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nord_1242_6
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Therapies of Tuberous Sclerosis
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TreatmentTreatment may require the coordinated efforts of a team of specialists. Pediatricians and general internists, neurologists, dermatologists, cardiologists, dental specialists, eye specialists, psychiatrists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Genetic counseling will be of benefit for affected individuals and their families. The treatment for tuberous sclerosis is supportive and symptomatic. Early developmental intervention is important to ensure that affected children reach their potential. Most affected children will benefit from occupational, physical and speech therapy. Various methods of rehabilitative and behavioral therapy may be beneficial. It is essential that therapies are continued on a year-round basis to promote development of new skills and to prevent regression. Additional medical, social and/or vocational services including special remedial education may be necessary. Psychosocial support for the entire family is essential as well. Anti-seizure drugs (anticonvulsants) may be prescribed to control seizures. The specific drug that is used will depend on several factors including the specific type of seizure, an affected individual’s age, other organ systems that are affected, and the severity of symptoms. Conventional anticonvulsants drugs that may be administered include phenobarbital, Dilantin (phenytoin), Klonopin (clonazepam), Depakene/Depakote (valproic acid/divalproex sodium), Tegretol (carbamazepine), Trileptal (oxcarbazepine), Topamax (topiramate), Lamictal (lamotrigine), Zonegran (zonisemide), Vimpat (lacosamide), Banzel (rufinamide), Onfi (clobazam), and others. All these anticonvulsants have potential side effects and require careful monitoring by a physician. Two drugs have been approved by the U.S. Food and Drug Administration (FDA) specifically for the treatment of seizures associated with tuberous sclerosis. FDA approved Afinitor (everolimus) for the treatment of seizures in adult and pediatric patients aged 2 years and older with tuberous sclerosis in 2018, and Epidiolex (cannabidiol) for patients one year and older in 2020. Sabril (vigabatrin) was approved in 2009 by the FDA to treat infantile spasms in children ages 1 month to 2 years. Treatment of children with tuberous sclerosis and infantile spasms with vigabatrin has been found to be effective. Visual field loss is an important safety concern with the use of this medication. The FDA has also approved adreno-corticotrophic hormone or ACTH (Acthar gel) for the treatment of infantile spasms. This medication has also been used to treat infants with tuberous sclerosis. These medications are used cautiously because of their side effects. No specific anti-seizure medication works for all affected individuals. Often, a combination of different drugs may be required to treat some individuals. Alternative treatments include the ketogenic diet or the glycemic diet. Sometimes, seizures can be difficult to treat and medications or diets that initially worked will no longer provide benefit (refractory seizures). In some instances, seizure surgery to remove areas of brain dysplasia may be necessary to help to control seizures that don’t respond or stop responding to medications. Less invasive surgical options to control seizures include the implanting of a vagal nerve stimulator (VNS device). This is a small electrical stimulator placed under the skin over the upper chest and connected to one vagal nerve in order to provide intermittent electrical stimulus, like a pacemaker to the brain. Surgery of other organs may be necessary if the ability of a particular organ to function properly is impaired by the presence of a tumor. For example, the obstruction of cerebrospinal fluid (CSF) circulation inside the brain (intracranial hypertension) because of a benign tumor may require a shunting procedure to drain the liquid or the surgical removal of the tumor. In 2012, the FDA approved the use of Afinitor (everolimus) for the treatment of children and adults with tuberous sclerosis who have a subependymal giant cell astrocytoma that cannot be removed or can be only partially removed by surgery. The FDA also approved everolimus for the treatment of adults with tuberous sclerosis who have an angiomyolipoma of the kidney that does not require surgery right away. In some instances, angiomyolipomas will require surgery or embolization therapy. Cutting off the blood supply (arterial embolization) to a kidney tumor may be used to shrink down the size of the tumor. Embolization is usually followed by treatment with corticosteroids and surgical removal (resection) of the tumor that spares the kidney or by destruction (ablation) of the tumor. Large cystic lesions of the kidneys may also require surgical decompression or removal. A benign tumor inside the heart (rhabdomyoma) may not cause symptoms and generally does not require treatment as they often regress on their own within the first several years after birth. If symptomatic, however, surgical removal (resection) may be necessary. Reports in the medical literature have detailed the off-label use of mTOR inhibitors to treat these tumors with positive results. Some affected individuals may be prescribed certain medications to treat irregular heartbeats (arrhythmias). Individuals taking mTOR inhibitors for internal tumors (e.g. SEGAs or angiomyolipomas) may see improvement in skin lesions. The FDA has also approved a topical treatment for facial angiofibroma associated with TSC. Available evidence suggests that topical sirolimus 0.2% as the most effective in terms of clinical improvement. Individuals with no immediate indication for mTOR inhibitor treatment may undergo certain procedures to improve the appearance of skin lesions including dermabrasion, laser therapy, or surgical removal (excision) of a lesion. In 2015, the FDA approved the use of mTOR inhibitors for the treatment of lung complications such as LAM in individuals with tuberous sclerosis. Because LAM occurs most often in young women of childbearing age, researchers have speculated that female hormones such as estrogen play a role in the development of the disorder. A link between LAM and female hormones has not been proven. However, many physicians have explored the use of agents that lower the production or effects of estrogen in the body. The results have varied greatly among individuals. Such agents may include medroxyprogesterone acetate. Estrogen-containing medications and dietary supplements should be discontinued in patients with LAM. Supplemental oxygen therapy may be necessary for some individuals with impaired lung function. In individuals with severe lung disease that is resistant to treatment, a lung transplant may ultimately become necessary.
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Therapies of Tuberous Sclerosis. TreatmentTreatment may require the coordinated efforts of a team of specialists. Pediatricians and general internists, neurologists, dermatologists, cardiologists, dental specialists, eye specialists, psychiatrists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Genetic counseling will be of benefit for affected individuals and their families. The treatment for tuberous sclerosis is supportive and symptomatic. Early developmental intervention is important to ensure that affected children reach their potential. Most affected children will benefit from occupational, physical and speech therapy. Various methods of rehabilitative and behavioral therapy may be beneficial. It is essential that therapies are continued on a year-round basis to promote development of new skills and to prevent regression. Additional medical, social and/or vocational services including special remedial education may be necessary. Psychosocial support for the entire family is essential as well. Anti-seizure drugs (anticonvulsants) may be prescribed to control seizures. The specific drug that is used will depend on several factors including the specific type of seizure, an affected individual’s age, other organ systems that are affected, and the severity of symptoms. Conventional anticonvulsants drugs that may be administered include phenobarbital, Dilantin (phenytoin), Klonopin (clonazepam), Depakene/Depakote (valproic acid/divalproex sodium), Tegretol (carbamazepine), Trileptal (oxcarbazepine), Topamax (topiramate), Lamictal (lamotrigine), Zonegran (zonisemide), Vimpat (lacosamide), Banzel (rufinamide), Onfi (clobazam), and others. All these anticonvulsants have potential side effects and require careful monitoring by a physician. Two drugs have been approved by the U.S. Food and Drug Administration (FDA) specifically for the treatment of seizures associated with tuberous sclerosis. FDA approved Afinitor (everolimus) for the treatment of seizures in adult and pediatric patients aged 2 years and older with tuberous sclerosis in 2018, and Epidiolex (cannabidiol) for patients one year and older in 2020. Sabril (vigabatrin) was approved in 2009 by the FDA to treat infantile spasms in children ages 1 month to 2 years. Treatment of children with tuberous sclerosis and infantile spasms with vigabatrin has been found to be effective. Visual field loss is an important safety concern with the use of this medication. The FDA has also approved adreno-corticotrophic hormone or ACTH (Acthar gel) for the treatment of infantile spasms. This medication has also been used to treat infants with tuberous sclerosis. These medications are used cautiously because of their side effects. No specific anti-seizure medication works for all affected individuals. Often, a combination of different drugs may be required to treat some individuals. Alternative treatments include the ketogenic diet or the glycemic diet. Sometimes, seizures can be difficult to treat and medications or diets that initially worked will no longer provide benefit (refractory seizures). In some instances, seizure surgery to remove areas of brain dysplasia may be necessary to help to control seizures that don’t respond or stop responding to medications. Less invasive surgical options to control seizures include the implanting of a vagal nerve stimulator (VNS device). This is a small electrical stimulator placed under the skin over the upper chest and connected to one vagal nerve in order to provide intermittent electrical stimulus, like a pacemaker to the brain. Surgery of other organs may be necessary if the ability of a particular organ to function properly is impaired by the presence of a tumor. For example, the obstruction of cerebrospinal fluid (CSF) circulation inside the brain (intracranial hypertension) because of a benign tumor may require a shunting procedure to drain the liquid or the surgical removal of the tumor. In 2012, the FDA approved the use of Afinitor (everolimus) for the treatment of children and adults with tuberous sclerosis who have a subependymal giant cell astrocytoma that cannot be removed or can be only partially removed by surgery. The FDA also approved everolimus for the treatment of adults with tuberous sclerosis who have an angiomyolipoma of the kidney that does not require surgery right away. In some instances, angiomyolipomas will require surgery or embolization therapy. Cutting off the blood supply (arterial embolization) to a kidney tumor may be used to shrink down the size of the tumor. Embolization is usually followed by treatment with corticosteroids and surgical removal (resection) of the tumor that spares the kidney or by destruction (ablation) of the tumor. Large cystic lesions of the kidneys may also require surgical decompression or removal. A benign tumor inside the heart (rhabdomyoma) may not cause symptoms and generally does not require treatment as they often regress on their own within the first several years after birth. If symptomatic, however, surgical removal (resection) may be necessary. Reports in the medical literature have detailed the off-label use of mTOR inhibitors to treat these tumors with positive results. Some affected individuals may be prescribed certain medications to treat irregular heartbeats (arrhythmias). Individuals taking mTOR inhibitors for internal tumors (e.g. SEGAs or angiomyolipomas) may see improvement in skin lesions. The FDA has also approved a topical treatment for facial angiofibroma associated with TSC. Available evidence suggests that topical sirolimus 0.2% as the most effective in terms of clinical improvement. Individuals with no immediate indication for mTOR inhibitor treatment may undergo certain procedures to improve the appearance of skin lesions including dermabrasion, laser therapy, or surgical removal (excision) of a lesion. In 2015, the FDA approved the use of mTOR inhibitors for the treatment of lung complications such as LAM in individuals with tuberous sclerosis. Because LAM occurs most often in young women of childbearing age, researchers have speculated that female hormones such as estrogen play a role in the development of the disorder. A link between LAM and female hormones has not been proven. However, many physicians have explored the use of agents that lower the production or effects of estrogen in the body. The results have varied greatly among individuals. Such agents may include medroxyprogesterone acetate. Estrogen-containing medications and dietary supplements should be discontinued in patients with LAM. Supplemental oxygen therapy may be necessary for some individuals with impaired lung function. In individuals with severe lung disease that is resistant to treatment, a lung transplant may ultimately become necessary.
| 1,242 |
Tuberous Sclerosis
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nord_1243_0
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Overview of Tularemia
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Tularemia, is caused by infection with the bacterium Francisella tularensis, which is found in small mammals such as rodents and rabbits, and arthropods, such as ticks. The bacterium that causes tularemia is most often transmitted to humans by tick or biting fly bite, handling of an infected animal, or inhalation or ingestion of the bacterium. People have not been known to transmit the infection to others. The severity of tularemia varies greatly. Some cases are mild and self-limiting, others may have serious complications, and a small percentage (less than 2 percent) of cases in the United States is fatal.
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Overview of Tularemia. Tularemia, is caused by infection with the bacterium Francisella tularensis, which is found in small mammals such as rodents and rabbits, and arthropods, such as ticks. The bacterium that causes tularemia is most often transmitted to humans by tick or biting fly bite, handling of an infected animal, or inhalation or ingestion of the bacterium. People have not been known to transmit the infection to others. The severity of tularemia varies greatly. Some cases are mild and self-limiting, others may have serious complications, and a small percentage (less than 2 percent) of cases in the United States is fatal.
| 1,243 |
Tularemia
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nord_1243_1
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Symptoms of Tularemia
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The symptoms of tularemia vary greatly among affected individuals. Some individuals may have no apparent symptoms (asymptomatic); others can develop serious complications affecting several organ systems with potentially life-threatening complications. After infection, the period of time it takes symptoms to appear (incubation period) is usually three to five days, but may take as long as two weeks.Most cases of tularemia begin with rapid onset of nonspecific, flu-like symptoms including fever, chills, headaches, muscle pain (myalgia), joint pain (arthralgia), loss of appetite, and a general feeling of ill health (malaise).Additional symptoms may occur depending upon how a person is infected. Infection through skin (e.g., tick bite or handling of infectious matter) may result in an ulcer or rash on the skin at the point of infection and swollen, painful lymph nodes (lymphadenopathy). These cases may be referred to as ulceroglandular tularemia. In some cases, individuals will have lymphadenopathy without any skin symptoms. These cases are referred to as glandular tularemia. Ulceroglandular and glandular tularemia account for more than 75 percent of cases.Infection through breathing in (inhalation) the bacterium may result in infection of the lungs (pneumonia), a collection of fluid around the lungs (pleural effusion), and lung abscesses. These cases are referred to as pneumonic tularemia. Eating undercooked, infected animal meat or drinking contaminated water may result in sore throat, nausea, vomiting, diarrhea, and abdominal pain. These cases are referred to as oropharyngeal tularemia. In rare cases, gastrointestinal bleeding may occur. Tularemia can also affect the eyes resulting in inflammation of the delicate membrane that lines the eyes (conjunctiva), a condition called conjunctivitis. Conjunctivitis can cause pain, redness, and itching of the eyes. Nearby lymph nodes may be swollen and painful. These cases are referred to oculoglandular tularemia.Some individuals may develop the typhoidal form of tularemia in which fever, myalgias, and general ill health (malaise) develop without accompanying skin lesions or lymphadenopathy. Because of the lack of obvious symptoms, this form of tularemia is difficult to diagnose.Tularemia has the potential to affect various organ systems of the body including the central nervous system, heart, and liver resulting in inflammation of the membranes surrounding the brain and spinal cord (meningitis), inflammation of the lining of the heart (endocarditis), and inflammation of the liver (hepatitis). Additional serious complications potentially associated with tularemia include infection of the blood (sepsis) and infection of various bones (osteomyelitis).
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Symptoms of Tularemia. The symptoms of tularemia vary greatly among affected individuals. Some individuals may have no apparent symptoms (asymptomatic); others can develop serious complications affecting several organ systems with potentially life-threatening complications. After infection, the period of time it takes symptoms to appear (incubation period) is usually three to five days, but may take as long as two weeks.Most cases of tularemia begin with rapid onset of nonspecific, flu-like symptoms including fever, chills, headaches, muscle pain (myalgia), joint pain (arthralgia), loss of appetite, and a general feeling of ill health (malaise).Additional symptoms may occur depending upon how a person is infected. Infection through skin (e.g., tick bite or handling of infectious matter) may result in an ulcer or rash on the skin at the point of infection and swollen, painful lymph nodes (lymphadenopathy). These cases may be referred to as ulceroglandular tularemia. In some cases, individuals will have lymphadenopathy without any skin symptoms. These cases are referred to as glandular tularemia. Ulceroglandular and glandular tularemia account for more than 75 percent of cases.Infection through breathing in (inhalation) the bacterium may result in infection of the lungs (pneumonia), a collection of fluid around the lungs (pleural effusion), and lung abscesses. These cases are referred to as pneumonic tularemia. Eating undercooked, infected animal meat or drinking contaminated water may result in sore throat, nausea, vomiting, diarrhea, and abdominal pain. These cases are referred to as oropharyngeal tularemia. In rare cases, gastrointestinal bleeding may occur. Tularemia can also affect the eyes resulting in inflammation of the delicate membrane that lines the eyes (conjunctiva), a condition called conjunctivitis. Conjunctivitis can cause pain, redness, and itching of the eyes. Nearby lymph nodes may be swollen and painful. These cases are referred to oculoglandular tularemia.Some individuals may develop the typhoidal form of tularemia in which fever, myalgias, and general ill health (malaise) develop without accompanying skin lesions or lymphadenopathy. Because of the lack of obvious symptoms, this form of tularemia is difficult to diagnose.Tularemia has the potential to affect various organ systems of the body including the central nervous system, heart, and liver resulting in inflammation of the membranes surrounding the brain and spinal cord (meningitis), inflammation of the lining of the heart (endocarditis), and inflammation of the liver (hepatitis). Additional serious complications potentially associated with tularemia include infection of the blood (sepsis) and infection of various bones (osteomyelitis).
| 1,243 |
Tularemia
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nord_1243_2
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Causes of Tularemia
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Tularemia is caused by the bacterium Francisella tularensis. Most cases occur from being bitten by flies or ticks carrying the bacterium or from exposure to tissue from an animal infected with the bacteria.Tularemia has been found in >100 animal species including rabbits, muskrats, squirrels and beavers. Handling infected animal tissue (e.g., skinning or dressing animal carcasses) or eating insufficiently cooked meat from an infected animal may result in tularemia. Domestic pets such as dogs and cats can be responsible for transmitting tularemia to humans as well. Dogs and cats may come in contact with infected animals or ticks and may spread the disease to humans through their saliva or claws.Tularemia may be also transmitted through the air by breathing in (inhalation) of aerosolized bacteria. Common activities including cutting brush or mowing lawns can aerosolize the bacteria from the environment and cause infection in humans.Francisella tularensis is an extremely resilient bacterium and able to survive in the environment (e.g., mud, water, or decaying animal carcasses) for weeks and, rarely, direct contact or ingestion of contaminated materials including water or soil may cause tularemia.No human-to-human transmission has been documented in the medical literature.Tularemia has gained more attention in recent years because of its potential for use in biological warfare.
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Causes of Tularemia. Tularemia is caused by the bacterium Francisella tularensis. Most cases occur from being bitten by flies or ticks carrying the bacterium or from exposure to tissue from an animal infected with the bacteria.Tularemia has been found in >100 animal species including rabbits, muskrats, squirrels and beavers. Handling infected animal tissue (e.g., skinning or dressing animal carcasses) or eating insufficiently cooked meat from an infected animal may result in tularemia. Domestic pets such as dogs and cats can be responsible for transmitting tularemia to humans as well. Dogs and cats may come in contact with infected animals or ticks and may spread the disease to humans through their saliva or claws.Tularemia may be also transmitted through the air by breathing in (inhalation) of aerosolized bacteria. Common activities including cutting brush or mowing lawns can aerosolize the bacteria from the environment and cause infection in humans.Francisella tularensis is an extremely resilient bacterium and able to survive in the environment (e.g., mud, water, or decaying animal carcasses) for weeks and, rarely, direct contact or ingestion of contaminated materials including water or soil may cause tularemia.No human-to-human transmission has been documented in the medical literature.Tularemia has gained more attention in recent years because of its potential for use in biological warfare.
| 1,243 |
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nord_1243_3
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Affects of Tularemia
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Tularemia affects males and females, although the majority of cases are males, probably because of greater outdoor exposure opportunities. The disease is rare in the United States with approximately 100-200 new cases reported each year. Some researchers believe that many cases of tularemia often go unreported or misdiagnosed, making it difficult to determine the true frequency of this disease in the general population.Although tularemia can occur anywhere in the United States, more than half of the cases reported each year occur in rural areas of Arkansas, Missouri, Oklahoma, and Kansas. Tularemia may be found in all parts of Europe and Asia with greater frequency in Siberia and Scandinavian countries.In Japan, tularemia may be known as yato-byo or Ohara’s disease, after Dr. Ohara who first described a rabbit-associated febrile disease.
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Affects of Tularemia. Tularemia affects males and females, although the majority of cases are males, probably because of greater outdoor exposure opportunities. The disease is rare in the United States with approximately 100-200 new cases reported each year. Some researchers believe that many cases of tularemia often go unreported or misdiagnosed, making it difficult to determine the true frequency of this disease in the general population.Although tularemia can occur anywhere in the United States, more than half of the cases reported each year occur in rural areas of Arkansas, Missouri, Oklahoma, and Kansas. Tularemia may be found in all parts of Europe and Asia with greater frequency in Siberia and Scandinavian countries.In Japan, tularemia may be known as yato-byo or Ohara’s disease, after Dr. Ohara who first described a rabbit-associated febrile disease.
| 1,243 |
Tularemia
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nord_1243_4
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Related disorders of Tularemia
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Symptoms of the following disorders can be similar to those of tularemia. Comparisons may be useful for a differential diagnosis:Tularemia must be differentiated from other, more common causes of fever, chronic fatigue, weakness, and other nonspecific flu-like symptoms, and should be highly suspected in individuals in endemic regions who may have been exposed to infected animals or recently received a tick or biting fly bite.Ulceroglandular or glandular tularemia can be hard to differentiate from cat-scratch disease. Severe tularemia infection can also present like plague.
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Related disorders of Tularemia. Symptoms of the following disorders can be similar to those of tularemia. Comparisons may be useful for a differential diagnosis:Tularemia must be differentiated from other, more common causes of fever, chronic fatigue, weakness, and other nonspecific flu-like symptoms, and should be highly suspected in individuals in endemic regions who may have been exposed to infected animals or recently received a tick or biting fly bite.Ulceroglandular or glandular tularemia can be hard to differentiate from cat-scratch disease. Severe tularemia infection can also present like plague.
| 1,243 |
Tularemia
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nord_1243_5
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Diagnosis of Tularemia
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A diagnosis of tularemia is made by a thorough clinical evaluation, a detailed patient history, and a variety of tests that may include an attempt to isolate the bacteria from blood or body tissue or through specialized blood tests (serologic tests) that measure the body’s immune system response against the bacterium.
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Diagnosis of Tularemia. A diagnosis of tularemia is made by a thorough clinical evaluation, a detailed patient history, and a variety of tests that may include an attempt to isolate the bacteria from blood or body tissue or through specialized blood tests (serologic tests) that measure the body’s immune system response against the bacterium.
| 1,243 |
Tularemia
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nord_1243_6
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Therapies of Tularemia
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Treatment
Tularemia is treated with antibiotics. Streptomycin is the drug of choice, but gentamicin is an acceptable alternative. Other antibiotics such as doxycycline and ciprofloxacin may also be used and can be taken by mouth (orally).Other treatment is symptomatic and supportive.
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Therapies of Tularemia. Treatment
Tularemia is treated with antibiotics. Streptomycin is the drug of choice, but gentamicin is an acceptable alternative. Other antibiotics such as doxycycline and ciprofloxacin may also be used and can be taken by mouth (orally).Other treatment is symptomatic and supportive.
| 1,243 |
Tularemia
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nord_1244_0
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Overview of Tumor Necrosis Factor Receptor-Associated Periodic Syndrome
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Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is a rare multisystem genetic disorder characterized by unexplained periodic episodes of fever associated with additional symptoms including muscle pain (myalgia), abdominal pain, headaches and skin rashes. The specific symptoms can vary greatly from one person to another. The duration of the characteristic episodes can also vary, lasting anywhere from a couple days to one week to more than one month. Onset is usually during infancy or childhood. TRAPS is caused by changes (variants or mutations) of the tumor necrosis factor receptor-1 (TNFRSF1A) gene that encodes the 55-kDa receptor for tumor necrosis factor (TNF) cytokine. Since its description in 1999, about 200 cases have been reported in the literature.
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Overview of Tumor Necrosis Factor Receptor-Associated Periodic Syndrome. Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is a rare multisystem genetic disorder characterized by unexplained periodic episodes of fever associated with additional symptoms including muscle pain (myalgia), abdominal pain, headaches and skin rashes. The specific symptoms can vary greatly from one person to another. The duration of the characteristic episodes can also vary, lasting anywhere from a couple days to one week to more than one month. Onset is usually during infancy or childhood. TRAPS is caused by changes (variants or mutations) of the tumor necrosis factor receptor-1 (TNFRSF1A) gene that encodes the 55-kDa receptor for tumor necrosis factor (TNF) cytokine. Since its description in 1999, about 200 cases have been reported in the literature.
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Tumor Necrosis Factor Receptor-Associated Periodic Syndrome
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nord_1244_1
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Symptoms of Tumor Necrosis Factor Receptor-Associated Periodic Syndrome
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The specific symptoms associated with TRAPS vary from one person to another. Nearly all affected individuals will develop recurrent episodes of high-grade fever, pain and inflammation. However, some individuals may only develop fever or only fever and abdominal pain. The duration of the episodes varies, but they usually last more than one week. Some individuals may experience constant inflammation.Characteristic febrile episodes may also be accompanied by chills, abdominal pain, headaches, joint pain (arthralgia), chest pain, and muscle pain (myalgia), stiffness and tightness. Abdominal pain may be associated with nausea, vomiting, diarrhea or constipation. Chest pain is caused by inflammation of the thin covering (pleura) that lines the lungs (pleuritis). In some people, muscle pain is severe.Muscle pain may be associated with skin lesions, specifically tender, warm, reddish (erythematous), raised plaques. Skin lesions develop during a febrile episode, and they move from the proximal toward distal sites of the body. Skin lesions may last anywhere from a few days to three weeks. Skin lesions associated with TRAPS usually begin as tiny bumps (macules or papules) that spread and come together to form larger lesions (plaques).When muscle pain (myalgia) underlies skin lesions, it also moves (migrates) following skin lesions. As muscle pain progresses, different joints and muscle groups become involved. Although joint pain occurs, arthritis rarely develops.Individuals with TRAPS may also develop painful inflammation of the delicate membranes that line the inside of the eyelids (conjunctivitis). This may occur with or without swelling of the eyelids (periorbital edema). Additional symptoms that have been reported in males with TRAPS include testicular pain and a higher rate of inguinal hernia than is found in the general population. Inguinal hernia is a condition in which a portion of the intestines protrudes through a tear in the lower abdominal wall.A serious complication that occurs in approximately 10-15 percent of TRAPS cases is amyloidosis, a condition in which specialized proteins called amyloids abnormally accumulate in various tissues and organs of the body. For example, amyloid may accumulate in the kidneys, impairing kidney function and potentially causing life-threatening complications such as kidney failure. Although the kidneys are most often affected, numerous other organs can potentially become involved. Nowadays, the incidence of amyloidosis in TRAPS is much lower due to earlier diagnosis and use of targeted therapies.
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Symptoms of Tumor Necrosis Factor Receptor-Associated Periodic Syndrome. The specific symptoms associated with TRAPS vary from one person to another. Nearly all affected individuals will develop recurrent episodes of high-grade fever, pain and inflammation. However, some individuals may only develop fever or only fever and abdominal pain. The duration of the episodes varies, but they usually last more than one week. Some individuals may experience constant inflammation.Characteristic febrile episodes may also be accompanied by chills, abdominal pain, headaches, joint pain (arthralgia), chest pain, and muscle pain (myalgia), stiffness and tightness. Abdominal pain may be associated with nausea, vomiting, diarrhea or constipation. Chest pain is caused by inflammation of the thin covering (pleura) that lines the lungs (pleuritis). In some people, muscle pain is severe.Muscle pain may be associated with skin lesions, specifically tender, warm, reddish (erythematous), raised plaques. Skin lesions develop during a febrile episode, and they move from the proximal toward distal sites of the body. Skin lesions may last anywhere from a few days to three weeks. Skin lesions associated with TRAPS usually begin as tiny bumps (macules or papules) that spread and come together to form larger lesions (plaques).When muscle pain (myalgia) underlies skin lesions, it also moves (migrates) following skin lesions. As muscle pain progresses, different joints and muscle groups become involved. Although joint pain occurs, arthritis rarely develops.Individuals with TRAPS may also develop painful inflammation of the delicate membranes that line the inside of the eyelids (conjunctivitis). This may occur with or without swelling of the eyelids (periorbital edema). Additional symptoms that have been reported in males with TRAPS include testicular pain and a higher rate of inguinal hernia than is found in the general population. Inguinal hernia is a condition in which a portion of the intestines protrudes through a tear in the lower abdominal wall.A serious complication that occurs in approximately 10-15 percent of TRAPS cases is amyloidosis, a condition in which specialized proteins called amyloids abnormally accumulate in various tissues and organs of the body. For example, amyloid may accumulate in the kidneys, impairing kidney function and potentially causing life-threatening complications such as kidney failure. Although the kidneys are most often affected, numerous other organs can potentially become involved. Nowadays, the incidence of amyloidosis in TRAPS is much lower due to earlier diagnosis and use of targeted therapies.
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Tumor Necrosis Factor Receptor-Associated Periodic Syndrome
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nord_1244_2
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Causes of Tumor Necrosis Factor Receptor-Associated Periodic Syndrome
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TRAPS can occur randomly due to a spontaneous genetic change (i.e., new variant) or it may be inherited in an autosomal dominant pattern (a variant that is received either from the father or the mother).Dominant genetic disorders occur when only a single copy of a gene variant is necessary for the appearance of the disease. The risk of passing the gene variant from affected parent to offspring is 50 percent for each pregnancy. The risk is the same for males and females.The TNFRSF1A gene contains instructions for creating (encoding) a specialized protein known as tumor necrosis factor receptor-1 (TNFR1, p55, CD120a). TNFR1 is found on the surface of most cells of the body and serves as a receptor for tumor necrosis factor (TNF). TNF is a protein that helps defend the body against infection and foreign substances. Specifically, TNF stimulates the body’s inflammatory response to infection. TNFR1 can receive and send signals that set off an inflammatory response within the body. Variants of the TNFRSF1A gene result in defective TNFR1 that cannot properly perform its normal functions, which causes an excessive inflammatory response by mutated blood cells. The exact process by which defective TNFR1 results in TRAPS is unclear.The characteristic episodes of TRAPS may be triggered or worsened due to stress, minor trauma and exercise. However, no specific trigger is necessary for the development of episodes.
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Causes of Tumor Necrosis Factor Receptor-Associated Periodic Syndrome. TRAPS can occur randomly due to a spontaneous genetic change (i.e., new variant) or it may be inherited in an autosomal dominant pattern (a variant that is received either from the father or the mother).Dominant genetic disorders occur when only a single copy of a gene variant is necessary for the appearance of the disease. The risk of passing the gene variant from affected parent to offspring is 50 percent for each pregnancy. The risk is the same for males and females.The TNFRSF1A gene contains instructions for creating (encoding) a specialized protein known as tumor necrosis factor receptor-1 (TNFR1, p55, CD120a). TNFR1 is found on the surface of most cells of the body and serves as a receptor for tumor necrosis factor (TNF). TNF is a protein that helps defend the body against infection and foreign substances. Specifically, TNF stimulates the body’s inflammatory response to infection. TNFR1 can receive and send signals that set off an inflammatory response within the body. Variants of the TNFRSF1A gene result in defective TNFR1 that cannot properly perform its normal functions, which causes an excessive inflammatory response by mutated blood cells. The exact process by which defective TNFR1 results in TRAPS is unclear.The characteristic episodes of TRAPS may be triggered or worsened due to stress, minor trauma and exercise. However, no specific trigger is necessary for the development of episodes.
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Affects of Tumor Necrosis Factor Receptor-Associated Periodic Syndrome
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TRAPS was first described in the medical literature in 1982 in a large Irish family and initially termed familial Hibernian fever. The name was later changed when numerous individuals from other ethnic groups were identified to have variants in the same gene, namely TNFRSF1A. TRAPS has been reported in individuals of many different ethnic groups. TRAPS is a rare disease that often goes undiagnosed or misdiagnosed making it difficult to determine the disorder’s true frequency in the general population.
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Affects of Tumor Necrosis Factor Receptor-Associated Periodic Syndrome. TRAPS was first described in the medical literature in 1982 in a large Irish family and initially termed familial Hibernian fever. The name was later changed when numerous individuals from other ethnic groups were identified to have variants in the same gene, namely TNFRSF1A. TRAPS has been reported in individuals of many different ethnic groups. TRAPS is a rare disease that often goes undiagnosed or misdiagnosed making it difficult to determine the disorder’s true frequency in the general population.
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Related disorders of Tumor Necrosis Factor Receptor-Associated Periodic Syndrome
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Symptoms of the following disorders can be similar to those of TRAPS. Comparisons may be useful for a differential diagnosis.Autoinflammatory syndromes are a group of disorders characterized by recurrent episodes of inflammation due to an abnormality of the innate immune system. Patients with autoinflammatory disorders present with chronic and recurrent bouts of systemic inflammation that are mediated by the cells of innate immunity. The onset of inflammation is often in childhood, sometimes as early as the neonatal period. Symptoms often include recurrent fevers, various types of skin rash, abdominal pain, joint pain, bone pain, central nervous system (CNS) inflammation and other characteristic findings associated with systemic chronic inflammation.The autoinflammatory diseases are inherited in an autosomal recessive pattern (two gene variants are inherited, one from the father and one from the mother) or in an autosomal dominant pattern but there are a considerable number of sporadic cases. These diseases have been associated with pathogenic variants in over 50 genes, and the number of disease-causing genes increases yearly due to the use of new sequencing technologies. Best known recessively inherited diseases include hyperimmunoglobulin D syndrome (HIDS), familial Mediterranean fever (FMF), deficiency of IL-1-receptor antagonist (DIRA), early-onset enterocolitis (IBD), deficiency of interleukin-36 receptor antagonist (DITRA), and immunoproteasome related diseases (CANDLE, JMP, Japanese autoinflammatory syndrome, PRAAS), sideroblastic anemia with immunodeficiency, fevers, and developmental delay (SIFD), periodic fever, immunodeficiency, and thrombocytopenia (PFIT), deficiency of ADA2 (DADA2) and otulin-deficiency (otulipenia). Of these diseases, FMF and DADA2 are the most prevalent. Dominantly inherited autoinflammatory diseases include the cryopyrin-associated periodic syndromes (familial cold autoinflammatory syndrome/FCAS1, NOMID/CINCA, and Muckle-Wells syndrome), the pyogenic arthritis, pyoderma gangrenosum, and acne syndrome (PAPA), familial cold autoinflammatory syndrome 2 (Guadeloupe fever), PLC2 associated diseases (PLAID/APLIAD), Blau’s syndrome, STING-associated diseases (SAVI), NLRC4-associated diseases and haploinsufficiency of A20 (HA20) (The Rare Disease Database currently has additional information available for some of the above mentioned conditions.)Hyper IgD syndrome (HIDS) is a rare inflammatory genetic disorder characterized by periodic episodes of fever associated with additional symptoms including joint pain (arthralgia), skin rash and abdominal pain. Most episodes last several days, and the disease onset is during infancy, often following vaccinations. The frequency of episodes and their severity vary greatly from person to person. HIDS is associated with decreased activity of the enzyme mevalonate kinase (MVK). Although many factors can set off a characteristic HIDS episode (e.g., minor infections), most episodes occur without a distinct precipitating event. HIDS is inherited in an autosomal recessive pattern and is usually found in patients of North European descent. Familial Mediterranean fever (FMF) is an inherited autoinflammatory disease characterized by recurrent episodes (attacks) of fever and acute inflammation of the membranes lining the abdomen, joints and lungs. Some affected individuals may develop skin rashes (erysipelas like erythema) affecting the lower legs. Less often, inflammation of the membrane lining the heart or covering the brain and spinal cord may occur. Some individuals may develop a serious condition known as amyloidosis, in which certain proteins called amyloid accumulate in various tissues of the body. In FMF, amyloid accumulates in the kidneys (renal amyloidosis) where it can impair kidney function potentially result in life-threatening complications such as kidney failure. The specific symptoms and severity of FMF are highly variable. Some individuals develop amyloidosis but none of the other symptoms associated with FMF. These cases are sometimes referred to as FMF type 2. FMF is caused by changes (mutations or pathogenic variants) of the MEFV gene and is usually inherited in an autosomal recessive pattern. Some cases of dominant inheritance have been described. (For more information on this disorder, choose “familial Mediterranean fever” as your search term in the Rare Disease Database.)Muckle-Wells syndrome (MWS) is one of the cryopyrin associated periodic syndromes (CAPS) caused by heterozygous de novo or dominantly inherited pathogenic variants in the NLRP3/CIAS1 gene. These syndromes are characterized by fever, rash and joint pain. Individuals with MWS often have episodic fever, chills and painful joints. Sometimes these symptoms are exacerbated by cold like the related condition familial cold autoinflammatory syndrome, however it can also be triggered by other stimuli. Most Muckle-Wells syndrome patients develop progressive hearing loss. In some people with MWS, amyloidosis develops later in life, a disease in which an abnormal accumulation of the protein amyloid occurs in a patient’s tissues and organs. Accumulation of amyloid in the kidneys results in damage and often kidney failure if untreated. (For more information on this disorder, choose “Muckle-Wells syndrome” as your search term in the Rare Disease Database.)Familial cold autoinflammatory syndrome (FCAS 1) is a milder form of CAPS and is characterized by intermittent episodes of rash, fever, joint pain and other signs/symptoms of systemic inflammation triggered by exposure to cold. The onset of FCAS occurs during infancy and early childhood and persists throughout the patient’s life. As in other CAPS, amyloidosis can rarely develop later in life in FCAS patients. (For more information on this disorder, choose “familial cold autoinflammatory syndrome” as your search term in the Rare Disease Database.)Neonatal-onset multisystem inflammatory disease (NOMID), the most severe form of CAPS, is also known as chronic infantile neurologic cutaneous articular (CINCA) syndrome. It is a rare, congenital, systemic, inflammatory condition distinguished by fever, rash, joint disease and central nervous (CNS) inflammation. The hallmark of NOMID is onset during early infancy. (For more information on this disorder, choose “neonatal-onset multisystem inflammatory disease” as your search term in the Rare Disease Database.)Familial cold autoinflammatory syndrome 2 (Guadeloupe fever), is a rare disease similar to FCAS1. It is caused by dominantly inherited variants in the NLRP12 gene. Patients present with weeklong episodic fevers triggered by cold exposure and associated with arthralgia, myalgia and other constitutional symptoms. Two affected members of one family had sensorineural hearing loss. Clinical manifestations are generally prevented by avoiding exposure to the cold.PAPA (pyogenic arthritis, pyoderma gangrenosum and acne) syndrome is a rare autosomal dominant auto-inflammatory disease arising from variants in the PSTPIP1/CD2BP1 gene. Symptoms typically start in early puberty and include painful flares of recurrent sterile arthritis with variable skin involvement that may present as ulcerations, pyoderma gangrenosum or severe cystic acne.DIRA and DITRA are recently described recessively inherited autoinflammatory diseases linked to activation of the IL-1 pathway. DIRA, an acronym for deficiency of the interleukin 1 (IL-1) receptor antagonist, patients present in the neonatal period with a severe “pustular” skin eruption, skin pathergy and osteolytic bone lesions. DITRA, an acronym for deficiency of the IL-36R antagonist (IL-36Ra), patients present with generalized pustular psoriasis.Variants in PSMB8, encoding the ß5i subunit of the immunoproteasome (a complex that degrades proteins in immune cells), have been shown to cause recessively inherited syndromes variously presenting with fever, panniculitis, lipodystrophy and early death. One such disorder has been denoted chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE). Subsequently, variants in three other genes, PSMA3, PSMB4, PSMB9, encoding proteasome subunits have been described including patients with a digenic inheritance (patient carries one variant in one gene and the second variant in another gene; both subunits need to be functional for the assembly of the proteasome complex). Recently, variants in regulatory proteins, POMP and PSMG2 have been linked to PRAAS.The treatment options for CANDLE patients are very limited. Therapies with new drugs JAK/STAT inhibitors have been promising in reducing inflammation in patients with CANDLE.
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Related disorders of Tumor Necrosis Factor Receptor-Associated Periodic Syndrome. Symptoms of the following disorders can be similar to those of TRAPS. Comparisons may be useful for a differential diagnosis.Autoinflammatory syndromes are a group of disorders characterized by recurrent episodes of inflammation due to an abnormality of the innate immune system. Patients with autoinflammatory disorders present with chronic and recurrent bouts of systemic inflammation that are mediated by the cells of innate immunity. The onset of inflammation is often in childhood, sometimes as early as the neonatal period. Symptoms often include recurrent fevers, various types of skin rash, abdominal pain, joint pain, bone pain, central nervous system (CNS) inflammation and other characteristic findings associated with systemic chronic inflammation.The autoinflammatory diseases are inherited in an autosomal recessive pattern (two gene variants are inherited, one from the father and one from the mother) or in an autosomal dominant pattern but there are a considerable number of sporadic cases. These diseases have been associated with pathogenic variants in over 50 genes, and the number of disease-causing genes increases yearly due to the use of new sequencing technologies. Best known recessively inherited diseases include hyperimmunoglobulin D syndrome (HIDS), familial Mediterranean fever (FMF), deficiency of IL-1-receptor antagonist (DIRA), early-onset enterocolitis (IBD), deficiency of interleukin-36 receptor antagonist (DITRA), and immunoproteasome related diseases (CANDLE, JMP, Japanese autoinflammatory syndrome, PRAAS), sideroblastic anemia with immunodeficiency, fevers, and developmental delay (SIFD), periodic fever, immunodeficiency, and thrombocytopenia (PFIT), deficiency of ADA2 (DADA2) and otulin-deficiency (otulipenia). Of these diseases, FMF and DADA2 are the most prevalent. Dominantly inherited autoinflammatory diseases include the cryopyrin-associated periodic syndromes (familial cold autoinflammatory syndrome/FCAS1, NOMID/CINCA, and Muckle-Wells syndrome), the pyogenic arthritis, pyoderma gangrenosum, and acne syndrome (PAPA), familial cold autoinflammatory syndrome 2 (Guadeloupe fever), PLC2 associated diseases (PLAID/APLIAD), Blau’s syndrome, STING-associated diseases (SAVI), NLRC4-associated diseases and haploinsufficiency of A20 (HA20) (The Rare Disease Database currently has additional information available for some of the above mentioned conditions.)Hyper IgD syndrome (HIDS) is a rare inflammatory genetic disorder characterized by periodic episodes of fever associated with additional symptoms including joint pain (arthralgia), skin rash and abdominal pain. Most episodes last several days, and the disease onset is during infancy, often following vaccinations. The frequency of episodes and their severity vary greatly from person to person. HIDS is associated with decreased activity of the enzyme mevalonate kinase (MVK). Although many factors can set off a characteristic HIDS episode (e.g., minor infections), most episodes occur without a distinct precipitating event. HIDS is inherited in an autosomal recessive pattern and is usually found in patients of North European descent. Familial Mediterranean fever (FMF) is an inherited autoinflammatory disease characterized by recurrent episodes (attacks) of fever and acute inflammation of the membranes lining the abdomen, joints and lungs. Some affected individuals may develop skin rashes (erysipelas like erythema) affecting the lower legs. Less often, inflammation of the membrane lining the heart or covering the brain and spinal cord may occur. Some individuals may develop a serious condition known as amyloidosis, in which certain proteins called amyloid accumulate in various tissues of the body. In FMF, amyloid accumulates in the kidneys (renal amyloidosis) where it can impair kidney function potentially result in life-threatening complications such as kidney failure. The specific symptoms and severity of FMF are highly variable. Some individuals develop amyloidosis but none of the other symptoms associated with FMF. These cases are sometimes referred to as FMF type 2. FMF is caused by changes (mutations or pathogenic variants) of the MEFV gene and is usually inherited in an autosomal recessive pattern. Some cases of dominant inheritance have been described. (For more information on this disorder, choose “familial Mediterranean fever” as your search term in the Rare Disease Database.)Muckle-Wells syndrome (MWS) is one of the cryopyrin associated periodic syndromes (CAPS) caused by heterozygous de novo or dominantly inherited pathogenic variants in the NLRP3/CIAS1 gene. These syndromes are characterized by fever, rash and joint pain. Individuals with MWS often have episodic fever, chills and painful joints. Sometimes these symptoms are exacerbated by cold like the related condition familial cold autoinflammatory syndrome, however it can also be triggered by other stimuli. Most Muckle-Wells syndrome patients develop progressive hearing loss. In some people with MWS, amyloidosis develops later in life, a disease in which an abnormal accumulation of the protein amyloid occurs in a patient’s tissues and organs. Accumulation of amyloid in the kidneys results in damage and often kidney failure if untreated. (For more information on this disorder, choose “Muckle-Wells syndrome” as your search term in the Rare Disease Database.)Familial cold autoinflammatory syndrome (FCAS 1) is a milder form of CAPS and is characterized by intermittent episodes of rash, fever, joint pain and other signs/symptoms of systemic inflammation triggered by exposure to cold. The onset of FCAS occurs during infancy and early childhood and persists throughout the patient’s life. As in other CAPS, amyloidosis can rarely develop later in life in FCAS patients. (For more information on this disorder, choose “familial cold autoinflammatory syndrome” as your search term in the Rare Disease Database.)Neonatal-onset multisystem inflammatory disease (NOMID), the most severe form of CAPS, is also known as chronic infantile neurologic cutaneous articular (CINCA) syndrome. It is a rare, congenital, systemic, inflammatory condition distinguished by fever, rash, joint disease and central nervous (CNS) inflammation. The hallmark of NOMID is onset during early infancy. (For more information on this disorder, choose “neonatal-onset multisystem inflammatory disease” as your search term in the Rare Disease Database.)Familial cold autoinflammatory syndrome 2 (Guadeloupe fever), is a rare disease similar to FCAS1. It is caused by dominantly inherited variants in the NLRP12 gene. Patients present with weeklong episodic fevers triggered by cold exposure and associated with arthralgia, myalgia and other constitutional symptoms. Two affected members of one family had sensorineural hearing loss. Clinical manifestations are generally prevented by avoiding exposure to the cold.PAPA (pyogenic arthritis, pyoderma gangrenosum and acne) syndrome is a rare autosomal dominant auto-inflammatory disease arising from variants in the PSTPIP1/CD2BP1 gene. Symptoms typically start in early puberty and include painful flares of recurrent sterile arthritis with variable skin involvement that may present as ulcerations, pyoderma gangrenosum or severe cystic acne.DIRA and DITRA are recently described recessively inherited autoinflammatory diseases linked to activation of the IL-1 pathway. DIRA, an acronym for deficiency of the interleukin 1 (IL-1) receptor antagonist, patients present in the neonatal period with a severe “pustular” skin eruption, skin pathergy and osteolytic bone lesions. DITRA, an acronym for deficiency of the IL-36R antagonist (IL-36Ra), patients present with generalized pustular psoriasis.Variants in PSMB8, encoding the ß5i subunit of the immunoproteasome (a complex that degrades proteins in immune cells), have been shown to cause recessively inherited syndromes variously presenting with fever, panniculitis, lipodystrophy and early death. One such disorder has been denoted chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE). Subsequently, variants in three other genes, PSMA3, PSMB4, PSMB9, encoding proteasome subunits have been described including patients with a digenic inheritance (patient carries one variant in one gene and the second variant in another gene; both subunits need to be functional for the assembly of the proteasome complex). Recently, variants in regulatory proteins, POMP and PSMG2 have been linked to PRAAS.The treatment options for CANDLE patients are very limited. Therapies with new drugs JAK/STAT inhibitors have been promising in reducing inflammation in patients with CANDLE.
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Diagnosis of Tumor Necrosis Factor Receptor-Associated Periodic Syndrome
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A diagnosis of TRAPS is made based upon a thorough clinical evaluation, identification of characteristic symptoms (e.g., long lasting fever episodes) and blood tests for inflammatory markers. A diagnosis of TRAPS is usually confirmed by molecular genetic testing, which can identify either de novo or dominantly inherited variants in the TNFRSF1A gene. All TRAPS pathogenic variants are clustered in exons 2-4, which encodes the extracellular domain of the protein. Most are missense nucleotide changes that affect the folding of the extracellular domain. Pathogenic variants in other protein domains may be associated with different symptoms. There is also evidence for gonadal mosaicism (gene variants occur after conception) in TRAPS, which can be found in patients with late- onset symptoms.
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Diagnosis of Tumor Necrosis Factor Receptor-Associated Periodic Syndrome. A diagnosis of TRAPS is made based upon a thorough clinical evaluation, identification of characteristic symptoms (e.g., long lasting fever episodes) and blood tests for inflammatory markers. A diagnosis of TRAPS is usually confirmed by molecular genetic testing, which can identify either de novo or dominantly inherited variants in the TNFRSF1A gene. All TRAPS pathogenic variants are clustered in exons 2-4, which encodes the extracellular domain of the protein. Most are missense nucleotide changes that affect the folding of the extracellular domain. Pathogenic variants in other protein domains may be associated with different symptoms. There is also evidence for gonadal mosaicism (gene variants occur after conception) in TRAPS, which can be found in patients with late- onset symptoms.
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Therapies of Tumor Necrosis Factor Receptor-Associated Periodic Syndrome
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Treatment
Therapy with high doses of corticosteroids (e.g., prednisone) is often successful at treating the characteristic episodes of TRAPS. However, the effectiveness of this drug often decreases over time and prolonged therapy with high doses of prednisone can cause serious side effects. Nonsteroidal anti-inflammatory drugs (NSAIDs) can be beneficial in treating fever but are not effective against other symptoms of TRAPS. Neither corticosteroids nor NSAIDs reduces the frequency of attacks. Genetic counseling is strongly recommended in families with TRAPS. Other treatment is symptomatic and supportive.
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Therapies of Tumor Necrosis Factor Receptor-Associated Periodic Syndrome. Treatment
Therapy with high doses of corticosteroids (e.g., prednisone) is often successful at treating the characteristic episodes of TRAPS. However, the effectiveness of this drug often decreases over time and prolonged therapy with high doses of prednisone can cause serious side effects. Nonsteroidal anti-inflammatory drugs (NSAIDs) can be beneficial in treating fever but are not effective against other symptoms of TRAPS. Neither corticosteroids nor NSAIDs reduces the frequency of attacks. Genetic counseling is strongly recommended in families with TRAPS. Other treatment is symptomatic and supportive.
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Overview of Turcot Syndrome
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Turcot syndrome is a rare inherited disorder characterized by the association of benign growths (adenomatous polyps) in the mucous lining of the gastrointestinal tract with tumors of the central nervous system. Symptoms associated with polyp formation may include diarrhea, bleeding from the end portion of the large intestine (rectum), fatigue, abdominal pain, and weight loss. Affected individuals may also experience neurological symptoms, depending upon the type, size and location of the associated brain tumor. Some researchers believe that Turcot syndrome is a variant of familial adenomatous polyposis. Others believe that it is a separate disorder. The exact cause of Turcot syndrome is not known.
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Overview of Turcot Syndrome. Turcot syndrome is a rare inherited disorder characterized by the association of benign growths (adenomatous polyps) in the mucous lining of the gastrointestinal tract with tumors of the central nervous system. Symptoms associated with polyp formation may include diarrhea, bleeding from the end portion of the large intestine (rectum), fatigue, abdominal pain, and weight loss. Affected individuals may also experience neurological symptoms, depending upon the type, size and location of the associated brain tumor. Some researchers believe that Turcot syndrome is a variant of familial adenomatous polyposis. Others believe that it is a separate disorder. The exact cause of Turcot syndrome is not known.
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Turcot Syndrome
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Symptoms of Turcot Syndrome
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Turcot syndrome is characterized by the formation of multiple benign growths (polyps) in the colon that occur in association with a primary brain tumor. These growths are associated with bleeding from the rectum, diarrhea, constipation, abdominal pain, and/or weight loss. The number and size of these polyps may vary greatly from case to case, ranging from fewer than 10 to more than 100. Some researchers have separated Turcot syndrome into two forms. type 1 is characterized by the presence of fewer than 100 colonic polyps. These polyps are large in size and more likely to become malignant (cancerous). Type 2 is characterized by smaller, more numerous colonic polyps. This type of Turcot syndrome closely resembles familial adenomatous polyposis. (For more information on familial adenomatous polyposis, see the Related Disorders section of this report.)Individuals with Turcot syndrome often have neurological abnormalities that vary, depending upon the type, size, and location of the associated brain tumor. In cases of Turcot syndrome, the brain tumor is often a glioma. Additional brain tumors that have been associated with Turcot syndrome include medulloblastomas, glioblastomas, ependymomas, and astrocytomas. Medulloblastomas occur with greater frequency in the type 2 form of Turcot syndrome. Individuals with Turcot syndrome have a much greater risk than the general population of developing colon cancer later in life. Affected individuals also have a predisposition to develop malignant (cancerous) tumors in areas outside the colon, including thyroid, adrenal, and/or abdominal tumors.Additional symptoms associated with Turcot syndrome include small, coffee-colored spots on the skin (cafe-au-lait spots), the formation of multiple, benign fatty tumors (lipomas), and/or the development of a type of skin cancer known as basal cell carcinoma. Basal cell carcinoma is characterized by the formation of small, shiny, firm masses of tissues (nodules); flat, scar-like lesions (plaques); or red patches covered by thick, dry, silvery scales on the skin.
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Symptoms of Turcot Syndrome. Turcot syndrome is characterized by the formation of multiple benign growths (polyps) in the colon that occur in association with a primary brain tumor. These growths are associated with bleeding from the rectum, diarrhea, constipation, abdominal pain, and/or weight loss. The number and size of these polyps may vary greatly from case to case, ranging from fewer than 10 to more than 100. Some researchers have separated Turcot syndrome into two forms. type 1 is characterized by the presence of fewer than 100 colonic polyps. These polyps are large in size and more likely to become malignant (cancerous). Type 2 is characterized by smaller, more numerous colonic polyps. This type of Turcot syndrome closely resembles familial adenomatous polyposis. (For more information on familial adenomatous polyposis, see the Related Disorders section of this report.)Individuals with Turcot syndrome often have neurological abnormalities that vary, depending upon the type, size, and location of the associated brain tumor. In cases of Turcot syndrome, the brain tumor is often a glioma. Additional brain tumors that have been associated with Turcot syndrome include medulloblastomas, glioblastomas, ependymomas, and astrocytomas. Medulloblastomas occur with greater frequency in the type 2 form of Turcot syndrome. Individuals with Turcot syndrome have a much greater risk than the general population of developing colon cancer later in life. Affected individuals also have a predisposition to develop malignant (cancerous) tumors in areas outside the colon, including thyroid, adrenal, and/or abdominal tumors.Additional symptoms associated with Turcot syndrome include small, coffee-colored spots on the skin (cafe-au-lait spots), the formation of multiple, benign fatty tumors (lipomas), and/or the development of a type of skin cancer known as basal cell carcinoma. Basal cell carcinoma is characterized by the formation of small, shiny, firm masses of tissues (nodules); flat, scar-like lesions (plaques); or red patches covered by thick, dry, silvery scales on the skin.
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Causes of Turcot Syndrome
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Recent research indicates that one type of Turcot syndrome is inherited as an autosomal recessive trait and the other as an autosomal dominant trait. Turcot syndrome type 1, sometimes called “true” Turcot syndrome, is inherited as an autosomal recessive trait. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait 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, 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 normal genes from both parents and be genetically normal for that particular trait is 25%. Researchers believe that mutations to two DNA mismatch repair genes (i.e., MLH1 and PMS2) may be responsible for development of this form of Turcot syndrome. MLH1 is located on the short arm (p) of chromosome 3 at band number 21.3. PMS2 is located on the short arm (p) of chromosome 7 at band number 22.Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Pairs of human chromosomes are numbered from 1 through 22, and an additional 23rd pair of sex chromosomes which include one X and one Y chromosome in males and two X chromosomes in females. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 3p21.3” refers to band 21 on the short arm of chromosome 3. The numbered bands specify the location of the thousands of genes that are present on each chromosome. The second type of Turcot syndrome, which is associated with familial adenomatous polyposis, is inherited as an autosomal dominant trait. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. 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.This form of Turcot syndrome results from mutations to the APC gene (for “adenomatous polyposis coli”), which has been mapped to the long arm (q) of chromosome 5 (5q21-q22). Evidence suggests that the APC gene functions as a tumor suppressor gene. Mutations to the APC gene are associated with familial adenomatous polyposis and Gardner syndrome.
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Causes of Turcot Syndrome. Recent research indicates that one type of Turcot syndrome is inherited as an autosomal recessive trait and the other as an autosomal dominant trait. Turcot syndrome type 1, sometimes called “true” Turcot syndrome, is inherited as an autosomal recessive trait. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait 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, 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 normal genes from both parents and be genetically normal for that particular trait is 25%. Researchers believe that mutations to two DNA mismatch repair genes (i.e., MLH1 and PMS2) may be responsible for development of this form of Turcot syndrome. MLH1 is located on the short arm (p) of chromosome 3 at band number 21.3. PMS2 is located on the short arm (p) of chromosome 7 at band number 22.Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Pairs of human chromosomes are numbered from 1 through 22, and an additional 23rd pair of sex chromosomes which include one X and one Y chromosome in males and two X chromosomes in females. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 3p21.3” refers to band 21 on the short arm of chromosome 3. The numbered bands specify the location of the thousands of genes that are present on each chromosome. The second type of Turcot syndrome, which is associated with familial adenomatous polyposis, is inherited as an autosomal dominant trait. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. 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.This form of Turcot syndrome results from mutations to the APC gene (for “adenomatous polyposis coli”), which has been mapped to the long arm (q) of chromosome 5 (5q21-q22). Evidence suggests that the APC gene functions as a tumor suppressor gene. Mutations to the APC gene are associated with familial adenomatous polyposis and Gardner syndrome.
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Turcot Syndrome
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Affects of Turcot Syndrome
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Turcot syndrome affects males and females in equal numbers. Approximately 150 cases have been reported in the medical literature.
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Affects of Turcot Syndrome. Turcot syndrome affects males and females in equal numbers. Approximately 150 cases have been reported in the medical literature.
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Related disorders of Turcot Syndrome
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Symptoms of the following disorders can be similar to those of Turcot syndrome. Comparisons may be useful for a differential diagnosis: Familial adenomatous polyposis is a group of rare inherited disorders of the gastrointestinal system. Initially the disorder is characterized by benign growths (adenomatous polyps) in the mucous lining of the gastrointestinal tract. Symptoms may include diarrhea, bleeding from the end portion of the large intestine (rectum), fatigue, abdominal pain, and weight loss. If left untreated, affected individuals usually develop cancer of the colon and/or rectum. Familial adenomatous polyposis is inherited as an autosomal dominant trait. (For more information on this disorder, choose “familial adenomatous polyposis” as your search term in the Rare Disease Database.)Gardner syndrome is a rare, inherited disorder characterized by multiple growths (polyps) in the colon (often 1,000 or more), extra teeth (supernumerary), bony tumors of the skull (osteomas), and fatty cysts and/or fibrous tumors in the skin (fibromas or epithelial cysts). Gardner syndrome is a variant of familial adenomatous polyposis, a rare group of disorders characterized by the growth of multiple polyps in the colon. Gardner syndrome is inherited as an autosomal dominant trait. (For more information on this disorder, choose “Gardner” as your search term in the Rare Disease Database.)Peutz-Jeghers syndrome (Intestinal Polyposis, Type II) is a rare, inherited gastrointestinal disorder characterized by the development of polyps on the mucous lining of the intestine and dark discolorations on the skin and mucous membranes. Symptoms include nausea, vomiting, and abdominal pain that occurs because of a form of intestinal obstruction (intussusception). Additional symptoms include bleeding from the rectum and dark skin discolorations around the lips, inside the cheeks, and on the arms. Severe rectal bleeding can cause anemia and episodes of recurring, severe abdominal pain. Peutz-Jeghers syndrome is inherited as an autosomal dominant trait. (For more information on this disorder, choose “Peutz-Jeghers” as your search term in the Rare Disease Database.)Cronkhite-Canada disease (allergic granulomatous angiitis) is an extremely rare gastrointestinal disorder characterized by the formation of polyps in the intestines, the loss of scalp hair (alopecia), abnormally dark discoloration of patches of skin (hyperpigmentation), and the loss of finger and/or toenails. Symptoms may include abdominal pain, cramping, and diarrhea. There is some evidence that this disease may be hereditary. (For more information on this disorder, choose “Cronkhite-Canada” as your search term in the Rare Disease Database.)Familial juvenile polyposis is characterized by small multiple growths (polyps) within the gastrointestinal system. Symptoms may include gastrointestinal bleeding, abdominal pain, diarrhea, rectal prolapse, collapse of a portion of the bowel into itself, and/or gastrointestinal obstruction. Some affected individuals may experience protein loss, malnutrition, and a feeling of general ill health (cachexia). Individuals affected by familial juvenile polyposis may have an increased risk of colon cancer. Other symptoms may include clubbing of the finger and toes, failure to thrive, low levels of circulating red blood cells (anemia). Familial juvenile polyposis is inherited as an autosomal dominant trait. Familial juvenile polyposis may be caused by mutations in the PTEN gene on the long arm of chromosome 10 (10q22.3-q24.1) or mutations in the SMAD4 gene also known as DPC4 gene, located on the long arm of chromosome 18 (18q21.1).
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Related disorders of Turcot Syndrome. Symptoms of the following disorders can be similar to those of Turcot syndrome. Comparisons may be useful for a differential diagnosis: Familial adenomatous polyposis is a group of rare inherited disorders of the gastrointestinal system. Initially the disorder is characterized by benign growths (adenomatous polyps) in the mucous lining of the gastrointestinal tract. Symptoms may include diarrhea, bleeding from the end portion of the large intestine (rectum), fatigue, abdominal pain, and weight loss. If left untreated, affected individuals usually develop cancer of the colon and/or rectum. Familial adenomatous polyposis is inherited as an autosomal dominant trait. (For more information on this disorder, choose “familial adenomatous polyposis” as your search term in the Rare Disease Database.)Gardner syndrome is a rare, inherited disorder characterized by multiple growths (polyps) in the colon (often 1,000 or more), extra teeth (supernumerary), bony tumors of the skull (osteomas), and fatty cysts and/or fibrous tumors in the skin (fibromas or epithelial cysts). Gardner syndrome is a variant of familial adenomatous polyposis, a rare group of disorders characterized by the growth of multiple polyps in the colon. Gardner syndrome is inherited as an autosomal dominant trait. (For more information on this disorder, choose “Gardner” as your search term in the Rare Disease Database.)Peutz-Jeghers syndrome (Intestinal Polyposis, Type II) is a rare, inherited gastrointestinal disorder characterized by the development of polyps on the mucous lining of the intestine and dark discolorations on the skin and mucous membranes. Symptoms include nausea, vomiting, and abdominal pain that occurs because of a form of intestinal obstruction (intussusception). Additional symptoms include bleeding from the rectum and dark skin discolorations around the lips, inside the cheeks, and on the arms. Severe rectal bleeding can cause anemia and episodes of recurring, severe abdominal pain. Peutz-Jeghers syndrome is inherited as an autosomal dominant trait. (For more information on this disorder, choose “Peutz-Jeghers” as your search term in the Rare Disease Database.)Cronkhite-Canada disease (allergic granulomatous angiitis) is an extremely rare gastrointestinal disorder characterized by the formation of polyps in the intestines, the loss of scalp hair (alopecia), abnormally dark discoloration of patches of skin (hyperpigmentation), and the loss of finger and/or toenails. Symptoms may include abdominal pain, cramping, and diarrhea. There is some evidence that this disease may be hereditary. (For more information on this disorder, choose “Cronkhite-Canada” as your search term in the Rare Disease Database.)Familial juvenile polyposis is characterized by small multiple growths (polyps) within the gastrointestinal system. Symptoms may include gastrointestinal bleeding, abdominal pain, diarrhea, rectal prolapse, collapse of a portion of the bowel into itself, and/or gastrointestinal obstruction. Some affected individuals may experience protein loss, malnutrition, and a feeling of general ill health (cachexia). Individuals affected by familial juvenile polyposis may have an increased risk of colon cancer. Other symptoms may include clubbing of the finger and toes, failure to thrive, low levels of circulating red blood cells (anemia). Familial juvenile polyposis is inherited as an autosomal dominant trait. Familial juvenile polyposis may be caused by mutations in the PTEN gene on the long arm of chromosome 10 (10q22.3-q24.1) or mutations in the SMAD4 gene also known as DPC4 gene, located on the long arm of chromosome 18 (18q21.1).
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Turcot Syndrome
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Diagnosis of Turcot Syndrome
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A diagnosis of Turcot syndrome is made based upon a detailed patient history, a thorough clinical evaluation, and a variety of specialized tests. Because children of an affected parent have a genetic risk of developing Turcot syndrome, regular screening via sigmoidoscopy is required until approximately age 35 to 40 to help ensure early detection and prompt, appropriate treatment. During sigmoidoscopy, a viewing instrument is used to examine the rectum and the last part of the large intestine (sigmoid colon). In addition, in some cases, DNA testing may be available to help detect family members who have inherited certain changes (mutations) of the APC gene or DNA mismatch repair genes, potentially diagnosing the disorder before polyp development. In addition, x-rays of the large intestine may reveal the presence of polyps. X-rays of the brain may reveal the presence of a central nervous system tumor.Diagnostic testing for Turcot syndrome also includes direct visual examination of the intestines by the insertion of a flexible, tube-like instrument (colonoscope) into the rectum (colonoscopy) or the removal and microscopic examination of small samples of rectal tissue (biopsy).
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Diagnosis of Turcot Syndrome. A diagnosis of Turcot syndrome is made based upon a detailed patient history, a thorough clinical evaluation, and a variety of specialized tests. Because children of an affected parent have a genetic risk of developing Turcot syndrome, regular screening via sigmoidoscopy is required until approximately age 35 to 40 to help ensure early detection and prompt, appropriate treatment. During sigmoidoscopy, a viewing instrument is used to examine the rectum and the last part of the large intestine (sigmoid colon). In addition, in some cases, DNA testing may be available to help detect family members who have inherited certain changes (mutations) of the APC gene or DNA mismatch repair genes, potentially diagnosing the disorder before polyp development. In addition, x-rays of the large intestine may reveal the presence of polyps. X-rays of the brain may reveal the presence of a central nervous system tumor.Diagnostic testing for Turcot syndrome also includes direct visual examination of the intestines by the insertion of a flexible, tube-like instrument (colonoscope) into the rectum (colonoscopy) or the removal and microscopic examination of small samples of rectal tissue (biopsy).
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Turcot Syndrome
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Therapies of Turcot Syndrome
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TreatmentThe treatment of Turcot syndrome is directed toward the specific symptoms that are apparent in each individual. Surgical removal of the large intestine and the rectum (proctocolectomy) may prevent the risk of such malignancies. However, if procedures are performed to remove the large intestine and surgically join the rectum and small intestine (ileoproctostomy), rectal polyps may regress. Therefore, some physicians may recommend such procedures as an alternative to proctocolectomy. In such cases, the remaining rectal region must be regularly examined through sigmoidoscopy to ensure prompt detection and surgical removal or destruction of any new polyps.In some affected individuals, rapid development of new polyps may necessitate additional surgical treatment, such as removal of the rectum and surgical creation of a connection between the small intestine and the abdominal wall (ileostomy). In other cases, physicians may initially recommend other surgical procedures, such as a technique in which the large intestine is removed (colectomy) and the small intestine and the anus are surgically joined (ileoanal anastomosis).Affected individuals should also receive periodic neurological screenings to test for the presence of a brain tumor. Treatment for brain tumors depends upon the type, size, and location of the tumor. It may include surgery to remove as much of the tumor as is possible without causing damage to the surrounding tissue. Surgery is often followed or accompanied by radiation and/or chemotherapy treatments.Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
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Therapies of Turcot Syndrome. TreatmentThe treatment of Turcot syndrome is directed toward the specific symptoms that are apparent in each individual. Surgical removal of the large intestine and the rectum (proctocolectomy) may prevent the risk of such malignancies. However, if procedures are performed to remove the large intestine and surgically join the rectum and small intestine (ileoproctostomy), rectal polyps may regress. Therefore, some physicians may recommend such procedures as an alternative to proctocolectomy. In such cases, the remaining rectal region must be regularly examined through sigmoidoscopy to ensure prompt detection and surgical removal or destruction of any new polyps.In some affected individuals, rapid development of new polyps may necessitate additional surgical treatment, such as removal of the rectum and surgical creation of a connection between the small intestine and the abdominal wall (ileostomy). In other cases, physicians may initially recommend other surgical procedures, such as a technique in which the large intestine is removed (colectomy) and the small intestine and the anus are surgically joined (ileoanal anastomosis).Affected individuals should also receive periodic neurological screenings to test for the presence of a brain tumor. Treatment for brain tumors depends upon the type, size, and location of the tumor. It may include surgery to remove as much of the tumor as is possible without causing damage to the surrounding tissue. Surgery is often followed or accompanied by radiation and/or chemotherapy treatments.Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
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Turcot Syndrome
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Overview of Turner Syndrome
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Summary
Turner syndrome is a rare chromosomal disorder that is caused by a partial or complete loss (monosomy) of an X chromosome. Turner syndrome is highly variable and can differ significantly from one person to another. Affected females can potentially develop a wide variety of symptoms involving many different organ systems. Common symptoms include short stature and premature ovarian failure, which can result in failure to attain puberty. Most people with Turner syndrome are infertile. A variety of additional symptoms can occur including abnormalities of the eyes and ears, skeletal malformations, heart anomalies and kidney abnormalities. Intelligence is usually normal, but affected individuals may experience certain learning disabilities. Turner syndrome may be diagnosed before birth or shortly after birth or during early childhood. However, in some cases, the disorder may not be diagnosed until well into adulthood, often as an incidental finding. Most cases do not run in families and appear to occur randomly for no apparent reason (sporadically).Introduction
Turner syndrome is named for Henry Turner who, in 1938, was one of the first doctors to report on the disorder in the medical literature. Turner syndrome is one of the most common chromosomal disorders and likely the most common genetic disorder in females.
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Overview of Turner Syndrome. Summary
Turner syndrome is a rare chromosomal disorder that is caused by a partial or complete loss (monosomy) of an X chromosome. Turner syndrome is highly variable and can differ significantly from one person to another. Affected females can potentially develop a wide variety of symptoms involving many different organ systems. Common symptoms include short stature and premature ovarian failure, which can result in failure to attain puberty. Most people with Turner syndrome are infertile. A variety of additional symptoms can occur including abnormalities of the eyes and ears, skeletal malformations, heart anomalies and kidney abnormalities. Intelligence is usually normal, but affected individuals may experience certain learning disabilities. Turner syndrome may be diagnosed before birth or shortly after birth or during early childhood. However, in some cases, the disorder may not be diagnosed until well into adulthood, often as an incidental finding. Most cases do not run in families and appear to occur randomly for no apparent reason (sporadically).Introduction
Turner syndrome is named for Henry Turner who, in 1938, was one of the first doctors to report on the disorder in the medical literature. Turner syndrome is one of the most common chromosomal disorders and likely the most common genetic disorder in females.
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Turner Syndrome
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Symptoms of Turner Syndrome
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The symptoms and severity of Turner syndrome can be quite variable from one person to another. Many features of the disorder are nonspecific, and others may develop slowly over time or can be subtle. It is important to note that affected individuals may not have all the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.Almost all individuals with Turner syndrome exhibit growth failure and attain a final height that is shorter than average (short stature). Children may initially display normal growth, usually for the first few years of life. However, in most cases, the growth rate eventually becomes slower than normal and affected children do not experience normal growth spurts (e.g., no growth spurt during puberty). If untreated, the final height in Turner syndrome is usually less than 5 feet.Another common feature of Turner syndrome is the failure of the ovaries to develop properly (gonadal dysgenesis). Gonadal dysgenesis can cause the loss of ovarian function early during childhood (premature ovarian failure). Normally, the ovaries produce sex hormones (e.g., estrogen and progesterone) at puberty. These hormones are necessary for the onset of puberty and the proper development of secondary sexual characteristics. Most affected females will require hormone replacement therapy to develop breasts and normal female body contours, undergo proper bone growth and to begin menstruation. Some affected individuals may begin to undergo breast development and may begin menstruating without therapy (spontaneous pubertal development), but most will stop developing sexually and stop menstruating at some later point during their teens or early adulthood. Intelligence is usually normal in females with Turner syndrome. However, affected females may develop learning disabilities, especially difficulties with visual-spatial relationships. An example would be right-left disorientation. Affected individuals may have difficulties with directional sense, learning math, nonverbal memory and attention. Affected females may also have trouble in certain social situations.Females with Turner syndrome may develop a variety of distinctive physical features including a short neck with a webbed appearance, a low hairline at the back of the head, low-set ears and narrow fingernails and toenails that are turned upward. A broad chest with widely spaced nipples may occur, which is sometimes referred to as “shield chest.” Some individuals may have swollen, puffy hands and feet. These symptoms may occur due to lymphedema, a condition affecting the lymphatic system. The lymphatic system is a circulatory network of vessels, ducts and nodes that filter and distribute certain protein-rich fluid (lymph) and blood cells throughout the body. Lymphedema is characterized by swelling due to fluid accumulation (edema) in the affected parts of the body.Additional physical findings may include a receding jaw (retrognathia), crossed eyes (strabismus), lazy eyes (amblyopia), drooping eyelids (ptosis) and a narrow, high-arched roof of the mouth (palate). Some individuals may have skeletal malformations including short bones of the hands, specifically the fourth metacarpals, arms that are turned out at the elbows and flat feet (pes planus). In approximately 10% of people with Turner syndrome, abnormal sideways curvature of the spine (scoliosis) may also occur.Congenital heart defects may be associated with Turner syndrome, especially in individuals with lymphedema. Such defects may include bicuspid aortic valve, in which the aortic valve has two flaps (leaflets) instead of three. The aorta is the main artery of the heart. The aortic valve regulates blood flow from the heart into the aorta. The flaps open and close to allow the passage of blood. Since there are only two flaps instead of three, the aortic valve does not function properly. A bicuspid aortic valve may or may not cause clinically apparent symptoms. Approximately 5-10% of individuals may have a congenital heart defect known as coarctation of the aorta, a condition characterized by narrowing of the aorta, which causes the heart to pump harder to force blood through constricted area. The condition can be mild and go undiagnosed until adulthood or be more serious, which can be associated with a variety of symptoms including pale skin, irritability, heavy sweating and difficulty breathing. If untreated, severe cases can result in insufficient blood flow to the organs of the body or eventually progress to congestive heart failure.The heart defects associated with some cases of Turner syndrome can increase the risk of severe, life-threatening complications including high blood pressure of the arteries of the lungs (pulmonary hypertension) or aortic dissection, a condition in which there is a tear in the inner wall of the aorta. Blood rushes into the middle layer of the aorta causing the middle and inner layers to separate (dissect). Aortic dissection can potentially cause the outer wall of the aorta to rupture.Kidney (renal) abnormalities may occur in some people with Turner syndrome including horseshoe kidneys or absence (agenesis) of a kidney.
Kidney abnormalities increase the risk of urinary tract infections and high blood pressure (hypertension). Liver abnormalities may include a fatty liver. Some affected individuals may have thyroid disease, which can cause decreased activity of the thyroid (hypothyroidism). Thyroid disease usually occurs because the immune system mistakenly attacks thyroid tissue, a condition known as Hashimoto’s syndrome (autoimmune thyroiditis). Symptoms can vary from one person to another, but can include fatigue, sluggishness, muscle aches, constipation, a hoarse voice and pale, dry skin.Some individuals with Turner syndrome may have multiple tiny colored spots (pigmented nevi) on their skin. This has not been correlated with an increase in skin cancer.Affected females may also be prone to infections of the middle ear (otitis media), especially during infancy and early childhood. Chronic otitis media may be associated with hearing loss due to blockage of sound waves (conductive hearing loss). This hearing loss usually resolves as a child ages and ear infections become less frequent. Hearing abnormalities in young children may affect or delay speech development. In adults, hearing loss due to an impaired ability of the auditory nerves to transmit sensory input to the brain (sensorineural hearing loss) may occur and may worsen with age.Certain individuals with Turner syndrome appear to be at greater risk than the general population for developing certain disorders including diabetes, celiac disease and osteoporosis. Osteoporosis is characterized by a general loss of bone density that can lead to an increased risk of fractures. Gastrointestinal problems including feeding difficulties and gastroesophageal reflux (GERD) may also occur.
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Symptoms of Turner Syndrome. The symptoms and severity of Turner syndrome can be quite variable from one person to another. Many features of the disorder are nonspecific, and others may develop slowly over time or can be subtle. It is important to note that affected individuals may not have all the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.Almost all individuals with Turner syndrome exhibit growth failure and attain a final height that is shorter than average (short stature). Children may initially display normal growth, usually for the first few years of life. However, in most cases, the growth rate eventually becomes slower than normal and affected children do not experience normal growth spurts (e.g., no growth spurt during puberty). If untreated, the final height in Turner syndrome is usually less than 5 feet.Another common feature of Turner syndrome is the failure of the ovaries to develop properly (gonadal dysgenesis). Gonadal dysgenesis can cause the loss of ovarian function early during childhood (premature ovarian failure). Normally, the ovaries produce sex hormones (e.g., estrogen and progesterone) at puberty. These hormones are necessary for the onset of puberty and the proper development of secondary sexual characteristics. Most affected females will require hormone replacement therapy to develop breasts and normal female body contours, undergo proper bone growth and to begin menstruation. Some affected individuals may begin to undergo breast development and may begin menstruating without therapy (spontaneous pubertal development), but most will stop developing sexually and stop menstruating at some later point during their teens or early adulthood. Intelligence is usually normal in females with Turner syndrome. However, affected females may develop learning disabilities, especially difficulties with visual-spatial relationships. An example would be right-left disorientation. Affected individuals may have difficulties with directional sense, learning math, nonverbal memory and attention. Affected females may also have trouble in certain social situations.Females with Turner syndrome may develop a variety of distinctive physical features including a short neck with a webbed appearance, a low hairline at the back of the head, low-set ears and narrow fingernails and toenails that are turned upward. A broad chest with widely spaced nipples may occur, which is sometimes referred to as “shield chest.” Some individuals may have swollen, puffy hands and feet. These symptoms may occur due to lymphedema, a condition affecting the lymphatic system. The lymphatic system is a circulatory network of vessels, ducts and nodes that filter and distribute certain protein-rich fluid (lymph) and blood cells throughout the body. Lymphedema is characterized by swelling due to fluid accumulation (edema) in the affected parts of the body.Additional physical findings may include a receding jaw (retrognathia), crossed eyes (strabismus), lazy eyes (amblyopia), drooping eyelids (ptosis) and a narrow, high-arched roof of the mouth (palate). Some individuals may have skeletal malformations including short bones of the hands, specifically the fourth metacarpals, arms that are turned out at the elbows and flat feet (pes planus). In approximately 10% of people with Turner syndrome, abnormal sideways curvature of the spine (scoliosis) may also occur.Congenital heart defects may be associated with Turner syndrome, especially in individuals with lymphedema. Such defects may include bicuspid aortic valve, in which the aortic valve has two flaps (leaflets) instead of three. The aorta is the main artery of the heart. The aortic valve regulates blood flow from the heart into the aorta. The flaps open and close to allow the passage of blood. Since there are only two flaps instead of three, the aortic valve does not function properly. A bicuspid aortic valve may or may not cause clinically apparent symptoms. Approximately 5-10% of individuals may have a congenital heart defect known as coarctation of the aorta, a condition characterized by narrowing of the aorta, which causes the heart to pump harder to force blood through constricted area. The condition can be mild and go undiagnosed until adulthood or be more serious, which can be associated with a variety of symptoms including pale skin, irritability, heavy sweating and difficulty breathing. If untreated, severe cases can result in insufficient blood flow to the organs of the body or eventually progress to congestive heart failure.The heart defects associated with some cases of Turner syndrome can increase the risk of severe, life-threatening complications including high blood pressure of the arteries of the lungs (pulmonary hypertension) or aortic dissection, a condition in which there is a tear in the inner wall of the aorta. Blood rushes into the middle layer of the aorta causing the middle and inner layers to separate (dissect). Aortic dissection can potentially cause the outer wall of the aorta to rupture.Kidney (renal) abnormalities may occur in some people with Turner syndrome including horseshoe kidneys or absence (agenesis) of a kidney.
Kidney abnormalities increase the risk of urinary tract infections and high blood pressure (hypertension). Liver abnormalities may include a fatty liver. Some affected individuals may have thyroid disease, which can cause decreased activity of the thyroid (hypothyroidism). Thyroid disease usually occurs because the immune system mistakenly attacks thyroid tissue, a condition known as Hashimoto’s syndrome (autoimmune thyroiditis). Symptoms can vary from one person to another, but can include fatigue, sluggishness, muscle aches, constipation, a hoarse voice and pale, dry skin.Some individuals with Turner syndrome may have multiple tiny colored spots (pigmented nevi) on their skin. This has not been correlated with an increase in skin cancer.Affected females may also be prone to infections of the middle ear (otitis media), especially during infancy and early childhood. Chronic otitis media may be associated with hearing loss due to blockage of sound waves (conductive hearing loss). This hearing loss usually resolves as a child ages and ear infections become less frequent. Hearing abnormalities in young children may affect or delay speech development. In adults, hearing loss due to an impaired ability of the auditory nerves to transmit sensory input to the brain (sensorineural hearing loss) may occur and may worsen with age.Certain individuals with Turner syndrome appear to be at greater risk than the general population for developing certain disorders including diabetes, celiac disease and osteoporosis. Osteoporosis is characterized by a general loss of bone density that can lead to an increased risk of fractures. Gastrointestinal problems including feeding difficulties and gastroesophageal reflux (GERD) may also occur.
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Turner Syndrome
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Causes of Turner Syndrome
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Turner syndrome is caused by a partial or complete loss (monosomy) of an X chromosome. Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual and they come in pairs. We receive one copy from each parent. Chromosomes are numbered from 1 through 22. The 23rd pair normally consists of one X and one Y chromosome for males and two X chromosomes for females. Thus, females with a normal chromosome make-up (karyotype) have 46 chromosomes, including two X chromosomes (46, XX karyotype). Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered.Turner syndrome occurs when all or a portion of an X chromosome is missing. The reason that this occurs is unknown and is believed to result from a random event. In some people, the chromosomal abnormality appears to arise spontaneously (de novo) due to an error in the division of a parent’s reproductive cells, either in the father’s sperm or the mother’s egg. This results in a missing X chromosome in all cells of the body.In many people with Turner syndrome, only a certain percentage of cells may be affected. This is referred to as mosaicism. Specifically, some cells have the normal 46 chromosomes (one cell line) while other cells do not have the normal 46 chromosomes (second cell line). This second cell line may contain various abnormalities such as partial or complete loss of the X chromosome. In these cases, the loss of genetic material from the X chromosome usually occurs because of spontaneous errors very early during fetal development. Theoretically, individuals with Turner syndrome mosaicism may have fewer developmental problems because fewer cells are affected. However, this is difficult to predict. Further research is necessary to completely understand the complicated factors involved in the development of the various symptoms associated with Turner syndrome.In some people, rarer chromosome abnormalities (other than complete or partial monosomy) can cause Turner syndrome. Such abnormalities include ring chromosome or isochromosome X. Ring chromosomes occur when the ends of a chromosome break off and the long and short arms join to form a ring. Isochromosomes occur when one arm of a chromosome is missing and is replaced by an identical version of the other arm.In rare cases, some cells have one copy of the X chromosome, while other cells have one copy of the X chromosome and some Y chromosome material. The amount of Y chromosome material may not be enough to cause the development of any male features but is associated with an increased risk of developing a form of cancer known as gonadoblastoma.Most symptoms of Turner syndrome occur due to the loss of specific genetic material from one of the X chromosomes. The SHOX gene has been conclusively shown to play a role in the development of Turner syndrome. This gene encodes a protein that helps to regulate other genes in the body. The protein product of the SHOX gene plays a role in the growth and maturation of the skeleton. Researchers believe that the loss of one SHOX gene on the altered X chromosome is the main cause of short stature in females with Turner syndrome.We are learning more about how the genes on the X chromosome are related to Turner syndrome. The SHOX gene is known to be involved in the development of short stature and other skeletal findings. The UTX gene may be involved in potential immune issues underlying the repeated episodes of otitis media, which are common. Most recently, the TIMP3 and TIMP1 genes have been identified to be involved in the development of bicuspid aortic valve and aortic abnormalities found in Turner syndrome.Researchers believe that additional, as-yet-unidentified genes on the X chromosome play a role in the development of other symptoms of Turner syndrome. For example, these genes may encode proteins that are involved in the proper development of the lymphatic and cardiovascular systems. More research is necessary to identify all the genes that play a role in the development of the clinical features of Turner syndrome.
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Causes of Turner Syndrome. Turner syndrome is caused by a partial or complete loss (monosomy) of an X chromosome. Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual and they come in pairs. We receive one copy from each parent. Chromosomes are numbered from 1 through 22. The 23rd pair normally consists of one X and one Y chromosome for males and two X chromosomes for females. Thus, females with a normal chromosome make-up (karyotype) have 46 chromosomes, including two X chromosomes (46, XX karyotype). Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered.Turner syndrome occurs when all or a portion of an X chromosome is missing. The reason that this occurs is unknown and is believed to result from a random event. In some people, the chromosomal abnormality appears to arise spontaneously (de novo) due to an error in the division of a parent’s reproductive cells, either in the father’s sperm or the mother’s egg. This results in a missing X chromosome in all cells of the body.In many people with Turner syndrome, only a certain percentage of cells may be affected. This is referred to as mosaicism. Specifically, some cells have the normal 46 chromosomes (one cell line) while other cells do not have the normal 46 chromosomes (second cell line). This second cell line may contain various abnormalities such as partial or complete loss of the X chromosome. In these cases, the loss of genetic material from the X chromosome usually occurs because of spontaneous errors very early during fetal development. Theoretically, individuals with Turner syndrome mosaicism may have fewer developmental problems because fewer cells are affected. However, this is difficult to predict. Further research is necessary to completely understand the complicated factors involved in the development of the various symptoms associated with Turner syndrome.In some people, rarer chromosome abnormalities (other than complete or partial monosomy) can cause Turner syndrome. Such abnormalities include ring chromosome or isochromosome X. Ring chromosomes occur when the ends of a chromosome break off and the long and short arms join to form a ring. Isochromosomes occur when one arm of a chromosome is missing and is replaced by an identical version of the other arm.In rare cases, some cells have one copy of the X chromosome, while other cells have one copy of the X chromosome and some Y chromosome material. The amount of Y chromosome material may not be enough to cause the development of any male features but is associated with an increased risk of developing a form of cancer known as gonadoblastoma.Most symptoms of Turner syndrome occur due to the loss of specific genetic material from one of the X chromosomes. The SHOX gene has been conclusively shown to play a role in the development of Turner syndrome. This gene encodes a protein that helps to regulate other genes in the body. The protein product of the SHOX gene plays a role in the growth and maturation of the skeleton. Researchers believe that the loss of one SHOX gene on the altered X chromosome is the main cause of short stature in females with Turner syndrome.We are learning more about how the genes on the X chromosome are related to Turner syndrome. The SHOX gene is known to be involved in the development of short stature and other skeletal findings. The UTX gene may be involved in potential immune issues underlying the repeated episodes of otitis media, which are common. Most recently, the TIMP3 and TIMP1 genes have been identified to be involved in the development of bicuspid aortic valve and aortic abnormalities found in Turner syndrome.Researchers believe that additional, as-yet-unidentified genes on the X chromosome play a role in the development of other symptoms of Turner syndrome. For example, these genes may encode proteins that are involved in the proper development of the lymphatic and cardiovascular systems. More research is necessary to identify all the genes that play a role in the development of the clinical features of Turner syndrome.
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Turner Syndrome
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Affects of Turner Syndrome
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Turner syndrome affects approximately 1 in 2,000-2,500 live female births. It is estimated that more than 70,000 females in the United States have Turner syndrome. There are no known racial or ethnic factors that influence frequency of the disorder. In some people, the disorder is diagnosed before birth or shortly after birth. However, mild cases can remain undiagnosed until later in life and even during adulthood.
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Affects of Turner Syndrome. Turner syndrome affects approximately 1 in 2,000-2,500 live female births. It is estimated that more than 70,000 females in the United States have Turner syndrome. There are no known racial or ethnic factors that influence frequency of the disorder. In some people, the disorder is diagnosed before birth or shortly after birth. However, mild cases can remain undiagnosed until later in life and even during adulthood.
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Turner Syndrome
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Related disorders of Turner Syndrome
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Noonan syndrome is a common genetic disorder that is typically evident at birth (congenital). The disorder is characterized by a wide spectrum of symptoms and physical features that vary greatly in range and severity. In many affected individuals, associated abnormalities include a distinctive facial appearance; a broad or webbed neck; a low posterior hairline; a typical chest deformity and short stature. Characteristic abnormalities of the head and facial (craniofacial) area may include widely set eyes (ocular hypertelorism); skin folds that may cover the eyes’ inner corners (epicanthal folds); drooping of the upper eyelids (ptosis); a small jaw (micrognathia); a depressed nasal root; a short nose with broad base; and low-set, posteriorly rotated ears (pinnae). Distinctive skeletal malformations are also typically present, such as abnormalities of the breastbone (sternum), curvature of the spine (kyphosis and/or scoliosis), and outward deviation of the elbows (cubitus valgus). Many infants with Noonan syndrome also have heart (cardiac) defects, such as obstruction of proper blood flow from the lower right chamber of the heart to the lungs (pulmonary valvular stenosis). Additional abnormalities may include malformations of certain blood and lymph vessels, blood clotting and platelet deficiencies, learning difficulties or mild intellectual disability, failure of the testes to descend into the scrotum (cryptorchidism) by the first year of life in affected males, and/or other symptoms and findings. Noonan syndrome is an autosomal dominant genetic disorder caused by abnormalities (mutations or pathogenic variants) in multiple single genes that make up the rasopathy pathway. Some symptoms associated with Noonan syndrome may superficially resemble those with Turner syndrome (due to certain findings that may be associated with both disorders, such as short stature, webbed neck, etc.). Consequently, in the past, Noonan syndrome has been referred to as “male Turner syndrome,” “female pseudo-Turner syndrome,” or “Turner phenotype with normal chromosomes karyotype.” However, there are many important differences between the two disorders. Noonan syndrome affects both males and females, and there is a normal chromosomal makeup (karyotype). Only females are affected by Turner syndrome, which is characterized by abnormalities affecting the X chromosome. (For more information on this disorder, choose “Noonan” as your search term in the Rare Disease Database.)
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Related disorders of Turner Syndrome. Noonan syndrome is a common genetic disorder that is typically evident at birth (congenital). The disorder is characterized by a wide spectrum of symptoms and physical features that vary greatly in range and severity. In many affected individuals, associated abnormalities include a distinctive facial appearance; a broad or webbed neck; a low posterior hairline; a typical chest deformity and short stature. Characteristic abnormalities of the head and facial (craniofacial) area may include widely set eyes (ocular hypertelorism); skin folds that may cover the eyes’ inner corners (epicanthal folds); drooping of the upper eyelids (ptosis); a small jaw (micrognathia); a depressed nasal root; a short nose with broad base; and low-set, posteriorly rotated ears (pinnae). Distinctive skeletal malformations are also typically present, such as abnormalities of the breastbone (sternum), curvature of the spine (kyphosis and/or scoliosis), and outward deviation of the elbows (cubitus valgus). Many infants with Noonan syndrome also have heart (cardiac) defects, such as obstruction of proper blood flow from the lower right chamber of the heart to the lungs (pulmonary valvular stenosis). Additional abnormalities may include malformations of certain blood and lymph vessels, blood clotting and platelet deficiencies, learning difficulties or mild intellectual disability, failure of the testes to descend into the scrotum (cryptorchidism) by the first year of life in affected males, and/or other symptoms and findings. Noonan syndrome is an autosomal dominant genetic disorder caused by abnormalities (mutations or pathogenic variants) in multiple single genes that make up the rasopathy pathway. Some symptoms associated with Noonan syndrome may superficially resemble those with Turner syndrome (due to certain findings that may be associated with both disorders, such as short stature, webbed neck, etc.). Consequently, in the past, Noonan syndrome has been referred to as “male Turner syndrome,” “female pseudo-Turner syndrome,” or “Turner phenotype with normal chromosomes karyotype.” However, there are many important differences between the two disorders. Noonan syndrome affects both males and females, and there is a normal chromosomal makeup (karyotype). Only females are affected by Turner syndrome, which is characterized by abnormalities affecting the X chromosome. (For more information on this disorder, choose “Noonan” as your search term in the Rare Disease Database.)
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Diagnosis of Turner Syndrome
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A detailed patient history, a thorough clinical evaluation, and a variety of specialized tests. Turner syndrome should be suspected in girls with growth deficiency or short stature of unknown cause.A diagnosis of Turner syndrome is often confirmed by chromosomal analysis, which is usually achieved by determining the karyotype. Karyotyping is a laboratory test that evaluates the number and structure of chromosomes. Karyotyping can be done on almost any type of tissue. In most cases, a blood sample is used to ascertain a person’s karyotype.Turner syndrome is being increasingly diagnosed before birth (prenatally). Screening for Turner syndrome and other chromosome abnormalities can be performed by noninvasive testing on a maternal blood sample. Definitive testing can be done by CVS or amniocentesis. CVS is performed at 10-12 weeks of pregnancy and involves the removal of tissue samples from a portion of the placenta, while amniocentesis is performed at 16-18 weeks gestation and involves taking a small sample of the fluid around the fetus.Sometimes, certain physical findings associated with Turner syndrome may be seen on a fetal ultrasound. For example, the accumulation of lymph fluid near the neck of a developing fetus can sometimes be seen on a routine fetal ultrasound. If prenatal testing shows a Turner syndrome karyotype but normal ultrasound findings, it can be difficult to predict the extent to which the baby will develop signs of Turner syndrome after birth.Clinical Testing and Work-Up
Specific imaging techniques such as magnetic resonance imaging (MRI) may be performed to look for symptoms potentially associated with Turner syndrome such as liver, kidney or heart abnormalities. An MRI uses a magnetic field and radio waves to produce cross-sectional images of organs and bodily tissues. Many individuals with a diagnosis of Turner syndrome undergo a complete cardiac workup to assess the structure and function of the heart. This will include an echocardiogram.Additional evaluation should be done on thyroid and liver function, bone age and growth. Hypertension screening should also be performed. Infants diagnosed at birth should receive a full ear, nose and throat examination including an auditory exam. Children, especially those who experience repeated ear infections, as well as adults, require periodic hearing evaluation. Affected individuals should also undergo thyroid function tests because of the potential for thyroid disease.
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Diagnosis of Turner Syndrome. A detailed patient history, a thorough clinical evaluation, and a variety of specialized tests. Turner syndrome should be suspected in girls with growth deficiency or short stature of unknown cause.A diagnosis of Turner syndrome is often confirmed by chromosomal analysis, which is usually achieved by determining the karyotype. Karyotyping is a laboratory test that evaluates the number and structure of chromosomes. Karyotyping can be done on almost any type of tissue. In most cases, a blood sample is used to ascertain a person’s karyotype.Turner syndrome is being increasingly diagnosed before birth (prenatally). Screening for Turner syndrome and other chromosome abnormalities can be performed by noninvasive testing on a maternal blood sample. Definitive testing can be done by CVS or amniocentesis. CVS is performed at 10-12 weeks of pregnancy and involves the removal of tissue samples from a portion of the placenta, while amniocentesis is performed at 16-18 weeks gestation and involves taking a small sample of the fluid around the fetus.Sometimes, certain physical findings associated with Turner syndrome may be seen on a fetal ultrasound. For example, the accumulation of lymph fluid near the neck of a developing fetus can sometimes be seen on a routine fetal ultrasound. If prenatal testing shows a Turner syndrome karyotype but normal ultrasound findings, it can be difficult to predict the extent to which the baby will develop signs of Turner syndrome after birth.Clinical Testing and Work-Up
Specific imaging techniques such as magnetic resonance imaging (MRI) may be performed to look for symptoms potentially associated with Turner syndrome such as liver, kidney or heart abnormalities. An MRI uses a magnetic field and radio waves to produce cross-sectional images of organs and bodily tissues. Many individuals with a diagnosis of Turner syndrome undergo a complete cardiac workup to assess the structure and function of the heart. This will include an echocardiogram.Additional evaluation should be done on thyroid and liver function, bone age and growth. Hypertension screening should also be performed. Infants diagnosed at birth should receive a full ear, nose and throat examination including an auditory exam. Children, especially those who experience repeated ear infections, as well as adults, require periodic hearing evaluation. Affected individuals should also undergo thyroid function tests because of the potential for thyroid disease.
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Therapies of Turner Syndrome
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Treatment
The treatment of Turner 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, pediatric specialists, surgeons, cardiologists, endocrinologists, speech pathologists, otolaryngologists, ophthalmologists, psychologists and other healthcare professionals may need to plan treatment systematically and comprehensively. Genetic counseling is recommended for affected individuals and their families.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease severity; the presence or absence of certain symptoms; an individual’s age and general health; and/or other elements. Decisions concerning the use of drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of their case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.There is no cure for Turner syndrome, but therapies have been developed that can improve physical development. With proper medical care, females with Turner syndrome should be able to lead full, productive lives. The primary therapies for affected individuals are growth hormone therapy and estrogen therapy.Individuals with Turner syndrome may benefit from growth hormone (GH) therapy, which can help to normalize height. The U.S. Food and Drug Administration (FDA) has approved the use of recombinant GH for the treatment of children with Turner syndrome. Recombinant GH is artificially created in a lab. The best age for beginning GH therapy and the optimum duration of therapy in females with Turner syndrome is unknown. Generally, the earlier GH therapy is started, the more beneficial it tends to be for affected individuals. However, there are many factors that ultimately determine the effectiveness of GH therapy. Decisions regarding GH therapy in individuals with Turner syndrome are best made after consultation with a pediatric endocrinologist.Most females with Turner syndrome require sex hormone replacement therapy to undergo normal development associated with puberty and to begin their menstrual periods. Estrogen and progesterone replacement therapy will generally promote puberty and the development of secondary sexual characteristics. Hormone replacement therapy usually begun around 12-14 years of age. This is the average age when girls enter puberty. The timing of initiating puberty should also consider growth progress on growth hormone replacement. Replacement therapy must be continued to maintain these characteristics and most females with Turner syndrome require estrogen and progesterone therapy until menopause.Most individuals with Turner syndrome are not able to conceive children. In vitro fertilization (IVF) with a donor egg and an implanted pregnancy is sometimes possible. In most cases, these pregnancies carry risks and require close consultation with a patient’s healthcare team. In recent years, some people with Turner syndrome have been able to preserve egg cells as a young person to use to achieve a future pregnancy.Individuals with Turner syndrome and Y chromosome material (Y chromosome mosaicism) are at an increased risk of developing a tumor of the gonads. When this is the case, it is recommended that the non-functioning gonadal tissue be removed.Additional treatment is symptomatic and supportive. For example, thyroid hormone replacement therapy may be used to treat individuals with thyroid disease. Correction of hearing loss with hearing aids is another important intervention which can help with learning and social interaction.Early intervention is important in ensuring that children with Turner syndrome reach their potential. Special services that may be beneficial to affected children may include special psychosocial support, speech therapy and other such services.
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Therapies of Turner Syndrome. Treatment
The treatment of Turner 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, pediatric specialists, surgeons, cardiologists, endocrinologists, speech pathologists, otolaryngologists, ophthalmologists, psychologists and other healthcare professionals may need to plan treatment systematically and comprehensively. Genetic counseling is recommended for affected individuals and their families.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease severity; the presence or absence of certain symptoms; an individual’s age and general health; and/or other elements. Decisions concerning the use of drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of their case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.There is no cure for Turner syndrome, but therapies have been developed that can improve physical development. With proper medical care, females with Turner syndrome should be able to lead full, productive lives. The primary therapies for affected individuals are growth hormone therapy and estrogen therapy.Individuals with Turner syndrome may benefit from growth hormone (GH) therapy, which can help to normalize height. The U.S. Food and Drug Administration (FDA) has approved the use of recombinant GH for the treatment of children with Turner syndrome. Recombinant GH is artificially created in a lab. The best age for beginning GH therapy and the optimum duration of therapy in females with Turner syndrome is unknown. Generally, the earlier GH therapy is started, the more beneficial it tends to be for affected individuals. However, there are many factors that ultimately determine the effectiveness of GH therapy. Decisions regarding GH therapy in individuals with Turner syndrome are best made after consultation with a pediatric endocrinologist.Most females with Turner syndrome require sex hormone replacement therapy to undergo normal development associated with puberty and to begin their menstrual periods. Estrogen and progesterone replacement therapy will generally promote puberty and the development of secondary sexual characteristics. Hormone replacement therapy usually begun around 12-14 years of age. This is the average age when girls enter puberty. The timing of initiating puberty should also consider growth progress on growth hormone replacement. Replacement therapy must be continued to maintain these characteristics and most females with Turner syndrome require estrogen and progesterone therapy until menopause.Most individuals with Turner syndrome are not able to conceive children. In vitro fertilization (IVF) with a donor egg and an implanted pregnancy is sometimes possible. In most cases, these pregnancies carry risks and require close consultation with a patient’s healthcare team. In recent years, some people with Turner syndrome have been able to preserve egg cells as a young person to use to achieve a future pregnancy.Individuals with Turner syndrome and Y chromosome material (Y chromosome mosaicism) are at an increased risk of developing a tumor of the gonads. When this is the case, it is recommended that the non-functioning gonadal tissue be removed.Additional treatment is symptomatic and supportive. For example, thyroid hormone replacement therapy may be used to treat individuals with thyroid disease. Correction of hearing loss with hearing aids is another important intervention which can help with learning and social interaction.Early intervention is important in ensuring that children with Turner syndrome reach their potential. Special services that may be beneficial to affected children may include special psychosocial support, speech therapy and other such services.
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Overview of Twin Anemia Polycythemia Sequence
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Twin anemia polycythemia sequence (TAPS) is a rare but severe complication in identical twin pregnancies that share a single placenta (monochorionic). TAPS is caused by an imbalance in red blood cells exchanged between the twins through tiny placental blood circulations (anastomoses). This leads to too few red blood cells (anemia) in the donor twin and too many red blood cells (polycythemia) in the recipient twin. TAPS was first described in 2006,1 and being a relatively “new” disease; it is sometimes confused with the better-known twin-to-twin transfusion syndrome (TTTS).However, TAPS is a separate disease with characteristic pathogenesis, diagnostic criteria, classification system, and outcome.TAPS is a chronic and slow imbalance in blood flow between the babies, happening at any time during the pregnancy. It causes chronic anemia and polycythemia without an imbalance in the amniotic fluid between the twins, a characteristic of TTTS that often leads to maternal symptoms due to the rapid growth of the mother's stomach.Unlike TTTS, TAPS has no physical symptoms due to no fluid differences in the babies and often remains undiagnosed. This is why Doppler ultrasound measurements on the mid-cerebral artery are vital during pregnancy, as this is the only reliable way to detect TAPS.Treatment options for TAPS before birth include expectant management ( “watch and wait”), premature delivery, intrauterine transfusion with or without partial exchange transfusion, laser surgery, and in very severe cases, selective reduction of the pregnancy.The best management option is currently still unknown. The management and outcome in TAPS can vary in severity from case to case, depending upon when during pregnancy the syndrome occurs, when a diagnosis is made, and what treatments are performed.
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Overview of Twin Anemia Polycythemia Sequence. Twin anemia polycythemia sequence (TAPS) is a rare but severe complication in identical twin pregnancies that share a single placenta (monochorionic). TAPS is caused by an imbalance in red blood cells exchanged between the twins through tiny placental blood circulations (anastomoses). This leads to too few red blood cells (anemia) in the donor twin and too many red blood cells (polycythemia) in the recipient twin. TAPS was first described in 2006,1 and being a relatively “new” disease; it is sometimes confused with the better-known twin-to-twin transfusion syndrome (TTTS).However, TAPS is a separate disease with characteristic pathogenesis, diagnostic criteria, classification system, and outcome.TAPS is a chronic and slow imbalance in blood flow between the babies, happening at any time during the pregnancy. It causes chronic anemia and polycythemia without an imbalance in the amniotic fluid between the twins, a characteristic of TTTS that often leads to maternal symptoms due to the rapid growth of the mother's stomach.Unlike TTTS, TAPS has no physical symptoms due to no fluid differences in the babies and often remains undiagnosed. This is why Doppler ultrasound measurements on the mid-cerebral artery are vital during pregnancy, as this is the only reliable way to detect TAPS.Treatment options for TAPS before birth include expectant management ( “watch and wait”), premature delivery, intrauterine transfusion with or without partial exchange transfusion, laser surgery, and in very severe cases, selective reduction of the pregnancy.The best management option is currently still unknown. The management and outcome in TAPS can vary in severity from case to case, depending upon when during pregnancy the syndrome occurs, when a diagnosis is made, and what treatments are performed.
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Symptoms of Twin Anemia Polycythemia Sequence
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Before birth, TAPS may go undetected due to lack of symptoms and the lack of excess amniotic fluid (polyhydramnios) like in TTTS. TAPS can be detected using Doppler ultrasound examination, focusing specifically on the blood flow (peak systolic velocity, PSV) in the middle cerebral artery (MCA). In the donor, the MCA-PSV is increased as a sign of fetal anemia. In the recipient, the MCA-PSV is decreased as a sign of polycythemia. Although routine MCA-PSV measurements are proven to be an adequate predictor for TAPS, it has been challenging to implement Doppler screening for TAPS in the bi-weekly ultrasound check-ups for monochorionic twins. Other signs on ultrasound may also be a starry sky liver in the recipient and placental dichotomy (a bright appearance to the donor's share of the placenta). At birth, signs and symptoms are more evident as the donor is strikingly pale and the recipient is purple/red color (plethoric). The placenta must be examined, and blood testing completed to confirm the diagnosis.
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Symptoms of Twin Anemia Polycythemia Sequence. Before birth, TAPS may go undetected due to lack of symptoms and the lack of excess amniotic fluid (polyhydramnios) like in TTTS. TAPS can be detected using Doppler ultrasound examination, focusing specifically on the blood flow (peak systolic velocity, PSV) in the middle cerebral artery (MCA). In the donor, the MCA-PSV is increased as a sign of fetal anemia. In the recipient, the MCA-PSV is decreased as a sign of polycythemia. Although routine MCA-PSV measurements are proven to be an adequate predictor for TAPS, it has been challenging to implement Doppler screening for TAPS in the bi-weekly ultrasound check-ups for monochorionic twins. Other signs on ultrasound may also be a starry sky liver in the recipient and placental dichotomy (a bright appearance to the donor's share of the placenta). At birth, signs and symptoms are more evident as the donor is strikingly pale and the recipient is purple/red color (plethoric). The placenta must be examined, and blood testing completed to confirm the diagnosis.
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Causes of Twin Anemia Polycythemia Sequence
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Tiny blood vessels in the shared placenta that connects the babies' umbilical cords and blood circulations (anastomoses) cause TAPS. These connections are present in all monochorionic twin pregnancies. In most cases, the blood flow stays relatively balanced through these connecting blood vessels. However, in TAPS, the blood between the two babies is not balanced. One baby, the donor, gives more blood to the other, the recipient, leading to the donor becoming anemic and the recipient polycythemic.
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Causes of Twin Anemia Polycythemia Sequence. Tiny blood vessels in the shared placenta that connects the babies' umbilical cords and blood circulations (anastomoses) cause TAPS. These connections are present in all monochorionic twin pregnancies. In most cases, the blood flow stays relatively balanced through these connecting blood vessels. However, in TAPS, the blood between the two babies is not balanced. One baby, the donor, gives more blood to the other, the recipient, leading to the donor becoming anemic and the recipient polycythemic.
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Affects of Twin Anemia Polycythemia Sequence
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TAPS is a rare disorder affecting a small number of monochorionic twin pregnancies. Many cases go undiagnosed and unrecorded; the actual frequency is unknown. All too often, TAPS is only diagnosed at birth when one baby is pale while the other is red. TAPS happens spontaneously in 5% of all monochorionic pregnancies (spontaneous TAPS) and can also occur in TTTS pregnancies after incomplete laser surgery (post-laser TAPS) due to small missed or incompletely sealed connections.
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Affects of Twin Anemia Polycythemia Sequence. TAPS is a rare disorder affecting a small number of monochorionic twin pregnancies. Many cases go undiagnosed and unrecorded; the actual frequency is unknown. All too often, TAPS is only diagnosed at birth when one baby is pale while the other is red. TAPS happens spontaneously in 5% of all monochorionic pregnancies (spontaneous TAPS) and can also occur in TTTS pregnancies after incomplete laser surgery (post-laser TAPS) due to small missed or incompletely sealed connections.
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Related disorders of Twin Anemia Polycythemia Sequence
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Symptoms of the following disorders can be similar to those of twin anemia polycythemia sequence. Comparisons may be helpful to show the differences.Twin-twin transfusion syndrome (TTTS): TAPS is often still confused with TTTS. Importantly, TTTS has other signs and is characterized by an imbalance in the amniotic fluid between the babies. The management and outcomes of TTTS are also different, and fetoscopic laser surgery has been proven to be the best treatment for TTTS. In TAPS, laser surgery is an option, but evidence for optimal treatment is still lacking. Acute peripartum TTTS: In uncomplicated monochorionic twins, a sudden shift of blood may occur during birth, leading to acute anemia and excess fluid in the blood (hypovolemia) in the donor and polycythemia and hypervolemia in the recipient. On physical examination, twins with acute peripartum TTTS have a similar look compared to twins with TAPS; in both cases, there is a pale and red pair of twins. A distinction with acute peripartum TTTS can be made by performing routine blood testing and examining the placenta. Blood tests in acute peripartum TTTS will reveal a significant hemoglobin difference (> 8 g/dL). However, unlike withTAPS, the reticulocyte count ratio will be lower (< 1.7) since the donor's reticulocyte counts will not be increased. Additionally, placentas in acute peripartum TTTS have no color difference on the maternal side. They will have large superficial anastomoses after color dye injection.
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Related disorders of Twin Anemia Polycythemia Sequence. Symptoms of the following disorders can be similar to those of twin anemia polycythemia sequence. Comparisons may be helpful to show the differences.Twin-twin transfusion syndrome (TTTS): TAPS is often still confused with TTTS. Importantly, TTTS has other signs and is characterized by an imbalance in the amniotic fluid between the babies. The management and outcomes of TTTS are also different, and fetoscopic laser surgery has been proven to be the best treatment for TTTS. In TAPS, laser surgery is an option, but evidence for optimal treatment is still lacking. Acute peripartum TTTS: In uncomplicated monochorionic twins, a sudden shift of blood may occur during birth, leading to acute anemia and excess fluid in the blood (hypovolemia) in the donor and polycythemia and hypervolemia in the recipient. On physical examination, twins with acute peripartum TTTS have a similar look compared to twins with TAPS; in both cases, there is a pale and red pair of twins. A distinction with acute peripartum TTTS can be made by performing routine blood testing and examining the placenta. Blood tests in acute peripartum TTTS will reveal a significant hemoglobin difference (> 8 g/dL). However, unlike withTAPS, the reticulocyte count ratio will be lower (< 1.7) since the donor's reticulocyte counts will not be increased. Additionally, placentas in acute peripartum TTTS have no color difference on the maternal side. They will have large superficial anastomoses after color dye injection.
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Twin Anemia Polycythemia Sequence
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Diagnosis of Twin Anemia Polycythemia Sequence
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TAPS can be detected during pregnancy by Doppler ultrasonography. Ultrasound findings in TAPS include twins of the same gender; a single, shared placenta (monochorionic), a thin membrane dividing the babies' amniotic sacs; no differences in amniotic fluid (TTTS); and the presence of discordant MCA-PSV Dopplers. The current staging system for TAPS follows the one proposed by Tollenaar et al.2. Like TTTS, this classification system may suggest that TAPS follows an orderly progression over time. However, this is not the case, and it can progress in highly variable and unpredictable ways. When physicians examine the placenta after delivery, this can confirm the twins' monochorionic status. The placenta must be injected with colored dye to detect the tiny connecting blood vessels because these are not visible to the naked eye. The maternal side of the placenta shows a remarkable color difference with a pale side of the donor and a darker and congested side of the recipient. At birth, doctors must check the hemoglobin and reticulocytes of the babies. In TAPS, hemoglobin discordance is more than 8 g/dL. The reticulocyte count in the donor is higher due to chronic anemia and increased red blood cell production (erythropoiesis). Reticulocyte ratios are measured by dividing the reticulocyte count of the donor by the recipient. In TAPS cases, the difference is more than 1.7.
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Diagnosis of Twin Anemia Polycythemia Sequence. TAPS can be detected during pregnancy by Doppler ultrasonography. Ultrasound findings in TAPS include twins of the same gender; a single, shared placenta (monochorionic), a thin membrane dividing the babies' amniotic sacs; no differences in amniotic fluid (TTTS); and the presence of discordant MCA-PSV Dopplers. The current staging system for TAPS follows the one proposed by Tollenaar et al.2. Like TTTS, this classification system may suggest that TAPS follows an orderly progression over time. However, this is not the case, and it can progress in highly variable and unpredictable ways. When physicians examine the placenta after delivery, this can confirm the twins' monochorionic status. The placenta must be injected with colored dye to detect the tiny connecting blood vessels because these are not visible to the naked eye. The maternal side of the placenta shows a remarkable color difference with a pale side of the donor and a darker and congested side of the recipient. At birth, doctors must check the hemoglobin and reticulocytes of the babies. In TAPS, hemoglobin discordance is more than 8 g/dL. The reticulocyte count in the donor is higher due to chronic anemia and increased red blood cell production (erythropoiesis). Reticulocyte ratios are measured by dividing the reticulocyte count of the donor by the recipient. In TAPS cases, the difference is more than 1.7.
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Therapies of Twin Anemia Polycythemia Sequence
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Outcome and TreatmentOutcomes in both spontaneous and post-laser TAPS are problematic and associated with an increased risk of permanent injury and death. Adverse effects of TAPS are mainly due to complications related to prematurity. Long-term outcomes in TAPS show an increased risk of bilateral deafness and neurodevelopmental impairment in donors 3. Hearing loss was detected in 15% of donors, but the cause is not entirely clear. Specialized hearing screening should be performed in all TAPS survivors to ensure that hearing loss is detected in a timely manner. Early intervention is vital to avoid speech and language developmental delays. Fetoscopic laser surgery is a treatment option for TAPS, but evidence for optimal treatment is still lacking. The TAPS Trial is working on determining the best treatment for TAPS by comparing laser surgery with other treatment methods.4
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Therapies of Twin Anemia Polycythemia Sequence. Outcome and TreatmentOutcomes in both spontaneous and post-laser TAPS are problematic and associated with an increased risk of permanent injury and death. Adverse effects of TAPS are mainly due to complications related to prematurity. Long-term outcomes in TAPS show an increased risk of bilateral deafness and neurodevelopmental impairment in donors 3. Hearing loss was detected in 15% of donors, but the cause is not entirely clear. Specialized hearing screening should be performed in all TAPS survivors to ensure that hearing loss is detected in a timely manner. Early intervention is vital to avoid speech and language developmental delays. Fetoscopic laser surgery is a treatment option for TAPS, but evidence for optimal treatment is still lacking. The TAPS Trial is working on determining the best treatment for TAPS by comparing laser surgery with other treatment methods.4
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Overview of Twin-Twin Transfusion Syndrome
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Twin-twin transfusion syndrome (TTTS) is a rare disorder that sometimes occurs when women are pregnant with identical (monozygotic) twins. It is a rare disease of the placenta, the organ that joins the mother to her offspring and provides nourishment to the developing fetuses. During the development of identical twins, there are always blood vessels in the fetuses' shared placenta that connect their blood circulations (placental anastomoses). In most cases, the blood flows properly through these vessels. However, in twin-twin transfusion syndrome, the blood begins to flow unevenly, with one fetal twin receiving too much blood (recipient) and one receiving too little (donor). The recipient twin may experience heart failure due to continual strain on its heart and blood vessels (cardiovascular system). The donor twin, on the other hand, may experience life-threatening anemia, insufficient nutrition and oxygen due to its inadequate supply of blood. Such an imbalance in blood flow (i.e., twin-twin transfusion) can occur at any time during the pregnancy, including during delivery.The effects of twin-twin transfusion syndrome can vary in severity from case to case, depending upon when during pregnancy the syndrome occurs, when it is diagnosed, and any treatment that may be given. The cause of this syndrome is not fully understood, although it is known that placental characteristics play an important role.
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Overview of Twin-Twin Transfusion Syndrome. Twin-twin transfusion syndrome (TTTS) is a rare disorder that sometimes occurs when women are pregnant with identical (monozygotic) twins. It is a rare disease of the placenta, the organ that joins the mother to her offspring and provides nourishment to the developing fetuses. During the development of identical twins, there are always blood vessels in the fetuses' shared placenta that connect their blood circulations (placental anastomoses). In most cases, the blood flows properly through these vessels. However, in twin-twin transfusion syndrome, the blood begins to flow unevenly, with one fetal twin receiving too much blood (recipient) and one receiving too little (donor). The recipient twin may experience heart failure due to continual strain on its heart and blood vessels (cardiovascular system). The donor twin, on the other hand, may experience life-threatening anemia, insufficient nutrition and oxygen due to its inadequate supply of blood. Such an imbalance in blood flow (i.e., twin-twin transfusion) can occur at any time during the pregnancy, including during delivery.The effects of twin-twin transfusion syndrome can vary in severity from case to case, depending upon when during pregnancy the syndrome occurs, when it is diagnosed, and any treatment that may be given. The cause of this syndrome is not fully understood, although it is known that placental characteristics play an important role.
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Symptoms of Twin-Twin Transfusion Syndrome
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Twin-twin transfusion syndrome (TTTS) is a rare disorder that sometimes occurs when women are pregnant with identical (monozygotic) twins. TTTS is a disease of the placenta, the organ that develops in the uterus during pregnancy, links the mother's blood supply to the fetuses', and provides nourishment to her offspring. The developing fetal twins are typically normal until abnormalities in blood flow within the placenta cause the TTTS disease process to occur. The majority of identical twins share a common placenta in which blood vessels connect the fetuses' umbilical cords and blood circulations (placental anastomoses). The umbilical cords join the fetal twins to the placenta. In most cases, the blood flow is balanced between the twins through these connecting blood vessels. However, when twin-twin transfusion syndrome occurs, the blood begins to flow unevenly through the connecting blood vessels. As a result, one fetal twin receives too much blood (recipient), while the other receives too little (donor). The fetal twins, though developing normally up to this point, may now begin to exhibit various symptoms, depending upon when in the pregnancy the imbalance in blood flow (twin-twin transfusion) has taken place. The twin-twin transfusion may occur at any time during pregnancy. If the imbalance in blood flow occurs early in the pregnancy (first trimester), one of the fetal twins may simply cease developing; as a result, only one fetus will be detected for the remainder of the pregnancy. If the transfusion occurs shortly before or during delivery, the twins may exhibit symptoms related to a sudden lack or excess of blood supply. However, should twin- twin transfusion syndrome occur during mid-pregnancy (second trimester), a variety of symptoms may occur. For example, the twin that receives extra blood (recipient) begins to produce more urine than normal (polyuria), resulting in excessive amniotic fluid surrounding the fetus within its amniotic sac (hydramnios). Such an excess of amniotic fluid can develop quickly, often over two to three weeks As a result, the mother's abdomen grows larger than normal for her stage of pregnancy. In most cases, this is the first symptom of twin-twin transfusion syndrome. Left untreated, the excess amniotic fluid can cause preterm labor or rupture the amniotic sac, resulting in potentially very early delivery. On the other hand, because the other fetal twin (donor) receives too little blood and has abnormally low levels of circulating fluid in its body (hypovolemia), its kidneys may stop producing urine (renal shutdown); there may therefore be very little fluid in the donor twin's amniotic sac (oligohydramnios). As a result, the sac's membranes (amnion) may collapse around the fetus. Because this fetal twin may appear stuck or “cocooned” within the collapsed membranes, it is sometimes called the “stuck twin”. During normal fetal development, most identical (monozygotic) twins grow at approximately the same rate and have similar weights when they are born. However, if fetal twins are affected by twin-twin transfusion syndrome by mid-pregnancy (second trimester), they may begin to vary greatly in development rate and size. While the recipient twin may become larger in size than normal, the donor twin may suffer from severe growth retardation. Some researchers believe that uneven sharing of portions of the common, shared placenta may also contribute to different rates of growth. The difference in sizes of the twins may persist even after birth through infancy. Both recipient and donor fetal twins may exhibit other symptoms as well. The extra blood supply to the recipient twin may cause heart failure resulting in fluid to accumulating in some of its body cavities (hydrops), such as in the abdominal cavity (ascites), around the lungs (pleural effusion), and/or around the heart (pericardial effusion). Receiving excess blood places continual strain on the fetus's heart and blood vessels (cardiovascular system), which may eventually cause congestive heart failure. On the other hand, the donor twin has an inadequate supply of blood, possibly causing a potentially life- threatening anemia and growth restriction. If the recipient twin develops hydrops or the donor twin develops severe growth restriction, inadequate supply of oxygen (hypoxia) to the developing brain may occur during pregnancy or from respiratory distress syndrome (RDS) associated with early (preterm) delivery. As a result, brain damage may occur, potentially causing Cerebral Palsy. (For more information on this disorder, use “Cerebral Palsy” as your search term in the Rare Disease Database.) When twin-twin transfusion syndrome occurs in mid-pregnancy, one of the fetal twins may die due to the effects of receiving too little blood, receiving too much blood, or having too small a share of the common placenta (severe placenta insufficiency). Blood may then pass from the live twin to the deceased twin, and the live twin may experience low blood pressure (hypotension) and/or inadequate blood flow to its tissues (severe hypoxia). Such decreased blood flow to certain areas of this fetal twin could be life-threatening or could result in a variety of developmental abnormalities, which might include malformations of the hands, arms, feet, and/or legs (terminal limb defects); underdevelopment of one side of the face (hemifacial microsomia); obstruction of the intestine (intestinal atresia); tissue damage and loss in the outer layer of the kidney (renal cortical necrosis); and/or a clot blocking an artery in the heart (coronary thrombosis). In some cases, severe injuries to the brain may occur, resulting in cysts or cavities in the brain's outer layer (porencephaly) and/or absence of the brain's cerebral hemispheres (hydranencephaly). (For more information on this disorder, choose “Hydranencephaly” as your search term in the Rare Disease Database.)
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Symptoms of Twin-Twin Transfusion Syndrome. Twin-twin transfusion syndrome (TTTS) is a rare disorder that sometimes occurs when women are pregnant with identical (monozygotic) twins. TTTS is a disease of the placenta, the organ that develops in the uterus during pregnancy, links the mother's blood supply to the fetuses', and provides nourishment to her offspring. The developing fetal twins are typically normal until abnormalities in blood flow within the placenta cause the TTTS disease process to occur. The majority of identical twins share a common placenta in which blood vessels connect the fetuses' umbilical cords and blood circulations (placental anastomoses). The umbilical cords join the fetal twins to the placenta. In most cases, the blood flow is balanced between the twins through these connecting blood vessels. However, when twin-twin transfusion syndrome occurs, the blood begins to flow unevenly through the connecting blood vessels. As a result, one fetal twin receives too much blood (recipient), while the other receives too little (donor). The fetal twins, though developing normally up to this point, may now begin to exhibit various symptoms, depending upon when in the pregnancy the imbalance in blood flow (twin-twin transfusion) has taken place. The twin-twin transfusion may occur at any time during pregnancy. If the imbalance in blood flow occurs early in the pregnancy (first trimester), one of the fetal twins may simply cease developing; as a result, only one fetus will be detected for the remainder of the pregnancy. If the transfusion occurs shortly before or during delivery, the twins may exhibit symptoms related to a sudden lack or excess of blood supply. However, should twin- twin transfusion syndrome occur during mid-pregnancy (second trimester), a variety of symptoms may occur. For example, the twin that receives extra blood (recipient) begins to produce more urine than normal (polyuria), resulting in excessive amniotic fluid surrounding the fetus within its amniotic sac (hydramnios). Such an excess of amniotic fluid can develop quickly, often over two to three weeks As a result, the mother's abdomen grows larger than normal for her stage of pregnancy. In most cases, this is the first symptom of twin-twin transfusion syndrome. Left untreated, the excess amniotic fluid can cause preterm labor or rupture the amniotic sac, resulting in potentially very early delivery. On the other hand, because the other fetal twin (donor) receives too little blood and has abnormally low levels of circulating fluid in its body (hypovolemia), its kidneys may stop producing urine (renal shutdown); there may therefore be very little fluid in the donor twin's amniotic sac (oligohydramnios). As a result, the sac's membranes (amnion) may collapse around the fetus. Because this fetal twin may appear stuck or “cocooned” within the collapsed membranes, it is sometimes called the “stuck twin”. During normal fetal development, most identical (monozygotic) twins grow at approximately the same rate and have similar weights when they are born. However, if fetal twins are affected by twin-twin transfusion syndrome by mid-pregnancy (second trimester), they may begin to vary greatly in development rate and size. While the recipient twin may become larger in size than normal, the donor twin may suffer from severe growth retardation. Some researchers believe that uneven sharing of portions of the common, shared placenta may also contribute to different rates of growth. The difference in sizes of the twins may persist even after birth through infancy. Both recipient and donor fetal twins may exhibit other symptoms as well. The extra blood supply to the recipient twin may cause heart failure resulting in fluid to accumulating in some of its body cavities (hydrops), such as in the abdominal cavity (ascites), around the lungs (pleural effusion), and/or around the heart (pericardial effusion). Receiving excess blood places continual strain on the fetus's heart and blood vessels (cardiovascular system), which may eventually cause congestive heart failure. On the other hand, the donor twin has an inadequate supply of blood, possibly causing a potentially life- threatening anemia and growth restriction. If the recipient twin develops hydrops or the donor twin develops severe growth restriction, inadequate supply of oxygen (hypoxia) to the developing brain may occur during pregnancy or from respiratory distress syndrome (RDS) associated with early (preterm) delivery. As a result, brain damage may occur, potentially causing Cerebral Palsy. (For more information on this disorder, use “Cerebral Palsy” as your search term in the Rare Disease Database.) When twin-twin transfusion syndrome occurs in mid-pregnancy, one of the fetal twins may die due to the effects of receiving too little blood, receiving too much blood, or having too small a share of the common placenta (severe placenta insufficiency). Blood may then pass from the live twin to the deceased twin, and the live twin may experience low blood pressure (hypotension) and/or inadequate blood flow to its tissues (severe hypoxia). Such decreased blood flow to certain areas of this fetal twin could be life-threatening or could result in a variety of developmental abnormalities, which might include malformations of the hands, arms, feet, and/or legs (terminal limb defects); underdevelopment of one side of the face (hemifacial microsomia); obstruction of the intestine (intestinal atresia); tissue damage and loss in the outer layer of the kidney (renal cortical necrosis); and/or a clot blocking an artery in the heart (coronary thrombosis). In some cases, severe injuries to the brain may occur, resulting in cysts or cavities in the brain's outer layer (porencephaly) and/or absence of the brain's cerebral hemispheres (hydranencephaly). (For more information on this disorder, choose “Hydranencephaly” as your search term in the Rare Disease Database.)
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Twin-Twin Transfusion Syndrome
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Causes of Twin-Twin Transfusion Syndrome
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The exact cause of TTTS is not fully understood. However, it is known that abnormalities during division of the mother's egg after it has been fertilized lead to the placental abnormalities that can ultimately result in twin-twin transfusion syndrome. The normal development of identical (monozygotic) twins begins with the fertilization of the mother's egg (ovum) by the father's sperm. Within the first three days after fertilization, the fertilized egg (zygote) divides into two complete, identical embryos. These two embryos, which are nourished by separate placentas (dichorionic) during the pregnancy, ultimately develop into two individuals (monozygotic twins) who have almost identical genetic make-ups. In some cases of monozygotic twin development, however, a zygote takes longer than three days to divide into two complete embryos. Scientists have observed that the longer it takes the zygote to divide, the more problems are likely to occur in identical twin pregnancies. If the zygote takes from four to eight days to divide, the twins share a common placenta (monochorionic) and the membrane that separates the fetal twins' two amniotic sacs is thin (diamnionic). If the fertilized egg divides in eight to twelve days, the twins share a common placenta (monochorionic) and no dividing membrane is present; therefore, the two fetuses essentially share one amniotic sac (monoamnionic). Twin-twin transfusion syndrome has been reported to occur in both of these types of pregnancies (monochorionic-diamnionic and monochorionic- monoamnionic); however, the vast majority of cases of TTTS occur in monochorionic-diamnionic pregnancies. It is not understood why a zygote divides into twins nor why it takes longer than normal to divide in some cases. In all monochorionic twin pregnancies, there are blood vessels in the shared placenta that connect the fetuses' umbilical cords and blood circulations together (anastomoses). The placenta, which is connected to the fetuses by their umbilical cords, links the mother's blood supply to her offspring's. This enables the exchange of waste products from the fetuses to the mother for excretion and enables the transfer of oxygen and nutrients from the mother's blood to the fetuses'. In most cases, the blood flow is relatively balanced through these connecting blood vessels. However, in twin-twin transfusion syndrome, the blood begins to flow unevenly through the anastomoses. Scientists do not understood what causes such an imbalance in blood flow to take place. However, it is believed that several different factors may play a role, including the degree to which the placenta may be unevenly shared by the twin fetuses, the type and number of connecting blood vessels (anastomoses) in the shared placenta, and changes in pressure within the mother's uterus (such as occurs with polyhydramnios or with uterine contractions during delivery).
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Causes of Twin-Twin Transfusion Syndrome. The exact cause of TTTS is not fully understood. However, it is known that abnormalities during division of the mother's egg after it has been fertilized lead to the placental abnormalities that can ultimately result in twin-twin transfusion syndrome. The normal development of identical (monozygotic) twins begins with the fertilization of the mother's egg (ovum) by the father's sperm. Within the first three days after fertilization, the fertilized egg (zygote) divides into two complete, identical embryos. These two embryos, which are nourished by separate placentas (dichorionic) during the pregnancy, ultimately develop into two individuals (monozygotic twins) who have almost identical genetic make-ups. In some cases of monozygotic twin development, however, a zygote takes longer than three days to divide into two complete embryos. Scientists have observed that the longer it takes the zygote to divide, the more problems are likely to occur in identical twin pregnancies. If the zygote takes from four to eight days to divide, the twins share a common placenta (monochorionic) and the membrane that separates the fetal twins' two amniotic sacs is thin (diamnionic). If the fertilized egg divides in eight to twelve days, the twins share a common placenta (monochorionic) and no dividing membrane is present; therefore, the two fetuses essentially share one amniotic sac (monoamnionic). Twin-twin transfusion syndrome has been reported to occur in both of these types of pregnancies (monochorionic-diamnionic and monochorionic- monoamnionic); however, the vast majority of cases of TTTS occur in monochorionic-diamnionic pregnancies. It is not understood why a zygote divides into twins nor why it takes longer than normal to divide in some cases. In all monochorionic twin pregnancies, there are blood vessels in the shared placenta that connect the fetuses' umbilical cords and blood circulations together (anastomoses). The placenta, which is connected to the fetuses by their umbilical cords, links the mother's blood supply to her offspring's. This enables the exchange of waste products from the fetuses to the mother for excretion and enables the transfer of oxygen and nutrients from the mother's blood to the fetuses'. In most cases, the blood flow is relatively balanced through these connecting blood vessels. However, in twin-twin transfusion syndrome, the blood begins to flow unevenly through the anastomoses. Scientists do not understood what causes such an imbalance in blood flow to take place. However, it is believed that several different factors may play a role, including the degree to which the placenta may be unevenly shared by the twin fetuses, the type and number of connecting blood vessels (anastomoses) in the shared placenta, and changes in pressure within the mother's uterus (such as occurs with polyhydramnios or with uterine contractions during delivery).
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Affects of Twin-Twin Transfusion Syndrome
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TTTS is a rare disorder that sometimes occurs when a mother is pregnant with identical (monozygotic) twins. There have been a few reported cases in which TTTS also affected identical triplets. Twin-twin transfusion syndrome affects approximately 5 to 15 percent of identical twin pregnancies, meaning that approximately 6,000 babies may be affected each year. However, it is difficult to determine the true frequency of TTTS in the general population since many cases are never diagnosed and many go unrecorded.
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Affects of Twin-Twin Transfusion Syndrome. TTTS is a rare disorder that sometimes occurs when a mother is pregnant with identical (monozygotic) twins. There have been a few reported cases in which TTTS also affected identical triplets. Twin-twin transfusion syndrome affects approximately 5 to 15 percent of identical twin pregnancies, meaning that approximately 6,000 babies may be affected each year. However, it is difficult to determine the true frequency of TTTS in the general population since many cases are never diagnosed and many go unrecorded.
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Related disorders of Twin-Twin Transfusion Syndrome
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Symptoms of the following disorders can be similar to those of twin-twin transfusion syndrome. Comparisons may be useful for a differential diagnosis: Acardiac twinning is a rare disorder that sometimes occurs when women are pregnant with identical (monozygotic) twins. A few cases have also been reported in identical triplets. In acardiac twinning, there is a direct connection of one of the two umbilical arteries of one twin to that of the other twin that has only one umbilical artery and vein. Some researchers believe that the fetal twins may initially experience normal very early embryonic development. However, very early in pregnancy, the blood begins to flow improperly through the fetuses' connecting umbilical artery to artery connection, and one twin (the “pump twin”) begins to provide circulation for both fetuses. Depending upon when in the pregnancy this imbalance in blood flow occurs, the other twin's developing heart may fail to develop normally, resulting in absence of a rccognizable cardiac structure or presence of very primitive cardiac structures. In all cases, this twin (acardiac twin) will also exhibit other major abnormalities, such as the absence of head structures or the brain (anencephaly). In most cases, the pump twin does not exhibit developmental malformations; however, the constant strain on its heart of having to provide blood to the other twin may cause it to experience heart failure. In acardiac twinning, an excess of amniotic fluid may occur (hydramnios), causing the mother's uterus to grow at a faster rate than normal for her stage of pregnancy. Early (preterm) labor often occurs. Some researchers believe that acardiac twinning is in fact an extreme form of twin-twin transfusion syndrome. The cause of acardiac twinning is not known.
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Related disorders of Twin-Twin Transfusion Syndrome. Symptoms of the following disorders can be similar to those of twin-twin transfusion syndrome. Comparisons may be useful for a differential diagnosis: Acardiac twinning is a rare disorder that sometimes occurs when women are pregnant with identical (monozygotic) twins. A few cases have also been reported in identical triplets. In acardiac twinning, there is a direct connection of one of the two umbilical arteries of one twin to that of the other twin that has only one umbilical artery and vein. Some researchers believe that the fetal twins may initially experience normal very early embryonic development. However, very early in pregnancy, the blood begins to flow improperly through the fetuses' connecting umbilical artery to artery connection, and one twin (the “pump twin”) begins to provide circulation for both fetuses. Depending upon when in the pregnancy this imbalance in blood flow occurs, the other twin's developing heart may fail to develop normally, resulting in absence of a rccognizable cardiac structure or presence of very primitive cardiac structures. In all cases, this twin (acardiac twin) will also exhibit other major abnormalities, such as the absence of head structures or the brain (anencephaly). In most cases, the pump twin does not exhibit developmental malformations; however, the constant strain on its heart of having to provide blood to the other twin may cause it to experience heart failure. In acardiac twinning, an excess of amniotic fluid may occur (hydramnios), causing the mother's uterus to grow at a faster rate than normal for her stage of pregnancy. Early (preterm) labor often occurs. Some researchers believe that acardiac twinning is in fact an extreme form of twin-twin transfusion syndrome. The cause of acardiac twinning is not known.
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Diagnosis of Twin-Twin Transfusion Syndrome
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TTTS can be detected during mid-pregnancy (second trimester) by ultrasonography, an instrument that creates a fetal image by measuring the reflection of sound waves. Ultrasound findings that may indicate twin-twin transfusion syndrome include the presence of same-sex twins; a single, shared placenta (monochorionic), a thin membrane dividing the fetuses' amniotic sacs; differences in the amount of amniotic fluid with polyhydramnios (defined as a largest vertical pocket of fluid greater than 8 cm in the larger twin) and oligohydramnios (defined as a largest vertical pocket of less than 2cm in the smaller twin), and a size difference of greater than 20%. Present staging or classification of the severity of the disease currently follows that proposed by Quintero in 1999. This staging system has been a useful tool to allow physicians to compare treatment results and for choosing between different management strategies as it incorporates the worsening severity of the disease process in each of the increasing stages. It does, however, create the impression that the natural history of TTTS follows an orderly progression over time. Unfortunately, clinical experience has shown that this is not the case and progression of the disease processes are highly variable and somewhat unpredictable. This staging system also does not include elements describing the fundamental cardiovascular changes that are key to understanding the disease and are present in subtle forms even at the earliest stages of the disease process.Examination of the placenta by physicians after delivery can confirm the twins' monochorionic status, the presence of connecting blood vessels (placental anastomoses), and the diagnosis of twin-twin transfusion syndrome.
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Diagnosis of Twin-Twin Transfusion Syndrome. TTTS can be detected during mid-pregnancy (second trimester) by ultrasonography, an instrument that creates a fetal image by measuring the reflection of sound waves. Ultrasound findings that may indicate twin-twin transfusion syndrome include the presence of same-sex twins; a single, shared placenta (monochorionic), a thin membrane dividing the fetuses' amniotic sacs; differences in the amount of amniotic fluid with polyhydramnios (defined as a largest vertical pocket of fluid greater than 8 cm in the larger twin) and oligohydramnios (defined as a largest vertical pocket of less than 2cm in the smaller twin), and a size difference of greater than 20%. Present staging or classification of the severity of the disease currently follows that proposed by Quintero in 1999. This staging system has been a useful tool to allow physicians to compare treatment results and for choosing between different management strategies as it incorporates the worsening severity of the disease process in each of the increasing stages. It does, however, create the impression that the natural history of TTTS follows an orderly progression over time. Unfortunately, clinical experience has shown that this is not the case and progression of the disease processes are highly variable and somewhat unpredictable. This staging system also does not include elements describing the fundamental cardiovascular changes that are key to understanding the disease and are present in subtle forms even at the earliest stages of the disease process.Examination of the placenta by physicians after delivery can confirm the twins' monochorionic status, the presence of connecting blood vessels (placental anastomoses), and the diagnosis of twin-twin transfusion syndrome.
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Therapies of Twin-Twin Transfusion Syndrome
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TreatmentThe U.S. Food and Drug Administration in 2006 approved a device known as the Karl Storz Rigid TTTS Fetoscopy Instrument Set under its Humanitarian Device Exemption (HDE) program for the treatment of twin-twin transfusion syndrome. These are surgical tools that include a telescopic camera used to view a fetus (fetoscope) or placenta. These tools are used to identify and obstruct (photocoagulate) the connecting blood vessels (anastamoses) on the placenta using a laser thereby separating the flow of blood within the placenta for each of the twins. The instrument set is manufactured by a company headquartered in Germany, Karl Storz Endoscopy, Inc. The company's U.S. office may be contacted at:Karl Storz Endoscopy-America, Inc.600 Corporate PointeCulver City, CA 90230-7600Email: [email protected]
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Therapies of Twin-Twin Transfusion Syndrome. TreatmentThe U.S. Food and Drug Administration in 2006 approved a device known as the Karl Storz Rigid TTTS Fetoscopy Instrument Set under its Humanitarian Device Exemption (HDE) program for the treatment of twin-twin transfusion syndrome. These are surgical tools that include a telescopic camera used to view a fetus (fetoscope) or placenta. These tools are used to identify and obstruct (photocoagulate) the connecting blood vessels (anastamoses) on the placenta using a laser thereby separating the flow of blood within the placenta for each of the twins. The instrument set is manufactured by a company headquartered in Germany, Karl Storz Endoscopy, Inc. The company's U.S. office may be contacted at:Karl Storz Endoscopy-America, Inc.600 Corporate PointeCulver City, CA 90230-7600Email: [email protected]
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Overview of Typhoid
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Typhoid fever is a bacterial infection that is rare in the United States. However, it is not rare in many other countries. Major symptoms may include unusually high fever, headache, loss of appetite, fatigue, abdominal pain and diarrhea.
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Overview of Typhoid. Typhoid fever is a bacterial infection that is rare in the United States. However, it is not rare in many other countries. Major symptoms may include unusually high fever, headache, loss of appetite, fatigue, abdominal pain and diarrhea.
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Typhoid
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Symptoms of Typhoid
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Typhoid is an intestinal infection caused by the bacterium Salmonella typhi. Antibodies to the bacteria can be detected in the blood (Widal's test). Salmonella typhi can be cultured from the patient's blood, urine and feces as well. The infection incubates for one or two weeks. A gradual development of headache, loss of appetite, fatigue and constipation occurs. During the following weeks there is a gradual rise in temperature to about 104 F, abdominal pain, a slowed pulse rate, nosebleeds, rose-colored spots on the chest and diarrhea. Intestinal ulceration and bleeding can lead to anemia and peritonitis. These conditions may be fatal if the patient is left untreated. Heart failure may also occur.Even after a complete recovery from Typhoid fever the patient may remain a carrier of the bacteria for a number of weeks, months or even years. Those who have had Typhoid should be very careful of personal hygiene and avoid handling food that other people eat until the bacteria is no longer present in the patient's feces.
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Symptoms of Typhoid. Typhoid is an intestinal infection caused by the bacterium Salmonella typhi. Antibodies to the bacteria can be detected in the blood (Widal's test). Salmonella typhi can be cultured from the patient's blood, urine and feces as well. The infection incubates for one or two weeks. A gradual development of headache, loss of appetite, fatigue and constipation occurs. During the following weeks there is a gradual rise in temperature to about 104 F, abdominal pain, a slowed pulse rate, nosebleeds, rose-colored spots on the chest and diarrhea. Intestinal ulceration and bleeding can lead to anemia and peritonitis. These conditions may be fatal if the patient is left untreated. Heart failure may also occur.Even after a complete recovery from Typhoid fever the patient may remain a carrier of the bacteria for a number of weeks, months or even years. Those who have had Typhoid should be very careful of personal hygiene and avoid handling food that other people eat until the bacteria is no longer present in the patient's feces.
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Typhoid
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Causes of Typhoid
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Typhoid is caused by the bacterium Salmonella Typhi. It is the most serious of the Salmonella infections. Contaminated food or water is most often the source of a Typhoid outbreak. Contact with a carrier of the bacterium, polluted water, infected food or milk, shellfish harvested from polluted water, or fresh vegetables grown in contaminated soil are all sources of the Salmonella Typhi bacterium. People who have had Typhoid are “carriers” until the bacteria is completely gone from their body. If they touch food served to other people when their hands are not properly washed, they can spread Typhoid to those who eat the food.
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Causes of Typhoid. Typhoid is caused by the bacterium Salmonella Typhi. It is the most serious of the Salmonella infections. Contaminated food or water is most often the source of a Typhoid outbreak. Contact with a carrier of the bacterium, polluted water, infected food or milk, shellfish harvested from polluted water, or fresh vegetables grown in contaminated soil are all sources of the Salmonella Typhi bacterium. People who have had Typhoid are “carriers” until the bacteria is completely gone from their body. If they touch food served to other people when their hands are not properly washed, they can spread Typhoid to those who eat the food.
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Typhoid
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Affects of Typhoid
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Typhoid affects males and females in equal numbers. In the United States there are only about 500 cases of typhoid diagnosed each year, and over 62% of these are contracted in other countries. The major sources of cases in the United States between the years 1975-1984 were Mexico (39%) and India (14%). In Mexico, Latin America, Asia, Africa and the Middle East where the fatality rate is as high as 10% each year, typhoid is still a serious health problem. In the U.S., outbreaks are usually traced to a typhoid carrier in the food handling business (e.g. restaurants, hotels, etc.).Centers for Disease Control (CDC) researchers investigated cases of typhoid fever diagnosed in the U.S. from June 1996 through May 1997. They found that, of the 282 cases for which complete clinical information exists, 81 percent involved foreign travel. (Typically, those who became ill were foreign visitors to the U.S. or foreign-born U.S. residents who had traveled recently to their native countries.) The part of the world most often implicated in this study was the Indian subcontinent. Half of the patients were younger than 21.
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Affects of Typhoid. Typhoid affects males and females in equal numbers. In the United States there are only about 500 cases of typhoid diagnosed each year, and over 62% of these are contracted in other countries. The major sources of cases in the United States between the years 1975-1984 were Mexico (39%) and India (14%). In Mexico, Latin America, Asia, Africa and the Middle East where the fatality rate is as high as 10% each year, typhoid is still a serious health problem. In the U.S., outbreaks are usually traced to a typhoid carrier in the food handling business (e.g. restaurants, hotels, etc.).Centers for Disease Control (CDC) researchers investigated cases of typhoid fever diagnosed in the U.S. from June 1996 through May 1997. They found that, of the 282 cases for which complete clinical information exists, 81 percent involved foreign travel. (Typically, those who became ill were foreign visitors to the U.S. or foreign-born U.S. residents who had traveled recently to their native countries.) The part of the world most often implicated in this study was the Indian subcontinent. Half of the patients were younger than 21.
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Typhoid
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Related disorders of Typhoid
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Symptoms of the following disorders can be similar to those of Typhoid fever. Comparisons may be useful for a differential diagnosis:Salmonella poisoning is a form of gastroenteritis. It is the most common cause of outbreaks of foodborne disease in the United States. This bacteria may infect meat, dairy and vegetable products. Outbreaks are most common in warm weather and in children under the age of seven. Nausea, vomiting, and chills are the most common initial symptoms. These are followed by abdominal pain, diarrhea and fever which may last from five days to several weeks. The CDC estimates that there are approximately 2 to 4 million Salmonellosis cases in the United States each year.Botulism is a form of gastroenteritis caused by a bacterial toxin. This toxin is a neuromuscular poison. It occurs in three forms: foodborne, wound, and infantile botulism. The most common form is foodborne. The patient may experience weakness, fatigue, headache, and dizziness as well as nausea, vomiting, diarrhea and abdominal pain. (For more information on this disorder, choose “Botulism” as your search term in the Rare Disease Database.)Ptomaine Poisoning is the fourth most common cause of bacterial foodborne disease in the United States. It is caused by a protein enterotoxin that is produced after eating infected food, usually meat products. The disease is characterized by severe abdominal cramps and diarrhea. Nausea often occurs as well. However, vomiting and fever are rare.Cholera is a bacterial infection involving the entire small intestine and marked by severe diarrhea and vomiting. Symptoms are caused by a toxin released by the Vibrio cholerae bacteria. Drinking water, or eating seafood, vegetables, and other foods contaminated with the excrement of Cholera patients spreads the disease. (For more information on this disorder, choose “Cholera” as your search term in the Rare Disease Database.)
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Related disorders of Typhoid. Symptoms of the following disorders can be similar to those of Typhoid fever. Comparisons may be useful for a differential diagnosis:Salmonella poisoning is a form of gastroenteritis. It is the most common cause of outbreaks of foodborne disease in the United States. This bacteria may infect meat, dairy and vegetable products. Outbreaks are most common in warm weather and in children under the age of seven. Nausea, vomiting, and chills are the most common initial symptoms. These are followed by abdominal pain, diarrhea and fever which may last from five days to several weeks. The CDC estimates that there are approximately 2 to 4 million Salmonellosis cases in the United States each year.Botulism is a form of gastroenteritis caused by a bacterial toxin. This toxin is a neuromuscular poison. It occurs in three forms: foodborne, wound, and infantile botulism. The most common form is foodborne. The patient may experience weakness, fatigue, headache, and dizziness as well as nausea, vomiting, diarrhea and abdominal pain. (For more information on this disorder, choose “Botulism” as your search term in the Rare Disease Database.)Ptomaine Poisoning is the fourth most common cause of bacterial foodborne disease in the United States. It is caused by a protein enterotoxin that is produced after eating infected food, usually meat products. The disease is characterized by severe abdominal cramps and diarrhea. Nausea often occurs as well. However, vomiting and fever are rare.Cholera is a bacterial infection involving the entire small intestine and marked by severe diarrhea and vomiting. Symptoms are caused by a toxin released by the Vibrio cholerae bacteria. Drinking water, or eating seafood, vegetables, and other foods contaminated with the excrement of Cholera patients spreads the disease. (For more information on this disorder, choose “Cholera” as your search term in the Rare Disease Database.)
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Diagnosis of Typhoid
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Diagnosis of Typhoid.
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Therapies of Typhoid
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Typhoid is treated with the antibiotic drugs chloramphenicol, ampicillin, cefoperazone, pefloxacin, co-trimoxazole or trimethoprim-sulfamethoxazole. Precautions to take, especially when visiting countries with unsanitary conditions, includes the practice of good personal hygiene and careful washing of hands. Avoid drinking untreated water, drinks served with ice, unpeeled fruits and vegetables, and other food that is cooked and not served hot. In food preparation; wash and sanitize utensils in hot water; carefully clean cutting boards, work areas and equipment; keep hot foods at 165 F and cold foods at 40 F or colder to avoid the possible growth of bacteria in food. Typhoid vaccination and food precautions are necessary before traveling to developing countries where this kind of disease is prevalent.
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Therapies of Typhoid. Typhoid is treated with the antibiotic drugs chloramphenicol, ampicillin, cefoperazone, pefloxacin, co-trimoxazole or trimethoprim-sulfamethoxazole. Precautions to take, especially when visiting countries with unsanitary conditions, includes the practice of good personal hygiene and careful washing of hands. Avoid drinking untreated water, drinks served with ice, unpeeled fruits and vegetables, and other food that is cooked and not served hot. In food preparation; wash and sanitize utensils in hot water; carefully clean cutting boards, work areas and equipment; keep hot foods at 165 F and cold foods at 40 F or colder to avoid the possible growth of bacteria in food. Typhoid vaccination and food precautions are necessary before traveling to developing countries where this kind of disease is prevalent.
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Overview of Tyrosine Hydroxylase Deficiency
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Tyrosine hydroxylase deficiency (THD) is a rare genetic disorder characterized by a wide spectrum of symptoms. These symptoms can vary widely in people who are affected, and even among members of the same family. Common symptoms include an uncoordinated manner of walking (abnormal gait) and dystonia. Dystonia is a general term describing involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions (postures). In THD, dystonia usually affects the legs, but can include other parts of the body (generalized dystonia). Additional symptoms may include a tendency to walk on tiptoes, difficulty walking, tremors, eye abnormalities, muscle weakness (hypotonia) and intellectual disability. However, there are fewer than 100 case reports of individuals with THD in the medical literature, so it is difficult to predict all the features of the disorder.THD is caused by changes (mutations) in the TH gene. This gene is important for making the enzyme, or protein, that is necessary to produce dopamine. Dopamine is an important chemical signal (neurotransmitter) that plays a role in motor control and movement. Mutations in the TH gene cause symptoms of THD when inherited in an autosomal recessive pattern.Symptoms can range in severity. Mild and moderate forms may resemble a movement disorder, but typically can be treated with a medication called levodopa. The most severe form of THD typically causes symptoms at a much younger age, with additional symptoms such as low muscle tone, decreased movement and intellectual disability. The severe form of THD often does not respond well to levodopa treatment. Historically, THD was characterized under two different subtypes (type A and B), but because there can be overlapping symptoms, the subtype designations are no longer widely used.
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Overview of Tyrosine Hydroxylase Deficiency. Tyrosine hydroxylase deficiency (THD) is a rare genetic disorder characterized by a wide spectrum of symptoms. These symptoms can vary widely in people who are affected, and even among members of the same family. Common symptoms include an uncoordinated manner of walking (abnormal gait) and dystonia. Dystonia is a general term describing involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions (postures). In THD, dystonia usually affects the legs, but can include other parts of the body (generalized dystonia). Additional symptoms may include a tendency to walk on tiptoes, difficulty walking, tremors, eye abnormalities, muscle weakness (hypotonia) and intellectual disability. However, there are fewer than 100 case reports of individuals with THD in the medical literature, so it is difficult to predict all the features of the disorder.THD is caused by changes (mutations) in the TH gene. This gene is important for making the enzyme, or protein, that is necessary to produce dopamine. Dopamine is an important chemical signal (neurotransmitter) that plays a role in motor control and movement. Mutations in the TH gene cause symptoms of THD when inherited in an autosomal recessive pattern.Symptoms can range in severity. Mild and moderate forms may resemble a movement disorder, but typically can be treated with a medication called levodopa. The most severe form of THD typically causes symptoms at a much younger age, with additional symptoms such as low muscle tone, decreased movement and intellectual disability. The severe form of THD often does not respond well to levodopa treatment. Historically, THD was characterized under two different subtypes (type A and B), but because there can be overlapping symptoms, the subtype designations are no longer widely used.
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Symptoms of Tyrosine Hydroxylase Deficiency
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THD represents a spectrum of disease, and the symptoms can vary greatly from one person to another. In the severe form, symptoms may be obvious early in infancy. In more moderate or mild cases, symptoms may arise later during infancy or even during early childhood.Mild THD
The mild form of THD is characterized by an abnormal manner of walking (gait) that usually becomes apparent sometime during early childhood. Affected children may appear clumsy or uncoordinated when walking or running. They also may or may not develop repetitive, involuntary movements of an arm or leg that force the body into abnormal, sometimes painful, movements and positions (limb dystonia). In some children, an early sign of THD may be the tendency to walk on tiptoes because of tightness or stiffness of leg muscles. Prolonged exercise or fatigue may trigger or worsen symptoms. In some children, symptoms may become worse or more pronounced in the afternoon and evening than in the morning after rest (diurnal fluctuation).Affected children may also experience tremors when attempting to hold certain poses or positions (postural tremors), and they may have abnormal, involuntary eye movements. The symptoms of mild THD slowly become more pronounced (progressive) as affected children age. Without treatment, individuals eventually need wheelchairs due to progressive motor disturbances.Moderate THD
Children with the moderate form of THD have an abnormal manner of walking (abnormal gait), dystonic posturing especially when walking and a tendency to walk on their tiptoes. Some affected children may be unable to coordinate voluntary movements or have involuntary muscle spasms that result in slow, stiff movements of the limbs (spasticity). Speech delays and abnormal eye movements may also occur. Abnormalities of eye movement may range from brief upward eye-rolling movements to oculogyric crisis, a condition characterized by eyes that roll upward for a sustained period of time. As opposed to the mild form of THD, children with the moderate form of THD typically display delays in achieving motor milestones (e.g., sitting up unassisted, crawling) and low muscle tone of the upper body (truncal hypotonia).Children with the moderate form of THD are sometimes referred to as having “infantile Parkinsonism.” This is because their symptoms may resemble those of Parkinson disease: involuntary, rhythmic, quivering movements (tremors), abnormal slowness of movement (bradykinesia) and an inability to remain in a stable or balanced position (postural instability).Severe THD
Symptoms of the severe form of THD are often obvious in the first six months of life and include poor control of voluntary muscles, delays in achieving motor milestones (e.g., sitting up unassisted, crawling), abnormal rigidity of the arms and legs, decreased motor function or activity (hypokinesia), and involuntary muscle spasms that result in slow, stiff movements of the limbs (spasticity). Some children may have diminished muscle tone (hypotonia), which can result in an inability to hold their head up or sit up unassisted. Affected infants may develop spasms of the neck muscles that lead to involuntary tilting of the head and twisting of the neck (torticollis). Additionally, children may have abnormal eye movements, drooping of the upper eyelids (ptosis) and eyes that appear crossed (strabismus). Individuals with the severe form of THD sometimes have other symptoms such as abnormal chewing or swallowing, inability to drink or feed, temperature imbalance, crying and general feelings of discomfort. This is caused by dysfunction of the autonomic nervous system. The autonomic nervous system is the portion of the nervous system that controls or regulates certain involuntary body functions including heart rate, blood pressure, sweating, production and release of certain hormones and bowel or bladder control. Low levels of dopamine can prevent the body from making other neurotransmitters that play important roles in the autonomic nervous system.As infants with severe THD age, they may experience behavioral problems including attention deficiency hyperactivity disorder (ADHD), impulsivity, anxiety, depression and obsessive-compulsive disorder (OCD). Affected children may experience delays in developing speech, learning disabilities or intellectual disability.In some patients, the severe form of THD is characterized by abnormal brain function that develops during infancy and slowly gets worse (progressive infantile encephalopathy). Affected children may also experience episodes of profuse sweating, general feelings of discomfort, lack of energy, irritability and excessive drooling. Infants usually do not show improvement of encephalopathy or motor abilities despite treatment with levodopa. As opposed to mild and moderate forms of THD, individuals with the severe form of THD typically do not experience dystonia or diurnal fluctuation of symptoms.
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Symptoms of Tyrosine Hydroxylase Deficiency. THD represents a spectrum of disease, and the symptoms can vary greatly from one person to another. In the severe form, symptoms may be obvious early in infancy. In more moderate or mild cases, symptoms may arise later during infancy or even during early childhood.Mild THD
The mild form of THD is characterized by an abnormal manner of walking (gait) that usually becomes apparent sometime during early childhood. Affected children may appear clumsy or uncoordinated when walking or running. They also may or may not develop repetitive, involuntary movements of an arm or leg that force the body into abnormal, sometimes painful, movements and positions (limb dystonia). In some children, an early sign of THD may be the tendency to walk on tiptoes because of tightness or stiffness of leg muscles. Prolonged exercise or fatigue may trigger or worsen symptoms. In some children, symptoms may become worse or more pronounced in the afternoon and evening than in the morning after rest (diurnal fluctuation).Affected children may also experience tremors when attempting to hold certain poses or positions (postural tremors), and they may have abnormal, involuntary eye movements. The symptoms of mild THD slowly become more pronounced (progressive) as affected children age. Without treatment, individuals eventually need wheelchairs due to progressive motor disturbances.Moderate THD
Children with the moderate form of THD have an abnormal manner of walking (abnormal gait), dystonic posturing especially when walking and a tendency to walk on their tiptoes. Some affected children may be unable to coordinate voluntary movements or have involuntary muscle spasms that result in slow, stiff movements of the limbs (spasticity). Speech delays and abnormal eye movements may also occur. Abnormalities of eye movement may range from brief upward eye-rolling movements to oculogyric crisis, a condition characterized by eyes that roll upward for a sustained period of time. As opposed to the mild form of THD, children with the moderate form of THD typically display delays in achieving motor milestones (e.g., sitting up unassisted, crawling) and low muscle tone of the upper body (truncal hypotonia).Children with the moderate form of THD are sometimes referred to as having “infantile Parkinsonism.” This is because their symptoms may resemble those of Parkinson disease: involuntary, rhythmic, quivering movements (tremors), abnormal slowness of movement (bradykinesia) and an inability to remain in a stable or balanced position (postural instability).Severe THD
Symptoms of the severe form of THD are often obvious in the first six months of life and include poor control of voluntary muscles, delays in achieving motor milestones (e.g., sitting up unassisted, crawling), abnormal rigidity of the arms and legs, decreased motor function or activity (hypokinesia), and involuntary muscle spasms that result in slow, stiff movements of the limbs (spasticity). Some children may have diminished muscle tone (hypotonia), which can result in an inability to hold their head up or sit up unassisted. Affected infants may develop spasms of the neck muscles that lead to involuntary tilting of the head and twisting of the neck (torticollis). Additionally, children may have abnormal eye movements, drooping of the upper eyelids (ptosis) and eyes that appear crossed (strabismus). Individuals with the severe form of THD sometimes have other symptoms such as abnormal chewing or swallowing, inability to drink or feed, temperature imbalance, crying and general feelings of discomfort. This is caused by dysfunction of the autonomic nervous system. The autonomic nervous system is the portion of the nervous system that controls or regulates certain involuntary body functions including heart rate, blood pressure, sweating, production and release of certain hormones and bowel or bladder control. Low levels of dopamine can prevent the body from making other neurotransmitters that play important roles in the autonomic nervous system.As infants with severe THD age, they may experience behavioral problems including attention deficiency hyperactivity disorder (ADHD), impulsivity, anxiety, depression and obsessive-compulsive disorder (OCD). Affected children may experience delays in developing speech, learning disabilities or intellectual disability.In some patients, the severe form of THD is characterized by abnormal brain function that develops during infancy and slowly gets worse (progressive infantile encephalopathy). Affected children may also experience episodes of profuse sweating, general feelings of discomfort, lack of energy, irritability and excessive drooling. Infants usually do not show improvement of encephalopathy or motor abilities despite treatment with levodopa. As opposed to mild and moderate forms of THD, individuals with the severe form of THD typically do not experience dystonia or diurnal fluctuation of symptoms.
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Causes of Tyrosine Hydroxylase Deficiency
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THD is caused by mutations of the tyrosine hydroxylase (TH) gene and is inherited in an autosomal 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 of having 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.The TH gene contains instructions for creating (encoding) the enzyme tyrosine hydroxylase. This enzyme converts the amino acid tyrosine into levodopa, which is then converted to dopamine. Dopamine is a neurotransmitter, a chemical that modifies, amplifies or transmits nerve impulses from one nerve cell (neuron) to another, allowing nerve cells to communicate. Dopamine is also converted into two additional neurotransmitters, norepinephrine and epinephrine (adrenaline), that are involved in the autonomic nervous system. Dopamine is critical for the proper function of certain processes of the brain, especially those that control movement. Mutations of the TH gene can result in deficient levels of tyrosine hydroxylase, which, in turn, causes a deficiency of levodopa, dopamine, norepinephrine and epinephrine, ultimately leading to the symptoms of THD.THD may be classified as: (1) a form of dystonia, (2) an inherited neurotransmitter disorder or (3) a metabolic disorder.1. Dystonia is a group of neuromuscular disorders in which involuntary muscle contractions force the body into abnormal, sometimes painful, movements and positions (postures).2. Pediatric inherited neurotransmitter disorders are an emerging group of rare disorders characterized by defects in the creation (synthesis) or function of one or more
neurotransmitters, causing a variety of neurological and neuromuscular symptoms. The disorders are differentiated by the specific neurotransmitter involved (e.g., dopamine in THD).3. Metabolism refers to the chemical processes in the body, including those in which complex substances are broken down into simpler ones (catabolism), and those in which complex
substances are built up from simpler ones (anabolism). Inborn errors of metabolism are metabolic disorders and result from abnormal functioning of a specific protein or enzyme that
accelerates particular chemical activities in the body (e.g., tyrosine hydroxylase in THD).
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Causes of Tyrosine Hydroxylase Deficiency. THD is caused by mutations of the tyrosine hydroxylase (TH) gene and is inherited in an autosomal 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 of having 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.The TH gene contains instructions for creating (encoding) the enzyme tyrosine hydroxylase. This enzyme converts the amino acid tyrosine into levodopa, which is then converted to dopamine. Dopamine is a neurotransmitter, a chemical that modifies, amplifies or transmits nerve impulses from one nerve cell (neuron) to another, allowing nerve cells to communicate. Dopamine is also converted into two additional neurotransmitters, norepinephrine and epinephrine (adrenaline), that are involved in the autonomic nervous system. Dopamine is critical for the proper function of certain processes of the brain, especially those that control movement. Mutations of the TH gene can result in deficient levels of tyrosine hydroxylase, which, in turn, causes a deficiency of levodopa, dopamine, norepinephrine and epinephrine, ultimately leading to the symptoms of THD.THD may be classified as: (1) a form of dystonia, (2) an inherited neurotransmitter disorder or (3) a metabolic disorder.1. Dystonia is a group of neuromuscular disorders in which involuntary muscle contractions force the body into abnormal, sometimes painful, movements and positions (postures).2. Pediatric inherited neurotransmitter disorders are an emerging group of rare disorders characterized by defects in the creation (synthesis) or function of one or more
neurotransmitters, causing a variety of neurological and neuromuscular symptoms. The disorders are differentiated by the specific neurotransmitter involved (e.g., dopamine in THD).3. Metabolism refers to the chemical processes in the body, including those in which complex substances are broken down into simpler ones (catabolism), and those in which complex
substances are built up from simpler ones (anabolism). Inborn errors of metabolism are metabolic disorders and result from abnormal functioning of a specific protein or enzyme that
accelerates particular chemical activities in the body (e.g., tyrosine hydroxylase in THD).
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Affects of Tyrosine Hydroxylase Deficiency
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The exact incidence of THD in the general population is unknown. Approximately 100 cases have been reported in the medical literature. Researchers believe that the disorder is often misdiagnosed or goes undiagnosed, making it difficult to determine its true frequency in the general population. THD is a type of dopa-responsive dystonia (DRD). DRD is a group of disorders that have childhood onset of limb dystonia and other symptoms. While the frequency of THD is difficult to determine, DRDs in general have an estimated prevalence of 0.5 to 1 per million worldwide. THD and guanosine triphosphate cyclohydrolase I deficiency (autosomal dominant Segawa syndrome) account for approximately 5-10% of all cases of primary dystonia in childhood.
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Affects of Tyrosine Hydroxylase Deficiency. The exact incidence of THD in the general population is unknown. Approximately 100 cases have been reported in the medical literature. Researchers believe that the disorder is often misdiagnosed or goes undiagnosed, making it difficult to determine its true frequency in the general population. THD is a type of dopa-responsive dystonia (DRD). DRD is a group of disorders that have childhood onset of limb dystonia and other symptoms. While the frequency of THD is difficult to determine, DRDs in general have an estimated prevalence of 0.5 to 1 per million worldwide. THD and guanosine triphosphate cyclohydrolase I deficiency (autosomal dominant Segawa syndrome) account for approximately 5-10% of all cases of primary dystonia in childhood.
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Related disorders of Tyrosine Hydroxylase Deficiency
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Symptoms of the following disorders can be similar to those of tyrosine hydroxylase deficiency. Comparisons may be useful for a differential diagnosis.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 early stages of development (fetal, perinatal, or early childhood stages). There may be problems associated with involuntary movements and seizures, vision, hearing, communication skills, perception levels and intellect. Individuals with cerebral palsy often experience delays in reaching developmental milestones. The specific symptoms associated with cerebral palsy vary greatly from person to person.There are additional metabolic disorders that have been identified in which certain enzyme deficiencies result in disrupted metabolism of one or more neurotransmitters. These disorders include GTP cyclohydrolase I deficiency (dopa-responsive dystonia, or Segawa syndrome) and aromatic L-amino acid decarboxylase deficiency. Although associated neurological and neuromuscular symptoms may vary, these disorders may have certain features that are similar to those associated with THD. Such abnormalities may include low muscle tone (hypotonia), delayed speech, cognitive, motor and other developmental milestones, limb dystonia, irritability, abnormal eye movements and other symptoms and findings. For example, GTP cyclohydrolase I deficiency is an autosomal dominant disorder, meaning that only one non-working copy of the gene is necessary to cause the condition. It is also typically characterized by increased muscle tone and stiffness (rigidity) resulting in involuntary, repeated, twisting movements and distorted posturing (dystonia). Additional findings may include involuntary and rhythmic quivering movements (tremors), abnormal slowness of movement (bradykinesia) and postural instability (i.e., Parkinsonism). In individuals with aromatic L-amino acid decarboxylase deficiency, an autosomal recessive disorder, features may include various movement abnormalities as well as drooping of the upper eyelids (ptosis), temperature instability and excessive sweating. Evidence suggests that there may be other currently unidentified metabolic disorders resulting in disrupted metabolism of neurotransmitters.There are other disorders of infancy or childhood that may be characterized by abnormally diminished muscle tone (hypotonia), psychomotor delays, dystonia, speech and language delays and other symptoms or findings similar to those potentially associated with THD.
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Related disorders of Tyrosine Hydroxylase Deficiency. Symptoms of the following disorders can be similar to those of tyrosine hydroxylase deficiency. Comparisons may be useful for a differential diagnosis.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 early stages of development (fetal, perinatal, or early childhood stages). There may be problems associated with involuntary movements and seizures, vision, hearing, communication skills, perception levels and intellect. Individuals with cerebral palsy often experience delays in reaching developmental milestones. The specific symptoms associated with cerebral palsy vary greatly from person to person.There are additional metabolic disorders that have been identified in which certain enzyme deficiencies result in disrupted metabolism of one or more neurotransmitters. These disorders include GTP cyclohydrolase I deficiency (dopa-responsive dystonia, or Segawa syndrome) and aromatic L-amino acid decarboxylase deficiency. Although associated neurological and neuromuscular symptoms may vary, these disorders may have certain features that are similar to those associated with THD. Such abnormalities may include low muscle tone (hypotonia), delayed speech, cognitive, motor and other developmental milestones, limb dystonia, irritability, abnormal eye movements and other symptoms and findings. For example, GTP cyclohydrolase I deficiency is an autosomal dominant disorder, meaning that only one non-working copy of the gene is necessary to cause the condition. It is also typically characterized by increased muscle tone and stiffness (rigidity) resulting in involuntary, repeated, twisting movements and distorted posturing (dystonia). Additional findings may include involuntary and rhythmic quivering movements (tremors), abnormal slowness of movement (bradykinesia) and postural instability (i.e., Parkinsonism). In individuals with aromatic L-amino acid decarboxylase deficiency, an autosomal recessive disorder, features may include various movement abnormalities as well as drooping of the upper eyelids (ptosis), temperature instability and excessive sweating. Evidence suggests that there may be other currently unidentified metabolic disorders resulting in disrupted metabolism of neurotransmitters.There are other disorders of infancy or childhood that may be characterized by abnormally diminished muscle tone (hypotonia), psychomotor delays, dystonia, speech and language delays and other symptoms or findings similar to those potentially associated with THD.
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Diagnosis of Tyrosine Hydroxylase Deficiency
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A diagnosis of THD is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic findings and a variety of specialized tests. These tests include examination of cerebrospinal fluid (CSF) to detect certain substances (metabolites) that are byproducts of metabolism. Identification of certain metabolites at specific levels can help to distinguish THD from other related neurotransmitter disorders. A sample of CSF is obtained through a procedure called a spinal tap (lumbar puncture) in which a needle is inserted into the spinal canal in the lower back.A diagnosis of THD can be confirmed through molecular genetic testing, which can reveal the precise mutations in the TH gene causing the condition. Molecular genetic testing is available on a clinical basis.
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Diagnosis of Tyrosine Hydroxylase Deficiency. A diagnosis of THD is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic findings and a variety of specialized tests. These tests include examination of cerebrospinal fluid (CSF) to detect certain substances (metabolites) that are byproducts of metabolism. Identification of certain metabolites at specific levels can help to distinguish THD from other related neurotransmitter disorders. A sample of CSF is obtained through a procedure called a spinal tap (lumbar puncture) in which a needle is inserted into the spinal canal in the lower back.A diagnosis of THD can be confirmed through molecular genetic testing, which can reveal the precise mutations in the TH gene causing the condition. Molecular genetic testing is available on a clinical basis.
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Therapies of Tyrosine Hydroxylase Deficiency
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TreatmentTHD is treated with medications to restore normal dopamine levels in the brain. All infants are initially treated with low levels of a medication called levodopa. Dopamine cannot cross the blood-brain barrier, a protective network of blood vessels and cells that allow some materials to enter the brain, while keeping other materials out. Therefore, dopamine would not be able to reach the brain if taken as a medication. Levodopa, however, can cross the blood-brain barrier, and can be given as a drug. In the body, levodopa is easily converted to dopamine after uptake from the gut. A second medication (usually carbidopa) is added to prevent the conversion of levodopa outside of the brain, ensuring that enough can effectively cross the blood-brain barrier.The response to levodopa therapy varies among individuals with THD. Some people, particularly those with mild THD, respond quickly and completely to levodopa therapy, seeing a full reversal of symptoms. In others, the response may take time and improvement is seen slowly over a few months. In some people with the severe form of THD, levodopa therapy may not be effective initially. These patients may require prolonged treatment to eventually lessen symptoms and lead to an overall improvement in motor skills.Some individuals with the severe form of THD are especially prone to the side effects of levodopa therapy including difficulties in performing voluntary movements (dyskinesia), gastroesophageal reflux, vomiting and suppression of appetite. In some patients, the dose of levodopa may need to be adjusted until the medication can effectively treat the disorder while being well tolerated.Genetic counseling is recommended for affected individuals and their families. Physical and speech therapy may be beneficial in some patients. Other treatments are symptomatic and supportive.
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Therapies of Tyrosine Hydroxylase Deficiency. TreatmentTHD is treated with medications to restore normal dopamine levels in the brain. All infants are initially treated with low levels of a medication called levodopa. Dopamine cannot cross the blood-brain barrier, a protective network of blood vessels and cells that allow some materials to enter the brain, while keeping other materials out. Therefore, dopamine would not be able to reach the brain if taken as a medication. Levodopa, however, can cross the blood-brain barrier, and can be given as a drug. In the body, levodopa is easily converted to dopamine after uptake from the gut. A second medication (usually carbidopa) is added to prevent the conversion of levodopa outside of the brain, ensuring that enough can effectively cross the blood-brain barrier.The response to levodopa therapy varies among individuals with THD. Some people, particularly those with mild THD, respond quickly and completely to levodopa therapy, seeing a full reversal of symptoms. In others, the response may take time and improvement is seen slowly over a few months. In some people with the severe form of THD, levodopa therapy may not be effective initially. These patients may require prolonged treatment to eventually lessen symptoms and lead to an overall improvement in motor skills.Some individuals with the severe form of THD are especially prone to the side effects of levodopa therapy including difficulties in performing voluntary movements (dyskinesia), gastroesophageal reflux, vomiting and suppression of appetite. In some patients, the dose of levodopa may need to be adjusted until the medication can effectively treat the disorder while being well tolerated.Genetic counseling is recommended for affected individuals and their families. Physical and speech therapy may be beneficial in some patients. Other treatments are symptomatic and supportive.
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Overview of Tyrosinemia Type 1
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Tyrosinemia type I is a rare autosomal recessive genetic metabolic disorder characterized by lack of the enzyme fumarylacetoacetate hydrolase (FAH), which is needed for the final break down of the amino acid tyrosine. Failure to properly break down tyrosine leads to abnormal accumulation of tyrosine and its metabolites in the liver, potentially resulting in severe liver disease. Tyrosine may also accumulate in the kidneys and central nervous system.Symptoms and physical findings associated with tyrosinemia type I appear in the first months of life and include failure to gain weight and grow at the expected rate (failure to thrive), fever, diarrhea, vomiting, an abnormally enlarged liver (hepatomegaly), and yellowing of the skin and the whites of the eyes (jaundice). Tyrosinemia type I may progress to more serious complications such as severe liver disease, cirrhosis, and hepatocarcinoma if left untreated. Treatment with nitisinone and a low-tyrosine diet should begin as soon as possible after the diagnosis is confirmed.
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Overview of Tyrosinemia Type 1. Tyrosinemia type I is a rare autosomal recessive genetic metabolic disorder characterized by lack of the enzyme fumarylacetoacetate hydrolase (FAH), which is needed for the final break down of the amino acid tyrosine. Failure to properly break down tyrosine leads to abnormal accumulation of tyrosine and its metabolites in the liver, potentially resulting in severe liver disease. Tyrosine may also accumulate in the kidneys and central nervous system.Symptoms and physical findings associated with tyrosinemia type I appear in the first months of life and include failure to gain weight and grow at the expected rate (failure to thrive), fever, diarrhea, vomiting, an abnormally enlarged liver (hepatomegaly), and yellowing of the skin and the whites of the eyes (jaundice). Tyrosinemia type I may progress to more serious complications such as severe liver disease, cirrhosis, and hepatocarcinoma if left untreated. Treatment with nitisinone and a low-tyrosine diet should begin as soon as possible after the diagnosis is confirmed.
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Symptoms of Tyrosinemia Type 1
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Symptoms associated with tyrosinemia type I often vary greatly from person to person. Infants with tyrosinemia type I typically present with either the acute or chronic form of the disorder.The acute form of tyrosinemia type I is present at birth (congenital) or during the first months of life. This form of the disorder is more common and severe than the chronic form. Infants with the acute form exhibit rapid onset of symptoms usually beginning with failure to gain weight and grow at the expected rate (failure to thrive). Additional early symptoms include fever, diarrhea, bloody stools (melena), and vomiting. Affected infants may also exhibit an abnormally enlarged liver (hepatomegaly), a tendency to bruise easily, jaundice, lethargy, and/or irritability. Some affected infants may develop a distinctive, cabbage-like odor.Eventually infants with the acute form of tyrosinemia type I experience developmental delays, an abnormally enlarged spleen (splenomegaly), and accumulation of fluid (edema) in the abdomen (ascites). The disorder may rapidly progresses to acute life-threatening liver failure and blood clotting abnormalities (coagulopathy).The chronic form of tyrosinemia type I occurs less frequently than the acute form and is characterized by a more gradual onset and less severe expression of the symptoms. Symptoms of tyrosinemia type I may not become apparent in infants with the chronic form of the disorder until after six months of age. Failure to thrive is often the first symptom. Additional symptoms include developmental delays and progressive scarring and impaired function (cirrhosis) of the liver resulting in chronic liver failure.Many infants with tyrosinemia type I develop kidney (renal) abnormalities such as renal Fanconi syndrome, a rare disorder characterized by kidney dysfunction that often leads to progressive softening and weakening of the bone structure (rickets). Fanconi syndrome is also associated with episodes of vomiting, dehydration, weakness, and fever.Approximately 40 percent of affected infants also experience episodes of disease affecting many nerves (polyneuropathy) often following a minor infection. These episodes, which may be referred to as neurological crises, are associated with severe pains in the legs and stomach, increased muscle tone (hypertonia), vomiting, obstruction of the intestines (ileus), an irregular heartbeat (tachycardia), and high blood pressure (hypertension). Some affected individuals may also exhibit self-mutilating behavior (e.g., biting one’s tongue or grinding the teeth) during these episodes. Neurological crises and respiratory failure may occur.Affected infants may also experience enlargement (hypertrophy) of the partition that separates the left and right ventricles of the heart and, in some children, of the left ventricular wall (hypertrophic cardiomyopathy). In addition, affected infants and children are at a greater risk than the general population to develop a form of liver cancer known as hepatocellular carcinoma.Treatment of affected children with nitisinone and a low-tyrosine diet has improved survival to over 90% and resulted in normal growth, improved liver function, prevention of cirrhosis, correction of kidney disease and improvement in rickets.
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Symptoms of Tyrosinemia Type 1. Symptoms associated with tyrosinemia type I often vary greatly from person to person. Infants with tyrosinemia type I typically present with either the acute or chronic form of the disorder.The acute form of tyrosinemia type I is present at birth (congenital) or during the first months of life. This form of the disorder is more common and severe than the chronic form. Infants with the acute form exhibit rapid onset of symptoms usually beginning with failure to gain weight and grow at the expected rate (failure to thrive). Additional early symptoms include fever, diarrhea, bloody stools (melena), and vomiting. Affected infants may also exhibit an abnormally enlarged liver (hepatomegaly), a tendency to bruise easily, jaundice, lethargy, and/or irritability. Some affected infants may develop a distinctive, cabbage-like odor.Eventually infants with the acute form of tyrosinemia type I experience developmental delays, an abnormally enlarged spleen (splenomegaly), and accumulation of fluid (edema) in the abdomen (ascites). The disorder may rapidly progresses to acute life-threatening liver failure and blood clotting abnormalities (coagulopathy).The chronic form of tyrosinemia type I occurs less frequently than the acute form and is characterized by a more gradual onset and less severe expression of the symptoms. Symptoms of tyrosinemia type I may not become apparent in infants with the chronic form of the disorder until after six months of age. Failure to thrive is often the first symptom. Additional symptoms include developmental delays and progressive scarring and impaired function (cirrhosis) of the liver resulting in chronic liver failure.Many infants with tyrosinemia type I develop kidney (renal) abnormalities such as renal Fanconi syndrome, a rare disorder characterized by kidney dysfunction that often leads to progressive softening and weakening of the bone structure (rickets). Fanconi syndrome is also associated with episodes of vomiting, dehydration, weakness, and fever.Approximately 40 percent of affected infants also experience episodes of disease affecting many nerves (polyneuropathy) often following a minor infection. These episodes, which may be referred to as neurological crises, are associated with severe pains in the legs and stomach, increased muscle tone (hypertonia), vomiting, obstruction of the intestines (ileus), an irregular heartbeat (tachycardia), and high blood pressure (hypertension). Some affected individuals may also exhibit self-mutilating behavior (e.g., biting one’s tongue or grinding the teeth) during these episodes. Neurological crises and respiratory failure may occur.Affected infants may also experience enlargement (hypertrophy) of the partition that separates the left and right ventricles of the heart and, in some children, of the left ventricular wall (hypertrophic cardiomyopathy). In addition, affected infants and children are at a greater risk than the general population to develop a form of liver cancer known as hepatocellular carcinoma.Treatment of affected children with nitisinone and a low-tyrosine diet has improved survival to over 90% and resulted in normal growth, improved liver function, prevention of cirrhosis, correction of kidney disease and improvement in rickets.
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Causes of Tyrosinemia Type 1
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Tyrosinemia is caused by mutations in the fumarylacetoacetate hydrolase (FAH) gene that is responsible for the production of the FAH enzyme. Deficiency of this enzyme leads to an accumulation of fumarylacetoacetate and accumulation of tyrosine and its metabolites in the liver, kidney, and central nervous system eventually causing tyrosinemia type I.Tyrosinemia type I is inherited as an autosomal recessive genetic condition.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.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.
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Causes of Tyrosinemia Type 1. Tyrosinemia is caused by mutations in the fumarylacetoacetate hydrolase (FAH) gene that is responsible for the production of the FAH enzyme. Deficiency of this enzyme leads to an accumulation of fumarylacetoacetate and accumulation of tyrosine and its metabolites in the liver, kidney, and central nervous system eventually causing tyrosinemia type I.Tyrosinemia type I is inherited as an autosomal recessive genetic condition.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.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.
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Affects of Tyrosinemia Type 1
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Tyrosinemia type I affects males and females in equal numbers. The prevalence has been estimated to be 1 in 100,000 to 120,000 births worldwide. In Quebec, Canada, the birth prevalence is estimated to be 1/16,000. The estimated prevalence in the Saguenay-Lac Saint-Jean region of Quebec is one in 1,850 births. In Norway, the birth prevalence is estimated to be 1 in 60,000 births.
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Affects of Tyrosinemia Type 1. Tyrosinemia type I affects males and females in equal numbers. The prevalence has been estimated to be 1 in 100,000 to 120,000 births worldwide. In Quebec, Canada, the birth prevalence is estimated to be 1/16,000. The estimated prevalence in the Saguenay-Lac Saint-Jean region of Quebec is one in 1,850 births. In Norway, the birth prevalence is estimated to be 1 in 60,000 births.
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Related disorders of Tyrosinemia Type 1
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Signs and symptoms of the following disorders can be similar to those of tyrosinemia type I. Comparisons may be useful for a differential diagnosis:Acute intermittent porphyria (AIP) is one of a group of inherited metabolic disorders known as the porphyrias. AIP is characterized by the deficiency of the enzyme porphobilinogen deaminase (PBG-D), also known as uroporphyrinogen I-synthase. Symptoms may include severe abdominal pain, nausea, vomiting, and constipation. Neurological symptoms similar to tyrosinemia type I may also be present including pain in arms and legs, muscle weakness, rapid heart rate, and increased blood pressure. Affected individuals may also experience hallucinations and seizures. AIP is inherited as an autosomal recessive genetic condition (For more information on this disorder, choose “acute intermittent porphyria” as your search term in the Rare Disease Database.)Galactosemia is a rare, inherited disorder of carbohydrate metabolism that affects the body’s ability to convert galactose (a sugar contained in milk, including human mother’s milk) to glucose (a different type of sugar). Galactose is converted to glucose by a series of three enzyme reactions. Galactosemia is caused by a deficiency of galactose-1-phosphate uridyl transferase enzyme which is vital to this process. Infants with galactosemia appear normal at birth, but within a few days or weeks lose their appetites (anorexia) and start vomiting excessively. Yellowing of the skin and the whites of the eyes (jaundice), enlargement of the liver (hepatomegaly), failure to gain weight and grow at the expected rate (failure to thrive), and, ultimately, accumulation of fluid in the abdominal cavity (ascites) and other swelling (edema) may also occur. Galactosemia is inherited as an autosomal recessive genetic condition. (For more information on this disorder, choose “galactosemia” as your search term in the Rare Disease Database.)Hereditary fructose intolerance (HFI) is a rare, inherited inability to digest fructose (fruit sugar) or its precursors (sugar, sorbitol and brown sugar). The disorder develops because of a deficiency or lack of the enzyme fructose-1-phosphate aldolase, resulting in an accumulation of fructose-1-phosphate in the liver, kidney, and small intestine. Infants with HFI usually develop a strong dislike for sweets and fruit. Soon after fructose is added to the diet of an infant with HFI, symptoms usually become apparent. These may include prolonged vomiting, failure to thrive, and yellowing of the skin and the whites of the eyes (jaundice). Additional symptoms include enlargement of the liver (hepatomegaly) and a tendency towards gastrointestinal bleeding because of abnormalities in the body’s ability to form blood clots. (For more information on this disorder, choose “hereditary fructose intolerance” as your search term in the Rare Disease Database.)Tyrosinemia type II is an autosomal recessive genetic disorder caused by a deficiency of the enzyme tyrosine aminotransferase. Affected children do not have liver abnormalities. Symptoms can include excessive tears from the eyes, eye pain and redness as well as painful skin lesions on the palms and soles and sensitivity to light (photophobia). Developmental delay and intellectual disability are sometimes present. Symptoms improve with a low phenylalanine and tyrosine diet.Tyrosinemia type III is an autosomal recessive genetic disorder caused by a deficiency of the enzyme 4-hydroxyphenylpyruvate dioxygenase. Affected children do not have liver abnormalities. This condition is extremely rare and few children have been described, but symptoms can include loss of balance and coordination (ataxia), skin and eye abnormalities and developmental delay. Symptoms improve with a low phenylalanine and tyrosine diet.
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Related disorders of Tyrosinemia Type 1. Signs and symptoms of the following disorders can be similar to those of tyrosinemia type I. Comparisons may be useful for a differential diagnosis:Acute intermittent porphyria (AIP) is one of a group of inherited metabolic disorders known as the porphyrias. AIP is characterized by the deficiency of the enzyme porphobilinogen deaminase (PBG-D), also known as uroporphyrinogen I-synthase. Symptoms may include severe abdominal pain, nausea, vomiting, and constipation. Neurological symptoms similar to tyrosinemia type I may also be present including pain in arms and legs, muscle weakness, rapid heart rate, and increased blood pressure. Affected individuals may also experience hallucinations and seizures. AIP is inherited as an autosomal recessive genetic condition (For more information on this disorder, choose “acute intermittent porphyria” as your search term in the Rare Disease Database.)Galactosemia is a rare, inherited disorder of carbohydrate metabolism that affects the body’s ability to convert galactose (a sugar contained in milk, including human mother’s milk) to glucose (a different type of sugar). Galactose is converted to glucose by a series of three enzyme reactions. Galactosemia is caused by a deficiency of galactose-1-phosphate uridyl transferase enzyme which is vital to this process. Infants with galactosemia appear normal at birth, but within a few days or weeks lose their appetites (anorexia) and start vomiting excessively. Yellowing of the skin and the whites of the eyes (jaundice), enlargement of the liver (hepatomegaly), failure to gain weight and grow at the expected rate (failure to thrive), and, ultimately, accumulation of fluid in the abdominal cavity (ascites) and other swelling (edema) may also occur. Galactosemia is inherited as an autosomal recessive genetic condition. (For more information on this disorder, choose “galactosemia” as your search term in the Rare Disease Database.)Hereditary fructose intolerance (HFI) is a rare, inherited inability to digest fructose (fruit sugar) or its precursors (sugar, sorbitol and brown sugar). The disorder develops because of a deficiency or lack of the enzyme fructose-1-phosphate aldolase, resulting in an accumulation of fructose-1-phosphate in the liver, kidney, and small intestine. Infants with HFI usually develop a strong dislike for sweets and fruit. Soon after fructose is added to the diet of an infant with HFI, symptoms usually become apparent. These may include prolonged vomiting, failure to thrive, and yellowing of the skin and the whites of the eyes (jaundice). Additional symptoms include enlargement of the liver (hepatomegaly) and a tendency towards gastrointestinal bleeding because of abnormalities in the body’s ability to form blood clots. (For more information on this disorder, choose “hereditary fructose intolerance” as your search term in the Rare Disease Database.)Tyrosinemia type II is an autosomal recessive genetic disorder caused by a deficiency of the enzyme tyrosine aminotransferase. Affected children do not have liver abnormalities. Symptoms can include excessive tears from the eyes, eye pain and redness as well as painful skin lesions on the palms and soles and sensitivity to light (photophobia). Developmental delay and intellectual disability are sometimes present. Symptoms improve with a low phenylalanine and tyrosine diet.Tyrosinemia type III is an autosomal recessive genetic disorder caused by a deficiency of the enzyme 4-hydroxyphenylpyruvate dioxygenase. Affected children do not have liver abnormalities. This condition is extremely rare and few children have been described, but symptoms can include loss of balance and coordination (ataxia), skin and eye abnormalities and developmental delay. Symptoms improve with a low phenylalanine and tyrosine diet.
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Diagnosis of Tyrosinemia Type 1
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A diagnosis of tyrosinemia type I is made based upon a thorough clinical evaluation, a detailed patient history, and specialized tests. A diagnosis of tyrosinemia type I may be suspected in infants who display failure to thrive and an enlarged liver (hepatomegaly) during the first three months of life. The diagnosis is likely when tyrosine metabolites and succinylacetone are detected in the urine. It is also possible to make the diagnosis based on decreased activity of FAH in liver tissue or cultured fibroblasts, but this test is not readily available. Molecular genetic testing for FAH gene mutations is available to confirm the diagnosis.Tyrosinemia type I may also be diagnosed through newborn screening programs. Succinylacetone can be measured on the newborn blood spot by tandem mass spectroscopy. Most states in the U.S. screen every newborn for tyrosinemia type 1. Early detection is important because prompt identification and treatment may prevent the development of serious problems during infancy.Carrier testing and prenatal diagnosis by DNA analysis are available if the specific gene-causing mutation has been identified in the family. Next Generation DNA sequencing techniques, like exome sequencing, whole genome sequencing (WGS) can help in identifying the mutations responsible for the disease. Prenatal diagnosis is also possible by detection of succinylacetone and DNA analysis in amniotic fluid.
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Diagnosis of Tyrosinemia Type 1. A diagnosis of tyrosinemia type I is made based upon a thorough clinical evaluation, a detailed patient history, and specialized tests. A diagnosis of tyrosinemia type I may be suspected in infants who display failure to thrive and an enlarged liver (hepatomegaly) during the first three months of life. The diagnosis is likely when tyrosine metabolites and succinylacetone are detected in the urine. It is also possible to make the diagnosis based on decreased activity of FAH in liver tissue or cultured fibroblasts, but this test is not readily available. Molecular genetic testing for FAH gene mutations is available to confirm the diagnosis.Tyrosinemia type I may also be diagnosed through newborn screening programs. Succinylacetone can be measured on the newborn blood spot by tandem mass spectroscopy. Most states in the U.S. screen every newborn for tyrosinemia type 1. Early detection is important because prompt identification and treatment may prevent the development of serious problems during infancy.Carrier testing and prenatal diagnosis by DNA analysis are available if the specific gene-causing mutation has been identified in the family. Next Generation DNA sequencing techniques, like exome sequencing, whole genome sequencing (WGS) can help in identifying the mutations responsible for the disease. Prenatal diagnosis is also possible by detection of succinylacetone and DNA analysis in amniotic fluid.
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Therapies of Tyrosinemia Type 1
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Treatment
In 2017, Nityr (nitisinone tablets) was approved by the U.S. Food and Drug Administration (FDA) for the treatment of hereditary tyrosinemia type 1. Nityr is manufactured by Cycle Pharmaceuticals.The FDA approved the orphan drug Orfadin, a capsule and oral suspension formulation of nitisinone, to treat tyrosinemia type I in 2002. Nitisinone was developed by Swedish Orphan International Biovitrum AB and is marketed by Sobi, Inc.These drugs should only be prescribed by physicians experienced in treating tyrosinemia type I since the correct dose must be adjusted for each patient according to specific biochemical tests and to the weight. Access to a nutritionist skilled in managing children with inborn errors of metabolism requiring a low protein diet is an important part of therapy. Blood tests should be monitored regularly to maintain the correct dose for the patient.Nitisinone must be used in conjunction with a diet restricted in the amino acids tyrosine and phenylalanine. Treatment with nitisinone and dietary management should begin as soon as possible after the diagnosis is confirmed.Infants with tyrosinemia type I are placed on a low protein diet that contains limited amounts of phenylalanine and tyrosine. Some affected infants have exhibited an improvement of liver and kidney abnormalities with dietary management alone. However, progression to cirrhosis, liver failure and potential hepatocellular carcinoma is still possible. Physicians often recommend that affected individuals observe a strict diet using special medical foods throughout their lifetime.Liver transplantation may be required for affected infants who have already developed end-stage liver failure by the time of diagnosis, have evidence of liver cancer (hepatocellular carcinoma), or do not respond to nitisinone therapy. In some children, liver transplantation improves kidney function.Genetic counseling is recommended for affected individuals and their families. Other treatments are symptomatic and supportive.
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Therapies of Tyrosinemia Type 1. Treatment
In 2017, Nityr (nitisinone tablets) was approved by the U.S. Food and Drug Administration (FDA) for the treatment of hereditary tyrosinemia type 1. Nityr is manufactured by Cycle Pharmaceuticals.The FDA approved the orphan drug Orfadin, a capsule and oral suspension formulation of nitisinone, to treat tyrosinemia type I in 2002. Nitisinone was developed by Swedish Orphan International Biovitrum AB and is marketed by Sobi, Inc.These drugs should only be prescribed by physicians experienced in treating tyrosinemia type I since the correct dose must be adjusted for each patient according to specific biochemical tests and to the weight. Access to a nutritionist skilled in managing children with inborn errors of metabolism requiring a low protein diet is an important part of therapy. Blood tests should be monitored regularly to maintain the correct dose for the patient.Nitisinone must be used in conjunction with a diet restricted in the amino acids tyrosine and phenylalanine. Treatment with nitisinone and dietary management should begin as soon as possible after the diagnosis is confirmed.Infants with tyrosinemia type I are placed on a low protein diet that contains limited amounts of phenylalanine and tyrosine. Some affected infants have exhibited an improvement of liver and kidney abnormalities with dietary management alone. However, progression to cirrhosis, liver failure and potential hepatocellular carcinoma is still possible. Physicians often recommend that affected individuals observe a strict diet using special medical foods throughout their lifetime.Liver transplantation may be required for affected infants who have already developed end-stage liver failure by the time of diagnosis, have evidence of liver cancer (hepatocellular carcinoma), or do not respond to nitisinone therapy. In some children, liver transplantation improves kidney function.Genetic counseling is recommended for affected individuals and their families. Other treatments are symptomatic and supportive.
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Tyrosinemia Type 1
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Overview of UGDH-Related Disorder
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UGDH-related disorder is a rare genetic neurodevelopmental disorder characterized by global developmental delay, speech impairment, seizures and moderate to severe intellectual disability. It is caused by changes (mutations or variants) in the UGDH gene and is inherited in an autosomal recessive pattern. There is no cure for this disorder and treatment is based on the specific symptoms present in each individual.
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Overview of UGDH-Related Disorder. UGDH-related disorder is a rare genetic neurodevelopmental disorder characterized by global developmental delay, speech impairment, seizures and moderate to severe intellectual disability. It is caused by changes (mutations or variants) in the UGDH gene and is inherited in an autosomal recessive pattern. There is no cure for this disorder and treatment is based on the specific symptoms present in each individual.
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Symptoms of UGDH-Related Disorder
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Individuals with UGDH-related disorder present with a combination of developmental delay, epilepsy and intellectual disability. The developmental delay impacts motor skills as well as speech and language development. Low muscle tone (hypotonia) has been reported in all affected individuals and contributes to the delayed motor skills, including delayed walking. Some affected individuals may present with spasticity, dystonia, ataxia, chorea or tremor. Most affected individuals are non-verbal; however, one patient has been reported to speak in simple phrases at six years of age. All affected individuals reported so far have moderate to severe intellectual disability.Onset of seizures can vary from the first few days of life to early childhood. Seizure types can be highly variable. Seizures tend to be severe with early onset in the neonatal period, but other seizure types have been reported and include infantile spasms, focal seizures, myoclonic jerks, febrile seizures, generalized tonic-clonic seizures and atonic seizures. Electroencephalography (EEG) is typically abnormal, and patterns include slow background activity, burst suppression patterns, multifocal spike-wave complexes and hypsarrhythmia. In many patients, seizures remain resistant to therapy, although two affected individuals have been reported to be seizure free on sodium valproate, and one showed good response to ketogenic diet.Most affected individuals have feeding difficulties, especially in the infancy period, with 60% requiring tube feeding, either via a naso-gastric or gastrostomy tube. Drooling is commonly reported in the affected individuals. Respiratory distress secondary to hypotonia has been noted in some patients.Facial features noted in patients with UGDH-related disorder include protruding ear lobes, drooping of eyelid (ptosis), deep set eyes, skin fold of upper eyelid covering the inner corner of the eye (epicanthal fold), short flat philtrum (vertical groove between the base of the nose and the order of the upper lip), full lower lip and pointed chin. Brain imaging usually demonstrates non-specific features, including delayed myelination, enlarged ventricles, cerebral atrophy, cerebellar atrophy and thin corpus callosum.Researchers have been able to identify a core group of symptoms in affected individuals with UGDH-related disorder, but much of this disorder is not fully understood. While most reported affected individuals present with these features, they may not exhibit all the clinical features listed above. Parents should talk to their child’s medical team about their specific case, associated symptoms and overall prognosis.
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Symptoms of UGDH-Related Disorder. Individuals with UGDH-related disorder present with a combination of developmental delay, epilepsy and intellectual disability. The developmental delay impacts motor skills as well as speech and language development. Low muscle tone (hypotonia) has been reported in all affected individuals and contributes to the delayed motor skills, including delayed walking. Some affected individuals may present with spasticity, dystonia, ataxia, chorea or tremor. Most affected individuals are non-verbal; however, one patient has been reported to speak in simple phrases at six years of age. All affected individuals reported so far have moderate to severe intellectual disability.Onset of seizures can vary from the first few days of life to early childhood. Seizure types can be highly variable. Seizures tend to be severe with early onset in the neonatal period, but other seizure types have been reported and include infantile spasms, focal seizures, myoclonic jerks, febrile seizures, generalized tonic-clonic seizures and atonic seizures. Electroencephalography (EEG) is typically abnormal, and patterns include slow background activity, burst suppression patterns, multifocal spike-wave complexes and hypsarrhythmia. In many patients, seizures remain resistant to therapy, although two affected individuals have been reported to be seizure free on sodium valproate, and one showed good response to ketogenic diet.Most affected individuals have feeding difficulties, especially in the infancy period, with 60% requiring tube feeding, either via a naso-gastric or gastrostomy tube. Drooling is commonly reported in the affected individuals. Respiratory distress secondary to hypotonia has been noted in some patients.Facial features noted in patients with UGDH-related disorder include protruding ear lobes, drooping of eyelid (ptosis), deep set eyes, skin fold of upper eyelid covering the inner corner of the eye (epicanthal fold), short flat philtrum (vertical groove between the base of the nose and the order of the upper lip), full lower lip and pointed chin. Brain imaging usually demonstrates non-specific features, including delayed myelination, enlarged ventricles, cerebral atrophy, cerebellar atrophy and thin corpus callosum.Researchers have been able to identify a core group of symptoms in affected individuals with UGDH-related disorder, but much of this disorder is not fully understood. While most reported affected individuals present with these features, they may not exhibit all the clinical features listed above. Parents should talk to their child’s medical team about their specific case, associated symptoms and overall prognosis.
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UGDH-Related Disorder
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nord_1252_2
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Causes of UGDH-Related Disorder
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UGDH-related disorder is caused by changes (mutations or variants) in the UGDH gene. The UGDH gene codes for UDP-glucose dehydrogenase (UDPGDH) protein, which converts UDP-glucose to UDP-glucuronate/UDP-glucuronic acid (UDP-GlcA). UDP-GlcA is a critical component involved in the extracellular matrix in the brain. When both copies of the UGDH gene have variants that affect and/or disrupt UDPGDH protein function, this leads to abnormal development of the brain and results in the clinical features seen in affected individuals.UGDH-related disorder is inherited in an autosomal recessive manner. 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 UGDH-Related Disorder. UGDH-related disorder is caused by changes (mutations or variants) in the UGDH gene. The UGDH gene codes for UDP-glucose dehydrogenase (UDPGDH) protein, which converts UDP-glucose to UDP-glucuronate/UDP-glucuronic acid (UDP-GlcA). UDP-GlcA is a critical component involved in the extracellular matrix in the brain. When both copies of the UGDH gene have variants that affect and/or disrupt UDPGDH protein function, this leads to abnormal development of the brain and results in the clinical features seen in affected individuals.UGDH-related disorder is inherited in an autosomal recessive manner. 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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nord_1252_3
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Affects of UGDH-Related Disorder
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UGDH-related disorder affects males and females in equal numbers. There are less than 50 affected individuals reported worldwide with this disorder. However, the exact number of affected individuals is unknown. Rare disorders often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. Conservative estimates project a prevalence of 1:14,000,000 to 1:2,000,000. In addition, a founder mutation (p.Arg317Gln) has been reported in the Saudi Arabian population.
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Affects of UGDH-Related Disorder. UGDH-related disorder affects males and females in equal numbers. There are less than 50 affected individuals reported worldwide with this disorder. However, the exact number of affected individuals is unknown. Rare disorders often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. Conservative estimates project a prevalence of 1:14,000,000 to 1:2,000,000. In addition, a founder mutation (p.Arg317Gln) has been reported in the Saudi Arabian population.
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UGDH-Related Disorder
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nord_1252_4
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Related disorders of UGDH-Related Disorder
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Clinical features of UGDH-related disorder can overlap with other disorders associated with developmental and epileptic encephalopathies.Barakat-Perenthaler syndrome is caused by variants in UGP2 gene and is inherited in an autosomal recessive pattern. UGP2 encodes for UDP-glucose pyrophosphorylase which is responsible for converting glucose-1-phosphate to UDP-glucose, the precursor for UDPGDH protein. Affected individuals with Barakat-Perenthaler syndrome present with similar features of developmental delay, epileptic encephalopathy and intellectual disability. In addition, these affected individuals develop progressive microcephaly and visual disturbance.
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Related disorders of UGDH-Related Disorder. Clinical features of UGDH-related disorder can overlap with other disorders associated with developmental and epileptic encephalopathies.Barakat-Perenthaler syndrome is caused by variants in UGP2 gene and is inherited in an autosomal recessive pattern. UGP2 encodes for UDP-glucose pyrophosphorylase which is responsible for converting glucose-1-phosphate to UDP-glucose, the precursor for UDPGDH protein. Affected individuals with Barakat-Perenthaler syndrome present with similar features of developmental delay, epileptic encephalopathy and intellectual disability. In addition, these affected individuals develop progressive microcephaly and visual disturbance.
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Diagnosis of UGDH-Related Disorder
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A diagnosis of UGDH-related disorder should be considered in a child presenting with epilepsy, developmental delay, intellectual disability, hypotonia and feeding difficulties. Molecular genetic testing of the UGDH gene is needed to confirm the diagnosis. This is usually done as part of an epilepsy panel or on whole exome/ genome sequencing.
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Diagnosis of UGDH-Related Disorder. A diagnosis of UGDH-related disorder should be considered in a child presenting with epilepsy, developmental delay, intellectual disability, hypotonia and feeding difficulties. Molecular genetic testing of the UGDH gene is needed to confirm the diagnosis. This is usually done as part of an epilepsy panel or on whole exome/ genome sequencing.
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Therapies of UGDH-Related Disorder
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TreatmentManagement of affected individuals with UGDH-related disorder is symptomatic and anticipatory. Each patient is treated for the specific symptoms that they have. There is no gene-specific treatment available currently.The care of affected individuals with UGDH-related disorder requires a multi-disciplinary team approach, consisting of neurologists, developmental pediatricians, geneticists, gastroenterologists, pulmonologist, neurorehabilitative therapists (including physical therapists, occupational therapists, and speech and language therapists) and dieticians.Management can include
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Therapies of UGDH-Related Disorder. TreatmentManagement of affected individuals with UGDH-related disorder is symptomatic and anticipatory. Each patient is treated for the specific symptoms that they have. There is no gene-specific treatment available currently.The care of affected individuals with UGDH-related disorder requires a multi-disciplinary team approach, consisting of neurologists, developmental pediatricians, geneticists, gastroenterologists, pulmonologist, neurorehabilitative therapists (including physical therapists, occupational therapists, and speech and language therapists) and dieticians.Management can include
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Overview of Ulcerative Colitis
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Ulcerative colitis is an inflammatory bowel disease (IBD) of unknown cause. It is characterized by chronic inflammation and ulceration of the lining of the major portion of the large intestine (colon). In most affected individuals, the lowest region of the large intestine, known as the rectum, is initially affected. As the disease progresses, some or all, of the colon may become involved. Although associated symptoms and findings usually become apparent during adolescence or young adulthood, some individuals may experience an initial episode between ages 50 to 70. In other cases, symptom onset may occur as early as the first year of life.Ulcerative colitis is usually a chronic disease with repeated episodes of symptoms and remission (relapsing-remitting). However, some affected individuals may have few episodes, whereas others may have severe, continuous symptoms. During an episode, affected individuals may experience attacks of watery diarrhea that may contain pus, blood, and/or mucus; abdominal pain; fever and chills; weight loss; and/or other symptoms and findings. In severe cases, individuals may be at risk for certain serious complications.For example, severe inflammation and ulceration may result in thinning of the wall of the colon, causing tearing (perforation) of the colon and potentially life-threatening complications. In addition, in some cases, individuals with the disorder may eventually develop more generalized (systemic) symptoms, such as certain inflammatory skin or eye conditions; inflammation, pain, and swelling of certain joints (arthritis); chronic inflammation of the liver (chronic active hepatitis); and/or other findings.The specific underlying cause of ulcerative colitis is unknown. However, genetic, immunologic, infectious, and/or psychologic factors are thought to play some causative role.
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Overview of Ulcerative Colitis. Ulcerative colitis is an inflammatory bowel disease (IBD) of unknown cause. It is characterized by chronic inflammation and ulceration of the lining of the major portion of the large intestine (colon). In most affected individuals, the lowest region of the large intestine, known as the rectum, is initially affected. As the disease progresses, some or all, of the colon may become involved. Although associated symptoms and findings usually become apparent during adolescence or young adulthood, some individuals may experience an initial episode between ages 50 to 70. In other cases, symptom onset may occur as early as the first year of life.Ulcerative colitis is usually a chronic disease with repeated episodes of symptoms and remission (relapsing-remitting). However, some affected individuals may have few episodes, whereas others may have severe, continuous symptoms. During an episode, affected individuals may experience attacks of watery diarrhea that may contain pus, blood, and/or mucus; abdominal pain; fever and chills; weight loss; and/or other symptoms and findings. In severe cases, individuals may be at risk for certain serious complications.For example, severe inflammation and ulceration may result in thinning of the wall of the colon, causing tearing (perforation) of the colon and potentially life-threatening complications. In addition, in some cases, individuals with the disorder may eventually develop more generalized (systemic) symptoms, such as certain inflammatory skin or eye conditions; inflammation, pain, and swelling of certain joints (arthritis); chronic inflammation of the liver (chronic active hepatitis); and/or other findings.The specific underlying cause of ulcerative colitis is unknown. However, genetic, immunologic, infectious, and/or psychologic factors are thought to play some causative role.
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Symptoms of Ulcerative Colitis
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In most cases, the symptoms associated with ulcerative colitis develop gradually; however, in some individuals, symptom onset may be rapid and severe (fulminant). Although the disorder is usually characterized by repeated recurrences and periods of remission, some affected individuals may have infrequent episodes and others may have severe symptoms that are ongoing.The range and severity of associated symptoms and findings may be variable from case to case, depending upon the amount of the colon affected, the degree of inflammation, and/or other factors. Those in whom the disease is limited to the lowest region of the large intestine (rectum) or the rectum and the lowest portion of the colon (sigmoid) tend to have mild disease with few generalized (systemic) symptoms. Other individuals with the disease may have involvement of varying lengths of the colon. Most may have mild to moderate symptoms; however, in some cases, the entire colon may become affected, causing severe symptoms, including systemic inflammatory conditions.The primary symptoms and findings associated with ulcerative colitis typically include a change in stool frequency; watery diarrhea that may contain blood, mucus, and/or pus; and abdominal bloating (distension), discomfort, cramping, and/or pain. Those with primary involvement of the rectum are often affected by rectal bleeding and ineffectual, persistent spasms of the rectum (tenesmus). In individuals with severe ulcerative colitis, episodes may be characterized by bloody, violent diarrhea; high fever and chills; abnormally high levels of certain circulating white blood cells (leukocytosis); excessive loss of fluid from bodily tissues (dehydration); lack of appetite (anorexia); and/or weight loss. Children with the disorder may also be affected by growth retardation.Individuals with severe ulcerative colitis may be at risk for certain complications. Due to chronic blood loss, there may be inadequate levels of iron and reduced levels of the oxygen-carrying component (hemoglobin) of red blood cells (iron-deficiency anemia). Severe inflammation and extensive ulceration may lead to thinning and subsequent perforation of the wall of the colon. In addition, severe inflammation and damage of the intestinal wall may inhibit the wavelike contractions that propel food through the intestines (peristalsis), leading to obstruction (ileus) and potentially massive enlargement of the colon (toxic megacolon).Associated symptoms and findings may include abdominal tenderness or pain, high fever, a high white blood cell count, and/or other abnormalities. Toxic megacolon may lead to perforation of the wall of the colon, allowing leakage of digestive juices and bacteria into the abdominal cavity, which may cause generalized inflammation of the abdominal lining (peritonitis), blood poisoning (septicemia), and potentially life-threatening complications.Some individuals with ulcerative colitis may also have a higher frequency of colon cancer than individuals in the general population. The risk for the development of colon cancer is highest in those with involvement of the entire colon (pancolitis) and who have disease of long duration. Evidence suggests that those with disease involvement limited to the rectum (ulcerative proctitis) do not appear to have an increased risk of colon cancer compared to the general population.Some affected individuals, particularly those with severe ulcerative colitis, may also develop more generalized (systemic) symptoms. Such symptoms and findings may include inflammation (arthritis), pain, and swelling of certain joints of the limbs (peripheral arthritis); inflammation of joints of the spine (ankylosing spondylitis); and/or inflammation of the pelvic joints (sacroiliitis). Some individuals may also develop certain inflammatory skin conditions including the formation of irregular, reddish-blue, pus-containing skin sores and/or multiple, inflammatory, potentially tender skin nodules (pyoderma gangrenosum and/or erythema nodosum).Inflammatory eye conditions may also develop in some cases, such as inflammation of the outermost layers (episcleritis) or the middle layers of the eye (uveitis). Certain of these inflammatory conditions may tend to flare up in association with intestinal symptoms (e.g., peripheral arthritis, episcleritis, skin conditions), while others may occur independently of colitis (e.g., ankylosing spondylitis, sacroiliitis, uveitis). Reports suggest that the latter conditions may develop years before symptoms of colitis.Many individuals with severe ulcerative colitis may also have minor changes in liver function. More rarely, affected individuals may have mild to severe liver disease, such as fatty liver; inflammation and narrowing of the bile ducts (primary sclerosing cholangitis); and/or chronic liver inflammation (chronic active hepatitis), potentially leading to internal scarring and impaired functioning of the liver (cirrhosis).
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Symptoms of Ulcerative Colitis. In most cases, the symptoms associated with ulcerative colitis develop gradually; however, in some individuals, symptom onset may be rapid and severe (fulminant). Although the disorder is usually characterized by repeated recurrences and periods of remission, some affected individuals may have infrequent episodes and others may have severe symptoms that are ongoing.The range and severity of associated symptoms and findings may be variable from case to case, depending upon the amount of the colon affected, the degree of inflammation, and/or other factors. Those in whom the disease is limited to the lowest region of the large intestine (rectum) or the rectum and the lowest portion of the colon (sigmoid) tend to have mild disease with few generalized (systemic) symptoms. Other individuals with the disease may have involvement of varying lengths of the colon. Most may have mild to moderate symptoms; however, in some cases, the entire colon may become affected, causing severe symptoms, including systemic inflammatory conditions.The primary symptoms and findings associated with ulcerative colitis typically include a change in stool frequency; watery diarrhea that may contain blood, mucus, and/or pus; and abdominal bloating (distension), discomfort, cramping, and/or pain. Those with primary involvement of the rectum are often affected by rectal bleeding and ineffectual, persistent spasms of the rectum (tenesmus). In individuals with severe ulcerative colitis, episodes may be characterized by bloody, violent diarrhea; high fever and chills; abnormally high levels of certain circulating white blood cells (leukocytosis); excessive loss of fluid from bodily tissues (dehydration); lack of appetite (anorexia); and/or weight loss. Children with the disorder may also be affected by growth retardation.Individuals with severe ulcerative colitis may be at risk for certain complications. Due to chronic blood loss, there may be inadequate levels of iron and reduced levels of the oxygen-carrying component (hemoglobin) of red blood cells (iron-deficiency anemia). Severe inflammation and extensive ulceration may lead to thinning and subsequent perforation of the wall of the colon. In addition, severe inflammation and damage of the intestinal wall may inhibit the wavelike contractions that propel food through the intestines (peristalsis), leading to obstruction (ileus) and potentially massive enlargement of the colon (toxic megacolon).Associated symptoms and findings may include abdominal tenderness or pain, high fever, a high white blood cell count, and/or other abnormalities. Toxic megacolon may lead to perforation of the wall of the colon, allowing leakage of digestive juices and bacteria into the abdominal cavity, which may cause generalized inflammation of the abdominal lining (peritonitis), blood poisoning (septicemia), and potentially life-threatening complications.Some individuals with ulcerative colitis may also have a higher frequency of colon cancer than individuals in the general population. The risk for the development of colon cancer is highest in those with involvement of the entire colon (pancolitis) and who have disease of long duration. Evidence suggests that those with disease involvement limited to the rectum (ulcerative proctitis) do not appear to have an increased risk of colon cancer compared to the general population.Some affected individuals, particularly those with severe ulcerative colitis, may also develop more generalized (systemic) symptoms. Such symptoms and findings may include inflammation (arthritis), pain, and swelling of certain joints of the limbs (peripheral arthritis); inflammation of joints of the spine (ankylosing spondylitis); and/or inflammation of the pelvic joints (sacroiliitis). Some individuals may also develop certain inflammatory skin conditions including the formation of irregular, reddish-blue, pus-containing skin sores and/or multiple, inflammatory, potentially tender skin nodules (pyoderma gangrenosum and/or erythema nodosum).Inflammatory eye conditions may also develop in some cases, such as inflammation of the outermost layers (episcleritis) or the middle layers of the eye (uveitis). Certain of these inflammatory conditions may tend to flare up in association with intestinal symptoms (e.g., peripheral arthritis, episcleritis, skin conditions), while others may occur independently of colitis (e.g., ankylosing spondylitis, sacroiliitis, uveitis). Reports suggest that the latter conditions may develop years before symptoms of colitis.Many individuals with severe ulcerative colitis may also have minor changes in liver function. More rarely, affected individuals may have mild to severe liver disease, such as fatty liver; inflammation and narrowing of the bile ducts (primary sclerosing cholangitis); and/or chronic liver inflammation (chronic active hepatitis), potentially leading to internal scarring and impaired functioning of the liver (cirrhosis).
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Causes of Ulcerative Colitis
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The exact cause of ulcerative colitis is not known. However, researchers indicate that genetic, immunologic, infectious, and/or other factors may play some contributing role. Because the disorder more commonly occurs in particular populations, such as in people of Jewish descent, and within certain families (kindreds), researchers suggest that genetic predisposition may be a factor in development of the disease. Some indicate that a genetic predisposition may lead to an abnormal intestinal immune response to particular infectious or other environmental agents. However, despite much research in this area, a specific bacterial, viral, fungal, or other infectious cause has not been identified. In addition, no causative immunologic abnormalities specific to ulcerative colitis have been determined.Because the disorder may initially occur or flare up in association with stressful life events, some suspect that emotional factors may play some role. Currently, there is no direct evidence relating the disorder's cause to psychological factors. However, because emotional distress, anxiety, and depression may occur as a reaction to symptoms, many researchers suggest that such factors may affect the course of the disease as well as an affected individual's specific response to treatment.
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Causes of Ulcerative Colitis. The exact cause of ulcerative colitis is not known. However, researchers indicate that genetic, immunologic, infectious, and/or other factors may play some contributing role. Because the disorder more commonly occurs in particular populations, such as in people of Jewish descent, and within certain families (kindreds), researchers suggest that genetic predisposition may be a factor in development of the disease. Some indicate that a genetic predisposition may lead to an abnormal intestinal immune response to particular infectious or other environmental agents. However, despite much research in this area, a specific bacterial, viral, fungal, or other infectious cause has not been identified. In addition, no causative immunologic abnormalities specific to ulcerative colitis have been determined.Because the disorder may initially occur or flare up in association with stressful life events, some suspect that emotional factors may play some role. Currently, there is no direct evidence relating the disorder's cause to psychological factors. However, because emotional distress, anxiety, and depression may occur as a reaction to symptoms, many researchers suggest that such factors may affect the course of the disease as well as an affected individual's specific response to treatment.
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Affects of Ulcerative Colitis
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Ulcerative colitis affects males and females in equal numbers. In the United States and Western Europe, the frequency (i.e., prevalence) of the disease is approximately 70 to 150 cases per 100,000 in the general population. Although symptoms associated with the disorder typically begin between the ages of approximately 15 to 35 years, some people may experience an initial episode between ages 50 to 70. In other cases, symptom onset may occur as early as the first year of life.Ulcerative colitis is more frequent among Caucasians than individuals of Asian or African descent. In addition, the disorder is approximately three to six times more prevalent in individuals of Jewish descent than those of non-Jewish ancestry. According to reports in the medical literature, the prevalence of the disease among closely related (first-degree) relatives appears to be between four to 16 percent.
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Affects of Ulcerative Colitis. Ulcerative colitis affects males and females in equal numbers. In the United States and Western Europe, the frequency (i.e., prevalence) of the disease is approximately 70 to 150 cases per 100,000 in the general population. Although symptoms associated with the disorder typically begin between the ages of approximately 15 to 35 years, some people may experience an initial episode between ages 50 to 70. In other cases, symptom onset may occur as early as the first year of life.Ulcerative colitis is more frequent among Caucasians than individuals of Asian or African descent. In addition, the disorder is approximately three to six times more prevalent in individuals of Jewish descent than those of non-Jewish ancestry. According to reports in the medical literature, the prevalence of the disease among closely related (first-degree) relatives appears to be between four to 16 percent.
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Related disorders of Ulcerative Colitis
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Symptoms of the following disorders may be similar to those of ulcerative colitis. Comparisons may be useful for a differential diagnosis:Crohn's disease is an inflammatory bowel disease (IBD) characterized by chronic inflammation that typically affects the entire thickness of the intestinal wall. (As mentioned above, ulcerative colitis is usually limited to the lining of the colon [except in cases of toxic megacolon and perforation].) Diseased regions may be separated by apparently normal areas (“skip lesions”). Although Crohn's cisease most commonly affects the lowest region of the small intestine (ileum) or the colon, it may involve any region of the gastrointestinal tract. In those with the disorder, chronic inflammation typically leads to thickening, scarring, and ulceration of the intestinal wall.The range and severity of symptoms may vary, depending upon the location of disease involvement, degree of inflammation, and other factors. However, symptoms may commonly include abdominal cramping and/or pain; diarrhea that often does not contain blood; fever; loss of appetite; nausea; weight loss; a general feeling of weakness and fatigue; and/or other features. Rectal bleeding is significantly less common than seen in ulcerative colitis. Chronic inflammation and associated changes may lead to certain complications, such as intestinal obstruction; the development of pockets of infection (abscesses); and/or abnormal channels (fistulas), such as between the intestine and the skin surface or joining different segments of the intestine.Many develop problems around the anal area, including abscesses, fistulas, and deep grooves or cracks (fissures) in the lining of the mucous membrane. Some individuals may also develop more systemic symptoms, such as inflammation (arthritis) of certain joints of the limbs, the spine (ankylosing spondylitis), and/or the pelvis (sacroiliitis); inflammation of the whites of the eyes; inflammatory skin conditions; and/or other abnormalities. The cause of Crohn's disease is unknown. However, it is thought to result from a genetic predisposition that may lead to an abnormal intestinal immune response to an infectious or other environmental agent. (For more information on this disorder, choose “Crohn” as your search term in the Rare Disease Database.)Inflammation of the colon (colitis) due to various other causes may also result in certain symptoms similar to those associated with ulcerative colitis. For example, sudden (acute) colitis may be caused by infection with various microorganisms (infectious colitis), including Salmonella, Shigella, and Entamoeba histolytica. (Intestinal infection with the latter is known as Amebiasis.) Infectious colitis may be characterized by bloody diarrhea, abdominal pain, fever, and, in severe cases, complications similar to those potentially associated with ulcerative colitis. Such features may also be associated with colitis resulting from the use of various antibiotics (antibiotic-associated colitis). Such antibiotics may alter the balance of certain bacteria in the intestine, permitting them to multiply. In most cases, antibiotic-associated colitis is due to the bacterium Clostridium difficile, which produces toxins that may damage the intestinal lining. Colitis may also be caused by radiation therapy to the pelvic or abdominal region (radiation colitis); poor blood supply to the colon (ischemic colitis), particularly in elderly individuals with narrowing of the arteries due to plaque formation (atherosclerosis); and other underlying conditions or disorders. In addition, certain acute, sexually transmitted infections of the rectum (e.g., herpesvirus, gonorrhea) may cause symptoms similar to those associated with ulcerative proctitis.Irritable bowel syndrome is a digestive disorder characterized by an abnormal increase in the motility of the intestines. Symptoms may include varying degrees of crampy abdominal pain or discomfort, constipation and/or diarrhea, and abdominal bloating. Affected individuals may also experience flatulence, nausea, headache, fatigue, anxiety, and/or depression. The cause of the disorder is unknown. However, in some cases, various factors, including emotional stress, certain foods, or medications, may appear to trigger or worsen heightened motility of the gastrointestinal tract. (For more information on this disorder, choose “Irritable Bowel” as your search term in the Rare Disease Database.)Diverticulitis is a digestive disorder characterized by inflammation of one or more of the sacs (diverticula) that can form due to protrusions of the inner lining of the colon. Diverticula most commonly appear within the lowest region of the colon. (Their presence within the colon is referred to as diverticulosis.) Inflammation of diverticula (i.e., diverticulitis) may lead to crampy pain in the lower abdomen; tenderness and rigidity of the abdomen; fever; rectal bleeding; and certain complications, including intestinal obstruction. (For more information on this disorder, choose “Diverticulitis” as your search term in the Rare Disease Database.)Other conditions or disorders may be characterized by diarrhea, rectal bleeding, abdominal pain, weight loss, fever, and/or other symptoms potentially associated with ulcerative colitis. (For further information on these disorders, choose the specific disease name in question as your search term in the Rare Disease Database.)
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Related disorders of Ulcerative Colitis. Symptoms of the following disorders may be similar to those of ulcerative colitis. Comparisons may be useful for a differential diagnosis:Crohn's disease is an inflammatory bowel disease (IBD) characterized by chronic inflammation that typically affects the entire thickness of the intestinal wall. (As mentioned above, ulcerative colitis is usually limited to the lining of the colon [except in cases of toxic megacolon and perforation].) Diseased regions may be separated by apparently normal areas (“skip lesions”). Although Crohn's cisease most commonly affects the lowest region of the small intestine (ileum) or the colon, it may involve any region of the gastrointestinal tract. In those with the disorder, chronic inflammation typically leads to thickening, scarring, and ulceration of the intestinal wall.The range and severity of symptoms may vary, depending upon the location of disease involvement, degree of inflammation, and other factors. However, symptoms may commonly include abdominal cramping and/or pain; diarrhea that often does not contain blood; fever; loss of appetite; nausea; weight loss; a general feeling of weakness and fatigue; and/or other features. Rectal bleeding is significantly less common than seen in ulcerative colitis. Chronic inflammation and associated changes may lead to certain complications, such as intestinal obstruction; the development of pockets of infection (abscesses); and/or abnormal channels (fistulas), such as between the intestine and the skin surface or joining different segments of the intestine.Many develop problems around the anal area, including abscesses, fistulas, and deep grooves or cracks (fissures) in the lining of the mucous membrane. Some individuals may also develop more systemic symptoms, such as inflammation (arthritis) of certain joints of the limbs, the spine (ankylosing spondylitis), and/or the pelvis (sacroiliitis); inflammation of the whites of the eyes; inflammatory skin conditions; and/or other abnormalities. The cause of Crohn's disease is unknown. However, it is thought to result from a genetic predisposition that may lead to an abnormal intestinal immune response to an infectious or other environmental agent. (For more information on this disorder, choose “Crohn” as your search term in the Rare Disease Database.)Inflammation of the colon (colitis) due to various other causes may also result in certain symptoms similar to those associated with ulcerative colitis. For example, sudden (acute) colitis may be caused by infection with various microorganisms (infectious colitis), including Salmonella, Shigella, and Entamoeba histolytica. (Intestinal infection with the latter is known as Amebiasis.) Infectious colitis may be characterized by bloody diarrhea, abdominal pain, fever, and, in severe cases, complications similar to those potentially associated with ulcerative colitis. Such features may also be associated with colitis resulting from the use of various antibiotics (antibiotic-associated colitis). Such antibiotics may alter the balance of certain bacteria in the intestine, permitting them to multiply. In most cases, antibiotic-associated colitis is due to the bacterium Clostridium difficile, which produces toxins that may damage the intestinal lining. Colitis may also be caused by radiation therapy to the pelvic or abdominal region (radiation colitis); poor blood supply to the colon (ischemic colitis), particularly in elderly individuals with narrowing of the arteries due to plaque formation (atherosclerosis); and other underlying conditions or disorders. In addition, certain acute, sexually transmitted infections of the rectum (e.g., herpesvirus, gonorrhea) may cause symptoms similar to those associated with ulcerative proctitis.Irritable bowel syndrome is a digestive disorder characterized by an abnormal increase in the motility of the intestines. Symptoms may include varying degrees of crampy abdominal pain or discomfort, constipation and/or diarrhea, and abdominal bloating. Affected individuals may also experience flatulence, nausea, headache, fatigue, anxiety, and/or depression. The cause of the disorder is unknown. However, in some cases, various factors, including emotional stress, certain foods, or medications, may appear to trigger or worsen heightened motility of the gastrointestinal tract. (For more information on this disorder, choose “Irritable Bowel” as your search term in the Rare Disease Database.)Diverticulitis is a digestive disorder characterized by inflammation of one or more of the sacs (diverticula) that can form due to protrusions of the inner lining of the colon. Diverticula most commonly appear within the lowest region of the colon. (Their presence within the colon is referred to as diverticulosis.) Inflammation of diverticula (i.e., diverticulitis) may lead to crampy pain in the lower abdomen; tenderness and rigidity of the abdomen; fever; rectal bleeding; and certain complications, including intestinal obstruction. (For more information on this disorder, choose “Diverticulitis” as your search term in the Rare Disease Database.)Other conditions or disorders may be characterized by diarrhea, rectal bleeding, abdominal pain, weight loss, fever, and/or other symptoms potentially associated with ulcerative colitis. (For further information on these disorders, choose the specific disease name in question as your search term in the Rare Disease Database.)
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Diagnosis of Ulcerative Colitis
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Diagnosis of Ulcerative Colitis.
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Therapies of Ulcerative Colitis
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TreatmentThe treatment of individuals with ulcerative colitis is directed at controlling inflammation; managing specific symptoms (e.g., diarrhea, rectal bleeding, abdominal pain, etc.); replacing any lost fluids or nutrients; and preventing recurrent episodes.In some cases, physicians may recommend that patients avoid raw vegetables and fruits, eliminate dairy products, and/or make other dietary changes to help alleviate symptoms. In addition, iron supplementation may be advised for individuals with anemia.The medications used to treat individuals with ulcerative colitis may vary, depending upon the extent and severity of the disease and associated symptoms. Certain medications may initially be recommended to help control diarrhea. However, such agents must be used with extreme caution, since they may precipitate enlargement of the colon (colonic dilation) and toxic megacolon in severe cases.In 2005, the FDA approved the biologic Remicade (also known as infliximab) as a treatment for patients with moderate to severe ulcerative colitis that have not completely responded to other treatments. (This drug has been used for several years as a treatment for Crohn's disease.. Remicade targets the immune system and blocks inflammation. It focuses on a protein called tumor necrosis factor (TNF), which is believed to cause inflammation. For information, contact the manufacturer:Centocor, Inc.800/850 Ridgeview DriveHorsham, PA 19044Tel.: (610) 651-6000Fax: (610) 651-6100www.centocor.comRemicade was approved by the FDA in 2011 to treat moderately to severely active ulcerative colitis in children 6 years and older who have had inadequate response to conventional therapy.About half of the people with ulcerative colitis respond to treatment with anti-inflammatory drugs, including a group known as aminosalicylates. For patients who don't respond to those drugs, corticosteroids may be prescribed, but these can cause side effects, including weight gain and acne.The anti-inflammatory agent known as balsalazide (COLAZAL) has been shown effective in alleviating symptoms and inducing remission. It has been approved by the FDA for the treatment of patients with mild to moderately active ulcerative colitis.The drug mesalamine (Asacol) has been approved as a treatment for mild to moderate flare-ups of ulcerative colitis and to maintain remission of ulcerative colitis. For information on this drug, contact the manufacturer, P&G Pharmaceuticals, or visit www.asacol.com.Some affected individuals, such as patients with moderately severe disease, may be prescribed oral corticosteroid therapy, such as prednisone. High-dose therapy with the anti-inflammatory prednisone frequently induces a remission. Once prednisone therapy alleviates inflammation, other medications may also be provided in some cases. The goal is to gradually reduce the dosage of prednisone and eventually withdraw such therapy if possible, since prolonged corticosteroid therapy typically causes certain side effects.Individuals with severe disease may require hospitalization and intravenous administration of corticosteroids and fluids. In addition, those with severe bleeding may also require blood transfusions.Humira (adalimumab) by Abbott Laboratories was approved by the FDA in 2012 as a treatment for moderate-to-severe ulcerative colitis in adults when immunosuppressant medicines like corticosteroids, azathioprine, and 6-mercaptopurine have not worked. Humira is an anti-tumor necrosis factor (TNF) that blocks proteins that play an important role in abnormal inflammatory and immune responses. For more information, please go to http://www.humira.com.Under certain circumstances, surgery may be recommended or required for individuals with ulcerative colitis. Such factors may include an insufficient response to drug therapies; the risk or development of unwanted side effects from medications; the occurrence of certain complications (e.g., perforation, toxic megacolon); or a risk for cancer as seen upon biopsies (see below). Surgery may involve removal of the colon (colectomy) and the rectum with ileostomy. Ileostomy refers to a surgically created connection between the lowest region of the small intestine (ileum) and an opening in the abdominal wall, enabling the discharge of fecal matter. In some cases, there may be alternative surgical procedures available that may maintain continence and avoid ileostomy.Toxic megacolon is a medical emergency that requires immediate, aggressive treatment. Therapy may include discontinuing any antidiarrheal drugs; providing no food by mouth; and administering intravenous fluids, electrolyte replacement, and blood transfusions as required. In addition, treatment is typically provided with intravenous corticosteroid therapy as well as antibiotics due to the possibility of perforation and the associated presence of bacteria in the blood (bacteremia). If perforation appears likely and there is not appropriate improvement, therapy typically includes emergency colectomy.Some individuals with ulcerative colitis may have an increased risk of colon cancer. Therefore, it is recommended that patients receive regular colonoscopies with multiple biopsies, preferably during symptom-free periods, beginning after about eight to 10 years of disease. The advised frequency for such examinations may vary, such as from every six months to two years. If cancer is diagnosed, recommended treatment typically includes colectomy. In addition, if abnormal cellular (dysplastic) changes are found (which may be precancerous), some physicians may suggest colectomy, while others may suggest continued surveillance with repeated colonoscopies. However, because evidence indicates that cancer can be found in association with dysplasia of any grade, definite, confirmed dysplasia is considered a strong indication for colectomy. Therefore, it is important for affected individuals to share any questions and concerns with their doctors regarding potential risks and benefits and the most appropriate options in their particular case.Additional treatment for this disorder is symptomatic and supportive.
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Therapies of Ulcerative Colitis. TreatmentThe treatment of individuals with ulcerative colitis is directed at controlling inflammation; managing specific symptoms (e.g., diarrhea, rectal bleeding, abdominal pain, etc.); replacing any lost fluids or nutrients; and preventing recurrent episodes.In some cases, physicians may recommend that patients avoid raw vegetables and fruits, eliminate dairy products, and/or make other dietary changes to help alleviate symptoms. In addition, iron supplementation may be advised for individuals with anemia.The medications used to treat individuals with ulcerative colitis may vary, depending upon the extent and severity of the disease and associated symptoms. Certain medications may initially be recommended to help control diarrhea. However, such agents must be used with extreme caution, since they may precipitate enlargement of the colon (colonic dilation) and toxic megacolon in severe cases.In 2005, the FDA approved the biologic Remicade (also known as infliximab) as a treatment for patients with moderate to severe ulcerative colitis that have not completely responded to other treatments. (This drug has been used for several years as a treatment for Crohn's disease.. Remicade targets the immune system and blocks inflammation. It focuses on a protein called tumor necrosis factor (TNF), which is believed to cause inflammation. For information, contact the manufacturer:Centocor, Inc.800/850 Ridgeview DriveHorsham, PA 19044Tel.: (610) 651-6000Fax: (610) 651-6100www.centocor.comRemicade was approved by the FDA in 2011 to treat moderately to severely active ulcerative colitis in children 6 years and older who have had inadequate response to conventional therapy.About half of the people with ulcerative colitis respond to treatment with anti-inflammatory drugs, including a group known as aminosalicylates. For patients who don't respond to those drugs, corticosteroids may be prescribed, but these can cause side effects, including weight gain and acne.The anti-inflammatory agent known as balsalazide (COLAZAL) has been shown effective in alleviating symptoms and inducing remission. It has been approved by the FDA for the treatment of patients with mild to moderately active ulcerative colitis.The drug mesalamine (Asacol) has been approved as a treatment for mild to moderate flare-ups of ulcerative colitis and to maintain remission of ulcerative colitis. For information on this drug, contact the manufacturer, P&G Pharmaceuticals, or visit www.asacol.com.Some affected individuals, such as patients with moderately severe disease, may be prescribed oral corticosteroid therapy, such as prednisone. High-dose therapy with the anti-inflammatory prednisone frequently induces a remission. Once prednisone therapy alleviates inflammation, other medications may also be provided in some cases. The goal is to gradually reduce the dosage of prednisone and eventually withdraw such therapy if possible, since prolonged corticosteroid therapy typically causes certain side effects.Individuals with severe disease may require hospitalization and intravenous administration of corticosteroids and fluids. In addition, those with severe bleeding may also require blood transfusions.Humira (adalimumab) by Abbott Laboratories was approved by the FDA in 2012 as a treatment for moderate-to-severe ulcerative colitis in adults when immunosuppressant medicines like corticosteroids, azathioprine, and 6-mercaptopurine have not worked. Humira is an anti-tumor necrosis factor (TNF) that blocks proteins that play an important role in abnormal inflammatory and immune responses. For more information, please go to http://www.humira.com.Under certain circumstances, surgery may be recommended or required for individuals with ulcerative colitis. Such factors may include an insufficient response to drug therapies; the risk or development of unwanted side effects from medications; the occurrence of certain complications (e.g., perforation, toxic megacolon); or a risk for cancer as seen upon biopsies (see below). Surgery may involve removal of the colon (colectomy) and the rectum with ileostomy. Ileostomy refers to a surgically created connection between the lowest region of the small intestine (ileum) and an opening in the abdominal wall, enabling the discharge of fecal matter. In some cases, there may be alternative surgical procedures available that may maintain continence and avoid ileostomy.Toxic megacolon is a medical emergency that requires immediate, aggressive treatment. Therapy may include discontinuing any antidiarrheal drugs; providing no food by mouth; and administering intravenous fluids, electrolyte replacement, and blood transfusions as required. In addition, treatment is typically provided with intravenous corticosteroid therapy as well as antibiotics due to the possibility of perforation and the associated presence of bacteria in the blood (bacteremia). If perforation appears likely and there is not appropriate improvement, therapy typically includes emergency colectomy.Some individuals with ulcerative colitis may have an increased risk of colon cancer. Therefore, it is recommended that patients receive regular colonoscopies with multiple biopsies, preferably during symptom-free periods, beginning after about eight to 10 years of disease. The advised frequency for such examinations may vary, such as from every six months to two years. If cancer is diagnosed, recommended treatment typically includes colectomy. In addition, if abnormal cellular (dysplastic) changes are found (which may be precancerous), some physicians may suggest colectomy, while others may suggest continued surveillance with repeated colonoscopies. However, because evidence indicates that cancer can be found in association with dysplasia of any grade, definite, confirmed dysplasia is considered a strong indication for colectomy. Therefore, it is important for affected individuals to share any questions and concerns with their doctors regarding potential risks and benefits and the most appropriate options in their particular case.Additional treatment for this disorder is symptomatic and supportive.
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Overview of Urachal Cancer
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Urachal cancer is a form of cancer that arises in a structure called the urachus. The urachus is a canal that exists when the fetus is developing before birth. This canal runs from the bladder of the fetus to the belly button (umbilicus). It drains the urinary bladder of the fetus. Between the fourth and fifth month of pregnancy, this canal breaks down (degenerates) into a fibrous band of tissue called a ligament. This ligament runs from the belly button to the top of the bladder and is called the median umbilical ligament. Sometimes, there are tissue remnants of the urachus in adults (about 1/3 of adults have urachal tissue remnants). This usually does not cause any problems. However, sometimes these remnants can potentially become cancerous (malignant). Urachal cancer will often extend into surrounding structures like the bladder and can potentially spread (metastasize) to other areas of the body. The exact, underlying cause of urachal cancer is not fully understood. Surgery is the most common treatment option.
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Overview of Urachal Cancer. Urachal cancer is a form of cancer that arises in a structure called the urachus. The urachus is a canal that exists when the fetus is developing before birth. This canal runs from the bladder of the fetus to the belly button (umbilicus). It drains the urinary bladder of the fetus. Between the fourth and fifth month of pregnancy, this canal breaks down (degenerates) into a fibrous band of tissue called a ligament. This ligament runs from the belly button to the top of the bladder and is called the median umbilical ligament. Sometimes, there are tissue remnants of the urachus in adults (about 1/3 of adults have urachal tissue remnants). This usually does not cause any problems. However, sometimes these remnants can potentially become cancerous (malignant). Urachal cancer will often extend into surrounding structures like the bladder and can potentially spread (metastasize) to other areas of the body. The exact, underlying cause of urachal cancer is not fully understood. Surgery is the most common treatment option.
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Symptoms of Urachal Cancer
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Much about the disorder is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of several factors (e.g., genetic and environmental factors) influencing the disorder prevent physicians from developing a complete picture of associated symptoms and prognosis. Therefore, it is important to note that affected individuals may not have all the symptoms discussed below.Some individuals may not have any symptoms (asymptomatic), and urachal cancer can develop for months or even years before any symptoms become apparent. The most common symptom associated with urachal cancer is blood in the urine (hematuria). Additional common symptoms include painful or difficult urination (dysuria), abdominal or pelvic pain, and irritative voiding, which means that there are changes in the frequency and urgency of urinating. Sometimes, a mass can be felt above the pubic area (suprapubic mass). A urachal cancer tumor often produces mucus, and some affected individuals will have mucus in their urine (mucinuria).Less common signs and symptoms include pus in the urine (pyuria), recurrent urinary tract infections and the discharge of pus, blood, or mucus from the belly button.Affected individuals also have nonspecific symptoms. These are symptoms that are common to many different disorders and include nausea, vomiting, diarrhea, fatigue, fever and unintended weight loss.
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Symptoms of Urachal Cancer. Much about the disorder is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of several factors (e.g., genetic and environmental factors) influencing the disorder prevent physicians from developing a complete picture of associated symptoms and prognosis. Therefore, it is important to note that affected individuals may not have all the symptoms discussed below.Some individuals may not have any symptoms (asymptomatic), and urachal cancer can develop for months or even years before any symptoms become apparent. The most common symptom associated with urachal cancer is blood in the urine (hematuria). Additional common symptoms include painful or difficult urination (dysuria), abdominal or pelvic pain, and irritative voiding, which means that there are changes in the frequency and urgency of urinating. Sometimes, a mass can be felt above the pubic area (suprapubic mass). A urachal cancer tumor often produces mucus, and some affected individuals will have mucus in their urine (mucinuria).Less common signs and symptoms include pus in the urine (pyuria), recurrent urinary tract infections and the discharge of pus, blood, or mucus from the belly button.Affected individuals also have nonspecific symptoms. These are symptoms that are common to many different disorders and include nausea, vomiting, diarrhea, fatigue, fever and unintended weight loss.
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Causes of Urachal Cancer
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The exact underlying cause of urachal cancer is unknown. The exact reason normal cells become cancerous is not known. Researchers speculate that multiple factors including genetic and environmental ones play a role in the development of the disorder. 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.Researchers are studying people with urachal cancer to see whether there are specific gene variants (mutations) that may predispose them to this form of cancer. A predisposition means that a person has gene variants for a particular disorder, but will not develop the disorder unless other factors, such as environmental or immunologic ones, trigger the disorder. Determining specific genetic factors in urachal cancer will open up new pathways for research into the treatment.Risk factors for urachal cancer are not well understood and no definitive risk factors have been identified.Most urachal cancers are adenocarcinomas. Adenocarcinomas arise from gland cells, which tend to secrete mucus. This is why a urachal tumor sometime produces mucus and why some affected individuals have mucus in the urine.
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Causes of Urachal Cancer. The exact underlying cause of urachal cancer is unknown. The exact reason normal cells become cancerous is not known. Researchers speculate that multiple factors including genetic and environmental ones play a role in the development of the disorder. 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.Researchers are studying people with urachal cancer to see whether there are specific gene variants (mutations) that may predispose them to this form of cancer. A predisposition means that a person has gene variants for a particular disorder, but will not develop the disorder unless other factors, such as environmental or immunologic ones, trigger the disorder. Determining specific genetic factors in urachal cancer will open up new pathways for research into the treatment.Risk factors for urachal cancer are not well understood and no definitive risk factors have been identified.Most urachal cancers are adenocarcinomas. Adenocarcinomas arise from gland cells, which tend to secrete mucus. This is why a urachal tumor sometime produces mucus and why some affected individuals have mucus in the urine.
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Affects of Urachal Cancer
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Urachal cancer is a rare disorder. The exact prevalence and incidence of this form of cancer in the general population is unknown. Rare disorders often go misdiagnosed or undiagnosed making it difficult to determine their true frequency in the general population. Urachal cancer accounts for less than 1% of bladder cancers. Males and females are affected. Most people are in their 40-50s when diagnosed with the disorder.
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Affects of Urachal Cancer. Urachal cancer is a rare disorder. The exact prevalence and incidence of this form of cancer in the general population is unknown. Rare disorders often go misdiagnosed or undiagnosed making it difficult to determine their true frequency in the general population. Urachal cancer accounts for less than 1% of bladder cancers. Males and females are affected. Most people are in their 40-50s when diagnosed with the disorder.
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Related disorders of Urachal Cancer
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Symptoms of the following disorders can be similar to those of urachal cancer. Comparisons may be useful for a differential diagnosis.Urachal cancer needs to be differentiated from various forms of bladder cancer, including primary bladder adenocarcinoma. Bladder cancer is one of the most common cancers in the United States. Bladder cancer usually arises from cells that line the inside of the bladder. Blood in the urine (hematuria) is the most common presenting sign. Painful urination, increased frequency of urination and pain in the pelvic or abdominal area are also symptoms. Sometimes, lower back pain may be present. Most forms of bladder cancer are highly treatable if detected early enough.Colorectal adenocarcinoma is a cancer that forms in the colon or the rectum. Adenocarcinomas make up about 90% of all colorectal cancers. Colorectal cancer is one of the most diagnosed cancers in males and females in the United States. This cancer often begins as a small growth called a polyp. Bleeding from the rectum may be a sign of colorectal adenocarcinoma. Fatigue, abdominal pain or discomfort, or a change in bowel habits may also occur.Malakoplakia is an inflammatory condition that most often occurs in the organs of the urinary and genital systems (urogenital tract). Malakoplakia can present as a mass called granuloma, which is a benign tumor made up of inflammatory tissue and certain immune system cells called histiocytes. Affected individuals may have blood in the urine and urinary tract infections.
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Related disorders of Urachal Cancer. Symptoms of the following disorders can be similar to those of urachal cancer. Comparisons may be useful for a differential diagnosis.Urachal cancer needs to be differentiated from various forms of bladder cancer, including primary bladder adenocarcinoma. Bladder cancer is one of the most common cancers in the United States. Bladder cancer usually arises from cells that line the inside of the bladder. Blood in the urine (hematuria) is the most common presenting sign. Painful urination, increased frequency of urination and pain in the pelvic or abdominal area are also symptoms. Sometimes, lower back pain may be present. Most forms of bladder cancer are highly treatable if detected early enough.Colorectal adenocarcinoma is a cancer that forms in the colon or the rectum. Adenocarcinomas make up about 90% of all colorectal cancers. Colorectal cancer is one of the most diagnosed cancers in males and females in the United States. This cancer often begins as a small growth called a polyp. Bleeding from the rectum may be a sign of colorectal adenocarcinoma. Fatigue, abdominal pain or discomfort, or a change in bowel habits may also occur.Malakoplakia is an inflammatory condition that most often occurs in the organs of the urinary and genital systems (urogenital tract). Malakoplakia can present as a mass called granuloma, which is a benign tumor made up of inflammatory tissue and certain immune system cells called histiocytes. Affected individuals may have blood in the urine and urinary tract infections.
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Diagnosis of Urachal Cancer
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A diagnosis of urachal cancer is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Signs that can indicate urachal cancer include blood in the urine, mucous-producing cells in affected tissue and a palpable mass near the bladder. Several different criteria for the diagnosis of urachal cancer have been proposed, but there is no consensus in the medical community on specific diagnostic criteria. The diagnosis of urachal cancer remains a challenge and, consequently, is often diagnosed at a late stage.Clinical Testing and Workup
A variety of tests can be used to aid in making a diagnosis and ruling out other conditions. Some individuals may undergo a cystoscopy. This is a procedure that allows physicians to examine the bladder. A small, thin tube called a cystoscope is run through the tiny tube that carries urine from the body (urethra). The cystoscope has a tiny camera attached to it and allows a physician to view the urethra and the bladder.Urachal tumors most commonly present as a midline, cystic mass near the dome of the bladder. Specialized imaging techniques, which may include ultrasound, computerized tomography (CT) scanning, and magnetic resonance imaging (MRI), are essential in making the diagnosis. These tests can help to pinpoint the location of a tumor and detect whether the cancer has spread to other areas of the body. These tests can also be very useful in helping physicians plan treatment. During an ultrasound, reflected sound waves are used to create an image of internal organs or structures. 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 organs and bodily tissues.If a tumor is found, physicians may surgically remove some of the tumor tissue and study it under a microscope (biopsy). The microscopic study of diseased tissue is called histology and will allow physicians to determine whether a tumor is cancerous and what type of cancer it is.Immunohistochemistry examination may also be performed. This examination involves using antibodies to diagnosis and differentiate cancer. Antibodies are specialized proteins of the immune system that work to help protect the body from foreign substances. Different antibodies react to specific substances, which are collectively called antigens. When doing immunohistochemistry, antibodies are linked to an enzyme or fluorescent dye and exposed to the tissue sample. Specific antibodies will bind to specific antigens and the enzyme or dye will allow physicians to see this under a microscope.
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Diagnosis of Urachal Cancer. A diagnosis of urachal cancer is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Signs that can indicate urachal cancer include blood in the urine, mucous-producing cells in affected tissue and a palpable mass near the bladder. Several different criteria for the diagnosis of urachal cancer have been proposed, but there is no consensus in the medical community on specific diagnostic criteria. The diagnosis of urachal cancer remains a challenge and, consequently, is often diagnosed at a late stage.Clinical Testing and Workup
A variety of tests can be used to aid in making a diagnosis and ruling out other conditions. Some individuals may undergo a cystoscopy. This is a procedure that allows physicians to examine the bladder. A small, thin tube called a cystoscope is run through the tiny tube that carries urine from the body (urethra). The cystoscope has a tiny camera attached to it and allows a physician to view the urethra and the bladder.Urachal tumors most commonly present as a midline, cystic mass near the dome of the bladder. Specialized imaging techniques, which may include ultrasound, computerized tomography (CT) scanning, and magnetic resonance imaging (MRI), are essential in making the diagnosis. These tests can help to pinpoint the location of a tumor and detect whether the cancer has spread to other areas of the body. These tests can also be very useful in helping physicians plan treatment. During an ultrasound, reflected sound waves are used to create an image of internal organs or structures. 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 organs and bodily tissues.If a tumor is found, physicians may surgically remove some of the tumor tissue and study it under a microscope (biopsy). The microscopic study of diseased tissue is called histology and will allow physicians to determine whether a tumor is cancerous and what type of cancer it is.Immunohistochemistry examination may also be performed. This examination involves using antibodies to diagnosis and differentiate cancer. Antibodies are specialized proteins of the immune system that work to help protect the body from foreign substances. Different antibodies react to specific substances, which are collectively called antigens. When doing immunohistochemistry, antibodies are linked to an enzyme or fluorescent dye and exposed to the tissue sample. Specific antibodies will bind to specific antigens and the enzyme or dye will allow physicians to see this under a microscope.
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Therapies of Urachal Cancer
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Treatment
The treatment of urachal cancer is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Specialists in diagnosing and treating cancer (medical oncologists), specialists in diagnosing and treating disorders of the urinary tract (urologists), surgeons, oncology nurses, psychiatrists and other healthcare professionals may need to plan treatment systematically and comprehensively. Psychosocial support for the entire family is essential as well.There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with urachal cancer.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease stage; tumor size; specific urachal cancer subtype; the presence or absence of certain symptoms; an individual’s age and general health and/or other elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of their case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference and other appropriate factors.Surgery is the main treatment option for urachal cancer. Complete removal (resection) of the urachus plus complete resection of the navel (umbilicus) and surrounding soft tissue is often done. This is usually combined with partial or complete removal of the bladder (cystectomy). The surgical removal of these structures is done at the same time (en bloc surgery). Partial cystectomy is associated with a higher quality of life and is the preferred method if possible. Sometimes, nearby lymph nodes are also removed (lymphadenopathy), but there is disagreement in the medical literature as to whether this is beneficial.Urachal cancer that has been successfully treated through surgery can come back (recur). Some affected individuals may need to undergo surgery again. Other individuals may be treated with chemotherapy or radiation therapy. Some individuals with metastatic disease have also been treated with chemotherapy or radiation therapy.Although there are some individual reports in the medical literature of people being treated with chemotherapy or radiation therapy, their effectiveness and safety for individuals with urachal cancer is unknown. Two chemotherapy regimens that have been used to treat urachal cancer include cisplatin-based combination therapies, which are commonly used to treat bladder cancer and 5-fluorouracil-based combination therapies. Clinical studies are necessary to determine what role, if any, and how effective and safe such therapies would be for urachal cancer.
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Therapies of Urachal Cancer. Treatment
The treatment of urachal cancer is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Specialists in diagnosing and treating cancer (medical oncologists), specialists in diagnosing and treating disorders of the urinary tract (urologists), surgeons, oncology nurses, psychiatrists and other healthcare professionals may need to plan treatment systematically and comprehensively. Psychosocial support for the entire family is essential as well.There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with urachal cancer.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease stage; tumor size; specific urachal cancer subtype; the presence or absence of certain symptoms; an individual’s age and general health and/or other elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of their case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference and other appropriate factors.Surgery is the main treatment option for urachal cancer. Complete removal (resection) of the urachus plus complete resection of the navel (umbilicus) and surrounding soft tissue is often done. This is usually combined with partial or complete removal of the bladder (cystectomy). The surgical removal of these structures is done at the same time (en bloc surgery). Partial cystectomy is associated with a higher quality of life and is the preferred method if possible. Sometimes, nearby lymph nodes are also removed (lymphadenopathy), but there is disagreement in the medical literature as to whether this is beneficial.Urachal cancer that has been successfully treated through surgery can come back (recur). Some affected individuals may need to undergo surgery again. Other individuals may be treated with chemotherapy or radiation therapy. Some individuals with metastatic disease have also been treated with chemotherapy or radiation therapy.Although there are some individual reports in the medical literature of people being treated with chemotherapy or radiation therapy, their effectiveness and safety for individuals with urachal cancer is unknown. Two chemotherapy regimens that have been used to treat urachal cancer include cisplatin-based combination therapies, which are commonly used to treat bladder cancer and 5-fluorouracil-based combination therapies. Clinical studies are necessary to determine what role, if any, and how effective and safe such therapies would be for urachal cancer.
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Overview of Urofacial Syndrome
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SummaryUrofacial syndrome (UFS) is an extremely rare inherited disorder characterized by an unusual facial expression and disorder of the urinary tract (uropathy). When the bladder tries to empty, the outlet closes, meaning that the urine goes back towards the kidneys rather than out of the body. This problem can be present at birth (congenital). When affected infants smile, their facial musculature turns upside down or “inverts” so that they appear to be grimacing or crying. The urinary abnormality is due to a failure of nerve signals between the bladder and the spinal cord resulting in incomplete emptying of the bladder (neurogenic or neuropathic bladder). In addition, neurogenic bladder may result in involuntary discharge of urine (enuresis), urinary tract infections and/or abnormal accumulation of urine in the kidneys (hydronephrosis). Additional abnormalities may include inflammation of the kidneys and pelvis (pyelonephritis), backflow of urine into the tubes that carry urine from the kidney to the bladder (vesicoureteral reflex) and constipation. Prompt diagnosis and treatment can reduce or potentially prevent severe, irreversible bladder and kidney damage. Intellect is not affected. Urofacial syndrome can occur due to disruption or changes (mutations or pathogenic variants) of the HPSE2 gene or the LRIG2 gene and is inherited in an autosomal recessive manner.IntroductionUrofacial syndrome was first described in the 1960s by Dr. Bernardo Ochoa, a urological surgeon and researcher from Colombia, South America. The disorder is also known as Ochoa syndrome and was originally believed to be a local disorder, unique to the region where it was first identified. Urofacial syndrome has since been identified in countries and ethnic groups worldwide.
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Overview of Urofacial Syndrome. SummaryUrofacial syndrome (UFS) is an extremely rare inherited disorder characterized by an unusual facial expression and disorder of the urinary tract (uropathy). When the bladder tries to empty, the outlet closes, meaning that the urine goes back towards the kidneys rather than out of the body. This problem can be present at birth (congenital). When affected infants smile, their facial musculature turns upside down or “inverts” so that they appear to be grimacing or crying. The urinary abnormality is due to a failure of nerve signals between the bladder and the spinal cord resulting in incomplete emptying of the bladder (neurogenic or neuropathic bladder). In addition, neurogenic bladder may result in involuntary discharge of urine (enuresis), urinary tract infections and/or abnormal accumulation of urine in the kidneys (hydronephrosis). Additional abnormalities may include inflammation of the kidneys and pelvis (pyelonephritis), backflow of urine into the tubes that carry urine from the kidney to the bladder (vesicoureteral reflex) and constipation. Prompt diagnosis and treatment can reduce or potentially prevent severe, irreversible bladder and kidney damage. Intellect is not affected. Urofacial syndrome can occur due to disruption or changes (mutations or pathogenic variants) of the HPSE2 gene or the LRIG2 gene and is inherited in an autosomal recessive manner.IntroductionUrofacial syndrome was first described in the 1960s by Dr. Bernardo Ochoa, a urological surgeon and researcher from Colombia, South America. The disorder is also known as Ochoa syndrome and was originally believed to be a local disorder, unique to the region where it was first identified. Urofacial syndrome has since been identified in countries and ethnic groups worldwide.
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Symptoms of Urofacial Syndrome
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As the term “urofacial” suggests, the disorder is characterized by urinary and facial problems. The initial finding that may be apparent in affected infants is an unusual “inverted” facial expression. When affected infants attempt to laugh or smile, their facial musculature “inverts” so that they appear to be grimacing or crying. The symptoms and severity of urofacial syndrome can vary greatly, even among affected members of the same family.The urinary abnormality is an obstructive disease of the urinary tract that can be present at birth (congenital obstructive uropathy). This uropathy occurs due to failure of nerve signals between the bladder and spinal cord causing incomplete emptying (voiding) of the bladder (neurogenic or neuropathic bladder). At the lowest point of the bladder, there is a circular band of muscle fibers (urethral sphincter) that opens into the urethra, the tubular structure through which urine is expelled. When the bladder fills with urine, signals are normally sent to the spinal cord. Nerve signals are then sent back that cause the urethral sphincter to relax. The bladder then contracts and sends urine through the urethra and out of the body. However, in affected individuals, there is a failure of such nerve signaling for unknown reasons, resulting in improper, incomplete emptying of the bladder (neurogenic bladder).Neurogenic bladder may lead to the backflow (reflux) of urine into the tubes that normally bring urine to the bladder (ureters) from the kidneys; an abnormal swelling (distention) of and accumulation of urine in the ureters (hydroureter) and kidneys (hydronephrosis). In affected individuals, hydroureter and hydronephrosis may range from mild to severe. An early symptom of such abnormalities may include an inability to hold urine during the day and/or at night during sleep (diurnal and nocturnal enuresis).Obstructive abnormalities of the urinary tract may result in urinary tract damage and repeated urinary tract infections. In some people, such infections may cause no symptoms (asymptomatic). However, in other people, a variety of symptoms may occur such as a frequent urge to urinate, the passage of an excessive amount of urine (polyuria), excessive thirst (polydipsia), a burning sensation when passing urine, painful or difficult urination (dysuria), loss of bladder control (incontinence), a general feeling of ill health (malaise), fever, pain in the lower abdomen and/or loins and/or, in severe infections, the presence of blood (hematuria) and/or pus in the urine. A urinary tract infection can spread to the bloodstream, a serious complication known as urosepsis. Without appropriate treatment, repeated urinary tract infections and chronic damage to the kidney tract may ultimately lead to chronic renal failure. Renal failure occurs when the kidneys lose their ability to excrete waste products through the urine, to regulate the balance of salt and water in the body and to perform their other vital functions. The exact proportion of affected individuals who eventually develop renal failure is unknown but early treatment can reduce the likelihood of this outcome. Some individuals with the disorder may also have high blood pressure (hypertension) due to kidney damage. This also requires active treatment to prevent further kidney damage.Approximately two thirds of affected individuals may experience infrequent or incomplete passing of stools (constipation). Some children may develop encopresis, a condition in which the failure to have bowel movements causes stool to accumulate in the colon or rectum.Some affected individuals are unable to fully close their eyelids when sleeping, a condition known as nocturnal lagophthalmos. This can cause the feeling of dry eyes upon awaking, a sensation that can be mild or severe. Lagophthalmos can cause various complications including inflammation of the cornea (keratitis), a scratched cornea (corneal abrasion), infection and poor sleep.
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Symptoms of Urofacial Syndrome. As the term “urofacial” suggests, the disorder is characterized by urinary and facial problems. The initial finding that may be apparent in affected infants is an unusual “inverted” facial expression. When affected infants attempt to laugh or smile, their facial musculature “inverts” so that they appear to be grimacing or crying. The symptoms and severity of urofacial syndrome can vary greatly, even among affected members of the same family.The urinary abnormality is an obstructive disease of the urinary tract that can be present at birth (congenital obstructive uropathy). This uropathy occurs due to failure of nerve signals between the bladder and spinal cord causing incomplete emptying (voiding) of the bladder (neurogenic or neuropathic bladder). At the lowest point of the bladder, there is a circular band of muscle fibers (urethral sphincter) that opens into the urethra, the tubular structure through which urine is expelled. When the bladder fills with urine, signals are normally sent to the spinal cord. Nerve signals are then sent back that cause the urethral sphincter to relax. The bladder then contracts and sends urine through the urethra and out of the body. However, in affected individuals, there is a failure of such nerve signaling for unknown reasons, resulting in improper, incomplete emptying of the bladder (neurogenic bladder).Neurogenic bladder may lead to the backflow (reflux) of urine into the tubes that normally bring urine to the bladder (ureters) from the kidneys; an abnormal swelling (distention) of and accumulation of urine in the ureters (hydroureter) and kidneys (hydronephrosis). In affected individuals, hydroureter and hydronephrosis may range from mild to severe. An early symptom of such abnormalities may include an inability to hold urine during the day and/or at night during sleep (diurnal and nocturnal enuresis).Obstructive abnormalities of the urinary tract may result in urinary tract damage and repeated urinary tract infections. In some people, such infections may cause no symptoms (asymptomatic). However, in other people, a variety of symptoms may occur such as a frequent urge to urinate, the passage of an excessive amount of urine (polyuria), excessive thirst (polydipsia), a burning sensation when passing urine, painful or difficult urination (dysuria), loss of bladder control (incontinence), a general feeling of ill health (malaise), fever, pain in the lower abdomen and/or loins and/or, in severe infections, the presence of blood (hematuria) and/or pus in the urine. A urinary tract infection can spread to the bloodstream, a serious complication known as urosepsis. Without appropriate treatment, repeated urinary tract infections and chronic damage to the kidney tract may ultimately lead to chronic renal failure. Renal failure occurs when the kidneys lose their ability to excrete waste products through the urine, to regulate the balance of salt and water in the body and to perform their other vital functions. The exact proportion of affected individuals who eventually develop renal failure is unknown but early treatment can reduce the likelihood of this outcome. Some individuals with the disorder may also have high blood pressure (hypertension) due to kidney damage. This also requires active treatment to prevent further kidney damage.Approximately two thirds of affected individuals may experience infrequent or incomplete passing of stools (constipation). Some children may develop encopresis, a condition in which the failure to have bowel movements causes stool to accumulate in the colon or rectum.Some affected individuals are unable to fully close their eyelids when sleeping, a condition known as nocturnal lagophthalmos. This can cause the feeling of dry eyes upon awaking, a sensation that can be mild or severe. Lagophthalmos can cause various complications including inflammation of the cornea (keratitis), a scratched cornea (corneal abrasion), infection and poor sleep.
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Causes of Urofacial Syndrome
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Urofacial syndrome is caused by changes (mutations or pathogenic variants) in one of two different genes, the HPSE2 gene or the LRIG2 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation 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.Some individuals with urofacial syndrome do not have mutations in either of the two known disease genes, suggesting that additional, as-yet-unidentified genes or difficult to detect variants in the two known genes may also cause the disorder in some people.Urofacial syndrome is inherited in an autosomal 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 Urofacial Syndrome. Urofacial syndrome is caused by changes (mutations or pathogenic variants) in one of two different genes, the HPSE2 gene or the LRIG2 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation 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.Some individuals with urofacial syndrome do not have mutations in either of the two known disease genes, suggesting that additional, as-yet-unidentified genes or difficult to detect variants in the two known genes may also cause the disorder in some people.Urofacial syndrome is inherited in an autosomal 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 Urofacial Syndrome
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Urofacial syndrome affects males and females in equal numbers. More than 150 cases have been reported in the medical literature. According to the literature, most families are from Columbia although affected families have also been reported in Turkey, the United States, the United Kingdom, Kuwait, Denmark, Germany, Netherlands, Australia and Spain.Because extremely rare disorders like urofacial syndrome often go unrecognized, these disorders are under-diagnosed, making it difficult to determine the true frequency of such disorders in the general population. However, as urofacial syndrome is inherited as an autosomal recessive condition it is more common in countries where consanguinity (close marriage between relatives) is more common.Some researchers suspect that many infants and children who experience abnormalities of the bladder, hydroureter, hydronephrosis and associated symptoms may have urofacial syndrome. However, recent research has revealed that most affected individuals with dysfunctional bladder without the characteristic facial findings may not be in the category of urofacial syndrome.
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Affects of Urofacial Syndrome. Urofacial syndrome affects males and females in equal numbers. More than 150 cases have been reported in the medical literature. According to the literature, most families are from Columbia although affected families have also been reported in Turkey, the United States, the United Kingdom, Kuwait, Denmark, Germany, Netherlands, Australia and Spain.Because extremely rare disorders like urofacial syndrome often go unrecognized, these disorders are under-diagnosed, making it difficult to determine the true frequency of such disorders in the general population. However, as urofacial syndrome is inherited as an autosomal recessive condition it is more common in countries where consanguinity (close marriage between relatives) is more common.Some researchers suspect that many infants and children who experience abnormalities of the bladder, hydroureter, hydronephrosis and associated symptoms may have urofacial syndrome. However, recent research has revealed that most affected individuals with dysfunctional bladder without the characteristic facial findings may not be in the category of urofacial syndrome.
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Related disorders of Urofacial Syndrome
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Symptoms of the following disorders can be similar to those of urofacial syndrome. Comparisons may be useful for a differential diagnosis:Hinman syndrome, also known as Hinman-Allen syndrome or non-neurogenic neurogenic bladder, is a rare voiding disorder that is believed to be neuropsychological in origin as no neurologic deficit is present. Affected individuals exhibit extremely similar clinical features to those seen in individuals with urofacial syndrome, except for abnormalities in facial expression, which does not occur.In additional to urofacial syndrome, additional congenital disorders may be characterized by urinary tract abnormalities such as neurogenic bladder, hydroureter, and/or hydronephrosis; genital tract malformations such as cryptorchidism in affected males; facial abnormalities; and/or other physical abnormalities similar to those potentially associated with urofacial syndrome.
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Related disorders of Urofacial Syndrome. Symptoms of the following disorders can be similar to those of urofacial syndrome. Comparisons may be useful for a differential diagnosis:Hinman syndrome, also known as Hinman-Allen syndrome or non-neurogenic neurogenic bladder, is a rare voiding disorder that is believed to be neuropsychological in origin as no neurologic deficit is present. Affected individuals exhibit extremely similar clinical features to those seen in individuals with urofacial syndrome, except for abnormalities in facial expression, which does not occur.In additional to urofacial syndrome, additional congenital disorders may be characterized by urinary tract abnormalities such as neurogenic bladder, hydroureter, and/or hydronephrosis; genital tract malformations such as cryptorchidism in affected males; facial abnormalities; and/or other physical abnormalities similar to those potentially associated with urofacial syndrome.
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Diagnosis of Urofacial Syndrome
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No formal diagnostic criteria have been established for urofacial syndrome. A diagnosis is suspected based upon identification of characteristic findings, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. Physicians, particularly pediatricians, nephrologists, and urologists, should be aware of the association of urinary voiding abnormalities and the unique facial expression that characterizes this disorder.A feature that may be apparent in affected infants is the “inverted” facial expression. Due to the strong association of this feature and urological abnormalities, the presence of inverted facial expressions should lead to a prompt, thorough examination of the urinary tract. Such evaluation may lead to early diagnosis of urofacial syndrome and specific associated features (e.g., urinary tract infection), playing an essential role in ensuring appropriate preventive steps and/or prompt treatment.During such urological evaluation, specialized imaging techniques may be used to examine the structure and assess the function of organs within the urinary tract (e.g. different portions of the kidneys, bladder and ureters). Such tests may include intravenous pyelography (IVP), during which a special contrast medium is injected, and x-rays are then taken, and urodynamic evaluation, which examines the movement and flow of liquids through the urinary tract.In addition to neuropathic bladder and obstructive abnormalities, such specialized imaging studies may also reveal structural abnormalities of the urinary tract. The bladder may have abnormal, anchoring bands and cords of connective tissue (trabeculation) and demonstrate overgrowth (hypertrophy) and abnormal hardening (sclerosis) of mucous membranes (mucosa), causing small sac-like protrusions (hernias) of tissue through the bladder’s muscular wall (diverticula). In addition, the bladder’s outer muscular layer (detrusor muscle) may demonstrate unusually increased reflex reactions (hyperreflexia) and abnormal, prolonged contractions (hypertonic contractures); the neck of the bladder may be abnormally enlarged (hypertrophic); and/or the urethra may have irregular spasms (spastic urethra) and have an abnormal diameter (caliber).Urinary tract infections may be diagnosed by clinical evaluation, microscopic examination and bacteriological culture of urine specimens.Molecular genetic testing can confirm a diagnosis of urofacial syndrome. Molecular genetic testing can detect pathogenic variants in the disease specific genes (i.e., HPSE2 or LRIG2) known to cause the disorder, but is available only as a diagnostic service at specialized laboratories.Prenatal diagnosis is possible in families with a history of urofacial syndrome and in whom the specific disease-causing gene mutation is known.
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Diagnosis of Urofacial Syndrome. No formal diagnostic criteria have been established for urofacial syndrome. A diagnosis is suspected based upon identification of characteristic findings, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. Physicians, particularly pediatricians, nephrologists, and urologists, should be aware of the association of urinary voiding abnormalities and the unique facial expression that characterizes this disorder.A feature that may be apparent in affected infants is the “inverted” facial expression. Due to the strong association of this feature and urological abnormalities, the presence of inverted facial expressions should lead to a prompt, thorough examination of the urinary tract. Such evaluation may lead to early diagnosis of urofacial syndrome and specific associated features (e.g., urinary tract infection), playing an essential role in ensuring appropriate preventive steps and/or prompt treatment.During such urological evaluation, specialized imaging techniques may be used to examine the structure and assess the function of organs within the urinary tract (e.g. different portions of the kidneys, bladder and ureters). Such tests may include intravenous pyelography (IVP), during which a special contrast medium is injected, and x-rays are then taken, and urodynamic evaluation, which examines the movement and flow of liquids through the urinary tract.In addition to neuropathic bladder and obstructive abnormalities, such specialized imaging studies may also reveal structural abnormalities of the urinary tract. The bladder may have abnormal, anchoring bands and cords of connective tissue (trabeculation) and demonstrate overgrowth (hypertrophy) and abnormal hardening (sclerosis) of mucous membranes (mucosa), causing small sac-like protrusions (hernias) of tissue through the bladder’s muscular wall (diverticula). In addition, the bladder’s outer muscular layer (detrusor muscle) may demonstrate unusually increased reflex reactions (hyperreflexia) and abnormal, prolonged contractions (hypertonic contractures); the neck of the bladder may be abnormally enlarged (hypertrophic); and/or the urethra may have irregular spasms (spastic urethra) and have an abnormal diameter (caliber).Urinary tract infections may be diagnosed by clinical evaluation, microscopic examination and bacteriological culture of urine specimens.Molecular genetic testing can confirm a diagnosis of urofacial syndrome. Molecular genetic testing can detect pathogenic variants in the disease specific genes (i.e., HPSE2 or LRIG2) known to cause the disorder, but is available only as a diagnostic service at specialized laboratories.Prenatal diagnosis is possible in families with a history of urofacial syndrome and in whom the specific disease-causing gene mutation is known.
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Therapies of Urofacial Syndrome
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TreatmentThe treatment of urofacial syndrome is geared 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 diagnosing and treating disorders of the urinary tract (urologists), physicians who specialize in disorders of the kidneys (nephrologists), surgeons, dieticians and/or other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment.Genetic counseling is recommended for affected individuals and families.Prompt recognition and early treatment of urofacial syndrome is critical in reducing or preventing the potentially severe, irreversible bladder and kidney damage that can develop in severe cases.Therapy for urinary tract infections usually includes antibiotics for the treatment and prevention of bacterial infections and pain relievers (e.g., analgesics). In some people, surgery may be conducted to eliminate urinary tract obstruction and reconstruct certain portions of the urinary tract (e.g., ureters, ureterovesicular junction). The surgical procedures performed depend upon the severity of the anatomical abnormalities and their associated symptoms.Specific medications, anti-cholinergic and alpha-1-adrenergic blockers, have been used to treat individuals with urofacial syndrome. Constipation should be treated by standard guidelines as in the general population.In affected children who experience chronic renal failure, treatment options may include certain procedures that regularly remove excess waste products from the blood (dialysis). Such procedures may include the removal of wastes by filtering the blood through a machine (hemodialysis) and/or by using a natural filtering membrane in the body’s abdomen (peritoneal dialysis). In some cases of severe renal failure, kidney transplantation may be considered.Early intervention is important to ensure that affected children reach their potential. Special services that may be beneficial may include special social support and other medical and/or social services.
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Therapies of Urofacial Syndrome. TreatmentThe treatment of urofacial syndrome is geared 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 diagnosing and treating disorders of the urinary tract (urologists), physicians who specialize in disorders of the kidneys (nephrologists), surgeons, dieticians and/or other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment.Genetic counseling is recommended for affected individuals and families.Prompt recognition and early treatment of urofacial syndrome is critical in reducing or preventing the potentially severe, irreversible bladder and kidney damage that can develop in severe cases.Therapy for urinary tract infections usually includes antibiotics for the treatment and prevention of bacterial infections and pain relievers (e.g., analgesics). In some people, surgery may be conducted to eliminate urinary tract obstruction and reconstruct certain portions of the urinary tract (e.g., ureters, ureterovesicular junction). The surgical procedures performed depend upon the severity of the anatomical abnormalities and their associated symptoms.Specific medications, anti-cholinergic and alpha-1-adrenergic blockers, have been used to treat individuals with urofacial syndrome. Constipation should be treated by standard guidelines as in the general population.In affected children who experience chronic renal failure, treatment options may include certain procedures that regularly remove excess waste products from the blood (dialysis). Such procedures may include the removal of wastes by filtering the blood through a machine (hemodialysis) and/or by using a natural filtering membrane in the body’s abdomen (peritoneal dialysis). In some cases of severe renal failure, kidney transplantation may be considered.Early intervention is important to ensure that affected children reach their potential. Special services that may be beneficial may include special social support and other medical and/or social services.
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Overview of Urothelial carcinoma of the renal pelvis and ureter
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Urothelial cell (UC) cancers of the renal pelvis and ureter are relatively rare (approximately 2 per 100,000 people) and make up approximately 5% of transitional cell cancers in the urinary tract. Of these 2 locations – the renal pelvis (located in the kidney) and the ureters (which connect the kidney to the bladder) – UC occurs twice as often in the renal pelvis. The most common initial symptom for these types of cancer is blood in the urine (hematuria). Risk factors for UC include smoking, genetics, painkiller abuse, excessive coffee drinking, and cyclophosphamide (a drug used in chemotherapy). Surgery is the most common treatment for these cancers, however higher stage cancers may also require chemotherapy or radiation. These cancers may most commonly spread down towards the bladder and can spread (metastasize) to other organs. The prognosis after surgery varies and highly depends on the cancer stage and a patients’ risk factors.SummaryCancer can arise from the transitional layer, also known as urothelial layer, of cells in the renal pelvis or ureter, which are parts of the upper urinary tract. These cancers may first present with blood in the urine and are most associated with a history of cigarette smoking. The current treatment for these cancers is surgery to remove the upper urinary tract and surveillance afterwards to ensure there is no recurrence. More research is ongoing into different treatments, diagnostic tools, and screening modalities for these types of cancer.IntroductionThe renal pelvis is located inside the kidney and acts as a collecting system for urine which then flows into the ureters. The ureters are 20-30 cm S-shaped tubes connecting the kidneys to the bladder which collects and stores the newly formed urine until urination. The inner layers (which directly contact urine) of both the renal pelvis and ureter are lined by a transitional cell epithelium (aka: urothelium) that are then surrounded by multiple layers of connective tissue and muscle. This specialized type of epithelium functions as an impermeable yet flexible barrier that allows both structures to stretch or shorten depending on urine flow. When this layer of epithelium becomes cancerous, it is damaged and may have abnormal blood vessel formation, resulting in painless red urine.
Although cancers of the renal pelvis and ureters make up only 5% of urinary tract cancers, nearly all cancers that occur here (95%) are the urothelial cell type. Cigarette smoking is strongly associated with these types of cancers, increasing a patient's risk 2.5 to 7 fold.
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Overview of Urothelial carcinoma of the renal pelvis and ureter. Urothelial cell (UC) cancers of the renal pelvis and ureter are relatively rare (approximately 2 per 100,000 people) and make up approximately 5% of transitional cell cancers in the urinary tract. Of these 2 locations – the renal pelvis (located in the kidney) and the ureters (which connect the kidney to the bladder) – UC occurs twice as often in the renal pelvis. The most common initial symptom for these types of cancer is blood in the urine (hematuria). Risk factors for UC include smoking, genetics, painkiller abuse, excessive coffee drinking, and cyclophosphamide (a drug used in chemotherapy). Surgery is the most common treatment for these cancers, however higher stage cancers may also require chemotherapy or radiation. These cancers may most commonly spread down towards the bladder and can spread (metastasize) to other organs. The prognosis after surgery varies and highly depends on the cancer stage and a patients’ risk factors.SummaryCancer can arise from the transitional layer, also known as urothelial layer, of cells in the renal pelvis or ureter, which are parts of the upper urinary tract. These cancers may first present with blood in the urine and are most associated with a history of cigarette smoking. The current treatment for these cancers is surgery to remove the upper urinary tract and surveillance afterwards to ensure there is no recurrence. More research is ongoing into different treatments, diagnostic tools, and screening modalities for these types of cancer.IntroductionThe renal pelvis is located inside the kidney and acts as a collecting system for urine which then flows into the ureters. The ureters are 20-30 cm S-shaped tubes connecting the kidneys to the bladder which collects and stores the newly formed urine until urination. The inner layers (which directly contact urine) of both the renal pelvis and ureter are lined by a transitional cell epithelium (aka: urothelium) that are then surrounded by multiple layers of connective tissue and muscle. This specialized type of epithelium functions as an impermeable yet flexible barrier that allows both structures to stretch or shorten depending on urine flow. When this layer of epithelium becomes cancerous, it is damaged and may have abnormal blood vessel formation, resulting in painless red urine.
Although cancers of the renal pelvis and ureters make up only 5% of urinary tract cancers, nearly all cancers that occur here (95%) are the urothelial cell type. Cigarette smoking is strongly associated with these types of cancers, increasing a patient's risk 2.5 to 7 fold.
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Symptoms of Urothelial carcinoma of the renal pelvis and ureter
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Painless blood in the urine (hematuria) is the most common symptom in patients with transitional cancers of the upper urinary tract. Other less common symptoms include lower back pain, pain with urination, or unexplained weight loss.
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Symptoms of Urothelial carcinoma of the renal pelvis and ureter. Painless blood in the urine (hematuria) is the most common symptom in patients with transitional cancers of the upper urinary tract. Other less common symptoms include lower back pain, pain with urination, or unexplained weight loss.
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Causes of Urothelial carcinoma of the renal pelvis and ureter
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Urothelial cell cancer is thought to be caused by a mutation leading to the loss of a tumor suppressor gene. Losing a tumor suppressor gene is like taking the brakes off a car, allowing cells to replicate uncontrollably, resulting in cancer. Cancers may be classified as low-grade or high-grade. Low-grade cancers are associated with mutations leading to a loss of functioning tumor suppressor genes such as p53, p19 and p16. High-grade cancers have additional mutations such as the loss of the RB1 tumor suppressor gene. More aggressive cancers tend to spread initially towards the bladder and may metastasize (spread) to other organs. Notably, loss of certain tumor suppressor genes (such as those listed above) does not reflect the patient prognosis (predicted outcome) and scientists are still studying how the loss of certain genes can affect prognosis in patients with different mutations. Due to family genetics, some people may be predisposed to loss of these tumor suppressor genes compared to others. Patients with Lynch syndrome are at an increased risk for transitional cell cancers.Cigarette smoking is the most well-documented contributor to urothelial cell cancer. Painkiller abuse, caffeine, cyclophosphamide, and occupational exposure to agents used in the plastic and tar industries may all increase one's risk to transitional cell cancer as well. These agents may induce mutations that cause the loss of tumor suppressor genes (as listed above) in the transitional (urothelial) cells lining the inside of the renal pelvis or ureter. More research is being done on these agents to determine the level of risk.
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Causes of Urothelial carcinoma of the renal pelvis and ureter. Urothelial cell cancer is thought to be caused by a mutation leading to the loss of a tumor suppressor gene. Losing a tumor suppressor gene is like taking the brakes off a car, allowing cells to replicate uncontrollably, resulting in cancer. Cancers may be classified as low-grade or high-grade. Low-grade cancers are associated with mutations leading to a loss of functioning tumor suppressor genes such as p53, p19 and p16. High-grade cancers have additional mutations such as the loss of the RB1 tumor suppressor gene. More aggressive cancers tend to spread initially towards the bladder and may metastasize (spread) to other organs. Notably, loss of certain tumor suppressor genes (such as those listed above) does not reflect the patient prognosis (predicted outcome) and scientists are still studying how the loss of certain genes can affect prognosis in patients with different mutations. Due to family genetics, some people may be predisposed to loss of these tumor suppressor genes compared to others. Patients with Lynch syndrome are at an increased risk for transitional cell cancers.Cigarette smoking is the most well-documented contributor to urothelial cell cancer. Painkiller abuse, caffeine, cyclophosphamide, and occupational exposure to agents used in the plastic and tar industries may all increase one's risk to transitional cell cancer as well. These agents may induce mutations that cause the loss of tumor suppressor genes (as listed above) in the transitional (urothelial) cells lining the inside of the renal pelvis or ureter. More research is being done on these agents to determine the level of risk.
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Affects of Urothelial carcinoma of the renal pelvis and ureter
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The average age of patients who develop upper urinary tract urothelial tumors is 65 years, and one’s risk of this cancer increases to a peak in their 70’s-80’s. Urothelial tumors are 3 times more common in men than women and twice as common in people of European descent compared to people of African descent. Patients with a smoking history are at highest risk for these cancers. A family history of transitional cell cancer, especially when a family member was diagnosed at a young age (<45 years old) without a history of smoking and/or Lynch syndrome may increase the risk for transitional cell cancers as well.
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Affects of Urothelial carcinoma of the renal pelvis and ureter. The average age of patients who develop upper urinary tract urothelial tumors is 65 years, and one’s risk of this cancer increases to a peak in their 70’s-80’s. Urothelial tumors are 3 times more common in men than women and twice as common in people of European descent compared to people of African descent. Patients with a smoking history are at highest risk for these cancers. A family history of transitional cell cancer, especially when a family member was diagnosed at a young age (<45 years old) without a history of smoking and/or Lynch syndrome may increase the risk for transitional cell cancers as well.
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Related disorders of Urothelial carcinoma of the renal pelvis and ureter
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Related Disorders
Urothelial carcinoma of the bladder: This cancer originates in the bladder rather than the renal pelvis or ureter. It is much more common and shares similar risk factors and causes. Compared to UC of the ureters or renal pelvis, the majority of bladder cancers are less likely to break through the inner cell layer and metastasize (spread) to other organs. Treatment typically involves surgery or ablation and may also include chemotherapy or immunotherapy.
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Related disorders of Urothelial carcinoma of the renal pelvis and ureter. Related Disorders
Urothelial carcinoma of the bladder: This cancer originates in the bladder rather than the renal pelvis or ureter. It is much more common and shares similar risk factors and causes. Compared to UC of the ureters or renal pelvis, the majority of bladder cancers are less likely to break through the inner cell layer and metastasize (spread) to other organs. Treatment typically involves surgery or ablation and may also include chemotherapy or immunotherapy.
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Diagnosis of Urothelial carcinoma of the renal pelvis and ureter
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Doctors will usually start by running urine and blood tests to check kidney function, liver function, bladder function, and assess for infection. They will also usually obtain some imaging such as a CT scan, which may show an irregular mass blocking the ureter or kidney suggestive of cancer. Doctors may get additional imaging tests such as a CT using contrast, known as a CT urogram. If the cancerous mass is small and is not obstructing the renal pelvis or ureters, it may not be initially detected by these imaging tests. A urologist, which is a doctor specializing in the urinary tract, may perform a procedure called a uroscopy, which is the use of a flexible scope inserted through the urethra (opening in the penis or above the vagina through which urine leaves the body) to directly visualize the cancerous mass in the ureter or renal pelvis and may remove small bits of tissue for further testing. Once a diagnosis is confirmed, doctors will stage the cancer by performing more imaging scans to see if it has spread to other parts of the body such as the lungs or lymph nodes. To help with staging, doctors may also perform genetic tests, urine cell tests, and biopsies. The prognosis for a diagnosed cancer varies greatly. Factors which may improve prognosis include non-smoker, lower-grade, lower-stage, lack of recurrence and younger age. A full work-up of a newly diagnosed transitional cell cancer helps guide the choice of therapy and better clarify the likely prognosis. Researchers are still investigating which factors or tests might provide the best insight into disease progression.
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Diagnosis of Urothelial carcinoma of the renal pelvis and ureter. Doctors will usually start by running urine and blood tests to check kidney function, liver function, bladder function, and assess for infection. They will also usually obtain some imaging such as a CT scan, which may show an irregular mass blocking the ureter or kidney suggestive of cancer. Doctors may get additional imaging tests such as a CT using contrast, known as a CT urogram. If the cancerous mass is small and is not obstructing the renal pelvis or ureters, it may not be initially detected by these imaging tests. A urologist, which is a doctor specializing in the urinary tract, may perform a procedure called a uroscopy, which is the use of a flexible scope inserted through the urethra (opening in the penis or above the vagina through which urine leaves the body) to directly visualize the cancerous mass in the ureter or renal pelvis and may remove small bits of tissue for further testing. Once a diagnosis is confirmed, doctors will stage the cancer by performing more imaging scans to see if it has spread to other parts of the body such as the lungs or lymph nodes. To help with staging, doctors may also perform genetic tests, urine cell tests, and biopsies. The prognosis for a diagnosed cancer varies greatly. Factors which may improve prognosis include non-smoker, lower-grade, lower-stage, lack of recurrence and younger age. A full work-up of a newly diagnosed transitional cell cancer helps guide the choice of therapy and better clarify the likely prognosis. Researchers are still investigating which factors or tests might provide the best insight into disease progression.
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Urothelial carcinoma of the renal pelvis and ureter
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nord_1256_6
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Therapies of Urothelial carcinoma of the renal pelvis and ureter
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The standard of therapy for transitional cell cancer of the renal pelvis and ureter is surgery. The most common surgery is known as a radical nephroureterectomy in which the kidney, ureter, adrenal gland, and nearby lymph nodes are removed. The surgery may be done laparoscopically via a camera with small incisions or robotically to minimize the complications and decrease hospitalization length, but larger or more aggressive tumors may require an open surgery. Most people fully recover from a nephroureterectomy within 6 weeks. Lower grade tumors may instead undergo an ablation of the tumor using a laser or a ureterectomy in which only a part of the ureter is removed to preserve the kidney function. The major risks associated with these surgeries include injury to major blood vessels or nerves, infection, side effects of anesthesia such as nausea and vomiting, and blood loss. Following radical nephroureterectomies, recurrence of the original cancer is not common but UC may arise in other parts of the urinary system such as the bladder. Patients should follow up with their doctor routinely to check for bladder cancer using a cystoscopy and selective urine cytology. The frequency of follow-up may depend on the stage of the original cancer as well as the likelihood for a recurrence. Most patients should follow-up every 3 months after their surgery during the first year and every six months after that. Patients with higher grade tumors who are not able to undergo radical therapy may instead receive topical or systemic chemotherapy either through a ureteral catheter or through a nephrostomy tube. In 2020, the FDA approved a treatment for low-grade renal pelvis and ureter transitional cell cancers called mitomycin pyelocalyceal (Jelmyto). This therapy utilizes a ureteral catheter or a nephrostomy tube to medically treat the cancer instead of surgery. Patients with metastasis to other organs may require systemic chemotherapy rather than targeted chemotherapy, but few studies have been done due to the relative rarity of the disease. Studies are also still being done on whether a combination of surgery and chemotherapy (known as adjuvant or neoadjuvant chemotherapy) provides a mortality benefit.
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Therapies of Urothelial carcinoma of the renal pelvis and ureter. The standard of therapy for transitional cell cancer of the renal pelvis and ureter is surgery. The most common surgery is known as a radical nephroureterectomy in which the kidney, ureter, adrenal gland, and nearby lymph nodes are removed. The surgery may be done laparoscopically via a camera with small incisions or robotically to minimize the complications and decrease hospitalization length, but larger or more aggressive tumors may require an open surgery. Most people fully recover from a nephroureterectomy within 6 weeks. Lower grade tumors may instead undergo an ablation of the tumor using a laser or a ureterectomy in which only a part of the ureter is removed to preserve the kidney function. The major risks associated with these surgeries include injury to major blood vessels or nerves, infection, side effects of anesthesia such as nausea and vomiting, and blood loss. Following radical nephroureterectomies, recurrence of the original cancer is not common but UC may arise in other parts of the urinary system such as the bladder. Patients should follow up with their doctor routinely to check for bladder cancer using a cystoscopy and selective urine cytology. The frequency of follow-up may depend on the stage of the original cancer as well as the likelihood for a recurrence. Most patients should follow-up every 3 months after their surgery during the first year and every six months after that. Patients with higher grade tumors who are not able to undergo radical therapy may instead receive topical or systemic chemotherapy either through a ureteral catheter or through a nephrostomy tube. In 2020, the FDA approved a treatment for low-grade renal pelvis and ureter transitional cell cancers called mitomycin pyelocalyceal (Jelmyto). This therapy utilizes a ureteral catheter or a nephrostomy tube to medically treat the cancer instead of surgery. Patients with metastasis to other organs may require systemic chemotherapy rather than targeted chemotherapy, but few studies have been done due to the relative rarity of the disease. Studies are also still being done on whether a combination of surgery and chemotherapy (known as adjuvant or neoadjuvant chemotherapy) provides a mortality benefit.
| 1,256 |
Urothelial carcinoma of the renal pelvis and ureter
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nord_1257_0
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Overview of Urticaria, Cold
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Cold urticaria is a chronic, reactive skin disorder. It is probably the most common form of physical urticaria (hives). Major symptoms may include abnormal reddening of the skin (erythema), hives and itching after exposure of the skin to cold temperatures.There are two forms of the disorder: essential (acquired) cold urticaria, and familial (hereditary) cold urticaria. The symptoms of the acquired form become obvious in two to five minutes after exposure to the triggering substance or situation, while it takes 24 to 48 hours for symptoms of familial cold urticaria to appear. Also, symptoms tend to last longer with the familial form, typically about 24 hours although they may remain for as long as 48 hours. With the acquired form, symptoms tend to last for one to two hours.
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Overview of Urticaria, Cold. Cold urticaria is a chronic, reactive skin disorder. It is probably the most common form of physical urticaria (hives). Major symptoms may include abnormal reddening of the skin (erythema), hives and itching after exposure of the skin to cold temperatures.There are two forms of the disorder: essential (acquired) cold urticaria, and familial (hereditary) cold urticaria. The symptoms of the acquired form become obvious in two to five minutes after exposure to the triggering substance or situation, while it takes 24 to 48 hours for symptoms of familial cold urticaria to appear. Also, symptoms tend to last longer with the familial form, typically about 24 hours although they may remain for as long as 48 hours. With the acquired form, symptoms tend to last for one to two hours.
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Urticaria, Cold
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