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Overview of Testicular Cancer
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Summary Testicular cancer is an uncommon form of cancer and accounts for only 1% of all cancers in men. However, it is the most common form of cancer in men between the ages of 15 and 35. In the United States, approximately 8,850 men are diagnosed annually. About 95% of testicular cancers are germ cell tumors. Symptoms can be similar to a variety of conditions. It is one of the most treatable forms of cancer and is usually curable with surgery and sometimes radiation therapy or chemotherapy. Introduction Testicular cancer is an uncommon form of cancer that arises in the testicles (testes). The testicles are the two small, egg-shaped glands that are located within the scrotum, which is the loose sack of skin found below the penis. The testicles produce sperm and male sex hormones. Germ cells are the cells that develop into the embryo and later on become the cells that make up the reproductive system of men and women.Approximately 95% of testicular cancers are germ cell tumors. Germ cells make up the reproductive system of men and women. Most germ cell tumors occur in the testes or ovaries (gonads) or the lower back. When these tumors occur outside of the gonads, they are known as extragonadal tumors. Testicular germ cell tumors are generally split into two main subtypes: seminomas and nonseminomatous germ cell tumors (NSGCTs). NSGCTs are sometimes referred to as nonseminomas. Each type accounts for about 50% of testicular germ cell tumors. There are several different types of nonseminomas including choriocarcinoma, yolk sac tumor, embryonal carcinoma, and teratoma. The 5% of people who develop a non-germ cell tumor may develop lymphoma affecting the testicles or a sex cord-stromal tumor, which is a tumor that arises from the supportive tissues of the testicles.
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Overview of Testicular Cancer. Summary Testicular cancer is an uncommon form of cancer and accounts for only 1% of all cancers in men. However, it is the most common form of cancer in men between the ages of 15 and 35. In the United States, approximately 8,850 men are diagnosed annually. About 95% of testicular cancers are germ cell tumors. Symptoms can be similar to a variety of conditions. It is one of the most treatable forms of cancer and is usually curable with surgery and sometimes radiation therapy or chemotherapy. Introduction Testicular cancer is an uncommon form of cancer that arises in the testicles (testes). The testicles are the two small, egg-shaped glands that are located within the scrotum, which is the loose sack of skin found below the penis. The testicles produce sperm and male sex hormones. Germ cells are the cells that develop into the embryo and later on become the cells that make up the reproductive system of men and women.Approximately 95% of testicular cancers are germ cell tumors. Germ cells make up the reproductive system of men and women. Most germ cell tumors occur in the testes or ovaries (gonads) or the lower back. When these tumors occur outside of the gonads, they are known as extragonadal tumors. Testicular germ cell tumors are generally split into two main subtypes: seminomas and nonseminomatous germ cell tumors (NSGCTs). NSGCTs are sometimes referred to as nonseminomas. Each type accounts for about 50% of testicular germ cell tumors. There are several different types of nonseminomas including choriocarcinoma, yolk sac tumor, embryonal carcinoma, and teratoma. The 5% of people who develop a non-germ cell tumor may develop lymphoma affecting the testicles or a sex cord-stromal tumor, which is a tumor that arises from the supportive tissues of the testicles.
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Symptoms of Testicular Cancer
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The initial sign of a testicular tumor is often a firm, painless bump (nodule) or swelling of one testicle. Some individuals have initially developed a dull ache in the abdomen or groin region, or a feeling of heaviness in the scrotum. Sometimes, there may be a collection of fluid in testicles. Discomfort or pain in the testicles may also be present upon touch. Less often, rapid, severe pain may develop in the affected testicle. In rare instances, tenderness or enlargement of the breasts or lower back pain may occur. In about 10% of affected individuals, the initial signs or symptoms of testicular cancer will develop because the cancer has spread (metastasized) away from the testicles. This can vary depending upon the specific area of the body to which the cancer has spread. This can include a mass in the neck; a cough or difficulty breathing if affecting the lungs; bone pain if affecting the skeleton; nausea and vomiting; unintended weight loss; and gastrointestinal bleeding if affecting the area behind the duodenum, which is the first part of the small intestine (retroduodenal area).
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Symptoms of Testicular Cancer. The initial sign of a testicular tumor is often a firm, painless bump (nodule) or swelling of one testicle. Some individuals have initially developed a dull ache in the abdomen or groin region, or a feeling of heaviness in the scrotum. Sometimes, there may be a collection of fluid in testicles. Discomfort or pain in the testicles may also be present upon touch. Less often, rapid, severe pain may develop in the affected testicle. In rare instances, tenderness or enlargement of the breasts or lower back pain may occur. In about 10% of affected individuals, the initial signs or symptoms of testicular cancer will develop because the cancer has spread (metastasized) away from the testicles. This can vary depending upon the specific area of the body to which the cancer has spread. This can include a mass in the neck; a cough or difficulty breathing if affecting the lungs; bone pain if affecting the skeleton; nausea and vomiting; unintended weight loss; and gastrointestinal bleeding if affecting the area behind the duodenum, which is the first part of the small intestine (retroduodenal area).
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Causes of Testicular Cancer
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The exact, underlying cause of testicular cancer is not fully understood, and researchers speculate that multiple factors are involved in its development. These factors can include genetic, environmental, infectious, and immunologic factors. In most people, testicular cancer develops randomly without a family history (sporadically). Cancer is characterized by abnormal, uncontrolled cellular growth that forms a tumor in the testicles and can invade surrounding tissues, possibly spreading (metastasizing) to distant bodily tissues or organs via the bloodstream, the lymphatic system, or other means. In most people with testicular cancer, the cancer arises in germ cells. Although the causes and genetic aspects of testicular cancer are not fully understood, several risk factors have been identified. Risk factors are anything that increases a person’s risk of developing a condition. Having a risk factor does not mean a person will develop that condition, and people who do not have any risk factors can still develop a condition. Risk factors for testicular cancer include age; race; failure of the testicles to descend into the scrotum, a condition called cryptorchidism; a rare chromosomal disorder called Klinefelter syndrome; defective development of the testicles or ovaries (gonadal dysgenesis); and a family history of testicular cancer. Testicular cancer is more common in men between 15-35 years of age. It occurs more often in Caucasian individuals then in African or Asian Americans. Doctors do not know why cryptorchidism increases the risk of testicular cancer, but this risk remains even after the testicles are surgically lowered into the scrotum, although the risk is lower after surgery. Klinefelter syndrome is a rare chromosome abnormality that affects the development of the testicles. Genetic factors can play a role in the development of cancer. When a genetic change (variation) in a certain gene or genes occurs in greater frequency in individuals with a specific type of cancer, this may be known as a genetic predisposition. A genetic predisposition means that a person has gene(s) for a disease, but the disease will not develop unless additional genetic or environmental factors are also present. Many germ cell tumors are characterized by extra copies of chromosome 12p. Chromosomes, which are present in the nucleus of human cells, carry the genetic information. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q” and a narrowed region at which the two arms are joined (centromere). An isochromosome is an abnormal chromosome with identical arms on each side of the centromere. More specifically, in certain cases of testicular cancer, there is duplication of the short arm of chromosome 12. Some researchers suggest that this may lead to abnormal activities on genes that cause germ cells to remain as immature cells called gonocytes. This can lead to overexpression of embryonic transcription factors, which are proteins that promote tumor cell growth, cell survival, and motility. Variations in single genes is not common in testicular cancer but has been reported. The genes that are most commonly altered in germ cell tumors are KIT, TP53, KRAS/NRAS, and BRAF. KIT, KRAS/NRAS, and BRAF are oncogenes, which control and promote cell growth. TP53 is a tumor suppressor gene, which controls cell division and ensures that cells die at the proper time.The underlying genetic factors associated with testicular cancer are very complex and more research is necessary for doctors to figure out all the genetic interactions that contribute to the development of these tumors.
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Causes of Testicular Cancer. The exact, underlying cause of testicular cancer is not fully understood, and researchers speculate that multiple factors are involved in its development. These factors can include genetic, environmental, infectious, and immunologic factors. In most people, testicular cancer develops randomly without a family history (sporadically). Cancer is characterized by abnormal, uncontrolled cellular growth that forms a tumor in the testicles and can invade surrounding tissues, possibly spreading (metastasizing) to distant bodily tissues or organs via the bloodstream, the lymphatic system, or other means. In most people with testicular cancer, the cancer arises in germ cells. Although the causes and genetic aspects of testicular cancer are not fully understood, several risk factors have been identified. Risk factors are anything that increases a person’s risk of developing a condition. Having a risk factor does not mean a person will develop that condition, and people who do not have any risk factors can still develop a condition. Risk factors for testicular cancer include age; race; failure of the testicles to descend into the scrotum, a condition called cryptorchidism; a rare chromosomal disorder called Klinefelter syndrome; defective development of the testicles or ovaries (gonadal dysgenesis); and a family history of testicular cancer. Testicular cancer is more common in men between 15-35 years of age. It occurs more often in Caucasian individuals then in African or Asian Americans. Doctors do not know why cryptorchidism increases the risk of testicular cancer, but this risk remains even after the testicles are surgically lowered into the scrotum, although the risk is lower after surgery. Klinefelter syndrome is a rare chromosome abnormality that affects the development of the testicles. Genetic factors can play a role in the development of cancer. When a genetic change (variation) in a certain gene or genes occurs in greater frequency in individuals with a specific type of cancer, this may be known as a genetic predisposition. A genetic predisposition means that a person has gene(s) for a disease, but the disease will not develop unless additional genetic or environmental factors are also present. Many germ cell tumors are characterized by extra copies of chromosome 12p. Chromosomes, which are present in the nucleus of human cells, carry the genetic information. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q” and a narrowed region at which the two arms are joined (centromere). An isochromosome is an abnormal chromosome with identical arms on each side of the centromere. More specifically, in certain cases of testicular cancer, there is duplication of the short arm of chromosome 12. Some researchers suggest that this may lead to abnormal activities on genes that cause germ cells to remain as immature cells called gonocytes. This can lead to overexpression of embryonic transcription factors, which are proteins that promote tumor cell growth, cell survival, and motility. Variations in single genes is not common in testicular cancer but has been reported. The genes that are most commonly altered in germ cell tumors are KIT, TP53, KRAS/NRAS, and BRAF. KIT, KRAS/NRAS, and BRAF are oncogenes, which control and promote cell growth. TP53 is a tumor suppressor gene, which controls cell division and ensures that cells die at the proper time.The underlying genetic factors associated with testicular cancer are very complex and more research is necessary for doctors to figure out all the genetic interactions that contribute to the development of these tumors.
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Affects of Testicular Cancer
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Testicular cancer is an uncommon form of cancer and accounts for only 1% of all cancers in men. However, it is the most common form of cancer in men between the ages of 15 and 35. Approximately 8,850 men are diagnosed with testicular cancer each year in the United States.
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Affects of Testicular Cancer. Testicular cancer is an uncommon form of cancer and accounts for only 1% of all cancers in men. However, it is the most common form of cancer in men between the ages of 15 and 35. Approximately 8,850 men are diagnosed with testicular cancer each year in the United States.
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Related disorders of Testicular Cancer
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A variety of conditions can cause signs and symptoms that are similar to those seen in testicular cancer. This can include testicular torsion, epididymitis, epididymoorchitis, hydrocele, varicocele, hematoma, spermatocele, and syphilitic gumma. Testicular torsion in when a testicle rotates and twists around the spermatic cord (a collection of vessels, nerves, and ducts that runs to and from the testicles). Epididymitis is inflammation of the long, narrow, tightly coiled tube (epididymis) found behind each testicle. The epididymis carries sperm from the testicle to the spermatic duct. Epididymoorchitis is inflammation of the epididymis and the testicles. Hydrocele occurs when fluid builds up in the sac that surrounds the testicle leading to swelling and heaviness or discomfort of the affected testicle. Varicocele is the abnormal enlargement of the veins within the scrotum that can cause a feeling of discomfort or pain and impair fertility. A hematoma is a collection or small mass made up of clotted blood. A spermatocele is a noncancerous (benign) cyst that forms close to a testicle. Syphilitic gumma is a small, growth that can form in some people with syphilis.
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Related disorders of Testicular Cancer. A variety of conditions can cause signs and symptoms that are similar to those seen in testicular cancer. This can include testicular torsion, epididymitis, epididymoorchitis, hydrocele, varicocele, hematoma, spermatocele, and syphilitic gumma. Testicular torsion in when a testicle rotates and twists around the spermatic cord (a collection of vessels, nerves, and ducts that runs to and from the testicles). Epididymitis is inflammation of the long, narrow, tightly coiled tube (epididymis) found behind each testicle. The epididymis carries sperm from the testicle to the spermatic duct. Epididymoorchitis is inflammation of the epididymis and the testicles. Hydrocele occurs when fluid builds up in the sac that surrounds the testicle leading to swelling and heaviness or discomfort of the affected testicle. Varicocele is the abnormal enlargement of the veins within the scrotum that can cause a feeling of discomfort or pain and impair fertility. A hematoma is a collection or small mass made up of clotted blood. A spermatocele is a noncancerous (benign) cyst that forms close to a testicle. Syphilitic gumma is a small, growth that can form in some people with syphilis.
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Diagnosis of Testicular Cancer
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A diagnosis of testicular cancer is based on identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation, and a variety of specialized tests. It may first be suspect because of a small bump or swelling in or on the one of the testicles. Prompt diagnosis and early treatment is essential in treating testicular cancer. Clinical Testing and Workup
If testicular cancer is suspected, the affected individual will undergo a scrotal ultrasound. An ultrasound uses reflected sound waves to create pictures of internal organs and other structures and are effective at detecting small areas of cancer that are near the surface of the body (superficially located). An ultrasound of the scrotum can detect a small bump or mass. It can also detect microlithiasis, a common condition in which tiny calcium deposits build up in the testicles. Some studies have shown a strong association between microlithiasis and testicular cancer, but no causative link has been demonstrated. Routine blood tests will be performed to look for serum tumor makers. A tumor marker is a chemical substance that is elevated in the blood, urine, or body tissues when a specific type of cancer is present. Tumor markers for testicular cancer include alpha-fetoprotein, the beta subunit of human chorionic gonadotropin (beta-hCG), and lactate dehydrogenase. Positive blood tests can help to diagnosis testicular cancer but are not definitive. A diagnosis can be confirmed with the surgical removal of the affected testicle. This is called a radical orchiectomy. It also serves as the first step of treatment for testicular cancer. In some individuals, doctors may be able to perform surgery that spares the testicle such as a partial orchiectomy. Routine x-rays (radiographs) and specialized imaging techniques may be performed to determine the extent of the cancer and whether it has spread to other areas of the body. X-rays of the lungs may be recommended. Computerized tomography (CT) scanning is a specialized imaging technique that uses a computer and x-rays to create cross-sectional images of certain tissue structures. A CT scan of the abdomen and pelvic areas can reveal cancer in these areas. Staging
When an individual is diagnosed with testicular cancer, assessment is also required to determine the extent or “stage” of the disease. Staging is important to help characterize the potential disease course and determine appropriate treatment approaches. A variety of diagnostic tests may be used in staging testicular cancer (e.g., blood tests, CT scanning). Testicular cancer can be staged by the American Joint Committee on Cancer (AJCC)/the Union for International Cancer Control (UICC) system, which is based on the tumor, node, and metastasis (TNM) classification system. A simple staging system for testicular cancer is: Stage 1: Cancer affects only one testicle Stage 2: Cancer has spread beyond the testicle to the lymph nodes of the pelvis and abdomen (retroperitoneal area) Stage 3: Cancer has spread to other organs
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Diagnosis of Testicular Cancer. A diagnosis of testicular cancer is based on identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation, and a variety of specialized tests. It may first be suspect because of a small bump or swelling in or on the one of the testicles. Prompt diagnosis and early treatment is essential in treating testicular cancer. Clinical Testing and Workup
If testicular cancer is suspected, the affected individual will undergo a scrotal ultrasound. An ultrasound uses reflected sound waves to create pictures of internal organs and other structures and are effective at detecting small areas of cancer that are near the surface of the body (superficially located). An ultrasound of the scrotum can detect a small bump or mass. It can also detect microlithiasis, a common condition in which tiny calcium deposits build up in the testicles. Some studies have shown a strong association between microlithiasis and testicular cancer, but no causative link has been demonstrated. Routine blood tests will be performed to look for serum tumor makers. A tumor marker is a chemical substance that is elevated in the blood, urine, or body tissues when a specific type of cancer is present. Tumor markers for testicular cancer include alpha-fetoprotein, the beta subunit of human chorionic gonadotropin (beta-hCG), and lactate dehydrogenase. Positive blood tests can help to diagnosis testicular cancer but are not definitive. A diagnosis can be confirmed with the surgical removal of the affected testicle. This is called a radical orchiectomy. It also serves as the first step of treatment for testicular cancer. In some individuals, doctors may be able to perform surgery that spares the testicle such as a partial orchiectomy. Routine x-rays (radiographs) and specialized imaging techniques may be performed to determine the extent of the cancer and whether it has spread to other areas of the body. X-rays of the lungs may be recommended. Computerized tomography (CT) scanning is a specialized imaging technique that uses a computer and x-rays to create cross-sectional images of certain tissue structures. A CT scan of the abdomen and pelvic areas can reveal cancer in these areas. Staging
When an individual is diagnosed with testicular cancer, assessment is also required to determine the extent or “stage” of the disease. Staging is important to help characterize the potential disease course and determine appropriate treatment approaches. A variety of diagnostic tests may be used in staging testicular cancer (e.g., blood tests, CT scanning). Testicular cancer can be staged by the American Joint Committee on Cancer (AJCC)/the Union for International Cancer Control (UICC) system, which is based on the tumor, node, and metastasis (TNM) classification system. A simple staging system for testicular cancer is: Stage 1: Cancer affects only one testicle Stage 2: Cancer has spread beyond the testicle to the lymph nodes of the pelvis and abdomen (retroperitoneal area) Stage 3: Cancer has spread to other organs
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Therapies of Testicular Cancer
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Treatment
The therapeutic management of individuals with testicular cancer may require the coordinated efforts of a team of medical professionals such as physicians who specialize in the diagnosis and treatment of diseases of the urinary system (urologists), physicians who specialize in the diagnosis and treatment of cancer (medical oncologists), physicians who specialize in the diagnosis and treatment of cancer with surgery (surgical oncologists), physicians who specialize in the use of radiation therapy for treatment of cancer (radiation oncologists), oncology nurses, psychiatrists, nutritionists, and other healthcare specialists. Psychosocial support for the entire family is essential as well. Specific therapeutic procedures and interventions may vary, depending on numerous factors such as disease stage, tumor size, specific testicular cancer subtype (e.g., seminoma versus nonseminomatous germ cell tumor), degree of elevation of tumor serum markers, whether the cancer has spread to other areas of the body, an individual’s age and general health, or other elements. Decisions concerning the use of drug regimens or other treatments should be made by physicians and other members of the healthcare team in careful consultation with the patient based on the specifics of his case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.Whenever possible, a baseline sperm count and sperm banking should be offered. A baseline is a starting point used for comparison. This means, prior to diagnosis and therapy, an affected individual’s sperm levels are measured, and this baseline value is used to compare sperm levels during and after treatment. Sperm banking, also known as cryopreservation, is when the sperm is collected, frozen, and stored in case affected individuals want to use the sperm in the future. Seminomas are generally slow-growing tumors. If testicular cancer is only found in one testicle (localized) and has not spread, then surgery to remove the affected testicular is usually curative. Following surgery, doctors may recommend watchful waiting, radiation therapy, or chemotherapy. Watchful waiting means that a person will be periodically monitored by physicians to detect if the cancer returns or if symptoms develop. Because of the low chance for the cancer to return, many affected individuals decide on watchful waiting. Surgical removal of one testicle usually does not affect a man’s ability to have a child, sex drive, or ability to have an erection. The risk of infertility is associated with other treatments, specifically radiation therapy or chemotherapy. Radiation therapy uses x-rays or similar forms of radiation to directly destroy cancer cells. Chemotherapy is the use of certain medications to slow down or stop the growth of cancer cells. Cancer cells grow and divide rapidly, which makes them susceptible to chemotherapy medications. Different combinations of medications may be used; this is called a chemotherapy regimen. When radiation therapy or chemotherapy is used following surgery, this is referred to as adjuvant therapies. This is to make sure that all of the cancer cells in the body are destroyed following the surgical removal of the tumor. Chemotherapy drugs that are approved for testicular cancer include bleomycin, cisplatin, dactinomycin, vinblastine sulfate, and etoposide. Nonseminomas grow faster and are more likely to spread to other areas of the body then seminomas. They are also less responsive to radiation therapy. All individuals with nonseminomas are recommended to undergo surgical removal of the affected testicle, followed by chemotherapy. The lymph nodes in pelvic area and the abdomen (retroperitoneal area) is where testicular cancer usually spreads to first. If the cancer has not spread (metastasized) further, then the affected lymph nodes are typically treated by surgical removal (and/or radiation treatment). The surgical removal of lymph nodes may be referred to as a lymph node dissection or lymphadenectomy. This surgery is necessary for individuals with stage 2 testicular cancer and sometimes recommended for all individuals with nonseminomas. If testicular cancer returns, individuals who have not been treated with chemotherapy will undergo treatment with a chemotherapeutic regimen. If the person has already undergone chemotherapy, they will most likely be treated with a different chemotherapy regimen. The drug ifosfamide (Ifex) has been approved by the U.S. Food and Drug Administration (FDA) for use, with other drugs, to treat testicular germ cell cancer in individuals who have undergone treatment with two other types of chemotherapy.Individuals who undergo surgical removal of a testicle are offered the option of an artificial (prosthetic) testicle. Side Effects and Late Effects
The major side effect of chemotherapy or radiation therapy is the risk of infertility. The surgical removal of one testicle will not affect a person’s ability to have a child. Chemotherapy and radiation therapy both carry the risk of temporarily or permanently lowering sperm counts and causing infertility. Other common side effects include including hair loss, fatigue, and nausea and vomiting. Because many individuals are young adults when they undergo therapy, there is risk of late effects from cancer therapy. Late effects from cancer therapy refer to various issues that may develop later in life because of the chemotherapy or radiation therapy they received during childhood. These risks can include chronic fatigue; cardiovascular disease; high blood pressure (hypertension); lung disease including scarring of the lungs; reduced production of hormones by the testicles (hypogonadism), which can cause infertility and sexual dysfunction; damage to the nerves including tingling, numbness, or a burning sensation in the feet (peripheral neuropathy); reduced kidney function; hearing loss or a ringing in the ears (tinnitus); or the development of a second, different cancer later in life.
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Therapies of Testicular Cancer. Treatment
The therapeutic management of individuals with testicular cancer may require the coordinated efforts of a team of medical professionals such as physicians who specialize in the diagnosis and treatment of diseases of the urinary system (urologists), physicians who specialize in the diagnosis and treatment of cancer (medical oncologists), physicians who specialize in the diagnosis and treatment of cancer with surgery (surgical oncologists), physicians who specialize in the use of radiation therapy for treatment of cancer (radiation oncologists), oncology nurses, psychiatrists, nutritionists, and other healthcare specialists. Psychosocial support for the entire family is essential as well. Specific therapeutic procedures and interventions may vary, depending on numerous factors such as disease stage, tumor size, specific testicular cancer subtype (e.g., seminoma versus nonseminomatous germ cell tumor), degree of elevation of tumor serum markers, whether the cancer has spread to other areas of the body, an individual’s age and general health, or other elements. Decisions concerning the use of drug regimens or other treatments should be made by physicians and other members of the healthcare team in careful consultation with the patient based on the specifics of his case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.Whenever possible, a baseline sperm count and sperm banking should be offered. A baseline is a starting point used for comparison. This means, prior to diagnosis and therapy, an affected individual’s sperm levels are measured, and this baseline value is used to compare sperm levels during and after treatment. Sperm banking, also known as cryopreservation, is when the sperm is collected, frozen, and stored in case affected individuals want to use the sperm in the future. Seminomas are generally slow-growing tumors. If testicular cancer is only found in one testicle (localized) and has not spread, then surgery to remove the affected testicular is usually curative. Following surgery, doctors may recommend watchful waiting, radiation therapy, or chemotherapy. Watchful waiting means that a person will be periodically monitored by physicians to detect if the cancer returns or if symptoms develop. Because of the low chance for the cancer to return, many affected individuals decide on watchful waiting. Surgical removal of one testicle usually does not affect a man’s ability to have a child, sex drive, or ability to have an erection. The risk of infertility is associated with other treatments, specifically radiation therapy or chemotherapy. Radiation therapy uses x-rays or similar forms of radiation to directly destroy cancer cells. Chemotherapy is the use of certain medications to slow down or stop the growth of cancer cells. Cancer cells grow and divide rapidly, which makes them susceptible to chemotherapy medications. Different combinations of medications may be used; this is called a chemotherapy regimen. When radiation therapy or chemotherapy is used following surgery, this is referred to as adjuvant therapies. This is to make sure that all of the cancer cells in the body are destroyed following the surgical removal of the tumor. Chemotherapy drugs that are approved for testicular cancer include bleomycin, cisplatin, dactinomycin, vinblastine sulfate, and etoposide. Nonseminomas grow faster and are more likely to spread to other areas of the body then seminomas. They are also less responsive to radiation therapy. All individuals with nonseminomas are recommended to undergo surgical removal of the affected testicle, followed by chemotherapy. The lymph nodes in pelvic area and the abdomen (retroperitoneal area) is where testicular cancer usually spreads to first. If the cancer has not spread (metastasized) further, then the affected lymph nodes are typically treated by surgical removal (and/or radiation treatment). The surgical removal of lymph nodes may be referred to as a lymph node dissection or lymphadenectomy. This surgery is necessary for individuals with stage 2 testicular cancer and sometimes recommended for all individuals with nonseminomas. If testicular cancer returns, individuals who have not been treated with chemotherapy will undergo treatment with a chemotherapeutic regimen. If the person has already undergone chemotherapy, they will most likely be treated with a different chemotherapy regimen. The drug ifosfamide (Ifex) has been approved by the U.S. Food and Drug Administration (FDA) for use, with other drugs, to treat testicular germ cell cancer in individuals who have undergone treatment with two other types of chemotherapy.Individuals who undergo surgical removal of a testicle are offered the option of an artificial (prosthetic) testicle. Side Effects and Late Effects
The major side effect of chemotherapy or radiation therapy is the risk of infertility. The surgical removal of one testicle will not affect a person’s ability to have a child. Chemotherapy and radiation therapy both carry the risk of temporarily or permanently lowering sperm counts and causing infertility. Other common side effects include including hair loss, fatigue, and nausea and vomiting. Because many individuals are young adults when they undergo therapy, there is risk of late effects from cancer therapy. Late effects from cancer therapy refer to various issues that may develop later in life because of the chemotherapy or radiation therapy they received during childhood. These risks can include chronic fatigue; cardiovascular disease; high blood pressure (hypertension); lung disease including scarring of the lungs; reduced production of hormones by the testicles (hypogonadism), which can cause infertility and sexual dysfunction; damage to the nerves including tingling, numbness, or a burning sensation in the feet (peripheral neuropathy); reduced kidney function; hearing loss or a ringing in the ears (tinnitus); or the development of a second, different cancer later in life.
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Overview of Tethered Cord Syndrome
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Tethered cord syndrome is a stretch-induced functional disorder associated with the fixation (tethering) effect of inelastic tissue on the caudal spinal cord, limiting its movement. This abnormal attachment is associated with progressive stretching and increased tension of the spinal cord as a child ages, potentially resulting in a variety of neurological and other symptoms. Due to the variation of the growth rate of the spinal cord and the spinal column, the progression of neurological signs and symptoms is highly variable. Some individuals present with tethered cord syndrome at birth (so-called congenital), while others develop the symptomatology in infancy or early childhood. Other individuals may not develop any noticeable symptoms until adulthood. Although some authors call these cases acquired, the majority of these cases are mostly developmental, corresponding to the progressive development of excess fibrous connective tissue (fibrosis) in the filum terminale. The filum terminale is a strand of tissue that bridges the spinal cord tip and the tailbone (sacrum). The inelastic structures in children originated from defective closure of the neural tube (the precursor of the spinal cord) during embryonic development, eventually forming a condition known as spina bifida. Because of its functional (physiological) nature, tethered cord syndrome can be reversible if surgically treated in its early stage.
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Overview of Tethered Cord Syndrome. Tethered cord syndrome is a stretch-induced functional disorder associated with the fixation (tethering) effect of inelastic tissue on the caudal spinal cord, limiting its movement. This abnormal attachment is associated with progressive stretching and increased tension of the spinal cord as a child ages, potentially resulting in a variety of neurological and other symptoms. Due to the variation of the growth rate of the spinal cord and the spinal column, the progression of neurological signs and symptoms is highly variable. Some individuals present with tethered cord syndrome at birth (so-called congenital), while others develop the symptomatology in infancy or early childhood. Other individuals may not develop any noticeable symptoms until adulthood. Although some authors call these cases acquired, the majority of these cases are mostly developmental, corresponding to the progressive development of excess fibrous connective tissue (fibrosis) in the filum terminale. The filum terminale is a strand of tissue that bridges the spinal cord tip and the tailbone (sacrum). The inelastic structures in children originated from defective closure of the neural tube (the precursor of the spinal cord) during embryonic development, eventually forming a condition known as spina bifida. Because of its functional (physiological) nature, tethered cord syndrome can be reversible if surgically treated in its early stage.
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Symptoms of Tethered Cord Syndrome
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The specific symptoms, severity and progression of tethered cord syndrome vary from one individual to another. In most cases, individuals experience symptoms during childhood. In some cases, symptoms are stabilized in childhood, but become apparent only in adulthood. A high percentage of pediatric cases, with tethered cord syndrome show cutaneous tufts of hair, skin tags, dimples, benign fatty tumors, skin discoloration or hemangiomas. Additional symptoms include lower back pain that worsens with activity and improves with rest (although rarely complained by young children, because of inability to express pain), leg pain or numbness, difficulty walking (gait disturbances), foot and spinal deformities, such as abnormal side-to-side curvature of the spine (scoliosis) or hollow lowback (exaggerated lordosis), high-arched feet and hammertoes, and less commonly difference in leg strength. Tethered cord syndrome can also cause difficulties with bladder and bowel control. Affected children may experience involuntary urination or defecation (incontinence) and repeated urinary tract infections. Symptoms in children may be slowly progressive. Adult onset of tethered cord syndrome was considered to be rare for many years, but an increasing number of cases have been reported in recent years. This trend is due to improvement in neurological examinations and in the interpretation of imaging studies. Symptoms common to adult tethered cord syndrome include constant, often severe back and leg pain, which may extend to the rectum and genital area in some cases. Progressive sensory and motor deficits may affect the legs potentially resulting in numbness, weakness or muscle wasting (atrophy) in the affected areas. More than 50 percent of the affected individuals experience bladder and bowel dysfunction, manifested by increased frequency or urgency of urination or constipation. In some cases, a fluid-filled cavity (syrinx) is found, sometimes associated with typical signs and symptoms syringomyelia, such as burning pain in the analgesic (painless on examination) area, decreased motor function and loss of muscle mass, or occasional headaches,
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Symptoms of Tethered Cord Syndrome. The specific symptoms, severity and progression of tethered cord syndrome vary from one individual to another. In most cases, individuals experience symptoms during childhood. In some cases, symptoms are stabilized in childhood, but become apparent only in adulthood. A high percentage of pediatric cases, with tethered cord syndrome show cutaneous tufts of hair, skin tags, dimples, benign fatty tumors, skin discoloration or hemangiomas. Additional symptoms include lower back pain that worsens with activity and improves with rest (although rarely complained by young children, because of inability to express pain), leg pain or numbness, difficulty walking (gait disturbances), foot and spinal deformities, such as abnormal side-to-side curvature of the spine (scoliosis) or hollow lowback (exaggerated lordosis), high-arched feet and hammertoes, and less commonly difference in leg strength. Tethered cord syndrome can also cause difficulties with bladder and bowel control. Affected children may experience involuntary urination or defecation (incontinence) and repeated urinary tract infections. Symptoms in children may be slowly progressive. Adult onset of tethered cord syndrome was considered to be rare for many years, but an increasing number of cases have been reported in recent years. This trend is due to improvement in neurological examinations and in the interpretation of imaging studies. Symptoms common to adult tethered cord syndrome include constant, often severe back and leg pain, which may extend to the rectum and genital area in some cases. Progressive sensory and motor deficits may affect the legs potentially resulting in numbness, weakness or muscle wasting (atrophy) in the affected areas. More than 50 percent of the affected individuals experience bladder and bowel dysfunction, manifested by increased frequency or urgency of urination or constipation. In some cases, a fluid-filled cavity (syrinx) is found, sometimes associated with typical signs and symptoms syringomyelia, such as burning pain in the analgesic (painless on examination) area, decreased motor function and loss of muscle mass, or occasional headaches,
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Tethered Cord Syndrome
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Causes of Tethered Cord Syndrome
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Tethered cord syndrome can be of a congenital (primary) origin or acquired (secondary or developmental). Various congenital anomalies, particularly spina bifida, are often associated with congenital tethered cord syndrome. Spina bifida is a birth defect due to incomplete closure of the posterior spinal cord and bony vertebral arch (lamina). Many cases with this anomaly leave a portion of the spinal cord protruded through the spinal canal, typically forming a myelomeningocele. Such birth defects, if located in the tail (caudal) end of the spinal cord, can cause tethered cord syndrome. In others, where the anomalous structure is attached to the wide area of the spinal cord, signs and symptoms reflect local effects on the spinal cord, and not stretched-induced dysfunction (tethered cord syndrome). Types of spina bifida associated with tethered cord syndrome include an abnormal connection of inelastic tissue to the caudal spinal cord, dermal sinus tract, which extends from the intraspinal connective tissue to the skin (dermal sinus tract), a split spinal cord (diastematomyelia), and a benign fatty mass or tumor (lipoma) continuous to the spinal cord. The other fatty anomaly is a lipomyelomeningocele, in which a lipoma extrudes from the spinal canal underneath the lining of the spinal cord (meninges), but covered by normal skin.In many individuals, tethered cord syndrome is caused mechanically by an inelastic often-thickened filum terminale. This structure, which is composed of glial tissue (the supportive structure of nerve cells) and covered by pia mater, is a delicate strand of fibrous tissue, bridging the spinal cord tip and the sacrum (the tailbone). Due to its high viscoelasticity, the filum allows movement of the spinal cord. If abnormal fibrous tissue grows into the filum and replaces glial tissue, the filum loses its elasticity and abnormally fixes (tethers) the spinal cord, and becomes the mechanical cause of tethered cord syndrome. The inelastic filum is commonly thickened in children, but found less frequently in adolescents and adults.Genetic factors are involved in development of anomalous caudal spine and spinal cord, e.g. myelomeningocele, and in some cases of lipomyelomeningocele. Since tethered cord syndrome is a physiological disorder and develops only when it is abnormally stretched, it cannot be connected to genetic factors, unless the congenital susceptibility of spinal cord to oxidative metabolic impairment is proven.Secondary causes of tethered cord syndrome include tumors, infection or the development of scar tissue (fibrosis) connected to the spinal cord. Tethered cord syndrome may develop as a complication of spinal surgery. Trauma to the spine results in a band of scar formation attached to the spinal cord and can cause tethered cord syndrome. However, some researchers believe that trauma alone is not enough to cause the disorder. They propose that tethering and abnormal tension were already present before the trauma, which worsened the condition. Some researchers have speculated that some cases of tethered cord syndrome that occur due to anomalies that can cause stretching of the spinal cord may have a genetic basis or that some individuals are genetically predisposed to developing the disorder in these specific cases. Although genetic factors are found in patients with myelominingocele, more research is necessary to determine the exact role that genetic factors play in the development of stretch-causing anomalies. Pathophysiologically, neuronal dysfunction in tethered cord syndrome results partly from inability for the spinal cord neurons to utilize oxygen, that is, the impaired oxidative metabolism, partly due to lack of oxygen supply (ischemic effect), and partly to ion channel dysfunction directly related neuronal membrane stretching. The spinal cord consists of a long bundle of neuronal fibers (axons) and the interneurons that connect sensory and motor fibers within the cord. During gestation, the spinal cord is continuous to the brain and runs in the spinal canal to the tailbone area. In general, the spinal cord is protected from external insult by two mechanisms; 1) encased in the spinal column, that is, a rigid structure, 2) floating free in the spinal fluid space of the spinal canal. In addition, the spinal cord is continuous to the filum terminale, which is extremely extensible because of its high viscoelasticity. If the spinal cord is tethered at its caudal end, and if the spinal cord is unable to grow as fast as the vertebral column in childhood, the spinal cord is stretched beyond its physiological tolerance. In turn, this causes various metabolic abnormalities in the spinal cord and, ultimately, the various neurological symptoms of this disorder.Normally, the spinal cord ascends in the spinal canal as the spinal column starts to grow faster than the spinal cord at 9th weeks of gestation. Consequently, the spinal cord is pulled upwards due to this growth difference. By three months of age, the tip of the spinal cord reaches the normal level between T12 and L2 vertebrae. An elastic, extremely extensible filum allows for the ascension of the less elastic spinal cord. If the filum becomes inelastic in an embryo, then the spinal cord tip is anchored and ceases to ascend. Compensatory to the stretching force, the lower (lumbosacral) spinal cord naturally grows more than seen in normal subjects, and becomes elongated. Associated with tethered cord syndrome, the elongated cord is often noted in children, but less often in adults. In most cases, the abnormal tension of the spinal cord increases over time, but disturbing symptoms often develop quickly during a few weeks. Certain activities such as flexing or extending the lower spinal column can put additional tension on the spinal cord and often worsen tethered cord syndrome. Participation in physical activities such as strenuous sports and ballet dancing with high kicks can worsen the signs and symptoms. Special physical features such as abnormal curvature of the spine (scoliosis and exaggerated lordosis) are the potential for symptomatic acceleration. It should be warned that slight flexion of the lower (lumbosacral) spine always aggravates back pain by spinal cord stretching.
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Causes of Tethered Cord Syndrome. Tethered cord syndrome can be of a congenital (primary) origin or acquired (secondary or developmental). Various congenital anomalies, particularly spina bifida, are often associated with congenital tethered cord syndrome. Spina bifida is a birth defect due to incomplete closure of the posterior spinal cord and bony vertebral arch (lamina). Many cases with this anomaly leave a portion of the spinal cord protruded through the spinal canal, typically forming a myelomeningocele. Such birth defects, if located in the tail (caudal) end of the spinal cord, can cause tethered cord syndrome. In others, where the anomalous structure is attached to the wide area of the spinal cord, signs and symptoms reflect local effects on the spinal cord, and not stretched-induced dysfunction (tethered cord syndrome). Types of spina bifida associated with tethered cord syndrome include an abnormal connection of inelastic tissue to the caudal spinal cord, dermal sinus tract, which extends from the intraspinal connective tissue to the skin (dermal sinus tract), a split spinal cord (diastematomyelia), and a benign fatty mass or tumor (lipoma) continuous to the spinal cord. The other fatty anomaly is a lipomyelomeningocele, in which a lipoma extrudes from the spinal canal underneath the lining of the spinal cord (meninges), but covered by normal skin.In many individuals, tethered cord syndrome is caused mechanically by an inelastic often-thickened filum terminale. This structure, which is composed of glial tissue (the supportive structure of nerve cells) and covered by pia mater, is a delicate strand of fibrous tissue, bridging the spinal cord tip and the sacrum (the tailbone). Due to its high viscoelasticity, the filum allows movement of the spinal cord. If abnormal fibrous tissue grows into the filum and replaces glial tissue, the filum loses its elasticity and abnormally fixes (tethers) the spinal cord, and becomes the mechanical cause of tethered cord syndrome. The inelastic filum is commonly thickened in children, but found less frequently in adolescents and adults.Genetic factors are involved in development of anomalous caudal spine and spinal cord, e.g. myelomeningocele, and in some cases of lipomyelomeningocele. Since tethered cord syndrome is a physiological disorder and develops only when it is abnormally stretched, it cannot be connected to genetic factors, unless the congenital susceptibility of spinal cord to oxidative metabolic impairment is proven.Secondary causes of tethered cord syndrome include tumors, infection or the development of scar tissue (fibrosis) connected to the spinal cord. Tethered cord syndrome may develop as a complication of spinal surgery. Trauma to the spine results in a band of scar formation attached to the spinal cord and can cause tethered cord syndrome. However, some researchers believe that trauma alone is not enough to cause the disorder. They propose that tethering and abnormal tension were already present before the trauma, which worsened the condition. Some researchers have speculated that some cases of tethered cord syndrome that occur due to anomalies that can cause stretching of the spinal cord may have a genetic basis or that some individuals are genetically predisposed to developing the disorder in these specific cases. Although genetic factors are found in patients with myelominingocele, more research is necessary to determine the exact role that genetic factors play in the development of stretch-causing anomalies. Pathophysiologically, neuronal dysfunction in tethered cord syndrome results partly from inability for the spinal cord neurons to utilize oxygen, that is, the impaired oxidative metabolism, partly due to lack of oxygen supply (ischemic effect), and partly to ion channel dysfunction directly related neuronal membrane stretching. The spinal cord consists of a long bundle of neuronal fibers (axons) and the interneurons that connect sensory and motor fibers within the cord. During gestation, the spinal cord is continuous to the brain and runs in the spinal canal to the tailbone area. In general, the spinal cord is protected from external insult by two mechanisms; 1) encased in the spinal column, that is, a rigid structure, 2) floating free in the spinal fluid space of the spinal canal. In addition, the spinal cord is continuous to the filum terminale, which is extremely extensible because of its high viscoelasticity. If the spinal cord is tethered at its caudal end, and if the spinal cord is unable to grow as fast as the vertebral column in childhood, the spinal cord is stretched beyond its physiological tolerance. In turn, this causes various metabolic abnormalities in the spinal cord and, ultimately, the various neurological symptoms of this disorder.Normally, the spinal cord ascends in the spinal canal as the spinal column starts to grow faster than the spinal cord at 9th weeks of gestation. Consequently, the spinal cord is pulled upwards due to this growth difference. By three months of age, the tip of the spinal cord reaches the normal level between T12 and L2 vertebrae. An elastic, extremely extensible filum allows for the ascension of the less elastic spinal cord. If the filum becomes inelastic in an embryo, then the spinal cord tip is anchored and ceases to ascend. Compensatory to the stretching force, the lower (lumbosacral) spinal cord naturally grows more than seen in normal subjects, and becomes elongated. Associated with tethered cord syndrome, the elongated cord is often noted in children, but less often in adults. In most cases, the abnormal tension of the spinal cord increases over time, but disturbing symptoms often develop quickly during a few weeks. Certain activities such as flexing or extending the lower spinal column can put additional tension on the spinal cord and often worsen tethered cord syndrome. Participation in physical activities such as strenuous sports and ballet dancing with high kicks can worsen the signs and symptoms. Special physical features such as abnormal curvature of the spine (scoliosis and exaggerated lordosis) are the potential for symptomatic acceleration. It should be warned that slight flexion of the lower (lumbosacral) spine always aggravates back pain by spinal cord stretching.
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Affects of Tethered Cord Syndrome
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Tethered cord syndrome affects males and females in equal numbers. The exact incidence of the disorder in the general population is unknown. In the past, the diagnosis of tethered cord syndrome has been controversial and the disorder often still remains unrecognized and underdiagnosed. After many years of skepticism, tethered cord syndrome is now considered a distinct clinical entity. In order to help clarify the situation, a proposed definition for true tethered cord syndrome limits that this disorder to individuals who exhibit neurological signs and symptoms due to inelastic structures anchoring the caudal end of the spinal cord. There are cases in which individuals have the symptoms and signs similar to true tethered cord syndrome, but have associated defects that cause compression and impaired blood flow of the spinal cord, or congenital neuronal dysgenesis (failure of neuronal development). For example, in myelomeningoceles and lipomyelomeningoceles that are directly connected to the entire dorsal surface of lumbosacral spinal cord, their neurological deficits are unrelated to spinal cord stretching (tethered cord syndrome). Symptomatically, patients with these anomalies present with complete or nearly complete paralsysis of lower limbs and total loss of bladder and rectal control. The most important signs that can be found in late teenagers and adults are back pain aggravated immediately on flexion of the lumbosacral spine, which elongates the lumbosacral spinal canal, simultaneously stretching the lower spinal cord. The 3-Bs sign is useful for initiating suspicion of tethered cords syndrome. They include 1) bending slightly (over the sink), 2) Buddha sitting with legs crossed (like the Yoga pose) and 3) Baby holding (or equivalent weight) at the waist level.
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Affects of Tethered Cord Syndrome. Tethered cord syndrome affects males and females in equal numbers. The exact incidence of the disorder in the general population is unknown. In the past, the diagnosis of tethered cord syndrome has been controversial and the disorder often still remains unrecognized and underdiagnosed. After many years of skepticism, tethered cord syndrome is now considered a distinct clinical entity. In order to help clarify the situation, a proposed definition for true tethered cord syndrome limits that this disorder to individuals who exhibit neurological signs and symptoms due to inelastic structures anchoring the caudal end of the spinal cord. There are cases in which individuals have the symptoms and signs similar to true tethered cord syndrome, but have associated defects that cause compression and impaired blood flow of the spinal cord, or congenital neuronal dysgenesis (failure of neuronal development). For example, in myelomeningoceles and lipomyelomeningoceles that are directly connected to the entire dorsal surface of lumbosacral spinal cord, their neurological deficits are unrelated to spinal cord stretching (tethered cord syndrome). Symptomatically, patients with these anomalies present with complete or nearly complete paralsysis of lower limbs and total loss of bladder and rectal control. The most important signs that can be found in late teenagers and adults are back pain aggravated immediately on flexion of the lumbosacral spine, which elongates the lumbosacral spinal canal, simultaneously stretching the lower spinal cord. The 3-Bs sign is useful for initiating suspicion of tethered cords syndrome. They include 1) bending slightly (over the sink), 2) Buddha sitting with legs crossed (like the Yoga pose) and 3) Baby holding (or equivalent weight) at the waist level.
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Tethered Cord Syndrome
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Related disorders of Tethered Cord Syndrome
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Symptoms of the following disorders may present with sign and symptoms similar to those of tethered cord syndrome. Comparisons may be useful for a differential diagnosis. They are extradural lesions, intradural-extramedullary lesions, intramedullary lesions extraspinal lesions, and peripheral neuropathy or myelpathy.Children with spina bifida, particularly with myelomeningoceles, show a wide variety of symptoms and physical findings depending on the severity of the defect. Anomalies connected to the caudal end of the spinal cord (true tethered cord syndrome) can be surgically repaired and result in excellent outcome from untethering. Some others who present with aforementioned complete paraplegia have no neurological benefit from the repair surgery. (For more information on this disorder, choose “spina bifida” as your search term in the Rare Disease Database.)
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Related disorders of Tethered Cord Syndrome. Symptoms of the following disorders may present with sign and symptoms similar to those of tethered cord syndrome. Comparisons may be useful for a differential diagnosis. They are extradural lesions, intradural-extramedullary lesions, intramedullary lesions extraspinal lesions, and peripheral neuropathy or myelpathy.Children with spina bifida, particularly with myelomeningoceles, show a wide variety of symptoms and physical findings depending on the severity of the defect. Anomalies connected to the caudal end of the spinal cord (true tethered cord syndrome) can be surgically repaired and result in excellent outcome from untethering. Some others who present with aforementioned complete paraplegia have no neurological benefit from the repair surgery. (For more information on this disorder, choose “spina bifida” as your search term in the Rare Disease Database.)
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Tethered Cord Syndrome
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Diagnosis of Tethered Cord Syndrome
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A diagnosis of tethered cord syndrome is made based upon identification of characteristic signs and symptoms (see the symptom section) that can neurologically locate the lesion to be above the attachment of the anomalies to the spinal cord. For this purpose, a detailed patient history and a thorough clinical evaluation and detailed MRI studies must be carried out. In children, typical imaging features such as a low lying spinal cord and a thickened filum terminale is confirmed by special imaging techniques such as magnetic resonance imaging (MRI) or computed tomography (CT) scan and ultrasound studies.An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. In addition, demonstration of spina bifida (bony defect of the lamina) supports a diagnosis of tethered cord syndrome.In late teenagers and adults, the displacement of the filum located posterior to the cauda equina (a bundle of nerve roots that originate from the lower spinal cord) is a consistent finding. This important feature is proved by the combination of MRI, endoscopy and surgical findings. During CT scanning (a computer tomography) and MRI special techniques are used to create cross-sectional images of vertebrae and nervous system. In some cases, electromyography (EMG) and nerve conduction studies may be used to assess nerve function. EMG is a test that records electrical activity in skeletal (voluntary) muscles at rest and during muscle contractions. The abnormalities in this examination are only shown in patients with an advanced stage of tethered cord syndrome.
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Diagnosis of Tethered Cord Syndrome. A diagnosis of tethered cord syndrome is made based upon identification of characteristic signs and symptoms (see the symptom section) that can neurologically locate the lesion to be above the attachment of the anomalies to the spinal cord. For this purpose, a detailed patient history and a thorough clinical evaluation and detailed MRI studies must be carried out. In children, typical imaging features such as a low lying spinal cord and a thickened filum terminale is confirmed by special imaging techniques such as magnetic resonance imaging (MRI) or computed tomography (CT) scan and ultrasound studies.An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. In addition, demonstration of spina bifida (bony defect of the lamina) supports a diagnosis of tethered cord syndrome.In late teenagers and adults, the displacement of the filum located posterior to the cauda equina (a bundle of nerve roots that originate from the lower spinal cord) is a consistent finding. This important feature is proved by the combination of MRI, endoscopy and surgical findings. During CT scanning (a computer tomography) and MRI special techniques are used to create cross-sectional images of vertebrae and nervous system. In some cases, electromyography (EMG) and nerve conduction studies may be used to assess nerve function. EMG is a test that records electrical activity in skeletal (voluntary) muscles at rest and during muscle contractions. The abnormalities in this examination are only shown in patients with an advanced stage of tethered cord syndrome.
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Tethered Cord Syndrome
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Therapies of Tethered Cord Syndrome
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TreatmentIn children, surgery to release "untether" the spinal cord is recommended to prevent or reverse progressive neurological symptoms. The type of surgery varies depending on the mechanical causes, such as an inelastic filum, myelomeningocele, lipomyelomeningocele, and dermal sinus. Accordingly, the surgical prognosis varies depending upon the presenting symptoms and tethering-producing anomalies. It has been said that treatment for adult patients with tethered cord syndrome is controversial However, it is clear that in both pediatric and adult patients who have firm evidence of tethered cord syndrome, prompt surgical intervention results in reversal, or at least stabilization, of symptoms in many cases.Parents should talk to their physician and medical team about their child's specific problems, associated symptoms and deformity of the spine and spinal cord. In an individual with only minimum complaint his/her physician may advise conservative treatment rather than surgery and will monitor the condition to see whether the symptoms progress Many experts of tethered cord syndrome recommend against surgery to individuals who present with the MRI finding of "cord elongation and thickened filum" but have no symptoms. Some neurosurgeons may prefer cutting the thickened filum in these cases for the prophylactic purpose.The responses to treatment for tethered cord syndrome by repairing myelomeningocele or removal of scarring formation, varies from one person to another. After the repair, the spinal cord may become "retethered" and additional surgery may be recommended.In individuals with severe arachnoiditis (adhesion of the meninges to the spinal cord) found by MRI or CT scan, careful evaluation of pain and neurological condition is required to find if surgical treatment is warranted. At surgery, release of arachnoid adhesion must be performed with meticulous technique. Or re-adhesion or extensive scar formation might follow the surgery. To circumvent this problem, two special surgical procedures have been advocated: 1) transection of the spinal cord to relieve severe back and leg pain, and 2) shortening of the spinal column by resection of one or two vertebrae to relieve spinal cord tension.
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Therapies of Tethered Cord Syndrome. TreatmentIn children, surgery to release "untether" the spinal cord is recommended to prevent or reverse progressive neurological symptoms. The type of surgery varies depending on the mechanical causes, such as an inelastic filum, myelomeningocele, lipomyelomeningocele, and dermal sinus. Accordingly, the surgical prognosis varies depending upon the presenting symptoms and tethering-producing anomalies. It has been said that treatment for adult patients with tethered cord syndrome is controversial However, it is clear that in both pediatric and adult patients who have firm evidence of tethered cord syndrome, prompt surgical intervention results in reversal, or at least stabilization, of symptoms in many cases.Parents should talk to their physician and medical team about their child's specific problems, associated symptoms and deformity of the spine and spinal cord. In an individual with only minimum complaint his/her physician may advise conservative treatment rather than surgery and will monitor the condition to see whether the symptoms progress Many experts of tethered cord syndrome recommend against surgery to individuals who present with the MRI finding of "cord elongation and thickened filum" but have no symptoms. Some neurosurgeons may prefer cutting the thickened filum in these cases for the prophylactic purpose.The responses to treatment for tethered cord syndrome by repairing myelomeningocele or removal of scarring formation, varies from one person to another. After the repair, the spinal cord may become "retethered" and additional surgery may be recommended.In individuals with severe arachnoiditis (adhesion of the meninges to the spinal cord) found by MRI or CT scan, careful evaluation of pain and neurological condition is required to find if surgical treatment is warranted. At surgery, release of arachnoid adhesion must be performed with meticulous technique. Or re-adhesion or extensive scar formation might follow the surgery. To circumvent this problem, two special surgical procedures have been advocated: 1) transection of the spinal cord to relieve severe back and leg pain, and 2) shortening of the spinal column by resection of one or two vertebrae to relieve spinal cord tension.
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Tethered Cord Syndrome
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Overview of Tetrahydrobiopterin Deficiency
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Summary
Tetrahydrobiopterin (BH4) deficiencies is a general term for a group of disorders characterized by abnormalities in the creation (biosynthesis) or regeneration of tetrahydrobiopterin, a naturally occurring compound that acts as a cofactor. A cofactor is a non-protein substance in the body that enhances or is necessary for the proper function of certain enzymes. When tetrahydrobiopterin is deficient, the chemical balance within the body is upset. In most of these disorders, there are abnormally high levels of the amino acid phenylalanine (hyperphenylalaninemia). Amino acids such as phenylalanine are chemical building blocks of proteins and are essential for proper growth and development. Most of these disorders also cause abnormally low levels of neurotransmitters. Neurotransmitters are chemicals that modify, amplify or transmit nerve impulses from one nerve cell to another, enabling nerve cells to communicate. These chemical imbalances can ultimately cause a wide variety of symptoms and physical findings including progressive neurological abnormalities, lack of muscle tone (hypotonia), overproduction of saliva (hypersalivation), loss of coordination, abnormal movements and/or delayed motor development. The specific symptoms can vary dramatically from one person to another and can range from mild to severe. Prompt diagnosis and treatment of these disorders can prevent potentially severe, irreversible neurological damage. Tetrahydrobiopterin deficiency is caused by changes (variants or mutations) in specific genes that encode enzymes required for the biosynthesis or regeneration of tetrahydrobiopterin. Most of these gene variants are inherited in an autosomal recessive pattern.Introduction
There are four main forms of tetrahydrobiopterin deficiency sometimes referred to as ‘classical’ tetrahydrobiopterin deficiency. They are guanosine triphosphate cyclohydrolase I (GTPCH) deficiency; 6-pyruvoyl tetrahydropterin synthase (PTPS) deficiency; pterin-4-alpha-carbinolamine dehydratase (PCD) deficiency and dihydropteridine reductase (DHPR) deficiency. The first two disorders are defects in tetrahydrobiopterin synthesis and the latter two are defects in tetrahydrobiopterin regeneration. Sepiapterin reductase deficiency is a related disorder affecting the third step of tetrahydrobiopterin biosynthesis; it differs from the other disorders in that elevated levels of phenylalanine do not develop. GTPCH deficiency can be broken down in the autosomal dominant form, also known as Segawa syndrome or autosomal dominant dopa-responsive dystonia, or the autosomal recessive form, which is covered in this report. NORD has separate, individual reports on sepiapterin reductase deficiency and Segawa syndrome.In the past, disorders of tetrahydrobiopterin deficiency were referred to as atypical phenylketonuria or malignant phenylketonuria because physicians believed they were forms of phenylketonuria that did not respond to the standard therapy for that disorder. These terms are now considered obsolete because disorders of tetrahydrobiopterin deficiency are now known to be distinct disorders that are treatable with different therapies.
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Overview of Tetrahydrobiopterin Deficiency. Summary
Tetrahydrobiopterin (BH4) deficiencies is a general term for a group of disorders characterized by abnormalities in the creation (biosynthesis) or regeneration of tetrahydrobiopterin, a naturally occurring compound that acts as a cofactor. A cofactor is a non-protein substance in the body that enhances or is necessary for the proper function of certain enzymes. When tetrahydrobiopterin is deficient, the chemical balance within the body is upset. In most of these disorders, there are abnormally high levels of the amino acid phenylalanine (hyperphenylalaninemia). Amino acids such as phenylalanine are chemical building blocks of proteins and are essential for proper growth and development. Most of these disorders also cause abnormally low levels of neurotransmitters. Neurotransmitters are chemicals that modify, amplify or transmit nerve impulses from one nerve cell to another, enabling nerve cells to communicate. These chemical imbalances can ultimately cause a wide variety of symptoms and physical findings including progressive neurological abnormalities, lack of muscle tone (hypotonia), overproduction of saliva (hypersalivation), loss of coordination, abnormal movements and/or delayed motor development. The specific symptoms can vary dramatically from one person to another and can range from mild to severe. Prompt diagnosis and treatment of these disorders can prevent potentially severe, irreversible neurological damage. Tetrahydrobiopterin deficiency is caused by changes (variants or mutations) in specific genes that encode enzymes required for the biosynthesis or regeneration of tetrahydrobiopterin. Most of these gene variants are inherited in an autosomal recessive pattern.Introduction
There are four main forms of tetrahydrobiopterin deficiency sometimes referred to as ‘classical’ tetrahydrobiopterin deficiency. They are guanosine triphosphate cyclohydrolase I (GTPCH) deficiency; 6-pyruvoyl tetrahydropterin synthase (PTPS) deficiency; pterin-4-alpha-carbinolamine dehydratase (PCD) deficiency and dihydropteridine reductase (DHPR) deficiency. The first two disorders are defects in tetrahydrobiopterin synthesis and the latter two are defects in tetrahydrobiopterin regeneration. Sepiapterin reductase deficiency is a related disorder affecting the third step of tetrahydrobiopterin biosynthesis; it differs from the other disorders in that elevated levels of phenylalanine do not develop. GTPCH deficiency can be broken down in the autosomal dominant form, also known as Segawa syndrome or autosomal dominant dopa-responsive dystonia, or the autosomal recessive form, which is covered in this report. NORD has separate, individual reports on sepiapterin reductase deficiency and Segawa syndrome.In the past, disorders of tetrahydrobiopterin deficiency were referred to as atypical phenylketonuria or malignant phenylketonuria because physicians believed they were forms of phenylketonuria that did not respond to the standard therapy for that disorder. These terms are now considered obsolete because disorders of tetrahydrobiopterin deficiency are now known to be distinct disorders that are treatable with different therapies.
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Tetrahydrobiopterin Deficiency
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Symptoms of Tetrahydrobiopterin Deficiency
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Although researchers have been able to establish distinct syndromes with characteristic or “core” symptoms, much about these disorders is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies and the possibility of other genes influencing the development and progression of these disorders prevent physicians from developing a complete picture of associated symptoms and prognosis.Disorders of tetrahydrobiopterin deficiency can be classified as transient, mild or severe, which is extremely important in determining specifics of therapy, such as the need for neurotransmitter precursors during treatment (see Standard Therapies below). The specific symptoms and severity associated with tetrahydrobiopterin deficiencies can vary greatly from one person to another, even among individuals with the same subtype or among individuals from the same family. Overall, the symptoms of GTPCH deficiency, PTPS deficiency and DHPR deficiency are extremely similar. Generally, PCD deficiency is less severe than the other disorders and affected infants often only exhibit temporary abnormalities of muscle tone and delays in motor development. They are, however, at risk for developing type 2 diabetes (MODY) after the age of 9 years.Tetrahydrobiopterin deficiencies usually present within the first six months of life and can be detected upon newborn screening because of elevated levels phenylalanine. Infants usually appear normal at birth, although some newborns, particularly in PTPS deficiency, may have a low birth weight. Failure to grow and gain weight (failure to thrive) may occur. Microcephaly, a condition defined as having a head circumference smaller than normally would be expected based on age and gender, is a common finding.In the severe forms, common, but variable symptoms include neurological dysfunction including convulsions or seizures, swallowing difficulties, poor muscle tone of the trunk of the body (truncal hypotonia) and excess muscle tone of the arms and legs so that they may be stiff and difficult to move (limb hypertonia). Abnormal movements are common and can include abnormal slowness of movement (bradykinesia), rapid, involuntary, purposeless (chorea), slow, involuntary, writhing movements (athetosis), a type of spasm in which the head and feet bend the backward and the back arches (opisthotonus).Affected children may also exhibit delays in reaching developmental milestones (developmental delays), delays in acquiring skills that require the coordination of mental and physical activities (psychomotor delay), and, in some children, intellectual disability.Neurological dysfunction is progressive and, during the school years, affected individuals may appear uncoordinated or clumsy such as having an abnormal manner of walking (gait abnormalities). In some children, this clumsiness is due, in part, to involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions (dystonia).Some affected individuals may develop abnormal movements of the eyes that can range from brief upward rolling of the eyes to oculogyric crises, in which the eyes roll upward for a sustained period. Sometimes, the eyes may roll downward or move toward each other (converge). Severe oculogyric crises can be associated with additional symptoms including the formation of tears (lacrimation), eye blinking, widening (dilation) of the pupils, drooling, backward flexion of the neck, restlessness or a general feeling of poor health (malaise).Additional symptoms that have been reported include excessive production of saliva, lethargy and irritability. Recurrent episodes of elevated body temperature (hyperthermia) that are not associated with infection may also occur. Certain symptoms may become noticeably worse or more pronounced in the afternoon and evening than in the morning (marked diurnal fluctuation). Swallowing difficulties and poor sucking ability in infants can result in poor feeding during infancy.
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Symptoms of Tetrahydrobiopterin Deficiency. Although researchers have been able to establish distinct syndromes with characteristic or “core” symptoms, much about these disorders is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies and the possibility of other genes influencing the development and progression of these disorders prevent physicians from developing a complete picture of associated symptoms and prognosis.Disorders of tetrahydrobiopterin deficiency can be classified as transient, mild or severe, which is extremely important in determining specifics of therapy, such as the need for neurotransmitter precursors during treatment (see Standard Therapies below). The specific symptoms and severity associated with tetrahydrobiopterin deficiencies can vary greatly from one person to another, even among individuals with the same subtype or among individuals from the same family. Overall, the symptoms of GTPCH deficiency, PTPS deficiency and DHPR deficiency are extremely similar. Generally, PCD deficiency is less severe than the other disorders and affected infants often only exhibit temporary abnormalities of muscle tone and delays in motor development. They are, however, at risk for developing type 2 diabetes (MODY) after the age of 9 years.Tetrahydrobiopterin deficiencies usually present within the first six months of life and can be detected upon newborn screening because of elevated levels phenylalanine. Infants usually appear normal at birth, although some newborns, particularly in PTPS deficiency, may have a low birth weight. Failure to grow and gain weight (failure to thrive) may occur. Microcephaly, a condition defined as having a head circumference smaller than normally would be expected based on age and gender, is a common finding.In the severe forms, common, but variable symptoms include neurological dysfunction including convulsions or seizures, swallowing difficulties, poor muscle tone of the trunk of the body (truncal hypotonia) and excess muscle tone of the arms and legs so that they may be stiff and difficult to move (limb hypertonia). Abnormal movements are common and can include abnormal slowness of movement (bradykinesia), rapid, involuntary, purposeless (chorea), slow, involuntary, writhing movements (athetosis), a type of spasm in which the head and feet bend the backward and the back arches (opisthotonus).Affected children may also exhibit delays in reaching developmental milestones (developmental delays), delays in acquiring skills that require the coordination of mental and physical activities (psychomotor delay), and, in some children, intellectual disability.Neurological dysfunction is progressive and, during the school years, affected individuals may appear uncoordinated or clumsy such as having an abnormal manner of walking (gait abnormalities). In some children, this clumsiness is due, in part, to involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions (dystonia).Some affected individuals may develop abnormal movements of the eyes that can range from brief upward rolling of the eyes to oculogyric crises, in which the eyes roll upward for a sustained period. Sometimes, the eyes may roll downward or move toward each other (converge). Severe oculogyric crises can be associated with additional symptoms including the formation of tears (lacrimation), eye blinking, widening (dilation) of the pupils, drooling, backward flexion of the neck, restlessness or a general feeling of poor health (malaise).Additional symptoms that have been reported include excessive production of saliva, lethargy and irritability. Recurrent episodes of elevated body temperature (hyperthermia) that are not associated with infection may also occur. Certain symptoms may become noticeably worse or more pronounced in the afternoon and evening than in the morning (marked diurnal fluctuation). Swallowing difficulties and poor sucking ability in infants can result in poor feeding during infancy.
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Causes of Tetrahydrobiopterin Deficiency
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Tetrahydrobiopterin deficiencies are caused by variants (mutations) in specific genes. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a variant of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the protein, this can affect many organ systems of the body, including the brain.GTPCH deficiency is caused by variants in the GCH1 gene; PTPS deficiency is caused by variants in the PTS gene; DHPR deficiency is caused by variants in the QDPR gene; PCD deficiency is caused by variants in the PCBD1 gene.The GCH1 gene provides information for creating (encoding) an enzyme called guanosine triphosphate cyclohydrolase I, which is essential in the first of three steps necessary for the creation (biosynthesis) of tetrahydrobiopterin. The PTS gene encodes an enzyme known as 6-pyruvoyl tetrahydropterin synthase, which is essential for the second step in tetrahydrobiopterin biosynthesis. The QDPR gene encodes an enzyme called quinoid dihydropteridine reductase, which is essential for the proper regeneration of tetrahydrobiopterin. The PCBD1 gene encodes for a double-function protein; an enzyme known as pterin-4-alpha-carbinolamine dehydratase, which is also essential for the proper regeneration of tetrahydrobiopterin and for the dimerizing cofactor of hepatocyte nuclear factor 1 (DCoH1).Variants in these genes result in low amounts of functional copies of the enzyme that is produced by the specific gene. Consequently, the synthesis or regeneration of tetrahydrobiopterin is affected, resulting in tetrahydrobiopterin deficiency. Because a PCBD1 gene variant is rarely associated with severe complications, researchers believe that other enzymes make up for the reduced activity of pterin-4-alpha-carbinolamine dehydratase.Tetrahydrobiopterin has several functions within the body including breaking down or processing certain amino acids, particular phenylalanine. Phenylalanine is a chemical building block of proteins and is essential for proper growth and development. Tetrahydrobiopterin deficiency results in abnormally elevated levels of phenylalanine (known as hyperphenylalaninemia) in various cells of the body including brain cells. Hyperphenylalaninemia can damage the affected cells, especially brain cells which are particularly sensitive to excess phenylalanine.Tetrahydrobiopterin is also necessary for the proper biosynthesis of amine neurotransmitters such as catecholamines (i.e., dopamine, norepinephrine, and epinephrine) and serotonin. Catecholamines are essential for the proper function of certain processes of the brain, especially those that control movement. Serotonin helps to regulate mood, appetite, memory, sleep cycles, and certain muscular functions. Lack of tetrahydrobiopterin results in a lack of these essential neurotransmitters.The variants that cause the forms of tetrahydrobiopterin deficiency discussed in this report are inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits an abnormal gene from each parent. If an individual receives one normal gene and one abnormal gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the abnormal gene and, therefore, have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
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Causes of Tetrahydrobiopterin Deficiency. Tetrahydrobiopterin deficiencies are caused by variants (mutations) in specific genes. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a variant of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the protein, this can affect many organ systems of the body, including the brain.GTPCH deficiency is caused by variants in the GCH1 gene; PTPS deficiency is caused by variants in the PTS gene; DHPR deficiency is caused by variants in the QDPR gene; PCD deficiency is caused by variants in the PCBD1 gene.The GCH1 gene provides information for creating (encoding) an enzyme called guanosine triphosphate cyclohydrolase I, which is essential in the first of three steps necessary for the creation (biosynthesis) of tetrahydrobiopterin. The PTS gene encodes an enzyme known as 6-pyruvoyl tetrahydropterin synthase, which is essential for the second step in tetrahydrobiopterin biosynthesis. The QDPR gene encodes an enzyme called quinoid dihydropteridine reductase, which is essential for the proper regeneration of tetrahydrobiopterin. The PCBD1 gene encodes for a double-function protein; an enzyme known as pterin-4-alpha-carbinolamine dehydratase, which is also essential for the proper regeneration of tetrahydrobiopterin and for the dimerizing cofactor of hepatocyte nuclear factor 1 (DCoH1).Variants in these genes result in low amounts of functional copies of the enzyme that is produced by the specific gene. Consequently, the synthesis or regeneration of tetrahydrobiopterin is affected, resulting in tetrahydrobiopterin deficiency. Because a PCBD1 gene variant is rarely associated with severe complications, researchers believe that other enzymes make up for the reduced activity of pterin-4-alpha-carbinolamine dehydratase.Tetrahydrobiopterin has several functions within the body including breaking down or processing certain amino acids, particular phenylalanine. Phenylalanine is a chemical building block of proteins and is essential for proper growth and development. Tetrahydrobiopterin deficiency results in abnormally elevated levels of phenylalanine (known as hyperphenylalaninemia) in various cells of the body including brain cells. Hyperphenylalaninemia can damage the affected cells, especially brain cells which are particularly sensitive to excess phenylalanine.Tetrahydrobiopterin is also necessary for the proper biosynthesis of amine neurotransmitters such as catecholamines (i.e., dopamine, norepinephrine, and epinephrine) and serotonin. Catecholamines are essential for the proper function of certain processes of the brain, especially those that control movement. Serotonin helps to regulate mood, appetite, memory, sleep cycles, and certain muscular functions. Lack of tetrahydrobiopterin results in a lack of these essential neurotransmitters.The variants that cause the forms of tetrahydrobiopterin deficiency discussed in this report are inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits an abnormal gene from each parent. If an individual receives one normal gene and one abnormal gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the abnormal gene and, therefore, have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
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Affects of Tetrahydrobiopterin Deficiency
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Tetrahydrobiopterin deficiencies affect males and females in equal numbers and have been diagnosed in a diversity of ethnic groups worldwide. In the United States, these disorders are estimated to affect 1% to 3% of infants diagnosed with high levels of phenylalanine (hyperphenylalaninemia) by newborn screening. Tetrahydrobiopterin deficiencies are estimated to affect approximately 1-2 in 1,000,000 individuals in the general population. Some cases, particularly mild or transient cases, may go undiagnosed or misdiagnosed, making it difficult to determine the true frequency of these disorders in the general population.
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Affects of Tetrahydrobiopterin Deficiency. Tetrahydrobiopterin deficiencies affect males and females in equal numbers and have been diagnosed in a diversity of ethnic groups worldwide. In the United States, these disorders are estimated to affect 1% to 3% of infants diagnosed with high levels of phenylalanine (hyperphenylalaninemia) by newborn screening. Tetrahydrobiopterin deficiencies are estimated to affect approximately 1-2 in 1,000,000 individuals in the general population. Some cases, particularly mild or transient cases, may go undiagnosed or misdiagnosed, making it difficult to determine the true frequency of these disorders in the general population.
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Related disorders of Tetrahydrobiopterin Deficiency
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Symptoms of the following disorders can be similar to those of tetrahydrobiopterin deficiencies. Comparisons may be useful for a differential diagnosis.Phenylketonuria (PKU) is an inborn error of metabolism that is detectable during the first days of life with appropriate blood testing (e.g., during routine neonatal screening). PKU is characterized by absence or deficiency of an enzyme (phenylalanine hydroxylase) that is responsible for processing the essential amino acid phenylalanine to another amino acid tyrosine. (For more information on this disorder, choose “phenylketonuria” as your search term in the Rare Disease Database.)There are additional metabolic disorders that have been identified in which certain enzyme deficiencies result in disrupted metabolism of a neurotransmitter or neurotransmitters. These disorders include autosomal dominant GTP cyclohydrolase I deficiency (Segawa syndrome or autosomal dominant dopa-responsive dystonia), sepiapterin reductase deficiency, aromatic L-amino acid decarboxylase deficiency and succinic semialdehyde dehydrogenase (SSADH). (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Cerebral palsy is a general term that covers a group of disorders that involve impairment of muscle control or coordination resulting from injury to the brain during its early stages of development (the fetal, perinatal or early childhood stages). The specific symptoms associated with cerebral palsy vary greatly from person to person but are quite common in patients with sepiapterin reductase deficiency. (For more information on this disorder, choose “cerebral palsy” as your search term in the Rare Disease Database.)
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Related disorders of Tetrahydrobiopterin Deficiency. Symptoms of the following disorders can be similar to those of tetrahydrobiopterin deficiencies. Comparisons may be useful for a differential diagnosis.Phenylketonuria (PKU) is an inborn error of metabolism that is detectable during the first days of life with appropriate blood testing (e.g., during routine neonatal screening). PKU is characterized by absence or deficiency of an enzyme (phenylalanine hydroxylase) that is responsible for processing the essential amino acid phenylalanine to another amino acid tyrosine. (For more information on this disorder, choose “phenylketonuria” as your search term in the Rare Disease Database.)There are additional metabolic disorders that have been identified in which certain enzyme deficiencies result in disrupted metabolism of a neurotransmitter or neurotransmitters. These disorders include autosomal dominant GTP cyclohydrolase I deficiency (Segawa syndrome or autosomal dominant dopa-responsive dystonia), sepiapterin reductase deficiency, aromatic L-amino acid decarboxylase deficiency and succinic semialdehyde dehydrogenase (SSADH). (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Cerebral palsy is a general term that covers a group of disorders that involve impairment of muscle control or coordination resulting from injury to the brain during its early stages of development (the fetal, perinatal or early childhood stages). The specific symptoms associated with cerebral palsy vary greatly from person to person but are quite common in patients with sepiapterin reductase deficiency. (For more information on this disorder, choose “cerebral palsy” as your search term in the Rare Disease Database.)
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Tetrahydrobiopterin Deficiency
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Diagnosis of Tetrahydrobiopterin Deficiency
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A diagnosis is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Disorders of tetrahydrobiopterin deficiency are often found by newborn screening that detects elevated levels of phenylalanine. Further testing is required to distinguish these disorders from other causes of hyperphenylalaninemia such as phenylketonuria, and to determine the specific type of tetrahydrobiopterin deficiency present. Additionally, phenylalanine levels may be normal when a newborn screening is done and can be formal during early infancy, therefore an evaluation for tetrahydrobiopterin deficiencies should be considered in any infant with unexplained neurological symptoms, particularly in parents who are related by blood.Biochemical Testing and Workup
Evaluation of urine and dried blood spots (DBS) can measure the levels of pterin metabolites, specifically biopterin and neopterin. Biopterin and neopterin are byproducts of the metabolism of tetrahydrobiopterin. In GTPCH deficiency, levels of biopterin and neopterin are abnormally low or even not detectable. In PTPS deficiency, neopterin is highly elevated and biopterin is very low or absent. In DHPR deficiency, biopterin is highly elevated and neopterin is normal or slightly elevated, but in some patients both metabolites can be normal (see below). In PCD deficiency, neopterin is initially very high, biopterin is slightly reduced, and primapterin (7-biopterin) is present.A BH4 (sapropterin dihydrochloride) loading test, in which infants suspected of tetrahydrobiopterin deficiency are administered BH4, may also be performed. These tests help to distinguish BH4-deficient disorders from the more common PKU. Elevated phenylalanine levels will drop following a BH4 challenge. In PKU, this drop is minimal to moderate (BH4-responsive PKU). Infants with DHPR deficiency can be missed with urinary or DBS pterins or a BH4 loading test. The activity of the enzyme, DHPR, is therefore an essential part of laboratory testing and can be measured (enzyme assay) in DBS taken during newborn screening. Reduced activity levels can indicate or confirm a diagnosis of DHPR deficiency. Pterins, neurotransmitter metabolites and folates can be measured in cerebrospinal fluid (CSF). These tests can help to distinguish tetrahydrobiopterin deficiencies from one another and to assess the potential severity of the disease.Molecular genetic testing can confirm a diagnosis of these disorders. Molecular genetic testing can detect variants in the specific genes known to cause tetrahydrobiopterin deficiency. DNA testing is necessary to confirm a diagnosis of a disorder of tetrahydrobiopterin deficiency.
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Diagnosis of Tetrahydrobiopterin Deficiency. A diagnosis is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Disorders of tetrahydrobiopterin deficiency are often found by newborn screening that detects elevated levels of phenylalanine. Further testing is required to distinguish these disorders from other causes of hyperphenylalaninemia such as phenylketonuria, and to determine the specific type of tetrahydrobiopterin deficiency present. Additionally, phenylalanine levels may be normal when a newborn screening is done and can be formal during early infancy, therefore an evaluation for tetrahydrobiopterin deficiencies should be considered in any infant with unexplained neurological symptoms, particularly in parents who are related by blood.Biochemical Testing and Workup
Evaluation of urine and dried blood spots (DBS) can measure the levels of pterin metabolites, specifically biopterin and neopterin. Biopterin and neopterin are byproducts of the metabolism of tetrahydrobiopterin. In GTPCH deficiency, levels of biopterin and neopterin are abnormally low or even not detectable. In PTPS deficiency, neopterin is highly elevated and biopterin is very low or absent. In DHPR deficiency, biopterin is highly elevated and neopterin is normal or slightly elevated, but in some patients both metabolites can be normal (see below). In PCD deficiency, neopterin is initially very high, biopterin is slightly reduced, and primapterin (7-biopterin) is present.A BH4 (sapropterin dihydrochloride) loading test, in which infants suspected of tetrahydrobiopterin deficiency are administered BH4, may also be performed. These tests help to distinguish BH4-deficient disorders from the more common PKU. Elevated phenylalanine levels will drop following a BH4 challenge. In PKU, this drop is minimal to moderate (BH4-responsive PKU). Infants with DHPR deficiency can be missed with urinary or DBS pterins or a BH4 loading test. The activity of the enzyme, DHPR, is therefore an essential part of laboratory testing and can be measured (enzyme assay) in DBS taken during newborn screening. Reduced activity levels can indicate or confirm a diagnosis of DHPR deficiency. Pterins, neurotransmitter metabolites and folates can be measured in cerebrospinal fluid (CSF). These tests can help to distinguish tetrahydrobiopterin deficiencies from one another and to assess the potential severity of the disease.Molecular genetic testing can confirm a diagnosis of these disorders. Molecular genetic testing can detect variants in the specific genes known to cause tetrahydrobiopterin deficiency. DNA testing is necessary to confirm a diagnosis of a disorder of tetrahydrobiopterin deficiency.
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Therapies of Tetrahydrobiopterin Deficiency
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Treatment
Prompt recognition and early treatment of tetrahydrobiopterin deficiency is critical in reducing or preventing the potentially severe, irreversible neurologic damage that can occur in severe cases. For GTPCH deficiency, PTPS deficiency and DHPR deficiency the focus of treatment is to control the level of phenylalanine in the body and restore the proper balance of neurotransmitters in the brain. PCD deficiency may not require any treatment or may require treatment with synthetic BH4 (sapropterin dihydrochloride) temporarily in symptomatic infants or children. Many affected individuals are treated in a specialty metabolic clinic, where they are seen by physicians with experience in treating these types of disorders.A diet that limits phenylalanine intake is recommended only in DHPR deficiency but may not be sufficient on its own in other BH4 disorders. Treatment for individuals with GTPCH deficiency and PTPS deficiency requires oral doses of synthetic tetrahydrobiopterin (sapropterin dihydrochloride). Individuals with DHPR deficiency may require additional therapy with folinic acid to prevent central nervous system folate deficiency.Treatment will also require restoring neurotransmitter balance. Affected individuals may be treated with a regimen of amine neurotransmitter precursors, which are substances that are converted into specific neurotransmitters by enzymes in the blood and brain. Specific precursors used to treat tetrahydrobiopterin deficiency are 5-hydroxytryptophan and levodopa (L-dopa) along with carbidopa. In most patiensts, supplemental therapy with neurotransmitter precursors is required for life.Maternal BH4 deficiency
Pregnancy care of patients with tetrahydrobiopterin deficiencies is a challenge for clinicians since knowledge about the risk of pregnancy and drug treatment are scarce. Data on 16 pregnancies in seven patients did not present any association between standard drug treatment with an increased rate of pregnancy complications, abnormal obstetrical or pediatric outcome. Intensive clinical and biochemical supervision by a multidisciplinary team before, during and after the pregnancy in any BH4 deficiency is, however, essential.
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Therapies of Tetrahydrobiopterin Deficiency. Treatment
Prompt recognition and early treatment of tetrahydrobiopterin deficiency is critical in reducing or preventing the potentially severe, irreversible neurologic damage that can occur in severe cases. For GTPCH deficiency, PTPS deficiency and DHPR deficiency the focus of treatment is to control the level of phenylalanine in the body and restore the proper balance of neurotransmitters in the brain. PCD deficiency may not require any treatment or may require treatment with synthetic BH4 (sapropterin dihydrochloride) temporarily in symptomatic infants or children. Many affected individuals are treated in a specialty metabolic clinic, where they are seen by physicians with experience in treating these types of disorders.A diet that limits phenylalanine intake is recommended only in DHPR deficiency but may not be sufficient on its own in other BH4 disorders. Treatment for individuals with GTPCH deficiency and PTPS deficiency requires oral doses of synthetic tetrahydrobiopterin (sapropterin dihydrochloride). Individuals with DHPR deficiency may require additional therapy with folinic acid to prevent central nervous system folate deficiency.Treatment will also require restoring neurotransmitter balance. Affected individuals may be treated with a regimen of amine neurotransmitter precursors, which are substances that are converted into specific neurotransmitters by enzymes in the blood and brain. Specific precursors used to treat tetrahydrobiopterin deficiency are 5-hydroxytryptophan and levodopa (L-dopa) along with carbidopa. In most patiensts, supplemental therapy with neurotransmitter precursors is required for life.Maternal BH4 deficiency
Pregnancy care of patients with tetrahydrobiopterin deficiencies is a challenge for clinicians since knowledge about the risk of pregnancy and drug treatment are scarce. Data on 16 pregnancies in seven patients did not present any association between standard drug treatment with an increased rate of pregnancy complications, abnormal obstetrical or pediatric outcome. Intensive clinical and biochemical supervision by a multidisciplinary team before, during and after the pregnancy in any BH4 deficiency is, however, essential.
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Overview of Tetralogy of Fallot
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SummaryTetralogy of Fallot is the most common form of cyanotic congenital heart disease. Cyanosis is the abnormal bluish discoloration of the skin that occurs because of low levels of circulating oxygen in the blood. Tetralogy of Fallot consists of the combination of four different heart defects: a ventricular septal defect (VSD); obstructed outflow of blood from the right ventricle to the lungs (pulmonary stenosis); a displaced aorta, which causes blood to flow into the aorta from both the right and left ventricles (dextroposition or overriding aorta); and abnormal enlargement of the right ventricle (right ventricular hypertrophy). The severity of the symptoms is related to the degree of blood flow obstruction from the right ventricle.IntroductionThe normal heart has four chambers. The two upper chambers known as atria are separated from each other by a fibrous partition known as the atrial septum. The two lower chambers are known as ventricles and are separated from each other by the ventricular septum. Valves connect the atria (left and right) to their respective ventricles. The valves allow for blood to be pumped through the chambers. Blood travels from the right ventricle through the pulmonary artery to the lungs where it receives oxygen. The blood returns to the heart through pulmonary veins and enters the left ventricle. The left ventricle sends the now oxygen-filled blood into the main artery of the body (aorta). The aorta sends the blood throughout the body.Ventricular Septal DefectThe heart has an inner wall that separates the two chambers, called a septum. The septum stops mixing of the blood between the two sides. A ventricular septal defect is a hole in the septum that causes oxygen-rich blood (left ventricle) and the oxygen-poor blood (right ventricle) to mix.Pulmonary Stenosis This defect is the narrowing of the pulmonary valve, which flows oxygen poor blood into the pulmonary artery and from there the blood travels to the lungs to pick up oxygen. Pulmonary stenosis is when the pulmonary valve cannot open fully, making the heart work harder and results in a lack of blood reaching the lung.Right Ventricular Hypertrophy The muscle of the right ventricle is thicker due to the right side of the heart receiving excessive blood flow from the left side of the heart through the ventricular septal defect and working harder.Overriding AortaIn a normal heart, the aorta is attached to the left ventricle and allows oxygen-rich blood to flow throughout the body. In a tetralogy of Fallot heart, the aorta is located between both the left and the right ventricle. This causes oxygen-poor blood from the right ventricle to flow into the aorta instead of the pulmonary artery. If infants with tetralogy of Fallot are not treated, the symptoms usually become progressively more severe. Blood flow to the lungs may be further decreased and severe cyanosis may cause life-threatening complications. The exact cause of tetralogy of Fallot is not known.
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Overview of Tetralogy of Fallot. SummaryTetralogy of Fallot is the most common form of cyanotic congenital heart disease. Cyanosis is the abnormal bluish discoloration of the skin that occurs because of low levels of circulating oxygen in the blood. Tetralogy of Fallot consists of the combination of four different heart defects: a ventricular septal defect (VSD); obstructed outflow of blood from the right ventricle to the lungs (pulmonary stenosis); a displaced aorta, which causes blood to flow into the aorta from both the right and left ventricles (dextroposition or overriding aorta); and abnormal enlargement of the right ventricle (right ventricular hypertrophy). The severity of the symptoms is related to the degree of blood flow obstruction from the right ventricle.IntroductionThe normal heart has four chambers. The two upper chambers known as atria are separated from each other by a fibrous partition known as the atrial septum. The two lower chambers are known as ventricles and are separated from each other by the ventricular septum. Valves connect the atria (left and right) to their respective ventricles. The valves allow for blood to be pumped through the chambers. Blood travels from the right ventricle through the pulmonary artery to the lungs where it receives oxygen. The blood returns to the heart through pulmonary veins and enters the left ventricle. The left ventricle sends the now oxygen-filled blood into the main artery of the body (aorta). The aorta sends the blood throughout the body.Ventricular Septal DefectThe heart has an inner wall that separates the two chambers, called a septum. The septum stops mixing of the blood between the two sides. A ventricular septal defect is a hole in the septum that causes oxygen-rich blood (left ventricle) and the oxygen-poor blood (right ventricle) to mix.Pulmonary Stenosis This defect is the narrowing of the pulmonary valve, which flows oxygen poor blood into the pulmonary artery and from there the blood travels to the lungs to pick up oxygen. Pulmonary stenosis is when the pulmonary valve cannot open fully, making the heart work harder and results in a lack of blood reaching the lung.Right Ventricular Hypertrophy The muscle of the right ventricle is thicker due to the right side of the heart receiving excessive blood flow from the left side of the heart through the ventricular septal defect and working harder.Overriding AortaIn a normal heart, the aorta is attached to the left ventricle and allows oxygen-rich blood to flow throughout the body. In a tetralogy of Fallot heart, the aorta is located between both the left and the right ventricle. This causes oxygen-poor blood from the right ventricle to flow into the aorta instead of the pulmonary artery. If infants with tetralogy of Fallot are not treated, the symptoms usually become progressively more severe. Blood flow to the lungs may be further decreased and severe cyanosis may cause life-threatening complications. The exact cause of tetralogy of Fallot is not known.
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Symptoms of Tetralogy of Fallot
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The symptoms of tetralogy of Fallot vary widely from person to person. The severity of the symptoms, which may range from mild to severe, is related to the degree of blood flow obstruction from the right ventricle.Tetralogy of Fallot may be present at birth or emerge within the first year of life. The most common symptom of this disorder is abnormal bluish discoloration of the skin (cyanosis). This may occur while the child is at rest or crying. The mucous membranes of the lips and mouth, fingertips, and toenails may be particularly blue due to the lack of oxygen. Affected infants may have difficulty breathing (dyspnea); as a result, they tend to play for short periods and then rest. Other symptoms may include a heart murmur, easy fatigability, poor appetite, slow weight gain, heart murmurs, an abnormal increase in the numbers of red blood cells (polycythemia), fingers and toes with wide, enlarged tips and overhanging nails (clubbing), and/or delayed physical growth.Some infants with tetralogy of Fallot may experience episodes of severe cyanosis and breathing difficulty (paroxysmal hypercyanotic attack or “blue” or “tet” spells). During these episodes, the infant may become restless, extremely cyanotic while gasping for air and nonresponsive to parent’s voices. In extreme situations, infants may pass out. A characteristic squatting position may be assumed to help assist breathing. Severe attacks may lead to the loss consciousness, and occasionally to convulsions or temporary paralysis on one side of the body (hemiparesis). These spells may last for a few minutes to a few hours and may be followed by periods of muscle weakness and a prolonged period of sleep.A variety of other complications may occur in association with tetralogy of Fallot. These may include mild anemia in infants, abnormal increase in the number of red blood cells (polycythemia) in older children, and blood clotting (coagulation) defects. These blood abnormalities may lead to the formation of blood clots that can travel through the blood stream (embolisms). These blood clots may cause the blood supply to the brain (cerebral infarctions) to be interrupted temporarily.
Additional complications may include infectious inflammation of the sinuses (sinusitis) and brain abscesses. In some cases, the connection between the aorta and the pulmonary artery, which normally closes before birth, may remain open (patent ductus arteriosus). The symptoms associated with this condition vary depending upon the size of the opening and may include rapid breathing, frequent respiratory infections, and easy fatigability. Congestive heart failure is rare, except in association with bacterial infection of the heart (endocarditis) or abnormal heart rhythms (arrhythmias). However, a common sign is a heart murmur, or an extra sound heard while listening to the heartbeat. The most severe form of tetralogy of Fallot is known as pseudotruncus arteriosus. Infants with this form of the disorder experience severe symptoms that relate to the profound obstruction of the right ventricular blood flow and severe underdevelopment of associated blood vessels and valves related to the lungs (pulmonary atresia). Ventricular septal defects are usually severe in this form of the disorder. Severe cyanosis, alarmingly low levels of circulating oxygen, and excessive circulating red blood cells (polycythemia) are the major features of pseudotruncus arteriosus. (For more information, see “Ventricular Septal Defect” in the Related Disorders section of this report.)
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Symptoms of Tetralogy of Fallot. The symptoms of tetralogy of Fallot vary widely from person to person. The severity of the symptoms, which may range from mild to severe, is related to the degree of blood flow obstruction from the right ventricle.Tetralogy of Fallot may be present at birth or emerge within the first year of life. The most common symptom of this disorder is abnormal bluish discoloration of the skin (cyanosis). This may occur while the child is at rest or crying. The mucous membranes of the lips and mouth, fingertips, and toenails may be particularly blue due to the lack of oxygen. Affected infants may have difficulty breathing (dyspnea); as a result, they tend to play for short periods and then rest. Other symptoms may include a heart murmur, easy fatigability, poor appetite, slow weight gain, heart murmurs, an abnormal increase in the numbers of red blood cells (polycythemia), fingers and toes with wide, enlarged tips and overhanging nails (clubbing), and/or delayed physical growth.Some infants with tetralogy of Fallot may experience episodes of severe cyanosis and breathing difficulty (paroxysmal hypercyanotic attack or “blue” or “tet” spells). During these episodes, the infant may become restless, extremely cyanotic while gasping for air and nonresponsive to parent’s voices. In extreme situations, infants may pass out. A characteristic squatting position may be assumed to help assist breathing. Severe attacks may lead to the loss consciousness, and occasionally to convulsions or temporary paralysis on one side of the body (hemiparesis). These spells may last for a few minutes to a few hours and may be followed by periods of muscle weakness and a prolonged period of sleep.A variety of other complications may occur in association with tetralogy of Fallot. These may include mild anemia in infants, abnormal increase in the number of red blood cells (polycythemia) in older children, and blood clotting (coagulation) defects. These blood abnormalities may lead to the formation of blood clots that can travel through the blood stream (embolisms). These blood clots may cause the blood supply to the brain (cerebral infarctions) to be interrupted temporarily.
Additional complications may include infectious inflammation of the sinuses (sinusitis) and brain abscesses. In some cases, the connection between the aorta and the pulmonary artery, which normally closes before birth, may remain open (patent ductus arteriosus). The symptoms associated with this condition vary depending upon the size of the opening and may include rapid breathing, frequent respiratory infections, and easy fatigability. Congestive heart failure is rare, except in association with bacterial infection of the heart (endocarditis) or abnormal heart rhythms (arrhythmias). However, a common sign is a heart murmur, or an extra sound heard while listening to the heartbeat. The most severe form of tetralogy of Fallot is known as pseudotruncus arteriosus. Infants with this form of the disorder experience severe symptoms that relate to the profound obstruction of the right ventricular blood flow and severe underdevelopment of associated blood vessels and valves related to the lungs (pulmonary atresia). Ventricular septal defects are usually severe in this form of the disorder. Severe cyanosis, alarmingly low levels of circulating oxygen, and excessive circulating red blood cells (polycythemia) are the major features of pseudotruncus arteriosus. (For more information, see “Ventricular Septal Defect” in the Related Disorders section of this report.)
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Causes of Tetralogy of Fallot
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The exact cause of tetralogy of Fallot is not known. However, some studies suggest that the disorder may be due to the interaction of several genetic and/or environmental factors (multifactorial). Therefore, researchers suspect that something may affect the genes in the developing fetus, causing this birth defect, but the exact nature of this trigger is not known.Some conditions that may increase the risk of having a child with tetralogy of Fallot are viral illnesses, alcohol use, diabetes, poor nutrition, and being pregnant over the age of 40.Approximately 25 percent of infants with tetralogy of Fallot also have other congenital birth defects that are not related to the function or structure of the heart.
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Causes of Tetralogy of Fallot. The exact cause of tetralogy of Fallot is not known. However, some studies suggest that the disorder may be due to the interaction of several genetic and/or environmental factors (multifactorial). Therefore, researchers suspect that something may affect the genes in the developing fetus, causing this birth defect, but the exact nature of this trigger is not known.Some conditions that may increase the risk of having a child with tetralogy of Fallot are viral illnesses, alcohol use, diabetes, poor nutrition, and being pregnant over the age of 40.Approximately 25 percent of infants with tetralogy of Fallot also have other congenital birth defects that are not related to the function or structure of the heart.
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Affects of Tetralogy of Fallot
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Tetralogy of Fallot is a rare congenital malformation of the heart that occurs more frequently in males than females. Approximately 1 percent of newborns have congenital heart defects. About 10 percent of these infants are diagnosed with tetralogy of Fallot. This heart defect is usually detected weeks or months after birth. The prevalence of tetralogy of Fallot is estimated to be 1 in 3,000 live births.Children with chromosome disorders, such as Down syndrome, often have tetralogy of Fallot and other congenital heart diseases.
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Affects of Tetralogy of Fallot. Tetralogy of Fallot is a rare congenital malformation of the heart that occurs more frequently in males than females. Approximately 1 percent of newborns have congenital heart defects. About 10 percent of these infants are diagnosed with tetralogy of Fallot. This heart defect is usually detected weeks or months after birth. The prevalence of tetralogy of Fallot is estimated to be 1 in 3,000 live births.Children with chromosome disorders, such as Down syndrome, often have tetralogy of Fallot and other congenital heart diseases.
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Related disorders of Tetralogy of Fallot
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Symptoms of the following disorders can be similar to those of tetralogy of Fallot. Comparisons may be useful for a differential diagnosis:Atrial septal defects (ASDs) are common congenital heart defects characterized by the presence of a small opening between the two atria of the heart. These defects lead to an increase in the workload on the right side of the heart as well as excessive blood flow to the lungs. The symptoms, which vary greatly, may become apparent during infancy, childhood, or adulthood, depend on the severity of the defect. The symptoms tend to be mild at first and may include difficulty breathing (dyspnea), increased susceptibility to respiratory infections, and abnormal bluish discoloration of the skin and/or mucous membranes (cyanosis). Some people with ASDs may be at increased risk for the formation of blood clots that can travel to the major arteries (embolism), blocking blood circulation. (For more information on this disorder, choose “Atrial Septal Defect” as your search term in the Rare Disease Database.)Ventricular septal defects (VSDs) are a group of common congenital heart defects characterized by the absence of one ventricle. Infants with these defects may have 2 atria and 1 large ventricle. Symptoms of these conditions are similar to those of other congenital heart defects and may include an abnormally rapid rate of breathing (tachypnea), blue color to the skin (cyanosis), wheezing, a rapid heart-beat (tachycardia), and/or an abnormally enlarged liver (hepatomegaly). VSDs can also cause the excessive accumulation of fluid around the heart, leading to congestive heart failure. (For more information on this disorder, choose “Ventricular Septal Defect” as your search term in the Rare Disease Database.)Atrioventricular septal defect (AVSD) is a rare heart defect that is present at birth (congenital) and is characterized by the improper development of the septa and valves of the heart. Infants with the complete form of the defect usually develop congestive heart failure. Excessive fluid accumulates in other areas of the body, especially the lungs. Pulmonary congestion may lead to difficulty breathing (dyspnea). Other symptoms may include a bluish discoloration of the skin (cyanosis), poor feeding habits, abnormally rapid breathing (tachypnea) and heart rate (tachycardia), and/or excessive sweating (hyperhidrosis). Adults with AVSD may experience abnormally low blood pressure, irregular heartbeats, and/or a rapid heartbeat. (For more information on this disorder, choose “Atrioventricular Septal Defect” as your search term in the Rare Disease Database.)Cor triatriatum is an extremely rare congenital heart defect characterized by the presence of an extra chamber above the left atrium of the heart. The pulmonary veins, returning blood from the lungs, drain into this extra “third atrium.” The symptoms of cor triatriatum vary greatly and depend on the size of the opening between the chambers. Symptoms may include abnormally rapid breathing (tachypnea), bluish discoloration to the skin (cyanosis), wheezing, coughing, and/or abnormal accumulation of fluid in the lungs (pulmonary congestion). (For more information on this disorder, choose “Cor Triatriatum” as your search term in the Rare Disease Database.)Cor triloculare biatriatum is an extremely rare congenital heart defect characterized by the absence of one ventricle. Infants with this defect have 2 atria and 1 large ventricle. The symptoms are similar to those of other congenital heart defects and may include breathing difficulties (dyspnea), excessive accumulation of fluid in the lungs and around the heart (pulmonary edema), and/or a bluish discoloration of the skin and mucous membranes (cyanosis). Other symptoms may include poor feeding habits, abnormally rapid breathing (tachypnea), and/or an abnormally rapid heartbeat (tachycardia).Mitral valve stenosis is a rare heart defect that may be present at birth (congenital) or acquired. It is characterized by the abnormal narrowing of the opening of the mitral valve. In the congenital form, the symptoms vary greatly and may include coughing, difficulty breathing, heart palpitations, and/or frequent respiratory infections. In acquired mitral valve stenosis, the symptoms may also include weakness, abdominal discomfort, chest pain (angina), and/or periodic loss of consciousness.
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Related disorders of Tetralogy of Fallot. Symptoms of the following disorders can be similar to those of tetralogy of Fallot. Comparisons may be useful for a differential diagnosis:Atrial septal defects (ASDs) are common congenital heart defects characterized by the presence of a small opening between the two atria of the heart. These defects lead to an increase in the workload on the right side of the heart as well as excessive blood flow to the lungs. The symptoms, which vary greatly, may become apparent during infancy, childhood, or adulthood, depend on the severity of the defect. The symptoms tend to be mild at first and may include difficulty breathing (dyspnea), increased susceptibility to respiratory infections, and abnormal bluish discoloration of the skin and/or mucous membranes (cyanosis). Some people with ASDs may be at increased risk for the formation of blood clots that can travel to the major arteries (embolism), blocking blood circulation. (For more information on this disorder, choose “Atrial Septal Defect” as your search term in the Rare Disease Database.)Ventricular septal defects (VSDs) are a group of common congenital heart defects characterized by the absence of one ventricle. Infants with these defects may have 2 atria and 1 large ventricle. Symptoms of these conditions are similar to those of other congenital heart defects and may include an abnormally rapid rate of breathing (tachypnea), blue color to the skin (cyanosis), wheezing, a rapid heart-beat (tachycardia), and/or an abnormally enlarged liver (hepatomegaly). VSDs can also cause the excessive accumulation of fluid around the heart, leading to congestive heart failure. (For more information on this disorder, choose “Ventricular Septal Defect” as your search term in the Rare Disease Database.)Atrioventricular septal defect (AVSD) is a rare heart defect that is present at birth (congenital) and is characterized by the improper development of the septa and valves of the heart. Infants with the complete form of the defect usually develop congestive heart failure. Excessive fluid accumulates in other areas of the body, especially the lungs. Pulmonary congestion may lead to difficulty breathing (dyspnea). Other symptoms may include a bluish discoloration of the skin (cyanosis), poor feeding habits, abnormally rapid breathing (tachypnea) and heart rate (tachycardia), and/or excessive sweating (hyperhidrosis). Adults with AVSD may experience abnormally low blood pressure, irregular heartbeats, and/or a rapid heartbeat. (For more information on this disorder, choose “Atrioventricular Septal Defect” as your search term in the Rare Disease Database.)Cor triatriatum is an extremely rare congenital heart defect characterized by the presence of an extra chamber above the left atrium of the heart. The pulmonary veins, returning blood from the lungs, drain into this extra “third atrium.” The symptoms of cor triatriatum vary greatly and depend on the size of the opening between the chambers. Symptoms may include abnormally rapid breathing (tachypnea), bluish discoloration to the skin (cyanosis), wheezing, coughing, and/or abnormal accumulation of fluid in the lungs (pulmonary congestion). (For more information on this disorder, choose “Cor Triatriatum” as your search term in the Rare Disease Database.)Cor triloculare biatriatum is an extremely rare congenital heart defect characterized by the absence of one ventricle. Infants with this defect have 2 atria and 1 large ventricle. The symptoms are similar to those of other congenital heart defects and may include breathing difficulties (dyspnea), excessive accumulation of fluid in the lungs and around the heart (pulmonary edema), and/or a bluish discoloration of the skin and mucous membranes (cyanosis). Other symptoms may include poor feeding habits, abnormally rapid breathing (tachypnea), and/or an abnormally rapid heartbeat (tachycardia).Mitral valve stenosis is a rare heart defect that may be present at birth (congenital) or acquired. It is characterized by the abnormal narrowing of the opening of the mitral valve. In the congenital form, the symptoms vary greatly and may include coughing, difficulty breathing, heart palpitations, and/or frequent respiratory infections. In acquired mitral valve stenosis, the symptoms may also include weakness, abdominal discomfort, chest pain (angina), and/or periodic loss of consciousness.
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Diagnosis of Tetralogy of Fallot
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The diagnosis of tetralogy of Fallot is confirmed by clinical evaluation and physical examination. A variety of specialized tests including electrocardiogram, echocardiogram, and cardiac catheterization may be performed to aid in diagnosis and therapy. When tetralogy of Fallot is present, x-ray studies usually reveal a normal-sized heart that is characteristically boot-shaped (coeur en sabot). Periodic measurements of systemic blood oxygen saturation and hemoglobin are also advisable. Infants with this disorder usually have a relatively loud murmur over the upper left breastbone.
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Diagnosis of Tetralogy of Fallot. The diagnosis of tetralogy of Fallot is confirmed by clinical evaluation and physical examination. A variety of specialized tests including electrocardiogram, echocardiogram, and cardiac catheterization may be performed to aid in diagnosis and therapy. When tetralogy of Fallot is present, x-ray studies usually reveal a normal-sized heart that is characteristically boot-shaped (coeur en sabot). Periodic measurements of systemic blood oxygen saturation and hemoglobin are also advisable. Infants with this disorder usually have a relatively loud murmur over the upper left breastbone.
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Therapies of Tetralogy of Fallot
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TreatmentThe definitive treatment for tetralogy of Fallot is surgery (i.e., Blalock-Taussig shunting procedure, aortic/pulmonary shunt, intracardiac repair, balloon pulmonary valvuloplasty and/or valve replacement). Surgical correction of this heart malformation is best accomplished during infancy. Selection of the exact surgical procedure is based on the severity of symptoms and extent of the malformation. The surgeon will widen the pulmonary valve and the passage from the right ventricle to the pulmonary artery is enlarged. A patch covers the hole in the septum to repair the ventricular septal defect. By resolving the VSD and the pulmonary valve problems, it fixes the other two defects.Temporary surgery may be recommended babies are too weak or small to have the full repair surgery; the full repair surgery will be performed when the baby is stronger. A tube or a “shunt” is placed between a large artery branching off the aorta and the pulmonary artery. It creates a pathway for blood to travel to the lungs to get oxygen. The tube is removed during the full repair surgery.When early repair is not possible, other surgical measures may be taken during infancy or early childhood. Prior to surgery, treatment to control symptoms (palliative) may include the maintenance of adequate fluid intake (hydration), monitoring of hemoglobin levels in the blood, and the avoidance of strenuous exercise. Heart medications (i.e., digitalis) may be prescribed to help control irregular heartbeats (arrhythmias), rapid heartbeats, and/or heart failure.Episodes of severe symptoms or “blue spells” (hypoxia) may require the administration of supplemental oxygen, morphine, and/or other drugs that improve oxygen concentration. The knee-chest position may also bring some symptomatic relief. Sodium bicarbonate may be administered to lower abnormally high levels of acid in the blood (acidosis). The drug propranolol may be given to help prevent future spells and to reduce their severity. Drugs that help to remove excess fluid from the body (diuretics), dietary salt restriction, and bed rest may be effective in treating congestive heart failure.Antibiotics may be prescribed to infants with tetralogy of Fallot to help prevent infections (prophylaxis) because children with this disorder are susceptible to bacterial infection of the heart (endocarditis). Respiratory infections must be treated vigorously and early. Children should be given antibiotics at times of predictable risk (e.g., tooth extractions and surgery). Other treatment is symptomatic and supportive.Although the risk for tetralogy of Fallot in the siblings of infants with this disorder is thought to be very low, genetic counseling may be of benefit for parents and other family members.
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Therapies of Tetralogy of Fallot. TreatmentThe definitive treatment for tetralogy of Fallot is surgery (i.e., Blalock-Taussig shunting procedure, aortic/pulmonary shunt, intracardiac repair, balloon pulmonary valvuloplasty and/or valve replacement). Surgical correction of this heart malformation is best accomplished during infancy. Selection of the exact surgical procedure is based on the severity of symptoms and extent of the malformation. The surgeon will widen the pulmonary valve and the passage from the right ventricle to the pulmonary artery is enlarged. A patch covers the hole in the septum to repair the ventricular septal defect. By resolving the VSD and the pulmonary valve problems, it fixes the other two defects.Temporary surgery may be recommended babies are too weak or small to have the full repair surgery; the full repair surgery will be performed when the baby is stronger. A tube or a “shunt” is placed between a large artery branching off the aorta and the pulmonary artery. It creates a pathway for blood to travel to the lungs to get oxygen. The tube is removed during the full repair surgery.When early repair is not possible, other surgical measures may be taken during infancy or early childhood. Prior to surgery, treatment to control symptoms (palliative) may include the maintenance of adequate fluid intake (hydration), monitoring of hemoglobin levels in the blood, and the avoidance of strenuous exercise. Heart medications (i.e., digitalis) may be prescribed to help control irregular heartbeats (arrhythmias), rapid heartbeats, and/or heart failure.Episodes of severe symptoms or “blue spells” (hypoxia) may require the administration of supplemental oxygen, morphine, and/or other drugs that improve oxygen concentration. The knee-chest position may also bring some symptomatic relief. Sodium bicarbonate may be administered to lower abnormally high levels of acid in the blood (acidosis). The drug propranolol may be given to help prevent future spells and to reduce their severity. Drugs that help to remove excess fluid from the body (diuretics), dietary salt restriction, and bed rest may be effective in treating congestive heart failure.Antibiotics may be prescribed to infants with tetralogy of Fallot to help prevent infections (prophylaxis) because children with this disorder are susceptible to bacterial infection of the heart (endocarditis). Respiratory infections must be treated vigorously and early. Children should be given antibiotics at times of predictable risk (e.g., tooth extractions and surgery). Other treatment is symptomatic and supportive.Although the risk for tetralogy of Fallot in the siblings of infants with this disorder is thought to be very low, genetic counseling may be of benefit for parents and other family members.
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Overview of Thoracic Outlet Syndrome
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*This condition is no longer considered rareThoracic outlet syndrome (TOS) is a condition presenting with arm complaints of pain, numbness, tingling and weakness. The cause is pressure in the neck against the nerves and blood vessels that go to the arm.There are three types of TOS depending on which structure is being compressed:
1. Neurogenic TOS-nerve compression comprises 95% of all TOS patients2. Venous TOS-compression of the main vein comprises 4% of all TOS patients3. Arterial TOS-compression of the main artery comprises less than 1% of all TOS patients4. Vascular TOS is a term sometimes used but there is no such entity as vascular TOS. The term refers to TOS due either to compression of an artery or vein (arterial or venous TOS). The appropriate terms, arterial or venous, should be employed and the term vascular discarded.The three types of TOS are very different from each other. Each will be described separately.
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Overview of Thoracic Outlet Syndrome. *This condition is no longer considered rareThoracic outlet syndrome (TOS) is a condition presenting with arm complaints of pain, numbness, tingling and weakness. The cause is pressure in the neck against the nerves and blood vessels that go to the arm.There are three types of TOS depending on which structure is being compressed:
1. Neurogenic TOS-nerve compression comprises 95% of all TOS patients2. Venous TOS-compression of the main vein comprises 4% of all TOS patients3. Arterial TOS-compression of the main artery comprises less than 1% of all TOS patients4. Vascular TOS is a term sometimes used but there is no such entity as vascular TOS. The term refers to TOS due either to compression of an artery or vein (arterial or venous TOS). The appropriate terms, arterial or venous, should be employed and the term vascular discarded.The three types of TOS are very different from each other. Each will be described separately.
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Symptoms of Thoracic Outlet Syndrome
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Neurogenic TOS presents with pain, weakness, numbness and tingling in the hand and arm. Additionally, neck pain and headache in the back of the head are common.Venous TOS, also known as Paget-Schroetter disease, presents with arm swelling, blue or dark discoloration, and a feeling of fullness or aching in the arm.Arterial TOS presents with coldness, numbness, tingling, pain, and white discoloration in the fingers or whole hand. Cramping of the forearm and hand with activity (claudication) is common. Pain usually involves the hand and arm, but not the neck or shoulder.
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Symptoms of Thoracic Outlet Syndrome. Neurogenic TOS presents with pain, weakness, numbness and tingling in the hand and arm. Additionally, neck pain and headache in the back of the head are common.Venous TOS, also known as Paget-Schroetter disease, presents with arm swelling, blue or dark discoloration, and a feeling of fullness or aching in the arm.Arterial TOS presents with coldness, numbness, tingling, pain, and white discoloration in the fingers or whole hand. Cramping of the forearm and hand with activity (claudication) is common. Pain usually involves the hand and arm, but not the neck or shoulder.
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Causes of Thoracic Outlet Syndrome
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Neurogenic TOS is most often caused by neck trauma, whiplash injuries or repetitive stress injury at work being the most common events that bring on symptoms. The injury results in over-stretching neck muscles which heal by forming scar tissue in the muscle. This in turn puts pressure against the nerves to the arm which causes the symptoms.Venous TOS is often caused by strenuous use of the arm which irritates the main vein to the arm (subclavian vein) lying behind the collar bone (the clavicle). Pressure against the vein is due to variations in normal anatomy. Most people have adequate room for the main vein to travel from the arm to reach the heart. However, some people are born with a very narrow space through which the vein travels. These people are the ones who can develop obstruction and clots in the vein from excessive arm and shoulder activity.Arterial TOS is caused by clot formation in the artery to the arm (subclavian artery) in the area just behind the collar bone. Even when a clot forms, most people do not develop symptoms until the clot breaks into small pieces which flow down the arm to block arterial circulation at the elbow or hand. The clot formation is due to changes in the artery as a result of a congenital extra rib, called a cervical rib or abnormal first rib.
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Causes of Thoracic Outlet Syndrome. Neurogenic TOS is most often caused by neck trauma, whiplash injuries or repetitive stress injury at work being the most common events that bring on symptoms. The injury results in over-stretching neck muscles which heal by forming scar tissue in the muscle. This in turn puts pressure against the nerves to the arm which causes the symptoms.Venous TOS is often caused by strenuous use of the arm which irritates the main vein to the arm (subclavian vein) lying behind the collar bone (the clavicle). Pressure against the vein is due to variations in normal anatomy. Most people have adequate room for the main vein to travel from the arm to reach the heart. However, some people are born with a very narrow space through which the vein travels. These people are the ones who can develop obstruction and clots in the vein from excessive arm and shoulder activity.Arterial TOS is caused by clot formation in the artery to the arm (subclavian artery) in the area just behind the collar bone. Even when a clot forms, most people do not develop symptoms until the clot breaks into small pieces which flow down the arm to block arterial circulation at the elbow or hand. The clot formation is due to changes in the artery as a result of a congenital extra rib, called a cervical rib or abnormal first rib.
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Affects of Thoracic Outlet Syndrome
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Affects of Thoracic Outlet Syndrome.
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Related disorders of Thoracic Outlet Syndrome
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Pectoralis minor syndrome (PMS) is a condition causing pain, numbness and tingling in the hand and arm. It often coexists with thoracic outlet syndrome (TOS) but can also occur alone.The symptoms are similar to those of TOS: Pain, weakness, numbness and tingling in the hand and arm. But in PMS there also is pain or tenderness in the chest wall below the collar bone and often in the arm pit as well. Like TOS, there may be pain above the shoulder blade in back as well as in the neck. While theoretically this can involve the nerves, vein, and artery to the arm, just like TOS, it rarely involves the vein and artery. It primarily puts pressure on the nerves.The cause is tightness in the pectoralis minor muscle (lying just below the collar bone) which is located just under the major pec muscle in the front of the chest, under the breast. The condition is often brought about by trauma to the neck or excessive stretching of the shoulder. It is important to note that the symptoms not only are similar to TOS but that the two condtions often exist together.The distinguishing feature of PMS is there is tenderness over the chest Wall just below the collar bone as well as tenderness in the arm pit. The best test for PMS is a pectoralis minor muscle block. Physical therapy is the initial treatment. Cutting the pectoralis minor tendon at its insertion on the bone below the collar bone (the coracoid process) is the surgical treatment.In children, Pectoralis minor syndrome (PMS) is often caused by competitive sports invoving use of the arm for vigorous throwing, such as swimming, baseball, baooeyball, and similar activities. It usually elecits neurogenic PMS, but occassionally eleicts venous PMS and rarely arterial PMS.
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Related disorders of Thoracic Outlet Syndrome. Pectoralis minor syndrome (PMS) is a condition causing pain, numbness and tingling in the hand and arm. It often coexists with thoracic outlet syndrome (TOS) but can also occur alone.The symptoms are similar to those of TOS: Pain, weakness, numbness and tingling in the hand and arm. But in PMS there also is pain or tenderness in the chest wall below the collar bone and often in the arm pit as well. Like TOS, there may be pain above the shoulder blade in back as well as in the neck. While theoretically this can involve the nerves, vein, and artery to the arm, just like TOS, it rarely involves the vein and artery. It primarily puts pressure on the nerves.The cause is tightness in the pectoralis minor muscle (lying just below the collar bone) which is located just under the major pec muscle in the front of the chest, under the breast. The condition is often brought about by trauma to the neck or excessive stretching of the shoulder. It is important to note that the symptoms not only are similar to TOS but that the two condtions often exist together.The distinguishing feature of PMS is there is tenderness over the chest Wall just below the collar bone as well as tenderness in the arm pit. The best test for PMS is a pectoralis minor muscle block. Physical therapy is the initial treatment. Cutting the pectoralis minor tendon at its insertion on the bone below the collar bone (the coracoid process) is the surgical treatment.In children, Pectoralis minor syndrome (PMS) is often caused by competitive sports invoving use of the arm for vigorous throwing, such as swimming, baseball, baooeyball, and similar activities. It usually elecits neurogenic PMS, but occassionally eleicts venous PMS and rarely arterial PMS.
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Diagnosis of Thoracic Outlet Syndrome
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Neurogenic TOS is diagnosed by using provocative maneuvers to elicit (or provoke) symptoms. These maneuvers put the neck and arms in certain positions which put stress on the nerves to the arm to bring on the symptoms of pain, numbness and tingling in the hand, arm, and neck. Some of these maneuvers have been shown to be unreliable because positive responses are found in many healthy individuals. These include the Adson test, Roos Test, and Wright Test. Other provocative maneuvers which provide greater reliability and seldom are positive in healthy people include rotating the neck or tilt the head to one side which causes symptoms to appear on the opposite side. Another provocative maneuver is extending one arm to the side, bending the wrist upward, and tilting the head to the opposite side (called the upper limb tension test). When all of these maneuvers elicit the same symptoms a diagnosis of neurogenic TOS is highly likely.Few tests are helpful in making the diagnosis of neurogenic TOS. The most helpful test is a scalene muscle block. This is performed by injecting a small amount of local anesthetic directly into the scalene muscles of the neck. A positive response is improvement of symptoms at rest as well as with the provocative maneuvers which occurs within one or two minutes of the injection. A similar muscle block test is helpful in diagnosing neurogenic PMS.Nerve tests such as EMG and NCV tests are usually normal. The one exception is that people who have an extra rib (cervical rib) plus arm weakness and atrophy of hand muscles usually have abnormal nerve tests indicating ulnar nerve abnormalities. However, recent introduction of a new nerve test, the MAC test (abreviation for medial antebrachial cutaneous nerve) has proven to be very useful, particularly in people who have symptoms in just one arm. In these people, the good arm serves as a baseline from which to compare the symptomatic arm.X-rays are usually normal but are worth obtaining as they may demonstrate an extra rib in the neck (cervical rib). While less than 5% of people with neurogenic TOS have an extra rib, when present it is helpful in confirming a diagnosis. Newer diagnostic tests which have yet to prove themselves include MRI of the brachial plexus and injection of dye around the brachial plexus (neurography). The problem with the latter tests is that many healthy individuals demonstrate abnormalities with these examinations.Arteriography is helpful in the diagnoses of arterial TOS and PMS but should not be used to diagnose neurogenic TOS or PMS. The reason is that healthy individuals can reveal narrowing in the artery when the arm is elevated. This makes demonstrating narrowing of an artery to the arm in patients with nerve symptoms of no value in the diagnosis of a nerve problem.Recognition of arterial and venous TOS is usually not too difficult as there are objective tests available to confirm the diagnosis and there are very few other conditions that resemble them. However, neurogenic TOS, by far the most common type of TOS, is more difficult to diagnose because other neurogenic conditions mimic it. An understanding of the anatomy of nerves to the arm is helpful. A nerve is like a telephone wire running from a telephone pole down the street into your house. Damage to the wire anywhere along its course will produce the same result namely cutting off the phone you pick up. Nerves to your hand begin in the neck and run to the fingers like a single wire. Pressure against the nerve anywhere along its course will produce the same symptoms in the hand, namely numbness, tingling, pain, and weakness. The pressure points where this is likely to occur are at the wrist causing carpal tunnel syndrome, in the forearm producing pronator or radial tunnel syndrome, at the elbow against the ulnar nerve causing cuboid tunnel syndrome, below the collar bone under the pectoralis minor muscle eliciting pectoralis minor syndrome, at the side of the neck causing thoracic outlet syndrome, or in the cervical spine produced by cervical disc disease or cervical arthritis. Therefore pressure at any of these points elicits symptoms similar to neurogenic TOS and each of these conditions must be looked for on physical examination and tested for by diagnostic nerve studies. To make diagnosis even more confusing, these other conditions can exist along with neurogenic TOS as associated conditions (called double crush syndrome) or they may be the primary diagnosis instead of neurogenic TOS.Venous TOS is fairly easily recognized by swelling of the entire arm and hand. Superficial veins that lie just under the skin are more prominent in the involved arm, shoulder, and over the chest wall of the involved side. The arm may or may not be dark in color.The only tests that help diagnose venous obstruction are Doppler or duplex examinations and venography (injecting dye in to the vein of the arm).Arterial TOS is recognized by a hand that is colder and paler than the opposite normal hand of that person. The pulse at the wrist is usually diminished or absent.Tests helpful in the diagnosis of arterial TOS are non-invasive pulse-volume recordings (non-invasive vascular lab studies) and arteriography (injecting dye into the artery).
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Diagnosis of Thoracic Outlet Syndrome. Neurogenic TOS is diagnosed by using provocative maneuvers to elicit (or provoke) symptoms. These maneuvers put the neck and arms in certain positions which put stress on the nerves to the arm to bring on the symptoms of pain, numbness and tingling in the hand, arm, and neck. Some of these maneuvers have been shown to be unreliable because positive responses are found in many healthy individuals. These include the Adson test, Roos Test, and Wright Test. Other provocative maneuvers which provide greater reliability and seldom are positive in healthy people include rotating the neck or tilt the head to one side which causes symptoms to appear on the opposite side. Another provocative maneuver is extending one arm to the side, bending the wrist upward, and tilting the head to the opposite side (called the upper limb tension test). When all of these maneuvers elicit the same symptoms a diagnosis of neurogenic TOS is highly likely.Few tests are helpful in making the diagnosis of neurogenic TOS. The most helpful test is a scalene muscle block. This is performed by injecting a small amount of local anesthetic directly into the scalene muscles of the neck. A positive response is improvement of symptoms at rest as well as with the provocative maneuvers which occurs within one or two minutes of the injection. A similar muscle block test is helpful in diagnosing neurogenic PMS.Nerve tests such as EMG and NCV tests are usually normal. The one exception is that people who have an extra rib (cervical rib) plus arm weakness and atrophy of hand muscles usually have abnormal nerve tests indicating ulnar nerve abnormalities. However, recent introduction of a new nerve test, the MAC test (abreviation for medial antebrachial cutaneous nerve) has proven to be very useful, particularly in people who have symptoms in just one arm. In these people, the good arm serves as a baseline from which to compare the symptomatic arm.X-rays are usually normal but are worth obtaining as they may demonstrate an extra rib in the neck (cervical rib). While less than 5% of people with neurogenic TOS have an extra rib, when present it is helpful in confirming a diagnosis. Newer diagnostic tests which have yet to prove themselves include MRI of the brachial plexus and injection of dye around the brachial plexus (neurography). The problem with the latter tests is that many healthy individuals demonstrate abnormalities with these examinations.Arteriography is helpful in the diagnoses of arterial TOS and PMS but should not be used to diagnose neurogenic TOS or PMS. The reason is that healthy individuals can reveal narrowing in the artery when the arm is elevated. This makes demonstrating narrowing of an artery to the arm in patients with nerve symptoms of no value in the diagnosis of a nerve problem.Recognition of arterial and venous TOS is usually not too difficult as there are objective tests available to confirm the diagnosis and there are very few other conditions that resemble them. However, neurogenic TOS, by far the most common type of TOS, is more difficult to diagnose because other neurogenic conditions mimic it. An understanding of the anatomy of nerves to the arm is helpful. A nerve is like a telephone wire running from a telephone pole down the street into your house. Damage to the wire anywhere along its course will produce the same result namely cutting off the phone you pick up. Nerves to your hand begin in the neck and run to the fingers like a single wire. Pressure against the nerve anywhere along its course will produce the same symptoms in the hand, namely numbness, tingling, pain, and weakness. The pressure points where this is likely to occur are at the wrist causing carpal tunnel syndrome, in the forearm producing pronator or radial tunnel syndrome, at the elbow against the ulnar nerve causing cuboid tunnel syndrome, below the collar bone under the pectoralis minor muscle eliciting pectoralis minor syndrome, at the side of the neck causing thoracic outlet syndrome, or in the cervical spine produced by cervical disc disease or cervical arthritis. Therefore pressure at any of these points elicits symptoms similar to neurogenic TOS and each of these conditions must be looked for on physical examination and tested for by diagnostic nerve studies. To make diagnosis even more confusing, these other conditions can exist along with neurogenic TOS as associated conditions (called double crush syndrome) or they may be the primary diagnosis instead of neurogenic TOS.Venous TOS is fairly easily recognized by swelling of the entire arm and hand. Superficial veins that lie just under the skin are more prominent in the involved arm, shoulder, and over the chest wall of the involved side. The arm may or may not be dark in color.The only tests that help diagnose venous obstruction are Doppler or duplex examinations and venography (injecting dye in to the vein of the arm).Arterial TOS is recognized by a hand that is colder and paler than the opposite normal hand of that person. The pulse at the wrist is usually diminished or absent.Tests helpful in the diagnosis of arterial TOS are non-invasive pulse-volume recordings (non-invasive vascular lab studies) and arteriography (injecting dye into the artery).
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Therapies of Thoracic Outlet Syndrome
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TreatmentThere are essentially two ways to treat TOS, non-surgical, which is called conservative, or surgical. Neurogenic TOS is always initially treated with physical therapy. Many patients improve with this treatment and nothing further is needed.Neurogenic TOS can be treated surgically if conservative therapy fails and a patient is still having significant symptoms. Surgery involves removing pressure from the nerves to the arm by either removing the scalene muscles in the neck, removing the first rib which requires detaching the scalene muscles, or doing both scalene muscle and first rib removal. The choice of operations depends on the experience of the surgeon as each of these operations has about the same success rate.Venous TOS is initially treated with thrombolytic drugs and anticoagulants (blood thinning drugs). Once the initial blood clot has been dissolved, surgery may be required to treat the underlying condition that caused the clot to prevent it from recurring.Venous TOS is surgically treated by first rib resection including removing the bands and ligaments that surround the subclavian vein. In patients where the vein is totally occluded a bypass graft is sometimes performed to restore venous circulation from the arm.Arterial TOS has no non-surgical treatment. Physical therapy does not help.Surgery for arterial TOS includes two steps: First removing the extra rib or the abnormal rib; then the damaged artery is excised and circulation restored by sewing the two ends of the artery together if the aneurysm was small, or with an arterial replacement graft.
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Therapies of Thoracic Outlet Syndrome. TreatmentThere are essentially two ways to treat TOS, non-surgical, which is called conservative, or surgical. Neurogenic TOS is always initially treated with physical therapy. Many patients improve with this treatment and nothing further is needed.Neurogenic TOS can be treated surgically if conservative therapy fails and a patient is still having significant symptoms. Surgery involves removing pressure from the nerves to the arm by either removing the scalene muscles in the neck, removing the first rib which requires detaching the scalene muscles, or doing both scalene muscle and first rib removal. The choice of operations depends on the experience of the surgeon as each of these operations has about the same success rate.Venous TOS is initially treated with thrombolytic drugs and anticoagulants (blood thinning drugs). Once the initial blood clot has been dissolved, surgery may be required to treat the underlying condition that caused the clot to prevent it from recurring.Venous TOS is surgically treated by first rib resection including removing the bands and ligaments that surround the subclavian vein. In patients where the vein is totally occluded a bypass graft is sometimes performed to restore venous circulation from the arm.Arterial TOS has no non-surgical treatment. Physical therapy does not help.Surgery for arterial TOS includes two steps: First removing the extra rib or the abnormal rib; then the damaged artery is excised and circulation restored by sewing the two ends of the artery together if the aneurysm was small, or with an arterial replacement graft.
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Overview of Three M Syndrome
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Three M syndrome is an extremely rare genetic disorder characterized by low birth weight, short stature (dwarfism), characteristic abnormalities of the head and facial (craniofacial) area, distinctive skeletal malformations, and/or other physical abnormalities. Characteristic craniofacial malformations typically include a long, narrow head (dolichocephaly), an unusually prominent forehead (frontal bossing), and a triangular-shaped face with a prominent, pointed chin, large ears, and/or abnormally flat cheeks. In addition, in some affected children, the teeth may be abnormally crowded together; as a result, the upper and lower teeth may not meet properly (malocclusion). Skeletal abnormalities associated with the disorder include unusually thin bones, particularly the shafts of the long bones of the arms and legs (diaphyses); abnormally long, thin bones of the spinal column (vertebrae); and/or distinctive malformations of the ribs and shoulder blades (scapulae). Affected individuals may also have additional abnormalities including permanent fixation of certain fingers in a bent position (clinodactyly), unusually short fifth fingers, and/or increased flexibility (hyperextensibility) of the joints. The range and severity of symptoms and physicial features may vary from case to case. Intelligence appears to be normal. Three M syndrome is inherited as an autosomal recessive genetic trait.The name “three M” refers to the last initials of three researchers (J.D. Miller, V.A. McKusick, P. Malvaux) who were among the first to identify the disorder and report their findings in the medical literature in 1972.
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Overview of Three M Syndrome. Three M syndrome is an extremely rare genetic disorder characterized by low birth weight, short stature (dwarfism), characteristic abnormalities of the head and facial (craniofacial) area, distinctive skeletal malformations, and/or other physical abnormalities. Characteristic craniofacial malformations typically include a long, narrow head (dolichocephaly), an unusually prominent forehead (frontal bossing), and a triangular-shaped face with a prominent, pointed chin, large ears, and/or abnormally flat cheeks. In addition, in some affected children, the teeth may be abnormally crowded together; as a result, the upper and lower teeth may not meet properly (malocclusion). Skeletal abnormalities associated with the disorder include unusually thin bones, particularly the shafts of the long bones of the arms and legs (diaphyses); abnormally long, thin bones of the spinal column (vertebrae); and/or distinctive malformations of the ribs and shoulder blades (scapulae). Affected individuals may also have additional abnormalities including permanent fixation of certain fingers in a bent position (clinodactyly), unusually short fifth fingers, and/or increased flexibility (hyperextensibility) of the joints. The range and severity of symptoms and physicial features may vary from case to case. Intelligence appears to be normal. Three M syndrome is inherited as an autosomal recessive genetic trait.The name “three M” refers to the last initials of three researchers (J.D. Miller, V.A. McKusick, P. Malvaux) who were among the first to identify the disorder and report their findings in the medical literature in 1972.
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Symptoms of Three M Syndrome
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Three M syndrome is an extremely rare inherited disorder characterized by low birth weight, delayed bone age, and short stature; characteristic malformations of the head and facial (craniofacial) area; and/or finger (digital) and/or skeletal malformations.In most cases, infants with Three M syndrome are unusually small and have a low birth weight despite being carried to term. This is due to growth delays during fetal development (intrauterine growth retardation). Growth delays and immature bone development (growth retardation and delayed bone maturation) typically continue after birth (postnatally), leading to short stature (dwarfism) with proportional development of the arms and legs (as opposed to short stature with abnormally small arms and legs [short-limbed dwarfism]). Many affected infants also have distinctive abnormalities of the head and facial (craniofacial) area. In most cases, premature closure of fibrous joints (sagittal sutures) between certain bones (parietal bones) of the skull may restrict lateral growth of the head, causing it to appear abnormally long and narrow (dolichocephaly). In addition, the forehead may be abnormally prominent (frontal bossing), and the face may be triangular shaped with a prominent, pointed chin. Infants with the disorder may also have abnormally flat cheeks and cheekbones (malar area), large ears, a prominent mouth with widely spread (patulous) lips, and/or underdeveloped upper jaw bones (maxillary hypoplasia). In addition, in some cases, the teeth may be abnormally crowded together, particularly toward the front of the mouth (anterior crowding); as a result, the upper and lower teeth may not meet properly (malocclusion). In many infants with Three M syndrome, the neck may be abnormally short and wide, the muscles that cover the upper, back portion of the neck and shoulders (trapezius muscles) may be unusually large and prominent, and the shoulders may appear square and high with wide, flared shoulder blades (winged scapulae). In many cases, affected individuals may also have additional skeletal malformations. For example, the shafts of the long bones (diaphyses) of the arms and legs may be abnormally slender, a condition that tends to become more pronounced with age. The ribs may be narrow, with abnormal, thin depressions (grooves) above their edges (costal margins). Due to abnormalities of the elongated bone forming the middle portion of the chest (sternum), the chest may be abnormally short and/or may appear sunken (pectus excavatum) or unusually prominent (pectus carinatum). Affected infants may also have malformations of bones of the spinal column (vertebrae) including abnormally long, thin vertebrae. In some cases, additional skeletal malformations may include abnormal smallness of bones of the hips (ischium) and the pubic area. In a few cases, affected infants may have a malformation of the spinal column in which incomplete closure of certain vertebrae leaves a portion of the spinal cord exposed (spina bifida). (For more information on this condition, please choose “Spina Bifida” as your search term in the Rare Disease Database.)In some cases, individuals with Three M syndrome may have additional abnormalities. Affected individuals may have permanent fixation of certain fingers in a bent position (clinodactyly), abnormally short fifth fingers, and/or increased flexibility (hyperextensibility) of the joints.In some cases, individuals who carry a single copy of the disease gene for Three M syndrome (heterozygotes) may exhibit some of the physical findings associated with the disorder. Such findings are typically milder than those associated with full expression of the disorder. Such individuals (heterozygotes) may exhibit subtle craniofacial abnormalities, abnormally thin bones, and/or unusually prominent ankle bones (talus).
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Symptoms of Three M Syndrome. Three M syndrome is an extremely rare inherited disorder characterized by low birth weight, delayed bone age, and short stature; characteristic malformations of the head and facial (craniofacial) area; and/or finger (digital) and/or skeletal malformations.In most cases, infants with Three M syndrome are unusually small and have a low birth weight despite being carried to term. This is due to growth delays during fetal development (intrauterine growth retardation). Growth delays and immature bone development (growth retardation and delayed bone maturation) typically continue after birth (postnatally), leading to short stature (dwarfism) with proportional development of the arms and legs (as opposed to short stature with abnormally small arms and legs [short-limbed dwarfism]). Many affected infants also have distinctive abnormalities of the head and facial (craniofacial) area. In most cases, premature closure of fibrous joints (sagittal sutures) between certain bones (parietal bones) of the skull may restrict lateral growth of the head, causing it to appear abnormally long and narrow (dolichocephaly). In addition, the forehead may be abnormally prominent (frontal bossing), and the face may be triangular shaped with a prominent, pointed chin. Infants with the disorder may also have abnormally flat cheeks and cheekbones (malar area), large ears, a prominent mouth with widely spread (patulous) lips, and/or underdeveloped upper jaw bones (maxillary hypoplasia). In addition, in some cases, the teeth may be abnormally crowded together, particularly toward the front of the mouth (anterior crowding); as a result, the upper and lower teeth may not meet properly (malocclusion). In many infants with Three M syndrome, the neck may be abnormally short and wide, the muscles that cover the upper, back portion of the neck and shoulders (trapezius muscles) may be unusually large and prominent, and the shoulders may appear square and high with wide, flared shoulder blades (winged scapulae). In many cases, affected individuals may also have additional skeletal malformations. For example, the shafts of the long bones (diaphyses) of the arms and legs may be abnormally slender, a condition that tends to become more pronounced with age. The ribs may be narrow, with abnormal, thin depressions (grooves) above their edges (costal margins). Due to abnormalities of the elongated bone forming the middle portion of the chest (sternum), the chest may be abnormally short and/or may appear sunken (pectus excavatum) or unusually prominent (pectus carinatum). Affected infants may also have malformations of bones of the spinal column (vertebrae) including abnormally long, thin vertebrae. In some cases, additional skeletal malformations may include abnormal smallness of bones of the hips (ischium) and the pubic area. In a few cases, affected infants may have a malformation of the spinal column in which incomplete closure of certain vertebrae leaves a portion of the spinal cord exposed (spina bifida). (For more information on this condition, please choose “Spina Bifida” as your search term in the Rare Disease Database.)In some cases, individuals with Three M syndrome may have additional abnormalities. Affected individuals may have permanent fixation of certain fingers in a bent position (clinodactyly), abnormally short fifth fingers, and/or increased flexibility (hyperextensibility) of the joints.In some cases, individuals who carry a single copy of the disease gene for Three M syndrome (heterozygotes) may exhibit some of the physical findings associated with the disorder. Such findings are typically milder than those associated with full expression of the disorder. Such individuals (heterozygotes) may exhibit subtle craniofacial abnormalities, abnormally thin bones, and/or unusually prominent ankle bones (talus).
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Three M Syndrome
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nord_1205_2
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Causes of Three M Syndrome
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Three M syndrome is inherited as an autosomal recessive genetic trait. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. Individuals who carry a single copy of the defective gene for Three M syndrome (heterozygotes) may exhibit some mild physical findings associated with the disorder (e.g., subtle craniofacial abnormalities and/or unusually slender bones). Mutations in one of three genes are now known to cause 3-M syndrome: CUL7, OBSL1, and CCDC8. Because mutations in the three genes identified to date do not account for 100% of patients affected with 3-M syndrome, it is postulated that mutations of other genes (potentially members of the same pathway) may be involved.
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Causes of Three M Syndrome. Three M syndrome is inherited as an autosomal recessive genetic trait. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. Individuals who carry a single copy of the defective gene for Three M syndrome (heterozygotes) may exhibit some mild physical findings associated with the disorder (e.g., subtle craniofacial abnormalities and/or unusually slender bones). Mutations in one of three genes are now known to cause 3-M syndrome: CUL7, OBSL1, and CCDC8. Because mutations in the three genes identified to date do not account for 100% of patients affected with 3-M syndrome, it is postulated that mutations of other genes (potentially members of the same pathway) may be involved.
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Three M Syndrome
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nord_1205_3
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Affects of Three M Syndrome
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Three M syndrome is an extremely rare inherited disorder that appears to affect males and females in equal numbers. Approximately 25 cases have been reported in the medical literature since the disorder was first described in 1972.
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Affects of Three M Syndrome. Three M syndrome is an extremely rare inherited disorder that appears to affect males and females in equal numbers. Approximately 25 cases have been reported in the medical literature since the disorder was first described in 1972.
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nord_1205_4
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Related disorders of Three M Syndrome
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Symptoms of the following disorders may be similar to those of Three M syndrome. Comparisons may be useful for a differential diagnosis: Russell-Silver syndrome is a rare genetic disorder characterized by growth delay before birth (prenatal or intrauterine growth retardation); overgrowth of one side of the body (hemihypertrophy or asymmetry); characteristic facial malformations; and/or other physical abnormalities. Affected newborns may be abnormally small and have low birth weight. Because growth delay and immature bone development (delayed bone age) continue after birth (postnatally), affected children may exhibit short stature and be unusually small and thin for their age. In most cases, asymmetry or overgrowth of one side of the body is also obvious at birth. Characteristic facial abnormalities may include a triangular-shaped face with a small, pointed chin; an abnormally prominent forehead (frontal bossing); bluish discoloration of the tough, outer membranes covering the eyeballs (blue sclera); an unusually small, wide mouth; down-turned corners of the mouth; and/or an abnormally small jaw (micrognathia). Additional abnormalities may include permanent fixation of the fifth fingers in a bent position (clinodactyly); webbing of the second and third toes (syndactyly); underdevelopment (hypoplasia) of certain bones of the fingers (phalanges); development of smooth, coffee-colored patches on the skin (cafe-au-lait spots); and/or abnormalities of the kidneys and urinary tract. The range and severity of symptoms associated with the disorder vary greatly from case to case. Most cases of Russell-Silver syndrome are the result of genetic changes (mutations) that occur randomly for no apparent reason (sporadic). (For more information on this disorder, choose “Russell Silver” as your search term in the Rare Disease Database.) Bloom syndrome, a rare inherited disorder, is characterized by short stature (dwarfism) due to growth deficiency before and after birth (prenatal and postnatal growth retardation) and distinctive skin abnormalities of the facial area including the development of abnormally red, inflamed areas that resemble a mild sunburn (erythema), sensitivity of the skin to sunlight (photosensitivity), and abnormal widening (dilation) of groups of small blood vessels (telangiectasia) causing redness. Such skin abnormalities of the facial area are typically in a “butterfly” pattern across the cheeks and the nose. However, in some cases, skin abnormalities may also affect the forearms, hands, ears, and/or neck. Individuals with Bloom syndrome may also have characteristic abnormalities of the head and facial (craniofacial) area including underdeveloped cheekbones (malar hypoplasia), abnormal narrowness of the face, a prominent nose, and/or an unusually small lower jaw (mandible). In addition, affected individuals may be more prone to developing certain malignancies (e.g., leukemia, etc.) than the general population. Bloom syndrome is inherited as an autosomal recessive genetic trait. (For more information on this disorder, choose “Bloom” as your search term in the Rare Disease Database.) There are other rare inherited disorders that may be characterized by low birth weight, short stature, and/or craniofacial, finger (digital), and/or skeletal abnormalities similar to those occurring in association with Three M syndrome. (For more information on these disorders, choose the exact disease name in question as your search term in the Rare Disease Database.)
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Related disorders of Three M Syndrome. Symptoms of the following disorders may be similar to those of Three M syndrome. Comparisons may be useful for a differential diagnosis: Russell-Silver syndrome is a rare genetic disorder characterized by growth delay before birth (prenatal or intrauterine growth retardation); overgrowth of one side of the body (hemihypertrophy or asymmetry); characteristic facial malformations; and/or other physical abnormalities. Affected newborns may be abnormally small and have low birth weight. Because growth delay and immature bone development (delayed bone age) continue after birth (postnatally), affected children may exhibit short stature and be unusually small and thin for their age. In most cases, asymmetry or overgrowth of one side of the body is also obvious at birth. Characteristic facial abnormalities may include a triangular-shaped face with a small, pointed chin; an abnormally prominent forehead (frontal bossing); bluish discoloration of the tough, outer membranes covering the eyeballs (blue sclera); an unusually small, wide mouth; down-turned corners of the mouth; and/or an abnormally small jaw (micrognathia). Additional abnormalities may include permanent fixation of the fifth fingers in a bent position (clinodactyly); webbing of the second and third toes (syndactyly); underdevelopment (hypoplasia) of certain bones of the fingers (phalanges); development of smooth, coffee-colored patches on the skin (cafe-au-lait spots); and/or abnormalities of the kidneys and urinary tract. The range and severity of symptoms associated with the disorder vary greatly from case to case. Most cases of Russell-Silver syndrome are the result of genetic changes (mutations) that occur randomly for no apparent reason (sporadic). (For more information on this disorder, choose “Russell Silver” as your search term in the Rare Disease Database.) Bloom syndrome, a rare inherited disorder, is characterized by short stature (dwarfism) due to growth deficiency before and after birth (prenatal and postnatal growth retardation) and distinctive skin abnormalities of the facial area including the development of abnormally red, inflamed areas that resemble a mild sunburn (erythema), sensitivity of the skin to sunlight (photosensitivity), and abnormal widening (dilation) of groups of small blood vessels (telangiectasia) causing redness. Such skin abnormalities of the facial area are typically in a “butterfly” pattern across the cheeks and the nose. However, in some cases, skin abnormalities may also affect the forearms, hands, ears, and/or neck. Individuals with Bloom syndrome may also have characteristic abnormalities of the head and facial (craniofacial) area including underdeveloped cheekbones (malar hypoplasia), abnormal narrowness of the face, a prominent nose, and/or an unusually small lower jaw (mandible). In addition, affected individuals may be more prone to developing certain malignancies (e.g., leukemia, etc.) than the general population. Bloom syndrome is inherited as an autosomal recessive genetic trait. (For more information on this disorder, choose “Bloom” as your search term in the Rare Disease Database.) There are other rare inherited disorders that may be characterized by low birth weight, short stature, and/or craniofacial, finger (digital), and/or skeletal abnormalities similar to those occurring in association with Three M syndrome. (For more information on these disorders, choose the exact disease name in question as your search term in the Rare Disease Database.)
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nord_1205_5
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Diagnosis of Three M Syndrome
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In some cases, growth retardation and/or other characteristic findings suggestive of Three M syndrome may be detected before birth (prenatally) by ultrasound. In fetal ultrasonography, reflected sound waves are used to create an image of the developing fetus.In most cases, Three M syndrome is diagnosed shortly after birth, based upon a thorough clinical evaluation, identification of characteristic physical findings (e.g., low birth weight, short stature, characteristic craniofacial and skeletal malformations, etc.), and/or a variety of specialized tests, such as advanced imaging techniques. Specialized x-ray studies may detect, confirm, and/or characterize certain craniofacial malformations (e.g., dolicocephaly, maxillary hypoplasia) as well as other skeletal abnormalities often associated with the disorder such as distinctive malformations of the vertebrae, the long bones, the ribs, and/or the shoulder blades. It is possible that the diagnosis is made later during infancy, since the clinical and radiological anomalies can appear secondarily.Molecular genetic testing for mutations in th. CUL7 (77.5 %), OBSL1 (16%) or CCDC8 (rare) genes is available to confirm a suspected diagnosis.
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Diagnosis of Three M Syndrome. In some cases, growth retardation and/or other characteristic findings suggestive of Three M syndrome may be detected before birth (prenatally) by ultrasound. In fetal ultrasonography, reflected sound waves are used to create an image of the developing fetus.In most cases, Three M syndrome is diagnosed shortly after birth, based upon a thorough clinical evaluation, identification of characteristic physical findings (e.g., low birth weight, short stature, characteristic craniofacial and skeletal malformations, etc.), and/or a variety of specialized tests, such as advanced imaging techniques. Specialized x-ray studies may detect, confirm, and/or characterize certain craniofacial malformations (e.g., dolicocephaly, maxillary hypoplasia) as well as other skeletal abnormalities often associated with the disorder such as distinctive malformations of the vertebrae, the long bones, the ribs, and/or the shoulder blades. It is possible that the diagnosis is made later during infancy, since the clinical and radiological anomalies can appear secondarily.Molecular genetic testing for mutations in th. CUL7 (77.5 %), OBSL1 (16%) or CCDC8 (rare) genes is available to confirm a suspected diagnosis.
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Three M Syndrome
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Therapies of Three M Syndrome
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TreatmentThe treatment of Three M syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, physicians who specialize in treating skeletal disorders (orthopedists), dental specialists, and/or other health care professionals may need to systematically and comprehensively plan an affected child's treatment.In some cases, orthopedic techniques, surgery, and/or other supportive techniques may be used to help treat certain skeletal abnormalities associated with Three M syndrome. Surgery and/or supportive measures may also be used to help treat or correct certain craniofacial, digital, and/or other abnormalities associated with the disorder. In addition, in affected individuals with dental abnormalities, braces, oral surgery, and/or other corrective techniques may be used to help treat or correct such malformations.Genetic counseling will be of benefit for affected individuals and their families. Family members of affected individuals should also receive regular clinical evaluations to detect any symptoms and physical characteristics that may be potentially associated with Three M syndrome or heterozygosity for the disorder. Other treatment for Three M syndrome is symptomatic and supportive.
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Therapies of Three M Syndrome. TreatmentThe treatment of Three M syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, physicians who specialize in treating skeletal disorders (orthopedists), dental specialists, and/or other health care professionals may need to systematically and comprehensively plan an affected child's treatment.In some cases, orthopedic techniques, surgery, and/or other supportive techniques may be used to help treat certain skeletal abnormalities associated with Three M syndrome. Surgery and/or supportive measures may also be used to help treat or correct certain craniofacial, digital, and/or other abnormalities associated with the disorder. In addition, in affected individuals with dental abnormalities, braces, oral surgery, and/or other corrective techniques may be used to help treat or correct such malformations.Genetic counseling will be of benefit for affected individuals and their families. Family members of affected individuals should also receive regular clinical evaluations to detect any symptoms and physical characteristics that may be potentially associated with Three M syndrome or heterozygosity for the disorder. Other treatment for Three M syndrome is symptomatic and supportive.
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Three M Syndrome
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nord_1206_0
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Overview of Thrombocytopenia Absent Radius Syndrome
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Thrombocytopenia-absent radius (TAR) syndrome is a rare disorder that is present at birth (congenital). It is characterized by low levels of platelets in the blood (thrombocytopenia) and absence (aplasia) of the long, thin bones of the forearms (radii). Other abnormalities are often present including additional skeletal defects such as absence or underdevelopment of the other bone of the forearm (ulna), structural malformations of the heart (congenital heart defects), and kidney (renal) defects. Affected individuals may be abnormally short for their age (short stature) and exhibit cow's milk intolerance. TAR syndrome is inherited as an autosomal recessive genetic disorder and caused by deletion and/or mutations in the RBM8A gene.
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Overview of Thrombocytopenia Absent Radius Syndrome. Thrombocytopenia-absent radius (TAR) syndrome is a rare disorder that is present at birth (congenital). It is characterized by low levels of platelets in the blood (thrombocytopenia) and absence (aplasia) of the long, thin bones of the forearms (radii). Other abnormalities are often present including additional skeletal defects such as absence or underdevelopment of the other bone of the forearm (ulna), structural malformations of the heart (congenital heart defects), and kidney (renal) defects. Affected individuals may be abnormally short for their age (short stature) and exhibit cow's milk intolerance. TAR syndrome is inherited as an autosomal recessive genetic disorder and caused by deletion and/or mutations in the RBM8A gene.
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Thrombocytopenia Absent Radius Syndrome
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nord_1206_1
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Symptoms of Thrombocytopenia Absent Radius Syndrome
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TAR syndrome can potentially affect multiple systems of the body, but it is especially associated with blood (hematological) and bone (skeletal) abnormalities. The two main findings are thrombocytopenia and radial aplasia. A variety of additional symptoms also occur. The specific symptoms vary from patient to patient. Affected individuals will not have all of the symptoms listed below. Some symptoms improve over time and may cause little or no problems in adulthood. Most affected individuals have normal intelligence, are able live independently, and many have married and have had their own children.Approximately 90 percent of affected individuals develop symptoms related to low levels of the platelets in the blood during the first year of life. Platelets are specialized blood cells that clump together to form clots to stop bleeding. In TAR syndrome certain specialized cells in the bone marrow known as megakaryocytes are defective or improperly developed (hypoplastic). Megakaryocytes normally develop into platelets. The normal maturation of megakaryocytes into platelets does not occur in individuals with TAR syndrome, causing the low levels of platelets, which may be referred to as (hypomegakaryocytic thrombocytopenia). The exact reason why megakaryocytes fail to develop into platelets is unknown.In individuals with TAR syndrome, the level of platelets in the blood goes up and down. Episodes of thrombocytopenia are most frequent during the first two years of life. Episodes may be preceded or triggered by certain infections, such as viral illnesses (particularly digestive [gastrointestinal] illnesses), surgery, stress, or other factors, such as intolerance to cow’s milk (see below).Low platelet levels can result in severe bleeding episodes (hemorrhaging). Specific symptoms of thrombocytopenia include frequent nosebleeds or gastrointestinal bleeding, which can result in the vomiting of blood (hematemesis) or bloody stools. In addition, affected individuals may develop bleeding (hemorrhages) within skin (dermal) layers or layers below the mucous membranes (submucosal), resulting in easy bruising (ecchymoses) and/or the appearance of pinpoint-sized, purplish or reddish spots on the skin (petechiae). In severely affected patients, bleeding episodes, particularly in the brain (intracranial hemorrhaging), may lead to potentially life-threatening complications during infancy. In addition, intellectual disability has been reported in some individuals who had a history of intracranial hemorrhaging. Otherwise, intelligence in individuals with TAR syndrome is usually unaffected.As mentioned above, thrombocytopenia typically is most severe during the first year of life. By adulthood, platelet levels may improve to almost normal ranges. Therefore, adults may have few associated symptoms; however, affected women may have unusually heavy or prolonged menstrual periods (menorrhagia).In addition to platelets, the two other main blood cell lines (red and white cells) may also be affected. Red blood cells deliver oxygen to the body and white blood cells help in fighting off infections. Low levels of circulating red cells (anemia) may occur. Anemia is associated with fatigue, pale skin, and weakness. Some affected children may have an excessive amount of white blood cells called a “leukemoid reaction”. This occurs in infants with extremely low platelet levels. There may also be enlargement of the liver and spleen (hepatosplenomegaly). In some patients, increased levels of a specific type of white blood cell called an eosinophil (eosinophilia) may also occur. The cause of eosinophilia is not known. It is often associated with allergy or asthma and may occur in children with TAR syndrome who have cow’s milk intolerance.A variety of skeletal abnormalities occur in individuals with TAR syndrome. The characteristic finding is absence (aplasia) of one of the bones of the forearm (radius). The radii of both arms are affected (bilateral). The radius is a long thin bone that extends from the elbow to the thumb side of the wrist. The thumbs are present in individuals with TAR syndrome, a finding that distinguishes it from other disorders involving radii. The hands, fingers and thumbs are almost always unaffected, although the fingers may be abnormally short.Additional skeletal abnormalities may also occur including underdevelopment or absence of the other bone of the forearm, the ulna. Sometimes the long bone of the upper arm (humerus), which extends from the shoulder to the elbow, may be underdeveloped. In some cases, the shoulder girdle may also be underdeveloped and affected individuals may have reduced upper body strength. In severe cases, the arms may be missing and the hands may be joined to the trunk by small, irregularly-shaped bone (phocomelia).In some patients, the lower limbs may be involved. The severity may range from barely noticeable changes to significant malformations. Affected individuals may exhibit abnormalities of the knees including a loose kneecap that does not slide properly within its groove (patellar subluxation) and can potentially slide completely out of the socket (dislocate), absence of the knee cap (patella) or, rarely, the bones of the knees may be fused together. Dislocation of the hip, in which the head of the long bone of the upper leg (femur) does not fit properly into its socket in the hip, may also occur. Additional lower limb abnormalities often occur including improper inward rotation of the long bones of the legs (femoral and tibial torsion), bowing of the legs, and abnormalities affecting the feet and toes. Lower limb abnormalities can potentially affect the ability to walk (mobility). Most individuals with severe involvement of the upper limbs are more likely to have abnormalities of the lower limbs.In addition, cow’s milk intolerance or allergy has frequently been reported in association with TAR syndrome. In these children, introduction of cow’s milk to the diet may precipitate thrombocytopenic, eosinophilic, and/or “leukemoid” episodes (see above). Cow’s milk intolerance can also cause a variety of gastrointestinal symptoms including nausea, vomiting, diarrhea, and failure to gain weight and grow at the expected rate (failure to thrive).Approximately one third of affected infants also have structural malformations of the heart (congenital heart defects). Such cardiac defects may include an abnormal opening in the fibrous partition (septum) that divides the upper chambers of the heart (atrial septal defect) or a malformation known as tetralogy of Fallot. The latter describes a combination of heart defects, including abnormal narrowing (stenosis) of the opening between the pulmonary artery (which carries blood to the lungs) and the lower right chamber (ventricle) of the heart, an abnormal opening in the partition between the lower chambers of the heart (ventricular septal defect); displacement of the major artery that transports oxygen-rich blood to most of the body (i.e., aorta); and enlargement of the right ventricle (hypertrophy).Some individuals with TAR syndrome may exhibit short stature. A variety of additional physical abnormalities have been reported to be associated with TAR syndrome including an abnormally small jaw (micrognathia), incomplete closure of the roof of the mouth (cleft palate), one or more pink or dark red irregularly shaped patches of skin (hemangiomas) on the face caused by dense collections of small blood vessels (capillaries), or minor abnormalities affecting the spine and ribs. Kidney (renal) defects may also be present, such as a malformation in which the two kidneys are abnormally joined at the base (horseshoe kidney) as well as underdevelopment (hypoplasia) and improper function of the kidneys. Some of these findings have only occurred in a few reported patients and researchers do not know whether these are coincidental occurrences or whether individuals with TAR syndrome have a greater risk of developing these manifestations.
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Symptoms of Thrombocytopenia Absent Radius Syndrome. TAR syndrome can potentially affect multiple systems of the body, but it is especially associated with blood (hematological) and bone (skeletal) abnormalities. The two main findings are thrombocytopenia and radial aplasia. A variety of additional symptoms also occur. The specific symptoms vary from patient to patient. Affected individuals will not have all of the symptoms listed below. Some symptoms improve over time and may cause little or no problems in adulthood. Most affected individuals have normal intelligence, are able live independently, and many have married and have had their own children.Approximately 90 percent of affected individuals develop symptoms related to low levels of the platelets in the blood during the first year of life. Platelets are specialized blood cells that clump together to form clots to stop bleeding. In TAR syndrome certain specialized cells in the bone marrow known as megakaryocytes are defective or improperly developed (hypoplastic). Megakaryocytes normally develop into platelets. The normal maturation of megakaryocytes into platelets does not occur in individuals with TAR syndrome, causing the low levels of platelets, which may be referred to as (hypomegakaryocytic thrombocytopenia). The exact reason why megakaryocytes fail to develop into platelets is unknown.In individuals with TAR syndrome, the level of platelets in the blood goes up and down. Episodes of thrombocytopenia are most frequent during the first two years of life. Episodes may be preceded or triggered by certain infections, such as viral illnesses (particularly digestive [gastrointestinal] illnesses), surgery, stress, or other factors, such as intolerance to cow’s milk (see below).Low platelet levels can result in severe bleeding episodes (hemorrhaging). Specific symptoms of thrombocytopenia include frequent nosebleeds or gastrointestinal bleeding, which can result in the vomiting of blood (hematemesis) or bloody stools. In addition, affected individuals may develop bleeding (hemorrhages) within skin (dermal) layers or layers below the mucous membranes (submucosal), resulting in easy bruising (ecchymoses) and/or the appearance of pinpoint-sized, purplish or reddish spots on the skin (petechiae). In severely affected patients, bleeding episodes, particularly in the brain (intracranial hemorrhaging), may lead to potentially life-threatening complications during infancy. In addition, intellectual disability has been reported in some individuals who had a history of intracranial hemorrhaging. Otherwise, intelligence in individuals with TAR syndrome is usually unaffected.As mentioned above, thrombocytopenia typically is most severe during the first year of life. By adulthood, platelet levels may improve to almost normal ranges. Therefore, adults may have few associated symptoms; however, affected women may have unusually heavy or prolonged menstrual periods (menorrhagia).In addition to platelets, the two other main blood cell lines (red and white cells) may also be affected. Red blood cells deliver oxygen to the body and white blood cells help in fighting off infections. Low levels of circulating red cells (anemia) may occur. Anemia is associated with fatigue, pale skin, and weakness. Some affected children may have an excessive amount of white blood cells called a “leukemoid reaction”. This occurs in infants with extremely low platelet levels. There may also be enlargement of the liver and spleen (hepatosplenomegaly). In some patients, increased levels of a specific type of white blood cell called an eosinophil (eosinophilia) may also occur. The cause of eosinophilia is not known. It is often associated with allergy or asthma and may occur in children with TAR syndrome who have cow’s milk intolerance.A variety of skeletal abnormalities occur in individuals with TAR syndrome. The characteristic finding is absence (aplasia) of one of the bones of the forearm (radius). The radii of both arms are affected (bilateral). The radius is a long thin bone that extends from the elbow to the thumb side of the wrist. The thumbs are present in individuals with TAR syndrome, a finding that distinguishes it from other disorders involving radii. The hands, fingers and thumbs are almost always unaffected, although the fingers may be abnormally short.Additional skeletal abnormalities may also occur including underdevelopment or absence of the other bone of the forearm, the ulna. Sometimes the long bone of the upper arm (humerus), which extends from the shoulder to the elbow, may be underdeveloped. In some cases, the shoulder girdle may also be underdeveloped and affected individuals may have reduced upper body strength. In severe cases, the arms may be missing and the hands may be joined to the trunk by small, irregularly-shaped bone (phocomelia).In some patients, the lower limbs may be involved. The severity may range from barely noticeable changes to significant malformations. Affected individuals may exhibit abnormalities of the knees including a loose kneecap that does not slide properly within its groove (patellar subluxation) and can potentially slide completely out of the socket (dislocate), absence of the knee cap (patella) or, rarely, the bones of the knees may be fused together. Dislocation of the hip, in which the head of the long bone of the upper leg (femur) does not fit properly into its socket in the hip, may also occur. Additional lower limb abnormalities often occur including improper inward rotation of the long bones of the legs (femoral and tibial torsion), bowing of the legs, and abnormalities affecting the feet and toes. Lower limb abnormalities can potentially affect the ability to walk (mobility). Most individuals with severe involvement of the upper limbs are more likely to have abnormalities of the lower limbs.In addition, cow’s milk intolerance or allergy has frequently been reported in association with TAR syndrome. In these children, introduction of cow’s milk to the diet may precipitate thrombocytopenic, eosinophilic, and/or “leukemoid” episodes (see above). Cow’s milk intolerance can also cause a variety of gastrointestinal symptoms including nausea, vomiting, diarrhea, and failure to gain weight and grow at the expected rate (failure to thrive).Approximately one third of affected infants also have structural malformations of the heart (congenital heart defects). Such cardiac defects may include an abnormal opening in the fibrous partition (septum) that divides the upper chambers of the heart (atrial septal defect) or a malformation known as tetralogy of Fallot. The latter describes a combination of heart defects, including abnormal narrowing (stenosis) of the opening between the pulmonary artery (which carries blood to the lungs) and the lower right chamber (ventricle) of the heart, an abnormal opening in the partition between the lower chambers of the heart (ventricular septal defect); displacement of the major artery that transports oxygen-rich blood to most of the body (i.e., aorta); and enlargement of the right ventricle (hypertrophy).Some individuals with TAR syndrome may exhibit short stature. A variety of additional physical abnormalities have been reported to be associated with TAR syndrome including an abnormally small jaw (micrognathia), incomplete closure of the roof of the mouth (cleft palate), one or more pink or dark red irregularly shaped patches of skin (hemangiomas) on the face caused by dense collections of small blood vessels (capillaries), or minor abnormalities affecting the spine and ribs. Kidney (renal) defects may also be present, such as a malformation in which the two kidneys are abnormally joined at the base (horseshoe kidney) as well as underdevelopment (hypoplasia) and improper function of the kidneys. Some of these findings have only occurred in a few reported patients and researchers do not know whether these are coincidental occurrences or whether individuals with TAR syndrome have a greater risk of developing these manifestations.
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Thrombocytopenia Absent Radius Syndrome
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nord_1206_2
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Causes of Thrombocytopenia Absent Radius Syndrome
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TAR syndrome is inherited as an autosomal recessive genetic disorder and caused by two different types of mutations in the RBM8A gene. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disorder but usually will not show symptoms. However, reports have been published that describe an affected child born to an affected parent. The risk for two carrier parents to both pass the defective gene and have an affected child is theoretically 25% with each pregnancy, but because the RBM8A gene deletion associated with TAR syndrome is often not inherited, but occurs as a new mutation in about 25% of those affected, the risk for affected sibs is lower. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.Some researchers suggest that TAR syndrome may result from mutations of different disease genes (genetic heterogeneity). Further research is required to determine the underlying genetic cause or causes of the disorder.
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Causes of Thrombocytopenia Absent Radius Syndrome. TAR syndrome is inherited as an autosomal recessive genetic disorder and caused by two different types of mutations in the RBM8A gene. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disorder but usually will not show symptoms. However, reports have been published that describe an affected child born to an affected parent. The risk for two carrier parents to both pass the defective gene and have an affected child is theoretically 25% with each pregnancy, but because the RBM8A gene deletion associated with TAR syndrome is often not inherited, but occurs as a new mutation in about 25% of those affected, the risk for affected sibs is lower. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.Some researchers suggest that TAR syndrome may result from mutations of different disease genes (genetic heterogeneity). Further research is required to determine the underlying genetic cause or causes of the disorder.
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Thrombocytopenia Absent Radius Syndrome
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nord_1206_3
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Affects of Thrombocytopenia Absent Radius Syndrome
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The prevalence of TAR syndrome is estimated at 1:200,000-1:100,000.The disorder was originally described in siblings in the 1950s. Over 100 cases have since been recorded in the medical literature.
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Affects of Thrombocytopenia Absent Radius Syndrome. The prevalence of TAR syndrome is estimated at 1:200,000-1:100,000.The disorder was originally described in siblings in the 1950s. Over 100 cases have since been recorded in the medical literature.
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Thrombocytopenia Absent Radius Syndrome
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nord_1206_4
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Related disorders of Thrombocytopenia Absent Radius Syndrome
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Symptoms of the following disorders may be similar to those of thrombocytopenia-absent radius (TAR) syndrome. Comparisons may be useful for a differential diagnosis:Fanconi anemia, also known as Fanconi pancytopenia syndrome, is a rare genetic disorder characterized by deficiency of all blood cell types (pancytopenia), including red blood cells, white blood cells, and platelets. Such abnormalities may lead to abnormal bleeding and easy bruising, paleness of the skin (pallor), recurrent infection, and other findings that typically become apparent from approximately three to 10 years of age. However, in some patients, pancytopenia and associated abnormalities (hematologic findings) may occur as early as infancy or as late as the third decade of life. Individuals with Fanconi anemia may also have abnormal, patchy, brownish discolorations of the skin, short stature; and certain congenital defects. These may include underdevelopment or absence of the thumbs and/or the bones on the thumb side of the forearms (radii), congenital hip dislocation; kidney (renal) malformations, cardiac defects, and/or other abnormalities. There are several different subtypes (complementation groups) of Fanconi anemia, each of which is thought to result from changes (mutations) of different disease genes. The disorder is known to be associated with a high frequency of chromosomal breakage, a finding that may be helpful in distinguishing Fanconi anemia from other disorders with similar symptoms and findings. Fanconi anemia is inherited in an autosomal recessive pattern. (For further information on this disorder, choose “Fanconi” as your search term in the Rare Disease Database.)Holt-Oram syndrome (HOS), also known as Cardiac-Limb syndrome, is a rare genetic disorder characterized by malformations of bones of the forearms and hands (upper limbs) and/or heart abnormalities. The thumbs may be absent (aplastic), underdeveloped (hypoplastic) or have an extra bone (triphalangy). Additional upper limb malformations may include defects of certain bones of the wrists (carpals), the middle portion of the hands (metacarpals), the thumb side of the forearms (radii), and/or the pinky side of the forearms (ulnae). Some affected individuals also have additional musculoskeletal abnormalities, such as malformations of the bones of the upper arms (humeri), shoulder blades (scapulae), and collarbones (clavicles); other skeletal defects; and restricted range of movements at the shoulders and elbows. Characteristic heart abnormalities may include structural cardiac defects, such as an abnormal opening in the fibrous partition (septum) between the upper (atrial) or lower (ventricular) chambers of the heart or abnormal transmission of electrical impulses that coordinate the heart’s muscular contractions (electrocardiographic conduction defects). In some instances, other abnormalities are also present. Holt-Oram syndrome may be inherited on an autosomal dominant pattern or appear to occur spontaneously due to new genetic mutations. (For further information, choose “Holt Oram” as your search term in the Rare Disease Database.)Roberts syndrome is a rare genetic disorder characterized by growth delays before and after birth; malformations of the arms and legs (limbs); distinctive abnormalities of the skull and facial (craniofacial) region; and/or other symptoms and findings. In infants with Roberts syndrome, the arms and legs may be incompletely developed (limb reduction abnormalities). Such abnormalities may range from phocomelia of all four limbs (tetraphocomelia) to less severe degrees of limb reduction, such as underdevelopment and/or absence of bones of the upper arms (humeri), forearms (radii and/or ulnae), thighs (femurs), shins (tibiae), and/or outside of the lower legs (fibulae). In addition, certain fingers and toes may be unusually short or absent (oligodactyly). Characteristic craniofacial abnormalities may include an unusually small, broad head (microbrachycephaly); incomplete development of the upper lip (bilateral cleft lip); incomplete development of both sides of the roof of the mouth (bilateral cleft palate); thin, small nostrils (hypoplastic nasal alae); and/or low-set, malformed (dysplastic) ears. Additional abnormalities may also be present, such as low levels of platelets in the blood (thrombocytopenia), congenital heart defects, kidney (renal) abnormalities, intellectual disability, and/or other findings. In some instances, the disorder is known to be associated with distinctive changes involving certain chromosomal regions (e.g., premature centromere separation). Roberts syndrome is inherited in an autosomal recessive pattern. (For further information, use “Roberts” as your search term in the Rare Disease Database.)Baller-Gerold syndrome is a rare genetic disorder characterized by distinctive malformations of the skull and facial (craniofacial) area and bones of the forearms and hands. In affected infants, there is premature fusion of the fibrous joints (cranial sutures) between certain bones in the skull (craniosynostosis). As a result, the head may appear unusually short and wide and/or pointed at the top (turribrachycephaly) or relatively triangular in shape (trigonocephaly). Additional craniofacial malformations may include a prominent forehead; downslanting eyelid folds (palpebral fissures); and/or small, malformed (dysplastic), low-set ears. Baller-Gerold syndrome is also characterized by underdevelopment (hypoplasia) or absence (aplasia) of the bone on the inner (or thumb) side of the forearms (radii). In addition, the bone on the pinky side of the forearms (ulnae) is unusually short and curved and the thumbs may be underdeveloped or absent. Some affected individuals also have congenital heart defects, such as an abnormal opening in the fibrous partition that separates the lower or upper chambers of the heart (ventricular or atrial septal defects) and/or patent ductus arteriosus (PDA). The latter is characterized by an abnormal opening between the artery that transports oxygen-rich blood to most of the body (aorta) and the pulmonary artery, which carries oxygen-deficient blood to the lungs. Some individuals with the disorder may also have kidney (renal) malformations, additional physical abnormalities, and/or intellectual disability. Baller-Gerold syndrome is inherited in an autosomal recessive pattern. (For further information, choose “Baller Gerold” as your search term in the Rare Disease Database.) Additional congenital disorders may be characterized by malformations of bones of the upper and lower limbs, hematologic abnormalities, short stature, congenital heart defects, and/or other symptoms and findings similar to those potentially associated with TAR syndrome. (For more information on these disorders, choose the exact disease name in question as your search term in the Rare Disease Database.)
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Related disorders of Thrombocytopenia Absent Radius Syndrome. Symptoms of the following disorders may be similar to those of thrombocytopenia-absent radius (TAR) syndrome. Comparisons may be useful for a differential diagnosis:Fanconi anemia, also known as Fanconi pancytopenia syndrome, is a rare genetic disorder characterized by deficiency of all blood cell types (pancytopenia), including red blood cells, white blood cells, and platelets. Such abnormalities may lead to abnormal bleeding and easy bruising, paleness of the skin (pallor), recurrent infection, and other findings that typically become apparent from approximately three to 10 years of age. However, in some patients, pancytopenia and associated abnormalities (hematologic findings) may occur as early as infancy or as late as the third decade of life. Individuals with Fanconi anemia may also have abnormal, patchy, brownish discolorations of the skin, short stature; and certain congenital defects. These may include underdevelopment or absence of the thumbs and/or the bones on the thumb side of the forearms (radii), congenital hip dislocation; kidney (renal) malformations, cardiac defects, and/or other abnormalities. There are several different subtypes (complementation groups) of Fanconi anemia, each of which is thought to result from changes (mutations) of different disease genes. The disorder is known to be associated with a high frequency of chromosomal breakage, a finding that may be helpful in distinguishing Fanconi anemia from other disorders with similar symptoms and findings. Fanconi anemia is inherited in an autosomal recessive pattern. (For further information on this disorder, choose “Fanconi” as your search term in the Rare Disease Database.)Holt-Oram syndrome (HOS), also known as Cardiac-Limb syndrome, is a rare genetic disorder characterized by malformations of bones of the forearms and hands (upper limbs) and/or heart abnormalities. The thumbs may be absent (aplastic), underdeveloped (hypoplastic) or have an extra bone (triphalangy). Additional upper limb malformations may include defects of certain bones of the wrists (carpals), the middle portion of the hands (metacarpals), the thumb side of the forearms (radii), and/or the pinky side of the forearms (ulnae). Some affected individuals also have additional musculoskeletal abnormalities, such as malformations of the bones of the upper arms (humeri), shoulder blades (scapulae), and collarbones (clavicles); other skeletal defects; and restricted range of movements at the shoulders and elbows. Characteristic heart abnormalities may include structural cardiac defects, such as an abnormal opening in the fibrous partition (septum) between the upper (atrial) or lower (ventricular) chambers of the heart or abnormal transmission of electrical impulses that coordinate the heart’s muscular contractions (electrocardiographic conduction defects). In some instances, other abnormalities are also present. Holt-Oram syndrome may be inherited on an autosomal dominant pattern or appear to occur spontaneously due to new genetic mutations. (For further information, choose “Holt Oram” as your search term in the Rare Disease Database.)Roberts syndrome is a rare genetic disorder characterized by growth delays before and after birth; malformations of the arms and legs (limbs); distinctive abnormalities of the skull and facial (craniofacial) region; and/or other symptoms and findings. In infants with Roberts syndrome, the arms and legs may be incompletely developed (limb reduction abnormalities). Such abnormalities may range from phocomelia of all four limbs (tetraphocomelia) to less severe degrees of limb reduction, such as underdevelopment and/or absence of bones of the upper arms (humeri), forearms (radii and/or ulnae), thighs (femurs), shins (tibiae), and/or outside of the lower legs (fibulae). In addition, certain fingers and toes may be unusually short or absent (oligodactyly). Characteristic craniofacial abnormalities may include an unusually small, broad head (microbrachycephaly); incomplete development of the upper lip (bilateral cleft lip); incomplete development of both sides of the roof of the mouth (bilateral cleft palate); thin, small nostrils (hypoplastic nasal alae); and/or low-set, malformed (dysplastic) ears. Additional abnormalities may also be present, such as low levels of platelets in the blood (thrombocytopenia), congenital heart defects, kidney (renal) abnormalities, intellectual disability, and/or other findings. In some instances, the disorder is known to be associated with distinctive changes involving certain chromosomal regions (e.g., premature centromere separation). Roberts syndrome is inherited in an autosomal recessive pattern. (For further information, use “Roberts” as your search term in the Rare Disease Database.)Baller-Gerold syndrome is a rare genetic disorder characterized by distinctive malformations of the skull and facial (craniofacial) area and bones of the forearms and hands. In affected infants, there is premature fusion of the fibrous joints (cranial sutures) between certain bones in the skull (craniosynostosis). As a result, the head may appear unusually short and wide and/or pointed at the top (turribrachycephaly) or relatively triangular in shape (trigonocephaly). Additional craniofacial malformations may include a prominent forehead; downslanting eyelid folds (palpebral fissures); and/or small, malformed (dysplastic), low-set ears. Baller-Gerold syndrome is also characterized by underdevelopment (hypoplasia) or absence (aplasia) of the bone on the inner (or thumb) side of the forearms (radii). In addition, the bone on the pinky side of the forearms (ulnae) is unusually short and curved and the thumbs may be underdeveloped or absent. Some affected individuals also have congenital heart defects, such as an abnormal opening in the fibrous partition that separates the lower or upper chambers of the heart (ventricular or atrial septal defects) and/or patent ductus arteriosus (PDA). The latter is characterized by an abnormal opening between the artery that transports oxygen-rich blood to most of the body (aorta) and the pulmonary artery, which carries oxygen-deficient blood to the lungs. Some individuals with the disorder may also have kidney (renal) malformations, additional physical abnormalities, and/or intellectual disability. Baller-Gerold syndrome is inherited in an autosomal recessive pattern. (For further information, choose “Baller Gerold” as your search term in the Rare Disease Database.) Additional congenital disorders may be characterized by malformations of bones of the upper and lower limbs, hematologic abnormalities, short stature, congenital heart defects, and/or other symptoms and findings similar to those potentially associated with TAR syndrome. (For more information on these disorders, choose the exact disease name in question as your search term in the Rare Disease Database.)
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Thrombocytopenia Absent Radius Syndrome
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nord_1206_5
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Diagnosis of Thrombocytopenia Absent Radius Syndrome
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In most cases, the diagnosis of TAR syndrome is made at birth based upon a thorough clinical examination, identification of characteristic physical findings, and a variety of specialized tests. Such testing may include blood studies to confirm the presence of thrombocytopenia, anemia, and/or other hematologic abnormalities as well as a radiograph (X-ray) of the forearm and renal ultrasonography of the kidneys.The first step in molecular genetic testing is deletion/duplication analysis for the region of chromosome band 1q21 that contains the RBM8A gene. Diagnosis of TAR syndrome is confirmed if a deletion is present in an individual with bilateral absence of the radius and presence of thumbs. However, lack of identification of this deletion is not sufficient to rule out the diagnosis. Sequence analysis of the RBM8A gene should be done if no deletion is identified, or to identify the second RBM8A gene mutation for confirmation of the diagnosis.Clinical Testing and Work-UpCardiac evaluation may also be recommended to detect any heart abnormalities that may be associated with the disorder. Such evaluation may include a thorough clinical examination, during which heart and lung sounds are assessed through use of a stethoscope, and specialized tests that enable physicians to evaluate the structure and function of the heart (e.g., x-ray studies, electrocardiography [EKG], echocardiography, cardiac catheterization).
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Diagnosis of Thrombocytopenia Absent Radius Syndrome. In most cases, the diagnosis of TAR syndrome is made at birth based upon a thorough clinical examination, identification of characteristic physical findings, and a variety of specialized tests. Such testing may include blood studies to confirm the presence of thrombocytopenia, anemia, and/or other hematologic abnormalities as well as a radiograph (X-ray) of the forearm and renal ultrasonography of the kidneys.The first step in molecular genetic testing is deletion/duplication analysis for the region of chromosome band 1q21 that contains the RBM8A gene. Diagnosis of TAR syndrome is confirmed if a deletion is present in an individual with bilateral absence of the radius and presence of thumbs. However, lack of identification of this deletion is not sufficient to rule out the diagnosis. Sequence analysis of the RBM8A gene should be done if no deletion is identified, or to identify the second RBM8A gene mutation for confirmation of the diagnosis.Clinical Testing and Work-UpCardiac evaluation may also be recommended to detect any heart abnormalities that may be associated with the disorder. Such evaluation may include a thorough clinical examination, during which heart and lung sounds are assessed through use of a stethoscope, and specialized tests that enable physicians to evaluate the structure and function of the heart (e.g., x-ray studies, electrocardiography [EKG], echocardiography, cardiac catheterization).
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Therapies of Thrombocytopenia Absent Radius Syndrome
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TreatmentThe treatment of TAR syndrome is directed toward the specific symptoms that are apparent in each individual. Such treatment may require the coordinated efforts of a team of medical professionals, such as pediatricians, surgeons, physicians who diagnose and treat disorders of the skeleton, joints, muscles, and related tissues (orthopedists), specialists in the study of the blood and blood-forming tissues (hematologists), physicians who specialize in heart disease (cardiologists), and/or other health care professionals.Physicians may recommend preventive measures to help affected infants and children avoid infection, stress, or other factors that may precipitate thrombocytopenia. In addition, experts indicate that cow’s milk should be avoided, since its introduction may precipitate thrombocytopenic, eosinophilic, or “leukemoid” episodes. (For further information, please see the “Symptoms” section of this report above.)Management of the disorder may include ongoing monitoring and supportive hematologic measures as required, such as platelet transfusions or transfusions with whole blood products. In some cases, the use of certain medications or other measures may be recommended to help prevent or treat hematologic complications. As noted above, thrombocytopenia typically improves with age.In individuals with TAR syndrome, various orthopedic techniques may also be recommended, such as splints, corrective braces, and/or certain surgical measures. In some cases, the use of adaptive and/or artificial devices (prosthetics) and mobility aids, such as wheelchairs or motorized carts, may also be beneficial.For affected individuals with congenital heart defects, treatment with certain medications, surgical intervention, and/or other measures may be necessary. The surgical procedures performed will depend upon the severity and location of the anatomical abnormalities, their associated symptoms, and other factors.Early intervention may be important to ensure that children with TAR syndrome reach their potential. Special services that may be beneficial include special education, physical therapy, and/or other medical, social, or vocational services.Genetic counseling is recommended for affected individuals and their families. Other treatment for this disorder is symptomatic and supportive.
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Therapies of Thrombocytopenia Absent Radius Syndrome. TreatmentThe treatment of TAR syndrome is directed toward the specific symptoms that are apparent in each individual. Such treatment may require the coordinated efforts of a team of medical professionals, such as pediatricians, surgeons, physicians who diagnose and treat disorders of the skeleton, joints, muscles, and related tissues (orthopedists), specialists in the study of the blood and blood-forming tissues (hematologists), physicians who specialize in heart disease (cardiologists), and/or other health care professionals.Physicians may recommend preventive measures to help affected infants and children avoid infection, stress, or other factors that may precipitate thrombocytopenia. In addition, experts indicate that cow’s milk should be avoided, since its introduction may precipitate thrombocytopenic, eosinophilic, or “leukemoid” episodes. (For further information, please see the “Symptoms” section of this report above.)Management of the disorder may include ongoing monitoring and supportive hematologic measures as required, such as platelet transfusions or transfusions with whole blood products. In some cases, the use of certain medications or other measures may be recommended to help prevent or treat hematologic complications. As noted above, thrombocytopenia typically improves with age.In individuals with TAR syndrome, various orthopedic techniques may also be recommended, such as splints, corrective braces, and/or certain surgical measures. In some cases, the use of adaptive and/or artificial devices (prosthetics) and mobility aids, such as wheelchairs or motorized carts, may also be beneficial.For affected individuals with congenital heart defects, treatment with certain medications, surgical intervention, and/or other measures may be necessary. The surgical procedures performed will depend upon the severity and location of the anatomical abnormalities, their associated symptoms, and other factors.Early intervention may be important to ensure that children with TAR syndrome reach their potential. Special services that may be beneficial include special education, physical therapy, and/or other medical, social, or vocational services.Genetic counseling is recommended for affected individuals and their families. Other treatment for this disorder is symptomatic and supportive.
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Overview of Thrombotic Thrombocytopenic Purpura
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Thrombotic thrombocytopenia purpura (TTP) is a rare, serious blood disease. Major symptoms may include a severe decrease in the number of blood platelets (thrombocytopenia), abnormal destruction of red blood cells (hemolytic anemia) and disturbances in the nervous system and other organs occur as a result of small clots that form in the smallest arteries. The exact cause of TTP is unknown.
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Overview of Thrombotic Thrombocytopenic Purpura. Thrombotic thrombocytopenia purpura (TTP) is a rare, serious blood disease. Major symptoms may include a severe decrease in the number of blood platelets (thrombocytopenia), abnormal destruction of red blood cells (hemolytic anemia) and disturbances in the nervous system and other organs occur as a result of small clots that form in the smallest arteries. The exact cause of TTP is unknown.
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Symptoms of Thrombotic Thrombocytopenic Purpura
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The thrombocytopenia and hemolytic anemia are a result of these small clots in the blood vessels of many organs, potentially blocking the normal flow of blood through the vessels. Disturbances affecting the nervous system may include headaches, mental changes, confusion, speech abnormalities, slight or partial paralysis (paresis), seizures or coma.Fever, blood plasma proteins in the urine (proteinuria), and a very small number of red blood cells in the urine (hematuria) may also occur. Affected individuals also exhibit red rash-like areas of skin or patches of purplish discoloration (purpura) resulting from abnormal bleeding into the mucous membranes (the thin, moist layer lining the body’s cavities) and into the skin that can be a sign of low platelets. Additional features of TTP can include abnormally heavy bleeding (hemorrhaging), weakness, fatigue, lack of color (pallor) and abdominal pain with nausea and vomiting. In half of individuals with TTP, increased levels of a chemical compound known as creatinine are found in the blood.Acute renal failure requiring kidney dialysis occurs in only about 10 percent of individuals with TTP. Within days, swelling of the feet, shortness of breath, headache, and fever may occur. Retention of water and salt in the blood may lead to high blood pressure, changes in brain metabolism, and congestion in the heart and lungs. Acute renal failure may lead to a buildup (accumulation) of potassium in the blood (hyperkalemia), which may cause irregular heartbeat.TTP can develop during pregnancy and there may be serious complications during pregnancy in females with TTP. In general, TTP often occurs suddenly with great severity and may recur in future pregnancies.
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Symptoms of Thrombotic Thrombocytopenic Purpura. The thrombocytopenia and hemolytic anemia are a result of these small clots in the blood vessels of many organs, potentially blocking the normal flow of blood through the vessels. Disturbances affecting the nervous system may include headaches, mental changes, confusion, speech abnormalities, slight or partial paralysis (paresis), seizures or coma.Fever, blood plasma proteins in the urine (proteinuria), and a very small number of red blood cells in the urine (hematuria) may also occur. Affected individuals also exhibit red rash-like areas of skin or patches of purplish discoloration (purpura) resulting from abnormal bleeding into the mucous membranes (the thin, moist layer lining the body’s cavities) and into the skin that can be a sign of low platelets. Additional features of TTP can include abnormally heavy bleeding (hemorrhaging), weakness, fatigue, lack of color (pallor) and abdominal pain with nausea and vomiting. In half of individuals with TTP, increased levels of a chemical compound known as creatinine are found in the blood.Acute renal failure requiring kidney dialysis occurs in only about 10 percent of individuals with TTP. Within days, swelling of the feet, shortness of breath, headache, and fever may occur. Retention of water and salt in the blood may lead to high blood pressure, changes in brain metabolism, and congestion in the heart and lungs. Acute renal failure may lead to a buildup (accumulation) of potassium in the blood (hyperkalemia), which may cause irregular heartbeat.TTP can develop during pregnancy and there may be serious complications during pregnancy in females with TTP. In general, TTP often occurs suddenly with great severity and may recur in future pregnancies.
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Causes of Thrombotic Thrombocytopenic Purpura
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The exact cause of TTP is not known. However, the disease is associated with a deficiency of an enzyme involved in blood clotting called the von Willebrand factor cleaving protease (also called ADAMTS13). The deficiency of this enzyme allows large complexes of the clotting protein known as von Willebrand factor to circulate in the blood, resulting in platelet clotting and the destruction of red blood cells.There is an acquired (non-inherited) form of TTP referred to as immune-mediated TTP (iTTP) and a familial form referred to as congenital TTP (cTTP). iTTP may appear later in life, in late childhood or adulthood, and affected individuals may have a single episode or recurring episodes. This form or TTP is considered to be an autoimmune disease and is caused when patients develop an antibody against the ADAMTS13 protease leading to low levels of the protease.If the disorder is present at birth (familial form), signs and symptoms may typically appear earlier, in infancy or early childhood. This is referred to as cTTP. Women with cTTP may also present with an acute TTP episode for the first time at the time of their first pregnancy.iTTP can occur as a consequence of AIDS, the AIDS-related complex, or the human immunodeficiency virus (HIV) infection or other autoimmune diseases. Patients with iTTP may also be diagnosed in the future with other autoimmune diseases as well.
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Causes of Thrombotic Thrombocytopenic Purpura. The exact cause of TTP is not known. However, the disease is associated with a deficiency of an enzyme involved in blood clotting called the von Willebrand factor cleaving protease (also called ADAMTS13). The deficiency of this enzyme allows large complexes of the clotting protein known as von Willebrand factor to circulate in the blood, resulting in platelet clotting and the destruction of red blood cells.There is an acquired (non-inherited) form of TTP referred to as immune-mediated TTP (iTTP) and a familial form referred to as congenital TTP (cTTP). iTTP may appear later in life, in late childhood or adulthood, and affected individuals may have a single episode or recurring episodes. This form or TTP is considered to be an autoimmune disease and is caused when patients develop an antibody against the ADAMTS13 protease leading to low levels of the protease.If the disorder is present at birth (familial form), signs and symptoms may typically appear earlier, in infancy or early childhood. This is referred to as cTTP. Women with cTTP may also present with an acute TTP episode for the first time at the time of their first pregnancy.iTTP can occur as a consequence of AIDS, the AIDS-related complex, or the human immunodeficiency virus (HIV) infection or other autoimmune diseases. Patients with iTTP may also be diagnosed in the future with other autoimmune diseases as well.
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Affects of Thrombotic Thrombocytopenic Purpura
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The current rate of occurrence for TTP is about 3.7 cases per million people each year. One estimate places the overall incidence rate at four of 100,000 individuals. Two-thirds of individuals with iTTP cases are women. It usually affects people between 20 to 50 years of age but people of any age may be affected.TTP is occasionally associated with pregnancy and collagen-vascular diseases (a group of diseases affecting connective tissue).TTP appears to occur more frequently in people who have human immunodeficiency virus (HIV) infection.
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Affects of Thrombotic Thrombocytopenic Purpura. The current rate of occurrence for TTP is about 3.7 cases per million people each year. One estimate places the overall incidence rate at four of 100,000 individuals. Two-thirds of individuals with iTTP cases are women. It usually affects people between 20 to 50 years of age but people of any age may be affected.TTP is occasionally associated with pregnancy and collagen-vascular diseases (a group of diseases affecting connective tissue).TTP appears to occur more frequently in people who have human immunodeficiency virus (HIV) infection.
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Related disorders of Thrombotic Thrombocytopenic Purpura
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Childhood-onset or iTTP often occurs concurrently with systemic lupus erythematosus (SLE). A search of the literature by investigators at the University of Toronto demonstrated that approximately half of the cases of childhood-onset TTP met criteria for “incipient or definite SLE”. The best indicator for the presence or later development of SLE appeared to be excessive serum proteins in the urine (high-grade proteinuria) at the time of diagnosis of TTP. The researchers recommended that physicians rule out concomitant SLE in all children who present with TTP.Symptoms of the following disorders can be similar to those of thrombotic thrombocytopenia purpura. Comparisons may be useful for a differential diagnosis:Hemolytic uremic syndrome (STEC HUS) is an uncommon disease that occurs in 5 to 15 percent of individuals, especially children, who are infected by the Escherichia coli (E. coli) bacterium. This organism releases toxins into the gut that are absorbed into the bloodstream and may be transported by white blood cells (leukocytes) to the kidneys. This results in acute renal injury. There may also be damage to the brain with seizures and even coma, the pancreas with pancreatitis and occasionally diabetes mellitus, and other organs. STEC HUS mainly affects young children between one and 10 years. The onset of HUS is preceded by an illness characterized by vomiting, abdominal pain, fever, and, usually, bloody diarrhea. (For more information on this disorder, choose “STEC HUS” as your search term in the Rare Disease Database.)Immune thrombocytopenic purpura (ITP) is a blood disease with no specific known cause (idiopathic). It is characterized by thrombocytopenia, abnormal bleeding into the skin and mucous membranes and anemia. ITP occurs most frequently in children and young adults, and more frequently in females than males. A viral infection may precede ITP especially in children. (For more information on this disorder, choose “ITP” as your search term in the Rare Disease Database.)Henoch-Schönlein purpura (HSP) is a rare inflammatory disease of the small blood vessels (capillaries) and is usually a self-limited disease. It is the most common form of childhood vascular inflammation (vasculitis) and results in inflammatory changes in the small blood vessels. The symptoms of HSP usually begin suddenly and may include headache, fever, loss of appetite, cramping, abdominal pain, painful menstruation, hives, bloody diarrhea and joint pain. Red or purple spots typically appear on the skin (petechiae). Inflammatory changes associated with HSP can also develop in the joints, kidneys, digestive system, and, in rare cases, the brain and spinal cord (central nervous system). The exact cause of HSP is not fully understood, although research demonstrates that it is related to an abnormal response by the immune system or, in some rare cases, an extreme allergic reaction to certain substances (e.g., foods or drugs). (For more information on this disorder, choose “Henoch” as your search term in the Rare Disease Database.)
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Related disorders of Thrombotic Thrombocytopenic Purpura. Childhood-onset or iTTP often occurs concurrently with systemic lupus erythematosus (SLE). A search of the literature by investigators at the University of Toronto demonstrated that approximately half of the cases of childhood-onset TTP met criteria for “incipient or definite SLE”. The best indicator for the presence or later development of SLE appeared to be excessive serum proteins in the urine (high-grade proteinuria) at the time of diagnosis of TTP. The researchers recommended that physicians rule out concomitant SLE in all children who present with TTP.Symptoms of the following disorders can be similar to those of thrombotic thrombocytopenia purpura. Comparisons may be useful for a differential diagnosis:Hemolytic uremic syndrome (STEC HUS) is an uncommon disease that occurs in 5 to 15 percent of individuals, especially children, who are infected by the Escherichia coli (E. coli) bacterium. This organism releases toxins into the gut that are absorbed into the bloodstream and may be transported by white blood cells (leukocytes) to the kidneys. This results in acute renal injury. There may also be damage to the brain with seizures and even coma, the pancreas with pancreatitis and occasionally diabetes mellitus, and other organs. STEC HUS mainly affects young children between one and 10 years. The onset of HUS is preceded by an illness characterized by vomiting, abdominal pain, fever, and, usually, bloody diarrhea. (For more information on this disorder, choose “STEC HUS” as your search term in the Rare Disease Database.)Immune thrombocytopenic purpura (ITP) is a blood disease with no specific known cause (idiopathic). It is characterized by thrombocytopenia, abnormal bleeding into the skin and mucous membranes and anemia. ITP occurs most frequently in children and young adults, and more frequently in females than males. A viral infection may precede ITP especially in children. (For more information on this disorder, choose “ITP” as your search term in the Rare Disease Database.)Henoch-Schönlein purpura (HSP) is a rare inflammatory disease of the small blood vessels (capillaries) and is usually a self-limited disease. It is the most common form of childhood vascular inflammation (vasculitis) and results in inflammatory changes in the small blood vessels. The symptoms of HSP usually begin suddenly and may include headache, fever, loss of appetite, cramping, abdominal pain, painful menstruation, hives, bloody diarrhea and joint pain. Red or purple spots typically appear on the skin (petechiae). Inflammatory changes associated with HSP can also develop in the joints, kidneys, digestive system, and, in rare cases, the brain and spinal cord (central nervous system). The exact cause of HSP is not fully understood, although research demonstrates that it is related to an abnormal response by the immune system or, in some rare cases, an extreme allergic reaction to certain substances (e.g., foods or drugs). (For more information on this disorder, choose “Henoch” as your search term in the Rare Disease Database.)
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Diagnosis of Thrombotic Thrombocytopenic Purpura
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Rapid diagnosis and immediate treatment is very important in TTP. A diagnosis may be made based upon a thorough clinical evaluation, a detailed patient history and identification of characteristic findings. The diagnosis is confirmed by the finding of severely deficient (<10%) ADAMTS13 activity and the presence of an anti-ADAMTS13 antibody in patients with iTTP.
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Diagnosis of Thrombotic Thrombocytopenic Purpura. Rapid diagnosis and immediate treatment is very important in TTP. A diagnosis may be made based upon a thorough clinical evaluation, a detailed patient history and identification of characteristic findings. The diagnosis is confirmed by the finding of severely deficient (<10%) ADAMTS13 activity and the presence of an anti-ADAMTS13 antibody in patients with iTTP.
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Therapies of Thrombotic Thrombocytopenic Purpura
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Treatment
In many cases, plasmapheresis, or plasma exchange, is used to remove the antibodies that inhibit the ADAMTS13 protease and also add back the functional ADAMTS13 protein. In this process, blood is removed by a machine from the affected individual, blood cells are separated from plasma, the patient’s plasma is replaced with healthy plasma, and the blood is then returned to the patient by the machine. Patients are also routinely given steroids to inhibit the production of the anti-ADAMTS13 antibodies. The anti-CD20 antibody rituximab is also used commonly in the treatment of iTTP to also suppress the production of the anti-ADAMTS13 antibodies with an effect that lasts much longer than steroids. The blood product SD plasma (VIPLAS/SD) has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of TTP.In 2019, the FDA approved Cablivi (caplacizumab-yhdp) as the first therapy specifically indicated, in combination with plasma exchange and immunosuppressive therapy, for the treatment of adult patients with acquired TTP. Cablivi is the first targeted treatment that inhibits the formation of blood clots.Genetic counseling is recommended for affected individuals and their families when congenital TTP has affected other family members. Other treatment is symptomatic and supportive.
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Therapies of Thrombotic Thrombocytopenic Purpura. Treatment
In many cases, plasmapheresis, or plasma exchange, is used to remove the antibodies that inhibit the ADAMTS13 protease and also add back the functional ADAMTS13 protein. In this process, blood is removed by a machine from the affected individual, blood cells are separated from plasma, the patient’s plasma is replaced with healthy plasma, and the blood is then returned to the patient by the machine. Patients are also routinely given steroids to inhibit the production of the anti-ADAMTS13 antibodies. The anti-CD20 antibody rituximab is also used commonly in the treatment of iTTP to also suppress the production of the anti-ADAMTS13 antibodies with an effect that lasts much longer than steroids. The blood product SD plasma (VIPLAS/SD) has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of TTP.In 2019, the FDA approved Cablivi (caplacizumab-yhdp) as the first therapy specifically indicated, in combination with plasma exchange and immunosuppressive therapy, for the treatment of adult patients with acquired TTP. Cablivi is the first targeted treatment that inhibits the formation of blood clots.Genetic counseling is recommended for affected individuals and their families when congenital TTP has affected other family members. Other treatment is symptomatic and supportive.
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Overview of Thymidine Kinase 2 Deficiency
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SummaryThymidine kinase 2 deficiency (TK2D) was first described in 2001 in 4 children with severe muscle disease and as of 2022, there have been less than 120 patients described in the medical literature. All patients described have some degree of muscle weakness but the severity, age of onset and disease progression varies from person to person. The most common symptom is weakness of the arms and legs that gets worse over time. Breathing difficulties, weakness of the eye muscles and trouble chewing and swallowing are also common. The small number of patients and the recent discovery of TK2D make it difficult to predict the exact disease course in any given patient. TK2D is caused by genetic changes (mutations) in the TK2 gene and inherited as an autosomal recessive genetic condition.IntroductionTK2D is one of the primary mitochondrial myopathies (PMM). PMM are a group of mitochondrial disorders that present predominantly with muscle manifestations. Mitochondria are found by the hundreds within every cell of the body. Mitochondria regulate the production of cellular energy and carry their own unique DNA known as mitochondrial DNA (mtDNA). Mitochondrial disorders can be caused by changes in genes within the mitochondria (mtDNA) or in genes outside the mitochondria (nuclear DNA). These genetic changes affect the ability of cells to produce energy. PMM can involve multiple body systems, but primarily affect the skeletal muscles. For more information, choose “primary mitochondrial myopathies” as your search term in the Rare Disease Database.
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Overview of Thymidine Kinase 2 Deficiency. SummaryThymidine kinase 2 deficiency (TK2D) was first described in 2001 in 4 children with severe muscle disease and as of 2022, there have been less than 120 patients described in the medical literature. All patients described have some degree of muscle weakness but the severity, age of onset and disease progression varies from person to person. The most common symptom is weakness of the arms and legs that gets worse over time. Breathing difficulties, weakness of the eye muscles and trouble chewing and swallowing are also common. The small number of patients and the recent discovery of TK2D make it difficult to predict the exact disease course in any given patient. TK2D is caused by genetic changes (mutations) in the TK2 gene and inherited as an autosomal recessive genetic condition.IntroductionTK2D is one of the primary mitochondrial myopathies (PMM). PMM are a group of mitochondrial disorders that present predominantly with muscle manifestations. Mitochondria are found by the hundreds within every cell of the body. Mitochondria regulate the production of cellular energy and carry their own unique DNA known as mitochondrial DNA (mtDNA). Mitochondrial disorders can be caused by changes in genes within the mitochondria (mtDNA) or in genes outside the mitochondria (nuclear DNA). These genetic changes affect the ability of cells to produce energy. PMM can involve multiple body systems, but primarily affect the skeletal muscles. For more information, choose “primary mitochondrial myopathies” as your search term in the Rare Disease Database.
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Symptoms of Thymidine Kinase 2 Deficiency
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The symptoms of TK2D vary in severity, age of onset and how quickly they progress. There are three main types of TK2D: the infantile-onset type, childhood-onset type and late-onset type. Infantile-Onset
The first symptoms of infantile-onset TK2D typically begin before one year of age. Early development and growth are normal. The first signs of TK2D are usually low muscle tone (hypotonia) and muscle weakness of the arms and legs. Other early signs include feeding problems and difficulty breathing. Some patients with infantile-onset TK2D also have a brain disease known as encephalopathy. This can lead to developmental and cognitive problems, hearing loss and seizures.The symptoms of infantile TK2D quickly get worse over time. Most children with this condition never walk or quickly lose the ability to walk. Because the muscles associated with breathing are affected, most children eventually require ventilator support. Death due to respiratory failure usually occurs a few years after the first symptoms occur. Childhood-Onset
Symptoms of childhood-onset TK2D appear between the ages of 1 and 12 years. The first signs are typically muscle weakness of the arms and legs. The facial muscles are also often involved leading to facial paralysis and droopy eyelids (ptosis). The muscles of the eyeballs may also be affected, leading to difficulties in moving the eyeballs (progressive external ophthalmoparesis or PEO). Childhood-onset TK2D is slowly progressive, and most children will need a wheelchair by age 10. The respiratory muscles become weak as well, and many children will require some type of ventilator to assist with breathing. Survival is variable, but many children die from respiratory failure in their teens. Late-Onset
Symptoms of the late-onset type of TK2D begin after age 12. The muscles of the limbs become weak, particularly shoulders, arms, hips and thighs (proximal muscle weakness). One of the first symptoms may be weakness of the shoulder muscles causing the shoulder blade to stick out (scapular winging). Facial muscle weakness can cause droopy eyelids (ptosis) and weakness of the muscles that move the eye (progressive external ophthalmoplegia or PEO). Other symptoms include difficulty swallowing and talking. Progression is different from person to person. Generally, the symptoms of late-onset TK2D get slowly worse over time. Most people do not lose the ability to walk, but often need some kind of assistance with mobility. The respiratory muscles are affected and become weak. Many people eventually need some type of ventilator support to help with breathing. Death usually occurs 20-30 years after the onset of symptoms and is usually due to respiratory failure.
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Symptoms of Thymidine Kinase 2 Deficiency. The symptoms of TK2D vary in severity, age of onset and how quickly they progress. There are three main types of TK2D: the infantile-onset type, childhood-onset type and late-onset type. Infantile-Onset
The first symptoms of infantile-onset TK2D typically begin before one year of age. Early development and growth are normal. The first signs of TK2D are usually low muscle tone (hypotonia) and muscle weakness of the arms and legs. Other early signs include feeding problems and difficulty breathing. Some patients with infantile-onset TK2D also have a brain disease known as encephalopathy. This can lead to developmental and cognitive problems, hearing loss and seizures.The symptoms of infantile TK2D quickly get worse over time. Most children with this condition never walk or quickly lose the ability to walk. Because the muscles associated with breathing are affected, most children eventually require ventilator support. Death due to respiratory failure usually occurs a few years after the first symptoms occur. Childhood-Onset
Symptoms of childhood-onset TK2D appear between the ages of 1 and 12 years. The first signs are typically muscle weakness of the arms and legs. The facial muscles are also often involved leading to facial paralysis and droopy eyelids (ptosis). The muscles of the eyeballs may also be affected, leading to difficulties in moving the eyeballs (progressive external ophthalmoparesis or PEO). Childhood-onset TK2D is slowly progressive, and most children will need a wheelchair by age 10. The respiratory muscles become weak as well, and many children will require some type of ventilator to assist with breathing. Survival is variable, but many children die from respiratory failure in their teens. Late-Onset
Symptoms of the late-onset type of TK2D begin after age 12. The muscles of the limbs become weak, particularly shoulders, arms, hips and thighs (proximal muscle weakness). One of the first symptoms may be weakness of the shoulder muscles causing the shoulder blade to stick out (scapular winging). Facial muscle weakness can cause droopy eyelids (ptosis) and weakness of the muscles that move the eye (progressive external ophthalmoplegia or PEO). Other symptoms include difficulty swallowing and talking. Progression is different from person to person. Generally, the symptoms of late-onset TK2D get slowly worse over time. Most people do not lose the ability to walk, but often need some kind of assistance with mobility. The respiratory muscles are affected and become weak. Many people eventually need some type of ventilator support to help with breathing. Death usually occurs 20-30 years after the onset of symptoms and is usually due to respiratory failure.
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Causes of Thymidine Kinase 2 Deficiency
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TK2D is caused by pathogenic variants (mutations) in the thymidine kinase 2 (TK2) gene. This gene makes a protein known as thymidine kinase 2, which helps make certain types of nucleotides which are the building blocks for DNA needed to maintain mitochondrial DNA. When the TK2 gene is not working correctly, the amount of mitochondrial DNA inside each mitochondrion decreases over time. The mitochondria are slowly unable to make energy for the body cells. This leads to progressive muscle weakness of the limbs, face, respiratory tract and other parts of the body. TK2D deficiency is inherited in a recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
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Causes of Thymidine Kinase 2 Deficiency. TK2D is caused by pathogenic variants (mutations) in the thymidine kinase 2 (TK2) gene. This gene makes a protein known as thymidine kinase 2, which helps make certain types of nucleotides which are the building blocks for DNA needed to maintain mitochondrial DNA. When the TK2 gene is not working correctly, the amount of mitochondrial DNA inside each mitochondrion decreases over time. The mitochondria are slowly unable to make energy for the body cells. This leads to progressive muscle weakness of the limbs, face, respiratory tract and other parts of the body. TK2D deficiency is inherited in a recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
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Affects of Thymidine Kinase 2 Deficiency
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The exact number of people with TK2D is unknown. In 2018, there were about 107 individuals reported in the medical literature with this condition. Because TK2D was first described in 2001 and is not a well-known cause of muscle weakness, it is likely that many people with this condition do not get diagnosed. TK2D doesn’t seem to occur more often in any one ethnic group or sex.
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Affects of Thymidine Kinase 2 Deficiency. The exact number of people with TK2D is unknown. In 2018, there were about 107 individuals reported in the medical literature with this condition. Because TK2D was first described in 2001 and is not a well-known cause of muscle weakness, it is likely that many people with this condition do not get diagnosed. TK2D doesn’t seem to occur more often in any one ethnic group or sex.
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Related disorders of Thymidine Kinase 2 Deficiency
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Symptoms of the following disorders can be similar to those of thymidine kinase 2 deficiency. Comparisons may be useful for a differential diagnosis:Spinal muscular atrophy (SMA) refers to a group of genetic disorders caused by loss of nerve cells in the spinal cord called lower motor neurons or anterior horn cells. The loss of lower motor neurons leads to progressive muscle weakness, muscle wasting (atrophy) and low muscle tone (hypotonia) that mainly affects the muscles of the shoulders, hips and back. The muscles that control feeding, swallowing and breathing can also be affected. There are at least 5 types of SMA which vary in severity and age at onset. All types of SMA are inherited in a recessive pattern. For more information, choose “spinal muscular atrophy” as your search term in the Rare Disease Database.Facioscapulohumeral dystrophy (FSHD) is characterized by muscle weakness and wasting (atrophy). The muscles most affected are those in the face (facio), around the shoulder blades (scapulo) and in the upper arms (humeral). Over time, other muscles may become affected as well. Symptoms usually appear before age 20 but can begin in infancy or later in adulthood. FSHD typically gets slowly worse over time. Symptoms and severity vary even among affected members of the same family. Life expectancy is not shortened. FSHD is usually inherited in an autosomal dominant pattern. For more information, choose “primary mitochondrial myopathies” as your search term in the Rare Disease Database.Chronic progressive external ophthalmoplegia (CPEO) is progressive weakness of the muscles involved in eye and eyelid movement. Signs and symptoms usually begin in early adulthood and can include weakness or paralysis of the muscles that move the eye (ophthalmoplegia) and drooping of the eyelids (ptosis). Some individuals also have weakness of the skeletal muscles (myopathy) which may be especially noticeable during exercise. CPEO can occur alone or as part of another condition. For more information, choose “chronic progressive external ophthalmoplegia” as your search term in the Rare Disease Database.Kearns-Sayre syndrome is characterized by droopy eyelids, paralysis of the muscles that control the eyes (chronic progressive external ophthalmoplegia or CPEO) and heart disease. In addition, abnormal accumulation of pigment in the retina of the eyes can occur, leading to poor night vision and vision loss. Other findings may include muscle weakness, short stature, sensorineural hearing loss and involuntary movements. Symptoms tend to get worse over time. In some people, KSS may be part of another condition. KSS is caused by mutations in a gene found in mitochondrial DNA and is inherited in a mitochondrial pattern. For more information, choose “Kearns Sayre syndrome” as your search term in the Rare Disease Database.MELAS (mitochondrial encephalopathy, lactic acidosis and stroke-like episodes) syndrome affects primarily the brain and the muscles. It is characterized by stroke-like episodes that lead to headaches, seizures and temporary muscle weakness. Other symptoms include loss of motor and cognitive skills and vision and hearing loss. Symptoms usually begin in childhood. Most cases of MELAS are caused by mutations in mitochondrial DNA and are inherited in a mitochondrial pattern. For more information, choose “MELAS syndrome” as your search term in the Rare Disease Database.MERRF (myoclonus epilepsy with ragged-red fibers) syndrome is a rare disorder that affects the nervous system, skeletal muscles and other body systems. Symptoms can begin at any age. People with MERRF develop muscle jerking (myoclonus) that can affect the limbs or entire body. They may also have seizures, uncoordinated movements (ataxia), muscle weakness (myopathy), difficulty exercising and a slow loss of intellectual function (dementia). Short stature, vision problems (optic atrophy), hearing loss, weak heart muscles (cardiomyopathy) and abnormal sensation from nerve damage (peripheral neuropathy) are other common symptoms. MERRF is inherited in a mitochondrial pattern. For more information, choose “MERRF syndrome” as your search term in the Rare Disease Database.Pompe disease is a rare progressive neurodegenerative disorder that affects many body systems. Symptoms can begin at any age and include muscle weakness that affects mobility and breathing. There are several types of Pompe disease. The most common and most severe type is the early-onset form. Infants with this form develop symptoms of muscle weakness by three months of age and have a characteristic heart defect known as hypertrophic cardiomyopathy. The symptoms of Pompe disease tend to get worse over time. This condition is inherited in a recessive pattern. For more information, choose “Pompe disease” as your search term in the Rare Disease Database.
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Related disorders of Thymidine Kinase 2 Deficiency. Symptoms of the following disorders can be similar to those of thymidine kinase 2 deficiency. Comparisons may be useful for a differential diagnosis:Spinal muscular atrophy (SMA) refers to a group of genetic disorders caused by loss of nerve cells in the spinal cord called lower motor neurons or anterior horn cells. The loss of lower motor neurons leads to progressive muscle weakness, muscle wasting (atrophy) and low muscle tone (hypotonia) that mainly affects the muscles of the shoulders, hips and back. The muscles that control feeding, swallowing and breathing can also be affected. There are at least 5 types of SMA which vary in severity and age at onset. All types of SMA are inherited in a recessive pattern. For more information, choose “spinal muscular atrophy” as your search term in the Rare Disease Database.Facioscapulohumeral dystrophy (FSHD) is characterized by muscle weakness and wasting (atrophy). The muscles most affected are those in the face (facio), around the shoulder blades (scapulo) and in the upper arms (humeral). Over time, other muscles may become affected as well. Symptoms usually appear before age 20 but can begin in infancy or later in adulthood. FSHD typically gets slowly worse over time. Symptoms and severity vary even among affected members of the same family. Life expectancy is not shortened. FSHD is usually inherited in an autosomal dominant pattern. For more information, choose “primary mitochondrial myopathies” as your search term in the Rare Disease Database.Chronic progressive external ophthalmoplegia (CPEO) is progressive weakness of the muscles involved in eye and eyelid movement. Signs and symptoms usually begin in early adulthood and can include weakness or paralysis of the muscles that move the eye (ophthalmoplegia) and drooping of the eyelids (ptosis). Some individuals also have weakness of the skeletal muscles (myopathy) which may be especially noticeable during exercise. CPEO can occur alone or as part of another condition. For more information, choose “chronic progressive external ophthalmoplegia” as your search term in the Rare Disease Database.Kearns-Sayre syndrome is characterized by droopy eyelids, paralysis of the muscles that control the eyes (chronic progressive external ophthalmoplegia or CPEO) and heart disease. In addition, abnormal accumulation of pigment in the retina of the eyes can occur, leading to poor night vision and vision loss. Other findings may include muscle weakness, short stature, sensorineural hearing loss and involuntary movements. Symptoms tend to get worse over time. In some people, KSS may be part of another condition. KSS is caused by mutations in a gene found in mitochondrial DNA and is inherited in a mitochondrial pattern. For more information, choose “Kearns Sayre syndrome” as your search term in the Rare Disease Database.MELAS (mitochondrial encephalopathy, lactic acidosis and stroke-like episodes) syndrome affects primarily the brain and the muscles. It is characterized by stroke-like episodes that lead to headaches, seizures and temporary muscle weakness. Other symptoms include loss of motor and cognitive skills and vision and hearing loss. Symptoms usually begin in childhood. Most cases of MELAS are caused by mutations in mitochondrial DNA and are inherited in a mitochondrial pattern. For more information, choose “MELAS syndrome” as your search term in the Rare Disease Database.MERRF (myoclonus epilepsy with ragged-red fibers) syndrome is a rare disorder that affects the nervous system, skeletal muscles and other body systems. Symptoms can begin at any age. People with MERRF develop muscle jerking (myoclonus) that can affect the limbs or entire body. They may also have seizures, uncoordinated movements (ataxia), muscle weakness (myopathy), difficulty exercising and a slow loss of intellectual function (dementia). Short stature, vision problems (optic atrophy), hearing loss, weak heart muscles (cardiomyopathy) and abnormal sensation from nerve damage (peripheral neuropathy) are other common symptoms. MERRF is inherited in a mitochondrial pattern. For more information, choose “MERRF syndrome” as your search term in the Rare Disease Database.Pompe disease is a rare progressive neurodegenerative disorder that affects many body systems. Symptoms can begin at any age and include muscle weakness that affects mobility and breathing. There are several types of Pompe disease. The most common and most severe type is the early-onset form. Infants with this form develop symptoms of muscle weakness by three months of age and have a characteristic heart defect known as hypertrophic cardiomyopathy. The symptoms of Pompe disease tend to get worse over time. This condition is inherited in a recessive pattern. For more information, choose “Pompe disease” as your search term in the Rare Disease Database.
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Diagnosis of Thymidine Kinase 2 Deficiency
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TK2D is diagnosed based on symptoms, a detailed patient history, clinical exam and both laboratory and genetic tests. Genetic testing for mutations in the TK2 gene can confirm the diagnosis.Other testing that may be done to support the diagnosis of TK2D includes creatine kinase (CK) that is typically elevated in blood. Electromyography (EMG) can show changes in muscle functions (myopathic changes).
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Diagnosis of Thymidine Kinase 2 Deficiency. TK2D is diagnosed based on symptoms, a detailed patient history, clinical exam and both laboratory and genetic tests. Genetic testing for mutations in the TK2 gene can confirm the diagnosis.Other testing that may be done to support the diagnosis of TK2D includes creatine kinase (CK) that is typically elevated in blood. Electromyography (EMG) can show changes in muscle functions (myopathic changes).
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Therapies of Thymidine Kinase 2 Deficiency
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There is no cure TK2D. Treatment is focused on managing the symptoms. This typically involves a team of specialists including a neurologist, pulmonologist, and physical and occupational therapists. Some patients will require a wheelchair for mobility. In addition, many people with TK2D need ventilator support to help with breathing. Genetic counseling is recommended for individuals with TK2D and their families.
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Therapies of Thymidine Kinase 2 Deficiency. There is no cure TK2D. Treatment is focused on managing the symptoms. This typically involves a team of specialists including a neurologist, pulmonologist, and physical and occupational therapists. Some patients will require a wheelchair for mobility. In addition, many people with TK2D need ventilator support to help with breathing. Genetic counseling is recommended for individuals with TK2D and their families.
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Overview of Thyroid Cancer
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Thyroid cancer (carcinoma) is cancer affecting the thyroid gland, a butterfly-shaped structure located at the base of the neck. The thyroid is part of the endocrine system, the network of glands that secrete hormones. Thyroid hormones regulate the chemical processes (metabolism) that influence the body's activities as well as regulating the heart rate, body temperature, and blood pressure. Hormones are secreted directly into the bloodstream where they travel to various areas of the body.In many people, there are no symptoms (asymptomatic) associated with thyroid cancer. Pain in the neck, hoarseness and swollen lymph nodes especially in the neck may be present in some people. Thyroid cancer is the most common form of cancer affecting the endocrine system. Most forms rarely cause pain or disability and are easily treated with surgery and follow-up therapy. However, some forms are aggressive and more difficult to treat.The term “cancer” refers to a group of diseases characterized by abnormal, uncontrolled cellular growth that invades surrounding tissues and may spread (metastasize) to distant bodily tissues or organs via the bloodstream, the lymphatic system, or other means. Different forms of cancer, including thyroid cancer, may be classified based upon the cell type involved, the specific nature of the malignancy, and the disease’s clinical course. The four main types of thyroid cancer are papillary, follicular, medullary and anaplastic. Rare forms of thyroid cancer include thyroid teratoma, lymphoma, and squamous cell carcinoma. Papillary cancer is by far the most common, comprising about 80% of all thyroid cancer.Malignant cells pass their abnormal changes on to all their “daughter” cells and typically grow and divide at an unusually rapid, uncontrolled rate that cannot be contained by the body’s natural immune defenses. Eventually, such proliferation of abnormal cells may result in formation of a mass known as a tumor (neoplasm). Disease progression may be characterized by invasion of surrounding tissues, infiltration of regional lymph nodes, and spread of the malignancy via the bloodstream, the lymphatic circulation, or other means to other bodily tissues and organs.
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Overview of Thyroid Cancer. Thyroid cancer (carcinoma) is cancer affecting the thyroid gland, a butterfly-shaped structure located at the base of the neck. The thyroid is part of the endocrine system, the network of glands that secrete hormones. Thyroid hormones regulate the chemical processes (metabolism) that influence the body's activities as well as regulating the heart rate, body temperature, and blood pressure. Hormones are secreted directly into the bloodstream where they travel to various areas of the body.In many people, there are no symptoms (asymptomatic) associated with thyroid cancer. Pain in the neck, hoarseness and swollen lymph nodes especially in the neck may be present in some people. Thyroid cancer is the most common form of cancer affecting the endocrine system. Most forms rarely cause pain or disability and are easily treated with surgery and follow-up therapy. However, some forms are aggressive and more difficult to treat.The term “cancer” refers to a group of diseases characterized by abnormal, uncontrolled cellular growth that invades surrounding tissues and may spread (metastasize) to distant bodily tissues or organs via the bloodstream, the lymphatic system, or other means. Different forms of cancer, including thyroid cancer, may be classified based upon the cell type involved, the specific nature of the malignancy, and the disease’s clinical course. The four main types of thyroid cancer are papillary, follicular, medullary and anaplastic. Rare forms of thyroid cancer include thyroid teratoma, lymphoma, and squamous cell carcinoma. Papillary cancer is by far the most common, comprising about 80% of all thyroid cancer.Malignant cells pass their abnormal changes on to all their “daughter” cells and typically grow and divide at an unusually rapid, uncontrolled rate that cannot be contained by the body’s natural immune defenses. Eventually, such proliferation of abnormal cells may result in formation of a mass known as a tumor (neoplasm). Disease progression may be characterized by invasion of surrounding tissues, infiltration of regional lymph nodes, and spread of the malignancy via the bloodstream, the lymphatic circulation, or other means to other bodily tissues and organs.
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Symptoms of Thyroid Cancer
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The vast majority individuals with thyroid cancer have no symptoms (asymptomatic). In most cases, a small growth or lump (nodule), discovered by the patient, health care provider, or incidentally on an imaging study (e.g., a CT scan, MRI, or carotid artery ultrasound), is the first sign of thyroid cancer. Thyroid “nodules” or lumps in the thyroid may be caused by a variety of conditions and do not necessarily mean that an individual has cancer. In fact, more than 90 percent of thyroid nodules are not cancerous (benign).Symptoms that may be associated with thyroid cancer include hoarseness, difficulty breathing or swallowing, swollen lymph nodes especially in the neck, and pain in the throat or neck.Cancer can arise from any of the types of cells found in the thyroid gland. Approximately 90 percent of thyroid cancers arise from follicular cells (the cells that comprise most of the thyroid and make thyroid hormone). Most of the remaining cases arise from C cells (parafollicular cells). Cancer arising from white blood cells (lymphocytes), known as lymphoma, may also occur. Extremely rare forms of thyroid cancer include squamous cell carcinoma and teratomas.Thyroid cancer may also be classified as well-differentiated or poorly differentiated. Differentiation refers to how abnormal the cells look under a microscope, how rapidly they grow, and whether they retain the features of normal thyroid cells, such as the ability to trap iodine. Well-differentiated cancers are made of cells that retain the look of the cells from which they arose (e.g., thyroid follicular cells). More “poorly differentiated” or “undifferentiated” cancers are made of cells that have undergone transformation and revert to a less specialized, more primitive form. Therefore, they are no longer capable of performing their “intended”, specialized functions within the tissue in question.Well-differentiated thyroid cancer usually refers to papillary or follicular forms of thyroid cancer. These forms of thyroid cancer are sometimes simply referred to as differentiated thyroid cancer or DTC. Insular thyroid carcinoma is referred to as poorly differentiated thyroid cancer. Anaplastic thyroid cancer is also known as undifferentiated thyroid cancer. Naturally, well-differentiated carcinomas have a better prognosis.Papillary Thyroid Carcinoma (PTC)
PTC is the most common form of thyroid cancer, accounting for approximately 80 percent of patients. PTC arises from the thyroid follicular cells. This form of thyroid cancer usually presents as a single lump in the thyroid and often progresses slowly. PTC has a propensity to spread (metastasize) via the lymph nodes and the lymphatic system, especially to local lymph nodes in the neck.PTC can affect individuals of any age including children, but most often affects people between 30 and 50 years of age. Women are affected more often than men.Variants of Papillary Thyroid Carcinoma
There are several subtypes or variants of PTC; common subtypes include follicular, tall cell, and diffuse sclerosing variants. These names refer to what the thyroid cancers look like under the microscope.The follicular variant of PTC, which is different from follicular thyroid carcinoma, is the most common subtype in the United States. The follicular variant is a slow growing form of cancer. The clinical behavior of this subtype is similar to PTC in general.The tall cell variant (TCV) of PTC is a relatively rare form of thyroid cancer. TCV can be more aggressive than PTC in general, and has higher rates of recurrence than PTC. Most cases tend to occur in older individuals. TCV gets its name because the height of the characteristic cells is two to three times greater than the width. More than 70% of cancer cells for this tumor must be “tall” cells for a diagnosis of tall cell variant thyroid cancer. Tumor size is generally larger than the tumor size generally associated with PTC. Some researchers believe that TCV is underdiagnosed.The diffuse sclerosing variant is more common in younger individuals, especially younger women. It often develops between the ages of 15-30. The first sign is often an enlarged thyroid (goiter). This subtype of PTC can spread to the lymph nodes or lungs. Recurrence is more likely with the diffuse sclerosing variant than with PTC.Follicular Thyroid Carcinoma (FTC)
Although FTC is the second most common form of thyroid cancer, it accounts for only approximately 10 percent of patients. As with papillary thyroid carcinoma, FTC also arises from thyroid follicular cells, but is far less likely to spread to the lymph nodes. It may spread to the lungs, brain, or bone. FTC is often classified as minimally invasive or widely invasive. FTC usually presents as a painless thyroid lump (nodule).Most individuals with FTC are more than 50 years of age. Women are affected more often than men by greater than a 2-1 ratio.Poorly differentiated (insular) thyroid carcinoma is a rare subtype of follicular thyroid carcinoma. It is extremely rare, but is aggressive and often spreads to the surrounding lymph nodes and other areas of the body, especially the lungs, bone or brain where it may cause life-threatening complications. This form of thyroid cancer also usually presents as a mass in the neck.Poorly differentiated thyroid carcinoma usually affects individuals 55 years old or older and affects women twice as often as men. While most of the medical literature classifies poorly differentiated thyroid carcinoma as a form of follicular thyroid carcinoma, its cellular makeup may also be related to papillary thyroid carcinoma.Hürthle Cell Carcinoma
The World Health Organization (WHO) classifies this form of thyroid cancer as a subtype of FTC, although recent research suggests that it is a distinct form of thyroid cancer. HCC accounts for approximately 3 percent of thyroid cancer. This form of thyroid cancer may affect any age group and usually occurs in individuals between 40-50 years of age. HCC affects women more often than men and is considered to have a worse prognosis than regular FTC. This form of thyroid cancer is also known as oncocytic thyroid carcinoma.The first sign of Hürthle cell carcinoma is usually a painless lump in the neck. Hürthle cell carcinoma may spread to affect the bone, liver, or lung. Rare cases have been described that have spread to the adrenal glands and brain.Medullary Thyroid Carcinoma (MTC)
This type of thyroid cancer accounts for approximately 2-3 percent of thyroid cancer. MTC arises from “C cells” (also called parafollicular cells); this type of cell produces the hormone calcitonin (which is why they are called “C cells”). Calcitonin helps to regulate calcium and sodium metabolism in animals, and may have effects to protect the skeleton from calcium loss in man. MTC is a more aggressive form of cancer than DTC, and may spread via the lymph nodes or bloodstream to affect other organs. The first sign of MTC is often a firm mass in the thyroid or abnormal enlargement of nearby lymph nodes (lymphadenopathy). In some cases, MTC may already have spread (metastasized) to other organs before a mass is detected.Most people with MTC develop it randomly for no known reason (sporadic cases). However, about 30% of patients may have a type that runs in families (familial MTC or FMTC), affecting only the thyroid or as part of a rare disorder known as multiple endocrine neoplasia (MEN Type 2).Anaplastic (Undifferentiated) Thyroid Carcinoma (ATC)
ATC accounts for approximately 5 percent of thyroid cancer and mostly affects individuals 70 years and older. ATC is highly aggressive and often spreads quickly to surrounding lymph nodes and organs especially the windpipe (trachea), lungs or bone. ATC may quickly result in life-threatening complications such as obstruction of the trachea or massive hemorrhaging. ATC often develops from an existing follicular or papillary cancer.Thyroid Lymphoma
Primary lymphoma of the thyroid does not arise from follicular or C cells, but instead arises from the immune system cells known as lymphocytes. Most lymphomas develop in the lymph nodes, but can occur in other organs such as the thyroid. Thyroid lymphoma is extremely rare accounting for less than 2 percent of thyroid cancers.Thyroid lymphoma spreads rapidly and quickly replaces thyroid tissue. Thyroid lymphoma usually affects individuals more than 70 years old and affects women three times more often than men. It occurs most commonly in women who have a history of hypothyroidism due to autoimmune (Hashimoto’s) thyroiditis.
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Symptoms of Thyroid Cancer. The vast majority individuals with thyroid cancer have no symptoms (asymptomatic). In most cases, a small growth or lump (nodule), discovered by the patient, health care provider, or incidentally on an imaging study (e.g., a CT scan, MRI, or carotid artery ultrasound), is the first sign of thyroid cancer. Thyroid “nodules” or lumps in the thyroid may be caused by a variety of conditions and do not necessarily mean that an individual has cancer. In fact, more than 90 percent of thyroid nodules are not cancerous (benign).Symptoms that may be associated with thyroid cancer include hoarseness, difficulty breathing or swallowing, swollen lymph nodes especially in the neck, and pain in the throat or neck.Cancer can arise from any of the types of cells found in the thyroid gland. Approximately 90 percent of thyroid cancers arise from follicular cells (the cells that comprise most of the thyroid and make thyroid hormone). Most of the remaining cases arise from C cells (parafollicular cells). Cancer arising from white blood cells (lymphocytes), known as lymphoma, may also occur. Extremely rare forms of thyroid cancer include squamous cell carcinoma and teratomas.Thyroid cancer may also be classified as well-differentiated or poorly differentiated. Differentiation refers to how abnormal the cells look under a microscope, how rapidly they grow, and whether they retain the features of normal thyroid cells, such as the ability to trap iodine. Well-differentiated cancers are made of cells that retain the look of the cells from which they arose (e.g., thyroid follicular cells). More “poorly differentiated” or “undifferentiated” cancers are made of cells that have undergone transformation and revert to a less specialized, more primitive form. Therefore, they are no longer capable of performing their “intended”, specialized functions within the tissue in question.Well-differentiated thyroid cancer usually refers to papillary or follicular forms of thyroid cancer. These forms of thyroid cancer are sometimes simply referred to as differentiated thyroid cancer or DTC. Insular thyroid carcinoma is referred to as poorly differentiated thyroid cancer. Anaplastic thyroid cancer is also known as undifferentiated thyroid cancer. Naturally, well-differentiated carcinomas have a better prognosis.Papillary Thyroid Carcinoma (PTC)
PTC is the most common form of thyroid cancer, accounting for approximately 80 percent of patients. PTC arises from the thyroid follicular cells. This form of thyroid cancer usually presents as a single lump in the thyroid and often progresses slowly. PTC has a propensity to spread (metastasize) via the lymph nodes and the lymphatic system, especially to local lymph nodes in the neck.PTC can affect individuals of any age including children, but most often affects people between 30 and 50 years of age. Women are affected more often than men.Variants of Papillary Thyroid Carcinoma
There are several subtypes or variants of PTC; common subtypes include follicular, tall cell, and diffuse sclerosing variants. These names refer to what the thyroid cancers look like under the microscope.The follicular variant of PTC, which is different from follicular thyroid carcinoma, is the most common subtype in the United States. The follicular variant is a slow growing form of cancer. The clinical behavior of this subtype is similar to PTC in general.The tall cell variant (TCV) of PTC is a relatively rare form of thyroid cancer. TCV can be more aggressive than PTC in general, and has higher rates of recurrence than PTC. Most cases tend to occur in older individuals. TCV gets its name because the height of the characteristic cells is two to three times greater than the width. More than 70% of cancer cells for this tumor must be “tall” cells for a diagnosis of tall cell variant thyroid cancer. Tumor size is generally larger than the tumor size generally associated with PTC. Some researchers believe that TCV is underdiagnosed.The diffuse sclerosing variant is more common in younger individuals, especially younger women. It often develops between the ages of 15-30. The first sign is often an enlarged thyroid (goiter). This subtype of PTC can spread to the lymph nodes or lungs. Recurrence is more likely with the diffuse sclerosing variant than with PTC.Follicular Thyroid Carcinoma (FTC)
Although FTC is the second most common form of thyroid cancer, it accounts for only approximately 10 percent of patients. As with papillary thyroid carcinoma, FTC also arises from thyroid follicular cells, but is far less likely to spread to the lymph nodes. It may spread to the lungs, brain, or bone. FTC is often classified as minimally invasive or widely invasive. FTC usually presents as a painless thyroid lump (nodule).Most individuals with FTC are more than 50 years of age. Women are affected more often than men by greater than a 2-1 ratio.Poorly differentiated (insular) thyroid carcinoma is a rare subtype of follicular thyroid carcinoma. It is extremely rare, but is aggressive and often spreads to the surrounding lymph nodes and other areas of the body, especially the lungs, bone or brain where it may cause life-threatening complications. This form of thyroid cancer also usually presents as a mass in the neck.Poorly differentiated thyroid carcinoma usually affects individuals 55 years old or older and affects women twice as often as men. While most of the medical literature classifies poorly differentiated thyroid carcinoma as a form of follicular thyroid carcinoma, its cellular makeup may also be related to papillary thyroid carcinoma.Hürthle Cell Carcinoma
The World Health Organization (WHO) classifies this form of thyroid cancer as a subtype of FTC, although recent research suggests that it is a distinct form of thyroid cancer. HCC accounts for approximately 3 percent of thyroid cancer. This form of thyroid cancer may affect any age group and usually occurs in individuals between 40-50 years of age. HCC affects women more often than men and is considered to have a worse prognosis than regular FTC. This form of thyroid cancer is also known as oncocytic thyroid carcinoma.The first sign of Hürthle cell carcinoma is usually a painless lump in the neck. Hürthle cell carcinoma may spread to affect the bone, liver, or lung. Rare cases have been described that have spread to the adrenal glands and brain.Medullary Thyroid Carcinoma (MTC)
This type of thyroid cancer accounts for approximately 2-3 percent of thyroid cancer. MTC arises from “C cells” (also called parafollicular cells); this type of cell produces the hormone calcitonin (which is why they are called “C cells”). Calcitonin helps to regulate calcium and sodium metabolism in animals, and may have effects to protect the skeleton from calcium loss in man. MTC is a more aggressive form of cancer than DTC, and may spread via the lymph nodes or bloodstream to affect other organs. The first sign of MTC is often a firm mass in the thyroid or abnormal enlargement of nearby lymph nodes (lymphadenopathy). In some cases, MTC may already have spread (metastasized) to other organs before a mass is detected.Most people with MTC develop it randomly for no known reason (sporadic cases). However, about 30% of patients may have a type that runs in families (familial MTC or FMTC), affecting only the thyroid or as part of a rare disorder known as multiple endocrine neoplasia (MEN Type 2).Anaplastic (Undifferentiated) Thyroid Carcinoma (ATC)
ATC accounts for approximately 5 percent of thyroid cancer and mostly affects individuals 70 years and older. ATC is highly aggressive and often spreads quickly to surrounding lymph nodes and organs especially the windpipe (trachea), lungs or bone. ATC may quickly result in life-threatening complications such as obstruction of the trachea or massive hemorrhaging. ATC often develops from an existing follicular or papillary cancer.Thyroid Lymphoma
Primary lymphoma of the thyroid does not arise from follicular or C cells, but instead arises from the immune system cells known as lymphocytes. Most lymphomas develop in the lymph nodes, but can occur in other organs such as the thyroid. Thyroid lymphoma is extremely rare accounting for less than 2 percent of thyroid cancers.Thyroid lymphoma spreads rapidly and quickly replaces thyroid tissue. Thyroid lymphoma usually affects individuals more than 70 years old and affects women three times more often than men. It occurs most commonly in women who have a history of hypothyroidism due to autoimmune (Hashimoto’s) thyroiditis.
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Causes of Thyroid Cancer
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The cause(s) of thyroid cancer are unknown. Researchers speculate that genetic and immunologic abnormalities, environmental factors (e.g., certain chemicals, ionizing radiation), diet, and/or other factors may play contributing roles in causing specific types of cancer. Rarely, thyroid cancer can be hereditary, especially medullary thyroid cancer, as noted above. Investigators are conducting ongoing basic research to learn more about the many factors that may result in cancer.Current research suggests that abnormalities of DNA (deoxyribonucleic acid), which is the carrier of the body’s genetic code, are the underlying basis of cellular malignant transformation. In individuals with cancer, including thyroid cancer, malignancies most often develop due to abnormalities in the structure of specific genes known as “oncogenes” or “tumor suppressor genes”. Oncogenes control cell growth; tumor suppressor genes control cell division and ensure that cells die at the proper time. These abnormal genetic changes may occur spontaneously for unknown reasons or, more rarely, may be inherited. Exposure to ionizing radiation from medical treatments or atomic fallout during childhood is the most well-established environmental factor.DNA mutations that cause papillary or follicular thyroid carcinoma have been found in several different genes located on various chromosomes. For example, some people with papillary thyroid carcinoma have mutations of the RET gene on chromosome 10. Mutations in the BRAF gene and the RAS family of genes are also commonly associated with papillary thyroid carcinoma. These genes normally regulate a cell’s growth and differentiation, and mutations can lead to unrestricted growth and de-differentiation. Most of these genetic mutations are acquired during life, are found only in the cancer cells and are not passed on to an affected individual’s children.In thyroid cancer, damage to DNA may occur from external radiation. Individuals who have undergone radiation therapy of the head and neck region, especially children, have a greater chance of developing thyroid cancer than the general population. Individuals who have been exposed as children or adolescents to radioactive particles such as those from atomic weapons tests or nuclear power plant accidents (e.g., Chernobyl) also have a higher risk of developing thyroid cancer. Diagnostic x-rays, such as chest x-rays, dental x-rays, and the like are not known to cause cancer.Medullary thyroid cancer may occur spontaneously for no known reason (sporadically), as part of an isolated inherited syndrome (i.e., familial medullary thyroid carcinoma [FMTC]), or as part of a more complex disorder called multiple endocrine neoplasia type II (MEN 2). (For more information on these disorders, see the Related Disorders section of this report.)DNA is the code that allows the body’s cells to make proteins. DNA forms genes, that are translated by the body’s cells into proteins that are needed for the body to function. Cells have two genes for each protein, one received from the father and one from the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. FMTC and MEN 2 are inherited as autosomal dominant traits. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child. FMTC and MEN 2 have been linked to mutations of the RET gene on chromosome 10.Individuals who have benign thyroid disease or have a family history of benign thyroid disease are at a greater risk of develop thyroid cancer than the general population. Benign thyroid disease includes goiter, thyroid nodules, or inflammation of the thyroid (thyroiditis).Individuals with certain genetic disorders are also at a greater risk of developing thyroid cancer. These disorders include familial adenomatous polyposis (FAP), Gardner syndrome, PTEN hamartoma tumor syndrome and Carney complex. (For more information on these disorders, choose the specific disorders name as your search term in the Rare Disease Database.)
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Causes of Thyroid Cancer. The cause(s) of thyroid cancer are unknown. Researchers speculate that genetic and immunologic abnormalities, environmental factors (e.g., certain chemicals, ionizing radiation), diet, and/or other factors may play contributing roles in causing specific types of cancer. Rarely, thyroid cancer can be hereditary, especially medullary thyroid cancer, as noted above. Investigators are conducting ongoing basic research to learn more about the many factors that may result in cancer.Current research suggests that abnormalities of DNA (deoxyribonucleic acid), which is the carrier of the body’s genetic code, are the underlying basis of cellular malignant transformation. In individuals with cancer, including thyroid cancer, malignancies most often develop due to abnormalities in the structure of specific genes known as “oncogenes” or “tumor suppressor genes”. Oncogenes control cell growth; tumor suppressor genes control cell division and ensure that cells die at the proper time. These abnormal genetic changes may occur spontaneously for unknown reasons or, more rarely, may be inherited. Exposure to ionizing radiation from medical treatments or atomic fallout during childhood is the most well-established environmental factor.DNA mutations that cause papillary or follicular thyroid carcinoma have been found in several different genes located on various chromosomes. For example, some people with papillary thyroid carcinoma have mutations of the RET gene on chromosome 10. Mutations in the BRAF gene and the RAS family of genes are also commonly associated with papillary thyroid carcinoma. These genes normally regulate a cell’s growth and differentiation, and mutations can lead to unrestricted growth and de-differentiation. Most of these genetic mutations are acquired during life, are found only in the cancer cells and are not passed on to an affected individual’s children.In thyroid cancer, damage to DNA may occur from external radiation. Individuals who have undergone radiation therapy of the head and neck region, especially children, have a greater chance of developing thyroid cancer than the general population. Individuals who have been exposed as children or adolescents to radioactive particles such as those from atomic weapons tests or nuclear power plant accidents (e.g., Chernobyl) also have a higher risk of developing thyroid cancer. Diagnostic x-rays, such as chest x-rays, dental x-rays, and the like are not known to cause cancer.Medullary thyroid cancer may occur spontaneously for no known reason (sporadically), as part of an isolated inherited syndrome (i.e., familial medullary thyroid carcinoma [FMTC]), or as part of a more complex disorder called multiple endocrine neoplasia type II (MEN 2). (For more information on these disorders, see the Related Disorders section of this report.)DNA is the code that allows the body’s cells to make proteins. DNA forms genes, that are translated by the body’s cells into proteins that are needed for the body to function. Cells have two genes for each protein, one received from the father and one from the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. FMTC and MEN 2 are inherited as autosomal dominant traits. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child. FMTC and MEN 2 have been linked to mutations of the RET gene on chromosome 10.Individuals who have benign thyroid disease or have a family history of benign thyroid disease are at a greater risk of develop thyroid cancer than the general population. Benign thyroid disease includes goiter, thyroid nodules, or inflammation of the thyroid (thyroiditis).Individuals with certain genetic disorders are also at a greater risk of developing thyroid cancer. These disorders include familial adenomatous polyposis (FAP), Gardner syndrome, PTEN hamartoma tumor syndrome and Carney complex. (For more information on these disorders, choose the specific disorders name as your search term in the Rare Disease Database.)
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Affects of Thyroid Cancer
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According to the American Cancer Society, approximately 53,000 new cases of thyroid cancer will be diagnosed in the United States in 2020. Of those cases, more than 41,000 will occur in women. In fact, thyroid cancer is now the 5th most common cancer in women. Thyroid cancer can affect individuals of any age and specific forms occur with greater frequency among different age groups. In general, thyroid nodules in children and adolescents are more likely may be malignant than those that occur in adults. In general, for unclear reasons, the rate of thyroid cancer incidence has been increasing rapidly over the past few decades. Some researchers believe that this increase in frequency is due to the greater use of imaging (e.g., chest CT scans, cervical spine MRI), with the result being an increase in the rate of detection of small thyroid cancers that may not ever have been detected while the individual was alive. However, there may also be an increase in the frequency of larger thyroid cancers, possibly the result of environmental factors.
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Affects of Thyroid Cancer. According to the American Cancer Society, approximately 53,000 new cases of thyroid cancer will be diagnosed in the United States in 2020. Of those cases, more than 41,000 will occur in women. In fact, thyroid cancer is now the 5th most common cancer in women. Thyroid cancer can affect individuals of any age and specific forms occur with greater frequency among different age groups. In general, thyroid nodules in children and adolescents are more likely may be malignant than those that occur in adults. In general, for unclear reasons, the rate of thyroid cancer incidence has been increasing rapidly over the past few decades. Some researchers believe that this increase in frequency is due to the greater use of imaging (e.g., chest CT scans, cervical spine MRI), with the result being an increase in the rate of detection of small thyroid cancers that may not ever have been detected while the individual was alive. However, there may also be an increase in the frequency of larger thyroid cancers, possibly the result of environmental factors.
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Related disorders of Thyroid Cancer
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Multiple endocrine neoplasia (MEN) type 2 is a rare genetic cancer syndrome in which tumors develop in the endocrine glands (e.g., thyroid, parathyroid, adrenal glands). Two main subtypes exist called MEN 2A and MEN 2B. Familial medullary thyroid carcinoma (FMTC) is considered a third subtype. Nearly all individuals with MEN 2 develop medullary thyroid carcinoma (MTC) at some point. (For more information on these disorders, choose “multiple endocrine neoplasia” as your search term in the Rare Disease Database.)
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Related disorders of Thyroid Cancer. Multiple endocrine neoplasia (MEN) type 2 is a rare genetic cancer syndrome in which tumors develop in the endocrine glands (e.g., thyroid, parathyroid, adrenal glands). Two main subtypes exist called MEN 2A and MEN 2B. Familial medullary thyroid carcinoma (FMTC) is considered a third subtype. Nearly all individuals with MEN 2 develop medullary thyroid carcinoma (MTC) at some point. (For more information on these disorders, choose “multiple endocrine neoplasia” as your search term in the Rare Disease Database.)
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Diagnosis of Thyroid Cancer
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The diagnosis of thyroid cancer is based upon a thorough clinical evaluation, including a detailed patient history and physical exam, and a variety of specialized blood tests and imaging tests. Such testing often includes microscopic evaluation of tumor cells obtained by fine needle aspiration biopsy. Rarely, affected individuals may notice a hard, fixed mass or lump (nodule) usually to the lower left or right of the Adam’s apple. Sometimes a physician or other health care provider may discover such a nodule upon a routine medical exam. Often, the nodule is found accidentally on radiology study performed for another purpose. Thyroid nodules are a common finding, and as people get older, the frequency increases; in some reports, up to 50-75% of older persons have a thyroid nodule that can be detected on a thyroid sonogram (ultrasound). Fortunately, more than 90 percent of them are non-cancerous (benign).Clinical Testing and Work-up
To confirm a diagnosis of thyroid cancer a variety of tests may be performed including blood tests, thyroid ultrasound, and fine-needle aspiration biopsy.Blood tests can reveal the overall function of the thyroid by determining thyroid-stimulating hormone (TSH) levels. TSH is hormone produced by the pituitary gland that promotes the growth of the thyroid and most likely stimulates thyroid cancer cells to grow. Most patients with thyroid cancer have normal thyroid function, however.During a thyroid ultrasound reflected sound waves create an image of the thyroid. A machine known as a transducer creates these sound waves and then records the pattern when they bounce back from the thyroid (echo pattern). Normal thyroid tissue and thyroid nodules have different echo patterns, so the physician can see whether the nodule has a suspicious appearance that may require further evaluation, typically with FNA biopsy. In addition, ultrasound examination of lymph nodes in the neck can be performed, and suspicious lymph nodes can be biopsied prior to surgery.Additional specialized imaging techniques may be used to help evaluate the size, placement, and extension of the tumor and to serve as an aid for future surgical procedures. Such imaging techniques may include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. Laboratory tests and specialized imaging tests may also be conducted to determine possible infiltration of regional lymph nodes and the presence of distant metastases.Fine-need aspiration biopsy (FNA) is the most accurate diagnostic test. FNA involves passing a thin, hollow needle through the skin and inserted into the nodule under ultrasound guidance to withdraw small samples of tissue from the nodule. This procedure may be repeated a few times to gather tissue samples from different sections of the nodule. If multiple nodules are present, the procedure may be performed on each one. The collected tissue is then smeared on to glass slides, stained with colored dye, and studied under a microscope. This is similar to what is done in a PAP test for cervical cancer. Newly developed genetic tests can also be performed on samples obtained by biopsy. These tests can help to clarify whether a nodule is more likely to be benign or malignant when the biopsy sample is “indeterminate”, i.e., neither clearly benign or malignant. Indeterminate biopsy results occur in about 25% of nodules.In cases where MTC is suspected, blood tests to determine the levels of calcitonin may be performed. Such individuals may undergo genetic testing to detect the presence of a RET gene mutation to confirm a diagnosis of familial MTC. Family members of individuals who have this mutation should also be evaluated for the presence of the RET mutation. Nearly 100% of individuals who have this mutation gene will eventually develop MTC. Consequently, many researchers recommend that individuals who have this specific genetic change undergo preventive (prophylactic) surgery as children to remove the thyroid. Removing the thyroid before cancer has a chance to develop has a very high probability of being curative.
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Diagnosis of Thyroid Cancer. The diagnosis of thyroid cancer is based upon a thorough clinical evaluation, including a detailed patient history and physical exam, and a variety of specialized blood tests and imaging tests. Such testing often includes microscopic evaluation of tumor cells obtained by fine needle aspiration biopsy. Rarely, affected individuals may notice a hard, fixed mass or lump (nodule) usually to the lower left or right of the Adam’s apple. Sometimes a physician or other health care provider may discover such a nodule upon a routine medical exam. Often, the nodule is found accidentally on radiology study performed for another purpose. Thyroid nodules are a common finding, and as people get older, the frequency increases; in some reports, up to 50-75% of older persons have a thyroid nodule that can be detected on a thyroid sonogram (ultrasound). Fortunately, more than 90 percent of them are non-cancerous (benign).Clinical Testing and Work-up
To confirm a diagnosis of thyroid cancer a variety of tests may be performed including blood tests, thyroid ultrasound, and fine-needle aspiration biopsy.Blood tests can reveal the overall function of the thyroid by determining thyroid-stimulating hormone (TSH) levels. TSH is hormone produced by the pituitary gland that promotes the growth of the thyroid and most likely stimulates thyroid cancer cells to grow. Most patients with thyroid cancer have normal thyroid function, however.During a thyroid ultrasound reflected sound waves create an image of the thyroid. A machine known as a transducer creates these sound waves and then records the pattern when they bounce back from the thyroid (echo pattern). Normal thyroid tissue and thyroid nodules have different echo patterns, so the physician can see whether the nodule has a suspicious appearance that may require further evaluation, typically with FNA biopsy. In addition, ultrasound examination of lymph nodes in the neck can be performed, and suspicious lymph nodes can be biopsied prior to surgery.Additional specialized imaging techniques may be used to help evaluate the size, placement, and extension of the tumor and to serve as an aid for future surgical procedures. Such imaging techniques may include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. Laboratory tests and specialized imaging tests may also be conducted to determine possible infiltration of regional lymph nodes and the presence of distant metastases.Fine-need aspiration biopsy (FNA) is the most accurate diagnostic test. FNA involves passing a thin, hollow needle through the skin and inserted into the nodule under ultrasound guidance to withdraw small samples of tissue from the nodule. This procedure may be repeated a few times to gather tissue samples from different sections of the nodule. If multiple nodules are present, the procedure may be performed on each one. The collected tissue is then smeared on to glass slides, stained with colored dye, and studied under a microscope. This is similar to what is done in a PAP test for cervical cancer. Newly developed genetic tests can also be performed on samples obtained by biopsy. These tests can help to clarify whether a nodule is more likely to be benign or malignant when the biopsy sample is “indeterminate”, i.e., neither clearly benign or malignant. Indeterminate biopsy results occur in about 25% of nodules.In cases where MTC is suspected, blood tests to determine the levels of calcitonin may be performed. Such individuals may undergo genetic testing to detect the presence of a RET gene mutation to confirm a diagnosis of familial MTC. Family members of individuals who have this mutation should also be evaluated for the presence of the RET mutation. Nearly 100% of individuals who have this mutation gene will eventually develop MTC. Consequently, many researchers recommend that individuals who have this specific genetic change undergo preventive (prophylactic) surgery as children to remove the thyroid. Removing the thyroid before cancer has a chance to develop has a very high probability of being curative.
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Therapies of Thyroid Cancer
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TreatmentThe therapeutic management of individuals with thyroid cancer may require the coordinated efforts of a team of medical professionals, such as specialists in the diagnosis and treatment of hormone-related disorders (endocrinologists), thyroid surgeons, specialists in the use of radioactive iodine (nuclear medicine physicians), physicians who use radiation to treat cancer (radiation oncologists), and other healthcare specialists. Physicians who specialize in the diagnosis and treatment of cancer (medical oncologists) are usually not involved in the care of thyroid cancer, except for rare advanced cases.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as primary tumor size and location, extent of the primary tumor (stage), and degree of malignancy (grade); whether the tumor has spread to lymph nodes or distant sites; individual’s age and general health; and/or other elements. Decisions concerning the use of particular interventions should be made by physicians and other members of the health care team in careful consultation with the patient, based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks; patient preference; and other appropriate factors.The various techniques used to treat thyroid cancer include surgery first, sometimes followed by radioactive iodine therapy, external beam radiation and rarely, chemotherapy. Thyroid hormone replacement therapy is used in conjunction with these therapies in patients who have undergone removal of all or part of their thyroid gland.SurgeryIn virtually all individuals with thyroid cancer, standard initial therapy involves surgical removal of the malignancy and affected tissue, including the entire thyroid (thyroidectomy). In many cases of follicular and papillary thyroid carcinoma, especially larger and more invasive tumors, surgical removal of as much of the thyroid as can be safely taken out (near-total thyroidectomy) is recommended. In such cases, near-total thyroidectomy reduces the chance of recurrence as opposed to surgery to remove only a portion of the thyroid (e.g., one lobe). On the other hand, removal of one lobe of the thyroid is sufficient in patients with uncomplicated tumors, e.g., tumors <4 cm. If any suspicious or cancerous lymph nodes are found preoperatively or intraoperatively, they will be removed as well.
Hormone Replacement TherapyAfter a thyroidectomy, individuals must take levothyroxine, to replace the hormones that the thyroid normally produces, so that individuals do not develop hypothyroidism. Levothyroxine also suppresses the activity of thyroid stimulating hormone (TSH), a hormone made by the pituitary gland that stimulates the growth of normal thyroid tissue as well as any remaining thyroid cancer cells. Many patients who have undergone a lobectomy will not require thyroid hormone therapy, as the remaining lobe can make enough thyroid hormone to maintain normal thyroid hormone levels.Radioactive IodineResearch has indicated that therapy with radioactive iodine may improve survival rates among individuals with more advanced follicular and papillary thyroid carcinoma. However, radioactive iodine therapy is not usually recommended for low-risk individuals, who comprise the majority of patients, whose prognosis after surgery is excellent even without radioactive iodine. Iodine is a chemical element used by the thyroid gland to synthesize thyroid hormones. Since iodine is also absorbed by differentiated thyroid cancer cells, radioactive iodine can be used to target thyroid cancer tissue while sparing the rest of the body.Radioactive iodine therapy destroys any normal thyroid tissue that remains after a near-total thyroidectomy, a process sometimes referred to as radioactive iodine ablation. It may also destroy any residual microscopic thyroid cancer, a process called “adjuvant therapy”. For radioactive iodine therapy to be most effective, blood TSH levels must be high. TSH stimulates both thyroid tissue and thyroid cancer cells to absorb iodine. Elevating the blood TSH levels can be accomplished by stopping hormone replacement therapy (which leads to low levels of thyroid hormone [hypothyroidism] and a large increase in TSH levels). However, many individuals made hypothyroid in this way feel sluggish, and have other symptoms such as cold intolerance, weight gain, and constipation. To minimize the effects of hypothyroidism, physicians may prescribe a synthetic form of T3 called Cytomel (liothyronine), but this may not prevent symptoms from developing, since this medication also has to be stopped prior to the radioiodine treatment.A synthetic form of TSH, Thyrogen (thyrotropin alfa), made in a laboratory is also available. This is injected into a patient’s arm or thigh muscle, thereby achieving high TSH levels without the patient needing to stop hormone replacement treatment. Prior to radioiodine therapy, patients are typically placed on a low iodine diet for 1-2 weeks prior to radioiodine administration. After raising TSH levels, prior to the actual treatment, patients may undergo a whole body radioiodine scan using a small amount of radioactive iodine, in order to see how much of the normal thyroid is still present in the neck. If the scan shows that there is a large thyroid remnant a larger treatment dose of radioactive iodine may be administered. Radioactive iodine therapy is often effective when thyroid cancer has spread to nearby lymph nodes or other organs of the body (metastases).Hürthle cell and poorly differentiated insular carcinoma are both treated with total or near-total thyroidectomy. These kinds of cancer often do not take up radioactive iodine, so it usually cannot be used to treat these forms of thyroid cancer.External Beam RadiationExternal beam radiation is another form of radiation therapy sometimes used to treat individuals with thyroid cancer. During this procedure a machine is used to deliver a beam of radiation that destroys cancer cells. External beam radiation therapy is typically used in patients with thyroid cancer who have residual disease after surgery, and who do not respond to radioactive therapy, or whose disease has spread beyond the thyroid. External beam radiation therapy may be also be used for medullary thyroid carcinoma and anaplastic thyroid carcinoma.Targeted drug therapiesTargeted therapies are being studied for the treatment of individuals with advanced thyroid cancer. Targeted therapies are drugs and other substances that prevent the growth and spread of cancer by blocking or inhibiting certain specific molecules (often proteins) that are involved in the growth and spread of specific cancers. Generally, targeted therapies are less toxic than other treatments for cancer. Targeted therapies being investigated for thyroid cancer include protein kinase inhibitors and angiogenesis inhibitors. Lenvima (lenvatinib) and Nexavar (sorafenib) are two protein kinase inhibitors approved by the U.S. Food and Drug Administration (FDA) for use in advanced DTC.Medullary Thyroid CarcinomaIndividuals with medullary thyroid carcinoma are also treated by the surgical removal of the entire thyroid. If the cancer has not spread beyond the thyroid, the prognosis is excellent. However, the cancer has usually spread to the local lymph nodes by the time medullary cancer is diagnosed. The prognosis depends upon several factors, including the size of the tumor, its rate of growth, and how far and to what organs the cancer has spread. Radioactive iodine therapy is not used in people with MTC because the tumors (which consist of C cells and not follicular cells) do not take up iodine. In some cases, external beam radiation therapy or chemotherapy is used to treat individuals with MTC.A drug called Caprelsa (vandetanib) is approved by the FDA as a treatment for advanced medullary thyroid cancer. Vandetanib is a kinase inhibitor indicated for the treatment of symptomatic or progressive medullary thyroid cancer in individuals with unresectable (non-operable) locally advanced or metastatic disease. A kinase inhibitor is a type of drug that specifically blocks or stops the activity of certain proteins known as kinases. Another kinase inhibitor called Retevmo (selpercatinib) was approved by the FDA in May 2020 to treat MTC and other types of thyroid cancer in patients whose tumors have an alteration in the RET gene. Retevmo is the first therapy approved specifically for patients with RET gene alterations. Anaplastic Thyroid CarcinomaIn individuals with anaplastic thyroid carcinoma, total or near-total thyroidectomy is often performed. However, in some cases, the primary tumor may be inoperable because it involves structures in the neck such as the windpipe or large blood vessels. Radioactive iodine therapy is ineffective because the undifferentiated cells do not absorb the iodine. External beam radiation therapy has been used to treat individuals with ATC and may shrink tumors. For some affected individuals therapy with certain anticancer drugs (chemotherapy) may also be used, possibly in combination with surgical procedures and/or radiation; physicians may recommend combination therapy with multiple chemotherapeutic drugs that have different modes of action in destroying tumor cells and/or preventing them from multiplying. In most cases, however, chemotherapy and external beam radiation therapy have had only limited success in slowing or stopping progression of ATC and cannot eliminate advanced disease.In 2018, the combination of Taflinar (dabrafenib) and Mekinist (trametinib) administered together was approved by the FDA to treat anaplastic thyroid cancer that cannot be removed by surgery or has spread to other parts of the body and has a V600E mutation in the BRAF gene.Follow-upIndividuals with thyroid cancer receive periodic evaluations to determine whether the cancer has returned. These evaluations include a thorough clinical evaluation, including a detailed patient history, physical examination of the neck and the rest of the body, and a variety of tests including blood tests to detect elevated levels of thyroglobulin, a thyroid protein. Thyroglobulin is only produced by thyroid tissue and DTC, so that after removal of the thyroid or radioactive iodine therapy, thyroglobulin should be absent from the bloodstream. Detection of thyroglobulin in the blood may indicate the return of thyroid cancer. Thyroglobulin is often abbreviated as Tg. Neck ultrasound to examine the central and lateral (the sides) of the neck is another cornerstone of thyroid cancer surveillance.In some cases, physicians may choose to repeat a whole body iodine scan to determine whether any thyroid cancer cells have returned. In the past, in order to achieve the elevated levels of TSH necessary to perform a whole body iodine scan, affected individuals have needed to stop hormone replacement therapy, which results in hypothyroidism. Thyrogen (thyrotropin alfa), a synthetic form of TSH, achieves the necessary TSH levels without requiring individuals to stop hormone replacement therapy.In individuals with MTC, physicians may order blood tests to determine the levels of calcitonin and carcinoembryonic antigen (CEA). Elevated levels of these substances may indicate a return of thyroid cancer, and physicians will often conduct imaging scans to check for residual cancer.
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Therapies of Thyroid Cancer. TreatmentThe therapeutic management of individuals with thyroid cancer may require the coordinated efforts of a team of medical professionals, such as specialists in the diagnosis and treatment of hormone-related disorders (endocrinologists), thyroid surgeons, specialists in the use of radioactive iodine (nuclear medicine physicians), physicians who use radiation to treat cancer (radiation oncologists), and other healthcare specialists. Physicians who specialize in the diagnosis and treatment of cancer (medical oncologists) are usually not involved in the care of thyroid cancer, except for rare advanced cases.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as primary tumor size and location, extent of the primary tumor (stage), and degree of malignancy (grade); whether the tumor has spread to lymph nodes or distant sites; individual’s age and general health; and/or other elements. Decisions concerning the use of particular interventions should be made by physicians and other members of the health care team in careful consultation with the patient, based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks; patient preference; and other appropriate factors.The various techniques used to treat thyroid cancer include surgery first, sometimes followed by radioactive iodine therapy, external beam radiation and rarely, chemotherapy. Thyroid hormone replacement therapy is used in conjunction with these therapies in patients who have undergone removal of all or part of their thyroid gland.SurgeryIn virtually all individuals with thyroid cancer, standard initial therapy involves surgical removal of the malignancy and affected tissue, including the entire thyroid (thyroidectomy). In many cases of follicular and papillary thyroid carcinoma, especially larger and more invasive tumors, surgical removal of as much of the thyroid as can be safely taken out (near-total thyroidectomy) is recommended. In such cases, near-total thyroidectomy reduces the chance of recurrence as opposed to surgery to remove only a portion of the thyroid (e.g., one lobe). On the other hand, removal of one lobe of the thyroid is sufficient in patients with uncomplicated tumors, e.g., tumors <4 cm. If any suspicious or cancerous lymph nodes are found preoperatively or intraoperatively, they will be removed as well.
Hormone Replacement TherapyAfter a thyroidectomy, individuals must take levothyroxine, to replace the hormones that the thyroid normally produces, so that individuals do not develop hypothyroidism. Levothyroxine also suppresses the activity of thyroid stimulating hormone (TSH), a hormone made by the pituitary gland that stimulates the growth of normal thyroid tissue as well as any remaining thyroid cancer cells. Many patients who have undergone a lobectomy will not require thyroid hormone therapy, as the remaining lobe can make enough thyroid hormone to maintain normal thyroid hormone levels.Radioactive IodineResearch has indicated that therapy with radioactive iodine may improve survival rates among individuals with more advanced follicular and papillary thyroid carcinoma. However, radioactive iodine therapy is not usually recommended for low-risk individuals, who comprise the majority of patients, whose prognosis after surgery is excellent even without radioactive iodine. Iodine is a chemical element used by the thyroid gland to synthesize thyroid hormones. Since iodine is also absorbed by differentiated thyroid cancer cells, radioactive iodine can be used to target thyroid cancer tissue while sparing the rest of the body.Radioactive iodine therapy destroys any normal thyroid tissue that remains after a near-total thyroidectomy, a process sometimes referred to as radioactive iodine ablation. It may also destroy any residual microscopic thyroid cancer, a process called “adjuvant therapy”. For radioactive iodine therapy to be most effective, blood TSH levels must be high. TSH stimulates both thyroid tissue and thyroid cancer cells to absorb iodine. Elevating the blood TSH levels can be accomplished by stopping hormone replacement therapy (which leads to low levels of thyroid hormone [hypothyroidism] and a large increase in TSH levels). However, many individuals made hypothyroid in this way feel sluggish, and have other symptoms such as cold intolerance, weight gain, and constipation. To minimize the effects of hypothyroidism, physicians may prescribe a synthetic form of T3 called Cytomel (liothyronine), but this may not prevent symptoms from developing, since this medication also has to be stopped prior to the radioiodine treatment.A synthetic form of TSH, Thyrogen (thyrotropin alfa), made in a laboratory is also available. This is injected into a patient’s arm or thigh muscle, thereby achieving high TSH levels without the patient needing to stop hormone replacement treatment. Prior to radioiodine therapy, patients are typically placed on a low iodine diet for 1-2 weeks prior to radioiodine administration. After raising TSH levels, prior to the actual treatment, patients may undergo a whole body radioiodine scan using a small amount of radioactive iodine, in order to see how much of the normal thyroid is still present in the neck. If the scan shows that there is a large thyroid remnant a larger treatment dose of radioactive iodine may be administered. Radioactive iodine therapy is often effective when thyroid cancer has spread to nearby lymph nodes or other organs of the body (metastases).Hürthle cell and poorly differentiated insular carcinoma are both treated with total or near-total thyroidectomy. These kinds of cancer often do not take up radioactive iodine, so it usually cannot be used to treat these forms of thyroid cancer.External Beam RadiationExternal beam radiation is another form of radiation therapy sometimes used to treat individuals with thyroid cancer. During this procedure a machine is used to deliver a beam of radiation that destroys cancer cells. External beam radiation therapy is typically used in patients with thyroid cancer who have residual disease after surgery, and who do not respond to radioactive therapy, or whose disease has spread beyond the thyroid. External beam radiation therapy may be also be used for medullary thyroid carcinoma and anaplastic thyroid carcinoma.Targeted drug therapiesTargeted therapies are being studied for the treatment of individuals with advanced thyroid cancer. Targeted therapies are drugs and other substances that prevent the growth and spread of cancer by blocking or inhibiting certain specific molecules (often proteins) that are involved in the growth and spread of specific cancers. Generally, targeted therapies are less toxic than other treatments for cancer. Targeted therapies being investigated for thyroid cancer include protein kinase inhibitors and angiogenesis inhibitors. Lenvima (lenvatinib) and Nexavar (sorafenib) are two protein kinase inhibitors approved by the U.S. Food and Drug Administration (FDA) for use in advanced DTC.Medullary Thyroid CarcinomaIndividuals with medullary thyroid carcinoma are also treated by the surgical removal of the entire thyroid. If the cancer has not spread beyond the thyroid, the prognosis is excellent. However, the cancer has usually spread to the local lymph nodes by the time medullary cancer is diagnosed. The prognosis depends upon several factors, including the size of the tumor, its rate of growth, and how far and to what organs the cancer has spread. Radioactive iodine therapy is not used in people with MTC because the tumors (which consist of C cells and not follicular cells) do not take up iodine. In some cases, external beam radiation therapy or chemotherapy is used to treat individuals with MTC.A drug called Caprelsa (vandetanib) is approved by the FDA as a treatment for advanced medullary thyroid cancer. Vandetanib is a kinase inhibitor indicated for the treatment of symptomatic or progressive medullary thyroid cancer in individuals with unresectable (non-operable) locally advanced or metastatic disease. A kinase inhibitor is a type of drug that specifically blocks or stops the activity of certain proteins known as kinases. Another kinase inhibitor called Retevmo (selpercatinib) was approved by the FDA in May 2020 to treat MTC and other types of thyroid cancer in patients whose tumors have an alteration in the RET gene. Retevmo is the first therapy approved specifically for patients with RET gene alterations. Anaplastic Thyroid CarcinomaIn individuals with anaplastic thyroid carcinoma, total or near-total thyroidectomy is often performed. However, in some cases, the primary tumor may be inoperable because it involves structures in the neck such as the windpipe or large blood vessels. Radioactive iodine therapy is ineffective because the undifferentiated cells do not absorb the iodine. External beam radiation therapy has been used to treat individuals with ATC and may shrink tumors. For some affected individuals therapy with certain anticancer drugs (chemotherapy) may also be used, possibly in combination with surgical procedures and/or radiation; physicians may recommend combination therapy with multiple chemotherapeutic drugs that have different modes of action in destroying tumor cells and/or preventing them from multiplying. In most cases, however, chemotherapy and external beam radiation therapy have had only limited success in slowing or stopping progression of ATC and cannot eliminate advanced disease.In 2018, the combination of Taflinar (dabrafenib) and Mekinist (trametinib) administered together was approved by the FDA to treat anaplastic thyroid cancer that cannot be removed by surgery or has spread to other parts of the body and has a V600E mutation in the BRAF gene.Follow-upIndividuals with thyroid cancer receive periodic evaluations to determine whether the cancer has returned. These evaluations include a thorough clinical evaluation, including a detailed patient history, physical examination of the neck and the rest of the body, and a variety of tests including blood tests to detect elevated levels of thyroglobulin, a thyroid protein. Thyroglobulin is only produced by thyroid tissue and DTC, so that after removal of the thyroid or radioactive iodine therapy, thyroglobulin should be absent from the bloodstream. Detection of thyroglobulin in the blood may indicate the return of thyroid cancer. Thyroglobulin is often abbreviated as Tg. Neck ultrasound to examine the central and lateral (the sides) of the neck is another cornerstone of thyroid cancer surveillance.In some cases, physicians may choose to repeat a whole body iodine scan to determine whether any thyroid cancer cells have returned. In the past, in order to achieve the elevated levels of TSH necessary to perform a whole body iodine scan, affected individuals have needed to stop hormone replacement therapy, which results in hypothyroidism. Thyrogen (thyrotropin alfa), a synthetic form of TSH, achieves the necessary TSH levels without requiring individuals to stop hormone replacement therapy.In individuals with MTC, physicians may order blood tests to determine the levels of calcitonin and carcinoembryonic antigen (CEA). Elevated levels of these substances may indicate a return of thyroid cancer, and physicians will often conduct imaging scans to check for residual cancer.
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Overview of Thyroid Eye Disease
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Summary Thyroid eye disease is a rare disease characterized by progressive inflammation and damage to tissues around the eyes, especially extraocular muscle, connective, and fatty tissue. Thyroid eye disease is characterized by an active disease phase in which progressive inflammation, swelling, and tissue changes occur. This phase is associated with a variety of symptoms including pain, a gritty feeling in the eyes, swelling or abnormal positioning of the eyelids, watery eyes, bulging eyes (proptosis) and double vision (diplopia). The active phase can last anywhere from approximately 6 months to 2 years. This is followed by an inactive phase in which the disease progression has stopped. However, some symptoms such as double vision and bulging eyes can remain. In some people, cosmetic changes and significant disability can develop. Although uncommon, in severe instances, vision loss can occur. Thyroid eye disease is an autoimmune disorder. An autoimmune disorder is one in which the body’s adaptive immune system, which protects the body from infectious or other foreign substances, mistakenly attacks healthy tissue instead. Introduction Thyroid eye disease most commonly occurs as part of Graves’ disease, which is an autoimmune disease that affects the thyroid and often the skin and eyes. The thyroid is a butterfly-shaped gland located at the base of the neck. The thyroid is part of the endocrine system, the network of glands that secrete hormones that regulate the chemical processes (metabolism) that influence the body’s activities as well as regulating the heart rate, body temperature, and blood pressure. Graves’ disease is characterized by abnormal enlargement of the thyroid (goiter) and increased secretion of thyroid hormone (hyperthyroidism). Some people with Graves’ disease eventually develop thyroid eye disease. Less often, thyroid eye disease can occur in people who have or have had an overactive thyroid (hyperthyroidism) or in individuals with an underactive thyroid (hypothyroidism) such as people who have a disorder called Hashimoto thyroiditis.
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Overview of Thyroid Eye Disease. Summary Thyroid eye disease is a rare disease characterized by progressive inflammation and damage to tissues around the eyes, especially extraocular muscle, connective, and fatty tissue. Thyroid eye disease is characterized by an active disease phase in which progressive inflammation, swelling, and tissue changes occur. This phase is associated with a variety of symptoms including pain, a gritty feeling in the eyes, swelling or abnormal positioning of the eyelids, watery eyes, bulging eyes (proptosis) and double vision (diplopia). The active phase can last anywhere from approximately 6 months to 2 years. This is followed by an inactive phase in which the disease progression has stopped. However, some symptoms such as double vision and bulging eyes can remain. In some people, cosmetic changes and significant disability can develop. Although uncommon, in severe instances, vision loss can occur. Thyroid eye disease is an autoimmune disorder. An autoimmune disorder is one in which the body’s adaptive immune system, which protects the body from infectious or other foreign substances, mistakenly attacks healthy tissue instead. Introduction Thyroid eye disease most commonly occurs as part of Graves’ disease, which is an autoimmune disease that affects the thyroid and often the skin and eyes. The thyroid is a butterfly-shaped gland located at the base of the neck. The thyroid is part of the endocrine system, the network of glands that secrete hormones that regulate the chemical processes (metabolism) that influence the body’s activities as well as regulating the heart rate, body temperature, and blood pressure. Graves’ disease is characterized by abnormal enlargement of the thyroid (goiter) and increased secretion of thyroid hormone (hyperthyroidism). Some people with Graves’ disease eventually develop thyroid eye disease. Less often, thyroid eye disease can occur in people who have or have had an overactive thyroid (hyperthyroidism) or in individuals with an underactive thyroid (hypothyroidism) such as people who have a disorder called Hashimoto thyroiditis.
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Symptoms of Thyroid Eye Disease
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The signs and symptoms can vary greatly from one person to another. Eye symptoms can range from mild to severe. For some individuals, the symptoms can lead to pain, disfigurement of the eye socket, and, eventually, potentially threaten eyesight. The disorder can vary greatly in expression as well. For some people, the disorder remains little changed for many years, while for others it will worsen or slightly improve. Occasionally people experience repeated episodes of worsening (exacerbations) of the disease, and improvement of the disease (remission).Initial symptoms include redness, irritation, and discomfort of the eyes and eyelids. Dry eyes and pain when moving the eyes may also occur. Eyelid retraction is also common which is when the upper eyelid is positioned too high and/or the lower eyelid too low thus exposing the eye. The most noticeable symptom can be exophthalmos or proptosis, which means that the eyes bulge or protrude outward out of the eye socket. Bulging of the eyes can cause a person to appear as if they are constantly ‘staring’.Additional symptoms and signs can include blurred vision, double vision (diplopia), misalignment of the eyes (strabismus), chronic bloody eyes, white area of eye inflamed, constant, watery eyes due to the excess formation of tears, swelling near the upper and lower eyelids, an intolerance of bright lights and difficulty moving the eyeballs.Progressive swelling can cause increased pressure within the eye socket and pain or headaches. In severe cases, additional symptoms can develop including corneal erosion, in which there is an eroded area on the clear (transparent) outer layer of the eye (cornea). In some, enlarged eye muscles can compress and cause damage to the optic nerve (optic neuropathy), which is the main nerve of the eye and carries nerve impulses to the brain. Corneal ulceration and optic neuropathy can, sometimes, progress to cause vision loss.Thyroid eye disease is a progressive disorder in which progressive damage to various tissues around the eyes can lead to scarring (fibrosis) and tissue remodeling. The extent of scarring and tissue remodeling tends to become apparent during the inactive phase, after inflammation and swelling has subsided. This can change the appearance of the eyes and lead to affected individuals looking tired all the time, or to appear different from people without such changes. These cosmetic issues can have a significant impact on emotional well-being and quality of life.
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Symptoms of Thyroid Eye Disease. The signs and symptoms can vary greatly from one person to another. Eye symptoms can range from mild to severe. For some individuals, the symptoms can lead to pain, disfigurement of the eye socket, and, eventually, potentially threaten eyesight. The disorder can vary greatly in expression as well. For some people, the disorder remains little changed for many years, while for others it will worsen or slightly improve. Occasionally people experience repeated episodes of worsening (exacerbations) of the disease, and improvement of the disease (remission).Initial symptoms include redness, irritation, and discomfort of the eyes and eyelids. Dry eyes and pain when moving the eyes may also occur. Eyelid retraction is also common which is when the upper eyelid is positioned too high and/or the lower eyelid too low thus exposing the eye. The most noticeable symptom can be exophthalmos or proptosis, which means that the eyes bulge or protrude outward out of the eye socket. Bulging of the eyes can cause a person to appear as if they are constantly ‘staring’.Additional symptoms and signs can include blurred vision, double vision (diplopia), misalignment of the eyes (strabismus), chronic bloody eyes, white area of eye inflamed, constant, watery eyes due to the excess formation of tears, swelling near the upper and lower eyelids, an intolerance of bright lights and difficulty moving the eyeballs.Progressive swelling can cause increased pressure within the eye socket and pain or headaches. In severe cases, additional symptoms can develop including corneal erosion, in which there is an eroded area on the clear (transparent) outer layer of the eye (cornea). In some, enlarged eye muscles can compress and cause damage to the optic nerve (optic neuropathy), which is the main nerve of the eye and carries nerve impulses to the brain. Corneal ulceration and optic neuropathy can, sometimes, progress to cause vision loss.Thyroid eye disease is a progressive disorder in which progressive damage to various tissues around the eyes can lead to scarring (fibrosis) and tissue remodeling. The extent of scarring and tissue remodeling tends to become apparent during the inactive phase, after inflammation and swelling has subsided. This can change the appearance of the eyes and lead to affected individuals looking tired all the time, or to appear different from people without such changes. These cosmetic issues can have a significant impact on emotional well-being and quality of life.
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Causes of Thyroid Eye Disease
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Thyroid eye disease is an autoimmune disorder, which means that a problem with the body’s adaptive immune system, which protects the body from infectious or other foreign substances, mistakenly attacks health tissue instead. The immune system normally produces specialized proteins call antibodies. Antibodies react against foreign materials (e.g. bacteria, viruses, toxins) in the body bringing about their destruction. Antibodies can directly kill microorganisms or coat them so they are more easily destroyed by white blood cells. Specific antibodies are created in response to specific materials or substances. A substance that stimulates an antibody to be produced is called an antigen.The exact underlying process by which thyroid eye disease occurs is not fully understood. In individuals with Graves’ disease, the immune system creates an abnormal antibody called thyroid-stimulating immunoglobulin. This antibody mimics the function of thyroid-stimulating hormone, which is normally produced by the pituitary gland. These abnormal antibodies also affect the cells surrounding the eyes causing the symptoms associated with the disorder. Researchers think that the affected eye tissue contains proteins that appear similar to proteins of the thyroid gland and the antibodies mistakenly target these proteins. Patients often also have overexpression of a protein called insulin-like growth factor 1 receptor (IGF-1R), and this is thought to play a significant role in the development of the disorder. However, not everyone with thyroid eye disease has these immune system abnormalities suggesting that other abnormal antibodies or other factors can cause thyroid eye disease in some people. Researchers are still investigating the underlying cause of the disorder.Individuals with thyroid eye disease may carry genes for, or have a genetic susceptibility to, thyroid eye disease. A person who is genetically predisposed to a disorder carries a gene (or genes) for the disease, but it may not be expressed unless it is triggered or “activated” under certain circumstances, such as due to particular environmental factors (multifactorial inheritance).Individuals who smoke are at a greater risk of developing thyroid eye disease. Individuals who have undergone radioactive iodine therapy as a prior treatment (e.g. for treatment of hyperthyroidism) are at a greater risk of developing thyroid eye disease. Individuals who have other disorders caused by malfunction of the immune system such as diabetes type 1 or rheumatoid arthritis may be at a greater risk of developing thyroid eye disease.
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Causes of Thyroid Eye Disease. Thyroid eye disease is an autoimmune disorder, which means that a problem with the body’s adaptive immune system, which protects the body from infectious or other foreign substances, mistakenly attacks health tissue instead. The immune system normally produces specialized proteins call antibodies. Antibodies react against foreign materials (e.g. bacteria, viruses, toxins) in the body bringing about their destruction. Antibodies can directly kill microorganisms or coat them so they are more easily destroyed by white blood cells. Specific antibodies are created in response to specific materials or substances. A substance that stimulates an antibody to be produced is called an antigen.The exact underlying process by which thyroid eye disease occurs is not fully understood. In individuals with Graves’ disease, the immune system creates an abnormal antibody called thyroid-stimulating immunoglobulin. This antibody mimics the function of thyroid-stimulating hormone, which is normally produced by the pituitary gland. These abnormal antibodies also affect the cells surrounding the eyes causing the symptoms associated with the disorder. Researchers think that the affected eye tissue contains proteins that appear similar to proteins of the thyroid gland and the antibodies mistakenly target these proteins. Patients often also have overexpression of a protein called insulin-like growth factor 1 receptor (IGF-1R), and this is thought to play a significant role in the development of the disorder. However, not everyone with thyroid eye disease has these immune system abnormalities suggesting that other abnormal antibodies or other factors can cause thyroid eye disease in some people. Researchers are still investigating the underlying cause of the disorder.Individuals with thyroid eye disease may carry genes for, or have a genetic susceptibility to, thyroid eye disease. A person who is genetically predisposed to a disorder carries a gene (or genes) for the disease, but it may not be expressed unless it is triggered or “activated” under certain circumstances, such as due to particular environmental factors (multifactorial inheritance).Individuals who smoke are at a greater risk of developing thyroid eye disease. Individuals who have undergone radioactive iodine therapy as a prior treatment (e.g. for treatment of hyperthyroidism) are at a greater risk of developing thyroid eye disease. Individuals who have other disorders caused by malfunction of the immune system such as diabetes type 1 or rheumatoid arthritis may be at a greater risk of developing thyroid eye disease.
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Affects of Thyroid Eye Disease
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Thyroid eye disease affects more women than men, although men are more likely to have a severe form of the disease. There is a genetic component to the disorder and people who have a family member with the disease or a family member with an autoimmune disease are at a greater risk of developing the disorder. The disorder is more likely to occur during middle age. The exact prevalence (i.e. the number of people who have a disorder in a specific population at a specific time) of thyroid eye disease is not known, but is estimated to be 16 per 100,000 women in the general population, and 2.9 per 100,000 men in the general population.
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Affects of Thyroid Eye Disease. Thyroid eye disease affects more women than men, although men are more likely to have a severe form of the disease. There is a genetic component to the disorder and people who have a family member with the disease or a family member with an autoimmune disease are at a greater risk of developing the disorder. The disorder is more likely to occur during middle age. The exact prevalence (i.e. the number of people who have a disorder in a specific population at a specific time) of thyroid eye disease is not known, but is estimated to be 16 per 100,000 women in the general population, and 2.9 per 100,000 men in the general population.
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Related disorders of Thyroid Eye Disease
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Symptoms of the following disorders can be similar to those of thyroid eye disease. Comparisons may be useful for a differential diagnosis.A variety of different disorders can be associated with symptoms similar to those seen in thyroid eye disease. These disorders include severe obesity, a painful, bacterial skin infection affecting the eye socket (orbital cellulitis), inflammation of the muscles of the eye socket (orbital myositis), and orbital tumors. Hay fever, allergies, and inflammation of the conjunctiva (conjunctivitis) can also cause symptoms similar to those seen in mild thyroid eye disease.Myasthenia gravis is a neuromuscular disorder primarily characterized by muscle weakness and muscle fatigue. Although the disorder usually becomes apparent during adulthood, symptom onset may occur at any age. The condition may be restricted to certain muscle groups, particularly those of the eyes (ocular myasthenia gravis), or may become more generalized (generalized myasthenia gravis), involving multiple muscle groups. Most individuals with myasthenia gravis develop weakness and drooping of the eyelids (ptosis); weakness of eye muscles, resulting in double vision (diplopia); and excessive muscle fatigue following activity. Additional features commonly include weakness of facial muscles; impaired speech (dysarthria); difficulties chewing and swallowing (dysphagia); and weakness of the upper arms and legs (proximal limb weakness). In addition, about 10% of affected individuals may develop potentially life-threatening complications due to severe involvement of muscles used during breathing (myasthenic crisis). Myasthenia gravis results from an abnormal immune reaction in which the body's natural immune defenses (i.e., antibodies) inappropriately attack and gradually destroy certain receptors in muscles that receive nerve impulses (antibody-mediated autoimmune response). (For more information on this disorder, choose “myasthenia gravis” as your search term in the Rare Disease Database.)Cushing syndrome is a rare endocrine disorder characterized by a variety of symptoms and physical abnormalities that occur due to excessive amounts of the hormone cortisol, a vital glucocorticoid. Glucocorticoids are a class of steroid hormones that are important in the regulation of the metabolism of glucose, and also modulate the response to stress. Although it may occur in children, Cushing syndrome most commonly affects adults between the ages of 25 to 40. It can be caused by prolonged exposure to elevated levels of glucocorticoids produced within the body (endogenous) or introduced from outside the body (exogenous). Symptoms can include weight gain, obesity, a rounded face, thin purple streaks (purple striae) which occur on the skin, increased fat around the neck, and slender arms and legs. Children with Cushing syndrome are typically obese and have delay in growth. (For more information on this disorder, choose “Cushing” as your search term in the Rare Disease Database.)
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Related disorders of Thyroid Eye Disease. Symptoms of the following disorders can be similar to those of thyroid eye disease. Comparisons may be useful for a differential diagnosis.A variety of different disorders can be associated with symptoms similar to those seen in thyroid eye disease. These disorders include severe obesity, a painful, bacterial skin infection affecting the eye socket (orbital cellulitis), inflammation of the muscles of the eye socket (orbital myositis), and orbital tumors. Hay fever, allergies, and inflammation of the conjunctiva (conjunctivitis) can also cause symptoms similar to those seen in mild thyroid eye disease.Myasthenia gravis is a neuromuscular disorder primarily characterized by muscle weakness and muscle fatigue. Although the disorder usually becomes apparent during adulthood, symptom onset may occur at any age. The condition may be restricted to certain muscle groups, particularly those of the eyes (ocular myasthenia gravis), or may become more generalized (generalized myasthenia gravis), involving multiple muscle groups. Most individuals with myasthenia gravis develop weakness and drooping of the eyelids (ptosis); weakness of eye muscles, resulting in double vision (diplopia); and excessive muscle fatigue following activity. Additional features commonly include weakness of facial muscles; impaired speech (dysarthria); difficulties chewing and swallowing (dysphagia); and weakness of the upper arms and legs (proximal limb weakness). In addition, about 10% of affected individuals may develop potentially life-threatening complications due to severe involvement of muscles used during breathing (myasthenic crisis). Myasthenia gravis results from an abnormal immune reaction in which the body's natural immune defenses (i.e., antibodies) inappropriately attack and gradually destroy certain receptors in muscles that receive nerve impulses (antibody-mediated autoimmune response). (For more information on this disorder, choose “myasthenia gravis” as your search term in the Rare Disease Database.)Cushing syndrome is a rare endocrine disorder characterized by a variety of symptoms and physical abnormalities that occur due to excessive amounts of the hormone cortisol, a vital glucocorticoid. Glucocorticoids are a class of steroid hormones that are important in the regulation of the metabolism of glucose, and also modulate the response to stress. Although it may occur in children, Cushing syndrome most commonly affects adults between the ages of 25 to 40. It can be caused by prolonged exposure to elevated levels of glucocorticoids produced within the body (endogenous) or introduced from outside the body (exogenous). Symptoms can include weight gain, obesity, a rounded face, thin purple streaks (purple striae) which occur on the skin, increased fat around the neck, and slender arms and legs. Children with Cushing syndrome are typically obese and have delay in growth. (For more information on this disorder, choose “Cushing” as your search term in the Rare Disease Database.)
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Diagnosis of Thyroid Eye Disease
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A diagnosis of thyroid eye disease is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Certain symptoms that occur in thyroid eye disease are often obvious and can lead to a diagnosis upon a physical examination. Some affected individuals have reported that their eyes “didn’t feel right” before symptoms of the disease began.Individuals suspected of having thyroid eye disease will undergo a complete eye examination. This may include measuring the degree of proptosis (eye bulging) using a device called an exophthalmometer. This small device enables an eye doctor to measure how far forward the eyes have moved (displacement).Clinical Testing and Workup
In moderate to severe disease, a specialized imaging technique called computerized tomography (CT) scanning may be used to assess whether the optic nerve is compressed by inflamed, enlarged muscles in the eye. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. Regular eye tests may be given to assess a person’s clarity of vision (visual acuity).Affected individuals may undergo thyroid function tests to detect an underlying cause of thyroid eye disease such as Graves’ disease or hypothyroidism. These tests can detect elevated levels of thyroid hormones or antibodies in the blood.
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Diagnosis of Thyroid Eye Disease. A diagnosis of thyroid eye disease is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Certain symptoms that occur in thyroid eye disease are often obvious and can lead to a diagnosis upon a physical examination. Some affected individuals have reported that their eyes “didn’t feel right” before symptoms of the disease began.Individuals suspected of having thyroid eye disease will undergo a complete eye examination. This may include measuring the degree of proptosis (eye bulging) using a device called an exophthalmometer. This small device enables an eye doctor to measure how far forward the eyes have moved (displacement).Clinical Testing and Workup
In moderate to severe disease, a specialized imaging technique called computerized tomography (CT) scanning may be used to assess whether the optic nerve is compressed by inflamed, enlarged muscles in the eye. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. Regular eye tests may be given to assess a person’s clarity of vision (visual acuity).Affected individuals may undergo thyroid function tests to detect an underlying cause of thyroid eye disease such as Graves’ disease or hypothyroidism. These tests can detect elevated levels of thyroid hormones or antibodies in the blood.
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Therapies of Thyroid Eye Disease
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Treatment
Treatment may require the coordinated efforts of a team of specialists, general internists, physicians who specialize in diagnosing and treating eye disorders (ophthalmologists) including eye doctors with experience treating thyroid eye disease, physicians who specialize in diagnosing and treating disorders of the hormone system (endocrinologists), psychologists, and other healthcare professionals may need to systematically and comprehensively plan treatment. Psychosocial support is essential as well.In January, 2020 the U.S. Food and Drug Administration (FDA) approved teprotumumab trbw (Tepezza®), the first approved drug indicated to treat thyroid eye disease. Teprotumumab is inhibits (or blocks) the activity of the protein insulin-like growth factor-1, which is believed to a play as significant role in the development of the disorder. Affected individuals have shown significant improvement in proptosis, double vision, and overall quality of life when taking teprotumumab.In affected individuals who have underlying Graves’ disease, treatment includes reversing hyperthyroidism. Treating hyperthyroidism of Graves’ disease is important, but will not improve symptoms of thyroid eye disease.Some individuals with mild thyroid eye disease may be treated with supportive measures such as dark sunglasses to treat sensitivity to light, ointments, artificial tears, and/or prisms that are attached to glasses. Prisms can help correct double vision. Some people may wear an eyepatch to manage double vision.Individuals with moderate-to-severe disease may receive corticosteroids, which are drugs that reduce inflammation and swelling, but do not affect diplopia and proptosis. Prednisone is a common corticosteroid that is used to treat individuals with thyroid eye disease.Some individuals with moderate-to-severe disease may eventually require surgery. Surgery is also used to treat individuals with severe disease. Generally, it is recommended to avoid surgery until after the active phase of the disease has ended. Doctors will treat the symptoms to the best of their ability and then perform surgery once the inflammation and swelling has reduced. Surgery may be necessary during the active phase if doctors feel that a person’s vision is at risk by the disease progression.Surgical options include orbital decompression, motility, and lid surgery. During orbital decompression surgery, a surgeon takes out the bone between the eye socket (orbit) and the sinuses. This allows the eye to fall back into its natural position within the eye socket. This surgery is generally reserved for individuals who are at risk of vision loss due to pressure on the optic nerve or in whom other treatment options have not worked.Surgical options can also help to improve bulging eyes (proptosis) and the position of the eyelids. Motility surgery involves repositioning certain muscles around the eyes to reduce or eliminate double vision.Thyroid eye disease can cause noticeable changes in a person’s facial appearance that cannot be treated completely. Depression is common in individuals with the disorder and cosmetic changes can cause significant emotional distress and affect emotional well-being. A psychologist is recommended to be part of a treatment plan for individuals with thyroid eye disease to work with affected individuals during and after treatment.
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Therapies of Thyroid Eye Disease. Treatment
Treatment may require the coordinated efforts of a team of specialists, general internists, physicians who specialize in diagnosing and treating eye disorders (ophthalmologists) including eye doctors with experience treating thyroid eye disease, physicians who specialize in diagnosing and treating disorders of the hormone system (endocrinologists), psychologists, and other healthcare professionals may need to systematically and comprehensively plan treatment. Psychosocial support is essential as well.In January, 2020 the U.S. Food and Drug Administration (FDA) approved teprotumumab trbw (Tepezza®), the first approved drug indicated to treat thyroid eye disease. Teprotumumab is inhibits (or blocks) the activity of the protein insulin-like growth factor-1, which is believed to a play as significant role in the development of the disorder. Affected individuals have shown significant improvement in proptosis, double vision, and overall quality of life when taking teprotumumab.In affected individuals who have underlying Graves’ disease, treatment includes reversing hyperthyroidism. Treating hyperthyroidism of Graves’ disease is important, but will not improve symptoms of thyroid eye disease.Some individuals with mild thyroid eye disease may be treated with supportive measures such as dark sunglasses to treat sensitivity to light, ointments, artificial tears, and/or prisms that are attached to glasses. Prisms can help correct double vision. Some people may wear an eyepatch to manage double vision.Individuals with moderate-to-severe disease may receive corticosteroids, which are drugs that reduce inflammation and swelling, but do not affect diplopia and proptosis. Prednisone is a common corticosteroid that is used to treat individuals with thyroid eye disease.Some individuals with moderate-to-severe disease may eventually require surgery. Surgery is also used to treat individuals with severe disease. Generally, it is recommended to avoid surgery until after the active phase of the disease has ended. Doctors will treat the symptoms to the best of their ability and then perform surgery once the inflammation and swelling has reduced. Surgery may be necessary during the active phase if doctors feel that a person’s vision is at risk by the disease progression.Surgical options include orbital decompression, motility, and lid surgery. During orbital decompression surgery, a surgeon takes out the bone between the eye socket (orbit) and the sinuses. This allows the eye to fall back into its natural position within the eye socket. This surgery is generally reserved for individuals who are at risk of vision loss due to pressure on the optic nerve or in whom other treatment options have not worked.Surgical options can also help to improve bulging eyes (proptosis) and the position of the eyelids. Motility surgery involves repositioning certain muscles around the eyes to reduce or eliminate double vision.Thyroid eye disease can cause noticeable changes in a person’s facial appearance that cannot be treated completely. Depression is common in individuals with the disorder and cosmetic changes can cause significant emotional distress and affect emotional well-being. A psychologist is recommended to be part of a treatment plan for individuals with thyroid eye disease to work with affected individuals during and after treatment.
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Overview of Tietze Syndrome
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Tietze syndrome is a rare, inflammatory disorder characterized by chest pain and swelling of the cartilage of one or more of the upper ribs (costochondral junction), specifically where the ribs attach to the breastbone (sternum). Onset of pain may be gradual or sudden and may spread to affect the arms and/or shoulders. Tietze syndrome is considered a benign syndrome and, in some cases, may resolve itself without treatment. The exact cause is not known. Tietze syndrome was first described in the medical literature in 1921 by Alexander Tietze, a German surgeon.
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Overview of Tietze Syndrome. Tietze syndrome is a rare, inflammatory disorder characterized by chest pain and swelling of the cartilage of one or more of the upper ribs (costochondral junction), specifically where the ribs attach to the breastbone (sternum). Onset of pain may be gradual or sudden and may spread to affect the arms and/or shoulders. Tietze syndrome is considered a benign syndrome and, in some cases, may resolve itself without treatment. The exact cause is not known. Tietze syndrome was first described in the medical literature in 1921 by Alexander Tietze, a German surgeon.
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Symptoms of Tietze Syndrome
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Tietze syndrome is characterized by mild to severe localized pain and tenderness in one or more of the upper four ribs. The second or third ribs are most often affected. In most people, the cartilage of only one rib is affected. A firm, spindle-shaped swelling occurs in the cartilage of the affected rib. An aching, gripping, sharp, dull, or neuralgic pain occurs in this area. Sometimes, the pain may spread to affect the neck, arms and shoulders. Redness (erythema) and warmth of the affected area may be present.The onset of pain may be gradual or sudden, and can vary in intensity. The pain associated with Tietze syndrome may worsen due to sneezing, coughing, or strenuous activity or exercise. The pain usually subsides after several weeks or months, but the swelling may persist.
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Symptoms of Tietze Syndrome. Tietze syndrome is characterized by mild to severe localized pain and tenderness in one or more of the upper four ribs. The second or third ribs are most often affected. In most people, the cartilage of only one rib is affected. A firm, spindle-shaped swelling occurs in the cartilage of the affected rib. An aching, gripping, sharp, dull, or neuralgic pain occurs in this area. Sometimes, the pain may spread to affect the neck, arms and shoulders. Redness (erythema) and warmth of the affected area may be present.The onset of pain may be gradual or sudden, and can vary in intensity. The pain associated with Tietze syndrome may worsen due to sneezing, coughing, or strenuous activity or exercise. The pain usually subsides after several weeks or months, but the swelling may persist.
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Causes of Tietze Syndrome
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The exact cause is not known (idiopathic). Some researchers have speculated that multiple microtrauma to the anterior chest wall may cause the development of Tietze syndrome. Sometimes, the development of the disorder may be preceded by chronic, excessive coughing, vomiting, trauma or impact to the chest, viral or bacterial infections, or surgery to the thoracic area.
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Causes of Tietze Syndrome. The exact cause is not known (idiopathic). Some researchers have speculated that multiple microtrauma to the anterior chest wall may cause the development of Tietze syndrome. Sometimes, the development of the disorder may be preceded by chronic, excessive coughing, vomiting, trauma or impact to the chest, viral or bacterial infections, or surgery to the thoracic area.
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Affects of Tietze Syndrome
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Tietze syndrome usually affects older children and young adults. Most cases occur before the age of 40, most often during the second or third decade of life. Although rare, Tietze syndrome has been reported in infants, children or the elderly. Males and females are affected in equal numbers. The exact incidence or prevalence of the disorder is unknown.
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Affects of Tietze Syndrome. Tietze syndrome usually affects older children and young adults. Most cases occur before the age of 40, most often during the second or third decade of life. Although rare, Tietze syndrome has been reported in infants, children or the elderly. Males and females are affected in equal numbers. The exact incidence or prevalence of the disorder is unknown.
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Tietze Syndrome
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nord_1211_4
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Related disorders of Tietze Syndrome
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Symptoms of the following conditions can resemble those of Tietze syndrome. Comparisons may be useful for a differential diagnosis:Chest wall pain is a general term given to several conditions characterized by anterior chest pain. A dull, aching pain occurs which varies in response to strain, inflammation, malposition or infiltration of muscles, ligaments, cartilage, or bones in the chest wall. Irritation of a nerve root from the neck or upper spine, or a fractured rib, can also cause chest wall pain. Treatment is aimed at the underlying cause of the pain. Tietze syndrome is part of this group of painful conditions.Costal chondritis or costochondritis is a common condition characterized by inflammation of the cartilage part of the rib. It may affect one or more rib (costal) cartilages. It is characterized by pain of the chest wall that may spread (radiate) to surrounding areas. Sometimes, the terms costochondritis and Tietze syndrome are used interchangeably. However, the two disorders are differentiated by the presence of swelling, in addition to pain, in Tietze syndrome. In costochondritis, there is no swelling. Costochondritis is more common, although not exclusively, in adults over 40 years of age.Spinal root lesions or compression can cause chest pain in the form of a deep, boring, aching discomfort, or a sharp sudden and piercing pain. This pain usually occurs after sudden movement of the body, such as sneezing, coughing, laughing or straining.Additional disorders that can cause symptoms similar to those seen in Tietze syndrome include seronegative arthritis, ankylosing spondylitis, fibromyalgia, pneumonia, and coronary heart disease. In some instances, certain forms of malignant lymphoma can cause chest pain and swelling similar to that in Tietze syndrome.
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Related disorders of Tietze Syndrome. Symptoms of the following conditions can resemble those of Tietze syndrome. Comparisons may be useful for a differential diagnosis:Chest wall pain is a general term given to several conditions characterized by anterior chest pain. A dull, aching pain occurs which varies in response to strain, inflammation, malposition or infiltration of muscles, ligaments, cartilage, or bones in the chest wall. Irritation of a nerve root from the neck or upper spine, or a fractured rib, can also cause chest wall pain. Treatment is aimed at the underlying cause of the pain. Tietze syndrome is part of this group of painful conditions.Costal chondritis or costochondritis is a common condition characterized by inflammation of the cartilage part of the rib. It may affect one or more rib (costal) cartilages. It is characterized by pain of the chest wall that may spread (radiate) to surrounding areas. Sometimes, the terms costochondritis and Tietze syndrome are used interchangeably. However, the two disorders are differentiated by the presence of swelling, in addition to pain, in Tietze syndrome. In costochondritis, there is no swelling. Costochondritis is more common, although not exclusively, in adults over 40 years of age.Spinal root lesions or compression can cause chest pain in the form of a deep, boring, aching discomfort, or a sharp sudden and piercing pain. This pain usually occurs after sudden movement of the body, such as sneezing, coughing, laughing or straining.Additional disorders that can cause symptoms similar to those seen in Tietze syndrome include seronegative arthritis, ankylosing spondylitis, fibromyalgia, pneumonia, and coronary heart disease. In some instances, certain forms of malignant lymphoma can cause chest pain and swelling similar to that in Tietze syndrome.
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Tietze Syndrome
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nord_1211_5
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Diagnosis of Tietze Syndrome
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A diagnosis of Tietze syndrome is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic symptoms, and exclusion of other causes of chest pain. A variety of tests including electrocardiogram, x-rays, and biopsies may be performed to rule out more serious causes of chest pain including cardiovascular disorders or malignant conditions. Magnetic resonance imaging (MRI) can show thickening and enlargement of affected cartilage.
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Diagnosis of Tietze Syndrome. A diagnosis of Tietze syndrome is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic symptoms, and exclusion of other causes of chest pain. A variety of tests including electrocardiogram, x-rays, and biopsies may be performed to rule out more serious causes of chest pain including cardiovascular disorders or malignant conditions. Magnetic resonance imaging (MRI) can show thickening and enlargement of affected cartilage.
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Tietze Syndrome
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Therapies of Tietze Syndrome
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Treatment
In some cases, pain associated with Tietze syndrome resolves itself without treatment. Specific treatment for individuals with Tietze syndrome consists of rest, avoidance of strenuous activity, the application of heat to the affected area, and pain medications such as nonsteroidal anti-inflammatory drugs (NSAIDs) or a mild pain reliever (analgesic). Local corticosteroid or lidocaine injections directly into the affected area may be beneficial for people who don’t respond to pain relievers (refractory cases). Usually the pain subsides after several weeks or months, but the palpable swellings may persist for some time.
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Therapies of Tietze Syndrome. Treatment
In some cases, pain associated with Tietze syndrome resolves itself without treatment. Specific treatment for individuals with Tietze syndrome consists of rest, avoidance of strenuous activity, the application of heat to the affected area, and pain medications such as nonsteroidal anti-inflammatory drugs (NSAIDs) or a mild pain reliever (analgesic). Local corticosteroid or lidocaine injections directly into the affected area may be beneficial for people who don’t respond to pain relievers (refractory cases). Usually the pain subsides after several weeks or months, but the palpable swellings may persist for some time.
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Tietze Syndrome
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nord_1212_0
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Overview of Timothy Syndrome
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SummaryTimothy syndrome (TS), also referred to as long QT syndrome type 8 (LQT8), is a rare multisystem genetic disorder affecting the heart and several other organs, including the skeleton, metabolic system, and brain [1–3]. The most relevant heart manifestation of TS is the prolongation of the time required by the heart to complete a cycle of its electrical activity, known as the “QT interval”. TS belongs to a heterogeneous group of diseases collectively classified as “long QT syndrome” or LQTS. The QT interval prolongation predisposes patients to a high risk of developing cardiac arrhythmias and experiencing cardiac arrest from a very young age [4].The main feature that distinguishes TS from other forms of LQTS is that it presents additional clinical manifestations, both heart (cardiac) and extra-cardiac. These include cardiac malformations, thickening of the cardiac walls (cardiac hypertrophy), fingers or toes that are fused together (syndactyly), facial differences, immunological defects, neurodevelopmental delay and episodes of low levels of sugar in the blood (hypoglycemia) [3]. The Timothy Syndrome Alliance states that with more cases being identified, gastrointestinal defects have become a major concern.These multisystem abnormalities are the result of a genetic modification that affects multiple organs and tissues of the body. TS is caused by changes (mutations) in the CACNA1C gene [3] that provides the instructions for the assembly of special proteins known as “calcium channels.” These channels are located on the external membrane of cells and allow calcium ions to flow into the cardiac cells. Since the calcium channels are present not only in the heart but in many other organs, multiple body systems are affected.Available treatments include orally administrated medications (“antiarrhythmics”) and implantable devices like pacemakers (PM) or implantable cardioverter defibrillators (ICD) [5].
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Overview of Timothy Syndrome. SummaryTimothy syndrome (TS), also referred to as long QT syndrome type 8 (LQT8), is a rare multisystem genetic disorder affecting the heart and several other organs, including the skeleton, metabolic system, and brain [1–3]. The most relevant heart manifestation of TS is the prolongation of the time required by the heart to complete a cycle of its electrical activity, known as the “QT interval”. TS belongs to a heterogeneous group of diseases collectively classified as “long QT syndrome” or LQTS. The QT interval prolongation predisposes patients to a high risk of developing cardiac arrhythmias and experiencing cardiac arrest from a very young age [4].The main feature that distinguishes TS from other forms of LQTS is that it presents additional clinical manifestations, both heart (cardiac) and extra-cardiac. These include cardiac malformations, thickening of the cardiac walls (cardiac hypertrophy), fingers or toes that are fused together (syndactyly), facial differences, immunological defects, neurodevelopmental delay and episodes of low levels of sugar in the blood (hypoglycemia) [3]. The Timothy Syndrome Alliance states that with more cases being identified, gastrointestinal defects have become a major concern.These multisystem abnormalities are the result of a genetic modification that affects multiple organs and tissues of the body. TS is caused by changes (mutations) in the CACNA1C gene [3] that provides the instructions for the assembly of special proteins known as “calcium channels.” These channels are located on the external membrane of cells and allow calcium ions to flow into the cardiac cells. Since the calcium channels are present not only in the heart but in many other organs, multiple body systems are affected.Available treatments include orally administrated medications (“antiarrhythmics”) and implantable devices like pacemakers (PM) or implantable cardioverter defibrillators (ICD) [5].
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Timothy Syndrome
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Symptoms of Timothy Syndrome
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Due to the multisystem nature of this disease, its clinical presentation is remarkably complex.TS’s key cardiac feature is the documentation of a markedly prolonged QT interval on the electrocardiogram (EKG). The QT interval is the electrocardiographic parameter representing the time required for the heart to complete a cycle of contraction and relaxation. The prolongation of this interval predisposes the heart to develop sudden alterations in the cardiac rhythm (known as arrhythmias). These cardiac arrhythmias can be very rapid and can impair the heart’s ability to pump blood to the brain, ultimately resulting in a sudden loss of consciousness (syncope), cardiac arrest, and potentially sudden cardiac death. Anesthesia and hypoglycemia are well-recognized triggers for arrhythmias in patients with TS [6–8]. Furthermore, when the QT interval is exceptionally prolonged, as is the case in patients with TS, a slowing in the conduction of the electrical impulses from the atria to the ventricles can occur. This phenomenon is called “atrioventricular block” and can result in a severe reduction of the heart rate (bradycardia).One of the most common and peculiar extra-cardiac signs of TS is the presence of syndactyly [2,9], a condition in which two or more digits are fused together. It can be bilateral and may involve both the hands and the feet. According to a recent research study [6], up to 20% of individuals with TS may not present with syndactyly. Therefore, genetic testing is crucial to establish the diagnosis of TS in these patients.
Some visible signs associated with TS are specific facial differences in about 50% of patients [3,6], including low-set ears, a lower nasal bridge, a small upper jaw, baldness at birth and small and widely spaced teeth with a predisposition to cavities.Additional extra-cardiac symptoms are a predisposition to infections (30-40% of patients [3,6]) secondary to an immunological defect and occasional episodes of low blood sugar (hypoglycemia), that may lead to fainting and, if untreated, death. Children with TS may also present with neurodevelopmental delay in up to 60% of patients [3,6]. The neurological features include autism spectrum disorders, seizures and intellectual disability.
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Symptoms of Timothy Syndrome. Due to the multisystem nature of this disease, its clinical presentation is remarkably complex.TS’s key cardiac feature is the documentation of a markedly prolonged QT interval on the electrocardiogram (EKG). The QT interval is the electrocardiographic parameter representing the time required for the heart to complete a cycle of contraction and relaxation. The prolongation of this interval predisposes the heart to develop sudden alterations in the cardiac rhythm (known as arrhythmias). These cardiac arrhythmias can be very rapid and can impair the heart’s ability to pump blood to the brain, ultimately resulting in a sudden loss of consciousness (syncope), cardiac arrest, and potentially sudden cardiac death. Anesthesia and hypoglycemia are well-recognized triggers for arrhythmias in patients with TS [6–8]. Furthermore, when the QT interval is exceptionally prolonged, as is the case in patients with TS, a slowing in the conduction of the electrical impulses from the atria to the ventricles can occur. This phenomenon is called “atrioventricular block” and can result in a severe reduction of the heart rate (bradycardia).One of the most common and peculiar extra-cardiac signs of TS is the presence of syndactyly [2,9], a condition in which two or more digits are fused together. It can be bilateral and may involve both the hands and the feet. According to a recent research study [6], up to 20% of individuals with TS may not present with syndactyly. Therefore, genetic testing is crucial to establish the diagnosis of TS in these patients.
Some visible signs associated with TS are specific facial differences in about 50% of patients [3,6], including low-set ears, a lower nasal bridge, a small upper jaw, baldness at birth and small and widely spaced teeth with a predisposition to cavities.Additional extra-cardiac symptoms are a predisposition to infections (30-40% of patients [3,6]) secondary to an immunological defect and occasional episodes of low blood sugar (hypoglycemia), that may lead to fainting and, if untreated, death. Children with TS may also present with neurodevelopmental delay in up to 60% of patients [3,6]. The neurological features include autism spectrum disorders, seizures and intellectual disability.
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Timothy Syndrome
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Causes of Timothy Syndrome
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In 2004 Splawski and colleagues [3] discovered that TS is caused by mutations in the CACNA1C gene, which is responsible for regulating the formation of a protein that moves calcium inside the cardiac cells (i.e. the “calcium channel”). The calcium channel is composed of a long sequence of smaller molecules, called “amino acids”. In the first cohort described by Splawski in 2004 [3], all patients had an identical mutation (G406R), which caused the substitution of the amino acid “glycine” (G) in position 406 with the amino acid “arginine” (R). When this gene is mutated, the closing of the channel is delayed causing too much calcium to enter the cells, which in turn determines the prolongation of the QT interval on the EKG.TS is a dominant genetic disorder. This means that only a single copy of an abnormal gene is sufficient to cause the disease to be inherited. The abnormal gene can be inherited from either parent or it can be the result of a new mutation in the affected individual. The latter occurrence is called a “de novo” mutation and represents the most common cause of TS. However, in about 10% of patients [3,6], one parent can be a carrier of the mutation, but not in all cells of his/her body, a situation called “parental mosaicism”. This results in the possible transmission of the disease to children even though neither parent has the clinical manifestations of the disease.From the original description in 2004, it was found that other mutations in the CACNA1C gene can cause TS. According to a recent research study, the G406R mutation is present in about 60% of patients with TS. Other mutations described in the medical literature as associated with a TS phenotype include the following: G402R [6], G402S [6], S405R [6], C1021R [6], I1166T [10], K1211E [6], A1473G [11] and G1911R [12].In recent years, the features associated with cardiac calcium channel mutations have greatly expanded. Some CACNA1C mutations can cause LQTS without other cardiac or extra-cardiac manifestations (deemed “CACNA1C-related LQTS”). Some examples include: A28T[13], P381S[14], M456I[14], A582D[14], L762F[15], P857R[16], R858H[14], R860G[13], I1166V[13], I1475M[13], E1496K[13], and G1783C[14]. These do not properly correspond to the definition of Timothy syndrome. However, other mutations (e.g. R518C, R518H) [17] have been associated with cardiac malformations and hypertrophy and they are classified under the name “cardiac-only Timothy syndrome” (COTS).
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Causes of Timothy Syndrome. In 2004 Splawski and colleagues [3] discovered that TS is caused by mutations in the CACNA1C gene, which is responsible for regulating the formation of a protein that moves calcium inside the cardiac cells (i.e. the “calcium channel”). The calcium channel is composed of a long sequence of smaller molecules, called “amino acids”. In the first cohort described by Splawski in 2004 [3], all patients had an identical mutation (G406R), which caused the substitution of the amino acid “glycine” (G) in position 406 with the amino acid “arginine” (R). When this gene is mutated, the closing of the channel is delayed causing too much calcium to enter the cells, which in turn determines the prolongation of the QT interval on the EKG.TS is a dominant genetic disorder. This means that only a single copy of an abnormal gene is sufficient to cause the disease to be inherited. The abnormal gene can be inherited from either parent or it can be the result of a new mutation in the affected individual. The latter occurrence is called a “de novo” mutation and represents the most common cause of TS. However, in about 10% of patients [3,6], one parent can be a carrier of the mutation, but not in all cells of his/her body, a situation called “parental mosaicism”. This results in the possible transmission of the disease to children even though neither parent has the clinical manifestations of the disease.From the original description in 2004, it was found that other mutations in the CACNA1C gene can cause TS. According to a recent research study, the G406R mutation is present in about 60% of patients with TS. Other mutations described in the medical literature as associated with a TS phenotype include the following: G402R [6], G402S [6], S405R [6], C1021R [6], I1166T [10], K1211E [6], A1473G [11] and G1911R [12].In recent years, the features associated with cardiac calcium channel mutations have greatly expanded. Some CACNA1C mutations can cause LQTS without other cardiac or extra-cardiac manifestations (deemed “CACNA1C-related LQTS”). Some examples include: A28T[13], P381S[14], M456I[14], A582D[14], L762F[15], P857R[16], R858H[14], R860G[13], I1166V[13], I1475M[13], E1496K[13], and G1783C[14]. These do not properly correspond to the definition of Timothy syndrome. However, other mutations (e.g. R518C, R518H) [17] have been associated with cardiac malformations and hypertrophy and they are classified under the name “cardiac-only Timothy syndrome” (COTS).
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Timothy Syndrome
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Affects of Timothy Syndrome
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TS has been diagnosed in less than 100 children around the world. Because of the multisystem nature of this syndrome, very few children live to adulthood. Thanks to improved recognition of this syndrome and improved medical care, there are a number of TS individuals now in their twenties and early 30s.
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Affects of Timothy Syndrome. TS has been diagnosed in less than 100 children around the world. Because of the multisystem nature of this syndrome, very few children live to adulthood. Thanks to improved recognition of this syndrome and improved medical care, there are a number of TS individuals now in their twenties and early 30s.
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Timothy Syndrome
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nord_1212_4
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Related disorders of Timothy Syndrome
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There are several genetic forms of long QT syndrome (LQTS) that are more common than TS. All LQTS share an abnormality of cardiac rhythm which can lead to fainting spells, cardiac arrest, and sudden death. LQTS typically presents between the pre-teen age through the twenties, but can occur anywhere from infancy through middle age. (For more information on these conditions, search for “long QT syndrome” in the Rare Disease Database.) Unlike TS, these LQTS variants are usually non-syndromic, meaning that patients do not exhibit extra-cardiac manifestations. However, other two examples of syndromic LQTS exist: the Andersen-Tawil syndrome (ATS) and the Jervell and Lange Nielsen syndrome (JLNS).Andersen-Tawil syndrome (ATS) [18,19] is characterized by a triad of symptoms: 1) specific EKG abnormalities and cardiac arrhythmias, 2) episodes of periodic paralysis of skeletal muscles and 3) physical features such as low set ears, crooked little fingers, syndactyly, and scoliosis. This syndrome is autosomal dominant and is caused by a mutation in the KCNJ2 gene, encoding for a specific potassium channel. Cardiac symptoms and periodic paralysis often occur in the first or second decade of life. (For more information on this condition, search for “Andersen-Tawil syndrome” in the Rare Disease Database.)Jervell and Lange Nielsen syndrome (JLNS) [20] is a form of LQTS inherited as an autosomal recessive genetic disorder. It is caused by mutations in the KCNQ1 gene [21] or in the KCNE1 gene [22], both encoding for specific potassium channels. This disease is characterized by profound hearing loss and markedly prolonged QT interval. Children with JLNS often present with deafness and fainting episodes associated with frightening, stress, or exercise. (For more information on this condition, search for “JLNS” in the Rare Disease Database.)LQT1 is a form of LQTS caused by mutations in the KCNQ1 gene and inherited in an autosomal dominant pattern. It is important to know that QT interval prolongation is not only caused by genetic diseases, but it can also occur in the presence of reduced levels of potassium in the blood or it may be caused by the intake of drugs that block potassium channels (these drugs are listed at https://crediblemeds.org/).Finally, syndactyly can be observed in many different disorders, such as Bardet-Biedl syndrome [23] and Smith-Lemli-Opitz syndrome [24]. However, the combination of LQT and syndactyly should prompt clinicians to perform a genetic test for TS.
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Related disorders of Timothy Syndrome. There are several genetic forms of long QT syndrome (LQTS) that are more common than TS. All LQTS share an abnormality of cardiac rhythm which can lead to fainting spells, cardiac arrest, and sudden death. LQTS typically presents between the pre-teen age through the twenties, but can occur anywhere from infancy through middle age. (For more information on these conditions, search for “long QT syndrome” in the Rare Disease Database.) Unlike TS, these LQTS variants are usually non-syndromic, meaning that patients do not exhibit extra-cardiac manifestations. However, other two examples of syndromic LQTS exist: the Andersen-Tawil syndrome (ATS) and the Jervell and Lange Nielsen syndrome (JLNS).Andersen-Tawil syndrome (ATS) [18,19] is characterized by a triad of symptoms: 1) specific EKG abnormalities and cardiac arrhythmias, 2) episodes of periodic paralysis of skeletal muscles and 3) physical features such as low set ears, crooked little fingers, syndactyly, and scoliosis. This syndrome is autosomal dominant and is caused by a mutation in the KCNJ2 gene, encoding for a specific potassium channel. Cardiac symptoms and periodic paralysis often occur in the first or second decade of life. (For more information on this condition, search for “Andersen-Tawil syndrome” in the Rare Disease Database.)Jervell and Lange Nielsen syndrome (JLNS) [20] is a form of LQTS inherited as an autosomal recessive genetic disorder. It is caused by mutations in the KCNQ1 gene [21] or in the KCNE1 gene [22], both encoding for specific potassium channels. This disease is characterized by profound hearing loss and markedly prolonged QT interval. Children with JLNS often present with deafness and fainting episodes associated with frightening, stress, or exercise. (For more information on this condition, search for “JLNS” in the Rare Disease Database.)LQT1 is a form of LQTS caused by mutations in the KCNQ1 gene and inherited in an autosomal dominant pattern. It is important to know that QT interval prolongation is not only caused by genetic diseases, but it can also occur in the presence of reduced levels of potassium in the blood or it may be caused by the intake of drugs that block potassium channels (these drugs are listed at https://crediblemeds.org/).Finally, syndactyly can be observed in many different disorders, such as Bardet-Biedl syndrome [23] and Smith-Lemli-Opitz syndrome [24]. However, the combination of LQT and syndactyly should prompt clinicians to perform a genetic test for TS.
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Timothy Syndrome
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nord_1212_5
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Diagnosis of Timothy Syndrome
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The occurrence of cardiac arrhythmias or the documentation of a prolonged QT interval on the EKG usually permits the establishment of diagnosis in the first days of life. In up to 25% of patients [6], TS may also be suspected before birth due to abnormal heart rate in the womb (“fetal bradycardia”) but occasionally the diagnosis is made later, during early infancy. Other distinctive features such as cardiac malformations or hypertrophy, syndactyly and typical facial abnormalities are suggestive of TS. Additional symptoms such as recurrent infections, episodes of paroxysmal hypoglycemia, autism spectrum disorders, seizures and intellectual disability may also contribute to the diagnosis. Once clinical suspicion has been raised, diagnosis can be confirmed through genetic testing for mutations in the CACNA1C gene. Once diagnosis is established, evaluations including cardiology, neurology, skeletal and metabolic consultations should be done to evaluate the extent of the disease and to undertake the appropriate therapeutic measures.
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Diagnosis of Timothy Syndrome. The occurrence of cardiac arrhythmias or the documentation of a prolonged QT interval on the EKG usually permits the establishment of diagnosis in the first days of life. In up to 25% of patients [6], TS may also be suspected before birth due to abnormal heart rate in the womb (“fetal bradycardia”) but occasionally the diagnosis is made later, during early infancy. Other distinctive features such as cardiac malformations or hypertrophy, syndactyly and typical facial abnormalities are suggestive of TS. Additional symptoms such as recurrent infections, episodes of paroxysmal hypoglycemia, autism spectrum disorders, seizures and intellectual disability may also contribute to the diagnosis. Once clinical suspicion has been raised, diagnosis can be confirmed through genetic testing for mutations in the CACNA1C gene. Once diagnosis is established, evaluations including cardiology, neurology, skeletal and metabolic consultations should be done to evaluate the extent of the disease and to undertake the appropriate therapeutic measures.
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Timothy Syndrome
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nord_1212_6
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Therapies of Timothy Syndrome
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TreatmentCardiac symptoms of TS can be managed through a variety of treatments, including drug therapies. An integrated approach based on different therapeutic options has made it possible to slightly improve the prognosis of patients with TS compared to the first reports in 2004 and 2005. However, the disease still has an extremely high mortality rate and few affected individuals reach adulthood.One common treatment is orally administrated drugs called “beta blockers” (BBs), which block the effect of epinephrine thus preventing sudden increases in heart rate. BBs are currently used with success to treat other forms of genetic LQTS. However, recent data from international registries [6,7] reported that 70% of patients were treated with BBs at the time of the cardiac arrest, suggesting that the effect of BBs in preventing sudden cardiac death is not satisfactory in this particular form of LQTS.The most effective treatment is the use of an implantable cardioverter defibrillator (ICD). This device is able to recognize when the heart experiences a life-threatening arrhythmia and delivers an electric shock that restores a normal heart rate. Considering the high mortality rate of the disease, the prophylactic implant of an ICD is often recommended in patients with TS [5]. Pacemakers (PM) are also frequently used in infants to prevent the excessive slowing of the heart rate (bradycardia) secondary to the aforementioned atrioventricular blocks [5].Other treatments address the management of the non-cardiac manifestations of the disease. Respiratory infections are common in TS and should be treated with antibiotics that do not cause QT prolongation. Surgical correction of syndactyly is possible, but it should involve careful monitoring of the heart for any complications, since the use of anesthetic drugs is a common trigger for cardiac arrhythmias in patients with TS [8].Monitoring of individuals with TS should include frequent blood sugar measurement and cardiac assessments. All drugs or dietary practices that may contribute to lengthening the QT interval or lowering blood sugar should be avoided.A medical team may be necessary to address the other non-cardiac issues that affect the quality of life of these children. Intestinal issues are of major concern along with bouts of hypoglycaemia. The neurodevelopmental delays observed in many TS individuals may require special educational needs and therapeutic interventions.
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Therapies of Timothy Syndrome. TreatmentCardiac symptoms of TS can be managed through a variety of treatments, including drug therapies. An integrated approach based on different therapeutic options has made it possible to slightly improve the prognosis of patients with TS compared to the first reports in 2004 and 2005. However, the disease still has an extremely high mortality rate and few affected individuals reach adulthood.One common treatment is orally administrated drugs called “beta blockers” (BBs), which block the effect of epinephrine thus preventing sudden increases in heart rate. BBs are currently used with success to treat other forms of genetic LQTS. However, recent data from international registries [6,7] reported that 70% of patients were treated with BBs at the time of the cardiac arrest, suggesting that the effect of BBs in preventing sudden cardiac death is not satisfactory in this particular form of LQTS.The most effective treatment is the use of an implantable cardioverter defibrillator (ICD). This device is able to recognize when the heart experiences a life-threatening arrhythmia and delivers an electric shock that restores a normal heart rate. Considering the high mortality rate of the disease, the prophylactic implant of an ICD is often recommended in patients with TS [5]. Pacemakers (PM) are also frequently used in infants to prevent the excessive slowing of the heart rate (bradycardia) secondary to the aforementioned atrioventricular blocks [5].Other treatments address the management of the non-cardiac manifestations of the disease. Respiratory infections are common in TS and should be treated with antibiotics that do not cause QT prolongation. Surgical correction of syndactyly is possible, but it should involve careful monitoring of the heart for any complications, since the use of anesthetic drugs is a common trigger for cardiac arrhythmias in patients with TS [8].Monitoring of individuals with TS should include frequent blood sugar measurement and cardiac assessments. All drugs or dietary practices that may contribute to lengthening the QT interval or lowering blood sugar should be avoided.A medical team may be necessary to address the other non-cardiac issues that affect the quality of life of these children. Intestinal issues are of major concern along with bouts of hypoglycaemia. The neurodevelopmental delays observed in many TS individuals may require special educational needs and therapeutic interventions.
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Timothy Syndrome
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nord_1213_0
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Overview of Tinnitus
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SummaryTinnitus is a common condition characterized by the perception or sensation of sound even though there is no identifiable external source for the sound. Tinnitus is often referred to as a “ringing in the ears.” However, the sounds associated with tinnitus have also been described as hissing, chirping, crickets, whooshing, or roaring sounds, amongst others, that can affect one or both ears. Tinnitus is generally broken down into two types: subjective and objective. Subjective tinnitus is very common and is defined as a sound that is audible only to the person with tinnitus. Subjective tinnitus is a purely electrochemical phenomenon and cannot be heard by an outside observer no matter how hard they try. Objective tinnitus, which is far less common, is defined as a sound that arises from an “objective” source, such as mechanical defect or a specific sound source, and can be heard by an outside observer under favorable conditions. The sounds from objective tinnitus occur somewhere within the body and reach the ears by conduction through various body tissues. Objective tinnitus is usually caused by disorders affecting the blood vessels (vascular system) or muscles (muscular system).IntroductionThe majority of cases of tinnitus are subjective. Objective tinnitus is far less common. However, a diagnosis of objective tinnitus is tied to how hard and well the objective (outside) listener tries to hear the sound in question. Because of this problem, some clinicians now simply refer to tinnitus as either rhythmic or non-rhythmic. Generally, rhythmic tinnitus correlates with objective tinnitus and non-rhythmic tinnitus correlates with subjective tinnitus. Specific forms of tinnitus such as pulsatile tinnitus and muscular tinnitus, which are forms of rhythmic tinnitus, are relatively rare. Pulsatile tinnitus may also be known as pulse-synchronous tinnitus. Properly identifying and distinguishing these less common forms of tinnitus is important because the underlying cause of pulsatile or muscular tinnitus can often be identified and treated.
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Overview of Tinnitus. SummaryTinnitus is a common condition characterized by the perception or sensation of sound even though there is no identifiable external source for the sound. Tinnitus is often referred to as a “ringing in the ears.” However, the sounds associated with tinnitus have also been described as hissing, chirping, crickets, whooshing, or roaring sounds, amongst others, that can affect one or both ears. Tinnitus is generally broken down into two types: subjective and objective. Subjective tinnitus is very common and is defined as a sound that is audible only to the person with tinnitus. Subjective tinnitus is a purely electrochemical phenomenon and cannot be heard by an outside observer no matter how hard they try. Objective tinnitus, which is far less common, is defined as a sound that arises from an “objective” source, such as mechanical defect or a specific sound source, and can be heard by an outside observer under favorable conditions. The sounds from objective tinnitus occur somewhere within the body and reach the ears by conduction through various body tissues. Objective tinnitus is usually caused by disorders affecting the blood vessels (vascular system) or muscles (muscular system).IntroductionThe majority of cases of tinnitus are subjective. Objective tinnitus is far less common. However, a diagnosis of objective tinnitus is tied to how hard and well the objective (outside) listener tries to hear the sound in question. Because of this problem, some clinicians now simply refer to tinnitus as either rhythmic or non-rhythmic. Generally, rhythmic tinnitus correlates with objective tinnitus and non-rhythmic tinnitus correlates with subjective tinnitus. Specific forms of tinnitus such as pulsatile tinnitus and muscular tinnitus, which are forms of rhythmic tinnitus, are relatively rare. Pulsatile tinnitus may also be known as pulse-synchronous tinnitus. Properly identifying and distinguishing these less common forms of tinnitus is important because the underlying cause of pulsatile or muscular tinnitus can often be identified and treated.
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Tinnitus
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nord_1213_1
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Symptoms of Tinnitus
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Individuals with tinnitus describe perceiving a wide variety of sounds including ringing, clicking, hissing, humming, chirping, buzzing, whistling, whooshing, roaring, and/or whirling. These sounds may be present at all times, or they may come and go. The volume, pitch or quality of tinnitus sounds can fluctuate as well. Some people report that their tinnitus is most obvious when outside sounds are low (i.e. during the night). Other individuals describe their tinnitus as loud even in the presence of external sounds or noise, and some describe it as exacerbated by sounds. Tinnitus can affect one ear or both ears. It can also sound like it is inside the head and not in the ears at all.The degree of loudness or annoyance caused by tinnitus varies greatly from one individual to another. Loudness and annoyance do not always covary. An individual with loud tinnitus may not be troubled, while an individual with soft tinnitus may be debilitated. Most individuals with subjective tinnitus have hearing loss that shows up in a standard clinical audiogram. Tinnitus can sometimes worsen or sometimes improve over time.Pulsatile tinnitus and muscular tinnitus are two forms that can be classified as rhythmic tinnitus. In pulsatile tinnitus, the characteristic sound mirrors or keeps pace (synchronizes) with a person’s heartbeat. It is rarely described as a ringing sound, but more often as a whooshing, pulsing, or screeching sound.In muscular tinnitus, the sound is often described as a “clicking” noise and is usually associated with myoclonus affecting muscles near – or in – the ear. Myoclonus is an involuntary spasm or jerking of a muscle or group of muscles caused by abnormal muscular contractions and relaxations.
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Symptoms of Tinnitus. Individuals with tinnitus describe perceiving a wide variety of sounds including ringing, clicking, hissing, humming, chirping, buzzing, whistling, whooshing, roaring, and/or whirling. These sounds may be present at all times, or they may come and go. The volume, pitch or quality of tinnitus sounds can fluctuate as well. Some people report that their tinnitus is most obvious when outside sounds are low (i.e. during the night). Other individuals describe their tinnitus as loud even in the presence of external sounds or noise, and some describe it as exacerbated by sounds. Tinnitus can affect one ear or both ears. It can also sound like it is inside the head and not in the ears at all.The degree of loudness or annoyance caused by tinnitus varies greatly from one individual to another. Loudness and annoyance do not always covary. An individual with loud tinnitus may not be troubled, while an individual with soft tinnitus may be debilitated. Most individuals with subjective tinnitus have hearing loss that shows up in a standard clinical audiogram. Tinnitus can sometimes worsen or sometimes improve over time.Pulsatile tinnitus and muscular tinnitus are two forms that can be classified as rhythmic tinnitus. In pulsatile tinnitus, the characteristic sound mirrors or keeps pace (synchronizes) with a person’s heartbeat. It is rarely described as a ringing sound, but more often as a whooshing, pulsing, or screeching sound.In muscular tinnitus, the sound is often described as a “clicking” noise and is usually associated with myoclonus affecting muscles near – or in – the ear. Myoclonus is an involuntary spasm or jerking of a muscle or group of muscles caused by abnormal muscular contractions and relaxations.
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Tinnitus
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nord_1213_2
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Causes of Tinnitus
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There are numerous, varied causes of non-rhythmic tinnitus, the most common of which are hearing loss and/or noise exposure. Rhythmic tinnitus is usually caused by disorders affecting the blood vessels (vascular system) or muscles (muscular system).Pulsatile tinnitus is generally caused by abnormalities or disorders affecting the blood vessels (vascular disorders), especially the blood vessels near or around the ears. Such abnormalities or disorders can cause a change in the blood flow through the affected blood vessels. The blood vessels could be weakened from damage caused by hardening of the arteries (atherosclerosis). For example, abnormalities affecting the carotid artery, the main artery serving the brain, can be associated with pulsatile tinnitus. A rare cause of pulsatile tinnitus is a disorder known as fibromuscular dysplasia (FMD), a condition characterized by abnormal development of the arterial wall. When the carotid artery is affected by FMD, pulsatile tinnitus can develop.It is possible that the most common cause of pulsatile tinnitus is sigmoid sinus diverticulum and dehiscence, which can be collectively referred to as sinus wall abnormalities or SSWA. The sigmoid sinus is a blood carrying channel on the side of the brain that receives blood from veins within the brain. The blood eventually exits through the internal jugular vein. Sigmoid sinus diverticulum refers to the formation of small sac-like pouches (diverticula) that protrude through the wall of the sigmoid sinus into the mastoid bone behind the ear. Dehiscence refers to absence of part of the bone that surrounds the sigmoid sinus in the mastoid. It is unknown whether these conditions represent different parts of one disease process or spectrum, or whether they are two distinct conditions. These abnormalities cause pressure, blood flow, and noise changes within the sigmoid sinus, which ultimately results in pulsatile tinnitus. Narrowing of the blood vessel that leads into the sigmoid sinus, known as the transverse sinus, has also been associated with pulsatile tinnitus.Superior semicircular canal dehiscence syndrome is another not uncommon cause of pulsatile tinnitus. The superior semicircular canal is one of three canals found in the vestibular apparatus of the inner ear. The vestibular apparatus helps to maintain equilibrium and balance. In this syndrome, a part of the temporal bone that overlies the superior semicircular canal is abnormally thin or absent. Superior semicircular canal dehiscence syndrome can affect both hearing and balance to different degrees.Additional conditions that can cause pulsatile tinnitus include arterial bruit, abnormal passages or connections between the blood vessels of the outermost layer of the membrane (dura) that covers the brain and spinal cord (dural arteriovenous shunts), or conditions that cause increased pressure within the skull such as idiopathic intracranial hypertension (pseudotumor cerebri). Sigmoid sinus dehiscence may be associated with pseudotumor, but this connection has not been firmly established. It possible that cases of pulsatile tinnitus associated with pseudotumor may be caused by an undiagnosed SSWA. Head trauma, surgery, middle ear conductive hearing loss, and certain tumors can also cause pulsatile tinnitus. Obstructions within in the vessels that connect the heart and brain can also cause pulsatile tinnitus.Muscular tinnitus can be caused by several degenerative diseases that affect the head and neck including amyotrophic lateral sclerosis or multiple sclerosis. Myoclonus can also cause muscular tinnitus, especially palatal myoclonus, which is characterized by abnormal contractions of the muscles of the roof of the mouth. Spasms of the stapedial muscle (which attaches to the stapes bone or stirrup), which is the smallest muscle in the body, and tensor tympani muscle, both of which are located in the middle ear, have also been associated with objective tinnitus. Myoclonus or muscle spasms may be caused by an underlying disorder such as a tumor, tissue death caused by lack of oxygen (infarction), or degenerative disease, but it is most commonly a benign and self-limiting problem.Patulous Eustachian tubes can be associated with tinnitus. The Eustachian tube is a small canal that connects the middle ear to the back of the nose and upper throat. The Eustachian tube normally remains closed. In individuals with a patulous Eustachian tube, the tube is abnormally open. Consequently, talking, chewing, swallowing and other similar actions can cause vibrations directly onto the ear drum. For example, affected individuals may hear blowing sounds that are synchronized with breathing.
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Causes of Tinnitus. There are numerous, varied causes of non-rhythmic tinnitus, the most common of which are hearing loss and/or noise exposure. Rhythmic tinnitus is usually caused by disorders affecting the blood vessels (vascular system) or muscles (muscular system).Pulsatile tinnitus is generally caused by abnormalities or disorders affecting the blood vessels (vascular disorders), especially the blood vessels near or around the ears. Such abnormalities or disorders can cause a change in the blood flow through the affected blood vessels. The blood vessels could be weakened from damage caused by hardening of the arteries (atherosclerosis). For example, abnormalities affecting the carotid artery, the main artery serving the brain, can be associated with pulsatile tinnitus. A rare cause of pulsatile tinnitus is a disorder known as fibromuscular dysplasia (FMD), a condition characterized by abnormal development of the arterial wall. When the carotid artery is affected by FMD, pulsatile tinnitus can develop.It is possible that the most common cause of pulsatile tinnitus is sigmoid sinus diverticulum and dehiscence, which can be collectively referred to as sinus wall abnormalities or SSWA. The sigmoid sinus is a blood carrying channel on the side of the brain that receives blood from veins within the brain. The blood eventually exits through the internal jugular vein. Sigmoid sinus diverticulum refers to the formation of small sac-like pouches (diverticula) that protrude through the wall of the sigmoid sinus into the mastoid bone behind the ear. Dehiscence refers to absence of part of the bone that surrounds the sigmoid sinus in the mastoid. It is unknown whether these conditions represent different parts of one disease process or spectrum, or whether they are two distinct conditions. These abnormalities cause pressure, blood flow, and noise changes within the sigmoid sinus, which ultimately results in pulsatile tinnitus. Narrowing of the blood vessel that leads into the sigmoid sinus, known as the transverse sinus, has also been associated with pulsatile tinnitus.Superior semicircular canal dehiscence syndrome is another not uncommon cause of pulsatile tinnitus. The superior semicircular canal is one of three canals found in the vestibular apparatus of the inner ear. The vestibular apparatus helps to maintain equilibrium and balance. In this syndrome, a part of the temporal bone that overlies the superior semicircular canal is abnormally thin or absent. Superior semicircular canal dehiscence syndrome can affect both hearing and balance to different degrees.Additional conditions that can cause pulsatile tinnitus include arterial bruit, abnormal passages or connections between the blood vessels of the outermost layer of the membrane (dura) that covers the brain and spinal cord (dural arteriovenous shunts), or conditions that cause increased pressure within the skull such as idiopathic intracranial hypertension (pseudotumor cerebri). Sigmoid sinus dehiscence may be associated with pseudotumor, but this connection has not been firmly established. It possible that cases of pulsatile tinnitus associated with pseudotumor may be caused by an undiagnosed SSWA. Head trauma, surgery, middle ear conductive hearing loss, and certain tumors can also cause pulsatile tinnitus. Obstructions within in the vessels that connect the heart and brain can also cause pulsatile tinnitus.Muscular tinnitus can be caused by several degenerative diseases that affect the head and neck including amyotrophic lateral sclerosis or multiple sclerosis. Myoclonus can also cause muscular tinnitus, especially palatal myoclonus, which is characterized by abnormal contractions of the muscles of the roof of the mouth. Spasms of the stapedial muscle (which attaches to the stapes bone or stirrup), which is the smallest muscle in the body, and tensor tympani muscle, both of which are located in the middle ear, have also been associated with objective tinnitus. Myoclonus or muscle spasms may be caused by an underlying disorder such as a tumor, tissue death caused by lack of oxygen (infarction), or degenerative disease, but it is most commonly a benign and self-limiting problem.Patulous Eustachian tubes can be associated with tinnitus. The Eustachian tube is a small canal that connects the middle ear to the back of the nose and upper throat. The Eustachian tube normally remains closed. In individuals with a patulous Eustachian tube, the tube is abnormally open. Consequently, talking, chewing, swallowing and other similar actions can cause vibrations directly onto the ear drum. For example, affected individuals may hear blowing sounds that are synchronized with breathing.
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Tinnitus
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nord_1213_3
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Affects of Tinnitus
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Tinnitus affects males and females in equal numbers. It can affect individuals of any age, even children. Tinnitus, collectively, is a very common condition and estimated to affect approximately 10% of the general population. Rhythmic tinnitus occurs far less frequently than non-rhythmic tinnitus, accounting for approximately 1% of all cases of tinnitus and is considered relatively rare in the general population. The exact prevalence or incidence of rhythmic tinnitus is unknown. Rhythmic tinnitus due to pseudotumor and sinus wall anomalies is found most commonly in overweight women in their 3rd to 6th decade of life. The onset of tinnitus can be abrupt or develop slowly over time.
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Affects of Tinnitus. Tinnitus affects males and females in equal numbers. It can affect individuals of any age, even children. Tinnitus, collectively, is a very common condition and estimated to affect approximately 10% of the general population. Rhythmic tinnitus occurs far less frequently than non-rhythmic tinnitus, accounting for approximately 1% of all cases of tinnitus and is considered relatively rare in the general population. The exact prevalence or incidence of rhythmic tinnitus is unknown. Rhythmic tinnitus due to pseudotumor and sinus wall anomalies is found most commonly in overweight women in their 3rd to 6th decade of life. The onset of tinnitus can be abrupt or develop slowly over time.
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Tinnitus
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nord_1213_4
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Related disorders of Tinnitus
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N/A
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Related disorders of Tinnitus. N/A
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Tinnitus
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nord_1213_5
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Diagnosis of Tinnitus
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A diagnosis of tinnitus is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and complete audiologic testing. These steps will help to differentiate rhythmic tinnitus from non-rhythmic tinnitus. It cannot be overemphasized that tinnitus is a symptom of another underlying condition and not a diagnosis in and of itself. Because of the high number of underlying causes of tinnitus, a variety of specialized tests to detect the specific cause may be necessary. Attempting to identify the underlying cause of tinnitus is the first step in evaluating a person with tinnitus.Clinical Testing and Workup
Affected individuals will first undergo a medical evaluation beginning with a hearing test (audiogram). An individual with tinnitus may also be asked to perform a series of movements including clenching one’s jaw or moving one’s neck or eyes. If these movements cause tinnitus to change, it can help a physician figure out the underlying cause.A diagnosis of rhythmic tinnitus may require a series of diagnostic tests in order to pinpoint the specific cause. The specific tests performed will vary for each individual case, based, in part, on the results of the initial medical evaluation.Generally, following the initial evaluation, individuals suspected of rhythmic tinnitus will undergo some form of specialized medical imaging. Individuals may undergo high resolution computed tomography (HRCT) or magnetic resonance angiography (MRA) to evaluate blood vessel abnormalities such as a vascular malformation that may be the cause of tinnitus. An HRCT scan can also be used to evaluate the temporal bone for sinus wall abnormalities and superior semicircular canal dehiscence. HRCT uses a narrow x-ray beam and advanced computer analysis to create highly detailed images of structures within the body such as blood vessels. An MRA is done with the same equipment use for magnetic resonance imaging (MRI). An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular structures or tissues within the body. An MRA provides detailed information about blood vessels. In some cases, before the scan, an intravenous line is inserted into a vein to release a special dye (contrast). This contrast highlights the blood vessels, thereby enhancing the results of the scan.These tests are usually performed instead of a traditional catheter angiography, which is more invasive and, while generally very safe, carries greater risk of complications. Angiography is an imaging technique that involves injecting dye into a small tube called a catheter that has been inserted into a blood vessel. An x-ray is then performed to assess the health of the vessels as well as the rate of blood flow.An ultrasound is another test that may be used to aid in the diagnosis of tinnitus. An ultrasound uses reflected high-frequency sound waves and their echoes to create images of structures within the body. An ultrasound can reveal how blood flows within vessels, but is only useful for accessible vessels. It is not helpful for blood vessels within the skull.A variety of additional tests may be performed to rule out other potential conditions or underlying causes of tinnitus depending upon the specifics of each individual case.
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Diagnosis of Tinnitus. A diagnosis of tinnitus is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and complete audiologic testing. These steps will help to differentiate rhythmic tinnitus from non-rhythmic tinnitus. It cannot be overemphasized that tinnitus is a symptom of another underlying condition and not a diagnosis in and of itself. Because of the high number of underlying causes of tinnitus, a variety of specialized tests to detect the specific cause may be necessary. Attempting to identify the underlying cause of tinnitus is the first step in evaluating a person with tinnitus.Clinical Testing and Workup
Affected individuals will first undergo a medical evaluation beginning with a hearing test (audiogram). An individual with tinnitus may also be asked to perform a series of movements including clenching one’s jaw or moving one’s neck or eyes. If these movements cause tinnitus to change, it can help a physician figure out the underlying cause.A diagnosis of rhythmic tinnitus may require a series of diagnostic tests in order to pinpoint the specific cause. The specific tests performed will vary for each individual case, based, in part, on the results of the initial medical evaluation.Generally, following the initial evaluation, individuals suspected of rhythmic tinnitus will undergo some form of specialized medical imaging. Individuals may undergo high resolution computed tomography (HRCT) or magnetic resonance angiography (MRA) to evaluate blood vessel abnormalities such as a vascular malformation that may be the cause of tinnitus. An HRCT scan can also be used to evaluate the temporal bone for sinus wall abnormalities and superior semicircular canal dehiscence. HRCT uses a narrow x-ray beam and advanced computer analysis to create highly detailed images of structures within the body such as blood vessels. An MRA is done with the same equipment use for magnetic resonance imaging (MRI). An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular structures or tissues within the body. An MRA provides detailed information about blood vessels. In some cases, before the scan, an intravenous line is inserted into a vein to release a special dye (contrast). This contrast highlights the blood vessels, thereby enhancing the results of the scan.These tests are usually performed instead of a traditional catheter angiography, which is more invasive and, while generally very safe, carries greater risk of complications. Angiography is an imaging technique that involves injecting dye into a small tube called a catheter that has been inserted into a blood vessel. An x-ray is then performed to assess the health of the vessels as well as the rate of blood flow.An ultrasound is another test that may be used to aid in the diagnosis of tinnitus. An ultrasound uses reflected high-frequency sound waves and their echoes to create images of structures within the body. An ultrasound can reveal how blood flows within vessels, but is only useful for accessible vessels. It is not helpful for blood vessels within the skull.A variety of additional tests may be performed to rule out other potential conditions or underlying causes of tinnitus depending upon the specifics of each individual case.
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Tinnitus
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nord_1213_6
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Therapies of Tinnitus
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TreatmentNON-RHYTHMIC TINNITUS
Because the most common cause of non-rhythmic tinnitus is hearing loss, the initial treatment in most cases is hearing rehabilitation with either hearing aids or surgery depending upon the specific cause.In some cases, a special audiologic device, which is worn like a hearing aid, may be prescribed. These devices, called masking agents, emit continuous, low-level white noises that suppress the tinnitus sounds. In some cases, a hearing aid may be recommended to help to suppress or diminish the sounds associated with tinnitus. A combination device (masker plus hearing aid) may also be used. Masking devices provide immediate relief by reducing or completely drowning out the tinnitus sound. However, when the masking device is removed, the tinnitus sound remains.Tinnitus habituation therapies, such as tinnitus retraining therapy (TRT), involve using low level sounds in a graduated fashion to decrease the perception of tinnitus. This differs from use of masking devices such as described earlier. TRT involves a wearable device that an affected individual can adjust so that the level of sound emitting from the device is about equal to or matches the tinnitus sound. This may be called the “mixing point” because the sound from the device and the tinnitus sound begin to mix together. An affected individual must repeatedly adjust the device so that the sound is at or just below the mixing point. TRT is supported by counseling with a trained professional who can teach the individual the proper techniques to maximize the effectiveness of TRT. Eventually, by following this method, affected individuals no longer need the external sound generating device. Affected individuals will become accustomed to the tinnitus sound (habituation), except when they choose to focus on it. Even then the sound will not be bothersome or troubling. The theory is akin to a person’s ability to ignore sounds such as the hum of air conditioner, the refrigerator motor turning on, or raindrops falling on the roof when driving a car in the rain.Some people with tinnitus may obtain relief by listening to background sounds that they find pleasant (e.g. ocean surf).RHYTHMIC TINNITUS
Treatment of the underlying primary disorder may help to improve or cure rhythmic tinnitus. For example, the treatment of blood vessel disorders (e.g. dural arteriovenous shunts) can include certain medications or surgery. A surgical procedure known as sinus wall reconstruction can successfully treat pulsatile tinnitus due to sigmoid sinus diverticulum and dehiscence. In fact, most individuals have experienced complete resolution of their tinnitus following this surgery. Surgery may also be necessary for rare cases of pulsatile tinnitus caused by a tumor.Muscular tinnitus may go away without treatment. If the sound persists, drugs that relax the muscles (muscle relaxants) may be tried. In some cases, surgery may be necessary.Individuals with rhythmic tinnitus without an identified cause may be treated by masking devices or TRT or other habituation techniques as described above.
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Therapies of Tinnitus. TreatmentNON-RHYTHMIC TINNITUS
Because the most common cause of non-rhythmic tinnitus is hearing loss, the initial treatment in most cases is hearing rehabilitation with either hearing aids or surgery depending upon the specific cause.In some cases, a special audiologic device, which is worn like a hearing aid, may be prescribed. These devices, called masking agents, emit continuous, low-level white noises that suppress the tinnitus sounds. In some cases, a hearing aid may be recommended to help to suppress or diminish the sounds associated with tinnitus. A combination device (masker plus hearing aid) may also be used. Masking devices provide immediate relief by reducing or completely drowning out the tinnitus sound. However, when the masking device is removed, the tinnitus sound remains.Tinnitus habituation therapies, such as tinnitus retraining therapy (TRT), involve using low level sounds in a graduated fashion to decrease the perception of tinnitus. This differs from use of masking devices such as described earlier. TRT involves a wearable device that an affected individual can adjust so that the level of sound emitting from the device is about equal to or matches the tinnitus sound. This may be called the “mixing point” because the sound from the device and the tinnitus sound begin to mix together. An affected individual must repeatedly adjust the device so that the sound is at or just below the mixing point. TRT is supported by counseling with a trained professional who can teach the individual the proper techniques to maximize the effectiveness of TRT. Eventually, by following this method, affected individuals no longer need the external sound generating device. Affected individuals will become accustomed to the tinnitus sound (habituation), except when they choose to focus on it. Even then the sound will not be bothersome or troubling. The theory is akin to a person’s ability to ignore sounds such as the hum of air conditioner, the refrigerator motor turning on, or raindrops falling on the roof when driving a car in the rain.Some people with tinnitus may obtain relief by listening to background sounds that they find pleasant (e.g. ocean surf).RHYTHMIC TINNITUS
Treatment of the underlying primary disorder may help to improve or cure rhythmic tinnitus. For example, the treatment of blood vessel disorders (e.g. dural arteriovenous shunts) can include certain medications or surgery. A surgical procedure known as sinus wall reconstruction can successfully treat pulsatile tinnitus due to sigmoid sinus diverticulum and dehiscence. In fact, most individuals have experienced complete resolution of their tinnitus following this surgery. Surgery may also be necessary for rare cases of pulsatile tinnitus caused by a tumor.Muscular tinnitus may go away without treatment. If the sound persists, drugs that relax the muscles (muscle relaxants) may be tried. In some cases, surgery may be necessary.Individuals with rhythmic tinnitus without an identified cause may be treated by masking devices or TRT or other habituation techniques as described above.
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Tinnitus
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nord_1214_0
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Overview of Tolosa Hunt Syndrome
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Tolosa-Hunt syndrome is a rare disorder characterized by severe periorbital headaches, along with decreased and painful eye movements (ophthalmoplegia). Symptoms usually affect only one eye (unilateral). In most cases, affected individuals experience intense sharp pain and decreased eye movements. Symptoms often will subside without intervention (spontaneous remission) and may recur without a distinct pattern (randomly). Affected individuals may exhibit signs of paralysis (palsy) of certain cranial nerves such as drooping of the upper eyelid (ptosis), double vision (diplopia), large pupil, and facial numbness. The affected eye often abnormally protrudes (proptosis). The exact cause of Tolosa-Hunt syndrome is not known, but the disorder is thought to be associated with inflammation of specific areas behind the eye (cavernous sinus and superior orbital fissure).
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Overview of Tolosa Hunt Syndrome. Tolosa-Hunt syndrome is a rare disorder characterized by severe periorbital headaches, along with decreased and painful eye movements (ophthalmoplegia). Symptoms usually affect only one eye (unilateral). In most cases, affected individuals experience intense sharp pain and decreased eye movements. Symptoms often will subside without intervention (spontaneous remission) and may recur without a distinct pattern (randomly). Affected individuals may exhibit signs of paralysis (palsy) of certain cranial nerves such as drooping of the upper eyelid (ptosis), double vision (diplopia), large pupil, and facial numbness. The affected eye often abnormally protrudes (proptosis). The exact cause of Tolosa-Hunt syndrome is not known, but the disorder is thought to be associated with inflammation of specific areas behind the eye (cavernous sinus and superior orbital fissure).
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Tolosa Hunt Syndrome
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nord_1214_1
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Symptoms of Tolosa Hunt Syndrome
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Many individuals with Tolosa-Hunt syndrome experience the sudden onset of severe periorbital headache, followed by painful and decreased eye movements (ophthalmoplegia). In some cases of severe ophthalmoplegia, the eye itself is unable to move or look in various directions (frozen globe).The major symptoms of Tolosa-Hunt syndrome include chronic periorbital headache, double vision, paralysis (palsy) of certain cranial nerves, and chronic fatigue. Affected individuals may also exhibit protrusion of the eye (proptosis), drooping of the upper eyelid (ptosis) and diminished vision. In most cases, symptoms associated with Tolosa-Hunt syndrome affect only one side (unilateral). Symptoms will usually subside without intervention (spontaneous remission) and may recur without a distinct pattern (randomly).
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Symptoms of Tolosa Hunt Syndrome. Many individuals with Tolosa-Hunt syndrome experience the sudden onset of severe periorbital headache, followed by painful and decreased eye movements (ophthalmoplegia). In some cases of severe ophthalmoplegia, the eye itself is unable to move or look in various directions (frozen globe).The major symptoms of Tolosa-Hunt syndrome include chronic periorbital headache, double vision, paralysis (palsy) of certain cranial nerves, and chronic fatigue. Affected individuals may also exhibit protrusion of the eye (proptosis), drooping of the upper eyelid (ptosis) and diminished vision. In most cases, symptoms associated with Tolosa-Hunt syndrome affect only one side (unilateral). Symptoms will usually subside without intervention (spontaneous remission) and may recur without a distinct pattern (randomly).
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Tolosa Hunt Syndrome
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