WHAT IS TUBEROUS SCLEROSIS?
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What is Tuberous Sclerosis?
Tuberous sclerosis--also called tuberous sclerosis complex (TSC)1--is a rare, multi-system genetic disease that causes benign tumors to grow in the brain and on other vital organs such as the kidneys, heart, eyes, lungs, and skin. It usually affects the central nervous system and results in a combination of symptoms including seizures, developmental delay, behavioral problems, skin abnormalities, and kidney disease.
The disorder affects as many as 25,000 to 40,000 individuals in the United States and about 1 to 2 million individuals worldwide, with an estimated prevalence of one in 6,000 newborns. TSC occurs in all races and ethnic groups, and in both genders.
The name tuberous sclerosis comes from the characteristic tuber or potato-like nodules in the brain, which calcify with age and become hard or sclerotic. The disorder--once known as epiloia or Bourneville's disease--was first identified by a French physician more than 100 years ago.
Many TSC patients show evidence of the disorder in the first year of life. However, clinical features can be subtle initially, and many signs and symptoms take years to develop. As a result, TSC can be unrecognized or misdiagnosed for years.
What causes Tuberous Sclerosis?
TSC is caused by defects, or mutations, on two genes-TSC1 and TSC2. Only one of the genes needs to be affected for TSC to be present. The TSC1 gene, discovered in 1997, is on chromosome 9 and produces a protein called hamartin. The TSC2 gene, discovered in 1993, is on chromosome 16 and produces the protein tuberin. Scientists believe these proteins act in a complex as growth suppressors by inhibiting the activation of a master, evolutionarily conserved kinase called mTOR. Loss of regulation of mTOR occurs in cells lacking either hamartin or tuberin, and this leads to abnormal differentiation and development, and to the generation of enlarged cells, as are seen in TSC brain lesions.
Is TSC inherited?
Although some individuals inherit the disorder from a parent with TSC, most cases occur as sporadic cases due to new, spontaneous mutations in TSC1 or TSC2. In this situation, neither parent has the disorder or the faulty gene(s). Instead, a faulty gene first occurs in the affected individual.
In familial cases, TSC is an autosomal dominant disorder, which means that the disorder can be transmitted directly from parent to child. In those cases, only one parent needs to have the faulty gene in order to pass it on to a child. If a parent has TSC, each offspring has a 50 percent chance of developing the disorder. Children who inherit TSC may not have the same symptoms as their parent and they may have either a milder or a more severe form of the disorder.
Rarely, individuals acquire TSC through a process called gonadal mosaicism. These patients have parents with no apparent defects in the two genes that cause the disorder. Yet these parents can have a child with TSC because a portion of one of the parent's reproductive cells (sperm or eggs) can contain the genetic mutation without the other cells of the body being involved. In cases of gonadal mosaicism, genetic testing of a blood sample might not reveal the potential for passing the disease to offspring.
What are the signs and symptoms of TSC?
TSC can affect many different systems of the body, causing a variety of signs and symptoms. Signs of the disorder vary depending on which system and which organs are involved. The natural course of TSC varies from individual to individual, with symptoms ranging from very mild to quite severe. In addition to the benign tumors that frequently occur in TSC, other common symptoms include seizures, mental retardation, behavior problems, and skin abnormalities. Tumors can grow in nearly any organ, but they most commonly occur in the brain, kidneys, heart, lungs, and skin. Malignant tumors are rare in TSC. Those that do occur primarily affect the kidneys.
Brain involvement in TSC Three types of brain lesions are seen in TSC: cortical tubers, for which the disease is named, generally form on the surface of the brain but may also appear in the deep areas of the brain: subependymal nodules (SEN), which form in the walls of the ventricles--the fluid-filled cavities of the brain; and subependymal giant-call astrocytomas (SEGA), which develop from SEN and grow such that they may block the flow of fluid within the brain, causing a buildup of fluid and pressure and leading to headaches and blurred vision.
TSC usually causes the greatest problems for those affected and their family members through effects on brain function. Most individuals with TSC will have seizures at some point during their life. Seizures of all types may occur, including infantile spasms; tonic-clonic seizures (also known as grand mal seizures); or tonic, akinetic, atypical absence, myoclonic, complex partial or generalized squires. Infantile spasms can occur as soon as the day of birth and are often difficult to recognize. Seizures can also be difficult to control by medication,and sometimes surgery or other measures are used.
Abut one-half to two-thirds of individuals with TSC have developmental delays ranging from mild learning disabilities to severe mental retardation. Behavior problems, including aggression, sudden rage, attention deficit hyperactivity disorder, acting out, obsessive-compulsive disorder, and repetitive, destructive, or self-harming behavior occur in children with TSC and can be difficult to manage. About one-third of children with TSC meet criteria for autism spectrum disorder.
Kidney problems such as cysts and angiomyolipomas occur in an estimated 70 to 80 percent of individuals with TSC, usually occurring between ages 15 and 30. Cysts are usually small, appear in limited numbers, and cause no serious problems. Approximately 2 percent of individuals with TSC develop large numbers of cysts in a pattern similar to polycystic kidney disease2 during childhood. In these cases, kidney function is compromised and kidney failure occurs. In rare instances, the cysts may bleed, leading to blood loss and anemia.
Angiomyolipomas-benign growths consisting of fatty tissue and muscle cells-are the most common kidney lesions in TSC. These growths are seen in the majority ofindividuals with TSC, but are also found in about one of every 300 people without TSC. Angiomyolipomas caused by TSC are usually found in both kidneys and in most cases they produce no symptoms. However, they can sometimes grow so large that they cause pain or kidney failure. Bleeding from angiomyolipomas may also occur, causing both pain and weakness. If severe bleeding does not stop naturally, there may severe blood loss, resulting in profound anemia and a life-threatening drop in blood pressure, warranting urgent medical attention.
Other rare kidney problems include renal cell carcinoma, developing from an angiomyolipoma, and oncocytomas, benign tumors unique to individuals with TSC.
Tumors called cardiac rhabdomyomas are often found in the hearts of infants and young children with TSC, and they are often seen on prenatal fetus ultrasound exams. If the tumors are large or there are multiple tumors, they can block circulation and cause death. However, if they do not cause problems at birth-when in most cases they are at their largest size-they usually become smaller with time and do not affect the individual in later life.
Benign tumors called phakomas are sometimes found in the eyes of individuals with TSC, appearing as white patches on the retina. Generally they do not cause vision loss or other vision problems, but they can be used to help diagnose the disease.
Additional tumors and cysts may be found in other areas of the body, including the liver, lung, and pancreas. Bone cysts, rectal polyps, gum fibromas, and dental pits may also occur.
A wide variety of skin abnormalities may occur in 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:
-Hypomelanic macules ("ash leaf spots"), which are white or lighter patches of skin that may appear anywhere on the body and are caused by a lack of skin pigment or melanin-the substance that gives skin its color.
- Reddish spots or bumps called facial angiofibromas (also called adenoma sebaceum), which appear on the face (sometimes resembling acne) and consist of blood vessels and fibrous tissue.
-Raised, discolored areas on the forehead called forehead plaques, which are common and unique to TSC and may help doctors diagnose the disorder.
-Areas of thick leathery, pebbly skin called shagreen patches, usually found on the lower back or nape of the neck.
-Small fleshy tumors called ungual orsubungual fibromas that grow around and under the toenails or fingernails and may need to be surgically removed if they enlarge or cause bleeding. These usually appear later in life, ages 20 - 50.
Other skin features that 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 spots or flat brown marks, and poliosis, a tuft or patch of white hair that may appear on the scalp or eyelids.
Lung lesions are present in about one-third of adult women with TSC and are much less commonly seen in men. Lung lesions include lymphangioleiomyomatosis (LAM) and multinodular multifocal pneumocyte hyperplasia (MMPH). LAM is a tumor-like disorder in which cells proliferate in the lungs, and there is lung destruction with cyst formation There is a range of symptoms with LAM, with many TSC individuals having no symptoms, while others suffer with breathlessness, which can progress and be severe. MMPH is a more benign tumor that occurs in men and women equally.
Thank you for reading and we appreciate all your support.
- Team Taiberius Foundation
Tuberous sclerosis--also called tuberous sclerosis complex (TSC)1--is a rare, multi-system genetic disease that causes benign tumors to grow in the brain and on other vital organs such as the kidneys, heart, eyes, lungs, and skin. It usually affects the central nervous system and results in a combination of symptoms including seizures, developmental delay, behavioral problems, skin abnormalities, and kidney disease.
The disorder affects as many as 25,000 to 40,000 individuals in the United States and about 1 to 2 million individuals worldwide, with an estimated prevalence of one in 6,000 newborns. TSC occurs in all races and ethnic groups, and in both genders.
The name tuberous sclerosis comes from the characteristic tuber or potato-like nodules in the brain, which calcify with age and become hard or sclerotic. The disorder--once known as epiloia or Bourneville's disease--was first identified by a French physician more than 100 years ago.
Many TSC patients show evidence of the disorder in the first year of life. However, clinical features can be subtle initially, and many signs and symptoms take years to develop. As a result, TSC can be unrecognized or misdiagnosed for years.
What causes Tuberous Sclerosis?
TSC is caused by defects, or mutations, on two genes-TSC1 and TSC2. Only one of the genes needs to be affected for TSC to be present. The TSC1 gene, discovered in 1997, is on chromosome 9 and produces a protein called hamartin. The TSC2 gene, discovered in 1993, is on chromosome 16 and produces the protein tuberin. Scientists believe these proteins act in a complex as growth suppressors by inhibiting the activation of a master, evolutionarily conserved kinase called mTOR. Loss of regulation of mTOR occurs in cells lacking either hamartin or tuberin, and this leads to abnormal differentiation and development, and to the generation of enlarged cells, as are seen in TSC brain lesions.
Is TSC inherited?
Although some individuals inherit the disorder from a parent with TSC, most cases occur as sporadic cases due to new, spontaneous mutations in TSC1 or TSC2. In this situation, neither parent has the disorder or the faulty gene(s). Instead, a faulty gene first occurs in the affected individual.
In familial cases, TSC is an autosomal dominant disorder, which means that the disorder can be transmitted directly from parent to child. In those cases, only one parent needs to have the faulty gene in order to pass it on to a child. If a parent has TSC, each offspring has a 50 percent chance of developing the disorder. Children who inherit TSC may not have the same symptoms as their parent and they may have either a milder or a more severe form of the disorder.
Rarely, individuals acquire TSC through a process called gonadal mosaicism. These patients have parents with no apparent defects in the two genes that cause the disorder. Yet these parents can have a child with TSC because a portion of one of the parent's reproductive cells (sperm or eggs) can contain the genetic mutation without the other cells of the body being involved. In cases of gonadal mosaicism, genetic testing of a blood sample might not reveal the potential for passing the disease to offspring.
What are the signs and symptoms of TSC?
TSC can affect many different systems of the body, causing a variety of signs and symptoms. Signs of the disorder vary depending on which system and which organs are involved. The natural course of TSC varies from individual to individual, with symptoms ranging from very mild to quite severe. In addition to the benign tumors that frequently occur in TSC, other common symptoms include seizures, mental retardation, behavior problems, and skin abnormalities. Tumors can grow in nearly any organ, but they most commonly occur in the brain, kidneys, heart, lungs, and skin. Malignant tumors are rare in TSC. Those that do occur primarily affect the kidneys.
Brain involvement in TSC Three types of brain lesions are seen in TSC: cortical tubers, for which the disease is named, generally form on the surface of the brain but may also appear in the deep areas of the brain: subependymal nodules (SEN), which form in the walls of the ventricles--the fluid-filled cavities of the brain; and subependymal giant-call astrocytomas (SEGA), which develop from SEN and grow such that they may block the flow of fluid within the brain, causing a buildup of fluid and pressure and leading to headaches and blurred vision.
TSC usually causes the greatest problems for those affected and their family members through effects on brain function. Most individuals with TSC will have seizures at some point during their life. Seizures of all types may occur, including infantile spasms; tonic-clonic seizures (also known as grand mal seizures); or tonic, akinetic, atypical absence, myoclonic, complex partial or generalized squires. Infantile spasms can occur as soon as the day of birth and are often difficult to recognize. Seizures can also be difficult to control by medication,and sometimes surgery or other measures are used.
Abut one-half to two-thirds of individuals with TSC have developmental delays ranging from mild learning disabilities to severe mental retardation. Behavior problems, including aggression, sudden rage, attention deficit hyperactivity disorder, acting out, obsessive-compulsive disorder, and repetitive, destructive, or self-harming behavior occur in children with TSC and can be difficult to manage. About one-third of children with TSC meet criteria for autism spectrum disorder.
Kidney problems such as cysts and angiomyolipomas occur in an estimated 70 to 80 percent of individuals with TSC, usually occurring between ages 15 and 30. Cysts are usually small, appear in limited numbers, and cause no serious problems. Approximately 2 percent of individuals with TSC develop large numbers of cysts in a pattern similar to polycystic kidney disease2 during childhood. In these cases, kidney function is compromised and kidney failure occurs. In rare instances, the cysts may bleed, leading to blood loss and anemia.
Angiomyolipomas-benign growths consisting of fatty tissue and muscle cells-are the most common kidney lesions in TSC. These growths are seen in the majority ofindividuals with TSC, but are also found in about one of every 300 people without TSC. Angiomyolipomas caused by TSC are usually found in both kidneys and in most cases they produce no symptoms. However, they can sometimes grow so large that they cause pain or kidney failure. Bleeding from angiomyolipomas may also occur, causing both pain and weakness. If severe bleeding does not stop naturally, there may severe blood loss, resulting in profound anemia and a life-threatening drop in blood pressure, warranting urgent medical attention.
Other rare kidney problems include renal cell carcinoma, developing from an angiomyolipoma, and oncocytomas, benign tumors unique to individuals with TSC.
Tumors called cardiac rhabdomyomas are often found in the hearts of infants and young children with TSC, and they are often seen on prenatal fetus ultrasound exams. If the tumors are large or there are multiple tumors, they can block circulation and cause death. However, if they do not cause problems at birth-when in most cases they are at their largest size-they usually become smaller with time and do not affect the individual in later life.
Benign tumors called phakomas are sometimes found in the eyes of individuals with TSC, appearing as white patches on the retina. Generally they do not cause vision loss or other vision problems, but they can be used to help diagnose the disease.
Additional tumors and cysts may be found in other areas of the body, including the liver, lung, and pancreas. Bone cysts, rectal polyps, gum fibromas, and dental pits may also occur.
A wide variety of skin abnormalities may occur in 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:
-Hypomelanic macules ("ash leaf spots"), which are white or lighter patches of skin that may appear anywhere on the body and are caused by a lack of skin pigment or melanin-the substance that gives skin its color.
- Reddish spots or bumps called facial angiofibromas (also called adenoma sebaceum), which appear on the face (sometimes resembling acne) and consist of blood vessels and fibrous tissue.
-Raised, discolored areas on the forehead called forehead plaques, which are common and unique to TSC and may help doctors diagnose the disorder.
-Areas of thick leathery, pebbly skin called shagreen patches, usually found on the lower back or nape of the neck.
-Small fleshy tumors called ungual orsubungual fibromas that grow around and under the toenails or fingernails and may need to be surgically removed if they enlarge or cause bleeding. These usually appear later in life, ages 20 - 50.
Other skin features that 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 spots or flat brown marks, and poliosis, a tuft or patch of white hair that may appear on the scalp or eyelids.
Lung lesions are present in about one-third of adult women with TSC and are much less commonly seen in men. Lung lesions include lymphangioleiomyomatosis (LAM) and multinodular multifocal pneumocyte hyperplasia (MMPH). LAM is a tumor-like disorder in which cells proliferate in the lungs, and there is lung destruction with cyst formation There is a range of symptoms with LAM, with many TSC individuals having no symptoms, while others suffer with breathlessness, which can progress and be severe. MMPH is a more benign tumor that occurs in men and women equally.
Thank you for reading and we appreciate all your support.
- Team Taiberius Foundation
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