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Related disorders of Idiopathic Intracranial Hypertension
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Symptoms of the following disorders can be similar to those of IIH. Comparisons may be useful for a differential diagnosis:Arachnoiditis is a progressive inflammatory disorder affecting the middle membrane surrounding the spinal cord and brain (arachnoid membrane). It may affect both the brain and the spinal cord and may be caused by foreign solutions (such as dye) being injected into the spine or arachnoid membrane. Symptoms may include severe headaches, vision disturbances, dizziness, nausea and/or vomiting. If the spine is involved, pain, unusual sensations, weakness and paralysis can develop.Epiduritis is characterized by inflammation of the tough, outer canvas-like covering surrounding the brain and spinal cord known as the dura mater. Symptoms of this disorder can be similar to IIH.Meningitis is an inflammation of the membranes around the brain and the spinal cord. It may occur as three different forms; adult, infantile and neonatal. It may also be caused by a number of different infectious agents such as bacteria, viruses, or fungi, or it may be caused by malignant tumors. Meningitis may develop suddenly or have a gradual onset. Symptoms may include fever, headache, a stiff neck, and vomiting. The patient may also be irritable, confused and go from drowsiness, to stupor to coma. (For more information on this disorder, choose “Meningitis” as your search term in the Rare Disease Database.)Brain tumors may also cause symptoms similar to IIH. Neuroimaging will help with this diagnosis.
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Related disorders of Idiopathic Intracranial Hypertension. Symptoms of the following disorders can be similar to those of IIH. Comparisons may be useful for a differential diagnosis:Arachnoiditis is a progressive inflammatory disorder affecting the middle membrane surrounding the spinal cord and brain (arachnoid membrane). It may affect both the brain and the spinal cord and may be caused by foreign solutions (such as dye) being injected into the spine or arachnoid membrane. Symptoms may include severe headaches, vision disturbances, dizziness, nausea and/or vomiting. If the spine is involved, pain, unusual sensations, weakness and paralysis can develop.Epiduritis is characterized by inflammation of the tough, outer canvas-like covering surrounding the brain and spinal cord known as the dura mater. Symptoms of this disorder can be similar to IIH.Meningitis is an inflammation of the membranes around the brain and the spinal cord. It may occur as three different forms; adult, infantile and neonatal. It may also be caused by a number of different infectious agents such as bacteria, viruses, or fungi, or it may be caused by malignant tumors. Meningitis may develop suddenly or have a gradual onset. Symptoms may include fever, headache, a stiff neck, and vomiting. The patient may also be irritable, confused and go from drowsiness, to stupor to coma. (For more information on this disorder, choose “Meningitis” as your search term in the Rare Disease Database.)Brain tumors may also cause symptoms similar to IIH. Neuroimaging will help with this diagnosis.
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Diagnosis of Idiopathic Intracranial Hypertension
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Diagnosis of Idiopathic Intracranial Hypertension.
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Therapies of Idiopathic Intracranial Hypertension
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Treatment should first and foremost involve lifestyle and dietary modifications in order to promote weight loss for those patients who are overweight or obese. This may even include consultation with a nutritionist or dietician.Medical treatment consists of using drugs called carbonic anhydrase inhibitors to suppress the production of CSF. The most commonly used of the carbonic anhydrase inhibitors is acetazolamide. A large multicenter, randomized, controlled trial published in 2014 demonstrated that acetazolamide combined with dietary weight loss resulted in improved visual field function, nerve swelling, and quality of life measures, compared to the treatment of dietary changes alone. Carbonic anhydrase inhibitors inhibit the enzyme system needed to produce CSF and control the pressure (by controlling the volume) to some degree. These drugs do not work in all cases and can have potentially serious side effects. Acetazolamide should be avoided in early (1st trimester) pregnancy, and should be used with caution in later stages of pregnancy.Topiramate is another, second-line, agent sometimes used to treat IH. While it has less potent carbonic anhydrase inhibition, it may be helpful in its capacity as a migraine headache medication. Other potential treatment options include methazolamide and furosemide, however these all of the above agents have not been evaluated as thoroughly as acetazolamide, and further study is needed to establish their utility. Corticosteroids, while used in the past to treat IH, are no longer recommended.When medical treatment fails and vision is at risk, surgical intervention may be necessary. One of two types of surgery may be performed: optic nerve sheath fenestration, neurosurgical shunt Optic nerve fenestration is a procedure in which a small opening is made in the sheath around the optic nerve in an attempt to relieve swelling (papilledema). Optic nerve sheath fenestration has a high rate of success in protecting vision, but usually does not significantly reduce headaches. Implantation of neurosurgical shunts (internal tubes) is used to drain CSF into other areas of the body. These shunts protect vision and reduce headache, but typically have a higher complication rate than optic nerve sheath fenestration.
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Therapies of Idiopathic Intracranial Hypertension. Treatment should first and foremost involve lifestyle and dietary modifications in order to promote weight loss for those patients who are overweight or obese. This may even include consultation with a nutritionist or dietician.Medical treatment consists of using drugs called carbonic anhydrase inhibitors to suppress the production of CSF. The most commonly used of the carbonic anhydrase inhibitors is acetazolamide. A large multicenter, randomized, controlled trial published in 2014 demonstrated that acetazolamide combined with dietary weight loss resulted in improved visual field function, nerve swelling, and quality of life measures, compared to the treatment of dietary changes alone. Carbonic anhydrase inhibitors inhibit the enzyme system needed to produce CSF and control the pressure (by controlling the volume) to some degree. These drugs do not work in all cases and can have potentially serious side effects. Acetazolamide should be avoided in early (1st trimester) pregnancy, and should be used with caution in later stages of pregnancy.Topiramate is another, second-line, agent sometimes used to treat IH. While it has less potent carbonic anhydrase inhibition, it may be helpful in its capacity as a migraine headache medication. Other potential treatment options include methazolamide and furosemide, however these all of the above agents have not been evaluated as thoroughly as acetazolamide, and further study is needed to establish their utility. Corticosteroids, while used in the past to treat IH, are no longer recommended.When medical treatment fails and vision is at risk, surgical intervention may be necessary. One of two types of surgery may be performed: optic nerve sheath fenestration, neurosurgical shunt Optic nerve fenestration is a procedure in which a small opening is made in the sheath around the optic nerve in an attempt to relieve swelling (papilledema). Optic nerve sheath fenestration has a high rate of success in protecting vision, but usually does not significantly reduce headaches. Implantation of neurosurgical shunts (internal tubes) is used to drain CSF into other areas of the body. These shunts protect vision and reduce headache, but typically have a higher complication rate than optic nerve sheath fenestration.
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Overview of Idiopathic Nodular Panniculitis
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SummaryIdiopathic nodular panniculitis is a rare spectrum of skin disorders characterized by single or multiple, tender or painful bumps below the surface of the skin (subcutaneous nodules) that can be open sores (ulcerated) and usually lead to inflammation of the subcutaneous layer of fat (panniculitis). These nodules tend to be 1-2 centimeters in size and most often affect the legs and feet (lower extremities). Rare cases involve panniculitis of the breast. In most patients, idiopathic nodular panniculitis is associated with fever, a general feeling of ill health (malaise), muscle pain (myalgia) and/or abdominal pain. These symptoms may subside after a few days or weeks and may recur weeks, months or years later and on multiple occasions. The exact cause of idiopathic nodular panniculitis is not known (idiopathic).IntroductionThe term Weber-Christian disease has been used to describe a group of syndromes or diseases characterized by nodular panniculitis and additional symptoms involving various organ systems of the body (systemic). However, the association of nodular panniculitis and systemic findings may occur due to a variety of causes or secondary to several different diseases, such as systemic lupus erythematous, alpha-1-antitrypsin disease and connective tissue disease. The term Weber-Christian disease has led to confusion in the medical literature and many researchers suggest that its use be abandoned.
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Overview of Idiopathic Nodular Panniculitis. SummaryIdiopathic nodular panniculitis is a rare spectrum of skin disorders characterized by single or multiple, tender or painful bumps below the surface of the skin (subcutaneous nodules) that can be open sores (ulcerated) and usually lead to inflammation of the subcutaneous layer of fat (panniculitis). These nodules tend to be 1-2 centimeters in size and most often affect the legs and feet (lower extremities). Rare cases involve panniculitis of the breast. In most patients, idiopathic nodular panniculitis is associated with fever, a general feeling of ill health (malaise), muscle pain (myalgia) and/or abdominal pain. These symptoms may subside after a few days or weeks and may recur weeks, months or years later and on multiple occasions. The exact cause of idiopathic nodular panniculitis is not known (idiopathic).IntroductionThe term Weber-Christian disease has been used to describe a group of syndromes or diseases characterized by nodular panniculitis and additional symptoms involving various organ systems of the body (systemic). However, the association of nodular panniculitis and systemic findings may occur due to a variety of causes or secondary to several different diseases, such as systemic lupus erythematous, alpha-1-antitrypsin disease and connective tissue disease. The term Weber-Christian disease has led to confusion in the medical literature and many researchers suggest that its use be abandoned.
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Symptoms of Idiopathic Nodular Panniculitis
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Idiopathic nodular panniculitis usually begins gradually. Abnormal bumps or masses (nodules) appear in the fatty layer under the skin (subcutaneous fat) of the legs, thighs and buttocks. In some patients, the arms, abdomen, and/or face may be involved. These nodules are usually 1-2 centimeters wide and may be either painful and tender or painless. In some patients, the affected area may become blue and red (erythema), ulcerated (open sore with yellow discharge) and waste away (atrophic), eventually healing and leaving a slight depression after a few weeks.Another common finding associated with idiopathic nodular panniculitis is recurrent episodes of fever. Additional symptoms include a general feeling of ill health (malaise), fatigue, muscle pain (myalgia), joint pain (arthralgia) and/or abdominal pain. In some patients, weight loss may occur and nausea may be present. Rarely, inflammation of skin near the eye (orbital inflammation) may result in abnormal protrusion of the eye (proptosis).In some patients, inflammation of the subcutaneous layer of fat (panniculitis) may affect additional organ systems of the body (systemic), potentially resulting in blood abnormalities such as low levels of circulating red blood cells (anemia), liver involvement such as an abnormally large liver (hepatomegaly), inflammation of blood vessels (vasculitis), sore muscles and joints (polyarthralgia and polymyalgia), piercing of the bowels (perforation) and lung involvement such as accumulation of fluid in the membrane surrounding the lungs (pleural effusion). These systemic events can be life threatening.
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Symptoms of Idiopathic Nodular Panniculitis. Idiopathic nodular panniculitis usually begins gradually. Abnormal bumps or masses (nodules) appear in the fatty layer under the skin (subcutaneous fat) of the legs, thighs and buttocks. In some patients, the arms, abdomen, and/or face may be involved. These nodules are usually 1-2 centimeters wide and may be either painful and tender or painless. In some patients, the affected area may become blue and red (erythema), ulcerated (open sore with yellow discharge) and waste away (atrophic), eventually healing and leaving a slight depression after a few weeks.Another common finding associated with idiopathic nodular panniculitis is recurrent episodes of fever. Additional symptoms include a general feeling of ill health (malaise), fatigue, muscle pain (myalgia), joint pain (arthralgia) and/or abdominal pain. In some patients, weight loss may occur and nausea may be present. Rarely, inflammation of skin near the eye (orbital inflammation) may result in abnormal protrusion of the eye (proptosis).In some patients, inflammation of the subcutaneous layer of fat (panniculitis) may affect additional organ systems of the body (systemic), potentially resulting in blood abnormalities such as low levels of circulating red blood cells (anemia), liver involvement such as an abnormally large liver (hepatomegaly), inflammation of blood vessels (vasculitis), sore muscles and joints (polyarthralgia and polymyalgia), piercing of the bowels (perforation) and lung involvement such as accumulation of fluid in the membrane surrounding the lungs (pleural effusion). These systemic events can be life threatening.
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Causes of Idiopathic Nodular Panniculitis
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The exact cause of idiopathic nodular panniculitis is unknown. There are numerous different causes that may be associated with the development of panniculitis including Sjogren’s syndrome, inflammatory bowel disease, gout, diabetes mellitus, systemic lupus erythematosus, subacute bacterial endocarditis, tuberculosis, iodide or bromide therapy, withdrawal from large doses of corticosteroids or pancreatitis. Sometimes the cause may be identified as an allergy or possibly a predisposition of fatty tissue to inflammation following cell injury due to an infection or toxin (granulomatous reaction). One hypothesis of the cause of disease is that fat is the trigger of an autoimmune reaction, causing white blood cells to invade the area and cause pathological damage to the subcutaneous fat resulting in the nodules.
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Causes of Idiopathic Nodular Panniculitis. The exact cause of idiopathic nodular panniculitis is unknown. There are numerous different causes that may be associated with the development of panniculitis including Sjogren’s syndrome, inflammatory bowel disease, gout, diabetes mellitus, systemic lupus erythematosus, subacute bacterial endocarditis, tuberculosis, iodide or bromide therapy, withdrawal from large doses of corticosteroids or pancreatitis. Sometimes the cause may be identified as an allergy or possibly a predisposition of fatty tissue to inflammation following cell injury due to an infection or toxin (granulomatous reaction). One hypothesis of the cause of disease is that fat is the trigger of an autoimmune reaction, causing white blood cells to invade the area and cause pathological damage to the subcutaneous fat resulting in the nodules.
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Affects of Idiopathic Nodular Panniculitis
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Idiopathic nodular panniculitis is a rare disorder that may affect males and females of any age group but rarely affects young children. Most cases are young adult females.
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Affects of Idiopathic Nodular Panniculitis. Idiopathic nodular panniculitis is a rare disorder that may affect males and females of any age group but rarely affects young children. Most cases are young adult females.
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Related disorders of Idiopathic Nodular Panniculitis
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Symptoms of the following disease may be similar to those of idiopathic nodular panniculitis. Comparisons may be useful for a differential diagnosis:Cytophagic histiocytic panniculitis is a rare disorder affecting the skin and the layers of fatty (adipose) tissue directly under the skin (subcutaneous). The first symptom of this disease is typically the appearance of reddened and tender nodules (lesions) under the skin. In addition, a fever may be present. Most affected individuals have a chronic form of the disease. As the disease progresses, the lesions may increase in size and number and the deeper layers of the skin and other organs of the body (e.g., bone marrow, lymphatic system, etc.) may also be affected. In severely affected patients, blood clotting (coagulation) abnormalities and liver malfunction may also be present. The exact cause of cytophagic histiocytic panniculitis is not known.Sweet syndrome is a rare skin disorder characterized by fever, inflammation of the joints (arthritis) and the sudden onset of a rash. The rash consists of bluish-red, tender papules that usually occur on the arms, legs, face or neck, most often on one side of the body (asymmetric). In approximately 80 percent of patients, Sweet syndrome occurs by itself for no known reason (idiopathic). In 10 percent to 20 percent of patients, the disorder is associated with an underlying malignancy, usually a hematologic malignancy such as certain types of leukemia. The exact cause of Sweet syndrome is unknown. (For more information on this disorder, choose “Sweet” as your search term in the Rare Disease Database.)Erythema nodosum is a group of skin disorders that are characterized by painful, red bumps or lesions (nodules) most often affecting the lower legs (extremities). Erythema nodosum is often associated with recurring episodes of fever, malaise, fatigue and joint pain. The exact cause of erythema nodosum is unknown.
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Related disorders of Idiopathic Nodular Panniculitis. Symptoms of the following disease may be similar to those of idiopathic nodular panniculitis. Comparisons may be useful for a differential diagnosis:Cytophagic histiocytic panniculitis is a rare disorder affecting the skin and the layers of fatty (adipose) tissue directly under the skin (subcutaneous). The first symptom of this disease is typically the appearance of reddened and tender nodules (lesions) under the skin. In addition, a fever may be present. Most affected individuals have a chronic form of the disease. As the disease progresses, the lesions may increase in size and number and the deeper layers of the skin and other organs of the body (e.g., bone marrow, lymphatic system, etc.) may also be affected. In severely affected patients, blood clotting (coagulation) abnormalities and liver malfunction may also be present. The exact cause of cytophagic histiocytic panniculitis is not known.Sweet syndrome is a rare skin disorder characterized by fever, inflammation of the joints (arthritis) and the sudden onset of a rash. The rash consists of bluish-red, tender papules that usually occur on the arms, legs, face or neck, most often on one side of the body (asymmetric). In approximately 80 percent of patients, Sweet syndrome occurs by itself for no known reason (idiopathic). In 10 percent to 20 percent of patients, the disorder is associated with an underlying malignancy, usually a hematologic malignancy such as certain types of leukemia. The exact cause of Sweet syndrome is unknown. (For more information on this disorder, choose “Sweet” as your search term in the Rare Disease Database.)Erythema nodosum is a group of skin disorders that are characterized by painful, red bumps or lesions (nodules) most often affecting the lower legs (extremities). Erythema nodosum is often associated with recurring episodes of fever, malaise, fatigue and joint pain. The exact cause of erythema nodosum is unknown.
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Diagnosis of Idiopathic Nodular Panniculitis
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A diagnosis of idiopathic nodular panniculitis is made based upon a detailed patient history, thorough clinical evaluation and identification of classic symptoms. In many patients, surgical removal (biopsy) and microscopic examination of small samples of deep skin tissue may reveal inflammation of subcutaneous layers of fat tissue. Diagnosis of nodular panniculitis can be made after all other forms of lobular panniculitis have been excluded.Laboratory tests for differentiation and exclusion of other diseases include C-reactive protein, serum protein electrophoresis, erythrocyte sedimentation rate, alpha-antitrypsin, pancreatic enzymes, angiotensin-converting enzyme and rheumatoid factor.
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Diagnosis of Idiopathic Nodular Panniculitis. A diagnosis of idiopathic nodular panniculitis is made based upon a detailed patient history, thorough clinical evaluation and identification of classic symptoms. In many patients, surgical removal (biopsy) and microscopic examination of small samples of deep skin tissue may reveal inflammation of subcutaneous layers of fat tissue. Diagnosis of nodular panniculitis can be made after all other forms of lobular panniculitis have been excluded.Laboratory tests for differentiation and exclusion of other diseases include C-reactive protein, serum protein electrophoresis, erythrocyte sedimentation rate, alpha-antitrypsin, pancreatic enzymes, angiotensin-converting enzyme and rheumatoid factor.
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Therapies of Idiopathic Nodular Panniculitis
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Treatment
Treatment of idiopathic nodular panniculitis is symptomatic and supportive. In some patients, skin lesions may heal spontaneously (remission). However, they often return (recur). Affected individuals should receive a thorough clinical examination to determine whether the idiopathic nodular panniculitis is actually occurring secondary to another condition, as treatment of that primary condition may alleviate the symptoms of idiopathic nodular panniculitis.Non-severe cases that do not include other body systems are treated with pain relieving analgesics (e.g. NSAIDS). If ulcers are present, dressing should be applied to reduce likelihood of infection. For supportive care in patients with severe, uncontrolled pain, opioids may be used. Initial therapy for severe cases includes surgical excision of the nodule and systemic therapy such as an antibiotic (e.g. dapsone, ceftriaxone), immunosuppressant (e.g., azathioprine) or the antimalarial agent hydroxychloroquine. Additional corticosteroid treatment (e.g. prednisone) may be effective under controlled conditions (e.g. limited duration).
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Therapies of Idiopathic Nodular Panniculitis. Treatment
Treatment of idiopathic nodular panniculitis is symptomatic and supportive. In some patients, skin lesions may heal spontaneously (remission). However, they often return (recur). Affected individuals should receive a thorough clinical examination to determine whether the idiopathic nodular panniculitis is actually occurring secondary to another condition, as treatment of that primary condition may alleviate the symptoms of idiopathic nodular panniculitis.Non-severe cases that do not include other body systems are treated with pain relieving analgesics (e.g. NSAIDS). If ulcers are present, dressing should be applied to reduce likelihood of infection. For supportive care in patients with severe, uncontrolled pain, opioids may be used. Initial therapy for severe cases includes surgical excision of the nodule and systemic therapy such as an antibiotic (e.g. dapsone, ceftriaxone), immunosuppressant (e.g., azathioprine) or the antimalarial agent hydroxychloroquine. Additional corticosteroid treatment (e.g. prednisone) may be effective under controlled conditions (e.g. limited duration).
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Overview of Idiopathic Pulmonary Fibrosis
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SummaryIdiopathic pulmonary fibrosis (IPF) is a chronic lung disorder characterized by thickening, stiffening and scarring (fibrosis) of tissue within the lungs. Affected individuals develop shortness of breath and progressive lung disease. Ultimately, IPF results in life-threatening complications such as respiratory failure. The rate of progression can vary greatly from one person to another. Over years, most individuals experience increasing respiratory symptoms, progressive scarring of the lungs and a gradual decline in lung function. Less often, affected individuals have mild scarring within the lungs and little to no change in the disease for many years. In some cases, the disorder can progress rapidly (acutely), causing life-threatening complications within several years of diagnosis. The term ‘idiopathic’ means that the underlying cause of the disorder is unknown or unproven, however, recently genetic susceptibility has been shown to account for 35-40% of the risk of developing this disease. Although there is no cure for IPF, various different treatments are available to manage the disorder and several newer therapeutic options are being studied. Ultimately, some affected individuals will require a lung transplant.IntroductionIPF is classified as a form of idiopathic interstitial pneumonia, which is a group of lung diseases that damage the lungs in a similar manner and occur due to unknown causes. This group of disorders is also known as diffuse parenchymal lung diseases. Collectively, these disorders are classified under the broader umbrella term, interstitial lung diseases (ILDs). ILDs a large group of disorders (more than 200) characterized by progressive scarring of the lungs. IPF is the most common form.
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Overview of Idiopathic Pulmonary Fibrosis. SummaryIdiopathic pulmonary fibrosis (IPF) is a chronic lung disorder characterized by thickening, stiffening and scarring (fibrosis) of tissue within the lungs. Affected individuals develop shortness of breath and progressive lung disease. Ultimately, IPF results in life-threatening complications such as respiratory failure. The rate of progression can vary greatly from one person to another. Over years, most individuals experience increasing respiratory symptoms, progressive scarring of the lungs and a gradual decline in lung function. Less often, affected individuals have mild scarring within the lungs and little to no change in the disease for many years. In some cases, the disorder can progress rapidly (acutely), causing life-threatening complications within several years of diagnosis. The term ‘idiopathic’ means that the underlying cause of the disorder is unknown or unproven, however, recently genetic susceptibility has been shown to account for 35-40% of the risk of developing this disease. Although there is no cure for IPF, various different treatments are available to manage the disorder and several newer therapeutic options are being studied. Ultimately, some affected individuals will require a lung transplant.IntroductionIPF is classified as a form of idiopathic interstitial pneumonia, which is a group of lung diseases that damage the lungs in a similar manner and occur due to unknown causes. This group of disorders is also known as diffuse parenchymal lung diseases. Collectively, these disorders are classified under the broader umbrella term, interstitial lung diseases (ILDs). ILDs a large group of disorders (more than 200) characterized by progressive scarring of the lungs. IPF is the most common form.
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Symptoms of Idiopathic Pulmonary Fibrosis
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In the early stages of IPF no symptoms may be present (asymptomatic). As stated above, the progression of the disorder is highly variable. Some individuals may experience ‘exacerbations’ in which symptoms worsen for a period of time, before improving somewhat. The initial, characteristic symptom is shortness of breath that is particularly noticeable during exertion such as exercise. This is known as breathlessness or dyspnea. Affected individuals may also exhibit a mild, dry cough that produces little to no sputum (nonproductive cough). Sputum is material that is coughed up from the respiratory tract and can include saliva, mucus and phlegm. This persistent, nonproductive cough lasts for more than 30 days.As the disease progresses, affected individuals develop breathlessness upon moderate exertion or exercise. They may exhibit fast, shallow breathing. The dry, hacking nonproductive cough may also occur. Eventually, breathlessness may develop upon minimal exertion or even at rest. Affected individuals may experience repeated bouts of coughing that cannot be controlled.Additional symptoms that may occur include abnormal fatigue, discomfort in the chest, gradual, unintended weight loss, and aching joints and muscles. Some individuals develop clubbing of the fingers or toes. Clubbing is when the tissue at the bottom of the fingernails and toenails swells, becoming wider and rounder. Affected individuals have an increased risk of developing repeated chest infections (chronic pneumonia).Ultimately, respiratory function in individuals with IPF declines to cause severe complications including respiratory failure. Pulmonary fibrosis can lead to other severe medical conditions including pneumonia (lung infection), collapsed lungs (pneumothorax), high blood pressure of the main artery of the lungs (pulmonary hypertension), blood clots in the lungs (pulmonary embolism), and heart failure. Individuals with IPF may be at an increased risk of developing lung cancer.Some individuals experience an ‘acute exacerbation,’ which describes a rapid progression of the disease and a rapid deterioration of lung function. Acute exacerbations may be associated with a complicating factor such as an infection, pulmonary embolism, pneumothorax or heart failure. However, in many cases, acute exacerbations occur without any identifiable cause.
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Symptoms of Idiopathic Pulmonary Fibrosis. In the early stages of IPF no symptoms may be present (asymptomatic). As stated above, the progression of the disorder is highly variable. Some individuals may experience ‘exacerbations’ in which symptoms worsen for a period of time, before improving somewhat. The initial, characteristic symptom is shortness of breath that is particularly noticeable during exertion such as exercise. This is known as breathlessness or dyspnea. Affected individuals may also exhibit a mild, dry cough that produces little to no sputum (nonproductive cough). Sputum is material that is coughed up from the respiratory tract and can include saliva, mucus and phlegm. This persistent, nonproductive cough lasts for more than 30 days.As the disease progresses, affected individuals develop breathlessness upon moderate exertion or exercise. They may exhibit fast, shallow breathing. The dry, hacking nonproductive cough may also occur. Eventually, breathlessness may develop upon minimal exertion or even at rest. Affected individuals may experience repeated bouts of coughing that cannot be controlled.Additional symptoms that may occur include abnormal fatigue, discomfort in the chest, gradual, unintended weight loss, and aching joints and muscles. Some individuals develop clubbing of the fingers or toes. Clubbing is when the tissue at the bottom of the fingernails and toenails swells, becoming wider and rounder. Affected individuals have an increased risk of developing repeated chest infections (chronic pneumonia).Ultimately, respiratory function in individuals with IPF declines to cause severe complications including respiratory failure. Pulmonary fibrosis can lead to other severe medical conditions including pneumonia (lung infection), collapsed lungs (pneumothorax), high blood pressure of the main artery of the lungs (pulmonary hypertension), blood clots in the lungs (pulmonary embolism), and heart failure. Individuals with IPF may be at an increased risk of developing lung cancer.Some individuals experience an ‘acute exacerbation,’ which describes a rapid progression of the disease and a rapid deterioration of lung function. Acute exacerbations may be associated with a complicating factor such as an infection, pulmonary embolism, pneumothorax or heart failure. However, in many cases, acute exacerbations occur without any identifiable cause.
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Causes of Idiopathic Pulmonary Fibrosis
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The exact, underlying cause of IPF is not fully understood. The disorder is occurs in families and also sporadically. Different factors, including immunologic, environmental, and genetic ones, are thought to play a role in the development of the disorder. The strongest risk factor, accounting for 30% of risk of developing IPF, is a variation in the MUC5B gene that results in more mucus production in the smallest airways in the lung (respiratory bronchioles). For many years, researchers believed that most cases resulted from generalized inflammation in the lungs that progressed to cause excessive scarring in the lungs. However, researchers now believe that most cases result from damage to certain cells that line the small airways and alveoli (epithelial cells). The alveoli are tiny, thin-walled air sacs found in large numbers in the lungs. Alveoli are where oxygen enters the blood and carbon dioxide exits the blood. Alveoli are found at the ends of small, narrow tubes called bronchioles, which branch off from the main airway passages within the lungs. Basically, air is breathed in through the nose and mouth and travels down the throat to the windpipe (trachea). The trachea divides into air passages called bronchial tubes to which the bronchioles are connected. Most likely, as a part of normal wound healing, the body attempts to repair the damaged epithelial cells. This response is abnormal leading to progressive scarring and damage to the alveoli and surrounding lung tissue.As explained, the underlying reason why the initial damage occurs is not always understood. Such damage may result from chronic exposure to an inciting or ‘triggering’ agent. Cigarette smoking is strongly associated with IPF, particularly in individuals with at least 20 ‘pack’ years of smoking history. Additional triggering agents include chronic breathing into the lungs of foreign material (chronic aspiration) and the chronic breathing in of certain environmental pollutants including various gases and fumes, inorganic dusts (e.g. silica and hard metal dusts), and organic dusts (e.g. bacteria and animal proteins). Viral or bacterial infections, radiation therapies, and certain medications including specific chemotherapeutic drugs, antibiotics and heart medications have also been linked to IPF. Autoimmune diseases such as rheumatoid arthritis, lupus or scleroderma are known to be associated with pulmonary fibrosis. In many cases, no inciting or triggering agent can be identified.Researchers suspect that certain affected individuals are genetically predisposed (susceptible) to developing IPF following such exposures described above. A person who is genetically predisposed to a disorder carries a gene (or genes) for the disease, but it may not be expressed unless it is triggered or “activated” under certain circumstances, such as due to particular environmental or immunologic factors. A number of genes have implicated in the development of IPF and in aggregate account for 35-40% of the risk of developing IPF. These genes include genes that preserve host defense, cell survival, and cell-cell interactions.Specific genetic abnormalities that may be associated with IPF in certain cases include mutations of the MUC5B gene, which produces a mucus protein; mutations of the SP-C gene, which encodes surfactant protein C (surfactant is a mixture of fats and proteins that reduces surface tension of fluids that coat the lungs); and mutations of the TERT and TERC genes, which are involved in the health and function of telomeres. Telomeres are structures found at the end of chromosomes that are essential in the replication and stability of chromosomes. Telomeres have been compared to the plastic tips of shoelaces because they prevent chromosomes from sticking together, becoming frayed or damaged and protect the vital genetic information on a chromosome. However, a variant controlling the expression of the MUC5B gene is the most important risk factor for the development of IPF, accounting for 30% of the risk of developing this disease. Most likely, IPF and idiopathic interstitial pneumonias in general, are caused in part by multiple genetic variations acting alone or in some combination. More research is necessary to determine the exact role such genetic mutations play in the development of IPF in specific cases.In 5-10% of the cases, IPF has occurred in more than one member of the same family unit (i.e. parent, children and siblings). When this occurs, the term familial idiopathic pulmonary fibrosis is used. The symptoms and objective signs of familial IPF are the same as those for sporadic IPF, but the disorder tends to occur at a slightly younger age.Pulmonary fibrosis can occur as part of a distinct genetic disorder such as Hermansky-Pudlack syndrome. HPS is characterized by albinism, vision abnormalities and platelet dysfunction leading to prolonged bleeding. In specific cases, affected individuals can develop pulmonary fibrosis. Mutations in several different genes are known to cause HPS; pulmonary fibrosis only appears to be associated with two specific mutations, the HPS1 gene and the HPS4 gene. (For more information on this disorder, choose “Hermansky Pudlak” as your search term in the Rare Disease Database.)Several conditions occur with greater frequency in individuals with IPF than in individuals within the general population including backflow (regurgitation) of the contents of the stomach into the esophagus (gastroesophageal reflux or GERD), obesity, emphysema and obstructive sleep apnea. The connection, if any, between these disorders is not fully understood. Some researchers believe that chronic GERD may be a risk factor for developing IPF because of repeated, unintentional aspiration of very small amounts of reflux material into the lungs.
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Causes of Idiopathic Pulmonary Fibrosis. The exact, underlying cause of IPF is not fully understood. The disorder is occurs in families and also sporadically. Different factors, including immunologic, environmental, and genetic ones, are thought to play a role in the development of the disorder. The strongest risk factor, accounting for 30% of risk of developing IPF, is a variation in the MUC5B gene that results in more mucus production in the smallest airways in the lung (respiratory bronchioles). For many years, researchers believed that most cases resulted from generalized inflammation in the lungs that progressed to cause excessive scarring in the lungs. However, researchers now believe that most cases result from damage to certain cells that line the small airways and alveoli (epithelial cells). The alveoli are tiny, thin-walled air sacs found in large numbers in the lungs. Alveoli are where oxygen enters the blood and carbon dioxide exits the blood. Alveoli are found at the ends of small, narrow tubes called bronchioles, which branch off from the main airway passages within the lungs. Basically, air is breathed in through the nose and mouth and travels down the throat to the windpipe (trachea). The trachea divides into air passages called bronchial tubes to which the bronchioles are connected. Most likely, as a part of normal wound healing, the body attempts to repair the damaged epithelial cells. This response is abnormal leading to progressive scarring and damage to the alveoli and surrounding lung tissue.As explained, the underlying reason why the initial damage occurs is not always understood. Such damage may result from chronic exposure to an inciting or ‘triggering’ agent. Cigarette smoking is strongly associated with IPF, particularly in individuals with at least 20 ‘pack’ years of smoking history. Additional triggering agents include chronic breathing into the lungs of foreign material (chronic aspiration) and the chronic breathing in of certain environmental pollutants including various gases and fumes, inorganic dusts (e.g. silica and hard metal dusts), and organic dusts (e.g. bacteria and animal proteins). Viral or bacterial infections, radiation therapies, and certain medications including specific chemotherapeutic drugs, antibiotics and heart medications have also been linked to IPF. Autoimmune diseases such as rheumatoid arthritis, lupus or scleroderma are known to be associated with pulmonary fibrosis. In many cases, no inciting or triggering agent can be identified.Researchers suspect that certain affected individuals are genetically predisposed (susceptible) to developing IPF following such exposures described above. A person who is genetically predisposed to a disorder carries a gene (or genes) for the disease, but it may not be expressed unless it is triggered or “activated” under certain circumstances, such as due to particular environmental or immunologic factors. A number of genes have implicated in the development of IPF and in aggregate account for 35-40% of the risk of developing IPF. These genes include genes that preserve host defense, cell survival, and cell-cell interactions.Specific genetic abnormalities that may be associated with IPF in certain cases include mutations of the MUC5B gene, which produces a mucus protein; mutations of the SP-C gene, which encodes surfactant protein C (surfactant is a mixture of fats and proteins that reduces surface tension of fluids that coat the lungs); and mutations of the TERT and TERC genes, which are involved in the health and function of telomeres. Telomeres are structures found at the end of chromosomes that are essential in the replication and stability of chromosomes. Telomeres have been compared to the plastic tips of shoelaces because they prevent chromosomes from sticking together, becoming frayed or damaged and protect the vital genetic information on a chromosome. However, a variant controlling the expression of the MUC5B gene is the most important risk factor for the development of IPF, accounting for 30% of the risk of developing this disease. Most likely, IPF and idiopathic interstitial pneumonias in general, are caused in part by multiple genetic variations acting alone or in some combination. More research is necessary to determine the exact role such genetic mutations play in the development of IPF in specific cases.In 5-10% of the cases, IPF has occurred in more than one member of the same family unit (i.e. parent, children and siblings). When this occurs, the term familial idiopathic pulmonary fibrosis is used. The symptoms and objective signs of familial IPF are the same as those for sporadic IPF, but the disorder tends to occur at a slightly younger age.Pulmonary fibrosis can occur as part of a distinct genetic disorder such as Hermansky-Pudlack syndrome. HPS is characterized by albinism, vision abnormalities and platelet dysfunction leading to prolonged bleeding. In specific cases, affected individuals can develop pulmonary fibrosis. Mutations in several different genes are known to cause HPS; pulmonary fibrosis only appears to be associated with two specific mutations, the HPS1 gene and the HPS4 gene. (For more information on this disorder, choose “Hermansky Pudlak” as your search term in the Rare Disease Database.)Several conditions occur with greater frequency in individuals with IPF than in individuals within the general population including backflow (regurgitation) of the contents of the stomach into the esophagus (gastroesophageal reflux or GERD), obesity, emphysema and obstructive sleep apnea. The connection, if any, between these disorders is not fully understood. Some researchers believe that chronic GERD may be a risk factor for developing IPF because of repeated, unintentional aspiration of very small amounts of reflux material into the lungs.
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Affects of Idiopathic Pulmonary Fibrosis
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The exact prevalence and incidence of IPF is unknown. Estimates have ranged from 2-29 people per 100,000 in the general population. This variation may be partially due to the lack of a uniform definition when attempting to identify the disorder. Additionally, many cases of IPF go undiagnosed or misdiagnosed, making it difficult to determine the true frequency in the general population. Familial IPF accounts for approximately 5-10% of all cases of IPF. IPF primarily affects older adults. Males tend to be affected more often than females.
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Affects of Idiopathic Pulmonary Fibrosis. The exact prevalence and incidence of IPF is unknown. Estimates have ranged from 2-29 people per 100,000 in the general population. This variation may be partially due to the lack of a uniform definition when attempting to identify the disorder. Additionally, many cases of IPF go undiagnosed or misdiagnosed, making it difficult to determine the true frequency in the general population. Familial IPF accounts for approximately 5-10% of all cases of IPF. IPF primarily affects older adults. Males tend to be affected more often than females.
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Related disorders of Idiopathic Pulmonary Fibrosis
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Symptoms of the following disorders can be similar to those of idiopathic pulmonary fibrosis. Comparisons may be useful for a differential diagnosis.There are numerous conditions affecting the lungs that can cause symptoms similar to those seen in IPF. The interstitial lung diseases alone comprise more than 200 different disorders. Specific disorders that are included in the differential diagnosis of IPF include asthma, bronchiectasis, chronic obstructive pulmonary disease, sarcoidosis, certain connective tissue disorders that can affect the lungs, drug-induced pulmonary toxicity, lung cancer, various forms of pneumonia, pulmonary alveolar proteinosis, pulmonary eosinophilia, and various forms of lung disease caused by occupational or environmental exposures such as silicosis or asbestos. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Related disorders of Idiopathic Pulmonary Fibrosis. Symptoms of the following disorders can be similar to those of idiopathic pulmonary fibrosis. Comparisons may be useful for a differential diagnosis.There are numerous conditions affecting the lungs that can cause symptoms similar to those seen in IPF. The interstitial lung diseases alone comprise more than 200 different disorders. Specific disorders that are included in the differential diagnosis of IPF include asthma, bronchiectasis, chronic obstructive pulmonary disease, sarcoidosis, certain connective tissue disorders that can affect the lungs, drug-induced pulmonary toxicity, lung cancer, various forms of pneumonia, pulmonary alveolar proteinosis, pulmonary eosinophilia, and various forms of lung disease caused by occupational or environmental exposures such as silicosis or asbestos. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Diagnosis of Idiopathic Pulmonary Fibrosis
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A diagnosis of idiopathic pulmonary fibrosis may be suspected based upon identification of characteristic symptoms, a detailed patient history, and a thorough clinical evaluation. A diagnosis may be confirmed based upon a variety of specialized tests including traditional chest x-rays (radiography), computer tomography (CT) scans, pulmonary function tests, blood tests, and the surgical removal and microscopic examination of lung tissue (lung biopsy).Detailed diagnostic criteria for IPF have been published by the combined efforts of several groups including the American Thoracic Society, the European Respiratory Society, the Japanese Respiratory Society, and the Latin American Thoracic Association (Wells AU, 2013).Clinical Testing and Workup
Traditional chest x-rays can demonstrate scarring within the lungs, which is suggestive but not diagnostic of IPF. Some individuals may have normal chest x-rays at the time of diagnosis. A special type of CT scanning known as high resolution computed tomography (HRCT) can be used to diagnose individuals with IPF. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. HRCT gives sharper, more detailed pictures of the lungs than traditional x-rays or conventional CT scanning. HRCT can reveal the presence of scar tissue and the extent of lung damage and in some cases the presence of specific findings can be adequate to establish a diagnosis. Many cases of IPF are associated with a distinct pattern of lung damage known as usual interstitial pneumonia (UIP). This pattern consists of patches of normal lung tissues that alternate with patches of dense scar tissue (fibrosis).Pulmonary function tests to measure how well the lungs take in and exhale oxygen and how efficiently they transfer oxygen to the blood may also be helpful. There are no blood tests for IPF, but certain blood tests can help to rule out other conditions. Exercise testing, in which blood pressure, oxygen saturation levels and heart function are monitored, may be recommended. Specific methods vary, but walking on a treadmill or riding a stationary bike are common methods used during exercise testing.A procedure known as bronchoalveolar lavage (BAL) may be used to help rule out other conditions. During BAL, a narrow tube (bronchoscope) is slid down the windpipe into the lungs and a sterile solution is passed through the tube washing out (lavaging) cells. This fluid is collected and then the tube is removed, allowing the cells to be studied.If a diagnosis of IPF cannot be confirmed by other tests, a lung biopsy or a video-assisted thoracoscopy may be necessary. A lung biopsy involves removing samples of lung tissue from several places within the lungs. A lung biopsy can rule out specific conditions and confirm a diagnosis of IPF. Video-assisted thoracoscopy involves inserting a narrow tube called an endoscope affixed with a tiny camera through a very small cut (incision) in the chest wall. This allows physicians to examine the lungs or other structures within the chest cavity.
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Diagnosis of Idiopathic Pulmonary Fibrosis. A diagnosis of idiopathic pulmonary fibrosis may be suspected based upon identification of characteristic symptoms, a detailed patient history, and a thorough clinical evaluation. A diagnosis may be confirmed based upon a variety of specialized tests including traditional chest x-rays (radiography), computer tomography (CT) scans, pulmonary function tests, blood tests, and the surgical removal and microscopic examination of lung tissue (lung biopsy).Detailed diagnostic criteria for IPF have been published by the combined efforts of several groups including the American Thoracic Society, the European Respiratory Society, the Japanese Respiratory Society, and the Latin American Thoracic Association (Wells AU, 2013).Clinical Testing and Workup
Traditional chest x-rays can demonstrate scarring within the lungs, which is suggestive but not diagnostic of IPF. Some individuals may have normal chest x-rays at the time of diagnosis. A special type of CT scanning known as high resolution computed tomography (HRCT) can be used to diagnose individuals with IPF. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. HRCT gives sharper, more detailed pictures of the lungs than traditional x-rays or conventional CT scanning. HRCT can reveal the presence of scar tissue and the extent of lung damage and in some cases the presence of specific findings can be adequate to establish a diagnosis. Many cases of IPF are associated with a distinct pattern of lung damage known as usual interstitial pneumonia (UIP). This pattern consists of patches of normal lung tissues that alternate with patches of dense scar tissue (fibrosis).Pulmonary function tests to measure how well the lungs take in and exhale oxygen and how efficiently they transfer oxygen to the blood may also be helpful. There are no blood tests for IPF, but certain blood tests can help to rule out other conditions. Exercise testing, in which blood pressure, oxygen saturation levels and heart function are monitored, may be recommended. Specific methods vary, but walking on a treadmill or riding a stationary bike are common methods used during exercise testing.A procedure known as bronchoalveolar lavage (BAL) may be used to help rule out other conditions. During BAL, a narrow tube (bronchoscope) is slid down the windpipe into the lungs and a sterile solution is passed through the tube washing out (lavaging) cells. This fluid is collected and then the tube is removed, allowing the cells to be studied.If a diagnosis of IPF cannot be confirmed by other tests, a lung biopsy or a video-assisted thoracoscopy may be necessary. A lung biopsy involves removing samples of lung tissue from several places within the lungs. A lung biopsy can rule out specific conditions and confirm a diagnosis of IPF. Video-assisted thoracoscopy involves inserting a narrow tube called an endoscope affixed with a tiny camera through a very small cut (incision) in the chest wall. This allows physicians to examine the lungs or other structures within the chest cavity.
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Therapies of Idiopathic Pulmonary Fibrosis
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TreatmentIn 2014, the U.S. Food and Drug Administration (FDA) approved two drugs for the treatment of IPF. Ofev (nintedanib), distributed by Boehringer Ingelheim Pharmaceuticals, Inc., is a kinase inhibitor that blocks multiple pathways that may be involved in the scarring of lung tissue.http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm418994.htm
Esbriet (pirfenidone), manufactured for InterMune, Inc., acts on multiple pathways that may be involved in the scarring of lung tissue.
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm418991.htmVarious other treatment options are aimed at treating the symptoms of IPF, slowing the progression of the disease, and helping affected individuals remain active and healthy and to maintain their quality of life.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease progression; the presence of additional, unrelated illnesses (co-morbidities); 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 his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.At some point in their lives, most individuals with IPF will require supplemental oxygen (oxygen therapy) to compensate for the inability of the lungs to transfer oxygen into the bloodstream. At first, oxygen therapy may be required only upon exertion, but in some cases may eventually be required continuously. Oxygen therapy can reduce breathlessness and allow individuals to be more active.Individuals with IPF may benefit from a program known as a pulmonary rehabilitation, a standard treatment option for individuals with chronic lung diseases. Pulmonary rehabilitation usually involves a team of specialists at a clinic experienced in lung disease. Pulmonary rehabilitation teaches individuals about exercise training; specific breathing strategies or techniques; nutritional counseling; and energy-conserving techniques. These specialists can also provide education on lung disease including how to best manage the disease and can provide psychological counseling.Affected individuals who smoke are strongly encouraged to stop. Influenza and pneumococcal polysaccharide vaccinations are strongly recommended as well because these infections are particularly harmful to individuals with IPF.Certain other medications have been used to treat individuals with IPF. For many years, corticosteroid medications such as prednisolone often along with an immunosuppressive drug such as azathioprine have been used to treat individuals with IPF. These drugs reduce inflammation and/or suppress the immune system. Another drug known as N-acetylcysteine (a naturally occurring antioxidant) is often added to this drug regimen. These drugs were usually recommended based upon the initial theory that generalized inflammation was a major component of IPF. However, the drugs were often ineffective or provided only minimal relief and there is no evidence that they improve long-term survival. In 2011 (Raghu, et al.), a consensus paper published by the American Thoracic Society stated that combination therapy involving prednisolone, azathioprine, and N-acetylcysteine is recommended only in a minority of patients.Individuals with IPF may eventually require a lung transplant. Such surgery is more likely in younger patients (under 65 years of age) with severe disease who have not responded to other treatments and who do not have other serious medical complications. Some medical centers consider lung transplantations for individuals over 65 who do not have other serious medical complications. As with any organ transplant, a lung transplant carries a risk of significant complications such as rejection or infection.Gastroesophageal reflux may be treated with standard medications that reduce or suppress the production of acid in the stomach. GERD treatment may be particularly important in individuals with IPF because some studies have shown longer survival times and lower fibrosis scores in individuals receiving treatment for GERD.Additional therapies are symptomatic and follow standard guidelines. For example, antibiotics may be prescribed for lung infections and cough medications and oral codeine may provide relief from chronic coughing.
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Therapies of Idiopathic Pulmonary Fibrosis. TreatmentIn 2014, the U.S. Food and Drug Administration (FDA) approved two drugs for the treatment of IPF. Ofev (nintedanib), distributed by Boehringer Ingelheim Pharmaceuticals, Inc., is a kinase inhibitor that blocks multiple pathways that may be involved in the scarring of lung tissue.http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm418994.htm
Esbriet (pirfenidone), manufactured for InterMune, Inc., acts on multiple pathways that may be involved in the scarring of lung tissue.
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm418991.htmVarious other treatment options are aimed at treating the symptoms of IPF, slowing the progression of the disease, and helping affected individuals remain active and healthy and to maintain their quality of life.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease progression; the presence of additional, unrelated illnesses (co-morbidities); 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 his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.At some point in their lives, most individuals with IPF will require supplemental oxygen (oxygen therapy) to compensate for the inability of the lungs to transfer oxygen into the bloodstream. At first, oxygen therapy may be required only upon exertion, but in some cases may eventually be required continuously. Oxygen therapy can reduce breathlessness and allow individuals to be more active.Individuals with IPF may benefit from a program known as a pulmonary rehabilitation, a standard treatment option for individuals with chronic lung diseases. Pulmonary rehabilitation usually involves a team of specialists at a clinic experienced in lung disease. Pulmonary rehabilitation teaches individuals about exercise training; specific breathing strategies or techniques; nutritional counseling; and energy-conserving techniques. These specialists can also provide education on lung disease including how to best manage the disease and can provide psychological counseling.Affected individuals who smoke are strongly encouraged to stop. Influenza and pneumococcal polysaccharide vaccinations are strongly recommended as well because these infections are particularly harmful to individuals with IPF.Certain other medications have been used to treat individuals with IPF. For many years, corticosteroid medications such as prednisolone often along with an immunosuppressive drug such as azathioprine have been used to treat individuals with IPF. These drugs reduce inflammation and/or suppress the immune system. Another drug known as N-acetylcysteine (a naturally occurring antioxidant) is often added to this drug regimen. These drugs were usually recommended based upon the initial theory that generalized inflammation was a major component of IPF. However, the drugs were often ineffective or provided only minimal relief and there is no evidence that they improve long-term survival. In 2011 (Raghu, et al.), a consensus paper published by the American Thoracic Society stated that combination therapy involving prednisolone, azathioprine, and N-acetylcysteine is recommended only in a minority of patients.Individuals with IPF may eventually require a lung transplant. Such surgery is more likely in younger patients (under 65 years of age) with severe disease who have not responded to other treatments and who do not have other serious medical complications. Some medical centers consider lung transplantations for individuals over 65 who do not have other serious medical complications. As with any organ transplant, a lung transplant carries a risk of significant complications such as rejection or infection.Gastroesophageal reflux may be treated with standard medications that reduce or suppress the production of acid in the stomach. GERD treatment may be particularly important in individuals with IPF because some studies have shown longer survival times and lower fibrosis scores in individuals receiving treatment for GERD.Additional therapies are symptomatic and follow standard guidelines. For example, antibiotics may be prescribed for lung infections and cough medications and oral codeine may provide relief from chronic coughing.
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Overview of Idiopathic Pulmonary Hemosiderosis
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SummaryIdiopathic pulmonary hemosiderosis (IPH) is a rare lung disease, mostly affecting children under 10 years old. “Idiopathic” means the cause is not yet known, “pulmonary” refers to involvement of the lungs, and “hemosiderosis” refers to the deposition of ‘hemosiderin’, a storage form of Iron in the human body. Patients with the disease experience bleeding into the lungs, resulting in recurrent episodes of shortness of breath and coughing, often with blood. The ongoing bleeding often leads to iron deficiency anemia, which causes fatigue and lack of growth in children. The disease injures the lungs, leading to inflammation and, in some people, irreversible scarring. Doctors use a flexible scope to access the lungs (bronchoscopy) and perform washing (bronchoalveolar lavage) to make the diagnosis. Sometimes, a lung biopsy could be necessary for a definite diagnosis. There is no known cure for IPH, and the prognosis is highly variable. The survival rate has improved over the past few decades as research and therapies improve. In the past, the average survival had ranged from 2.5 to 5 years after diagnosis. Standard therapies include steroids and immunosuppressants to help control the bleeding into the lungs, blood transfusions to correct the anemia and other supportive measures.
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Overview of Idiopathic Pulmonary Hemosiderosis. SummaryIdiopathic pulmonary hemosiderosis (IPH) is a rare lung disease, mostly affecting children under 10 years old. “Idiopathic” means the cause is not yet known, “pulmonary” refers to involvement of the lungs, and “hemosiderosis” refers to the deposition of ‘hemosiderin’, a storage form of Iron in the human body. Patients with the disease experience bleeding into the lungs, resulting in recurrent episodes of shortness of breath and coughing, often with blood. The ongoing bleeding often leads to iron deficiency anemia, which causes fatigue and lack of growth in children. The disease injures the lungs, leading to inflammation and, in some people, irreversible scarring. Doctors use a flexible scope to access the lungs (bronchoscopy) and perform washing (bronchoalveolar lavage) to make the diagnosis. Sometimes, a lung biopsy could be necessary for a definite diagnosis. There is no known cure for IPH, and the prognosis is highly variable. The survival rate has improved over the past few decades as research and therapies improve. In the past, the average survival had ranged from 2.5 to 5 years after diagnosis. Standard therapies include steroids and immunosuppressants to help control the bleeding into the lungs, blood transfusions to correct the anemia and other supportive measures.
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Symptoms of Idiopathic Pulmonary Hemosiderosis
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Some patients may not show any symptoms early in the disease, but the most common symptoms include:– Coughing with blood (hemoptysis)
– Shortness of breath (dyspnea)
– Long, unrelenting cough
– Anemia (due to bleeding in the lungs and Iron deficiency)
– Fatigue
– Fever
– Chest pain
– Failure to thrive (deficient growth)
– Enlarged liver and spleen (hepatosplenomegaly)
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Symptoms of Idiopathic Pulmonary Hemosiderosis. Some patients may not show any symptoms early in the disease, but the most common symptoms include:– Coughing with blood (hemoptysis)
– Shortness of breath (dyspnea)
– Long, unrelenting cough
– Anemia (due to bleeding in the lungs and Iron deficiency)
– Fatigue
– Fever
– Chest pain
– Failure to thrive (deficient growth)
– Enlarged liver and spleen (hepatosplenomegaly)
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Causes of Idiopathic Pulmonary Hemosiderosis
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The cause of IPH is still not known but it is considered to be an autoimmune disease. Many patients also have celiac disease, another autoimmune disease, and the combination of celiac disease and IPH is known as Lane-Hamilton syndrome. In most patients with Lane-Hamilton syndrome, eliminating gluten from the diet also improved the symptoms of IPH. The autoimmune hypothesis theorizes that the cells responsible for providing immunity are somehow responsible for causing bleeding into the lungs and irreversible scarring over time. Although the exact mechanism is unknown, scientists have hypothesized that the offending agents could be bioactive proteins (such as histamine, ECP or VEGF). When triggered by a yet to be discovered antigen(s), the immune cells are inappropriately activated, causing the release of these factors and prompting bleeding in the lungs. Some studies also suggest that IPH may have a genetic component because it has been reported in siblings and children of IPH patients. Moreover, patients with Down syndrome could be at a higher risk of developing IPH. Other research suggests there may be an environmental component to the disease, including secondhand smoking and mold exposure. More research is needed to evaluate these hypotheses. Due to the rarity of the disease, research can be difficult and take longer than other, more common diseases.
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Causes of Idiopathic Pulmonary Hemosiderosis. The cause of IPH is still not known but it is considered to be an autoimmune disease. Many patients also have celiac disease, another autoimmune disease, and the combination of celiac disease and IPH is known as Lane-Hamilton syndrome. In most patients with Lane-Hamilton syndrome, eliminating gluten from the diet also improved the symptoms of IPH. The autoimmune hypothesis theorizes that the cells responsible for providing immunity are somehow responsible for causing bleeding into the lungs and irreversible scarring over time. Although the exact mechanism is unknown, scientists have hypothesized that the offending agents could be bioactive proteins (such as histamine, ECP or VEGF). When triggered by a yet to be discovered antigen(s), the immune cells are inappropriately activated, causing the release of these factors and prompting bleeding in the lungs. Some studies also suggest that IPH may have a genetic component because it has been reported in siblings and children of IPH patients. Moreover, patients with Down syndrome could be at a higher risk of developing IPH. Other research suggests there may be an environmental component to the disease, including secondhand smoking and mold exposure. More research is needed to evaluate these hypotheses. Due to the rarity of the disease, research can be difficult and take longer than other, more common diseases.
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Affects of Idiopathic Pulmonary Hemosiderosis
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Approximately 80% of cases occur in children, mostly under 10 years old and 20% of cases occur in adults (majority under 30 years old). IPH may affect more girls than boys and more adult men than women, according to some studies.
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Affects of Idiopathic Pulmonary Hemosiderosis. Approximately 80% of cases occur in children, mostly under 10 years old and 20% of cases occur in adults (majority under 30 years old). IPH may affect more girls than boys and more adult men than women, according to some studies.
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Related disorders of Idiopathic Pulmonary Hemosiderosis
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The following conditions have signs and symptoms that are similar to IPH: Goodpasture syndrome, acute respiratory distress syndrome (ARDS), lung infections, systemic lupus erythematous, Henoch-Schoenlein purpura, ANCA vasculitis, and mixed connective tissue disease.
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Related disorders of Idiopathic Pulmonary Hemosiderosis. The following conditions have signs and symptoms that are similar to IPH: Goodpasture syndrome, acute respiratory distress syndrome (ARDS), lung infections, systemic lupus erythematous, Henoch-Schoenlein purpura, ANCA vasculitis, and mixed connective tissue disease.
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Diagnosis of Idiopathic Pulmonary Hemosiderosis
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Since it is a rare disease, diagnosing IPH involves ruling out all other possible causes of bleeding or scarring in the lungs. This may include various blood tests (iron studies, blood cell counts and antibody levels), sputum tests, imaging (x-rays, CT scans), bronchoscopy and biopsies. A multidisciplinary team is often involved and may include pulmonologists, hospitalists, rheumatologists, respiratory therapists, intensivists and thoracic surgeons. Early recognition and treatment can help avoid serious complications and disease progression. IPH is typically diagnosed using a camera (bronchoscope) that takes samples of the fluid in the lungs, known as a bronchoalveolar lavage. The pulmonologist will also take biopsies of the lungs to confirm the diagnosis under the microscope.
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Diagnosis of Idiopathic Pulmonary Hemosiderosis. Since it is a rare disease, diagnosing IPH involves ruling out all other possible causes of bleeding or scarring in the lungs. This may include various blood tests (iron studies, blood cell counts and antibody levels), sputum tests, imaging (x-rays, CT scans), bronchoscopy and biopsies. A multidisciplinary team is often involved and may include pulmonologists, hospitalists, rheumatologists, respiratory therapists, intensivists and thoracic surgeons. Early recognition and treatment can help avoid serious complications and disease progression. IPH is typically diagnosed using a camera (bronchoscope) that takes samples of the fluid in the lungs, known as a bronchoalveolar lavage. The pulmonologist will also take biopsies of the lungs to confirm the diagnosis under the microscope.
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Therapies of Idiopathic Pulmonary Hemosiderosis
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TreatmentThe goal of treatment is to suppress this immune response and decrease the damage by preventing repeated bleeding episodes. There is no gold standard treatment for IPH yet. Physicians determine the best therapies based on their experience and available research.Some commonly accepted therapies include: Steroids—These medications may control bleeding into the lungs and scarring that happens afterward.Immunosuppressants– In addition to steroids, these medications subdue the immune system further and assist in preventing bleeding in the lungs. These drugs may include 6-mercaptopurine/azathioprine, hydroxychloroquine, cyclophosphamide, mycophenolate mofetil or rituximab.Blood transfusions– Replacing the blood lost due to lung bleeding may help the symptoms of anemia.Stem cell transplant—This experimental therapy uses the body’s own stem cells to modulate the immune system and prevent bleeding.Extracorporeal membrane oxygenation (ECMO)—This is a temporary life support system during acute severe bleeding or end-stage lung disease until a lung transplant can be accomplished for appropriate patients.Lung transplant—This is a final resort for severe IPH. IPH may recur in the transplanted lung, but few lung transplant cases have been reported.
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Therapies of Idiopathic Pulmonary Hemosiderosis. TreatmentThe goal of treatment is to suppress this immune response and decrease the damage by preventing repeated bleeding episodes. There is no gold standard treatment for IPH yet. Physicians determine the best therapies based on their experience and available research.Some commonly accepted therapies include: Steroids—These medications may control bleeding into the lungs and scarring that happens afterward.Immunosuppressants– In addition to steroids, these medications subdue the immune system further and assist in preventing bleeding in the lungs. These drugs may include 6-mercaptopurine/azathioprine, hydroxychloroquine, cyclophosphamide, mycophenolate mofetil or rituximab.Blood transfusions– Replacing the blood lost due to lung bleeding may help the symptoms of anemia.Stem cell transplant—This experimental therapy uses the body’s own stem cells to modulate the immune system and prevent bleeding.Extracorporeal membrane oxygenation (ECMO)—This is a temporary life support system during acute severe bleeding or end-stage lung disease until a lung transplant can be accomplished for appropriate patients.Lung transplant—This is a final resort for severe IPH. IPH may recur in the transplanted lung, but few lung transplant cases have been reported.
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Overview of Idiopathic Subglottic Stenosis
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Summary Idiopathic subglottic stenosis (iSGS) is a narrowing (stenosis) of a specific portion of the windpipe (trachea) known as the subglottis (just below the vocal cords). Idiopathic means that the underlying cause of this narrowing is unknown. Most patients have scar tissue (fibrosis) and inflammation in the affected area. Symptoms may include shortness of breath upon exertion (dyspnea), hoarseness, and a high-pitched wheezing sound when breathing in or out (stridor). The disorder occurs almost exclusively in women. The condition often recurs despite treatment.
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Overview of Idiopathic Subglottic Stenosis. Summary Idiopathic subglottic stenosis (iSGS) is a narrowing (stenosis) of a specific portion of the windpipe (trachea) known as the subglottis (just below the vocal cords). Idiopathic means that the underlying cause of this narrowing is unknown. Most patients have scar tissue (fibrosis) and inflammation in the affected area. Symptoms may include shortness of breath upon exertion (dyspnea), hoarseness, and a high-pitched wheezing sound when breathing in or out (stridor). The disorder occurs almost exclusively in women. The condition often recurs despite treatment.
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Symptoms of Idiopathic Subglottic Stenosis
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Stridor and dyspnea are the most common symptoms. The noisy breathing that characterizes stridor can resemble (and is often mistaken for) wheezing. These symptoms often lead affected individuals to be misdiagnosed with asthma and can result in a delay in diagnosis. Stridor can become progressively worse over time. Shortness of breath upon exertion can also be slowly progressive, worsening over a period of years so that affected individuals are gasping for breath after simple activities or even at rest.Other symptoms that have been reported in adults with idiopathic subglottic stenosis include voice changes, increased mucus production, and persistent cough.
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Symptoms of Idiopathic Subglottic Stenosis. Stridor and dyspnea are the most common symptoms. The noisy breathing that characterizes stridor can resemble (and is often mistaken for) wheezing. These symptoms often lead affected individuals to be misdiagnosed with asthma and can result in a delay in diagnosis. Stridor can become progressively worse over time. Shortness of breath upon exertion can also be slowly progressive, worsening over a period of years so that affected individuals are gasping for breath after simple activities or even at rest.Other symptoms that have been reported in adults with idiopathic subglottic stenosis include voice changes, increased mucus production, and persistent cough.
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Causes of Idiopathic Subglottic Stenosis
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By definition, the exact, underlying cause of idiopathic subglottic stenosis is unknown. Inflammation and scarring of the affected area is usually present. In the largest study to date, the investigators of the North American Airway Collaborative (NoAAC) examined 1056 iSGS patients across 40 participating institutions: they were otherwise healthy, perimenopausal (mean age 50.4 years), Caucasian (95%) and female (98%).The remarkable consistency of the iSGS population (nearly all white females) would appear to offer support for the idea that a conserved and consistent biologic process is driving a singular disease. While the clinical similarity would suggest a sex-linked genetic abnormality, the relatively mature age of presentation argues against a purely genetic etiology (as genetic diseases most commonly arise in infancy or childhood). Within the NoAAC iSGS1000 cohort there are 15 familial pairs (i.e. mother and daughter both have iSGS, or two sisters both have iSGS). Additionally, 3 other familial cases have been reported, Dumoulin et al. 2012.The nearly universal involvement of females, and the age of presentation (~50 years) coinciding with the hormonal alterations observed in near menopause (average age 50), would support a hormonally-mediated process. There are also more than 50 women in NoAAC iSGS1000 cohort that report their symptoms began in pregnancy (itself marked by high maternal estrogen). Yet the role of estrogen in the fibroinflammatory scarring of the airway remains to be defined. Alternative causes for iSGS have been put forward; including a subtle manifestation of collagen vascular disease, an anatomic predisposition of the smaller female subglottis, mechanical trauma from coughing, as well as gastroesophageal reflux disease. Yet these concepts have not proven applicable to the majority of patients, nor when applied therapeutically have they brought tangible benefits.Although several theories have been proposed to address the underlying causes, no conclusive evidence for any one theory exists. It is possible that multiple factors (e.g. environmental, genetic, and immunologic) may be necessary for the development of the disorder. More research is necessary to determine the specific causes and underlying mechanisms that ultimately lead to the development of idiopathic subglottic stenosis. Symptoms occur because of narrowing of a specific area of the windpipe known as the subglottis. The windpipe, or trachea, is the tube or passageway that connects the mouth and the nose to the lungs. The windpipe is located in the front of the neck and begins below the voice box (larynx) in the throat. The area of the larynx consisting of the vocal cords and the slit-like opening in between them is called the glottis. The subglottis is the region that runs from below the glottis to the top of the windpipe. The windpipe is made up of 15-20 C-shaped rings; the first two rings of the windpipe (tracheal rings) are often affected. The subglottic area is contained within the cricoid cartilage, the only complete ring of cartilage in the airway.
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Causes of Idiopathic Subglottic Stenosis. By definition, the exact, underlying cause of idiopathic subglottic stenosis is unknown. Inflammation and scarring of the affected area is usually present. In the largest study to date, the investigators of the North American Airway Collaborative (NoAAC) examined 1056 iSGS patients across 40 participating institutions: they were otherwise healthy, perimenopausal (mean age 50.4 years), Caucasian (95%) and female (98%).The remarkable consistency of the iSGS population (nearly all white females) would appear to offer support for the idea that a conserved and consistent biologic process is driving a singular disease. While the clinical similarity would suggest a sex-linked genetic abnormality, the relatively mature age of presentation argues against a purely genetic etiology (as genetic diseases most commonly arise in infancy or childhood). Within the NoAAC iSGS1000 cohort there are 15 familial pairs (i.e. mother and daughter both have iSGS, or two sisters both have iSGS). Additionally, 3 other familial cases have been reported, Dumoulin et al. 2012.The nearly universal involvement of females, and the age of presentation (~50 years) coinciding with the hormonal alterations observed in near menopause (average age 50), would support a hormonally-mediated process. There are also more than 50 women in NoAAC iSGS1000 cohort that report their symptoms began in pregnancy (itself marked by high maternal estrogen). Yet the role of estrogen in the fibroinflammatory scarring of the airway remains to be defined. Alternative causes for iSGS have been put forward; including a subtle manifestation of collagen vascular disease, an anatomic predisposition of the smaller female subglottis, mechanical trauma from coughing, as well as gastroesophageal reflux disease. Yet these concepts have not proven applicable to the majority of patients, nor when applied therapeutically have they brought tangible benefits.Although several theories have been proposed to address the underlying causes, no conclusive evidence for any one theory exists. It is possible that multiple factors (e.g. environmental, genetic, and immunologic) may be necessary for the development of the disorder. More research is necessary to determine the specific causes and underlying mechanisms that ultimately lead to the development of idiopathic subglottic stenosis. Symptoms occur because of narrowing of a specific area of the windpipe known as the subglottis. The windpipe, or trachea, is the tube or passageway that connects the mouth and the nose to the lungs. The windpipe is located in the front of the neck and begins below the voice box (larynx) in the throat. The area of the larynx consisting of the vocal cords and the slit-like opening in between them is called the glottis. The subglottis is the region that runs from below the glottis to the top of the windpipe. The windpipe is made up of 15-20 C-shaped rings; the first two rings of the windpipe (tracheal rings) are often affected. The subglottic area is contained within the cricoid cartilage, the only complete ring of cartilage in the airway.
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Affects of Idiopathic Subglottic Stenosis
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Idiopathic subglottic stenosis is a rare disorder that affects women almost exclusively. The disorder most often occurs in women between the ages of 30 and 50, but has been reported in younger women, and elderly adults as well. Idiopathic subglottic stenosis only accounts for approximately 15% of all cases of subglottic stenosis. However, the exact incidence and prevalence is unknown. Because people may go undiagnosed or misdiagnosed, determining the true frequency of idiopathic subglottic stenosis in the general population is difficult.
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Affects of Idiopathic Subglottic Stenosis. Idiopathic subglottic stenosis is a rare disorder that affects women almost exclusively. The disorder most often occurs in women between the ages of 30 and 50, but has been reported in younger women, and elderly adults as well. Idiopathic subglottic stenosis only accounts for approximately 15% of all cases of subglottic stenosis. However, the exact incidence and prevalence is unknown. Because people may go undiagnosed or misdiagnosed, determining the true frequency of idiopathic subglottic stenosis in the general population is difficult.
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Related disorders of Idiopathic Subglottic Stenosis
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There are a variety of known causes of subglottic stenosis. Most often, this results from prolonged intubation (i.e. having a breathing tube in place for several days), but can result from intubation for only a short period of time as well. Subglottic stenosis also occurs as part of autoimmune disorders such as Wegener’s granulomatosis or relapsing polychondritis. Rarely, some infants are born with the disorder (congenital subglottic stenosis). Affected individuals are often misdiagnosed with asthma or recurrent bronchitis. Chronic obstructive pulmonary disease can also cause symptoms similar to those seen idiopathic subglottic stenosis.
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Related disorders of Idiopathic Subglottic Stenosis. There are a variety of known causes of subglottic stenosis. Most often, this results from prolonged intubation (i.e. having a breathing tube in place for several days), but can result from intubation for only a short period of time as well. Subglottic stenosis also occurs as part of autoimmune disorders such as Wegener’s granulomatosis or relapsing polychondritis. Rarely, some infants are born with the disorder (congenital subglottic stenosis). Affected individuals are often misdiagnosed with asthma or recurrent bronchitis. Chronic obstructive pulmonary disease can also cause symptoms similar to those seen idiopathic subglottic stenosis.
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Diagnosis of Idiopathic Subglottic Stenosis
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Diagnosis of idiopathic subglottic stenosis is basically one of exclusion, in which the known causes of subglottic scarring are ruled out. A diagnosis is obtained through identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Clinical Testing and Workup
A diagnosis of subglottic stenosis may be suspected based on the results of pulmonary function tests. These tests, which require an individual to breathe into a machine called a spirometry to measure how much air they can breathe out or take in, can reveal reduced airflow and reduced air volume. The narrowed (stenotic) region can be seen with a computerized tomography (CT) scan of the neck. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. Additionally, standard chest x-rays (radiographs) can provide information on the location and degree of stenosis. Blood tests will be performed to look for antibodies that indicate the presence of certain autoimmune disorders such as Wegener’s granulomatosis known to cause subglottic stenosis. A diagnosis of subglottic stenosis can be confirmed based on direct examination of the subglottic area of the windpipe through a procedure known as endoscopy. During this procedure, a physician runs a small tube called an endoscope down the throat. The endoscope allows a physician to view the lower recesses of the throat and the upper portion of the windpipe including the subglottic region. An endoscopic exam can reveal the narrowed portion of the subglottic area.
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Diagnosis of Idiopathic Subglottic Stenosis. Diagnosis of idiopathic subglottic stenosis is basically one of exclusion, in which the known causes of subglottic scarring are ruled out. A diagnosis is obtained through identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Clinical Testing and Workup
A diagnosis of subglottic stenosis may be suspected based on the results of pulmonary function tests. These tests, which require an individual to breathe into a machine called a spirometry to measure how much air they can breathe out or take in, can reveal reduced airflow and reduced air volume. The narrowed (stenotic) region can be seen with a computerized tomography (CT) scan of the neck. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. Additionally, standard chest x-rays (radiographs) can provide information on the location and degree of stenosis. Blood tests will be performed to look for antibodies that indicate the presence of certain autoimmune disorders such as Wegener’s granulomatosis known to cause subglottic stenosis. A diagnosis of subglottic stenosis can be confirmed based on direct examination of the subglottic area of the windpipe through a procedure known as endoscopy. During this procedure, a physician runs a small tube called an endoscope down the throat. The endoscope allows a physician to view the lower recesses of the throat and the upper portion of the windpipe including the subglottic region. An endoscopic exam can reveal the narrowed portion of the subglottic area.
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Therapies of Idiopathic Subglottic Stenosis
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Treatment
There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disorder, 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 therapeutic interventions for individuals with idiopathic subglottic stenosis. Specific therapies that have been used to treat affected individuals include medications and/or surgery. Affected individuals who have a mild case of idiopathic subglottic stenosis (e.g. no symptoms) may not require treatment. Instead they may be best treated by periodic observation to see whether symptoms develop or if the narrowing progresses (i.e. narrows further). Several different surgical procedures have been used to treat idiopathic subglottic stenosis, but are generally categorized into: 1) endoscopic dilation of the tracheal stenosis (accomplished with rigid instruments or inflatable balloons); 2) endoscopic resection of the stenosis (with prolonged medical therapy after surgery); or 3) open neck surgery with resection of the affected tracheal segment with end-to-end anastomosis. All approaches have unique benefits and drawbacks which can significantly impact the patient’s quality of life and day-to-day existence. Comparative data on the success of each approach or the drawbacks have never been systematically evaluated.In endoscopic dilation the patient undergoes exposure of the tracheal scar with endoscopes through the mouth in the operating room. Dilation of the scar is accomplished by either rigid instrument, or inflatable balloon. Laser surgery, in which a laser in used to cut away the narrowed portion of the windpipe, has also been used in conjunction with endoscopic dilation. Endoscopic dilation is a minimally invasive procedure that is often done as an outpatient procedure. However, this procedure often only provides temporary relief and reports in the medical literature suggest a high recurrence rate, meaning the affected area with become narrow again and additional dilations (or another treatment) will be required. Somewhat similarly, in endoscopic resection the patient undergoes exposure of the tracheal scar with endoscopes through the mouth, however a CO2 laser is then utilized to resect a significant portion of the scar, followed by long-term adjuvant medical therapy (Anti-reflux, antibacterial, and inhaled corticosteroid). In individuals who do not respond to less invasive surgical options, open airway surgery may be performed. In open surgery (also called cricotracheal resection or laryngotracheoplasty), the trachea is approached via an external incision (or cut) on the front of the neck. During this procedure the narrowed area of tissue is cut away (resected) and the affected areas of the larynx and windpipe are surgically reconstructed. In cricotracheal resection a portion of the cricoid cartilage is taken with the scar and the ends of the airway are sewn back together. If the narrowed portion extends to the vocal cords, this surgery risks significant voice changes post-operatively. Laryngotracheoplasty in another form of open surgery that has been used to treat affected individuals. During this procedure, the cricoid is split open and some of the narrowed tissue is removed. Then, a piece of cartilage, usually taken from a rib, is molded into an elliptical shape and grafted into the affected area to widen the area and provide support. This surgery may require the temporary placement of a T-tube (a special type of stent) and a breathing tube (tracheostomy).Tracheal resection and laryngotracheoplasty are forms of open surgery and generally have been reserved for individuals with severe narrowing (a long and scarred area of narrowing) who haven’t responded to other therapeutic options. These procedures require hospitalization and carry greater risk than the less invasive options, but reports suggest excellent long-term results. One main concern of this surgery is the proximity of the scar to the vocal cords and the potential for post-operative voice changes (lowering the pitch of the voice). Despite the greater risk, some physicians believe that tracheal resection and laryngotracheoplasty should be considered earlier as treatment options because of the may provide greater long-term results rather than requiring affected individuals to undergo repeated balloon dilations or laser therapy. Rarely, affected individuals may require the insertion of a tube into the windpipe through an incision in the neck (tracheostomy). This procedure has been used to help secure the airway for subsequent endoscopic or open surgical procedures. In patients with acute airway distress, tracheostomy may be the initial treatment option. Additional Medical Therapies
A medication known as mitomycin-C has been used at the time of surgery. Mitomycin-C was thought to slow the process of scarring in the windpipe and was believed to delay the recurrence of stenosis following surgery. However, most studies have not shown that mitomycin-C resulted in a significant delay of disease recurrence.Some individuals may respond to corticosteroid therapy to treat the inflammation associated with idiopathic subglottic stenosis. These steroids can be delivered via an inhaler, injected directly thru the skin, or taken orally. No studies have defined which patients respond best to steroids or if there is a difference in effectiveness between the different routes of delivery. Affected individuals may also be treated with medications that treat gastroesophageal reflux (GERD). Case reports in the medical literature indicate improvement in certain individuals who received anti-reflux therapy (such as individuals who have a history of GERD). This therapy is usually combined with dietary and lifestyle changes (such as avoiding foods/drinks that worsen reflux).
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Therapies of Idiopathic Subglottic Stenosis. Treatment
There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disorder, 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 therapeutic interventions for individuals with idiopathic subglottic stenosis. Specific therapies that have been used to treat affected individuals include medications and/or surgery. Affected individuals who have a mild case of idiopathic subglottic stenosis (e.g. no symptoms) may not require treatment. Instead they may be best treated by periodic observation to see whether symptoms develop or if the narrowing progresses (i.e. narrows further). Several different surgical procedures have been used to treat idiopathic subglottic stenosis, but are generally categorized into: 1) endoscopic dilation of the tracheal stenosis (accomplished with rigid instruments or inflatable balloons); 2) endoscopic resection of the stenosis (with prolonged medical therapy after surgery); or 3) open neck surgery with resection of the affected tracheal segment with end-to-end anastomosis. All approaches have unique benefits and drawbacks which can significantly impact the patient’s quality of life and day-to-day existence. Comparative data on the success of each approach or the drawbacks have never been systematically evaluated.In endoscopic dilation the patient undergoes exposure of the tracheal scar with endoscopes through the mouth in the operating room. Dilation of the scar is accomplished by either rigid instrument, or inflatable balloon. Laser surgery, in which a laser in used to cut away the narrowed portion of the windpipe, has also been used in conjunction with endoscopic dilation. Endoscopic dilation is a minimally invasive procedure that is often done as an outpatient procedure. However, this procedure often only provides temporary relief and reports in the medical literature suggest a high recurrence rate, meaning the affected area with become narrow again and additional dilations (or another treatment) will be required. Somewhat similarly, in endoscopic resection the patient undergoes exposure of the tracheal scar with endoscopes through the mouth, however a CO2 laser is then utilized to resect a significant portion of the scar, followed by long-term adjuvant medical therapy (Anti-reflux, antibacterial, and inhaled corticosteroid). In individuals who do not respond to less invasive surgical options, open airway surgery may be performed. In open surgery (also called cricotracheal resection or laryngotracheoplasty), the trachea is approached via an external incision (or cut) on the front of the neck. During this procedure the narrowed area of tissue is cut away (resected) and the affected areas of the larynx and windpipe are surgically reconstructed. In cricotracheal resection a portion of the cricoid cartilage is taken with the scar and the ends of the airway are sewn back together. If the narrowed portion extends to the vocal cords, this surgery risks significant voice changes post-operatively. Laryngotracheoplasty in another form of open surgery that has been used to treat affected individuals. During this procedure, the cricoid is split open and some of the narrowed tissue is removed. Then, a piece of cartilage, usually taken from a rib, is molded into an elliptical shape and grafted into the affected area to widen the area and provide support. This surgery may require the temporary placement of a T-tube (a special type of stent) and a breathing tube (tracheostomy).Tracheal resection and laryngotracheoplasty are forms of open surgery and generally have been reserved for individuals with severe narrowing (a long and scarred area of narrowing) who haven’t responded to other therapeutic options. These procedures require hospitalization and carry greater risk than the less invasive options, but reports suggest excellent long-term results. One main concern of this surgery is the proximity of the scar to the vocal cords and the potential for post-operative voice changes (lowering the pitch of the voice). Despite the greater risk, some physicians believe that tracheal resection and laryngotracheoplasty should be considered earlier as treatment options because of the may provide greater long-term results rather than requiring affected individuals to undergo repeated balloon dilations or laser therapy. Rarely, affected individuals may require the insertion of a tube into the windpipe through an incision in the neck (tracheostomy). This procedure has been used to help secure the airway for subsequent endoscopic or open surgical procedures. In patients with acute airway distress, tracheostomy may be the initial treatment option. Additional Medical Therapies
A medication known as mitomycin-C has been used at the time of surgery. Mitomycin-C was thought to slow the process of scarring in the windpipe and was believed to delay the recurrence of stenosis following surgery. However, most studies have not shown that mitomycin-C resulted in a significant delay of disease recurrence.Some individuals may respond to corticosteroid therapy to treat the inflammation associated with idiopathic subglottic stenosis. These steroids can be delivered via an inhaler, injected directly thru the skin, or taken orally. No studies have defined which patients respond best to steroids or if there is a difference in effectiveness between the different routes of delivery. Affected individuals may also be treated with medications that treat gastroesophageal reflux (GERD). Case reports in the medical literature indicate improvement in certain individuals who received anti-reflux therapy (such as individuals who have a history of GERD). This therapy is usually combined with dietary and lifestyle changes (such as avoiding foods/drinks that worsen reflux).
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Overview of IgA Nephropathy
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Summary
IgA nephropathy is a kidney disease in which IgA, a protein meant to defend the body against foreign invaders, accumulates in the kidneys and damages them. This impairs their filtering function. As a result, the kidneys begin to let substances such as blood and protein leak into the urine.This condition most often occurs in Caucasian and Asian males. It usually appears when people are in their teens to late 30’s but can occur at any age. Many cases resolve over time. However, in a subset of patients, the disease may not resolve and thus can lead to end-stage renal disease (ESRD) after 20-25 years. Rarely the condition can progress much more rapidly leading to renal failure within a few years, if not treated.People who have this condition most often present with one or recurrent episodes of having blood in their urine (visible hematuria). These episodes usually occur during or right after an upper respiratory tract infection such as a cold, sore throat or a gastrointestinal infection. Treatment includes drugs that aim to slow progression of the disease and others that aim to reduce inflammation. The choice of treatment is made based on a variety of factors including blood pressure, the amount of protein in the urine and the estimated kidney function.Introduction
The kidneys are two fist sized organs located in the back under the rib cage that serve as a filter for blood. They remove excess fluid and waste as urine, while reabsorbing the proper amount of water and other chemicals that the body needs to function. The name IgA nephropathy comes from the fact that that the protein depositing in the kidney has the characteristics of a normal circulating immunoglobulin protein designated IgA. In the disease, the normal protein is changed somewhat causing it to deposit in the filters of the kidney and it to leak blood and or protein. It is also named Berger’s disease as it was first described by Berger and Hinglais in 1968.
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Overview of IgA Nephropathy. Summary
IgA nephropathy is a kidney disease in which IgA, a protein meant to defend the body against foreign invaders, accumulates in the kidneys and damages them. This impairs their filtering function. As a result, the kidneys begin to let substances such as blood and protein leak into the urine.This condition most often occurs in Caucasian and Asian males. It usually appears when people are in their teens to late 30’s but can occur at any age. Many cases resolve over time. However, in a subset of patients, the disease may not resolve and thus can lead to end-stage renal disease (ESRD) after 20-25 years. Rarely the condition can progress much more rapidly leading to renal failure within a few years, if not treated.People who have this condition most often present with one or recurrent episodes of having blood in their urine (visible hematuria). These episodes usually occur during or right after an upper respiratory tract infection such as a cold, sore throat or a gastrointestinal infection. Treatment includes drugs that aim to slow progression of the disease and others that aim to reduce inflammation. The choice of treatment is made based on a variety of factors including blood pressure, the amount of protein in the urine and the estimated kidney function.Introduction
The kidneys are two fist sized organs located in the back under the rib cage that serve as a filter for blood. They remove excess fluid and waste as urine, while reabsorbing the proper amount of water and other chemicals that the body needs to function. The name IgA nephropathy comes from the fact that that the protein depositing in the kidney has the characteristics of a normal circulating immunoglobulin protein designated IgA. In the disease, the normal protein is changed somewhat causing it to deposit in the filters of the kidney and it to leak blood and or protein. It is also named Berger’s disease as it was first described by Berger and Hinglais in 1968.
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Symptoms of IgA Nephropathy
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Patients with IgA nephropathy often present with:• red colored urine (visible hematuria)
• pain in the sides of their back (flank pain)
• swelling in the ankles
• high blood pressureWhen these symptoms are present during or directly after a respiratory infection such as a sore throat or a cold, there is a higher likelihood that the person has IgA nephropathy.Some patients who have either the rapidly progressive type of IgA nephropathy or chronic asymptomatic disease may present with symptoms of end-stage renal disease (ESRD):• high blood pressure
• little or no urination
• edema
• feeling tired
• drowsiness
• generalized itching or numbness
• dry skin
• headaches
• weight loss
• appetite loss
• nausea
• vomiting
• sleep problems
• trouble concentrating
• darkened skin
• muscle cramps
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Symptoms of IgA Nephropathy. Patients with IgA nephropathy often present with:• red colored urine (visible hematuria)
• pain in the sides of their back (flank pain)
• swelling in the ankles
• high blood pressureWhen these symptoms are present during or directly after a respiratory infection such as a sore throat or a cold, there is a higher likelihood that the person has IgA nephropathy.Some patients who have either the rapidly progressive type of IgA nephropathy or chronic asymptomatic disease may present with symptoms of end-stage renal disease (ESRD):• high blood pressure
• little or no urination
• edema
• feeling tired
• drowsiness
• generalized itching or numbness
• dry skin
• headaches
• weight loss
• appetite loss
• nausea
• vomiting
• sleep problems
• trouble concentrating
• darkened skin
• muscle cramps
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Causes of IgA Nephropathy
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As mentioned above, the kidneys serve as filters for the blood. Each kidney consists of about 1 million “mini-filters” called nephrons.Each nephron consists of a Bowman’s capsule and tubules. The Bowman’s capsule contains many important structures such as the glomerulus, which is a series of tiny blood vessels where the initial filtration takes place. Once the fluid has been filtered by the glomerulus, it travels along the tubules, where chemicals and water are either added or removed from the filtered fluid based on the body’s needs. Once the fluid has passed through the tubules, it leaves the body as urine.For an unknown reason, patients with IgA nephropathy create abnormal IgA proteins that the body recognizes as foreign. As a result, the body attacks them, which leads to the formation of clusters of proteins called immune complexes. These immune complexes are what are deposited in the kidneys and causes damage. Due to this phenomenon, IgA nephropathy can be considered an autoimmune disease. The IgA protein immune complexes specifically deposit in the central area of the glomerulus in the mesangial area. Once these immune complexes are deposited, the glomerulus (filter) become inflamed and damaged. As a result, their filtering function is damaged allowing substances such as red blood cells and proteins to pass through the damaged filter into the urine.When patients have respiratory infections such as a cough or sore throat, IgA immune complexes are higher in circulation. Therefore, many of them end up depositing in the kidneys and this is when patients with IgA nephropathy typically present with symptoms such as hematuria (blood in the urine). Some patients may also experience episodes of IgA nephropathy when they have gastrointestinal infections such as in stomach flu or even after exercise.There is evidence to suggest that genetic factors play a role in this disease. It has been suggested that IgA nephropathy is a complex polygenic disease meaning that there are many genes and environmental factors that contribute to an individual developing the condition.
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Causes of IgA Nephropathy. As mentioned above, the kidneys serve as filters for the blood. Each kidney consists of about 1 million “mini-filters” called nephrons.Each nephron consists of a Bowman’s capsule and tubules. The Bowman’s capsule contains many important structures such as the glomerulus, which is a series of tiny blood vessels where the initial filtration takes place. Once the fluid has been filtered by the glomerulus, it travels along the tubules, where chemicals and water are either added or removed from the filtered fluid based on the body’s needs. Once the fluid has passed through the tubules, it leaves the body as urine.For an unknown reason, patients with IgA nephropathy create abnormal IgA proteins that the body recognizes as foreign. As a result, the body attacks them, which leads to the formation of clusters of proteins called immune complexes. These immune complexes are what are deposited in the kidneys and causes damage. Due to this phenomenon, IgA nephropathy can be considered an autoimmune disease. The IgA protein immune complexes specifically deposit in the central area of the glomerulus in the mesangial area. Once these immune complexes are deposited, the glomerulus (filter) become inflamed and damaged. As a result, their filtering function is damaged allowing substances such as red blood cells and proteins to pass through the damaged filter into the urine.When patients have respiratory infections such as a cough or sore throat, IgA immune complexes are higher in circulation. Therefore, many of them end up depositing in the kidneys and this is when patients with IgA nephropathy typically present with symptoms such as hematuria (blood in the urine). Some patients may also experience episodes of IgA nephropathy when they have gastrointestinal infections such as in stomach flu or even after exercise.There is evidence to suggest that genetic factors play a role in this disease. It has been suggested that IgA nephropathy is a complex polygenic disease meaning that there are many genes and environmental factors that contribute to an individual developing the condition.
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Affects of IgA Nephropathy
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In North America and Europe, males are two times more likely to get the disease, while in Asia, females are just as likely as males to be affected. In terms of ethnicity, Asians are much more likely than Caucasians who are, in turn, much more likely than black population to get IgA nephropathy. This disease most often presents between teenage years to late 30’s but can present at any age.
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Affects of IgA Nephropathy. In North America and Europe, males are two times more likely to get the disease, while in Asia, females are just as likely as males to be affected. In terms of ethnicity, Asians are much more likely than Caucasians who are, in turn, much more likely than black population to get IgA nephropathy. This disease most often presents between teenage years to late 30’s but can present at any age.
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Related disorders of IgA Nephropathy
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Symptoms of the following disorders can be similar to those of IgA nephropathy. Comparisons may be useful for a differential diagnosis:• Henoch-Schönlein purpura (now considered a type of IgA that predominantly affects the small blood vessels of the body including the kidney) – For more information on this disorder choose “Henoch-Schönlein Purpura” as your search term in the Rare Disease Database.
• Alport syndrome (hereditary nephritis) – For more information on this disorder choose “Alport Syndrome” as your search term in the Rare Disease Database.
• thin basement membrane disease (TMBD)
• acute post infectious glomerulonephritis
• membranoproliferative glomerulonephritis
• lupus nephritis
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Related disorders of IgA Nephropathy. Symptoms of the following disorders can be similar to those of IgA nephropathy. Comparisons may be useful for a differential diagnosis:• Henoch-Schönlein purpura (now considered a type of IgA that predominantly affects the small blood vessels of the body including the kidney) – For more information on this disorder choose “Henoch-Schönlein Purpura” as your search term in the Rare Disease Database.
• Alport syndrome (hereditary nephritis) – For more information on this disorder choose “Alport Syndrome” as your search term in the Rare Disease Database.
• thin basement membrane disease (TMBD)
• acute post infectious glomerulonephritis
• membranoproliferative glomerulonephritis
• lupus nephritis
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Diagnosis of IgA Nephropathy
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IgA nephropathy might be suspected when a patient has bloody (red) or dark urine following a respiratory tract illness such as a sore throat or a cold.Although a doctor may have a high index of suspicion that their patient has IgA nephropathy based on history, physical exam, urine tests and blood tests, the only way to truly diagnose IgA nephropathy is through a kidney biopsy.A kidney biopsy is when a small needle is inserted into a person’s kidney in order to take a small sample of tissue. This tissue is then examined under a microscope to look for certain characteristic markers of the disease.Clinical Testing and Work-Up
Aside from the kidney biopsy, patients should expect to have regular blood and urine tests. For patients with mild disease (normal blood pressure, low amount of protein in urine), they can expect to have tests done every 6-12 months. Patients who have more severe forms of the disease can expect more regular monitoring.
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Diagnosis of IgA Nephropathy. IgA nephropathy might be suspected when a patient has bloody (red) or dark urine following a respiratory tract illness such as a sore throat or a cold.Although a doctor may have a high index of suspicion that their patient has IgA nephropathy based on history, physical exam, urine tests and blood tests, the only way to truly diagnose IgA nephropathy is through a kidney biopsy.A kidney biopsy is when a small needle is inserted into a person’s kidney in order to take a small sample of tissue. This tissue is then examined under a microscope to look for certain characteristic markers of the disease.Clinical Testing and Work-Up
Aside from the kidney biopsy, patients should expect to have regular blood and urine tests. For patients with mild disease (normal blood pressure, low amount of protein in urine), they can expect to have tests done every 6-12 months. Patients who have more severe forms of the disease can expect more regular monitoring.
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Therapies of IgA Nephropathy
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Treatment
Unfortunately, there is not yet a cure for IgA nephropathy. However, many cases resolve on their own.Treatment for this condition falls under two main categories:Non-immunosuppressive drugs – Those aimed at preventing progression of the disease.Immunosuppressive drugs – Those aimed at reducing inflammation.The non-immunosuppressive drugs used are angiotensin converting enzyme inhibitors (ACE inhibitors) and angiotensin receptor blockers (ARBs). They help prevent progression of the disease through reducing the amount of protein that filters through the damaged glomerulus and enters the urine and by lowering blood pressure.In 2021, budesonide (Tarpeyo) was approved by the U.S. Food and Drug Administration (FDA) to reduce urine protein level in adults with primary IgA nephropathy who are at risk of rapid disease progression.In 2023, sparsentan (Filspari) a drug that combines an endothelin type A receptor antagonist with an angiotensin II type I receptor antagonist, was approved by the FDA for the treatment of IgA patients at high risk of progression.
Although still not FDA approved, there have been several articles showing the benefits of use of SGLT2 inhibitors in the treatment of patients with IgA nephropathy at high risk of progression.The immunosuppressive drugs used most often are corticosteroids. They reduce inflammation by limiting the inflammatory response.
In summary treatment for IgA nephropathy falls under two categories:Non-immunosuppressive• ACE inhibitors
• ARBs
• Sparsentan (combined Enothelin and ARB antagonist)
• SGLT2 inhibitorsImmunosuppressive• corticosteroids (such as prednisone)
• cyclophosphamideSome patients may also be prescribed a statin, which is a cholesterol lowering drug given to lower the risk of developing cardiovascular disease.Prevention
Diet and Nutrition
Although researchers have not found that diet and nutrition play a role in causing or preventing the disease, health care providers may recommend the following dietary changes to patients who have the condition to maximize their renal health:• limit dietary sodium
• eating a diet low in saturated fat and cholesterol
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Therapies of IgA Nephropathy. Treatment
Unfortunately, there is not yet a cure for IgA nephropathy. However, many cases resolve on their own.Treatment for this condition falls under two main categories:Non-immunosuppressive drugs – Those aimed at preventing progression of the disease.Immunosuppressive drugs – Those aimed at reducing inflammation.The non-immunosuppressive drugs used are angiotensin converting enzyme inhibitors (ACE inhibitors) and angiotensin receptor blockers (ARBs). They help prevent progression of the disease through reducing the amount of protein that filters through the damaged glomerulus and enters the urine and by lowering blood pressure.In 2021, budesonide (Tarpeyo) was approved by the U.S. Food and Drug Administration (FDA) to reduce urine protein level in adults with primary IgA nephropathy who are at risk of rapid disease progression.In 2023, sparsentan (Filspari) a drug that combines an endothelin type A receptor antagonist with an angiotensin II type I receptor antagonist, was approved by the FDA for the treatment of IgA patients at high risk of progression.
Although still not FDA approved, there have been several articles showing the benefits of use of SGLT2 inhibitors in the treatment of patients with IgA nephropathy at high risk of progression.The immunosuppressive drugs used most often are corticosteroids. They reduce inflammation by limiting the inflammatory response.
In summary treatment for IgA nephropathy falls under two categories:Non-immunosuppressive• ACE inhibitors
• ARBs
• Sparsentan (combined Enothelin and ARB antagonist)
• SGLT2 inhibitorsImmunosuppressive• corticosteroids (such as prednisone)
• cyclophosphamideSome patients may also be prescribed a statin, which is a cholesterol lowering drug given to lower the risk of developing cardiovascular disease.Prevention
Diet and Nutrition
Although researchers have not found that diet and nutrition play a role in causing or preventing the disease, health care providers may recommend the following dietary changes to patients who have the condition to maximize their renal health:• limit dietary sodium
• eating a diet low in saturated fat and cholesterol
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Overview of Immune Thrombocytopenia
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Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder characterized by abnormally low levels of blood cells called platelets, a situation referred to as thrombocytopenia. Platelets are specialized blood cells that help maintain the integrity of the walls of blood vessels and help prevent and stop bleeding by accelerating clotting where it is needed. A normal platelet count ranges from approximately 150,000 to 400,000 per microliter (µL) of blood depending on the laboratory. However substantial bleeding does not usually occur until the platelet count is less than 50,000 or even 30,000/µl.If someone has a platelet count lower than 100,000/µL of blood with no other reason for having low platelets, that person might have ITP. Platelet counts of 100-150,000/µL are frequent, have many possible causes and are usually less clinically important. There is currently no definitive laboratory test to diagnose ITP. Measurement of anti-platelet antibody levels is not considered to be diagnostic. Rather ITP is a “diagnosis of exclusion” meaning that other causes have been considered and are either eliminated or are unlikely. Tests to exclude other causes of thrombocytopenia depend on severity, symptoms, personal and family medical history and experience of the treating physician.As the platelet count falls, the risk of developing bleeding symptoms increases, especially below 50,000/L (if platelet function is relatively normal). ITP can often be discovered incidentally in patients who are asymptomatic (meaning they do not have symptoms of ITP other than a low platelet count). Such incidental cases arise when a blood count is obtained for another reason, such as a routine yearly checkup or before a surgical procedure or during pregnancy. More often, patients with ITP develop symptoms unexpectedly, such as abnormal bleeding into the skin resulting in either bruising (purpura), or tiny red dots on the skin called petechiae. Bleeding from mucous membranes such as the nose and mouth, and less commonly the stomach, gastrointestinal and urinary tracts may also occur and may subsequently result in low levels of circulating red blood cells (anemia) especially in women who are having very heavy periods (menses). Fortunately, internal bleeding is uncommon. The most concerning, but rare, form of this is bleeding in the brain called an intracranial hemorrhage (ICH).ITP is called “newly diagnosed” when it has been present for less than 3 months, “persistent” when present for 3-12 months, and “chronic” when present for longer than one year. The term “acute” is no longer used.At least half of all adults with ITP disclose that they experience fatigue and an impaired quality of mental and emotional health, physical health, and social functioning. ITP can impact so many aspects of a patient’s and family’s life that school, work, relationships and sometimes daily living becomes challenging. Symptoms that often interfere with daily activities include anxiety, fear, depression, embarrassment because of unexplained bruising and other bleeding symptoms such as nose bleeds (epistaxis) or oral blood blisters, isolation, social inadequacy and frustration with a patient’s inability to control their body and their health. This list does not include the side effects of treatments which, while possibly improving platelet counts, can exacerbate some of these associated complications, such as the use of corticosteroids, a common first-line treatment. Together, the multi-faceted effects of ITP can take a significant toll on a patient’s and family’s quality of life.Children have similar types of bleeding symptoms. At diagnosis their platelet counts may be lower than seen in adults, so they may have more skin or oral bleeding but are less likely than older adults to have serious, life-threatening bleeding. Since small children often feel normal when they present, their parents are usually more worried and feel worse than the children do. Adolescents behave more like adults. Children are less able to describe their symptoms but studies using an ITP survey called the Kid’s Tool Kit have demonstrated impaired quality of life. Small children may reflect irritability instead of fatigue.
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Overview of Immune Thrombocytopenia. Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder characterized by abnormally low levels of blood cells called platelets, a situation referred to as thrombocytopenia. Platelets are specialized blood cells that help maintain the integrity of the walls of blood vessels and help prevent and stop bleeding by accelerating clotting where it is needed. A normal platelet count ranges from approximately 150,000 to 400,000 per microliter (µL) of blood depending on the laboratory. However substantial bleeding does not usually occur until the platelet count is less than 50,000 or even 30,000/µl.If someone has a platelet count lower than 100,000/µL of blood with no other reason for having low platelets, that person might have ITP. Platelet counts of 100-150,000/µL are frequent, have many possible causes and are usually less clinically important. There is currently no definitive laboratory test to diagnose ITP. Measurement of anti-platelet antibody levels is not considered to be diagnostic. Rather ITP is a “diagnosis of exclusion” meaning that other causes have been considered and are either eliminated or are unlikely. Tests to exclude other causes of thrombocytopenia depend on severity, symptoms, personal and family medical history and experience of the treating physician.As the platelet count falls, the risk of developing bleeding symptoms increases, especially below 50,000/L (if platelet function is relatively normal). ITP can often be discovered incidentally in patients who are asymptomatic (meaning they do not have symptoms of ITP other than a low platelet count). Such incidental cases arise when a blood count is obtained for another reason, such as a routine yearly checkup or before a surgical procedure or during pregnancy. More often, patients with ITP develop symptoms unexpectedly, such as abnormal bleeding into the skin resulting in either bruising (purpura), or tiny red dots on the skin called petechiae. Bleeding from mucous membranes such as the nose and mouth, and less commonly the stomach, gastrointestinal and urinary tracts may also occur and may subsequently result in low levels of circulating red blood cells (anemia) especially in women who are having very heavy periods (menses). Fortunately, internal bleeding is uncommon. The most concerning, but rare, form of this is bleeding in the brain called an intracranial hemorrhage (ICH).ITP is called “newly diagnosed” when it has been present for less than 3 months, “persistent” when present for 3-12 months, and “chronic” when present for longer than one year. The term “acute” is no longer used.At least half of all adults with ITP disclose that they experience fatigue and an impaired quality of mental and emotional health, physical health, and social functioning. ITP can impact so many aspects of a patient’s and family’s life that school, work, relationships and sometimes daily living becomes challenging. Symptoms that often interfere with daily activities include anxiety, fear, depression, embarrassment because of unexplained bruising and other bleeding symptoms such as nose bleeds (epistaxis) or oral blood blisters, isolation, social inadequacy and frustration with a patient’s inability to control their body and their health. This list does not include the side effects of treatments which, while possibly improving platelet counts, can exacerbate some of these associated complications, such as the use of corticosteroids, a common first-line treatment. Together, the multi-faceted effects of ITP can take a significant toll on a patient’s and family’s quality of life.Children have similar types of bleeding symptoms. At diagnosis their platelet counts may be lower than seen in adults, so they may have more skin or oral bleeding but are less likely than older adults to have serious, life-threatening bleeding. Since small children often feel normal when they present, their parents are usually more worried and feel worse than the children do. Adolescents behave more like adults. Children are less able to describe their symptoms but studies using an ITP survey called the Kid’s Tool Kit have demonstrated impaired quality of life. Small children may reflect irritability instead of fatigue.
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Symptoms of Immune Thrombocytopenia
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A child or adult may display no symptoms (be asymptomatic) when a low platelet count is first discovered, or bleeding symptoms may appear first and then the platelet count is discovered to be low. Such symptoms may include:• Skin that bruises very easily and even spontaneously.
• A rash consisting of small red dots (petechiae) that represent small hemorrhages.
• Bleeding from the gums.
• Frequent nose bleeds that are long-lasting and hard to stop.
• Blood blisters on the inside of cheeks.
• Excessive and/or prolonged menstrual bleeding.
• Less commonly, signs of internal bleeding with blood in urine, vomit or bowel movements.
• In rare cases, serious bleeding into the brain (intracranial hemorrhage). This occurs in < 1% of children and increases in frequency in adults especially over the age of 60.
• Bleeding can lead to anemia, which may itself cause fatigue. Impaired quality of life from fatigue, anxiety and side effects of treatment.
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Symptoms of Immune Thrombocytopenia. A child or adult may display no symptoms (be asymptomatic) when a low platelet count is first discovered, or bleeding symptoms may appear first and then the platelet count is discovered to be low. Such symptoms may include:• Skin that bruises very easily and even spontaneously.
• A rash consisting of small red dots (petechiae) that represent small hemorrhages.
• Bleeding from the gums.
• Frequent nose bleeds that are long-lasting and hard to stop.
• Blood blisters on the inside of cheeks.
• Excessive and/or prolonged menstrual bleeding.
• Less commonly, signs of internal bleeding with blood in urine, vomit or bowel movements.
• In rare cases, serious bleeding into the brain (intracranial hemorrhage). This occurs in < 1% of children and increases in frequency in adults especially over the age of 60.
• Bleeding can lead to anemia, which may itself cause fatigue. Impaired quality of life from fatigue, anxiety and side effects of treatment.
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Causes of Immune Thrombocytopenia
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The fundamental abnormality in ITP is that the patient’s immune system tags their own platelets as “foreign”, leading their B-lymphocytes and plasma cells to produce self-reactive anti-platelet antibodies that attach to platelet surfaces. A type of white blood cells in the spleen and in other organs, called macrophages, normally recognize antibody-coated particles. In ITP, antibody-coated platelets are ingested and subsequently destroyed within the macrophages. The bone marrow attempts to compensate but is often unable to keep up with the destruction, especially in severe cases. Platelet production may also be impaired when anti-platelet antibodies bind to the cells in the bone marrow called megakaryocytes that produce platelets. However, ITP is heterogeneous with respect to pathophysiology, clinical symptoms such as risk of bleeding and thrombosis or of fatigue, coincident autoimmune disease, and responses to treatments.Antibodies are normally produced by the body’s immune system in response to foreign substances known as antigens, for example on viruses and bacteria, after vaccination, or on red blood cells or tissue from unrelated people. Autoimmune diseases like ITP belong to a group of disorders in which the body’s natural immune defenses inappropriately act against its own cells or tissues. In ITP, this abnormal immune reaction leads to destruction of the individual’s own platelets. For reasons that are unknown, platelets are recognized as foreign by the immune system, stimulating lymphocytes in the bone marrow, spleen and elsewhere to produce antibodies that attach to platelet surfaces. In most affected individuals, the platelets are the only target of the misdirected immune response and there is no underlying broad autoimmune disease, and this case the disorder is called primary ITP or just ITP. However, in perhaps in 1 in 5 individuals with ITP, it develops in the context of another disorder that predisposes to making autoantibodies to additional targets in addition to platelets. This is called secondary ITP and is discussed below. In most individuals, however, the disorder restricted to platelets and no connection to another disease is evident although the cause of anti-platelet antibody production remains unknown.The autoantibodies in ITP bind to otherwise normal platelets in the blood that circulates through the spleen, liver and elsewhere. The antibody-platelet complexes are recognized by tissue macrophages, which ingest and destroy antibody-coated platelets as they would normally when then encounter any antibody-coated foreign particle. The bone marrow attempts to compensate by producing more platelets, but the rate of platelet destruction may exceed the marrow capacity to make new platelets and thrombocytopenia develops. Platelet production in the bone marrow may also be impaired when the same autoantibodies that bind to the platelets attach to the platelet precursors called megakaryocytes or when T cells attack them. Therefore, the mechanisms underlying ITP and the resulting very low platelet counts can involve increased platelet destruction, reduced or inadequate platelet production, or both. It is not currently possible to define the relative importance of these two contributing factors in a specific patient.In children, ITP often appears soon after an otherwise unremarkable viral infection. This suggests that antibodies produced to fight foreign viral substances (antigens) may “cross-react” with similar appearing antigens on platelets, which in turn lead to platelet destruction. This has been shown in the case of chicken pox, for example. However, there isn’t a reliable way to predict which child (or adult) will get better and who will develop chronic ITP. The general pathophysiology of ITP in children is similar to that of adults but children seem to be able to recover spontaneously at a higher rate. It is quite rare for patients with ITP to have a family history of low platelet counts. When there is a family history of thrombocytopenia, an inherited (genetic) platelet disorder should be considered. Inherited thrombocytopenias are uncommon but are under-diagnosed. In addition to a family history of low platelet counts, the size (usually large) and shape of the platelets on a blood smear, syndromic features and failure to respond to steroids and/or IVIg should all suggest consideration of an inherited platelet disorder. An Inherited thrombocytopenia is not considered a secondary cause of ITP although in certain cases, such as with 22q11.2 deletion syndrome and Wiskott-Aldrich syndrome, secondary ITP can develop in inherited thrombocytopenia. Genetic testing can be used to diagnose many forms of inherited, i.e., familial, platelet disorders but many such cases remain undiagnosed even after such testing. Secondary ITP can also be caused by certain autoimmune disorders such as lupus, inherited immune disorders such as common variable immunodeficiency (CVID), autoimmune lymphoproliferative syndrome (ALPS), and Evans syndrome, in which antibody-mediated red cell destruction accompanies ITP. Secondary ITP can also be caused by persistent infections (such as HIV, hepatitis B or C, or CMV), in addition to the ulcer-causing stomach bacterium such as Helicobacter pylori (primarily in certain countries, such as Japan and Italy), and lymphoproliferative disorders (such as chronic lymphocytic leukemia) that impair the immune system. A few cases resembling ITP result from the use of certain drugs. Secondary ITP can also occur in children after vaccination for measles-mumps-rubella (MMR) although rare. Recent cases of ITP have also been reported infrequently after both COVID infection and vaccination to prevent it.
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Causes of Immune Thrombocytopenia. The fundamental abnormality in ITP is that the patient’s immune system tags their own platelets as “foreign”, leading their B-lymphocytes and plasma cells to produce self-reactive anti-platelet antibodies that attach to platelet surfaces. A type of white blood cells in the spleen and in other organs, called macrophages, normally recognize antibody-coated particles. In ITP, antibody-coated platelets are ingested and subsequently destroyed within the macrophages. The bone marrow attempts to compensate but is often unable to keep up with the destruction, especially in severe cases. Platelet production may also be impaired when anti-platelet antibodies bind to the cells in the bone marrow called megakaryocytes that produce platelets. However, ITP is heterogeneous with respect to pathophysiology, clinical symptoms such as risk of bleeding and thrombosis or of fatigue, coincident autoimmune disease, and responses to treatments.Antibodies are normally produced by the body’s immune system in response to foreign substances known as antigens, for example on viruses and bacteria, after vaccination, or on red blood cells or tissue from unrelated people. Autoimmune diseases like ITP belong to a group of disorders in which the body’s natural immune defenses inappropriately act against its own cells or tissues. In ITP, this abnormal immune reaction leads to destruction of the individual’s own platelets. For reasons that are unknown, platelets are recognized as foreign by the immune system, stimulating lymphocytes in the bone marrow, spleen and elsewhere to produce antibodies that attach to platelet surfaces. In most affected individuals, the platelets are the only target of the misdirected immune response and there is no underlying broad autoimmune disease, and this case the disorder is called primary ITP or just ITP. However, in perhaps in 1 in 5 individuals with ITP, it develops in the context of another disorder that predisposes to making autoantibodies to additional targets in addition to platelets. This is called secondary ITP and is discussed below. In most individuals, however, the disorder restricted to platelets and no connection to another disease is evident although the cause of anti-platelet antibody production remains unknown.The autoantibodies in ITP bind to otherwise normal platelets in the blood that circulates through the spleen, liver and elsewhere. The antibody-platelet complexes are recognized by tissue macrophages, which ingest and destroy antibody-coated platelets as they would normally when then encounter any antibody-coated foreign particle. The bone marrow attempts to compensate by producing more platelets, but the rate of platelet destruction may exceed the marrow capacity to make new platelets and thrombocytopenia develops. Platelet production in the bone marrow may also be impaired when the same autoantibodies that bind to the platelets attach to the platelet precursors called megakaryocytes or when T cells attack them. Therefore, the mechanisms underlying ITP and the resulting very low platelet counts can involve increased platelet destruction, reduced or inadequate platelet production, or both. It is not currently possible to define the relative importance of these two contributing factors in a specific patient.In children, ITP often appears soon after an otherwise unremarkable viral infection. This suggests that antibodies produced to fight foreign viral substances (antigens) may “cross-react” with similar appearing antigens on platelets, which in turn lead to platelet destruction. This has been shown in the case of chicken pox, for example. However, there isn’t a reliable way to predict which child (or adult) will get better and who will develop chronic ITP. The general pathophysiology of ITP in children is similar to that of adults but children seem to be able to recover spontaneously at a higher rate. It is quite rare for patients with ITP to have a family history of low platelet counts. When there is a family history of thrombocytopenia, an inherited (genetic) platelet disorder should be considered. Inherited thrombocytopenias are uncommon but are under-diagnosed. In addition to a family history of low platelet counts, the size (usually large) and shape of the platelets on a blood smear, syndromic features and failure to respond to steroids and/or IVIg should all suggest consideration of an inherited platelet disorder. An Inherited thrombocytopenia is not considered a secondary cause of ITP although in certain cases, such as with 22q11.2 deletion syndrome and Wiskott-Aldrich syndrome, secondary ITP can develop in inherited thrombocytopenia. Genetic testing can be used to diagnose many forms of inherited, i.e., familial, platelet disorders but many such cases remain undiagnosed even after such testing. Secondary ITP can also be caused by certain autoimmune disorders such as lupus, inherited immune disorders such as common variable immunodeficiency (CVID), autoimmune lymphoproliferative syndrome (ALPS), and Evans syndrome, in which antibody-mediated red cell destruction accompanies ITP. Secondary ITP can also be caused by persistent infections (such as HIV, hepatitis B or C, or CMV), in addition to the ulcer-causing stomach bacterium such as Helicobacter pylori (primarily in certain countries, such as Japan and Italy), and lymphoproliferative disorders (such as chronic lymphocytic leukemia) that impair the immune system. A few cases resembling ITP result from the use of certain drugs. Secondary ITP can also occur in children after vaccination for measles-mumps-rubella (MMR) although rare. Recent cases of ITP have also been reported infrequently after both COVID infection and vaccination to prevent it.
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Affects of Immune Thrombocytopenia
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ITP occurs in people of all races and ethnicities. ITP can occur at any age from 3 months to over 100 years of age. About 40% of all patients diagnosed with ITP are children younger than 10 years of age. The incidence is highest between 2 to 4 years of age, and males and females are affected equally until adolescence. Between adolescence and the age of 60, ITP is more common in females. The highest prevalence is among males and females over the age of 60. The incidence (how many people are diagnosed each year) of adult ITP in the USA is roughly estimated to be 3.3 per 100,000/year. The prevalence (how many have ITP at any time) is 9.5 per 100,000. In a study that analyzed data from the Maryland Health Care Commission, the prevalence of ITP was estimated to be 9.5 per 100,000 children ages 1-5, 7.3 per 100,000 in children ages 6-10, and 4.1 per 100,000 in children of ages 11-14. Since children with ITP usually recover, the number of children who have ITP at any one time is almost equal to those diagnosed annually. Worldwide, it is estimated that there are well over 200,000 people affected by ITP.In 80% of children who present with ITP, the disorder is self-limiting and resolves with or without treatment (i.e., spontaneously) within 12 months, usually sooner. In contrast, the proportion of adults with ITP who have a life-long chronic condition is much higher, approximately 50-70%, although firm data is lacking. One study suggested that 60% of adults diagnosed with ITP will improve within 3 years. ITP that develops in adolescents most often follows the clinical course seen in adults.
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Affects of Immune Thrombocytopenia. ITP occurs in people of all races and ethnicities. ITP can occur at any age from 3 months to over 100 years of age. About 40% of all patients diagnosed with ITP are children younger than 10 years of age. The incidence is highest between 2 to 4 years of age, and males and females are affected equally until adolescence. Between adolescence and the age of 60, ITP is more common in females. The highest prevalence is among males and females over the age of 60. The incidence (how many people are diagnosed each year) of adult ITP in the USA is roughly estimated to be 3.3 per 100,000/year. The prevalence (how many have ITP at any time) is 9.5 per 100,000. In a study that analyzed data from the Maryland Health Care Commission, the prevalence of ITP was estimated to be 9.5 per 100,000 children ages 1-5, 7.3 per 100,000 in children ages 6-10, and 4.1 per 100,000 in children of ages 11-14. Since children with ITP usually recover, the number of children who have ITP at any one time is almost equal to those diagnosed annually. Worldwide, it is estimated that there are well over 200,000 people affected by ITP.In 80% of children who present with ITP, the disorder is self-limiting and resolves with or without treatment (i.e., spontaneously) within 12 months, usually sooner. In contrast, the proportion of adults with ITP who have a life-long chronic condition is much higher, approximately 50-70%, although firm data is lacking. One study suggested that 60% of adults diagnosed with ITP will improve within 3 years. ITP that develops in adolescents most often follows the clinical course seen in adults.
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Related disorders of Immune Thrombocytopenia
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Thrombocytopenia can also be due several other disorders that can resemble ITP in addition to inherited and secondary thrombocytopenia. It is important that physicians develop a differential diagnosis for other possible causes of thrombocytopenia, to consider the full spectrum of what could be underlying the thrombocytopenia. The most likely underlying conditions depend on patient age, sex and many other features of the presentation. Clinical judgment is important since it is not possible to do testing for every other cause of thrombocytopenia. Occasionally patients may have enlarged lymph nodes, a history of recurrent infections or other findings not typical for ITP. Thrombocytopenia can also be caused by many other blood (hematological) disorders that reduce the ability of the bone marrow to produce platelets. One example is called myelodysplasia which in its mildest form must be considered in the differential diagnosis of ITP, especially in the elderly. Myelodysplasia is suspected based on abnormalities in the blood smear and can often be diagnosed with a bone marrow examination. Other causes of bone marrow failure include aplastic anemia, leukemia or rarely folate or B12 deficiency.Platelets can dwell (pool) in an enlarged spleen (splenomegaly) from any cause or can be destroyed because of an overactive spleen (hypersplenism). Hypersplenism is often caused by liver disease due to viral hepatitis or alcohol. Thrombocytopenia due to splenomegaly or hypersplenism is usually not as severe as in ITP. The diagnosis may be suspected on physical examination or by abdominal imaging.As mentioned above, immune thrombocytopenia can be secondary to a systemic autoimmune disorder such as systemic lupus erythematosus. Adverse drug reactions (drug-induced thrombocytopenia) are also potential causes of thrombocytopenia. Quinidine, quinine, valproate and heparin are examples drugs associated with the development of immune thrombocytopenia. Infections can result in thrombocytopenia that may be hard to distinguish from ITP. These infections include HIV, hepatitis B and C, H Pylori and CMV, among others. Thrombocytopenia in these settings may not be immunologically mediated as in ITP. The presence of an infection may be suspected by finding abnormal liver tests and/or atypical lymphocytes on blood smear and then confirmed with specific diagnostic tests.There are some disorders in which thrombocytopenia is accompanied by thrombosis or vessel injury. Thrombotic thrombocytopenia purpura (TTP) is a rare, but quite serious blood disease. In adults it is found most commonly in young females; the rare cases in children are more common in adolescent females. Major symptoms may include disturbances (interruptions) in blood supply due to clotting that can involve any of several organs including the brain, severe thrombocytopenia and accelerated destruction of red blood cells leading to their characteristic fragmented appearance on the blood film (microangiopathic hemolytic anemia). Thrombotic thrombocytopenia purpura is most often caused by an autoantibody that lowers the level of or blocks the function of an enzyme known as ADAMTS13 that helps to control blood clotting. Treatment includes immediate plasma exchange although caplicizumab, which inhibits von Willebrand factor action, also works very quickly. Steroids are typically administered on day 1 and anti-CD20 is often added to the therapeutic regimen. Another form of TTP is an inherited absence of ADAMTS13 and requires replacement therapy with cryoprecipitate or plasma. ADAMTS13 concentrates are in development. These cases may present when exacerbated by infection. (For more information on this disorder, choose “thrombotic thrombocytopenia purpura” as your search term in the Rare Disease Database). Hemolytic uremic syndrome (HUS) is another cause of thrombocytopenia, anemia, and thrombosis. The epidemic form occurs in very small children/infants and presents with anemia and thrombocytopenia in the setting of acute renal failure. It is caused by a toxin produced by certain E Coli bacteria. Classically, there is bloody diarrhea which resolves followed several days later by HUS. There are also inherited forms called “atypical HUS” due to genetic abnormalities in the alternative pathway of complement. HUS also occurs in adults, during pregnancy or rarely as a side effect of certain medications. Heparin-induced thrombocytopenia (HIT) is the most common drug-induced, antibody-mediated thrombocytopenic-thrombotic disorder. Heparin is often used to prevent blood clotting (anticoagulant). HIT generally occurs a week after first exposure to the drug and sooner with subsequent exposures. The antibodies in HIT bind to heparin in combination with a protein released from platelets called PF4. HIT antibodies activate platelets and other cell types, predisposing to formation of blood clots (thrombosis) in veins or arteries. This is a disorder recognized in hospitalized patients but not in outpatients taking low doses of heparin subcutaneously to prevent clot formation. HIT is rare in children.The antiphospholipid syndrome (APS) is a disorder associated with autoantibodies to various phospholipids that make up the membranes of cells, such as cardiolipin, and to proteins that bind to such phospholipids, such as beta-2-glycoprotein 1. Patients with APS may present with arterial or venous thrombosis in any organ or have gestational complications, including recurrent miscarriages or fetal losses. Immune thrombocytopenia, not usually severe, may be superimposed on the thrombotic complications. Some patients with ITP also have anti-phospholipid antibodies but do not necessarily develop thrombotic or gestational complications as a result.Henoch-Schonlein purpura (HSP) is a rare disease involving the small blood vessels (capillaries) that is usually self-limited. It is the most common form of inflammation involving small vessels (vasculitis) occurring in childhood. The symptoms usually begin suddenly and may include headache, fever, loss of appetite, cramping abdominal pain and/or joint pain. The resemblance to ITP is that red or purple spots typically appear on the skin that may resemble bruises, but thrombocytopenia is quite uncommon. A major diagnostic clue to HSP is that the signs are predominantly on the lower extremities rather than distributed all over. Furthermore, unlike ITP, the “bruises” are often palpable. Inflammatory changes an also develop in the joints, kidneys, digestive system and, in rare cases, the brain and spinal cord (central nervous system). The cause of HSP has not been established, although research suggests that it may be an autoimmune disease, such as a severe allergic reaction to offending substances (e.g., foods or drugs). (For more information on this disorder, choose “Henoch-Schonlein purpura” as your search term in the Rare Disease Database).Anti-thyroid autoantibodies are detected commonly in patients with ITP, especially in young women. Assessment of thyroid function may therefore be indicated in many patients especially women of child-bearing age. Other autoantibodies such as the ANA are reported less commonly but may be important if strongly positive.
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Related disorders of Immune Thrombocytopenia. Thrombocytopenia can also be due several other disorders that can resemble ITP in addition to inherited and secondary thrombocytopenia. It is important that physicians develop a differential diagnosis for other possible causes of thrombocytopenia, to consider the full spectrum of what could be underlying the thrombocytopenia. The most likely underlying conditions depend on patient age, sex and many other features of the presentation. Clinical judgment is important since it is not possible to do testing for every other cause of thrombocytopenia. Occasionally patients may have enlarged lymph nodes, a history of recurrent infections or other findings not typical for ITP. Thrombocytopenia can also be caused by many other blood (hematological) disorders that reduce the ability of the bone marrow to produce platelets. One example is called myelodysplasia which in its mildest form must be considered in the differential diagnosis of ITP, especially in the elderly. Myelodysplasia is suspected based on abnormalities in the blood smear and can often be diagnosed with a bone marrow examination. Other causes of bone marrow failure include aplastic anemia, leukemia or rarely folate or B12 deficiency.Platelets can dwell (pool) in an enlarged spleen (splenomegaly) from any cause or can be destroyed because of an overactive spleen (hypersplenism). Hypersplenism is often caused by liver disease due to viral hepatitis or alcohol. Thrombocytopenia due to splenomegaly or hypersplenism is usually not as severe as in ITP. The diagnosis may be suspected on physical examination or by abdominal imaging.As mentioned above, immune thrombocytopenia can be secondary to a systemic autoimmune disorder such as systemic lupus erythematosus. Adverse drug reactions (drug-induced thrombocytopenia) are also potential causes of thrombocytopenia. Quinidine, quinine, valproate and heparin are examples drugs associated with the development of immune thrombocytopenia. Infections can result in thrombocytopenia that may be hard to distinguish from ITP. These infections include HIV, hepatitis B and C, H Pylori and CMV, among others. Thrombocytopenia in these settings may not be immunologically mediated as in ITP. The presence of an infection may be suspected by finding abnormal liver tests and/or atypical lymphocytes on blood smear and then confirmed with specific diagnostic tests.There are some disorders in which thrombocytopenia is accompanied by thrombosis or vessel injury. Thrombotic thrombocytopenia purpura (TTP) is a rare, but quite serious blood disease. In adults it is found most commonly in young females; the rare cases in children are more common in adolescent females. Major symptoms may include disturbances (interruptions) in blood supply due to clotting that can involve any of several organs including the brain, severe thrombocytopenia and accelerated destruction of red blood cells leading to their characteristic fragmented appearance on the blood film (microangiopathic hemolytic anemia). Thrombotic thrombocytopenia purpura is most often caused by an autoantibody that lowers the level of or blocks the function of an enzyme known as ADAMTS13 that helps to control blood clotting. Treatment includes immediate plasma exchange although caplicizumab, which inhibits von Willebrand factor action, also works very quickly. Steroids are typically administered on day 1 and anti-CD20 is often added to the therapeutic regimen. Another form of TTP is an inherited absence of ADAMTS13 and requires replacement therapy with cryoprecipitate or plasma. ADAMTS13 concentrates are in development. These cases may present when exacerbated by infection. (For more information on this disorder, choose “thrombotic thrombocytopenia purpura” as your search term in the Rare Disease Database). Hemolytic uremic syndrome (HUS) is another cause of thrombocytopenia, anemia, and thrombosis. The epidemic form occurs in very small children/infants and presents with anemia and thrombocytopenia in the setting of acute renal failure. It is caused by a toxin produced by certain E Coli bacteria. Classically, there is bloody diarrhea which resolves followed several days later by HUS. There are also inherited forms called “atypical HUS” due to genetic abnormalities in the alternative pathway of complement. HUS also occurs in adults, during pregnancy or rarely as a side effect of certain medications. Heparin-induced thrombocytopenia (HIT) is the most common drug-induced, antibody-mediated thrombocytopenic-thrombotic disorder. Heparin is often used to prevent blood clotting (anticoagulant). HIT generally occurs a week after first exposure to the drug and sooner with subsequent exposures. The antibodies in HIT bind to heparin in combination with a protein released from platelets called PF4. HIT antibodies activate platelets and other cell types, predisposing to formation of blood clots (thrombosis) in veins or arteries. This is a disorder recognized in hospitalized patients but not in outpatients taking low doses of heparin subcutaneously to prevent clot formation. HIT is rare in children.The antiphospholipid syndrome (APS) is a disorder associated with autoantibodies to various phospholipids that make up the membranes of cells, such as cardiolipin, and to proteins that bind to such phospholipids, such as beta-2-glycoprotein 1. Patients with APS may present with arterial or venous thrombosis in any organ or have gestational complications, including recurrent miscarriages or fetal losses. Immune thrombocytopenia, not usually severe, may be superimposed on the thrombotic complications. Some patients with ITP also have anti-phospholipid antibodies but do not necessarily develop thrombotic or gestational complications as a result.Henoch-Schonlein purpura (HSP) is a rare disease involving the small blood vessels (capillaries) that is usually self-limited. It is the most common form of inflammation involving small vessels (vasculitis) occurring in childhood. The symptoms usually begin suddenly and may include headache, fever, loss of appetite, cramping abdominal pain and/or joint pain. The resemblance to ITP is that red or purple spots typically appear on the skin that may resemble bruises, but thrombocytopenia is quite uncommon. A major diagnostic clue to HSP is that the signs are predominantly on the lower extremities rather than distributed all over. Furthermore, unlike ITP, the “bruises” are often palpable. Inflammatory changes an also develop in the joints, kidneys, digestive system and, in rare cases, the brain and spinal cord (central nervous system). The cause of HSP has not been established, although research suggests that it may be an autoimmune disease, such as a severe allergic reaction to offending substances (e.g., foods or drugs). (For more information on this disorder, choose “Henoch-Schonlein purpura” as your search term in the Rare Disease Database).Anti-thyroid autoantibodies are detected commonly in patients with ITP, especially in young women. Assessment of thyroid function may therefore be indicated in many patients especially women of child-bearing age. Other autoantibodies such as the ANA are reported less commonly but may be important if strongly positive.
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Immune Thrombocytopenia
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nord_634_5
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Diagnosis of Immune Thrombocytopenia
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Most patients with ITP present with some form of bleeding, typically in the skin. On occasion, a low platelet count may be detected incidentally by a complete blood count (CBC) ordered for other purposes such as for infection, before surgery or on a routine checkup in an individual without apparent symptoms (asymptomatic). Most ITP patients have “isolated” thrombocytopenia with normal appearing red cells and white cells, but anemia can result from bleeding and iron deficiency and changes in the white blood cell count can occur with recent infection. If there are lower or higher than normal WBC or RBC counts, the chance this is NOT ITP increases substantially. Secondary forms of ITP are suspected when an individual has a history of recurrent infections, fever or weight loss, enlarged lymph nodes, joint pains, is post vaccination, etc.The diagnosis of ITP is usually made by excluding other causes of isolated thrombocytopenia, including certain medications and disorders that affect the bone marrow and reduce platelet production. Inspection of the blood smear under the microscope will verify platelets are truly reduced in number and not simply clumped together or too big to be counted by automated machines as platelets. When clumping is seen, the platelet count should be measured using blood collected in a blue top (citrate) tube or directly from the finger to establish whether the platelet count in the body is low. The platelets in ITP are normal in size or the size may vary with some platelets somewhat larger than normal, but not uniformly very small or exceeding large (giant platelets) as seen in some hereditary thrombocytopenias. The red blood cells and white blood cells are usually normal in number and appear normal, helping to exclude consideration of leukemia or myelodysplasia, among other causes of thrombocytopenia. The presence of unusual appearing white blood cells in the blood or additional abnormalities in the blood counts might indicate the need for other testing including a bone marrow examination to exclude other causes of impaired platelet production.In a patient who is in good health, who has not recently started a new medication, and is found to have thrombocytopenia with no other abnormality identified in a complete blood count or upon inspection of the blood smear, has no family history of thrombocytopenia, and, if available, has a normal platelet count in the past, the diagnosis of new onset ITP is likely. There is no definitive test (including measurement of platelet autoantibodies) to make the diagnosis or to exclude the diagnosis of ITP. However, a robust response to ITP-specific treatments such as intravenous immunoglobulin (IVIG) or glucocorticoids (described below) provides strong evidence in favor of the diagnosis.
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Diagnosis of Immune Thrombocytopenia. Most patients with ITP present with some form of bleeding, typically in the skin. On occasion, a low platelet count may be detected incidentally by a complete blood count (CBC) ordered for other purposes such as for infection, before surgery or on a routine checkup in an individual without apparent symptoms (asymptomatic). Most ITP patients have “isolated” thrombocytopenia with normal appearing red cells and white cells, but anemia can result from bleeding and iron deficiency and changes in the white blood cell count can occur with recent infection. If there are lower or higher than normal WBC or RBC counts, the chance this is NOT ITP increases substantially. Secondary forms of ITP are suspected when an individual has a history of recurrent infections, fever or weight loss, enlarged lymph nodes, joint pains, is post vaccination, etc.The diagnosis of ITP is usually made by excluding other causes of isolated thrombocytopenia, including certain medications and disorders that affect the bone marrow and reduce platelet production. Inspection of the blood smear under the microscope will verify platelets are truly reduced in number and not simply clumped together or too big to be counted by automated machines as platelets. When clumping is seen, the platelet count should be measured using blood collected in a blue top (citrate) tube or directly from the finger to establish whether the platelet count in the body is low. The platelets in ITP are normal in size or the size may vary with some platelets somewhat larger than normal, but not uniformly very small or exceeding large (giant platelets) as seen in some hereditary thrombocytopenias. The red blood cells and white blood cells are usually normal in number and appear normal, helping to exclude consideration of leukemia or myelodysplasia, among other causes of thrombocytopenia. The presence of unusual appearing white blood cells in the blood or additional abnormalities in the blood counts might indicate the need for other testing including a bone marrow examination to exclude other causes of impaired platelet production.In a patient who is in good health, who has not recently started a new medication, and is found to have thrombocytopenia with no other abnormality identified in a complete blood count or upon inspection of the blood smear, has no family history of thrombocytopenia, and, if available, has a normal platelet count in the past, the diagnosis of new onset ITP is likely. There is no definitive test (including measurement of platelet autoantibodies) to make the diagnosis or to exclude the diagnosis of ITP. However, a robust response to ITP-specific treatments such as intravenous immunoglobulin (IVIG) or glucocorticoids (described below) provides strong evidence in favor of the diagnosis.
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Immune Thrombocytopenia
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nord_634_6
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Therapies of Immune Thrombocytopenia
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Treatment OverviewManagement of adults depends on severity of symptoms, platelet count, age, lifestyle, response to therapy and its side effects, the presence of other medical issues that affect the risks of bleeding and other complications including medications taken, quality of life as discussed above, and the personal preferences of both the patient/their caregivers and treating physicians as they relate to work, lifestyle, family support and expectations, among other factors.While there is no well-established treatment that cures patients with ITP, fortunately almost all patients find that their platelet count will improve following treatment. What proves difficult for many ITP patients who benefit from treatment is finding the treatment that works for them without unwanted side effects and that they can access. In some individuals, especially children, the disease can go into remission usually for the remainder of a person’s life. However, ITP can also recur at any time and there is currently no way to reliably predict the course of the disease other than the clearly better prognosis of children compared to adults. Changes in diet or lifestyle may improve (or worsen) the sense of well-being, but the impact on platelet count is less certain. It is also important that the patient and physician have an ongoing dialogue involving all concerns and decisions concerning treatment options including whether any treatment is needed.For children, management at disease onset is often expectant based on the degree of and risk of bleeding rather than the platelet count. Treatment is more routinely administered in the chronic phase and is most commonly thrombopoietin (TPO) agents in preference to other second line agents. Risk of bleeding and side effects of treatments such as corticosteroids differs from adults and depends on the child’s age. Input from the child’s caregiver and child to the extent possible, also factors into treatment decisions. Extensive studies of children have explored treatment of those with chronic disease and a recent study of children with ITP at presentation, the TIKI trial, validated the expectant approach in children with only grade 1 and 2 bleeding but simultaneously demonstrated a degree of curative effect following IVIG treatment.Criteria for TreatmentIn most children and some adults, therapy may not be necessary at the time they first see their physician and the disorder may resolve spontaneously. The decision to initiate treatment depends on the severity of bleeding, the severity of the thrombocytopenia (especially in adults) the age of the patient (increased risk of bleeding in the elderly), coincidental disorders that might predispose to bleeding (tendency to fall, concurrent anti-platelet drugs or anticoagulants), lifestyle (such as young and athletic or jobs such as construction) and risks, side effects and costs and time away from work required for each intervention. In addition, after careful and comprehensive investigation, treatment may also be indicated to improve quality of life. These factors contribute to deciding if treatment is indicated and which treatment to use.The goal of therapy in adults and children is to prevent bleeding, stabilize and hopefully improve the platelet count, and help restore the patient’s ability to have a normal lifestyle. When treatment is deemed necessary, there are many options that have proven successful. Treatments differ in likelihood of benefit and attendant risks. Some are considered more toxic and are, therefore, generally deferred unless it is proven they are needed. Treatments also differ in their intended effect: e.g., short term increase in platelets above dangerous levels versus long-term maintenance of a stable platelet count versus cure. It is important to understand both the success rate and potential side effects before beginning any form of treatment. Hematologists may recommend combining several treatments that act in different ways to increase their success rate and minimize their side effects by avoiding the highest doses required when agents are used individually.First Line/Emergency TherapyTreatment with corticosteroids (e.g., high doses of prednisone, dexamethasone, methylprednisolone) is usually the mainstay of initial therapy. These drugs function by initially suppressing the clearance of antibody-coated platelets and perhaps with more prolonged use by increasing platelet production. They may also decrease the risk of bleeding by improving the function of the cells lining the blood vessels. Use of high doses of dexamethasone for several days may accelerate response compared with daily oral prednisone and may have less lasting toxicity because of its 4-day course of treatment. However, tolerability of high-dose dexamethasone may be lower than that of prednisone and certain patients will refuse to use it again. In general, the duration and dose of corticosteroids should be minimized (less than 6 weeks) because of their immediate and long-term side effects. Therefore, corticosteroids are used to control the disease until a transition can been made to other forms of treatment in patients who do not achieve a spontaneous stabilization at an adequate count or a remission.If platelet counts do not improve after corticosteroid treatment or when individuals present with severe bleeding, initial treatment includes adding intravenous immunoglobulin (IVIG). IVIG is typically given as needed every 2-4 weeks based on the platelet count and signs of bleeding, but rarely leads to a cure.Platelet transfusions are reserved for the most emergent situations because they are likely to be destroyed relatively quickly by the autoantibodies. Even more than steroids, they may be widely overused according to a recent study.The orphan drug anti-D (WinRho SDF, Rhophylac), a specific form of gamma globulin, was approved by the U.S. Food and Drug Administration (FDA) to treat ITP in individuals who are red blood cell RhD antigen positive, do not already have antibodies on their red cells and have not undergone splenectomy. The drug can be used repeatedly, including in children who have newly diagnosed, persistent or chronic ITP. However, concerns have been raised because of a small fraction of individuals who have had severe side effects from brisk red cell destruction and its consequences soon after infusion.Response can be based on cessation of bleeding (clinical response) and/or attaining a platelet count above 20-30,000/µl or higher for procedures or delivery (partial response). A response in platelets to greater than 100,000/µL is usually termed a complete response, but this should not be confused with cure when a patient is on or has recently completed therapy. Failure to respond to first line therapy, as opposed to responding but then relapsing, should prompt reconsideration of the diagnosis of ITP.Second Line TherapyThe criteria for determining whether second line therapy is needed are the same as those involving initiation of treatment plus patients with suboptimal and/or short-lived responses to first line approaches. As mentioned, corticosteroids should be used for the shortest duration possible (ideally less than 6 weeks) to achieve these objectives and to provide a bridge to less toxic alternatives if treatment continues to be required. Many adults and some children will need long-term management because their platelet count fell once the dose of corticosteroids is tapered and IVIG is stopped.One second-line option is thrombopoietin receptor agonists (TPO-RAs). TPO-RAs function by stimulating the body’s production of platelets by megakaryocytes in the bone marrow, which release proplatelets that mature into platelets. By increasing the rate at which platelets are produced in the body, TPO-RAs may overcome the heightened rate of platelet destruction caused by antiplatelet antibodies and their ability to impair megakaryocyte platelet production. Three TPO-RAs are approved by the FDA for use in ITP: eltrombopag (Promacta/Revolade) romiplostim (Nplate) and avatrombopag (Doptelet); only the first two are approved in children. Other TPO-RAs are in development or approved for related indications, such as thrombocytopenia in liver disease.In 2008, the FDA approved both romiplostim (Nplate) and eltrombopag (Promacta) to treat both children and adults with ITP who have had an insufficient response to corticosteroids, immunoglobulins or splenectomy. Romiplostim is typically given by weekly subcutaneous injection, most often in a physician’s office. Eltrombopag has two extremely important dietary restrictions that are needed to allow this oral agent, which is administered once daily, to be effective: it must be taken on an empty stomach meaning no food for at least 1 hour before and 2 hours after and no high calcium food such as dairy, for 4 hours before and 4 hours after ingestion. In 2015, eltrombopag was approved for the treatment of children 1 year and older with ITP who have had an insufficient response to corticosteroids, immunoglobulins or splenectomy; romiplostim was similarly approved in late 2018. Response rate, depending upon the definition of response, to both agents ranges from 40-80% and, once a stable response is obtained, is generally durable with ongoing treatment. The drugs are generally well tolerated and long-term safety studies have mitigated initial concerns about thrombosis and especially bone marrow scarring. Some patients (an unknown percent but perhaps approaching 30%) will experience sufficient improvement in their ITP over 1-2 years taking a TPO agent to discontinue and remain off treatment.In 2019, the FDA approved avatrombopag (Doptelet) to treat ITP in adults with chronic ITP who have had insufficient response to a previous treatment. This is the only oral TPO-RA medication approved to treat ITP that can be taken with food. Avatrombopag is generally considered safe and well tolerated. Recent data suggests that patients who fail to respond (or who have a side effect) to one oral TPO-RA may show a good response (or not develop the same side effect) when they switch to an alternative TPO-RA.Another option is anti-CD20 antibody, rituximab (Rituxan) which now has several biosimilars although their mechanism of action remains poorly understood. Provided intravenously, the standard dose and administration is one infusion every 7 days for four weeks consecutively at 375mg/m2 per infusion. Other approaches have been used including 100mg weekly x 4 and 1000mg biweekly x 2. About half of ITP patients respond initially. Women of child-bearing age of duration of ITP Third Line TherapyA small percentage of patients fail to respond or tolerate first- or second-line treatments. For those, options include dapsone, Imuran (azathioprine), Cytoxan (cyclophosphamide), Sandimmune (cyclosporine), Danocrine (danazol), Cellcept (mycophenolate mofetil), Vincristine (vinca alkaloids) or combinations of these and first or second-line agents. It is important to recognize that the division between 2nd and 3rd line therapy may be somewhat arbitrary and many clinicians would consider, for example, mycophenolate mofetil a second line treatment.Several novel forms of treatment are in clinical trials such as FcRn inhibitors, BTK inhibitors, and inhibitors of complement.If the patient has antibodies or evidence of Helicobacter pylori infection, treatment with antibiotics and proton pump inhibitors to eradicate the infection may ameliorate the condition. However, antibiotic associated remission of ITP is much more common in Asia i.e., Japan, and in some parts of Europe, especially Italy, than in patients who have lived their entire life in North America.Some patients report improved health-related quality of life with complementary therapies such as vitamins, supplements, diet changes, herbs such as papaya and turmeric, meditation and visualization, and energy work such as Reiki. However, there are no controlled trials in ITP patients demonstrating utility or safety of any of these agents.Prominent complaints in patients with ITP include not only bleeding, thrombosis, and side effects of medication, especially steroids, but also persistent symptoms of fatigue and impaired health-related quality of life. The I-WISh 1.0 study showed these often persist even if the ITP is better and successful treatment of platelets does not always ameliorate these symptoms.Certain measures can be taken to help reduce bleeding in addition to raising the platelet count. These include use of anti-fibrinolytics for heavy menses or problematic epistaxis; iron and thyroid replacement if needed; hormonal therapy (especially progesterone-based to not worsen the ITP with estrogen) for heavy menses; exploration of viral PCRs for ongoing infection such as CMV; and attention to gingival hygiene for gum bleeding. Similarly, certain approaches may improve quality of life without necessarily affecting the platelet count.
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Therapies of Immune Thrombocytopenia. Treatment OverviewManagement of adults depends on severity of symptoms, platelet count, age, lifestyle, response to therapy and its side effects, the presence of other medical issues that affect the risks of bleeding and other complications including medications taken, quality of life as discussed above, and the personal preferences of both the patient/their caregivers and treating physicians as they relate to work, lifestyle, family support and expectations, among other factors.While there is no well-established treatment that cures patients with ITP, fortunately almost all patients find that their platelet count will improve following treatment. What proves difficult for many ITP patients who benefit from treatment is finding the treatment that works for them without unwanted side effects and that they can access. In some individuals, especially children, the disease can go into remission usually for the remainder of a person’s life. However, ITP can also recur at any time and there is currently no way to reliably predict the course of the disease other than the clearly better prognosis of children compared to adults. Changes in diet or lifestyle may improve (or worsen) the sense of well-being, but the impact on platelet count is less certain. It is also important that the patient and physician have an ongoing dialogue involving all concerns and decisions concerning treatment options including whether any treatment is needed.For children, management at disease onset is often expectant based on the degree of and risk of bleeding rather than the platelet count. Treatment is more routinely administered in the chronic phase and is most commonly thrombopoietin (TPO) agents in preference to other second line agents. Risk of bleeding and side effects of treatments such as corticosteroids differs from adults and depends on the child’s age. Input from the child’s caregiver and child to the extent possible, also factors into treatment decisions. Extensive studies of children have explored treatment of those with chronic disease and a recent study of children with ITP at presentation, the TIKI trial, validated the expectant approach in children with only grade 1 and 2 bleeding but simultaneously demonstrated a degree of curative effect following IVIG treatment.Criteria for TreatmentIn most children and some adults, therapy may not be necessary at the time they first see their physician and the disorder may resolve spontaneously. The decision to initiate treatment depends on the severity of bleeding, the severity of the thrombocytopenia (especially in adults) the age of the patient (increased risk of bleeding in the elderly), coincidental disorders that might predispose to bleeding (tendency to fall, concurrent anti-platelet drugs or anticoagulants), lifestyle (such as young and athletic or jobs such as construction) and risks, side effects and costs and time away from work required for each intervention. In addition, after careful and comprehensive investigation, treatment may also be indicated to improve quality of life. These factors contribute to deciding if treatment is indicated and which treatment to use.The goal of therapy in adults and children is to prevent bleeding, stabilize and hopefully improve the platelet count, and help restore the patient’s ability to have a normal lifestyle. When treatment is deemed necessary, there are many options that have proven successful. Treatments differ in likelihood of benefit and attendant risks. Some are considered more toxic and are, therefore, generally deferred unless it is proven they are needed. Treatments also differ in their intended effect: e.g., short term increase in platelets above dangerous levels versus long-term maintenance of a stable platelet count versus cure. It is important to understand both the success rate and potential side effects before beginning any form of treatment. Hematologists may recommend combining several treatments that act in different ways to increase their success rate and minimize their side effects by avoiding the highest doses required when agents are used individually.First Line/Emergency TherapyTreatment with corticosteroids (e.g., high doses of prednisone, dexamethasone, methylprednisolone) is usually the mainstay of initial therapy. These drugs function by initially suppressing the clearance of antibody-coated platelets and perhaps with more prolonged use by increasing platelet production. They may also decrease the risk of bleeding by improving the function of the cells lining the blood vessels. Use of high doses of dexamethasone for several days may accelerate response compared with daily oral prednisone and may have less lasting toxicity because of its 4-day course of treatment. However, tolerability of high-dose dexamethasone may be lower than that of prednisone and certain patients will refuse to use it again. In general, the duration and dose of corticosteroids should be minimized (less than 6 weeks) because of their immediate and long-term side effects. Therefore, corticosteroids are used to control the disease until a transition can been made to other forms of treatment in patients who do not achieve a spontaneous stabilization at an adequate count or a remission.If platelet counts do not improve after corticosteroid treatment or when individuals present with severe bleeding, initial treatment includes adding intravenous immunoglobulin (IVIG). IVIG is typically given as needed every 2-4 weeks based on the platelet count and signs of bleeding, but rarely leads to a cure.Platelet transfusions are reserved for the most emergent situations because they are likely to be destroyed relatively quickly by the autoantibodies. Even more than steroids, they may be widely overused according to a recent study.The orphan drug anti-D (WinRho SDF, Rhophylac), a specific form of gamma globulin, was approved by the U.S. Food and Drug Administration (FDA) to treat ITP in individuals who are red blood cell RhD antigen positive, do not already have antibodies on their red cells and have not undergone splenectomy. The drug can be used repeatedly, including in children who have newly diagnosed, persistent or chronic ITP. However, concerns have been raised because of a small fraction of individuals who have had severe side effects from brisk red cell destruction and its consequences soon after infusion.Response can be based on cessation of bleeding (clinical response) and/or attaining a platelet count above 20-30,000/µl or higher for procedures or delivery (partial response). A response in platelets to greater than 100,000/µL is usually termed a complete response, but this should not be confused with cure when a patient is on or has recently completed therapy. Failure to respond to first line therapy, as opposed to responding but then relapsing, should prompt reconsideration of the diagnosis of ITP.Second Line TherapyThe criteria for determining whether second line therapy is needed are the same as those involving initiation of treatment plus patients with suboptimal and/or short-lived responses to first line approaches. As mentioned, corticosteroids should be used for the shortest duration possible (ideally less than 6 weeks) to achieve these objectives and to provide a bridge to less toxic alternatives if treatment continues to be required. Many adults and some children will need long-term management because their platelet count fell once the dose of corticosteroids is tapered and IVIG is stopped.One second-line option is thrombopoietin receptor agonists (TPO-RAs). TPO-RAs function by stimulating the body’s production of platelets by megakaryocytes in the bone marrow, which release proplatelets that mature into platelets. By increasing the rate at which platelets are produced in the body, TPO-RAs may overcome the heightened rate of platelet destruction caused by antiplatelet antibodies and their ability to impair megakaryocyte platelet production. Three TPO-RAs are approved by the FDA for use in ITP: eltrombopag (Promacta/Revolade) romiplostim (Nplate) and avatrombopag (Doptelet); only the first two are approved in children. Other TPO-RAs are in development or approved for related indications, such as thrombocytopenia in liver disease.In 2008, the FDA approved both romiplostim (Nplate) and eltrombopag (Promacta) to treat both children and adults with ITP who have had an insufficient response to corticosteroids, immunoglobulins or splenectomy. Romiplostim is typically given by weekly subcutaneous injection, most often in a physician’s office. Eltrombopag has two extremely important dietary restrictions that are needed to allow this oral agent, which is administered once daily, to be effective: it must be taken on an empty stomach meaning no food for at least 1 hour before and 2 hours after and no high calcium food such as dairy, for 4 hours before and 4 hours after ingestion. In 2015, eltrombopag was approved for the treatment of children 1 year and older with ITP who have had an insufficient response to corticosteroids, immunoglobulins or splenectomy; romiplostim was similarly approved in late 2018. Response rate, depending upon the definition of response, to both agents ranges from 40-80% and, once a stable response is obtained, is generally durable with ongoing treatment. The drugs are generally well tolerated and long-term safety studies have mitigated initial concerns about thrombosis and especially bone marrow scarring. Some patients (an unknown percent but perhaps approaching 30%) will experience sufficient improvement in their ITP over 1-2 years taking a TPO agent to discontinue and remain off treatment.In 2019, the FDA approved avatrombopag (Doptelet) to treat ITP in adults with chronic ITP who have had insufficient response to a previous treatment. This is the only oral TPO-RA medication approved to treat ITP that can be taken with food. Avatrombopag is generally considered safe and well tolerated. Recent data suggests that patients who fail to respond (or who have a side effect) to one oral TPO-RA may show a good response (or not develop the same side effect) when they switch to an alternative TPO-RA.Another option is anti-CD20 antibody, rituximab (Rituxan) which now has several biosimilars although their mechanism of action remains poorly understood. Provided intravenously, the standard dose and administration is one infusion every 7 days for four weeks consecutively at 375mg/m2 per infusion. Other approaches have been used including 100mg weekly x 4 and 1000mg biweekly x 2. About half of ITP patients respond initially. Women of child-bearing age of duration of ITP Third Line TherapyA small percentage of patients fail to respond or tolerate first- or second-line treatments. For those, options include dapsone, Imuran (azathioprine), Cytoxan (cyclophosphamide), Sandimmune (cyclosporine), Danocrine (danazol), Cellcept (mycophenolate mofetil), Vincristine (vinca alkaloids) or combinations of these and first or second-line agents. It is important to recognize that the division between 2nd and 3rd line therapy may be somewhat arbitrary and many clinicians would consider, for example, mycophenolate mofetil a second line treatment.Several novel forms of treatment are in clinical trials such as FcRn inhibitors, BTK inhibitors, and inhibitors of complement.If the patient has antibodies or evidence of Helicobacter pylori infection, treatment with antibiotics and proton pump inhibitors to eradicate the infection may ameliorate the condition. However, antibiotic associated remission of ITP is much more common in Asia i.e., Japan, and in some parts of Europe, especially Italy, than in patients who have lived their entire life in North America.Some patients report improved health-related quality of life with complementary therapies such as vitamins, supplements, diet changes, herbs such as papaya and turmeric, meditation and visualization, and energy work such as Reiki. However, there are no controlled trials in ITP patients demonstrating utility or safety of any of these agents.Prominent complaints in patients with ITP include not only bleeding, thrombosis, and side effects of medication, especially steroids, but also persistent symptoms of fatigue and impaired health-related quality of life. The I-WISh 1.0 study showed these often persist even if the ITP is better and successful treatment of platelets does not always ameliorate these symptoms.Certain measures can be taken to help reduce bleeding in addition to raising the platelet count. These include use of anti-fibrinolytics for heavy menses or problematic epistaxis; iron and thyroid replacement if needed; hormonal therapy (especially progesterone-based to not worsen the ITP with estrogen) for heavy menses; exploration of viral PCRs for ongoing infection such as CMV; and attention to gingival hygiene for gum bleeding. Similarly, certain approaches may improve quality of life without necessarily affecting the platelet count.
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Overview of Immunotactoid Glomerulopathy
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SummaryImmunotactoid glomerulopathy is a rare kidney disease of the glomerulus, the site where blood and waste are filtered from the body. Microtubule proteins plug the glomerulus, causing damage. It can cause blood and protein in the urine (hematuria and proteinuria, respectively), which makes urine look red or foamy. Other symptoms include decreased kidney function (renal insufficiency), swelling in the legs or feet and high blood pressure (hypertension). It is diagnosed with a kidney biopsy. While the exact cause is unknown, it is most often found in patients with chronic lymphocytic leukemia (CLL), B cell lymphomas and multiple myeloma. It has also been diagnosed in patients with a history of hepatitis C virus (HCV) infection. Treatment is typically aimed at the associated diseases since no treatments have been demonstrated to be effective for immunotactoid glomerulopathy yet. 40-50% of patients with immunotactoid glomerulopathy will progress to end stage renal disease within two to six years, depending on the severity. These patients will eventually need a kidney transplant and dialysis. The disease may return even after a kidney transplant, but it is usually less severe.IntroductionImmunotactoid glomerulopathy and fibrillary glomerulonephritis, a similar but slightly more common condition, are two forms of non-amyloid fibrillary glomerular deposition diseases. Microtubules and antibodies (immunoglobulins) plug the glomerulus, the body’s filter in the kidneys. Under normal conditions, the glomerulus filters the blood to form urine and keeps the antibodies to help fight infections and microtubules to maintain cell structure. The word “immunotactoid” refers to these rod-like structures (“-tactoid”) produced by the immune system (“immuno”). “Glomerulopathy” refers to the abnormal buildup of these proteins, which causes swelling and eventually irreversible kidney damage. Scientists do not fully understand why these antibodies begin depositing in the glomerulus, but most that suspect certain underlying diseases play a role. Over time, the damaged filters spill proteins into the urine and eventually lose their ability to filter blood altogether.
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Overview of Immunotactoid Glomerulopathy . SummaryImmunotactoid glomerulopathy is a rare kidney disease of the glomerulus, the site where blood and waste are filtered from the body. Microtubule proteins plug the glomerulus, causing damage. It can cause blood and protein in the urine (hematuria and proteinuria, respectively), which makes urine look red or foamy. Other symptoms include decreased kidney function (renal insufficiency), swelling in the legs or feet and high blood pressure (hypertension). It is diagnosed with a kidney biopsy. While the exact cause is unknown, it is most often found in patients with chronic lymphocytic leukemia (CLL), B cell lymphomas and multiple myeloma. It has also been diagnosed in patients with a history of hepatitis C virus (HCV) infection. Treatment is typically aimed at the associated diseases since no treatments have been demonstrated to be effective for immunotactoid glomerulopathy yet. 40-50% of patients with immunotactoid glomerulopathy will progress to end stage renal disease within two to six years, depending on the severity. These patients will eventually need a kidney transplant and dialysis. The disease may return even after a kidney transplant, but it is usually less severe.IntroductionImmunotactoid glomerulopathy and fibrillary glomerulonephritis, a similar but slightly more common condition, are two forms of non-amyloid fibrillary glomerular deposition diseases. Microtubules and antibodies (immunoglobulins) plug the glomerulus, the body’s filter in the kidneys. Under normal conditions, the glomerulus filters the blood to form urine and keeps the antibodies to help fight infections and microtubules to maintain cell structure. The word “immunotactoid” refers to these rod-like structures (“-tactoid”) produced by the immune system (“immuno”). “Glomerulopathy” refers to the abnormal buildup of these proteins, which causes swelling and eventually irreversible kidney damage. Scientists do not fully understand why these antibodies begin depositing in the glomerulus, but most that suspect certain underlying diseases play a role. Over time, the damaged filters spill proteins into the urine and eventually lose their ability to filter blood altogether.
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Symptoms of Immunotactoid Glomerulopathy
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The most common symptoms of immunotactoid glomerulopathy include:
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Symptoms of Immunotactoid Glomerulopathy . The most common symptoms of immunotactoid glomerulopathy include:
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Causes of Immunotactoid Glomerulopathy
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The causes of immunotactoid glomerulopathy are still unknown and are being researched. Microtubules build up in the glomerulus, often in patients with an underlying disease such as cancer (particularly leukemia, lymphoma and multiple myeloma) or a previous hepatitis C viral infection.
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Causes of Immunotactoid Glomerulopathy . The causes of immunotactoid glomerulopathy are still unknown and are being researched. Microtubules build up in the glomerulus, often in patients with an underlying disease such as cancer (particularly leukemia, lymphoma and multiple myeloma) or a previous hepatitis C viral infection.
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Affects of Immunotactoid Glomerulopathy
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Adults with a history of leukemia, lymphoma, multiple myeloma or another monoclonal gammopathy are most at risk for immunotactoid glomerulopathy. Some evidence also shows an association between a previous hepatitis C viral infection and immunotactoid glomerulopathy. However, many cases have no identifiable underlying disease and the cause is unknown.
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Affects of Immunotactoid Glomerulopathy . Adults with a history of leukemia, lymphoma, multiple myeloma or another monoclonal gammopathy are most at risk for immunotactoid glomerulopathy. Some evidence also shows an association between a previous hepatitis C viral infection and immunotactoid glomerulopathy. However, many cases have no identifiable underlying disease and the cause is unknown.
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Related disorders of Immunotactoid Glomerulopathy
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Fibrillary glomerulonephritis– a similar disease in which fibril proteins affect the glomerulus rather than microtubules and antibodies.Fibronectin glomerulopathy– a similar disease in which a protein called fibronectin-1 affects the glomerulus rather than microtubules and antibodies.Collagenofibrotic glomerulopathy (collagen type III glomerulopathy). – a similar disease in which collagen affects the glomerulus rather than microtubules and antibodies.
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Related disorders of Immunotactoid Glomerulopathy . Fibrillary glomerulonephritis– a similar disease in which fibril proteins affect the glomerulus rather than microtubules and antibodies.Fibronectin glomerulopathy– a similar disease in which a protein called fibronectin-1 affects the glomerulus rather than microtubules and antibodies.Collagenofibrotic glomerulopathy (collagen type III glomerulopathy). – a similar disease in which collagen affects the glomerulus rather than microtubules and antibodies.
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Diagnosis of Immunotactoid Glomerulopathy
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A diagnosis is made from a kidney biopsy to look at the microtubules under an electron microscope and immunofluorescence microscope. Routine lab tests may detect the blood and protein in the urine, but a biopsy is the only way to determine which proteins are affecting the glomerulus.Clinical Testing and Work-upAbnormal results from routine blood and urine tests are the first line of evidence for kidney damage. Kidney function tests can then detect the level of kidney damage. After a kidney biopsy confirms the diagnosis of immunotactoid glomerulopathy, a physician will likely order more blood tests and imaging. These tests are important to find any underlying cancer, hepatitis or autoimmune disease which may be associated with the glomerulonephritis. In some patients, finding and treating the underlying condition can decrease the severity of the kidney disease. When an underlying condition is not found, treatment focuses on controlling the hypertension, protein in the urine and progression of the kidney disease.
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Diagnosis of Immunotactoid Glomerulopathy . A diagnosis is made from a kidney biopsy to look at the microtubules under an electron microscope and immunofluorescence microscope. Routine lab tests may detect the blood and protein in the urine, but a biopsy is the only way to determine which proteins are affecting the glomerulus.Clinical Testing and Work-upAbnormal results from routine blood and urine tests are the first line of evidence for kidney damage. Kidney function tests can then detect the level of kidney damage. After a kidney biopsy confirms the diagnosis of immunotactoid glomerulopathy, a physician will likely order more blood tests and imaging. These tests are important to find any underlying cancer, hepatitis or autoimmune disease which may be associated with the glomerulonephritis. In some patients, finding and treating the underlying condition can decrease the severity of the kidney disease. When an underlying condition is not found, treatment focuses on controlling the hypertension, protein in the urine and progression of the kidney disease.
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Therapies of Immunotactoid Glomerulopathy
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TreatmentThere is currently no approved therapy to treat immunotactoid glomerulopathy with unknown cause. Many therapies have been unsuccessful including steroids, plasmapheresis, cyclophosphamide and cyclosporine. Clinicians will likely focus instead on controlling the symptoms of hypertension, proteinuria and kidney insufficiency. If an underlying condition is present (see Affected Populations), clinicians will instead focus on treating the underlying condition, which may improve symptoms of immunotactoid glomerulopathy.Patients who progress to end-stage renal disease will likely need kidney transplants and/or dialysis, although immunotactoid glomerulopathy can recur after a kidney transplant.
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Therapies of Immunotactoid Glomerulopathy . TreatmentThere is currently no approved therapy to treat immunotactoid glomerulopathy with unknown cause. Many therapies have been unsuccessful including steroids, plasmapheresis, cyclophosphamide and cyclosporine. Clinicians will likely focus instead on controlling the symptoms of hypertension, proteinuria and kidney insufficiency. If an underlying condition is present (see Affected Populations), clinicians will instead focus on treating the underlying condition, which may improve symptoms of immunotactoid glomerulopathy.Patients who progress to end-stage renal disease will likely need kidney transplants and/or dialysis, although immunotactoid glomerulopathy can recur after a kidney transplant.
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Overview of Imperforate Anus
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Imperforate anus is a rare inborn abnormality characterized by the absence or abnormal localization of the anus. The rectum or the colon may be connected to the vagina or the bladder by a tunnel (fistula). With surgical correction, normal elimination can become possible.
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Overview of Imperforate Anus. Imperforate anus is a rare inborn abnormality characterized by the absence or abnormal localization of the anus. The rectum or the colon may be connected to the vagina or the bladder by a tunnel (fistula). With surgical correction, normal elimination can become possible.
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Symptoms of Imperforate Anus
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Imperforate anus is an abnormality present at birth, and characterized by the absence of the normal opening of the anus. Elimination of feces may not be possible until surgery is performed. In some cases the rectum opens into the lower part of the vagina in females, or close to the scrotum in males.
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Symptoms of Imperforate Anus. Imperforate anus is an abnormality present at birth, and characterized by the absence of the normal opening of the anus. Elimination of feces may not be possible until surgery is performed. In some cases the rectum opens into the lower part of the vagina in females, or close to the scrotum in males.
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Causes of Imperforate Anus
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Imperforate anus is a birth defect that usually appears to occur randomly for unknown reasons (sporadically). Less commonly, the condition may be familial, suggesting autosomal dominant, autosomal recessive, or X-linked recessive inheritance. In addition, some researchers suggest that the condition may be caused by changes (mutations) of one or more genes, possibly in association with particular environmental factors (multifactorial inheritance). Human traits, including the classic genetic diseases, are the product of the interaction of two genes for that condition, one received from the father and one from the mother.In autosomal dominant disorders, a single copy of the disease gene (received from either the mother or father) will be expressed “dominating” the other normal gene and resulting in the appearance of the disease. The risk of transmitting the disorder from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child. The risk is the same for each pregnancy.In autosomal recessive disorders, the condition does not appear unless a person inherits the same defective 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 of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy. X-linked recessive disorders are conditions that are coded on the X chromosome. Females have two X chromosomes, but males have one X chromosome and one Y chromosome. Therefore, in females, disease traits on the X chromosome may be “masked” by the normal gene on the other X chromosome (random X chromosome inactivation). Since males only have one X chromosome, if they inherit a gene for a disease present on the X, it will be expressed. Men with X-linked disorders transmit the gene to all their daughters, who are carriers, but never to their sons. Women who are carriers of an X-linked disorder have a 50 percent risk of transmitting the carrier condition to their daughters and a 50 percent risk of transmitting the disease to their sons. Thus, in summary, when a disorder is inherited as an X-linked recessive trait, the condition is usually fully expressed in males only.In some cases, imperforate anus occurs as part of a malformation syndrome, such as VACTERL association, a rare disorder that may be characterized by a spectrum of birth defects, including anal, skeletal, kidney (renal), heart (cardiac), and/or other abnormalities. (For further information on this disorder, please choose “VACTERL” as your search term in the Rare Disease Database.)
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Causes of Imperforate Anus. Imperforate anus is a birth defect that usually appears to occur randomly for unknown reasons (sporadically). Less commonly, the condition may be familial, suggesting autosomal dominant, autosomal recessive, or X-linked recessive inheritance. In addition, some researchers suggest that the condition may be caused by changes (mutations) of one or more genes, possibly in association with particular environmental factors (multifactorial inheritance). Human traits, including the classic genetic diseases, are the product of the interaction of two genes for that condition, one received from the father and one from the mother.In autosomal dominant disorders, a single copy of the disease gene (received from either the mother or father) will be expressed “dominating” the other normal gene and resulting in the appearance of the disease. The risk of transmitting the disorder from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child. The risk is the same for each pregnancy.In autosomal recessive disorders, the condition does not appear unless a person inherits the same defective 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 of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy. X-linked recessive disorders are conditions that are coded on the X chromosome. Females have two X chromosomes, but males have one X chromosome and one Y chromosome. Therefore, in females, disease traits on the X chromosome may be “masked” by the normal gene on the other X chromosome (random X chromosome inactivation). Since males only have one X chromosome, if they inherit a gene for a disease present on the X, it will be expressed. Men with X-linked disorders transmit the gene to all their daughters, who are carriers, but never to their sons. Women who are carriers of an X-linked disorder have a 50 percent risk of transmitting the carrier condition to their daughters and a 50 percent risk of transmitting the disease to their sons. Thus, in summary, when a disorder is inherited as an X-linked recessive trait, the condition is usually fully expressed in males only.In some cases, imperforate anus occurs as part of a malformation syndrome, such as VACTERL association, a rare disorder that may be characterized by a spectrum of birth defects, including anal, skeletal, kidney (renal), heart (cardiac), and/or other abnormalities. (For further information on this disorder, please choose “VACTERL” as your search term in the Rare Disease Database.)
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Affects of Imperforate Anus
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Imperforate anus and other related abnormalities of the anus and rectum (anorectal malformations) occur in approximately one in 4,000 to 5,000 newborns in the United States. Reported instances of imperforate anus include affected individuals in whom the condition appeared to occur sporadically, members of certain multigenerational families (kindreds), and individuals in whom the condition occurred in association with other birth defects or malformation syndromes (e.g., VACTERL association).
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Affects of Imperforate Anus. Imperforate anus and other related abnormalities of the anus and rectum (anorectal malformations) occur in approximately one in 4,000 to 5,000 newborns in the United States. Reported instances of imperforate anus include affected individuals in whom the condition appeared to occur sporadically, members of certain multigenerational families (kindreds), and individuals in whom the condition occurred in association with other birth defects or malformation syndromes (e.g., VACTERL association).
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Related disorders of Imperforate Anus
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Symptoms of the following disorder can be similar to those of Imperforate anus. Comparisons may be useful for a differential diagnosis:Colon Atresia (Colon Stenosis) is a hereditary disorder characterized by closure or excessive narrowing of the lower intestines with distention of the abdomen and constipation. The closure may not be noticed at birth. Abnormalities of the bladder, abdominal wall, pubic area and rectum may occur as associated symptoms. Surgery may correct the abnormality and provide a normal sized opening.
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Related disorders of Imperforate Anus. Symptoms of the following disorder can be similar to those of Imperforate anus. Comparisons may be useful for a differential diagnosis:Colon Atresia (Colon Stenosis) is a hereditary disorder characterized by closure or excessive narrowing of the lower intestines with distention of the abdomen and constipation. The closure may not be noticed at birth. Abnormalities of the bladder, abdominal wall, pubic area and rectum may occur as associated symptoms. Surgery may correct the abnormality and provide a normal sized opening.
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Imperforate Anus
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Diagnosis of Imperforate Anus
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Diagnosis of Imperforate Anus.
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Therapies of Imperforate Anus
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Imperforate anus is surgically corrected by dilating, enlarging or repositioning the external opening, or other ways of providing an adequate rectal opening. Genetic counseling may be of benefit to patients and their families.
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Therapies of Imperforate Anus. Imperforate anus is surgically corrected by dilating, enlarging or repositioning the external opening, or other ways of providing an adequate rectal opening. Genetic counseling may be of benefit to patients and their families.
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Imperforate Anus
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Overview of Incontinentia Pigmenti
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SummaryIncontinentia pigmenti (IP) is a genetic ectodermal dysplasia affecting the skin, hair, teeth, microvasculature and central nervous system. Progressive skin changes occur in four stages, the first of which appear in early infancy or can be present at birth. IP is an X-linked dominant genetic disorder caused by changes (variants or mutations) in the IKBKG gene.Introduction
IP was named based on the appearance of the skin under the microscope during the later stages of the condition.
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Overview of Incontinentia Pigmenti. SummaryIncontinentia pigmenti (IP) is a genetic ectodermal dysplasia affecting the skin, hair, teeth, microvasculature and central nervous system. Progressive skin changes occur in four stages, the first of which appear in early infancy or can be present at birth. IP is an X-linked dominant genetic disorder caused by changes (variants or mutations) in the IKBKG gene.Introduction
IP was named based on the appearance of the skin under the microscope during the later stages of the condition.
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Symptoms of Incontinentia Pigmenti
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Skin
Skin changes are the most characteristic and common features in IP. They are described in four stages. In all the stages, the lesions appear in lines on the arms and legs or a swirled pattern on the trunk. They can be on the face and scalp. They do not always occur in order, may occur at the same time and the later stages may be permanent once they appear.1) The first stage of IP may be present at birth or appear during early infancy. This phase consists of redness or inflammation of the skin (erythema), blisters and boils, most often affecting the extremities and the scalp. It can fade and come back again and again, commonly when there is an illness with fever. These recurrences may happen for years, even into adulthood.2) The second stage may overlap the first and may be present at birth. During this phase, the blisters develop a raised, wart-like (verrucous) appearance, and the lesions look like warts. There can be thick crusts or scabs with healing and areas of darkened skin (increased pigmentation). The extremities are involved almost exclusively in this stage. These recurrences may happen for years.3) The third stage may be present at birth in a small number of affected individuals, but usually appears between the ages of 6 and 12 months. In this phase, the skin is darkened (hyperpigmented). On the trunk, the dark skin occurs in a swirled pattern and is sometimes described as a “marble cake” appearance. Hyperpigmentation does not necessarily appear where the stage 1 and 2 rashes happen. The heavy pigmentation may fade over time, though it is permanent in many patients.4) The “atrophic stage” is called the fourth stage, but there are suggestions that it may be present, but not obvious, at birth. These skin changes are pale or hypopigmented and hairless. There may be a diminished number of sweat glands.Teeth
Between 50 to 75 percent of individuals with IP have dental abnormalities. These abnormalities include a delay in the eruption of primary teeth; abnormal shape (contour) of teeth, giving them a peg-like or cone-shaped appearance; or the congenital absence of both primary and secondary teeth (anodontia); or small teeth (microdontia).Nails
Some individuals with IP have ridged, pitted, thickened (onychogryposis), or missing nails on the hands and/or feet. In some patients, painful growths may develop under the nail. These changes can be permanent.Hair
Approximately 50 percent of individuals with IP have abnormal bald patches on the scalp (alopecia). This may happen where the stage one and two lesions have left scars or as part of a congenital skin dysplasia. The hair may be coarse, wiry, hard to comb, and/or lusterless.Eyes
Nearly one-third of individuals have eye (ocular) abnormalities. The most serious, but least frequent, is a congenitally small, abnormal eye. In any patient there can be an abnormality in the growth of blood vessels in the membrane lining the eyes (retina). If it is going to occur, it typically happens before the age of five. This problem may be treated if detected early. If left untreated, it may cause retinal detachment leading to permanent visual impairment or total blindness.Nervous System
Most individuals with IP will have no involvement of the nervous system and normal intellectual development. Severe neurologic complications can occur because of IP, the most serious of which is congenital or neonatal strokes. Some affected individuals may experience episodes of uncontrolled electrical disturbances in the brain (seizures). About 30 percent of children with IP will have slow motor development, muscle weakness in one or both sides of the body, intellectual disability and/or seizures. Severe problems are unusual and may be most associated with early strokes. Other
Abnormalities in the development of the breast, ranging from extra nipples to complete absence of the breast, are sometimes seen in individuals with IP. Whether this is more common than in the general population has not been studied.There are anecdotal reports of heat intolerance or lack of normal sweating in people with IP, but this has not been formally studied.
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Symptoms of Incontinentia Pigmenti. Skin
Skin changes are the most characteristic and common features in IP. They are described in four stages. In all the stages, the lesions appear in lines on the arms and legs or a swirled pattern on the trunk. They can be on the face and scalp. They do not always occur in order, may occur at the same time and the later stages may be permanent once they appear.1) The first stage of IP may be present at birth or appear during early infancy. This phase consists of redness or inflammation of the skin (erythema), blisters and boils, most often affecting the extremities and the scalp. It can fade and come back again and again, commonly when there is an illness with fever. These recurrences may happen for years, even into adulthood.2) The second stage may overlap the first and may be present at birth. During this phase, the blisters develop a raised, wart-like (verrucous) appearance, and the lesions look like warts. There can be thick crusts or scabs with healing and areas of darkened skin (increased pigmentation). The extremities are involved almost exclusively in this stage. These recurrences may happen for years.3) The third stage may be present at birth in a small number of affected individuals, but usually appears between the ages of 6 and 12 months. In this phase, the skin is darkened (hyperpigmented). On the trunk, the dark skin occurs in a swirled pattern and is sometimes described as a “marble cake” appearance. Hyperpigmentation does not necessarily appear where the stage 1 and 2 rashes happen. The heavy pigmentation may fade over time, though it is permanent in many patients.4) The “atrophic stage” is called the fourth stage, but there are suggestions that it may be present, but not obvious, at birth. These skin changes are pale or hypopigmented and hairless. There may be a diminished number of sweat glands.Teeth
Between 50 to 75 percent of individuals with IP have dental abnormalities. These abnormalities include a delay in the eruption of primary teeth; abnormal shape (contour) of teeth, giving them a peg-like or cone-shaped appearance; or the congenital absence of both primary and secondary teeth (anodontia); or small teeth (microdontia).Nails
Some individuals with IP have ridged, pitted, thickened (onychogryposis), or missing nails on the hands and/or feet. In some patients, painful growths may develop under the nail. These changes can be permanent.Hair
Approximately 50 percent of individuals with IP have abnormal bald patches on the scalp (alopecia). This may happen where the stage one and two lesions have left scars or as part of a congenital skin dysplasia. The hair may be coarse, wiry, hard to comb, and/or lusterless.Eyes
Nearly one-third of individuals have eye (ocular) abnormalities. The most serious, but least frequent, is a congenitally small, abnormal eye. In any patient there can be an abnormality in the growth of blood vessels in the membrane lining the eyes (retina). If it is going to occur, it typically happens before the age of five. This problem may be treated if detected early. If left untreated, it may cause retinal detachment leading to permanent visual impairment or total blindness.Nervous System
Most individuals with IP will have no involvement of the nervous system and normal intellectual development. Severe neurologic complications can occur because of IP, the most serious of which is congenital or neonatal strokes. Some affected individuals may experience episodes of uncontrolled electrical disturbances in the brain (seizures). About 30 percent of children with IP will have slow motor development, muscle weakness in one or both sides of the body, intellectual disability and/or seizures. Severe problems are unusual and may be most associated with early strokes. Other
Abnormalities in the development of the breast, ranging from extra nipples to complete absence of the breast, are sometimes seen in individuals with IP. Whether this is more common than in the general population has not been studied.There are anecdotal reports of heat intolerance or lack of normal sweating in people with IP, but this has not been formally studied.
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Incontinentia Pigmenti
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Causes of Incontinentia Pigmenti
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IP is an X-linked dominant genetic disorder caused by changes (variants or mutations) in the IKBKG gene (formerly called NEMO). IKBKG codes for a protein that helps regulate other proteins that help protect cells from self-destruction in response to specific triggers.X-linked dominant disorders are caused by an abnormal gene on the X chromosome and occur mostly in females. Females with these rare conditions are affected when they have an X chromosome with the abnormality causing a particular disease. Males with an abnormal gene for an X-linked dominant disorder are more severely affected than females and often do not survive pregnancy. Affected males who survive may have an IKBKG gene mutation with relatively mild effects, an IKBKG mutation in only some of the body’s cells (mosaicism), or an extra copy of the X chromosome in each cell.
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Causes of Incontinentia Pigmenti. IP is an X-linked dominant genetic disorder caused by changes (variants or mutations) in the IKBKG gene (formerly called NEMO). IKBKG codes for a protein that helps regulate other proteins that help protect cells from self-destruction in response to specific triggers.X-linked dominant disorders are caused by an abnormal gene on the X chromosome and occur mostly in females. Females with these rare conditions are affected when they have an X chromosome with the abnormality causing a particular disease. Males with an abnormal gene for an X-linked dominant disorder are more severely affected than females and often do not survive pregnancy. Affected males who survive may have an IKBKG gene mutation with relatively mild effects, an IKBKG mutation in only some of the body’s cells (mosaicism), or an extra copy of the X chromosome in each cell.
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Incontinentia Pigmenti
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Affects of Incontinentia Pigmenti
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IP affects all racial and ethnic groups. As of 2014 there were more than 2000 female with IP reported in the scientific literature and this number, along with reports of affected males, continues to rise. Current estimates from public health and analytical systems put the birth prevalence at 0.6-2.1/1,000,000. Orphanet reports an estimated birth prevalence of 1.2/100,000 in the European Union which is likely more accurate. The female:male ratio is 20:1.
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Affects of Incontinentia Pigmenti. IP affects all racial and ethnic groups. As of 2014 there were more than 2000 female with IP reported in the scientific literature and this number, along with reports of affected males, continues to rise. Current estimates from public health and analytical systems put the birth prevalence at 0.6-2.1/1,000,000. Orphanet reports an estimated birth prevalence of 1.2/100,000 in the European Union which is likely more accurate. The female:male ratio is 20:1.
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Incontinentia Pigmenti
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Related disorders of Incontinentia Pigmenti
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Mutations in IKBKG can also cause ectodermal dysplasia and Immunodeficiency 1 (OLEDAID). This is an X-linked recessive disorder with variable ectodermal and immunologic features. There is most often reduced sweating (hypohydrosis) or lack of sweating (anhidrosis). There can be abnormal teeth and nails. The infection patterns are of differing severity.Symptoms of the following disorders can be similar to IP. Comparisons may be useful for a differential diagnosis:Interleukin 1 receptor antagonist deficiency (DIRA) has blistering skin lesions that can be present at birth but does not follow a linear or swirled pattern. The nails can be abnormal, and biopsy of the skin shares some features with the first stage of IP. Patients with DIRA have bone abnormalities, particularly periosteal elevation. Both sexes are equally affected. DIRA has a medical treatment.IP achromians is characterized by diminished skin pigmentations similar only in pattern to discolorations of IP. The lack of skin coloration is easily contrasted with the excess discoloration characteristic of IP although diminished skin pigmentations can appear late in the course of some cases of IP. Associated neurological problems are similar. A variety of other developmental abnormalities and/or conditions may also occur in conjunction with this illness. Skin color tends to normalize with aging. This disorder is inherited in an autosomal dominant pattern.Franceschetti-Jadassohn syndrome is marked by skin pigmentation changes similar to those of IP, but symptoms begin during adolescence and do not follow inflammatory skin changes. Additionally, skin may thicken on the hands and/or feet, ability to sweat may become impaired and yellow mottling of the teeth may occur. This disorder appears to be inherited in an autosomal dominant pattern.Caffey disease is characterized by discolorations accompanied by soft tissue swellings over benign bone growths typically capped by cartilage. Fever and irritability may also occur. Symptoms tend to fluctuate in severity. This disorder, also known as infantile cortical hyperostosis, primarily affects infants under six months of age and often resolves with age. It is caused by mutations in the gene for a type of collagen (COL1A1).The term hypomelanosis of Ito (HI) encompasses a heterogeneous group of disorders characterized by hypopigmented whorls and streaks. It may be associated with other symptoms such as intellectual disability, seizures, a lack of sweating on the areas of hypopigmentation, crossed eyes (strabismus), nearsightedness, a cleft along the edge of the eyeball (coloboma), overgrowth of brain tissue and/or a small head. Hypomelanosis of Ito may occur sporadically, or it may be inherited as an autosomal dominant trait. (For more information on this disorder, choose “Hypomelanosis of Ito” as your search term in the Rare Disease Database.)There are congenital skin abnormalities such as linear nevus that can occur in a linear or swirled pattern without change or any accompanying features.
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Related disorders of Incontinentia Pigmenti. Mutations in IKBKG can also cause ectodermal dysplasia and Immunodeficiency 1 (OLEDAID). This is an X-linked recessive disorder with variable ectodermal and immunologic features. There is most often reduced sweating (hypohydrosis) or lack of sweating (anhidrosis). There can be abnormal teeth and nails. The infection patterns are of differing severity.Symptoms of the following disorders can be similar to IP. Comparisons may be useful for a differential diagnosis:Interleukin 1 receptor antagonist deficiency (DIRA) has blistering skin lesions that can be present at birth but does not follow a linear or swirled pattern. The nails can be abnormal, and biopsy of the skin shares some features with the first stage of IP. Patients with DIRA have bone abnormalities, particularly periosteal elevation. Both sexes are equally affected. DIRA has a medical treatment.IP achromians is characterized by diminished skin pigmentations similar only in pattern to discolorations of IP. The lack of skin coloration is easily contrasted with the excess discoloration characteristic of IP although diminished skin pigmentations can appear late in the course of some cases of IP. Associated neurological problems are similar. A variety of other developmental abnormalities and/or conditions may also occur in conjunction with this illness. Skin color tends to normalize with aging. This disorder is inherited in an autosomal dominant pattern.Franceschetti-Jadassohn syndrome is marked by skin pigmentation changes similar to those of IP, but symptoms begin during adolescence and do not follow inflammatory skin changes. Additionally, skin may thicken on the hands and/or feet, ability to sweat may become impaired and yellow mottling of the teeth may occur. This disorder appears to be inherited in an autosomal dominant pattern.Caffey disease is characterized by discolorations accompanied by soft tissue swellings over benign bone growths typically capped by cartilage. Fever and irritability may also occur. Symptoms tend to fluctuate in severity. This disorder, also known as infantile cortical hyperostosis, primarily affects infants under six months of age and often resolves with age. It is caused by mutations in the gene for a type of collagen (COL1A1).The term hypomelanosis of Ito (HI) encompasses a heterogeneous group of disorders characterized by hypopigmented whorls and streaks. It may be associated with other symptoms such as intellectual disability, seizures, a lack of sweating on the areas of hypopigmentation, crossed eyes (strabismus), nearsightedness, a cleft along the edge of the eyeball (coloboma), overgrowth of brain tissue and/or a small head. Hypomelanosis of Ito may occur sporadically, or it may be inherited as an autosomal dominant trait. (For more information on this disorder, choose “Hypomelanosis of Ito” as your search term in the Rare Disease Database.)There are congenital skin abnormalities such as linear nevus that can occur in a linear or swirled pattern without change or any accompanying features.
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Incontinentia Pigmenti
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Diagnosis of Incontinentia Pigmenti
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The diagnosis of IP is based on clinical evaluation, detailed patient history, and molecular genetic testing for mutations in the IKBKG gene. IKBKG is the only gene known to be associated with IP and 65% of patients have a specific deletion within the gene. Another 20% or so have mutations found by gene sequencing. IKBKG is appropriately studied using Sanger sequencing. Next generation sequencing (NGS) such as is found in multi-gene testing panels or exome sequencing will not identify IKBKG variants. There is a related pseudogene very similar to IKBKG (has sequence homology) that interferes with NGS testing technology. A skin biopsy to confirm the diagnosis in a female may be diagnostic but can be considered a secondary or follow-up test given the widespread availability and sensitivity of molecular genetic testing. Skin biopsy may be helpful in confirming the diagnosis in a female with borderline or questionable findings in whom molecular genetic testing has not identified a disease-causing mutation.Clinical Testing and Work-Up
It is very important for babies born with IP to have an eye examination by a pediatric ophthalmologist. This should be done monthly until age four months, then every three months from age four months to one year, every six months from age one to three years, and annually after age three years. The eye problems associated with IP can be severe but may be effectively managed if recognized early.The following evaluations may be done to determine the severity of disease in those affected with IP: Physical examination with particular emphasis on the skin, hair, nails, and neurologic system: electroencephalography (EEG) and brain magnetic resonance imaging (MRI) or angiography (MRA) if seizures, other neurologic abnormalities, or retinal abnormalities are present and developmental screening.Because IP can be very mild, even in infancy, an affected female may not know that she has it. It is important that a full evaluation of the mother be done by a geneticist, dermatologist or other physician after the birth of a child with IP.
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Diagnosis of Incontinentia Pigmenti. The diagnosis of IP is based on clinical evaluation, detailed patient history, and molecular genetic testing for mutations in the IKBKG gene. IKBKG is the only gene known to be associated with IP and 65% of patients have a specific deletion within the gene. Another 20% or so have mutations found by gene sequencing. IKBKG is appropriately studied using Sanger sequencing. Next generation sequencing (NGS) such as is found in multi-gene testing panels or exome sequencing will not identify IKBKG variants. There is a related pseudogene very similar to IKBKG (has sequence homology) that interferes with NGS testing technology. A skin biopsy to confirm the diagnosis in a female may be diagnostic but can be considered a secondary or follow-up test given the widespread availability and sensitivity of molecular genetic testing. Skin biopsy may be helpful in confirming the diagnosis in a female with borderline or questionable findings in whom molecular genetic testing has not identified a disease-causing mutation.Clinical Testing and Work-Up
It is very important for babies born with IP to have an eye examination by a pediatric ophthalmologist. This should be done monthly until age four months, then every three months from age four months to one year, every six months from age one to three years, and annually after age three years. The eye problems associated with IP can be severe but may be effectively managed if recognized early.The following evaluations may be done to determine the severity of disease in those affected with IP: Physical examination with particular emphasis on the skin, hair, nails, and neurologic system: electroencephalography (EEG) and brain magnetic resonance imaging (MRI) or angiography (MRA) if seizures, other neurologic abnormalities, or retinal abnormalities are present and developmental screening.Because IP can be very mild, even in infancy, an affected female may not know that she has it. It is important that a full evaluation of the mother be done by a geneticist, dermatologist or other physician after the birth of a child with IP.
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Incontinentia Pigmenti
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Therapies of Incontinentia Pigmenti
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TreatmentSkin abnormalities characteristic of IP may disappear by adolescence or adulthood without any treatment. The Stage 1 and 2 lesions may recur with routine febrile illness well into adulthood. There are no directed treatments for these skin lesions. Topical steroids are not effective. The lesions and surrounding skin should be kept clean, and irritation minimized to avoid secondary infection. Neurological symptoms such as seizures, muscle spasms, or paralysis may be controlled with various drugs and/or medical devices. Developmental delays and/or intellectual disabilities should be managed as needed with targeted therapies and school assistance.Cryotherapy and laser photocoagulation may be used to treat affected individuals with retinal neovascularization that predisposes to retinal detachment.Dental abnormalities can often be treated effectively by dentists who may provide implants in childhood as needed. If dental abnormalities interfere with chewing and/or speech, assistance from a speech pathologist and/or pediatric nutritionist may be necessary.Hair problems may require the attention of a dermatologist, although they are usually not severe.Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.
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Therapies of Incontinentia Pigmenti. TreatmentSkin abnormalities characteristic of IP may disappear by adolescence or adulthood without any treatment. The Stage 1 and 2 lesions may recur with routine febrile illness well into adulthood. There are no directed treatments for these skin lesions. Topical steroids are not effective. The lesions and surrounding skin should be kept clean, and irritation minimized to avoid secondary infection. Neurological symptoms such as seizures, muscle spasms, or paralysis may be controlled with various drugs and/or medical devices. Developmental delays and/or intellectual disabilities should be managed as needed with targeted therapies and school assistance.Cryotherapy and laser photocoagulation may be used to treat affected individuals with retinal neovascularization that predisposes to retinal detachment.Dental abnormalities can often be treated effectively by dentists who may provide implants in childhood as needed. If dental abnormalities interfere with chewing and/or speech, assistance from a speech pathologist and/or pediatric nutritionist may be necessary.Hair problems may require the attention of a dermatologist, although they are usually not severe.Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.
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Incontinentia Pigmenti
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Overview of Infantile Myofibromatosis
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SummaryInfantile myofibromatosis is a rare disorder characterized by the growth of one or more noncancerous (benign) tumors affecting the skin, bone, muscle, soft tissue, and rarely the internal organs (viscera). The severity and specific symptoms, including the specific location and number of tumors can vary greatly from one person to another. These tumors do not spread (metastasize), but can grow large enough to cause symptoms by compressing or damaging nearby organs or other parts of the body. Most cases have onset in infants or young children, but adult-onset cases have also been described in the medical literature. Most cases of infantile myofibromatosis occur randomly, for no apparent reason. Rare familial cases (in which more than one family member is affected) have been identified and genetic changes (mutations) in two different genes (PDGFRB and NOTCH3) have been found to cause the condition in most of these cases. Treatment depends upon the location of the lesion(s). Spontaneous regression has been reported to occur in many cases; however, recurrence of the lesions has also been reported. Surgery is the main treatment option.IntroductionInfantile myofibromatosis was first described as a distinct entity in the medical literature in 1954 by Dr. A.P. Stout. The disorder was initially referred to as congenital generalized fibromatosis. Additional cases were reported in the medical literature under a variety of names including multiple congenital fibromatosis, multiple hamartomas, multiple vascular leiomyomatosis of the newborn, and multiple congenital fibromatosis. In 1981, Drs. Chung and Enzinger provided a detailed review of the disorder and introduced the name infantile myofibromatosis.
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Overview of Infantile Myofibromatosis. SummaryInfantile myofibromatosis is a rare disorder characterized by the growth of one or more noncancerous (benign) tumors affecting the skin, bone, muscle, soft tissue, and rarely the internal organs (viscera). The severity and specific symptoms, including the specific location and number of tumors can vary greatly from one person to another. These tumors do not spread (metastasize), but can grow large enough to cause symptoms by compressing or damaging nearby organs or other parts of the body. Most cases have onset in infants or young children, but adult-onset cases have also been described in the medical literature. Most cases of infantile myofibromatosis occur randomly, for no apparent reason. Rare familial cases (in which more than one family member is affected) have been identified and genetic changes (mutations) in two different genes (PDGFRB and NOTCH3) have been found to cause the condition in most of these cases. Treatment depends upon the location of the lesion(s). Spontaneous regression has been reported to occur in many cases; however, recurrence of the lesions has also been reported. Surgery is the main treatment option.IntroductionInfantile myofibromatosis was first described as a distinct entity in the medical literature in 1954 by Dr. A.P. Stout. The disorder was initially referred to as congenital generalized fibromatosis. Additional cases were reported in the medical literature under a variety of names including multiple congenital fibromatosis, multiple hamartomas, multiple vascular leiomyomatosis of the newborn, and multiple congenital fibromatosis. In 1981, Drs. Chung and Enzinger provided a detailed review of the disorder and introduced the name infantile myofibromatosis.
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Infantile Myofibromatosis
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Symptoms of Infantile Myofibromatosis
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More than 90% of cases of juvenile myofibromatosis have onset in infancy, although the disorder can first present later in childhood or less often in adults. The tumors can continue to develop throughout an individual’s life.The specific symptoms of infantile myofibromatosis are broad, and the severity can vary. Some infants have mild disease that resolves on its own without treatment (spontaneous regression). Others develop extensive disease that involves internal organs and can cause life-threatening complications if left untreated. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below and that every individual case is unique. Parents should talk to their child’s physician and medical team about their specific case, associated symptoms and overall prognosis.The tumors or lesions that characterize infantile myofibromatosis are usually seen as firm, flesh or purple covered bumps (nodules) on the skin or just underneath the top layer of the skin (subcutaneous layer). These superficial lesions may be freely movable; deeper lesions are generally immobile. Skin lesions may be crusted or hardened (indurated). The lesions are usually not painful or tender. The overlying skin may be discolored red or purple and ulcerated. Lesions are also commonly found in muscle, soft tissue and bone, and very rarely the internal organs. Although the tumors that characterize infantile myofibromatosis do not spread (metastasize), they can grow large enough to damage or compress nearby structures in the body. Pain, which occurs when tumors press against adjacent nerves, can develop. In some cases, tumor growth can also cause bone destruction, disfigurement, and even physical limitations. Infantile myofibromatosis is sometimes broken down into separate types, specifically solitary, multicentric, and multicentric with visceral involvement. The solitary form is most common, accounting for approximately 75% of cases of infantile myofibromatosis. This form occurs predominantly in males and is characterized by one nodule or lesion that most commonly occurs in the skin, often extending into subcutaneous tissue and/or muscle tissue. The nodule is usually found in the head, neck or trunk areas. A solitary nodule of the bone can also occur, but is extremely rare. The multicentric forms are more common in females. The multicentric form without visceral involvement is characterized by multiple nodules that can arise in different areas of the skin, subcutaneous tissue or muscle. The multicentric form with visceral involvement is the most severe form of the disorder and is characterized by multiple growths of the skin, muscles, and bones along with the involvement of the internal organs such as the lungs, heart, and gastrointestinal tract. In some cases, only one organ may be involved; in other cases visceral involvement is widespread. This form of infantile myofibromatosis can cause severe, life-threatening complications depending upon the exact location of the lesion and the specific organs involved.
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Symptoms of Infantile Myofibromatosis. More than 90% of cases of juvenile myofibromatosis have onset in infancy, although the disorder can first present later in childhood or less often in adults. The tumors can continue to develop throughout an individual’s life.The specific symptoms of infantile myofibromatosis are broad, and the severity can vary. Some infants have mild disease that resolves on its own without treatment (spontaneous regression). Others develop extensive disease that involves internal organs and can cause life-threatening complications if left untreated. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below and that every individual case is unique. Parents should talk to their child’s physician and medical team about their specific case, associated symptoms and overall prognosis.The tumors or lesions that characterize infantile myofibromatosis are usually seen as firm, flesh or purple covered bumps (nodules) on the skin or just underneath the top layer of the skin (subcutaneous layer). These superficial lesions may be freely movable; deeper lesions are generally immobile. Skin lesions may be crusted or hardened (indurated). The lesions are usually not painful or tender. The overlying skin may be discolored red or purple and ulcerated. Lesions are also commonly found in muscle, soft tissue and bone, and very rarely the internal organs. Although the tumors that characterize infantile myofibromatosis do not spread (metastasize), they can grow large enough to damage or compress nearby structures in the body. Pain, which occurs when tumors press against adjacent nerves, can develop. In some cases, tumor growth can also cause bone destruction, disfigurement, and even physical limitations. Infantile myofibromatosis is sometimes broken down into separate types, specifically solitary, multicentric, and multicentric with visceral involvement. The solitary form is most common, accounting for approximately 75% of cases of infantile myofibromatosis. This form occurs predominantly in males and is characterized by one nodule or lesion that most commonly occurs in the skin, often extending into subcutaneous tissue and/or muscle tissue. The nodule is usually found in the head, neck or trunk areas. A solitary nodule of the bone can also occur, but is extremely rare. The multicentric forms are more common in females. The multicentric form without visceral involvement is characterized by multiple nodules that can arise in different areas of the skin, subcutaneous tissue or muscle. The multicentric form with visceral involvement is the most severe form of the disorder and is characterized by multiple growths of the skin, muscles, and bones along with the involvement of the internal organs such as the lungs, heart, and gastrointestinal tract. In some cases, only one organ may be involved; in other cases visceral involvement is widespread. This form of infantile myofibromatosis can cause severe, life-threatening complications depending upon the exact location of the lesion and the specific organs involved.
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Infantile Myofibromatosis
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nord_638_2
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Causes of Infantile Myofibromatosis
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Most cases of infantile myofibromatosis are believed to occur spontaneously and without a known family history of the disorder. In these cases, the underlying cause of the disorder is unknown. Rare cases of myofibromatosis have been identified that run in families, and mutations in two genes have been identified as causing the disorder in some cases. These genes are the platelet-derived growth factor receptor beta (PDGFRB) gene and the neurogenic locus notch homolog protein 3 (NOTCH3) 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 particular protein, this can affect the body.Infantile myofibromatosis caused by mutations in the platelet-derived growth factor receptor beta (PGDFRB) gene is passed from one generation to the next following autosomal dominant mode of inheritance. Dominant genetic disorders occur when only a single mutation (affecting one of the two copies of the relevant gene) is necessary for the disease to manifest. The disease causing genetic change can be inherited from either parent or can occur new (de novo) in the affected individual. Genetic testing of the child and both parents can differentiate these two possibilities. The risk of passing the genetic change from an individual who carries the mutation to a child is 50% (or 1 in 2) for each pregnancy, regardless of the sex of the child. In de novo cases when the genetic change was not inherited from the mother or the father, there is a very low chance the parents will have another affected child. Autosomal dominant forms of infantile myofibromatosis may manifest slightly differently in different members of the family who carry the same mutation. Not all family members will have myofibromas in exactly the same place or at exactly the same age.Mutations in the NOTCH3 gene have been described in one family with myofibromatosis and in this case the inheritance is believed to be autosomal recessive. Recessive genetic disorders occur when an individual inherits 2 mutations in the same gene, one from each parent. If a person carries a mutation in one of the two copies of the relevant gene, the person is a carrier and generally does not manifest symptoms of the condition. The risk for two carrier parents to both pass on the mutation and have an affected child is 25% for each pregnancy, regardless of the sex of the child.
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Causes of Infantile Myofibromatosis. Most cases of infantile myofibromatosis are believed to occur spontaneously and without a known family history of the disorder. In these cases, the underlying cause of the disorder is unknown. Rare cases of myofibromatosis have been identified that run in families, and mutations in two genes have been identified as causing the disorder in some cases. These genes are the platelet-derived growth factor receptor beta (PDGFRB) gene and the neurogenic locus notch homolog protein 3 (NOTCH3) 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 particular protein, this can affect the body.Infantile myofibromatosis caused by mutations in the platelet-derived growth factor receptor beta (PGDFRB) gene is passed from one generation to the next following autosomal dominant mode of inheritance. Dominant genetic disorders occur when only a single mutation (affecting one of the two copies of the relevant gene) is necessary for the disease to manifest. The disease causing genetic change can be inherited from either parent or can occur new (de novo) in the affected individual. Genetic testing of the child and both parents can differentiate these two possibilities. The risk of passing the genetic change from an individual who carries the mutation to a child is 50% (or 1 in 2) for each pregnancy, regardless of the sex of the child. In de novo cases when the genetic change was not inherited from the mother or the father, there is a very low chance the parents will have another affected child. Autosomal dominant forms of infantile myofibromatosis may manifest slightly differently in different members of the family who carry the same mutation. Not all family members will have myofibromas in exactly the same place or at exactly the same age.Mutations in the NOTCH3 gene have been described in one family with myofibromatosis and in this case the inheritance is believed to be autosomal recessive. Recessive genetic disorders occur when an individual inherits 2 mutations in the same gene, one from each parent. If a person carries a mutation in one of the two copies of the relevant gene, the person is a carrier and generally does not manifest symptoms of the condition. The risk for two carrier parents to both pass on the mutation and have an affected child is 25% for each pregnancy, regardless of the sex of the child.
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Infantile Myofibromatosis
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nord_638_3
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Affects of Infantile Myofibromatosis
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Infantile myofibromatosis affects males and females in equal numbers. Some reports have noted that males are affected more often by the solitary form and females are affected more often by multicentric forms. The exact incidence is unknown, but is estimated to be between 1 in 150,000 to 400,000 live births, reported in different ethnic and geographical groups. Because cases of this rare condition can go undiagnosed or misdiagnosed, determining the true frequency in the general population is difficult. Although rare, infantile myofibromatosis is the most common fibrous tissue tumor in infancy and early childhood.
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Affects of Infantile Myofibromatosis. Infantile myofibromatosis affects males and females in equal numbers. Some reports have noted that males are affected more often by the solitary form and females are affected more often by multicentric forms. The exact incidence is unknown, but is estimated to be between 1 in 150,000 to 400,000 live births, reported in different ethnic and geographical groups. Because cases of this rare condition can go undiagnosed or misdiagnosed, determining the true frequency in the general population is difficult. Although rare, infantile myofibromatosis is the most common fibrous tissue tumor in infancy and early childhood.
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Infantile Myofibromatosis
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nord_638_4
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Related disorders of Infantile Myofibromatosis
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Symptoms of the following disorders can be similar to those of infantile myofibromatosis. Comparisons may be useful for a differential diagnosis.There are numerous benign or malignant soft tissue and other types of tumors with superficial location (i.e. skin) that can resemble the lesions associated with infantile fibromatosis. Such conditions include nodular fasciitis, pediatric sarcomas, desmoid tumors, inflammatory myofibroblastic tumors, neurofibromas, hemangiomas, lymphangiomas, infantile fibrosarcomas, fibrous hamartomas of infancy, and dermoid or epidermoid tumors. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)There are a number of additional syndromes such as neurofibromatosis type 1 that may be characterized by the formation of single or multiple soft tissue, bony, and/or other tumors that superficially resemble those associated with infantile myofibromatosis. However, such syndromes typically may be distinguished by the presence of other characteristic symptoms and physical findings. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Related disorders of Infantile Myofibromatosis. Symptoms of the following disorders can be similar to those of infantile myofibromatosis. Comparisons may be useful for a differential diagnosis.There are numerous benign or malignant soft tissue and other types of tumors with superficial location (i.e. skin) that can resemble the lesions associated with infantile fibromatosis. Such conditions include nodular fasciitis, pediatric sarcomas, desmoid tumors, inflammatory myofibroblastic tumors, neurofibromas, hemangiomas, lymphangiomas, infantile fibrosarcomas, fibrous hamartomas of infancy, and dermoid or epidermoid tumors. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)There are a number of additional syndromes such as neurofibromatosis type 1 that may be characterized by the formation of single or multiple soft tissue, bony, and/or other tumors that superficially resemble those associated with infantile myofibromatosis. However, such syndromes typically may be distinguished by the presence of other characteristic symptoms and physical findings. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Infantile Myofibromatosis
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nord_638_5
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Diagnosis of Infantile Myofibromatosis
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A diagnosis of infantile myofibromatosis is based on the microscopic examination of the tissue in a patient with characteristic symptoms and physical examination. Imaging studies including ultrasound and MRI are most often used to visualize the extent of the growths. Imaging techniques may be used to assess the extent of the growths, the progression of the growths, and to diagnose recurrence of a growth. Imaging may be used to help evaluate the size, placement, and extension of lesions and to aid surgical procedures.A definitive diagnosis of infantile myofibromatosis requires removal and microscopic (pathological) examination of the affected tissue. Detecting the unique characteristics of the affected tissue distinguishes infantile myofibromatosis from other growths or masses that appear similar clinically and on imaging studies.Molecular genetic testing (DNA testing) from a blood sample can confirm a genetic cause for infantile myofibromatosis in some cases by detecting mutations in specific genes known to cause the disorder, such as PDGFRB and NOTCH3. Establishing a genetic diagnosis helps the genetic counselling process by allowing testing of other family members and informing the recurrence risk for future pregnancies.
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Diagnosis of Infantile Myofibromatosis. A diagnosis of infantile myofibromatosis is based on the microscopic examination of the tissue in a patient with characteristic symptoms and physical examination. Imaging studies including ultrasound and MRI are most often used to visualize the extent of the growths. Imaging techniques may be used to assess the extent of the growths, the progression of the growths, and to diagnose recurrence of a growth. Imaging may be used to help evaluate the size, placement, and extension of lesions and to aid surgical procedures.A definitive diagnosis of infantile myofibromatosis requires removal and microscopic (pathological) examination of the affected tissue. Detecting the unique characteristics of the affected tissue distinguishes infantile myofibromatosis from other growths or masses that appear similar clinically and on imaging studies.Molecular genetic testing (DNA testing) from a blood sample can confirm a genetic cause for infantile myofibromatosis in some cases by detecting mutations in specific genes known to cause the disorder, such as PDGFRB and NOTCH3. Establishing a genetic diagnosis helps the genetic counselling process by allowing testing of other family members and informing the recurrence risk for future pregnancies.
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Therapies of Infantile Myofibromatosis
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TreatmentThe treatment of infantile myofibromatosis is directed toward the specific symptoms in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, orthopedists, dermatologists, and other healthcare professionals may need to work together to plan a child’s treatment. Genetic counseling is recommended for families. 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 conducted on a large group of patients. Experiences with various treatments have been reported in the medical literature in single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and efficacy of specific medications and treatments for individuals with infantile myofibromatosis.Specific therapeutic procedures and interventions may vary, depending on the size, number and location(s) of the lesion(s) and symptoms. Decisions concerning the use of particular drug regimens, surgical treatments and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based on the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects, patient preferences, and other appropriate factors.In many cases, infantile myofibromatosis lesions go away on their own without treatment (spontaneous remission). The initial treatment option for many individuals is watchful waiting and observation with appropriate patient education. Watchful waiting or “wait and watch” refers to when physicians follow certain patients with infantile myofibromatosis (i.e. those without visceral involvement or problematic symptoms) without giving treatment until progression of the disease occurs. This allows some people to avoid undergoing surgery or other treatment options for many years or all together in cases with eventual spontaneous remission.The main treatment option for individuals with infantile myofibromatosis is surgery, which is performed to prevent complications or improve prognosis. Surgical removal of lesions is reserved for cases where there is involvement of internal organs (viscera), symptomatic lesions, or lesions that present an immediate threat due to their location near vital organs and/or if they have shown progression. In approximately 10% of cases, lesions may recur after surgery.Chemotherapy may be used to treat cases where there is involvement of the internal organs and surgery was unsuccessful (i.e. lesions recur) or where surgery is not possible (unresectable) due to the location of the lesions (e.g. too close to a vital organ). Affected children have been successfully treated with a combination of methotrexate and vinblastine. In other cases, interferon alfa or a combination of vincristine, actinomycin D, and cyclophosphamide have also been used successfully, but may be reserved for individuals with rapid progression of symptoms.
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Therapies of Infantile Myofibromatosis. TreatmentThe treatment of infantile myofibromatosis is directed toward the specific symptoms in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, orthopedists, dermatologists, and other healthcare professionals may need to work together to plan a child’s treatment. Genetic counseling is recommended for families. 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 conducted on a large group of patients. Experiences with various treatments have been reported in the medical literature in single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and efficacy of specific medications and treatments for individuals with infantile myofibromatosis.Specific therapeutic procedures and interventions may vary, depending on the size, number and location(s) of the lesion(s) and symptoms. Decisions concerning the use of particular drug regimens, surgical treatments and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based on the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects, patient preferences, and other appropriate factors.In many cases, infantile myofibromatosis lesions go away on their own without treatment (spontaneous remission). The initial treatment option for many individuals is watchful waiting and observation with appropriate patient education. Watchful waiting or “wait and watch” refers to when physicians follow certain patients with infantile myofibromatosis (i.e. those without visceral involvement or problematic symptoms) without giving treatment until progression of the disease occurs. This allows some people to avoid undergoing surgery or other treatment options for many years or all together in cases with eventual spontaneous remission.The main treatment option for individuals with infantile myofibromatosis is surgery, which is performed to prevent complications or improve prognosis. Surgical removal of lesions is reserved for cases where there is involvement of internal organs (viscera), symptomatic lesions, or lesions that present an immediate threat due to their location near vital organs and/or if they have shown progression. In approximately 10% of cases, lesions may recur after surgery.Chemotherapy may be used to treat cases where there is involvement of the internal organs and surgery was unsuccessful (i.e. lesions recur) or where surgery is not possible (unresectable) due to the location of the lesions (e.g. too close to a vital organ). Affected children have been successfully treated with a combination of methotrexate and vinblastine. In other cases, interferon alfa or a combination of vincristine, actinomycin D, and cyclophosphamide have also been used successfully, but may be reserved for individuals with rapid progression of symptoms.
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Overview of Infective Endocarditis
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SummaryInfective endocarditis (IE) is an infection of the inner lining of the heart muscle (endocardium) caused by bacteria, fungi, or germs that enter through the bloodstream. IE occurs most frequently in patients with abnormal (leaky or narrow) heart valves, artificial (prosthetic) heart valve or in people who have a pacemaker lead. Any structural heart disease can predispose a person to developing IE. In the past, rheumatic fever was the main precursor to IE and still remains a common predisposition in developing countries. The presenting symptoms are a low-grade persistent fever without an obvious cause, fatigue and shortness of breath on exertion. Patients also may have joint and muscle pain and their health care provider may hear a new or changing murmur.The endocardium covers the heart valves, and it is these valves which are primarily affected by infective endocarditis. If the infection remains untreated, multiplying bacteria may eventually destroy the valves and result in heart failure. Bacteria may also form small clots (emboli) which move through the blood and block small arteries. These clots may lodge in various parts of the body including the brain and cause serious damage.The prevalence of cases of IE has risen in the United States due to the increase in the number of elderly patients receiving invasive surgeries as well as the rise in the number of individuals using IV drugs. Other risk factors include congenital heart disease, prior episode of IE and mitral valve prolapse with leaky valve. Therefore, early diagnosis is key to improve clinical outcomes and survival. Antibiotics are essential for treatment and are most effective if the disease is caught early. However, in many cases heart surgery also is needed.Introduction Endocarditis was first described by William Osler in 1885. Developments in medical science and research in microbiology have contributed to a better understanding of the disease. The most common risk factors for infective endocarditis are previous heart damage, recent heart surgery or poor dental hygiene.
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Overview of Infective Endocarditis. SummaryInfective endocarditis (IE) is an infection of the inner lining of the heart muscle (endocardium) caused by bacteria, fungi, or germs that enter through the bloodstream. IE occurs most frequently in patients with abnormal (leaky or narrow) heart valves, artificial (prosthetic) heart valve or in people who have a pacemaker lead. Any structural heart disease can predispose a person to developing IE. In the past, rheumatic fever was the main precursor to IE and still remains a common predisposition in developing countries. The presenting symptoms are a low-grade persistent fever without an obvious cause, fatigue and shortness of breath on exertion. Patients also may have joint and muscle pain and their health care provider may hear a new or changing murmur.The endocardium covers the heart valves, and it is these valves which are primarily affected by infective endocarditis. If the infection remains untreated, multiplying bacteria may eventually destroy the valves and result in heart failure. Bacteria may also form small clots (emboli) which move through the blood and block small arteries. These clots may lodge in various parts of the body including the brain and cause serious damage.The prevalence of cases of IE has risen in the United States due to the increase in the number of elderly patients receiving invasive surgeries as well as the rise in the number of individuals using IV drugs. Other risk factors include congenital heart disease, prior episode of IE and mitral valve prolapse with leaky valve. Therefore, early diagnosis is key to improve clinical outcomes and survival. Antibiotics are essential for treatment and are most effective if the disease is caught early. However, in many cases heart surgery also is needed.Introduction Endocarditis was first described by William Osler in 1885. Developments in medical science and research in microbiology have contributed to a better understanding of the disease. The most common risk factors for infective endocarditis are previous heart damage, recent heart surgery or poor dental hygiene.
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Symptoms of Infective Endocarditis
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Infective endocarditis is an infection of the valves and/or lining of the heart. The presenting symptoms are a low-grade persistent fever without an obvious cause and fatigue and shortness of breath on exertion. Patients also may have joint pain (arthralgia) and muscle pain (myalgia) and their health care provider may hear a new or changing murmur. In addition, the following signs and symptoms occur:Infection on the heart valve results in destruction of the leaflet tissue, leaking of the valve and heart failure. Extension of infection into tissue next to valve may result in an abscess with rupture between different chambers of the heart. Clots (emboli) resulting from infective endocarditis may produce serious damage. Symptoms depend upon the location of the clot. In 20-40% of individuals with infective endocarditis, clots lodge in the brain and may cause weakness on one side of the body, loss of vision or stroke. Clots may also cause abdominal pain, flank pain, or arterial insufficiency in an extremity. An eye doctor might see bleeding in the back of the eye (Roth spots). Damage from clots may be temporary or permanent.
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Symptoms of Infective Endocarditis. Infective endocarditis is an infection of the valves and/or lining of the heart. The presenting symptoms are a low-grade persistent fever without an obvious cause and fatigue and shortness of breath on exertion. Patients also may have joint pain (arthralgia) and muscle pain (myalgia) and their health care provider may hear a new or changing murmur. In addition, the following signs and symptoms occur:Infection on the heart valve results in destruction of the leaflet tissue, leaking of the valve and heart failure. Extension of infection into tissue next to valve may result in an abscess with rupture between different chambers of the heart. Clots (emboli) resulting from infective endocarditis may produce serious damage. Symptoms depend upon the location of the clot. In 20-40% of individuals with infective endocarditis, clots lodge in the brain and may cause weakness on one side of the body, loss of vision or stroke. Clots may also cause abdominal pain, flank pain, or arterial insufficiency in an extremity. An eye doctor might see bleeding in the back of the eye (Roth spots). Damage from clots may be temporary or permanent.
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Causes of Infective Endocarditis
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Bacteria that cause infective endocarditis reach the heart through the bloodstream. Normally, heart valves are highly resistant to the attachment of bacteria and resulting infection. Damage to the heart valves and inner lining of the heart is the main risk factor for infective endocarditis because it leaves the tissue susceptible to bacterial overgrowth. As the microorganisms quickly move past the damaged valve lining, those strains that can most strongly adhere to the surface are bacteria that have the best chance of producing infective endocarditis. Clumps of bacteria and cells called vegetations form on the heart valves affecting proper function of the heart. If left untreated, this vegetation may cause the valve to leak or may result in an abscess next to the valve or in the heart muscles leading to tissue damage and blockage of the normal electrical conduction pathways. In addition, the vegetation may break loose and cause damage to the brain (stroke), kidneys or lungs.Risk factors that contribute to the onset of Infective Endocarditis include:People who are on immunosuppressive medication (such as after heart transplantation) also are at higher risk. In patients with risk factors, any dental procedure (including routine dental cleaning) risks the spread of bacteria which is prevented by treatment with antibiotics just before dental procedures in people at highest risk. Infections elsewhere in the body and chronic indwelling catheters (such as for chemotherapy) also increase the risk of infective endocarditis.Approximately 80% of infective endocarditis cases are caused by the bacteria streptococci and staphylococci. The third most common bacteria causing this disease is enterococci, and, like staphylococci, is commonly associated with healthcare-associated infective endocarditis. While very rare, infections due to gram-negative and fungal pathogens are often acquired in healthcare settings.Prevention The mouth is a major portal for bacteria to enter the body, specifically streptococcal bacteremia. Historically, prophylactic treatment with antibiotics was used for all patients at high risk for developing IE when undergoing surgical, dental or other invasive procedures. The American Heart Association recommended penicillin prophylaxis in 1955 for patients with congenital heart disease and rheumatic heart disease prior to undergoing any dental procedures. Emerging resistance to antibiotics due to overuse and lack of research to support the use of prophylaxis led the USA and Europe to restrict the use of antibiotics by 2009. The United Kingdom went on to abandon the use of antibiotic prophylaxis entirely. The USA reserves this treatment for those with prosthetic heart valves, prior IE, congenital heart disease and cardiac transplant recipients.
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Causes of Infective Endocarditis. Bacteria that cause infective endocarditis reach the heart through the bloodstream. Normally, heart valves are highly resistant to the attachment of bacteria and resulting infection. Damage to the heart valves and inner lining of the heart is the main risk factor for infective endocarditis because it leaves the tissue susceptible to bacterial overgrowth. As the microorganisms quickly move past the damaged valve lining, those strains that can most strongly adhere to the surface are bacteria that have the best chance of producing infective endocarditis. Clumps of bacteria and cells called vegetations form on the heart valves affecting proper function of the heart. If left untreated, this vegetation may cause the valve to leak or may result in an abscess next to the valve or in the heart muscles leading to tissue damage and blockage of the normal electrical conduction pathways. In addition, the vegetation may break loose and cause damage to the brain (stroke), kidneys or lungs.Risk factors that contribute to the onset of Infective Endocarditis include:People who are on immunosuppressive medication (such as after heart transplantation) also are at higher risk. In patients with risk factors, any dental procedure (including routine dental cleaning) risks the spread of bacteria which is prevented by treatment with antibiotics just before dental procedures in people at highest risk. Infections elsewhere in the body and chronic indwelling catheters (such as for chemotherapy) also increase the risk of infective endocarditis.Approximately 80% of infective endocarditis cases are caused by the bacteria streptococci and staphylococci. The third most common bacteria causing this disease is enterococci, and, like staphylococci, is commonly associated with healthcare-associated infective endocarditis. While very rare, infections due to gram-negative and fungal pathogens are often acquired in healthcare settings.Prevention The mouth is a major portal for bacteria to enter the body, specifically streptococcal bacteremia. Historically, prophylactic treatment with antibiotics was used for all patients at high risk for developing IE when undergoing surgical, dental or other invasive procedures. The American Heart Association recommended penicillin prophylaxis in 1955 for patients with congenital heart disease and rheumatic heart disease prior to undergoing any dental procedures. Emerging resistance to antibiotics due to overuse and lack of research to support the use of prophylaxis led the USA and Europe to restrict the use of antibiotics by 2009. The United Kingdom went on to abandon the use of antibiotic prophylaxis entirely. The USA reserves this treatment for those with prosthetic heart valves, prior IE, congenital heart disease and cardiac transplant recipients.
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Affects of Infective Endocarditis
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Infective endocarditis appears to be approximately twice as common in men as women. In the past, disease onset occurred at an average age of 35 years of age. However, with more patients having artificial heart valves and pacemakers, the average age at onset has increased to over 50 years. Infective endocarditis has an incidence rate of 3-10 cases in every 100,000 people. No race or ethnicity is more affected than others. Prognosis of infective endocarditis remains poor despite advances in diagnosis and therapies. Mortality rates are approximately 25% even with the best therapies available.Infective endocarditis most commonly affects people who:For those with heart valve replacements, the risk of infection is highest within the first year after the procedure takes place. Those who have had this type of procedure remain at higher risk for infective endocarditis for the rest of their life compared to those who have not had these procedures.Acute bacterial endocarditis is usually caused by staphylococcus aureus bacteria and occasionally by the bacterial strains brucella and listeria. This form of infective endocarditis, compared to other forms, is more likely to affect normal heart valves.Subacute bacterial endocarditis is usually caused by streptococcal bacteria. This form of the disease usually develops on damaged valves after dental surgery involving infected gums, reproductive or urinary (genitourinary tract) surgery or operations on the gastrointestinal tract. A history of a preceding dental, genital or urologic procedure is common. Symptoms usually begin within two weeks following the procedure, but diagnosis is often delayed because symptoms are subtle and patients may not seek care immediately and because diagnosis can be difficult, especially early in the disease course. A previous history of heart disease is present in most individuals with subacute bacterial endocarditis.In developing countries, heart damage caused by rheumatic heart disease is the leading predisposing condition for infective endocarditis; however in developed countries, rheumatic heart disease is implicated in less than 5% of infective endocarditis cases.Prosthetic valvular endocarditis (PVE) develops in 2% to 3% of individuals in the year following artificial (prosthetic) valve placement or tissue valve replacement, occasionally resulting from organisms accidentally implanted during surgery. The number of reported cases of prosthetic valvular endocarditis is highest with artificial aortic valve replacement. These infections frequently result from contamination during an operation. Approximately 30% of the reported cases are caused by staphylococcus.
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Affects of Infective Endocarditis. Infective endocarditis appears to be approximately twice as common in men as women. In the past, disease onset occurred at an average age of 35 years of age. However, with more patients having artificial heart valves and pacemakers, the average age at onset has increased to over 50 years. Infective endocarditis has an incidence rate of 3-10 cases in every 100,000 people. No race or ethnicity is more affected than others. Prognosis of infective endocarditis remains poor despite advances in diagnosis and therapies. Mortality rates are approximately 25% even with the best therapies available.Infective endocarditis most commonly affects people who:For those with heart valve replacements, the risk of infection is highest within the first year after the procedure takes place. Those who have had this type of procedure remain at higher risk for infective endocarditis for the rest of their life compared to those who have not had these procedures.Acute bacterial endocarditis is usually caused by staphylococcus aureus bacteria and occasionally by the bacterial strains brucella and listeria. This form of infective endocarditis, compared to other forms, is more likely to affect normal heart valves.Subacute bacterial endocarditis is usually caused by streptococcal bacteria. This form of the disease usually develops on damaged valves after dental surgery involving infected gums, reproductive or urinary (genitourinary tract) surgery or operations on the gastrointestinal tract. A history of a preceding dental, genital or urologic procedure is common. Symptoms usually begin within two weeks following the procedure, but diagnosis is often delayed because symptoms are subtle and patients may not seek care immediately and because diagnosis can be difficult, especially early in the disease course. A previous history of heart disease is present in most individuals with subacute bacterial endocarditis.In developing countries, heart damage caused by rheumatic heart disease is the leading predisposing condition for infective endocarditis; however in developed countries, rheumatic heart disease is implicated in less than 5% of infective endocarditis cases.Prosthetic valvular endocarditis (PVE) develops in 2% to 3% of individuals in the year following artificial (prosthetic) valve placement or tissue valve replacement, occasionally resulting from organisms accidentally implanted during surgery. The number of reported cases of prosthetic valvular endocarditis is highest with artificial aortic valve replacement. These infections frequently result from contamination during an operation. Approximately 30% of the reported cases are caused by staphylococcus.
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Related disorders of Infective Endocarditis
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Related disorders of Infective Endocarditis.
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Diagnosis of Infective Endocarditis
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The key step in the diagnosis of endocarditis is obtaining blood cultures before antibiotics are started. People with risk factors for endocarditis, particularly those with prosthetic valves and pacemakers, should know the symptoms of endocarditis and should insist on blood culture when they have an unexplained fever. Diagnosis of infective endocarditis can be done based on pathology or by meeting certain clinical diagnostic criteria. These criteria are known as the Duke Clinical Criteria and a patient must show either: 2 major, 1 major and 3 minor, or 5 minor criteria to be diagnosed with infective endocarditis. These includeMajor Clinical Criteria Minor Clinical CriteriaCardiac CT scan (computed tomography), an imaging test, may be indicated in the event the results of TTE and TEE are inconclusive and clinical presentation is consistent with IE.
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Diagnosis of Infective Endocarditis. The key step in the diagnosis of endocarditis is obtaining blood cultures before antibiotics are started. People with risk factors for endocarditis, particularly those with prosthetic valves and pacemakers, should know the symptoms of endocarditis and should insist on blood culture when they have an unexplained fever. Diagnosis of infective endocarditis can be done based on pathology or by meeting certain clinical diagnostic criteria. These criteria are known as the Duke Clinical Criteria and a patient must show either: 2 major, 1 major and 3 minor, or 5 minor criteria to be diagnosed with infective endocarditis. These includeMajor Clinical Criteria Minor Clinical CriteriaCardiac CT scan (computed tomography), an imaging test, may be indicated in the event the results of TTE and TEE are inconclusive and clinical presentation is consistent with IE.
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Infective Endocarditis
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Therapies of Infective Endocarditis
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Treatment
Without prompt, appropriate treatment, infective endocarditis results in serious heart damage or death. Mortality rate within the first 30 days of infection has been reported to be ~20% but survival without antibiotic therapy is unlikely. Therefore, early diagnosis and aggressive therapy are critical for successful treatment. Therapeutic measures typically include intravenous infusion of high doses of appropriate antibiotic drugs. Antibiotic therapy is needed for at least six or eight weeks and is provided intravenously for at least 2 weeks and often for the entire treatment duration. The specific drugs or drug combinations used may depend upon the bacterium responsible for the infection and other factors (e.g., bacterial strain resistance to certain antibiotics). The specific antibiotics uses in each patient are selected based on the blood culture results and determining which antibiotics kill the specific bacteria isolated in each patient. Often more than one antibiotic is given together to increase effectiveness. The type of antibiotic needed will be determined in consultation with infectious disease specialists. In many affected individuals, antibiotics alone are not sufficient to control the infection, because the antibiotics cannot reach the infected valve material or abscess. In patients with a prosthetic heart valve or other implanted material, surgery is almost always needed to remove the infected artificial material and repair the heart. Surgery also is needed if there is an abscess with blockage of the heart electrical signal, rupture between chambers of the heart, or persistent infection even with antibiotic therapy. In patients with an infected pacemaker or lead, the entire pacemaker system usually needs to be removed to control the infection. Surgery may also be recommended if there is heart failure due to severe valve leakage or if vegetation is large to prevent stroke. In many cases, heart surgery may be recommended urgently, during the same hospitalization. In other patients, surgery may be done at a later date, after completing antibiotic treatment. In 2015, The European Society of Cardiology developed guidelines for the treatment of infective endocarditis. These guidelines provide clear, simple recommendations for health care providers in diagnosis and treatment of IE: https://academic.oup.com/eurheartj/article/36/44/3075/2293384#108779576
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Therapies of Infective Endocarditis. Treatment
Without prompt, appropriate treatment, infective endocarditis results in serious heart damage or death. Mortality rate within the first 30 days of infection has been reported to be ~20% but survival without antibiotic therapy is unlikely. Therefore, early diagnosis and aggressive therapy are critical for successful treatment. Therapeutic measures typically include intravenous infusion of high doses of appropriate antibiotic drugs. Antibiotic therapy is needed for at least six or eight weeks and is provided intravenously for at least 2 weeks and often for the entire treatment duration. The specific drugs or drug combinations used may depend upon the bacterium responsible for the infection and other factors (e.g., bacterial strain resistance to certain antibiotics). The specific antibiotics uses in each patient are selected based on the blood culture results and determining which antibiotics kill the specific bacteria isolated in each patient. Often more than one antibiotic is given together to increase effectiveness. The type of antibiotic needed will be determined in consultation with infectious disease specialists. In many affected individuals, antibiotics alone are not sufficient to control the infection, because the antibiotics cannot reach the infected valve material or abscess. In patients with a prosthetic heart valve or other implanted material, surgery is almost always needed to remove the infected artificial material and repair the heart. Surgery also is needed if there is an abscess with blockage of the heart electrical signal, rupture between chambers of the heart, or persistent infection even with antibiotic therapy. In patients with an infected pacemaker or lead, the entire pacemaker system usually needs to be removed to control the infection. Surgery may also be recommended if there is heart failure due to severe valve leakage or if vegetation is large to prevent stroke. In many cases, heart surgery may be recommended urgently, during the same hospitalization. In other patients, surgery may be done at a later date, after completing antibiotic treatment. In 2015, The European Society of Cardiology developed guidelines for the treatment of infective endocarditis. These guidelines provide clear, simple recommendations for health care providers in diagnosis and treatment of IE: https://academic.oup.com/eurheartj/article/36/44/3075/2293384#108779576
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Overview of IRF6-Related Disorders
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IRF6-related disorders are a group of orofacial clefting disorders including Van der Woude syndrome (VWS) and popliteal pterygium syndrome (PPS). These conditions are caused by mutations in the interferon regulatory factor 6 (IRF6) gene.Individuals with VWS are at the least severe end of the spectrum. They can have lip pits or cleft lip or cleft palate, or any combination of these anomalies. Individuals with PPS usually have the lip pits, cleft lip and/or cleft palate, with additional skin and limb abnormalities including webbed skin (pterygium) on the backs of both legs (popliteal) and between the legs (intercrural), malformation and/or genital anomalies, webbing or fusion of the fingers and/or toes (syndactyly), adhesion of upper and lower jaw (intraoral adhesions), and adhesion of upper and lower eyelids (ankyloblepharon). A cone-shaped fold of skin on the nail of the big toe is a characteristic finding in PPS.
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Overview of IRF6-Related Disorders. IRF6-related disorders are a group of orofacial clefting disorders including Van der Woude syndrome (VWS) and popliteal pterygium syndrome (PPS). These conditions are caused by mutations in the interferon regulatory factor 6 (IRF6) gene.Individuals with VWS are at the least severe end of the spectrum. They can have lip pits or cleft lip or cleft palate, or any combination of these anomalies. Individuals with PPS usually have the lip pits, cleft lip and/or cleft palate, with additional skin and limb abnormalities including webbed skin (pterygium) on the backs of both legs (popliteal) and between the legs (intercrural), malformation and/or genital anomalies, webbing or fusion of the fingers and/or toes (syndactyly), adhesion of upper and lower jaw (intraoral adhesions), and adhesion of upper and lower eyelids (ankyloblepharon). A cone-shaped fold of skin on the nail of the big toe is a characteristic finding in PPS.
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Symptoms of IRF6-Related Disorders
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The symptoms of IRF6-related disorders vary greatly from person to person. Some affected individuals may have mild clinical signs, while others may exhibit a more severe form of the disease (variable expressivity).Individuals with VWS can have lip pits alone, cleft lip or cleft palate alone, or any combination of these anomalies. Lip pits usually occur on the lower lip as paired depressions. Less commonly in VWS, one will see conical elevations of the lip, a single lip pit, partial absence of the teeth, incomplete cleft palate, and restricted movement of the tongue (ankyloglossia).Individuals with PPS typically have a thick web of skin (pterygium) on the backs of both legs (popliteal), extending from the hip (ischial tuberosity) to the heel (calcaneus). In some patients, this abnormal webbing may be present on one leg (unilateral). Such webbing may lead to difficulty walking since full extension of the legs may be limited or the legs may be abnormally rotated (inward or outward).In most patients, webbed skin may also be present between the legs in the area of the upper inner thighs (intercrural pterygium). Certain joints may be permanently fixed in a flexed position (joint contractures), particularly the knees. Infants with PPS may also exhibit webbing or fusion of one or more fingers and/or toes (syndactyly) and some children may have a triangular (pyramidal) fold of skin that covers the toenails, especially of the big toe. Dimples in the skin of the elbows and knees may also be present.PPS may also be associated with abnormalities of the face. Most infants have incomplete closure of the roof of mouth (cleft palate) and/or in the upper lip (cleft lip). Children with cleft palate may also be prone to repeated infections of the middle ear (otitis media). Children with PPS may also have abnormal bands of fibrous tissue on the gums (gingival synechiae) and/or between the upper (maxilla) and lower (mandible) bones of the jaws (syngnathia), causing difficulties in opening the mouth. In addition, some affected individuals may have abnormal fibrous tissue connecting the edges of the eyelids (ankyloblepharon filiform) and may exhibit restricted movement of the tongue (ankyloglossia). Many of these facial abnormalities, especially the presence of a cleft palate, can contribute to feeding problems, breathing difficulties, and/or speech impairment.Individuals affected with PPS may also have abnormalities of the sexual organs (genitalia). In some females, the two long folds of skin on either side of the vaginal opening (labia majora), and/or the uterus may be underdeveloped (hypoplastic). In some patients, the clitoris may be underdeveloped. In some males with this disorder, the scrotum may be abnormally divided (bifid). Rarely, the scrotum may be small (hypoplastic) or absent and, as a result, the testes may remain in the abdomen (undescended testicles). In approximately 40% of affected males who have a scrotum, the testes may also fail to descend from the abdomen into the scrotum (cryptorchidism).In severe cases of PPS, malformations of the arms and legs (extremities) may be present including absence (agenesis) or underdevelopment (hypoplasia) of the fingers and/or toes, abnormal outward (valgus) or inward (varus) bending of the feet, and/or malformation (dysplasia) of the nails.Growth and intelligence are usually normal in IRF6-related disorders. Exceptions would be if the IRF6 genetic change is related to a chromosome change or rearrangement involving the IRF6 gene and other genes.
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Symptoms of IRF6-Related Disorders. The symptoms of IRF6-related disorders vary greatly from person to person. Some affected individuals may have mild clinical signs, while others may exhibit a more severe form of the disease (variable expressivity).Individuals with VWS can have lip pits alone, cleft lip or cleft palate alone, or any combination of these anomalies. Lip pits usually occur on the lower lip as paired depressions. Less commonly in VWS, one will see conical elevations of the lip, a single lip pit, partial absence of the teeth, incomplete cleft palate, and restricted movement of the tongue (ankyloglossia).Individuals with PPS typically have a thick web of skin (pterygium) on the backs of both legs (popliteal), extending from the hip (ischial tuberosity) to the heel (calcaneus). In some patients, this abnormal webbing may be present on one leg (unilateral). Such webbing may lead to difficulty walking since full extension of the legs may be limited or the legs may be abnormally rotated (inward or outward).In most patients, webbed skin may also be present between the legs in the area of the upper inner thighs (intercrural pterygium). Certain joints may be permanently fixed in a flexed position (joint contractures), particularly the knees. Infants with PPS may also exhibit webbing or fusion of one or more fingers and/or toes (syndactyly) and some children may have a triangular (pyramidal) fold of skin that covers the toenails, especially of the big toe. Dimples in the skin of the elbows and knees may also be present.PPS may also be associated with abnormalities of the face. Most infants have incomplete closure of the roof of mouth (cleft palate) and/or in the upper lip (cleft lip). Children with cleft palate may also be prone to repeated infections of the middle ear (otitis media). Children with PPS may also have abnormal bands of fibrous tissue on the gums (gingival synechiae) and/or between the upper (maxilla) and lower (mandible) bones of the jaws (syngnathia), causing difficulties in opening the mouth. In addition, some affected individuals may have abnormal fibrous tissue connecting the edges of the eyelids (ankyloblepharon filiform) and may exhibit restricted movement of the tongue (ankyloglossia). Many of these facial abnormalities, especially the presence of a cleft palate, can contribute to feeding problems, breathing difficulties, and/or speech impairment.Individuals affected with PPS may also have abnormalities of the sexual organs (genitalia). In some females, the two long folds of skin on either side of the vaginal opening (labia majora), and/or the uterus may be underdeveloped (hypoplastic). In some patients, the clitoris may be underdeveloped. In some males with this disorder, the scrotum may be abnormally divided (bifid). Rarely, the scrotum may be small (hypoplastic) or absent and, as a result, the testes may remain in the abdomen (undescended testicles). In approximately 40% of affected males who have a scrotum, the testes may also fail to descend from the abdomen into the scrotum (cryptorchidism).In severe cases of PPS, malformations of the arms and legs (extremities) may be present including absence (agenesis) or underdevelopment (hypoplasia) of the fingers and/or toes, abnormal outward (valgus) or inward (varus) bending of the feet, and/or malformation (dysplasia) of the nails.Growth and intelligence are usually normal in IRF6-related disorders. Exceptions would be if the IRF6 genetic change is related to a chromosome change or rearrangement involving the IRF6 gene and other genes.
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Causes of IRF6-Related Disorders
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Mutations in the interferon regulatory factor 6 (IRF6) gene are associated with IRF6-related disorders.IRF6-related disorders are inherited as autosomal dominant genetic conditions. The autosomes are the 22 pairs of chromosomes similar in both males and females. All autosomal genes are paired with one copy from each parent. Autosomal dominant genetic disorders occur when only one copy of an autosomal gene pair is abnormal and causes the appearance of the disorder. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. Most individuals with IRF6-related disorders have an affected parent. The risk of an affected parent passing the abnormal gene to offspring is about 50% for each pregnancy, with children of both sexes being at equal risk.
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Causes of IRF6-Related Disorders. Mutations in the interferon regulatory factor 6 (IRF6) gene are associated with IRF6-related disorders.IRF6-related disorders are inherited as autosomal dominant genetic conditions. The autosomes are the 22 pairs of chromosomes similar in both males and females. All autosomal genes are paired with one copy from each parent. Autosomal dominant genetic disorders occur when only one copy of an autosomal gene pair is abnormal and causes the appearance of the disorder. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. Most individuals with IRF6-related disorders have an affected parent. The risk of an affected parent passing the abnormal gene to offspring is about 50% for each pregnancy, with children of both sexes being at equal risk.
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Affects of IRF6-Related Disorders
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VWS is the most common single gene cause of cleft lip and palate. The prevalence is in the range of 1/35,000-1/100,000 in Europe and Asia. The prevalence of PPS is approximately 1/300,000.
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Affects of IRF6-Related Disorders. VWS is the most common single gene cause of cleft lip and palate. The prevalence is in the range of 1/35,000-1/100,000 in Europe and Asia. The prevalence of PPS is approximately 1/300,000.
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Related disorders of IRF6-Related Disorders
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Symptoms of the following disorders can be similar to those of IRF6-related disorders. Comparisons may be useful for a differential diagnosis:Van der Woude syndrome 2 (VWS2) is an autosomal dominant orofacial clefting disorder that is nearly identical to VWS. They differ in two ways. First, the phenotypic spectrum of VWS2 is identical to VWS. Thus, it is impossible to distinguish an individual case of VWS from VWS2 based on clinical criteria alone. However, individuals with VWS2 are more likely to have a cleft palate and less likely to have lip pits. Second, VWS2 is a GRHL3-related disorder because it is caused by mutations in the gene that encodes for the transcription factor GRHL3. While 70% of VWS cases are due to mutations in IRF6, 5% of VWS cases are due to mutations in GRHL3. Kabuki syndrome, also called Niikawa-Kuroki syndrome, is a rare disorder characterized by intellectual disability, short stature, unusual facial features (reminiscent of Kabuki make-up), abnormalities of the skeleton and unusual skin ridge patterns on the fingers, toes, palms of the hands and soles of the feet. Cleft lip and cleft palate are relatively common findings in Kabuki syndrome. In addition, cases of Kabuki syndrome were reported to have cleft palate and lip pits, as seen in the IRF6-related disorders. (For more information choose “Kabuki” as your search term in the Rare Disease Database.)Hirschsprung disease (HSCR) is characterized by aganglionic megacolon. However, cases have been reported to include cleft palate, and in one case, a submucous cleft palate and lip pits. (For more information choose “Hirschsprung” as your search term in the Rare Disease Database.)Oro-facio-digital syndrome (OFD) is an X-linked dominant disorder that is lethal in males. Affected females have a highly variable phenotype characterized by oral, facial and digital abnormalities, and can include abnormalities of kidney and brain. The oral abnormalities include, but are not limited to, high-arched or cleft palate and/or median cleft lip. In one reported case, an affected individual had a medial pit in the lower lip. (For more information choose “(For more information choose “Orofaciodigital” as your search term in the Rare Disease Database.)” as your search term in the Rare Disease Database.)Branchio-oculo-facial syndrome (BOFS) is a very rare genetic disorder that is apparent at birth (congenital). The disorder may be characterized by low birth weight; presence of an abnormal pit, observed as an opening (cleft), or tumor-like skin abnormality (hemangiomatous or atrophic skin lesion) behind both ears (postauricular area); distinctive malformations of the head and facial (craniofacial) area; abnormalities of the eyes; premature graying of the scalp hair during adolescence; and/or other abnormalities. Some individuals with BOFS have cleft lip and/or cleft palate while others may have an unusually wide, prominent ridge of the upper lip (philtrum) that resembles a surgically repaired cleft lip (pseudocleft). Additional craniofacial abnormalities may include a broad, misshapen (dysplastic) nose and malformed ears. In individuals with the disorder, characteristic eye (ocular) abnormalities may include unusually small eyes (microphthalmia); clouding of the lenses of the eyes (cataracts); crossing of the eyes at birth (congenital strabismus); widely spaced eyes (ocular hypertelorism); and/or absence of tissue (coloboma) from the colored portion of the eyes (iris), giving the iris a “keyhole” appearance. BOFS is inherited as an autosomal dominant genetic trait. (For more information choose “BOFS” as your search term in the Rare Disease Database.)Bartsocas-Papas syndrome is a disorder that can also include clefts of the lip or palate and pterygia similar to what are seen in PPS. It has a more severe phenotype and can be lethal in some, but not all, cases. It has an autosomal recessive inheritance pattern and was found to have mutations in the RIPK4 gene in at least some cases. In addition, a recent molecular study found that RIPK4 activates IRF6 function, providing a mechanistic rationale for the observed overlapping phenotypes.Isolated cleft lip and palate (iCLP), also called non-syndromic cleft lip and palate, is a disorder that only includes an orofacial cleft and no other abnormality characteristic of a syndrome. Isolated CLP is special because it is related to IRF6-related disorders in two ways, phenotypically and genotypically. It is related phenotypically because as many as 15% of individuals with VWS lack identifiable lip pits. Since these individuals with VWS only have an orofacial cleft, then their phenotype is identical to individuals with iCLP. In most such cases, they were diagnosed with VWS because another affected family member had lip pits along with the orofacial cleft. Thus, clinicians can distinguish these two disorders only through careful analysis of the family pedigree. Isolated CLP is related genotypically to IRF6-related disorders because common DNA variants in IRF6, while they do not cause an IRF6-related disorder, can increase the risk for having an orofacial cleft. The role of IRF6 mutations in iCLP is less clear because of the phenotypic overlap between iCLP and the IRF6-related disorders. Data from 2472 families identified a rare mutation in IRF6 in 0.24-0.44% of apparently iCLP families. Being able to distinguish between the autosomal dominant IRF6-related disorders and iCLP is significant because the recurrence risk for an individual with an iCLP (3%) while higher than the general population risk (0.1%), is much less than a recurrence risk approaching 50% for individuals with IRF6 mutations (i.e., those with IRF6-related disorders (VWS and PPS)).
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Related disorders of IRF6-Related Disorders. Symptoms of the following disorders can be similar to those of IRF6-related disorders. Comparisons may be useful for a differential diagnosis:Van der Woude syndrome 2 (VWS2) is an autosomal dominant orofacial clefting disorder that is nearly identical to VWS. They differ in two ways. First, the phenotypic spectrum of VWS2 is identical to VWS. Thus, it is impossible to distinguish an individual case of VWS from VWS2 based on clinical criteria alone. However, individuals with VWS2 are more likely to have a cleft palate and less likely to have lip pits. Second, VWS2 is a GRHL3-related disorder because it is caused by mutations in the gene that encodes for the transcription factor GRHL3. While 70% of VWS cases are due to mutations in IRF6, 5% of VWS cases are due to mutations in GRHL3. Kabuki syndrome, also called Niikawa-Kuroki syndrome, is a rare disorder characterized by intellectual disability, short stature, unusual facial features (reminiscent of Kabuki make-up), abnormalities of the skeleton and unusual skin ridge patterns on the fingers, toes, palms of the hands and soles of the feet. Cleft lip and cleft palate are relatively common findings in Kabuki syndrome. In addition, cases of Kabuki syndrome were reported to have cleft palate and lip pits, as seen in the IRF6-related disorders. (For more information choose “Kabuki” as your search term in the Rare Disease Database.)Hirschsprung disease (HSCR) is characterized by aganglionic megacolon. However, cases have been reported to include cleft palate, and in one case, a submucous cleft palate and lip pits. (For more information choose “Hirschsprung” as your search term in the Rare Disease Database.)Oro-facio-digital syndrome (OFD) is an X-linked dominant disorder that is lethal in males. Affected females have a highly variable phenotype characterized by oral, facial and digital abnormalities, and can include abnormalities of kidney and brain. The oral abnormalities include, but are not limited to, high-arched or cleft palate and/or median cleft lip. In one reported case, an affected individual had a medial pit in the lower lip. (For more information choose “(For more information choose “Orofaciodigital” as your search term in the Rare Disease Database.)” as your search term in the Rare Disease Database.)Branchio-oculo-facial syndrome (BOFS) is a very rare genetic disorder that is apparent at birth (congenital). The disorder may be characterized by low birth weight; presence of an abnormal pit, observed as an opening (cleft), or tumor-like skin abnormality (hemangiomatous or atrophic skin lesion) behind both ears (postauricular area); distinctive malformations of the head and facial (craniofacial) area; abnormalities of the eyes; premature graying of the scalp hair during adolescence; and/or other abnormalities. Some individuals with BOFS have cleft lip and/or cleft palate while others may have an unusually wide, prominent ridge of the upper lip (philtrum) that resembles a surgically repaired cleft lip (pseudocleft). Additional craniofacial abnormalities may include a broad, misshapen (dysplastic) nose and malformed ears. In individuals with the disorder, characteristic eye (ocular) abnormalities may include unusually small eyes (microphthalmia); clouding of the lenses of the eyes (cataracts); crossing of the eyes at birth (congenital strabismus); widely spaced eyes (ocular hypertelorism); and/or absence of tissue (coloboma) from the colored portion of the eyes (iris), giving the iris a “keyhole” appearance. BOFS is inherited as an autosomal dominant genetic trait. (For more information choose “BOFS” as your search term in the Rare Disease Database.)Bartsocas-Papas syndrome is a disorder that can also include clefts of the lip or palate and pterygia similar to what are seen in PPS. It has a more severe phenotype and can be lethal in some, but not all, cases. It has an autosomal recessive inheritance pattern and was found to have mutations in the RIPK4 gene in at least some cases. In addition, a recent molecular study found that RIPK4 activates IRF6 function, providing a mechanistic rationale for the observed overlapping phenotypes.Isolated cleft lip and palate (iCLP), also called non-syndromic cleft lip and palate, is a disorder that only includes an orofacial cleft and no other abnormality characteristic of a syndrome. Isolated CLP is special because it is related to IRF6-related disorders in two ways, phenotypically and genotypically. It is related phenotypically because as many as 15% of individuals with VWS lack identifiable lip pits. Since these individuals with VWS only have an orofacial cleft, then their phenotype is identical to individuals with iCLP. In most such cases, they were diagnosed with VWS because another affected family member had lip pits along with the orofacial cleft. Thus, clinicians can distinguish these two disorders only through careful analysis of the family pedigree. Isolated CLP is related genotypically to IRF6-related disorders because common DNA variants in IRF6, while they do not cause an IRF6-related disorder, can increase the risk for having an orofacial cleft. The role of IRF6 mutations in iCLP is less clear because of the phenotypic overlap between iCLP and the IRF6-related disorders. Data from 2472 families identified a rare mutation in IRF6 in 0.24-0.44% of apparently iCLP families. Being able to distinguish between the autosomal dominant IRF6-related disorders and iCLP is significant because the recurrence risk for an individual with an iCLP (3%) while higher than the general population risk (0.1%), is much less than a recurrence risk approaching 50% for individuals with IRF6 mutations (i.e., those with IRF6-related disorders (VWS and PPS)).
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Diagnosis of IRF6-Related Disorders
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The diagnosis of IRF6-related disorders is based on physical features with confirmation by molecular genetic testing.A diagnosis of VWS should be considered if a child is born with cleft lip and/or cleft palate, even if lip pits are not present. However, current practice does not include IRF6 sequencing for such individuals because the cost is too high and the yield is too low (<0.5%).
Molecular genetic testing can be used to confirm a diagnosis based on physical features. Traditionally, molecular genetic testing used the Sanger method to sequence each of the 9 exons of IRF6. For VWS, more mutations were identified in exons 3, 4, 7 and 9, suggesting a two-tiered approach for optimal screening. For PPS, nearly all mutations were identified in exons 3, 4 and 9, providing a strong rationale for a two-tiered screening approach. In addition, a mutation was found in MCS9.7 in a family with VWS. MCS9.7 is a 600 bp sequence located 9.7 kb upstream of the IRF6 gene. Studies showed that MCS9.7 is an enhancer element, a DNA sequence that functions as a regulatory switch for producing IRF6 gene products. The mutation identified in this VWS family reduced the activity of the MCS9.7 enhancer, suggesting that it is likely the cause of the phenotype in the affected individuals. Thus, recent molecular genetic testing protocols also include the MCS9.7 region. To date, approximately 70% of individuals with VWS have a detectable mutation in the IRF6 gene. Approximately 97% of individuals with PPS have a detectable mutation in the IRF6 gene.If a diagnosis of a suspected IRF6-related disorder is not molecularly confirmed, at least two hypotheses exist for the inability to find all mutations. First, traditional methods for molecular genetic testing did not screen the entire IRF6 and surrounding region for mutations in potential regulatory sequences. In support of this hypothesis, a highly penetrant mutation in the MCS9.7 enhancer of IRF6 was identified in a family with VWS. Second, mutations in other genes may account for the IRF6-related phenotypes in some families; this includes the 5% of VWS families that have mutations at the VWS2 locus in GRHL3 and 2-3% of PPS cases with mutations in RIPK4 or other genes in related pterygium syndromes (e.g., SFN and IKKA). With time, molecular genetic screens are converting to next generation sequencing platforms that allow whole exomes (all exons in the genome) and whole genomes to be sequenced. These platforms will provide a more complete assessment of the IRF6 gene and regulatory elements in order to find all mutations in IRF6-related disorders.If a diagnosis of an IRF6-related disorder is confirmed, the parents of the affected individual should have a careful physical examination to determine if they have any signs of the disorder. For example, the presence of an abnormality in the lower lip or the presence of the pyramidal skin fold on the nail of the big toe.Prenatal diagnosis and preimplantation genetic diagnosis for IRF6-related disorders is available if a specific IRF6 mutation has been identified. Molecular genetic testing for the specific IRF6 mutation can be performed on fetal cells obtained by amniocentesis at 16-18 weeks gestation or chorionic villus sampling at 10-12 weeks gestation. Preimplantation genetic diagnosis involves in vitro fertilization and testing for a gene mutation in cells taken from a blastocyst. Only those embryos which do not have the mutation will be implanted.
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Diagnosis of IRF6-Related Disorders. The diagnosis of IRF6-related disorders is based on physical features with confirmation by molecular genetic testing.A diagnosis of VWS should be considered if a child is born with cleft lip and/or cleft palate, even if lip pits are not present. However, current practice does not include IRF6 sequencing for such individuals because the cost is too high and the yield is too low (<0.5%).
Molecular genetic testing can be used to confirm a diagnosis based on physical features. Traditionally, molecular genetic testing used the Sanger method to sequence each of the 9 exons of IRF6. For VWS, more mutations were identified in exons 3, 4, 7 and 9, suggesting a two-tiered approach for optimal screening. For PPS, nearly all mutations were identified in exons 3, 4 and 9, providing a strong rationale for a two-tiered screening approach. In addition, a mutation was found in MCS9.7 in a family with VWS. MCS9.7 is a 600 bp sequence located 9.7 kb upstream of the IRF6 gene. Studies showed that MCS9.7 is an enhancer element, a DNA sequence that functions as a regulatory switch for producing IRF6 gene products. The mutation identified in this VWS family reduced the activity of the MCS9.7 enhancer, suggesting that it is likely the cause of the phenotype in the affected individuals. Thus, recent molecular genetic testing protocols also include the MCS9.7 region. To date, approximately 70% of individuals with VWS have a detectable mutation in the IRF6 gene. Approximately 97% of individuals with PPS have a detectable mutation in the IRF6 gene.If a diagnosis of a suspected IRF6-related disorder is not molecularly confirmed, at least two hypotheses exist for the inability to find all mutations. First, traditional methods for molecular genetic testing did not screen the entire IRF6 and surrounding region for mutations in potential regulatory sequences. In support of this hypothesis, a highly penetrant mutation in the MCS9.7 enhancer of IRF6 was identified in a family with VWS. Second, mutations in other genes may account for the IRF6-related phenotypes in some families; this includes the 5% of VWS families that have mutations at the VWS2 locus in GRHL3 and 2-3% of PPS cases with mutations in RIPK4 or other genes in related pterygium syndromes (e.g., SFN and IKKA). With time, molecular genetic screens are converting to next generation sequencing platforms that allow whole exomes (all exons in the genome) and whole genomes to be sequenced. These platforms will provide a more complete assessment of the IRF6 gene and regulatory elements in order to find all mutations in IRF6-related disorders.If a diagnosis of an IRF6-related disorder is confirmed, the parents of the affected individual should have a careful physical examination to determine if they have any signs of the disorder. For example, the presence of an abnormality in the lower lip or the presence of the pyramidal skin fold on the nail of the big toe.Prenatal diagnosis and preimplantation genetic diagnosis for IRF6-related disorders is available if a specific IRF6 mutation has been identified. Molecular genetic testing for the specific IRF6 mutation can be performed on fetal cells obtained by amniocentesis at 16-18 weeks gestation or chorionic villus sampling at 10-12 weeks gestation. Preimplantation genetic diagnosis involves in vitro fertilization and testing for a gene mutation in cells taken from a blastocyst. Only those embryos which do not have the mutation will be implanted.
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Therapies of IRF6-Related Disorders
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TreatmentGenetic counseling is an important intervention for affected individuals and their families. The recurrence risk for IRF6-related disorders is as high as 50%, as expected for autosomal dominant inheritance with high penetrance. In addition, a specific set of mutations in IRF6 (missense mutations that alter amino acids predicted to interact directly with the DNA) are associated with, but not determinate for, PPS. In other words, individuals with VWS who carry one of these PPS-associated mutations, are potentially at risk for having a child with the more severe PPS phenotype. Conversely, individuals with PPS can have a child with the less severe VWS phenotype. At this time, the factors that modify the phenotype in either direction are unknown. Thus, while the risk for having a child with an IRF6-related disorder is predictable, the severity of the phenotype for the at-risk offspring is not predictable. Cleft lip and cleft palate are treated with surgery and orthodontics. Individuals with cleft palate usually also need speech therapy and hearing testing. Lip pits can be surgically excised for cosmetic reasons or for lip function.The treatment of PPS is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians; plastic, orthopedic, and maxillofacial surgeons; speech pathologists; and specialists who treat the ears, nose, and throat (otolaryngologists) may need to systematically and comprehensively plan an affected child's diagnosis and treatment.The webs of skin (pterygium) behind the legs (popliteal) may be surgically removed. Corrective surgery should be performed as early as possible since the webs of skin (pterygium) may limit an affected individual's ability to extend the legs and may inhibit normal walking. However, in many cases, surgery can be complicated, since the bundle of nerves (e.g., sciatic nerve and its branches) and blood vessels that extend down through the legs (neurovascular bundle) may be embedded within the web of skin. In these cases, surgeons must remove the nerves and blood vessels from the extra skin and attempt to place them in their normal location within the legs.The web of skin between the legs (intercrural pterygium) may also be surgically removed, since it may limit the individual's ability to open, close, and independently move the legs, interfering with normal walking. Webbing or fusion of one or more fingers or toes (syndactyly) may also be corrected surgically. Abnormal fibrous strands in the mouth (oral synechiae), such as those connecting the jaws (syngnathia) or gums (gingival synechiae), and abnormal fibrous tissue connecting the edges of the eyelids (ankyloblepharon filiform) may also be surgically corrected.Surgery may also be performed to correct genital abnormalities that may be associated with PPS but may result in infertility. In females, plastic surgery may help to reconstruct the vagina and associated structures (labia majora, clitoris). In males, surgery may be performed to move undescended testes into the scrotum and attach them so that they will not retract (orchiopexy). Plastic surgery may also be performed to correct abnormal division of the scrotum. Treatment with an endocrinologist may be necessary to address the small penis (micropenis) which may also be present.A supportive apparatus that initiates movement (dynamic splint) and/or surgery may be used to treat joint contractures. Physical therapy is also helpful for children who have joint contractures.A team approach for infants with this disorder may be of benefit and may include special social support, speech therapy, physical therapy, and other medical services. Other treatment is symptomatic and supportive. All children born with cleft lip and or cleft palate are best managed by a cleft palate or craniofacial team.
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Therapies of IRF6-Related Disorders. TreatmentGenetic counseling is an important intervention for affected individuals and their families. The recurrence risk for IRF6-related disorders is as high as 50%, as expected for autosomal dominant inheritance with high penetrance. In addition, a specific set of mutations in IRF6 (missense mutations that alter amino acids predicted to interact directly with the DNA) are associated with, but not determinate for, PPS. In other words, individuals with VWS who carry one of these PPS-associated mutations, are potentially at risk for having a child with the more severe PPS phenotype. Conversely, individuals with PPS can have a child with the less severe VWS phenotype. At this time, the factors that modify the phenotype in either direction are unknown. Thus, while the risk for having a child with an IRF6-related disorder is predictable, the severity of the phenotype for the at-risk offspring is not predictable. Cleft lip and cleft palate are treated with surgery and orthodontics. Individuals with cleft palate usually also need speech therapy and hearing testing. Lip pits can be surgically excised for cosmetic reasons or for lip function.The treatment of PPS is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians; plastic, orthopedic, and maxillofacial surgeons; speech pathologists; and specialists who treat the ears, nose, and throat (otolaryngologists) may need to systematically and comprehensively plan an affected child's diagnosis and treatment.The webs of skin (pterygium) behind the legs (popliteal) may be surgically removed. Corrective surgery should be performed as early as possible since the webs of skin (pterygium) may limit an affected individual's ability to extend the legs and may inhibit normal walking. However, in many cases, surgery can be complicated, since the bundle of nerves (e.g., sciatic nerve and its branches) and blood vessels that extend down through the legs (neurovascular bundle) may be embedded within the web of skin. In these cases, surgeons must remove the nerves and blood vessels from the extra skin and attempt to place them in their normal location within the legs.The web of skin between the legs (intercrural pterygium) may also be surgically removed, since it may limit the individual's ability to open, close, and independently move the legs, interfering with normal walking. Webbing or fusion of one or more fingers or toes (syndactyly) may also be corrected surgically. Abnormal fibrous strands in the mouth (oral synechiae), such as those connecting the jaws (syngnathia) or gums (gingival synechiae), and abnormal fibrous tissue connecting the edges of the eyelids (ankyloblepharon filiform) may also be surgically corrected.Surgery may also be performed to correct genital abnormalities that may be associated with PPS but may result in infertility. In females, plastic surgery may help to reconstruct the vagina and associated structures (labia majora, clitoris). In males, surgery may be performed to move undescended testes into the scrotum and attach them so that they will not retract (orchiopexy). Plastic surgery may also be performed to correct abnormal division of the scrotum. Treatment with an endocrinologist may be necessary to address the small penis (micropenis) which may also be present.A supportive apparatus that initiates movement (dynamic splint) and/or surgery may be used to treat joint contractures. Physical therapy is also helpful for children who have joint contractures.A team approach for infants with this disorder may be of benefit and may include special social support, speech therapy, physical therapy, and other medical services. Other treatment is symptomatic and supportive. All children born with cleft lip and or cleft palate are best managed by a cleft palate or craniofacial team.
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IRF6-Related Disorders
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Overview of Isovaleric Acidemia
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SummaryIsovaleric acidemia is a hereditary metabolic disorder, caused by a change (mutation) in the gene encoding the enzyme isovaleryl-CoA dehydrogenase, resulting in deficient or absent activity. This enzyme is responsible for helping break down leucine, an amino acid, and its deficiency leads to a buildup of chemicals in the blood that cause symptoms. The disorder can present with acute intermittent attacks in infancy or later in childhood. The acute attacks are characterized by vomiting, refusal to eat, listlessness, abnormal lab values, and a sweaty foot odor. Chronic symptoms include failure to thrive and developmental delay. Management for this disease includes a low protein diet with leucine restriction, avoiding triggers of acute attacks, and supplementation with carnitine and/or glycine. Though there is no cure, but as patients age, acute attacks become less frequent.
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Overview of Isovaleric Acidemia. SummaryIsovaleric acidemia is a hereditary metabolic disorder, caused by a change (mutation) in the gene encoding the enzyme isovaleryl-CoA dehydrogenase, resulting in deficient or absent activity. This enzyme is responsible for helping break down leucine, an amino acid, and its deficiency leads to a buildup of chemicals in the blood that cause symptoms. The disorder can present with acute intermittent attacks in infancy or later in childhood. The acute attacks are characterized by vomiting, refusal to eat, listlessness, abnormal lab values, and a sweaty foot odor. Chronic symptoms include failure to thrive and developmental delay. Management for this disease includes a low protein diet with leucine restriction, avoiding triggers of acute attacks, and supplementation with carnitine and/or glycine. Though there is no cure, but as patients age, acute attacks become less frequent.
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Symptoms of Isovaleric Acidemia
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Isovaleric acidemia is a rare metabolic disorder that ranges in severity from asymptomatic to mild or life-threatening symptoms depending on the mutation and factors predisposing acute attacks. Two major clinical scenarios are often described, an acute form and a chronic intermittent form, but in reality the disease is best thought of as a continuous spectrum from asymptomatic to life threatening. A characteristic ‘sweaty feet’ odor is often present in patient sweat or cerumen due to a buildup of isovaleric acid. Patients may develop aversion early to protein-rich foods.Acute, early symptoms present soon after birth with increasing lethargy, poor feeding and vomiting, progressing to coma. These findings are related to chemical imbalances in the baby including an increase in acid, ammonia, and specific toxic compounds derived from isovaleric acid. Prolonged metabolic stress can lead to low levels of certain types of white blood cells (neutropenia) and other cell types (pancytopenia). Patients may also present with lowered body temperature (hypothermia). After resolution of this first attack, patients typically show the chronic intermittent form of the disease unless severe neurologic damage has occurred due to the original presentation.After the newborn period chronic intermittent symptoms are usual. Patients can have slowed growth rates (failure to thrive), developmental delay, intellectual disability or symptoms affecting the nervous system such as seizures and spasticity, most commonly related to early acute damage. Patients can also experience acute attacks similar to the newborn period, typically triggered by other illnesses such as infections. Patients can exhibit a chronic picture even if a newborn acute attack has not occurred. Recognition of acute neonatal symptoms has led to newborn screening for isovaleric acidemia in the United States and many other developed studies. If identified prior to the development of symptoms, outcomes are generally better, with normal growth and development. About half of babies identified through newborn screening have a very mild deficiency that remains asymptomatic and requires no therapy.
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Symptoms of Isovaleric Acidemia. Isovaleric acidemia is a rare metabolic disorder that ranges in severity from asymptomatic to mild or life-threatening symptoms depending on the mutation and factors predisposing acute attacks. Two major clinical scenarios are often described, an acute form and a chronic intermittent form, but in reality the disease is best thought of as a continuous spectrum from asymptomatic to life threatening. A characteristic ‘sweaty feet’ odor is often present in patient sweat or cerumen due to a buildup of isovaleric acid. Patients may develop aversion early to protein-rich foods.Acute, early symptoms present soon after birth with increasing lethargy, poor feeding and vomiting, progressing to coma. These findings are related to chemical imbalances in the baby including an increase in acid, ammonia, and specific toxic compounds derived from isovaleric acid. Prolonged metabolic stress can lead to low levels of certain types of white blood cells (neutropenia) and other cell types (pancytopenia). Patients may also present with lowered body temperature (hypothermia). After resolution of this first attack, patients typically show the chronic intermittent form of the disease unless severe neurologic damage has occurred due to the original presentation.After the newborn period chronic intermittent symptoms are usual. Patients can have slowed growth rates (failure to thrive), developmental delay, intellectual disability or symptoms affecting the nervous system such as seizures and spasticity, most commonly related to early acute damage. Patients can also experience acute attacks similar to the newborn period, typically triggered by other illnesses such as infections. Patients can exhibit a chronic picture even if a newborn acute attack has not occurred. Recognition of acute neonatal symptoms has led to newborn screening for isovaleric acidemia in the United States and many other developed studies. If identified prior to the development of symptoms, outcomes are generally better, with normal growth and development. About half of babies identified through newborn screening have a very mild deficiency that remains asymptomatic and requires no therapy.
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Causes of Isovaleric Acidemia
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Isovaleric acidemia is a genetic disorder 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. In patients with isovaleric acidemia, there is a mutation in the IVD gene that inactivates the enzyme isovaleryl-Co-enzyme A (CoA) dehydrogenase. This enzyme is needed for the breakdown of the amino acid leucine into energy.
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Causes of Isovaleric Acidemia. Isovaleric acidemia is a genetic disorder 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. In patients with isovaleric acidemia, there is a mutation in the IVD gene that inactivates the enzyme isovaleryl-Co-enzyme A (CoA) dehydrogenase. This enzyme is needed for the breakdown of the amino acid leucine into energy.
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Affects of Isovaleric Acidemia
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Isovaleric acidemia is a rare disorder that presents either soon after birth or during infancy. It may present up to adolescence. It affects an equal number of males and females. The prevalence of this condition is 1 per 526,000 in Western populations and the incidence is 1 per 250,000 in the US.
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Affects of Isovaleric Acidemia. Isovaleric acidemia is a rare disorder that presents either soon after birth or during infancy. It may present up to adolescence. It affects an equal number of males and females. The prevalence of this condition is 1 per 526,000 in Western populations and the incidence is 1 per 250,000 in the US.
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Related disorders of Isovaleric Acidemia
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Organic acidemias are a group of disorders in which there is a genetic mutation in genes for enzyme(s) responsible for breaking down amino acids. There is an accumulation of organic acid metabolites that cause symptoms in a patient. Many organic acidemias present similarly, including during acute attacks, often in the neonatal period. Below are examples of some organic acidemias.Methylmalonic acidemias may be caused either by a deficiency of the enzyme methylmalonyl-CoA mutase, methylmalonyl racemase, or adenosylcobalamin (a vitamin B12 derivative) synthetic enzymes. Excretion of methylmalonate (a product of amino acid metabolism) in the urine is abnormally high. (For more information, choose “methylmalonic acidemia” as your search term in the Rare Disease Database.)Propionic acidemia is characterized by a deficiency of the coenzyme propionyl CoA carboxylase, one of the enzymes necessary in the process of breaking down amino acids, isoleucine, valine, threonine, and methionine. Propionic acidemia presents most often in the neonatal or infancy period. Acute attacks, without treatment, can lead to dehydration, drowsiness, lethargy, vomiting and in some cases coma. Rarely, this disorder can also present later in life and be associated with less severe symptoms. (For more information on this disorder, choose “propionic acidemia” as your search term in the Rare Disease Database.)Maple syrup urine disease (MSUD) is a hereditary disorder resulting from abnormal metabolism of the three “branched chain” amino acids (BCAAs), leucine, isoleucine, and valine. There are multiple types of MSUD with varying severity and age of onset. Acute attacks (metabolic decompensation), especially without treatment, present as spasticity alternating with poor muscle tone, convulsions, and coma. It derives its name from the odor of the patients’ urine and sweat. (For more information on this disorder, choose “maple syrup urine” as your search term in the Rare Disease Database.)Nonketotic hyperglycinemia is a genetic disorder characterized as an inborn error of amino acid metabolism, specifically glycine. Large amounts of the amino acid glycine accumulate in body fluids, particularly in the cerebrospinal fluid. There are varying presentations of this disorder including a severe classical form which presents with severe, often fatal, illness beginning soon after birth, an attenuated classical form with varying severity of developmental delay, and a variant form whose symptoms depend on the specific gene mutation. (For more information on this disorder, choose “nonketotic hyperglycinemia” as your search term in the Rare Disease Database.)Glutaric aciduria type I (glutaric acidemia type I) is caused by a mutation in the enzyme glutaryl-CoA dehydrogenase (GCDH). This enzyme is involved in the metabolism of the amino acid lysine. It is part of the group of disorders known as cerebral organic acidemias and acute attacks, without treatment, can be characterized by symptoms related to the brain damage (acute encephalopathic crisis) such as confusion, seizures or loss of tone and permanent injury to the brain causing movement problems. It, along with other disorders listed in this section, are part of newborn screening in many US states and countries. (For more information on this disorder, choose “glutaric aciduria type I” as your search term in the Rare Disease Database.)Glutaric aciduria type II (glutaric acidemia II, multiple acyl-CoA dehydrogenase deficiency [MADD]) is characterized by genetic mutations in the metabolism of the vitamin riboflavin, necessary for isovaleryl-CoA dehydrogenase and other related enzymes to properly function. This defect leads to absent or reduced activity of over a dozen enzymes including isovaleryl-CoA dehydrogenase. Symptoms can occur in newborns through adulthood and overlap those of isovalderic acidemia. (For more information on this disorder, choose “glutaric aciduria type II” as your search term in the Rare Disease Database”).There are other organic acidemias that can mimic isovaleric acidemias. A list of many of these disorders can be found on the website of our NORD member organization, Organic Acidemia Association: https://www.oaanews.org/oa-disorders.html
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Related disorders of Isovaleric Acidemia. Organic acidemias are a group of disorders in which there is a genetic mutation in genes for enzyme(s) responsible for breaking down amino acids. There is an accumulation of organic acid metabolites that cause symptoms in a patient. Many organic acidemias present similarly, including during acute attacks, often in the neonatal period. Below are examples of some organic acidemias.Methylmalonic acidemias may be caused either by a deficiency of the enzyme methylmalonyl-CoA mutase, methylmalonyl racemase, or adenosylcobalamin (a vitamin B12 derivative) synthetic enzymes. Excretion of methylmalonate (a product of amino acid metabolism) in the urine is abnormally high. (For more information, choose “methylmalonic acidemia” as your search term in the Rare Disease Database.)Propionic acidemia is characterized by a deficiency of the coenzyme propionyl CoA carboxylase, one of the enzymes necessary in the process of breaking down amino acids, isoleucine, valine, threonine, and methionine. Propionic acidemia presents most often in the neonatal or infancy period. Acute attacks, without treatment, can lead to dehydration, drowsiness, lethargy, vomiting and in some cases coma. Rarely, this disorder can also present later in life and be associated with less severe symptoms. (For more information on this disorder, choose “propionic acidemia” as your search term in the Rare Disease Database.)Maple syrup urine disease (MSUD) is a hereditary disorder resulting from abnormal metabolism of the three “branched chain” amino acids (BCAAs), leucine, isoleucine, and valine. There are multiple types of MSUD with varying severity and age of onset. Acute attacks (metabolic decompensation), especially without treatment, present as spasticity alternating with poor muscle tone, convulsions, and coma. It derives its name from the odor of the patients’ urine and sweat. (For more information on this disorder, choose “maple syrup urine” as your search term in the Rare Disease Database.)Nonketotic hyperglycinemia is a genetic disorder characterized as an inborn error of amino acid metabolism, specifically glycine. Large amounts of the amino acid glycine accumulate in body fluids, particularly in the cerebrospinal fluid. There are varying presentations of this disorder including a severe classical form which presents with severe, often fatal, illness beginning soon after birth, an attenuated classical form with varying severity of developmental delay, and a variant form whose symptoms depend on the specific gene mutation. (For more information on this disorder, choose “nonketotic hyperglycinemia” as your search term in the Rare Disease Database.)Glutaric aciduria type I (glutaric acidemia type I) is caused by a mutation in the enzyme glutaryl-CoA dehydrogenase (GCDH). This enzyme is involved in the metabolism of the amino acid lysine. It is part of the group of disorders known as cerebral organic acidemias and acute attacks, without treatment, can be characterized by symptoms related to the brain damage (acute encephalopathic crisis) such as confusion, seizures or loss of tone and permanent injury to the brain causing movement problems. It, along with other disorders listed in this section, are part of newborn screening in many US states and countries. (For more information on this disorder, choose “glutaric aciduria type I” as your search term in the Rare Disease Database.)Glutaric aciduria type II (glutaric acidemia II, multiple acyl-CoA dehydrogenase deficiency [MADD]) is characterized by genetic mutations in the metabolism of the vitamin riboflavin, necessary for isovaleryl-CoA dehydrogenase and other related enzymes to properly function. This defect leads to absent or reduced activity of over a dozen enzymes including isovaleryl-CoA dehydrogenase. Symptoms can occur in newborns through adulthood and overlap those of isovalderic acidemia. (For more information on this disorder, choose “glutaric aciduria type II” as your search term in the Rare Disease Database”).There are other organic acidemias that can mimic isovaleric acidemias. A list of many of these disorders can be found on the website of our NORD member organization, Organic Acidemia Association: https://www.oaanews.org/oa-disorders.html
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Diagnosis of Isovaleric Acidemia
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In the United States and some developed countries, isovaleric acidemia is routinely identified by newborn screening through a blood test called tandem mass spectrometry, often designated as MS/MS. In other countries, the diagnosis must be suspected clinically before it can be diagnosed. Laboratory studies that can be useful in symptomatic patients include checking for high levels of acid and ketones (ketoacidosis) in blood, high levels of glycine in the blood or urine (hyperglycinemia and hyperglycinuria), high levels of ammonia (hyperammonemia), or low levels of certain white blood cells (neutropenia), platelets (thrombocytopenia) or all blood cell types (pancytopenia). The diagnosis is then confirmed by DNA testing. Less commonly, certain types of cells from the body (white blood cells, skin cells) may be sampled from the patient and tested to confirm decreased or deficient activity of the enzyme isovaleryl-CoA dehydrogenase.In families in whom a previous child has been affected, isovaleric acidemia can be diagnosed before birth (prenatally) by measuring the concentration of abnormal metabolites in amniotic fluid, the activity of the isovaleryl-CoA dehydrogenase enzyme in fluid or tissue samples obtained from the fetus or uterus during pregnancy (amniocentesis or chorionic villus sampling [CVS], or testing of fetal tissue or amniocytes for a DNA changes (mutations) identified in the first child
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Diagnosis of Isovaleric Acidemia. In the United States and some developed countries, isovaleric acidemia is routinely identified by newborn screening through a blood test called tandem mass spectrometry, often designated as MS/MS. In other countries, the diagnosis must be suspected clinically before it can be diagnosed. Laboratory studies that can be useful in symptomatic patients include checking for high levels of acid and ketones (ketoacidosis) in blood, high levels of glycine in the blood or urine (hyperglycinemia and hyperglycinuria), high levels of ammonia (hyperammonemia), or low levels of certain white blood cells (neutropenia), platelets (thrombocytopenia) or all blood cell types (pancytopenia). The diagnosis is then confirmed by DNA testing. Less commonly, certain types of cells from the body (white blood cells, skin cells) may be sampled from the patient and tested to confirm decreased or deficient activity of the enzyme isovaleryl-CoA dehydrogenase.In families in whom a previous child has been affected, isovaleric acidemia can be diagnosed before birth (prenatally) by measuring the concentration of abnormal metabolites in amniotic fluid, the activity of the isovaleryl-CoA dehydrogenase enzyme in fluid or tissue samples obtained from the fetus or uterus during pregnancy (amniocentesis or chorionic villus sampling [CVS], or testing of fetal tissue or amniocytes for a DNA changes (mutations) identified in the first child
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Therapies of Isovaleric Acidemia
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Treatment
While there is no cure of isovaleric acidemia, outcome is usually good if severe neonatal symptoms are avoided or treated rapidly. Patients should be followed regularly by a geneticist or metabolic physician familiar with management of organic acidemias. Frequency of follow-up is determined by the severity of the disease and the frequency of acute attacks. Patient should be monitored for growth, development, and dietary history. Additional testing should include blood acid levels, blood counts, and electrolytes. Additionally, physicians may monitor for complications and do examinations of the nervous system, liver, or other organs. Supplementation with L-carnitine or glycine allows increased removal of acids form the blood by the kidney. Patients typically require a low protein diet to avoid overconsumption of the amino acid leucine. However, patients need enough protein in their diet to meet the body’s demands, which increase over time with growth. However, it may be impossible for patients with severe disease to eat enough natural protein to meet bodily requirements. In this case, use of medical foods that do not include leucine is necessary. A dietician should be available to also help families with creating a low-protein diet for the patient.During acute attacks, protein should be reduced or withheld for 24 hours with a subsequent increase in low protein, high sugar foods to maintain calorie intake. If a patient cannot eat, hospitalization is required so that glucose can be provided by intravenous fluids. Other metabolic abnormalities such as high ammonia may need to be corrected depending on the individual patient’s clinical findings. A return to the patient’s standard diet can usually be achieved over the course of a few days.
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Therapies of Isovaleric Acidemia. Treatment
While there is no cure of isovaleric acidemia, outcome is usually good if severe neonatal symptoms are avoided or treated rapidly. Patients should be followed regularly by a geneticist or metabolic physician familiar with management of organic acidemias. Frequency of follow-up is determined by the severity of the disease and the frequency of acute attacks. Patient should be monitored for growth, development, and dietary history. Additional testing should include blood acid levels, blood counts, and electrolytes. Additionally, physicians may monitor for complications and do examinations of the nervous system, liver, or other organs. Supplementation with L-carnitine or glycine allows increased removal of acids form the blood by the kidney. Patients typically require a low protein diet to avoid overconsumption of the amino acid leucine. However, patients need enough protein in their diet to meet the body’s demands, which increase over time with growth. However, it may be impossible for patients with severe disease to eat enough natural protein to meet bodily requirements. In this case, use of medical foods that do not include leucine is necessary. A dietician should be available to also help families with creating a low-protein diet for the patient.During acute attacks, protein should be reduced or withheld for 24 hours with a subsequent increase in low protein, high sugar foods to maintain calorie intake. If a patient cannot eat, hospitalization is required so that glucose can be provided by intravenous fluids. Other metabolic abnormalities such as high ammonia may need to be corrected depending on the individual patient’s clinical findings. A return to the patient’s standard diet can usually be achieved over the course of a few days.
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Overview of Ivemark Syndrome
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Ivemark syndrome is a rare disorder that affects multiple organ systems of the body. It is characterized by the absence (asplenia) or underdevelopment (hypoplasia) of the spleen, malformations of the heart and the abnormal arrangement of the internal organs of the chest and abdomen. The symptoms of Ivemark syndrome can vary greatly depending upon the specific abnormalities present. Many infants have symptoms associated with abnormalities affecting the heart including bluish discoloration to the skin due to a lack of oxygen in the blood (cyanosis), heart murmurs, and signs of congestive heart failure. Ivemark syndrome often causes life-threatening complications during infancy. The exact cause of Ivemark syndrome is not known.The medical terminology used to describe Ivemark syndrome and related disorders is extremely complicated and confusing. Ivemark syndrome is classified as a heterotaxy disorder or a laterality disorder. These terms refer to the failure of the internal organs of the chest and abdomen to be arranged in the proper location within the body. Additional terms used when discussing Ivemark syndrome may include situs solitus (which refers to the normal positioning of these organs); situs inversus (which refers to the complete reversal of the organs so that those normally on the left side are on the right and vice versa); and situs ambiguous (which refers to the random positioning of the organs, with some in the correct place and others in the wrong location). Ivemark syndrome is usually referred to as a specific form of situs ambiguous.
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Overview of Ivemark Syndrome. Ivemark syndrome is a rare disorder that affects multiple organ systems of the body. It is characterized by the absence (asplenia) or underdevelopment (hypoplasia) of the spleen, malformations of the heart and the abnormal arrangement of the internal organs of the chest and abdomen. The symptoms of Ivemark syndrome can vary greatly depending upon the specific abnormalities present. Many infants have symptoms associated with abnormalities affecting the heart including bluish discoloration to the skin due to a lack of oxygen in the blood (cyanosis), heart murmurs, and signs of congestive heart failure. Ivemark syndrome often causes life-threatening complications during infancy. The exact cause of Ivemark syndrome is not known.The medical terminology used to describe Ivemark syndrome and related disorders is extremely complicated and confusing. Ivemark syndrome is classified as a heterotaxy disorder or a laterality disorder. These terms refer to the failure of the internal organs of the chest and abdomen to be arranged in the proper location within the body. Additional terms used when discussing Ivemark syndrome may include situs solitus (which refers to the normal positioning of these organs); situs inversus (which refers to the complete reversal of the organs so that those normally on the left side are on the right and vice versa); and situs ambiguous (which refers to the random positioning of the organs, with some in the correct place and others in the wrong location). Ivemark syndrome is usually referred to as a specific form of situs ambiguous.
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Ivemark Syndrome
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Symptoms of Ivemark Syndrome
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The symptoms of Ivemark syndrome are due to the abnormal arrangement and malformation of certain internal organs. The organs of the chest and abdomen normally develop with specific left-right asymmetry, which means that the internal organs on the left side of the body are different than those on the right. In Ivemark syndrome, there are several characteristic findings involving the internal organs of the chest and abdomen including misplacement of the liver near the center of the body, abnormal positioning of the intestines (intestinal malrotation), and severe underdevelopment (hypoplasia) or absence (asplenia) of the spleen. Ivemark syndrome may also be known as right isomerism sequence because the left side of the body is identical to the right. For example, the right and left sides of the heart and lungs, which normally are distinct, may not be clearly defined. Infants with Ivemark syndrome often have several heart defects that are present at birth (congenital heart defects) due to the failure of normal right-left asymmetry. The heart is normally located in the middle of the chest. The right and left sides of the heart are different and have different functions. The normal heart has four chambers. The two upper chambers are known as atria; one is located on the left side of the heart and one on the right side. They are separated from each other by a fibrous partition known as the atrial septum. The two lower chambers are known as ventricles; one is located on the left side and the other on the right. They are separated from each other by the ventricular septum. Valves connect the atria (left and right) to their respective ventricles. The valves allow for blood to be pumped through the chambers. Blood travels from the right ventricle through the pulmonary artery to the lungs where it receives oxygen. The blood returns to the heart through pulmonary veins and enters the left ventricle. The left ventricle sends the now oxygen-filled blood into the main artery of the body (aorta). The aorta sends the blood throughout the body.Heart defects commonly associated with Ivemark syndrome include double outlet right ventricle, in which the main artery of the body (aorta) and the main artery of the lungs (pulmonary artery) both arise from the upper right chamber of the heart (ventricle) instead of the left; transposition of the great vessels, in which the aorta and the pulmonary artery are reversed; and ventricular or atrial septal defects, which are “holes” in the thin membrane (septum) that separates the chambers of the heart. These various heart defects may cause a moderate or significant bluish discoloration to the skin of an affected infant due to a lack of oxygen in the blood (cyanosis). Some infants may develop heart murmurs or signs of congestive heart failure such as lack of energy and shortness of breath. The heart abnormalities associated with Ivemark syndrome can cause life-threatening complications early during infancy. Infants with Ivemark syndrome may have an underdeveloped spleen, or the spleen may be missing altogether (asplenia). The spleen is an organ located in upper left part of the abdomen that filters out worn out blood cells. A missing or poorly functioning spleen may leave individuals more susceptible to repeated infections including infection of the blood (sepsis). In some cases, additional findings have been reported including sudden, severe pain in the abdomen (acute abdomen) often due to abnormal twisting or the intestines (volvulus), narrowing (atresia) of the ducts that carry bile from the liver to the gallbladder (biliary atresia) and kidney abnormalities. Alterations of form, size and position of the pancreas may also be anticipated, and, in the rare instance of absence of the pancreas (pancreatic aplasia), total pancreatic insufficiency would be an additional complication of the affected neonate. The pancreas is a small organ located behind the stomach that secretes enzymes that travel to the intestines and aid in digestion. The pancreas also secretes other hormones such as insulin, which helps break down sugar.
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Symptoms of Ivemark Syndrome. The symptoms of Ivemark syndrome are due to the abnormal arrangement and malformation of certain internal organs. The organs of the chest and abdomen normally develop with specific left-right asymmetry, which means that the internal organs on the left side of the body are different than those on the right. In Ivemark syndrome, there are several characteristic findings involving the internal organs of the chest and abdomen including misplacement of the liver near the center of the body, abnormal positioning of the intestines (intestinal malrotation), and severe underdevelopment (hypoplasia) or absence (asplenia) of the spleen. Ivemark syndrome may also be known as right isomerism sequence because the left side of the body is identical to the right. For example, the right and left sides of the heart and lungs, which normally are distinct, may not be clearly defined. Infants with Ivemark syndrome often have several heart defects that are present at birth (congenital heart defects) due to the failure of normal right-left asymmetry. The heart is normally located in the middle of the chest. The right and left sides of the heart are different and have different functions. The normal heart has four chambers. The two upper chambers are known as atria; one is located on the left side of the heart and one on the right side. They are separated from each other by a fibrous partition known as the atrial septum. The two lower chambers are known as ventricles; one is located on the left side and the other on the right. They are separated from each other by the ventricular septum. Valves connect the atria (left and right) to their respective ventricles. The valves allow for blood to be pumped through the chambers. Blood travels from the right ventricle through the pulmonary artery to the lungs where it receives oxygen. The blood returns to the heart through pulmonary veins and enters the left ventricle. The left ventricle sends the now oxygen-filled blood into the main artery of the body (aorta). The aorta sends the blood throughout the body.Heart defects commonly associated with Ivemark syndrome include double outlet right ventricle, in which the main artery of the body (aorta) and the main artery of the lungs (pulmonary artery) both arise from the upper right chamber of the heart (ventricle) instead of the left; transposition of the great vessels, in which the aorta and the pulmonary artery are reversed; and ventricular or atrial septal defects, which are “holes” in the thin membrane (septum) that separates the chambers of the heart. These various heart defects may cause a moderate or significant bluish discoloration to the skin of an affected infant due to a lack of oxygen in the blood (cyanosis). Some infants may develop heart murmurs or signs of congestive heart failure such as lack of energy and shortness of breath. The heart abnormalities associated with Ivemark syndrome can cause life-threatening complications early during infancy. Infants with Ivemark syndrome may have an underdeveloped spleen, or the spleen may be missing altogether (asplenia). The spleen is an organ located in upper left part of the abdomen that filters out worn out blood cells. A missing or poorly functioning spleen may leave individuals more susceptible to repeated infections including infection of the blood (sepsis). In some cases, additional findings have been reported including sudden, severe pain in the abdomen (acute abdomen) often due to abnormal twisting or the intestines (volvulus), narrowing (atresia) of the ducts that carry bile from the liver to the gallbladder (biliary atresia) and kidney abnormalities. Alterations of form, size and position of the pancreas may also be anticipated, and, in the rare instance of absence of the pancreas (pancreatic aplasia), total pancreatic insufficiency would be an additional complication of the affected neonate. The pancreas is a small organ located behind the stomach that secretes enzymes that travel to the intestines and aid in digestion. The pancreas also secretes other hormones such as insulin, which helps break down sugar.
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Causes of Ivemark Syndrome
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The exact cause of Ivemark syndrome is unknown. Most cases seem to occur randomly for no apparent reason (sporadic cases). Researchers believe that multiple factors (e.g., genetic and environmental) play a role in the development of the disorder. Ivemark syndrome has occurred in multiple members of the same family suggesting that an inherited genetic predisposition may have been a factor in the development the disorder in these cases. During embryonic development, the internal organs normally develop and are finally positioned either on the right or left side of the body. In Ivemark syndrome and related disorders, there is a failure to establish this normal left-right asymmetry. Researchers believe that mutations in certain genes essential for the development of normal left-right asymmetry are most likely involved in heterotaxy disorders. Although some genes are known to be involved with heterotaxy, no specific gene(s) have been conclusively linked to Ivemark syndrome. In 1995, researchers identified mutations of the connexin43 gap junction gene in a group of individuals with Ivemark syndrome. However, several other researchers failed to identify this gene mutation in other individuals with Ivemark syndrome. More research is necessary to locate which genes are involved in Ivemark syndrome and to determine the specific, complex factors that cause Ivemark syndrome and other similar disorders.
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Causes of Ivemark Syndrome. The exact cause of Ivemark syndrome is unknown. Most cases seem to occur randomly for no apparent reason (sporadic cases). Researchers believe that multiple factors (e.g., genetic and environmental) play a role in the development of the disorder. Ivemark syndrome has occurred in multiple members of the same family suggesting that an inherited genetic predisposition may have been a factor in the development the disorder in these cases. During embryonic development, the internal organs normally develop and are finally positioned either on the right or left side of the body. In Ivemark syndrome and related disorders, there is a failure to establish this normal left-right asymmetry. Researchers believe that mutations in certain genes essential for the development of normal left-right asymmetry are most likely involved in heterotaxy disorders. Although some genes are known to be involved with heterotaxy, no specific gene(s) have been conclusively linked to Ivemark syndrome. In 1995, researchers identified mutations of the connexin43 gap junction gene in a group of individuals with Ivemark syndrome. However, several other researchers failed to identify this gene mutation in other individuals with Ivemark syndrome. More research is necessary to locate which genes are involved in Ivemark syndrome and to determine the specific, complex factors that cause Ivemark syndrome and other similar disorders.
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Ivemark Syndrome
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Affects of Ivemark Syndrome
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According to the medical literature, Ivemark syndrome affects boys more often than girls. The exact incidence of Ivemark syndrome is unknown. The incidence of laterality disorders taken together is estimated to be 1 in 15,000 people in the general population.
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Affects of Ivemark Syndrome. According to the medical literature, Ivemark syndrome affects boys more often than girls. The exact incidence of Ivemark syndrome is unknown. The incidence of laterality disorders taken together is estimated to be 1 in 15,000 people in the general population.
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Ivemark Syndrome
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nord_642_4
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Related disorders of Ivemark Syndrome
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Symptoms of the following disorders can be similar to those of Ivemark syndrome. Comparisons may be useful for a differential diagnosis.Polysplenia syndrome is a form of heterotaxy that is characterized by congenital heart defects, the presence of multiple, usually underdeveloped, spleens and the location of organs normally found on the left side of the chest and abdomen on the right. Polysplenia syndrome is also known as bilateral left-sidedness sequence or left isomerism sequence and is often grouped with Ivemark syndrome as “heterotaxy syndrome”. As with individuals with Ivemark syndrome, intestinal malrotation may also occur in individuals with polysplenia syndrome. Signs of congestive heart failure such as a moderate or significant bluish discoloration to the skin of an affected infant due to a lack of oxygen in the blood often occur early during infancy and may be the presenting sign of polysplenia syndrome. Some affected infants may develop yellowing of the skin or the whites of the eyes (jaundice) because of narrowing (atresia) or blockage of the tubes that carry bile from the liver to the gallbladder. The multiple spleen found in polysplenia syndrome are usually underdeveloped and do not function properly. Consequently, affected individuals are at risk of developing repeated infections. The exact cause of polysplenia syndrome is unknown. Multiple different factors are believed to cause the development of the disorder. Kartagener syndrome is a rare disorder characterized by chronic inflammation of the sinuses (sinusitis), complete reversal of the internal organs of the chest and abdomen (situs inversus) and bronchiectasis, a condition in which the respiratory passages become enlarged due to mucus build up. Brochiectasis can result in damage and scarring to the respiratory tubes, which allows more mucus and potentially bacteria to build up eventually resulting in chronic respiratory infections. Additional symptoms associated with Kartagener syndrome including underdevelopment or lack of a spleen (asplenia), chronic middle ear infections (otitis media), inflammation of the nasal passages (rhinitis), and improper location of the heart on the right side of the chest (dextrocardia). Kartagener syndrome is caused by defects affecting the cilia, the thin hair-like structures that cover most of the cells in the body. The cilia of cells in the respiratory tract are defective and fail to clear the respiratory passages of mucus and other secretions. Kartagener syndrome is inherited as an autosomal recessive trait. (For more information on this disorder, choose “Kartagener” as your search term in the Rare Disease Database.)X-linked visceral heterotaxy is a rare genetic disorder characterized by various heart defects including the improper location of the heart on the right side of the chest (dextrocardia), complete reversal of the internal organs (situs inversus viscerum) so that they are the opposite side of the body than normal, and the absence of the spleen (asplenia) or the presence of multiple spleens (polysplenia). X-linked visceral heterotaxy is caused by disruptions or changes (mutations) to the zinc finger protein of cerebellum 3 (ZIC3) gene located on the X chromosome.
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Related disorders of Ivemark Syndrome. Symptoms of the following disorders can be similar to those of Ivemark syndrome. Comparisons may be useful for a differential diagnosis.Polysplenia syndrome is a form of heterotaxy that is characterized by congenital heart defects, the presence of multiple, usually underdeveloped, spleens and the location of organs normally found on the left side of the chest and abdomen on the right. Polysplenia syndrome is also known as bilateral left-sidedness sequence or left isomerism sequence and is often grouped with Ivemark syndrome as “heterotaxy syndrome”. As with individuals with Ivemark syndrome, intestinal malrotation may also occur in individuals with polysplenia syndrome. Signs of congestive heart failure such as a moderate or significant bluish discoloration to the skin of an affected infant due to a lack of oxygen in the blood often occur early during infancy and may be the presenting sign of polysplenia syndrome. Some affected infants may develop yellowing of the skin or the whites of the eyes (jaundice) because of narrowing (atresia) or blockage of the tubes that carry bile from the liver to the gallbladder. The multiple spleen found in polysplenia syndrome are usually underdeveloped and do not function properly. Consequently, affected individuals are at risk of developing repeated infections. The exact cause of polysplenia syndrome is unknown. Multiple different factors are believed to cause the development of the disorder. Kartagener syndrome is a rare disorder characterized by chronic inflammation of the sinuses (sinusitis), complete reversal of the internal organs of the chest and abdomen (situs inversus) and bronchiectasis, a condition in which the respiratory passages become enlarged due to mucus build up. Brochiectasis can result in damage and scarring to the respiratory tubes, which allows more mucus and potentially bacteria to build up eventually resulting in chronic respiratory infections. Additional symptoms associated with Kartagener syndrome including underdevelopment or lack of a spleen (asplenia), chronic middle ear infections (otitis media), inflammation of the nasal passages (rhinitis), and improper location of the heart on the right side of the chest (dextrocardia). Kartagener syndrome is caused by defects affecting the cilia, the thin hair-like structures that cover most of the cells in the body. The cilia of cells in the respiratory tract are defective and fail to clear the respiratory passages of mucus and other secretions. Kartagener syndrome is inherited as an autosomal recessive trait. (For more information on this disorder, choose “Kartagener” as your search term in the Rare Disease Database.)X-linked visceral heterotaxy is a rare genetic disorder characterized by various heart defects including the improper location of the heart on the right side of the chest (dextrocardia), complete reversal of the internal organs (situs inversus viscerum) so that they are the opposite side of the body than normal, and the absence of the spleen (asplenia) or the presence of multiple spleens (polysplenia). X-linked visceral heterotaxy is caused by disruptions or changes (mutations) to the zinc finger protein of cerebellum 3 (ZIC3) gene located on the X chromosome.
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Ivemark Syndrome
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Diagnosis of Ivemark Syndrome
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A diagnosis of Ivemark syndrome is made based upon a detailed patient history, a thorough clinical evaluation, identification of characteristic symptoms and a variety of specialized tests. Blood samples may be taken to detect the presence of Howell-Jolly bodies, which are small fragments of DNA found in red blood cells that indicate problems with the function of the spleen (or the lack of a spleen). In addition, a test that uses sound waves to make a picture of the heart (echocardiogram) can confirm the presence and severity of heart defects.Ivemark syndrome can be detected before birth through a fetal ultrasound, a test that uses high-frequency sound waves to create a picture of a developing fetus. A fetal ultrasound can detect specific abnormalities associated with Ivemark syndrome including the lack of a spleen and the presence of heart defects.
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Diagnosis of Ivemark Syndrome. A diagnosis of Ivemark syndrome is made based upon a detailed patient history, a thorough clinical evaluation, identification of characteristic symptoms and a variety of specialized tests. Blood samples may be taken to detect the presence of Howell-Jolly bodies, which are small fragments of DNA found in red blood cells that indicate problems with the function of the spleen (or the lack of a spleen). In addition, a test that uses sound waves to make a picture of the heart (echocardiogram) can confirm the presence and severity of heart defects.Ivemark syndrome can be detected before birth through a fetal ultrasound, a test that uses high-frequency sound waves to create a picture of a developing fetus. A fetal ultrasound can detect specific abnormalities associated with Ivemark syndrome including the lack of a spleen and the presence of heart defects.
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Ivemark Syndrome
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