostic certainty:
- Definite – Either two major features or one major feature plus two minor features.
- Probable – One major plus one minor feature.
- Suspect – Either one major feature or two or more minor features.
Due to the wide variety of mutations leading to TSC, there are no simple genetic tests
Genetic testing
Genetic testing is among the newest and most sophisticated of techniques used to test for genetic disorders which involves direct examination of the DNA molecule itself. Other genetic tests include biochemical tests for such gene products as enzymes and other proteins and for microscopic...
available to identify new cases. Nor are there any biochemical markers
Biomarker (medicine)
In medicine, a biomarker is a term often used to refer to a protein measured in blood whose concentration reflects the severity or presence of some disease state...
for the gene defects. 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
Somatic
The term somatic means 'of the body',, relating to the body. In medicine, somatic illness is bodily, not mental, illness. The term is often used in biology to refer to the cells of the body in contrast to the germ line cells which usually give rise to the gametes...
mosaicism
Mosaic (genetics)
In genetic medicine, a mosaic or mosaicism denotes the presence of two populations of cells with different genotypes in one individual who has developed from a single fertilized egg...
. If successful, this information can be used to identify affected family members, including prenatal diagnosis
Prenatal diagnosis
Prenatal diagnosis or prenatal screening is testing for diseases or conditions in a fetus or embryo before it is born. The aim is to detect birth defects such as neural tube defects, Down syndrome, chromosome abnormalities, genetic diseases and other conditions, such as spina bifida, cleft palate,...
. , preimplantation diagnosis is not widely available.
Management
Drug therapy for some of the manifestations of TSC is currently in the developmental stage. For example, a 2008 study found that treatment with rapamycin rescued learning and memory deficits in a mouse model of tuberous sclerosis. Community TSC is a distributed computing project to find drugs to treat TSC.The patients usually have relapse of symptoms in the clinical course. Unless any vital function is affected, life expectancy is good. Majority of patients will require some medications to control symptoms, e.g., anti-epileptics to control seizures.
In 2010 everolimus
Everolimus
Everolimus is the 40-O- derivative of sirolimus and works similarly to sirolimus as an mTOR inhibitor....
was approved for the treatment of subependymal giant cell astrocytoma.
Other drugs used include:
- VigabatrinVigabatrinVigabatrin is an antiepileptic drug that inhibits the catabolism of gamma-aminobutyric acid by irreversibly inhibiting GABA transaminase. It is an analog of GABA, but it is not a receptor agonist...
- ACTH
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.A study of 30 TSC patients in Egypt found that "...earlier age of seizures commencement (<6 months) is associated with poor seizure outcome and poor intellectual capabilities. Infantile spasms and severely epileptogenic EEG patterns are related to the poor seizure outcome, poor intellectual capabilities and autistic behavior. Higher tubers numbers is associated with poor seizure outcome and autistic behavior. Left sided tuber burden is associated with poor intellect, while frontal location is more encountered in ASD. So, close follow up for the mental development and early control of seizures are recommended in a trial to reduce the risk factors of poor outcome. Also early diagnosis of autism will allow for earlier treatment and the potential for better outcome for children with TSC."
Leading causes of death include renal disease, brain tumour, lymphangiomyomatosis of the lung, and status epilepticus or bronchopneumonia in those with severe mental handicap. 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. 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.
Detection of the disease should prompt one for genetic
counselling. It is also important to know that even though
the disease does not have a cure, symptoms can be treated
symptomatically. Hence, awareness regarding different
organ manifestations of tuberous sclerosis is important.
Epidemiology
Tuberous sclerosis occurs in all races and ethnic groups, and in both genders. The live-birthLive birth
In human reproduction, a live birth occurs when a fetus, whatever its gestational age, exits the maternal body and subsequently shows any sign of life, such as voluntary movement, heartbeat, or pulsation of the umbilical cord, for however brief a time and regardless of whether the umbilical cord or...
prevalence
Prevalence
In epidemiology, the prevalence of a health-related state in a statistical population is defined as the total number of cases of the risk factor in the population at a given time, or the total number of cases in the population, divided by the number of individuals in the population...
is estimated to be between 10 and 16 cases per 100,000. A 1998 study estimated total population prevalence between about 7 and 12 cases per 100,000, with more than half of these cases undetected. 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
Medical ultrasonography
Diagnostic sonography is an ultrasound-based diagnostic imaging technique used for visualizing subcutaneous body structures including tendons, muscles, joints, vessels and internal organs for possible pathology or lesions...
scanning have enabled the diagnosis of many non-symptomatic cases. Prior to this, the diagnosis of tuberous sclerosis was largely restricted to severely affected individuals with Vogt's triad of learning disability, seizures and facial angiofibroma. The total population prevalence figures have steadily increased from 1:150,000 in 1956, to 1:100,000 in 1968, to 1:70,000 in 1971, to 1:34,200 in 1984, to the present figure of 1:12,500 in 1998. Whilst still regarded as a rare disease
Rare disease
A rare disease, also referred to as an orphan disease, is any disease that affects a small percentage of the population.Most rare diseases are genetic, and thus are present throughout the person's entire life, even if symptoms do not immediately appear...
, it is common when compared to many other genetic diseases.
History
Friedrich Daniel von Recklinghausen
Friedrich Daniel von Recklinghausen was a German pathologist who practiced medicine in Würzburg and Strassburg . Born in Gütersloh, Westphalia, he was the father of physiologist Heinrich von Recklinghausen ....
(1862) who identified heart and brain tumours in a newborn that had only briefly lived. However, Bourneville
Désiré-Magloire Bourneville
Désiré-Magloire Bourneville was a French neurologist born in Garencières. He studied medicine in Paris, and was an intern at the Salpêtrière and Bicêtre Hospitals....
(1880) is credited with having first characterized the disease, coining the name tuberous sclerosis, thus earning the eponym
Eponym
An eponym is the name of a person or thing, whether real or fictitious, after which a particular place, tribe, era, discovery, or other item is named or thought to be named...
Bourneville's disease. The neurologist Vogt
Heinrich Vogt
Heinrich Vogt was a German neurologist. He published papers on tuberous sclerosis and Batten disease. Later he became a professor of psychiatry and published a handbook on the treatment of nervous diseases...
(1908) established a diagnostic triad of epilepsy, idiocy, and adenoma sebaceum (an obsolete term for facial angiofibroma).
Symptoms were periodically added to the clinical picture. The disease as presently understood was first fully described by Gomez
Manuel Rodríguez Gómez
Manuel Rodríguez Gómez was an American neurologist most noted for his work on tuberous sclerosis, a rare genetic disorder.-Life:...
(1979). The invention of medical ultrasound
Medical ultrasonography
Diagnostic sonography is an ultrasound-based diagnostic imaging technique used for visualizing subcutaneous body structures including tendons, muscles, joints, vessels and internal organs for possible pathology or lesions...
, CT
Computed tomography
X-ray computed tomography or Computer tomography , is a medical imaging method employing tomography created by computer processing...
and MRI
Magnetic resonance imaging
Magnetic resonance imaging , nuclear magnetic resonance imaging , or magnetic resonance tomography is a medical imaging technique used in radiology to visualize detailed internal structures...
has allowed physicians to examine the internal organs of live patients and greatly improved diagnostic ability.
Two genetic loci associated with tuberous sclerosis, TSC1 and TSC2
TSC2
Tuberous sclerosis protein 2, also known as TSC2 and Tuberin, is a human protein and gene.-Interactions:TSC2 has been shown to interact with FOXO1, GSK3B, Peptidylglycine alpha-amidating monooxygenase, RAP1A, MAPK1, AKT1, AXIN1, TSC1, PTK2, Protein kinase, AMP-activated, alpha 1, YWHAZ, RPS6KA1,...
, were discovered in 1997 and 1992 respectively. This has enabled the use of genetic testing as a diagnostic tool. The proteins associated with TSC1 and TSC2, harmartin and tuberin, function as a complex in the mTOR
Mammalian target of rapamycin
The mammalian target of rapamycin also known as mechanistic target of rapamycin or FK506 binding protein 12-rapamycin associated protein 1 is a protein which in humans is encoded by the FRAP1 gene...
signalling pathway that controls cell growth and cell division. The importance of this pathway in cancer therapy has stimulated further research into Tuberous Sclerosis.
In 2002, treatment with rapamycin was found to be effective at shrinking tumours in animals. This has led to human trials of rapamycin as a drug to treat several of the tumors associated with Tuberous Sclerosis.
External links
- GeneReview/NCBI/NIH/UW entry on Tuberous Sclerosis Complex
- The Tuberous Sclerosis Alliance in the United States offers a comprehensive Web site, online discussion groups, and free publications.
- The HUGOHuman Genome OrganisationThe Human Genome Organisation is an organization involved in the Human Genome Project, a project about mapping the human genome. HUGO was established in 1989 as an international organization, primarily to foster collaboration between genome scientists around the world...
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 computingDistributed computingDistributed computing is a field of computer science that studies distributed systems. A distributed system consists of multiple autonomous computers that communicate through a computer network. The computers interact with each other in order to achieve a common goal...
project called CommunityTSCCommunityTSCCommunityTSC Drug Design Optimization Lab , ended on April 15, 2009, was 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... - Dermatlas: Images of Tuberous sclerosis
- Mass General Hospital's Living with TSC
- The Tuberous Sclerosis Association in the UK has a comprehensive Web site