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nord_1257_1
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Symptoms of Urticaria, Cold
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In cold urticaria, the skin has an abnormal reaction to cold. This may, for instance, occur after exposure to cold weather or to swimming in cold water. The skin usually turns red, and develops welts and itching. This may be accompanied by fever, headache, anxiety, tiredness, and, sometimes, even fainting. Some persons may also have palpitations or wheezing.Symptoms of familial cold urticaria may begin to appear as soon as 30 minutes after exposure to cold. They may persist for up to 48 hours after exposure. The redness and itching of the skin may be accompanied by fever, headache, tiredness, pain in the joints (arthralgia), and the presence of excessive white blood cells (leucocytosis) in the blood.Essential (acquired) cold urticaria consists, according to some clinicians, of several sub-categories such as primary acquired cold urticaria, delayed cold urticaria, localized cold urticaria, reflex cold urticaria or secondary cold urticaria, which are explained below:Primary acquired cold urticaria can occur five to 30 minutes after exposure to cold. The reaction may occur in the cold itself, but more often during the rewarming phase. Itching and reddening of the skin may develop first, followed by a burning sensation. Hives appear, usually lasting 30 minutes. The affected person may also experience headache, palpitations, wheezing or fainting.Delayed cold urticaria may appear several hours after contact with the cold.Localized cold urticaria has been reported to occur after exposure to cold at the sites of previous ragweed injections for allergies or ladybug bites.Reflex cold urticaria is characterized by widespread appearance of welts occurring in response to a drop in body temperature after localized exposure to cold applications (e.g. an ice pack).Secondary cold urticaria can occur in connection with various blood disorders associated with viral infections such as mononucleosis.
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Symptoms of Urticaria, Cold. In cold urticaria, the skin has an abnormal reaction to cold. This may, for instance, occur after exposure to cold weather or to swimming in cold water. The skin usually turns red, and develops welts and itching. This may be accompanied by fever, headache, anxiety, tiredness, and, sometimes, even fainting. Some persons may also have palpitations or wheezing.Symptoms of familial cold urticaria may begin to appear as soon as 30 minutes after exposure to cold. They may persist for up to 48 hours after exposure. The redness and itching of the skin may be accompanied by fever, headache, tiredness, pain in the joints (arthralgia), and the presence of excessive white blood cells (leucocytosis) in the blood.Essential (acquired) cold urticaria consists, according to some clinicians, of several sub-categories such as primary acquired cold urticaria, delayed cold urticaria, localized cold urticaria, reflex cold urticaria or secondary cold urticaria, which are explained below:Primary acquired cold urticaria can occur five to 30 minutes after exposure to cold. The reaction may occur in the cold itself, but more often during the rewarming phase. Itching and reddening of the skin may develop first, followed by a burning sensation. Hives appear, usually lasting 30 minutes. The affected person may also experience headache, palpitations, wheezing or fainting.Delayed cold urticaria may appear several hours after contact with the cold.Localized cold urticaria has been reported to occur after exposure to cold at the sites of previous ragweed injections for allergies or ladybug bites.Reflex cold urticaria is characterized by widespread appearance of welts occurring in response to a drop in body temperature after localized exposure to cold applications (e.g. an ice pack).Secondary cold urticaria can occur in connection with various blood disorders associated with viral infections such as mononucleosis.
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nord_1257_2
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Causes of Urticaria, Cold
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Cold urticaria can occur for unknown (idiopathic) reasons, or it may be transmitted as an autosomal dominant trait. 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 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. The familial form of cold urticaria has been traced to the long arm of chromosome one (1q40). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females.Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q”. Chromosomes are further subdivided into bands that are numbered. For example, chromosome 1q40 refers to band 40 on the long arm of chromosome 1.Some forms of cold urticaria are also diseases of the autoimmune system. Autoimmune disorders are caused when the body's natural defenses against “foreign” or invading organisms (e.g., antibodies) begin to attack healthy tissue for unknown reasons.Exposure of the skin to cold triggers symptoms of the disorder. Even such commonplace activities as walking in cold weather, swimming in cold water, or even bathing in cool water may trigger an episode.
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Causes of Urticaria, Cold. Cold urticaria can occur for unknown (idiopathic) reasons, or it may be transmitted as an autosomal dominant trait. 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 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. The familial form of cold urticaria has been traced to the long arm of chromosome one (1q40). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females.Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q”. Chromosomes are further subdivided into bands that are numbered. For example, chromosome 1q40 refers to band 40 on the long arm of chromosome 1.Some forms of cold urticaria are also diseases of the autoimmune system. Autoimmune disorders are caused when the body's natural defenses against “foreign” or invading organisms (e.g., antibodies) begin to attack healthy tissue for unknown reasons.Exposure of the skin to cold triggers symptoms of the disorder. Even such commonplace activities as walking in cold weather, swimming in cold water, or even bathing in cool water may trigger an episode.
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Urticaria, Cold
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nord_1257_3
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Affects of Urticaria, Cold
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Cold urticaria affects males and females in equal numbers. Essential cold urticaria makes up about 1% to 3% of all urticaria cases, and occurs most often among young adults. Familial cold urticaria is rare.
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Affects of Urticaria, Cold. Cold urticaria affects males and females in equal numbers. Essential cold urticaria makes up about 1% to 3% of all urticaria cases, and occurs most often among young adults. Familial cold urticaria is rare.
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Urticaria, Cold
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nord_1257_4
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Related disorders of Urticaria, Cold
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Symptoms of the following disorders can be similar to those of Cold Urticaria. Comparisons may be useful for a differential diagnosis:Raynaud's Disease is a vascular disorder that is triggered by exposure to cold. It is characterized by spasms of blood vessels occurring especially in the fingers and toes. Intermittent attacks of pain, pallor or blue coloring (cyanosis) of the fingers or toes are precipitated by exposure to cold or by emotional upsets. The attacks last for minutes to hours, but are rarely severe enough to result in tissue loss. Rewarming the affected digits results in normal blood circulation and a return to normal color and sensation. Onset usually occurs in the first or second decade of life. (For more information on this disorder, choose “Raynaud” as your search term in the Rare Disease Database.)Cold Agglutination Disease is a blood disorder which occurs when the temperature of the blood is below body temperature. It is most pronounced below 25 C. Although it is seen occasionally in the blood of apparently healthy persons, it is more frequent in individuals with scarlet fever, staphylococcal infections, primary atypical pneumonia, certain hemolytic anemias, and trypanosomiasis.Paroxysmal Cold Hemoglobinuria is a disorder that makes the red blood corpuscles abnormally susceptible to antibodies which try to destroy them. It is triggered by exposure to cold. (For more information on thia disorder, chooose “Hemoglobinuria” as your search term in the Rare Disease Database.)
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Related disorders of Urticaria, Cold. Symptoms of the following disorders can be similar to those of Cold Urticaria. Comparisons may be useful for a differential diagnosis:Raynaud's Disease is a vascular disorder that is triggered by exposure to cold. It is characterized by spasms of blood vessels occurring especially in the fingers and toes. Intermittent attacks of pain, pallor or blue coloring (cyanosis) of the fingers or toes are precipitated by exposure to cold or by emotional upsets. The attacks last for minutes to hours, but are rarely severe enough to result in tissue loss. Rewarming the affected digits results in normal blood circulation and a return to normal color and sensation. Onset usually occurs in the first or second decade of life. (For more information on this disorder, choose “Raynaud” as your search term in the Rare Disease Database.)Cold Agglutination Disease is a blood disorder which occurs when the temperature of the blood is below body temperature. It is most pronounced below 25 C. Although it is seen occasionally in the blood of apparently healthy persons, it is more frequent in individuals with scarlet fever, staphylococcal infections, primary atypical pneumonia, certain hemolytic anemias, and trypanosomiasis.Paroxysmal Cold Hemoglobinuria is a disorder that makes the red blood corpuscles abnormally susceptible to antibodies which try to destroy them. It is triggered by exposure to cold. (For more information on thia disorder, chooose “Hemoglobinuria” as your search term in the Rare Disease Database.)
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Urticaria, Cold
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nord_1257_5
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Diagnosis of Urticaria, Cold
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Cold urticaria may be diagnosed by placing an ice cube on the skin of the subject's forearm for about four or five minutes. A positive response is indicated by the appearance of a "hive" in the shape of the ice cube, within 10 minutes after the stimulus is removed. This two-step process suggests that exposure to cold is required, but hive formation actually occurs as the skin temperature rises.A negative response does NOT rule out Familial Cold urticaria. In some cases, cold-air exposure for 20 to 30 minutes is required to bring out the characteristic response.
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Diagnosis of Urticaria, Cold. Cold urticaria may be diagnosed by placing an ice cube on the skin of the subject's forearm for about four or five minutes. A positive response is indicated by the appearance of a "hive" in the shape of the ice cube, within 10 minutes after the stimulus is removed. This two-step process suggests that exposure to cold is required, but hive formation actually occurs as the skin temperature rises.A negative response does NOT rule out Familial Cold urticaria. In some cases, cold-air exposure for 20 to 30 minutes is required to bring out the characteristic response.
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Urticaria, Cold
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nord_1257_6
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Therapies of Urticaria, Cold
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TherapyTreatment consists of patient education, stimulus avoidance and medication. The newer antihistamines (H1 receptor blockers) may be very effective. H2 receptor blockers such as Tegamet may also be effective. The induction of tolerance by repeated regional or generalized cold exposure has had variable results. If attempted at all, such cold exposure should be performed on an in-patient basis and requires a well-motivated patient.Treatment of cold urticaria may include the use of the drugs epinephrine, diphenhydramine, cyproheptadine, hydrochloride and cetirizine. Symptoms may be prevented with the use of warm clothing during cold weather. The avoidance of cold baths, swimming in cold water, etc., is recommended since loss of consciousness may occur in extreme cases, possibly even resulting in drowning.
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Therapies of Urticaria, Cold. TherapyTreatment consists of patient education, stimulus avoidance and medication. The newer antihistamines (H1 receptor blockers) may be very effective. H2 receptor blockers such as Tegamet may also be effective. The induction of tolerance by repeated regional or generalized cold exposure has had variable results. If attempted at all, such cold exposure should be performed on an in-patient basis and requires a well-motivated patient.Treatment of cold urticaria may include the use of the drugs epinephrine, diphenhydramine, cyproheptadine, hydrochloride and cetirizine. Symptoms may be prevented with the use of warm clothing during cold weather. The avoidance of cold baths, swimming in cold water, etc., is recommended since loss of consciousness may occur in extreme cases, possibly even resulting in drowning.
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Urticaria, Cold
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nord_1258_0
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Overview of Urticaria, Papular
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Papular urticaria, usually called hives, is characterized by large numbers of very itchy red bumps (papules) that come and go every few days over a period of a month or so. The bumps are usually between 0.2 and 2 cm. in size and some may develop into fluid-filled blisters (bullae). This condition is usually triggered by allergic reactions to insect bites, sensitivity to drugs, or other environmental causes. In some cases, swelling of the soft tissues of the face, neck, and hands (angioedema) may also occur.Because it is difficult for children and adults to resist scratching these itchy crusted bumps, the possibility of infection is great and caution must be taken. Papular urticaria may accompany, or even be the first symptom of various viral infections including hepatitis, infectious mononucleosis, or German measles (rubella). Some acute reactions are unexplained, even when recurrent.
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Overview of Urticaria, Papular. Papular urticaria, usually called hives, is characterized by large numbers of very itchy red bumps (papules) that come and go every few days over a period of a month or so. The bumps are usually between 0.2 and 2 cm. in size and some may develop into fluid-filled blisters (bullae). This condition is usually triggered by allergic reactions to insect bites, sensitivity to drugs, or other environmental causes. In some cases, swelling of the soft tissues of the face, neck, and hands (angioedema) may also occur.Because it is difficult for children and adults to resist scratching these itchy crusted bumps, the possibility of infection is great and caution must be taken. Papular urticaria may accompany, or even be the first symptom of various viral infections including hepatitis, infectious mononucleosis, or German measles (rubella). Some acute reactions are unexplained, even when recurrent.
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Urticaria, Papular
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nord_1258_1
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Symptoms of Urticaria, Papular
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The first symptom of papular urticaria is usually itching (pruritus). This is followed shortly by the appearance of elevated ridges (wheals) that may remain small or become large. The larger wheals tend to be clear in the center, and may be noticed first as large rings of redness of the skin (erythema) and swelling (edema). Ordinarily, crops of hives come and go. A lesion may remain for several hours, then disappear only to reappear elsewhere.Angioedema is a more diffuse swelling of loose tissue under the skin usually affecting the back of hands or feet, lips, genitalia and mucous membranes. Swelling (edema) of the upper airway may produce respiratory distress, and the high-pitched tone of difficult breathing may be mistaken for asthma.
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Symptoms of Urticaria, Papular. The first symptom of papular urticaria is usually itching (pruritus). This is followed shortly by the appearance of elevated ridges (wheals) that may remain small or become large. The larger wheals tend to be clear in the center, and may be noticed first as large rings of redness of the skin (erythema) and swelling (edema). Ordinarily, crops of hives come and go. A lesion may remain for several hours, then disappear only to reappear elsewhere.Angioedema is a more diffuse swelling of loose tissue under the skin usually affecting the back of hands or feet, lips, genitalia and mucous membranes. Swelling (edema) of the upper airway may produce respiratory distress, and the high-pitched tone of difficult breathing may be mistaken for asthma.
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Urticaria, Papular
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nord_1258_2
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Causes of Urticaria, Papular
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Acute papular urticaria and angioedema are essentially exaggerated allergic reactions limited to the skin and tissues just under the skin (subcutaneous tissues). The reaction may be caused by a drug allergy, by insect stings or bites, by desensitization injections (allergy shots) or ingestion of certain foods (particularly eggs, shellfish, nuts or fruits) by people who are allergic to these substances. In some cases (such as reactions to strawberries), the reaction may occur only after overindulgence, and possibly result from direct toxic histamine release into the blood. If acute angioedema is recurrent, progressive, and never associated with urticaria, a hereditary enzyme deficiency should be suspected.
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Causes of Urticaria, Papular. Acute papular urticaria and angioedema are essentially exaggerated allergic reactions limited to the skin and tissues just under the skin (subcutaneous tissues). The reaction may be caused by a drug allergy, by insect stings or bites, by desensitization injections (allergy shots) or ingestion of certain foods (particularly eggs, shellfish, nuts or fruits) by people who are allergic to these substances. In some cases (such as reactions to strawberries), the reaction may occur only after overindulgence, and possibly result from direct toxic histamine release into the blood. If acute angioedema is recurrent, progressive, and never associated with urticaria, a hereditary enzyme deficiency should be suspected.
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Urticaria, Papular
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nord_1258_3
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Affects of Urticaria, Papular
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Children from 2 to 7 years are most commonly, but not exclusively, affected by papular urticaria. Children are especially susceptible in the summertime when the insect population increases. It is more rare in adults, perhaps in part because adults build up a tolerance.
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Affects of Urticaria, Papular. Children from 2 to 7 years are most commonly, but not exclusively, affected by papular urticaria. Children are especially susceptible in the summertime when the insect population increases. It is more rare in adults, perhaps in part because adults build up a tolerance.
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Urticaria, Papular
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nord_1258_4
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Related disorders of Urticaria, Papular
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Physical urticaria is a condition in which red allergic skin lesions and itching are produced by exposure to cold temperatures, water or mild trauma.Cholinergic urticaria is a condition characterized by red spots on the skin, itching and possibly abdominal cramps, diarrhea, faintness, weakness and sweating. It is caused by sensitivity to heat, sunlight, exercise, etc. For more information on these disorders and other types of urticaria, choose “urticaria” as your search term in the Rare Disease Database.)
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Related disorders of Urticaria, Papular. Physical urticaria is a condition in which red allergic skin lesions and itching are produced by exposure to cold temperatures, water or mild trauma.Cholinergic urticaria is a condition characterized by red spots on the skin, itching and possibly abdominal cramps, diarrhea, faintness, weakness and sweating. It is caused by sensitivity to heat, sunlight, exercise, etc. For more information on these disorders and other types of urticaria, choose “urticaria” as your search term in the Rare Disease Database.)
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Urticaria, Papular
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nord_1258_5
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Diagnosis of Urticaria, Papular
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Diagnosis of Urticaria, Papular.
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Urticaria, Papular
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nord_1258_6
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Therapies of Urticaria, Papular
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Acute papular urticaria is a self-limited condition that generally subsides in 1 to 7 days. Therefore, treatment is chiefly symptomatic. If the cause is not obvious, all nonessential medication should be stopped until the reaction has subsided. Symptoms such as itching and swelling can usually be relieved with a topical soothing agent such as calamine lotion or oral antihistamine. Corticosteroids (e.g. prednisone) may be necessary for the more severe reactions, particularly when associated with angioedema. Topical corticosteroids are of no value. More serious attacks may bring on airway obstruction that may require an opening in the trachea (tracheotomy).Although the specific cause of chronic papular urticaria can seldom be identified and removed, spontaneous remissions usually occur within 2 years in about half of the cases. Control of stressful life situations often helps. Certain drugs (e.g. aspirin) may aggravate symptoms, as can alcoholic beverages, coffee and tobacco. If so, they should be avoided.Oral antihistamines are beneficial in most cases. All reasonable measures should be used before resorting to corticosteroids, which are frequently effective but have significant side effects after chronic use. A few patients with urticaria that doesn't respond to treatment (intractable) may have a hyperthyroid condition.
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Therapies of Urticaria, Papular. Acute papular urticaria is a self-limited condition that generally subsides in 1 to 7 days. Therefore, treatment is chiefly symptomatic. If the cause is not obvious, all nonessential medication should be stopped until the reaction has subsided. Symptoms such as itching and swelling can usually be relieved with a topical soothing agent such as calamine lotion or oral antihistamine. Corticosteroids (e.g. prednisone) may be necessary for the more severe reactions, particularly when associated with angioedema. Topical corticosteroids are of no value. More serious attacks may bring on airway obstruction that may require an opening in the trachea (tracheotomy).Although the specific cause of chronic papular urticaria can seldom be identified and removed, spontaneous remissions usually occur within 2 years in about half of the cases. Control of stressful life situations often helps. Certain drugs (e.g. aspirin) may aggravate symptoms, as can alcoholic beverages, coffee and tobacco. If so, they should be avoided.Oral antihistamines are beneficial in most cases. All reasonable measures should be used before resorting to corticosteroids, which are frequently effective but have significant side effects after chronic use. A few patients with urticaria that doesn't respond to treatment (intractable) may have a hyperthyroid condition.
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Urticaria, Papular
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nord_1259_0
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Overview of Urticaria, Physical
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Physical urticaria is a condition in which red (erythematous) allergic skin lesions and itching (pruritus) are produced by exposure to heat, cold, or contact with chemicals or plants. These are called wheals by the medical community and may range in size from a couple of millimeters to a couple of centimeters. The center of the lesion may range in color from white to red, and it is usually surrounded by a flare of red skin. The disorder occurs most commonly in children.
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Overview of Urticaria, Physical. Physical urticaria is a condition in which red (erythematous) allergic skin lesions and itching (pruritus) are produced by exposure to heat, cold, or contact with chemicals or plants. These are called wheals by the medical community and may range in size from a couple of millimeters to a couple of centimeters. The center of the lesion may range in color from white to red, and it is usually surrounded by a flare of red skin. The disorder occurs most commonly in children.
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Urticaria, Physical
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nord_1259_1
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Symptoms of Urticaria, Physical
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The most common symptoms of physical urticaria are itching (pruritus) and hives consisting of red rings around white ridges (wheals). Sensitivity to cold is usually manifested by these eruptions on the skin, itching, and swelling under the skin (angioedema). These symptoms develop most typically after exposure to cold is terminated and during or after swimming or bathing. Contraction of the muscles around the bronchi (bronchospasm) and even histamine-mediated shock may occur in extreme cases. If this happens during swimming, drowning may present a danger.Sensitivity to cold can be passively transferred with serum that contains a specific immunoglobulin (IgE) antibody, suggesting an allergic reaction involving a physically altered skin protein as the cause of the allergic reaction. The serum of a few patients with cold-induced symptoms of physical urticaria contains cryoglobulins or cryofibrinogen, these abnormal proteins can also be associated with a serious underlying disorder such as a malignancy, a collagen vascular disease, or chronic infection. Cold may aggravate asthma or vasomotor rhinitis, but cold urticaria is independent of any other known allergic tendencies.Dermatographia, dermographism, or autographism describes welts or wheels produced by scratching or firmly stroking the skin. According to some dermatologists, dermographism is the most common form of physical urticaria. This sign can appear quite suddenly and may become apparent in hot weather or after a hot shower or bath. Occasionally it is the first sign of an urticarial drug reaction. Physical urticaria has also occurred following persistent vibration of the skin, and even after exposure to water (aquagenic urticaria).
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Symptoms of Urticaria, Physical. The most common symptoms of physical urticaria are itching (pruritus) and hives consisting of red rings around white ridges (wheals). Sensitivity to cold is usually manifested by these eruptions on the skin, itching, and swelling under the skin (angioedema). These symptoms develop most typically after exposure to cold is terminated and during or after swimming or bathing. Contraction of the muscles around the bronchi (bronchospasm) and even histamine-mediated shock may occur in extreme cases. If this happens during swimming, drowning may present a danger.Sensitivity to cold can be passively transferred with serum that contains a specific immunoglobulin (IgE) antibody, suggesting an allergic reaction involving a physically altered skin protein as the cause of the allergic reaction. The serum of a few patients with cold-induced symptoms of physical urticaria contains cryoglobulins or cryofibrinogen, these abnormal proteins can also be associated with a serious underlying disorder such as a malignancy, a collagen vascular disease, or chronic infection. Cold may aggravate asthma or vasomotor rhinitis, but cold urticaria is independent of any other known allergic tendencies.Dermatographia, dermographism, or autographism describes welts or wheels produced by scratching or firmly stroking the skin. According to some dermatologists, dermographism is the most common form of physical urticaria. This sign can appear quite suddenly and may become apparent in hot weather or after a hot shower or bath. Occasionally it is the first sign of an urticarial drug reaction. Physical urticaria has also occurred following persistent vibration of the skin, and even after exposure to water (aquagenic urticaria).
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Urticaria, Physical
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nord_1259_2
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Causes of Urticaria, Physical
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The underlying cause of physical urticaria is unknown in most cases. Some clinicians believe that an auto-immunological process is responsible.
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Causes of Urticaria, Physical. The underlying cause of physical urticaria is unknown in most cases. Some clinicians believe that an auto-immunological process is responsible.
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Urticaria, Physical
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nord_1259_3
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Affects of Urticaria, Physical
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Cold urticaria occurs most often in infants, although it sometimes occurs in adults.
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Affects of Urticaria, Physical. Cold urticaria occurs most often in infants, although it sometimes occurs in adults.
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Urticaria, Physical
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nord_1259_4
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Related disorders of Urticaria, Physical
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Cholinergic urticaria is a specific physical urticaria characterized by red spots on the skin, hives, itching and sometimes abdominal cramps, diarrhea, faintness, and weakness. Symptoms come about as a result of sweating from exposure to heat, sunlight, exercise, etc.Papular urticaria, more commonly known as hives, is characterized by local elevated ridges (wheals) and redness (erythema) of the skin, usually caused by allergic reactions to insect bites, sensitivity to drugs or other environmental causes. (For more information on this disorder, choose “physical urticaria” as your search term in the Rare Disease Database.)Aquagenic urticaria is an itching condition caused by exposure to water. It is another physical urticaria. Contact urticaria refers to the non-allergic stinging reaction to certain plants, animals or medicines. Contact dermatitis is an acute or chronic inflammation of the skin, often sharply demarcated, produced by substances in contact with the skin to which a person is allergic. (For more information on this disorder, choose “Contact Dermatitis” as your search term in the Rare Disease Database.)
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Related disorders of Urticaria, Physical. Cholinergic urticaria is a specific physical urticaria characterized by red spots on the skin, hives, itching and sometimes abdominal cramps, diarrhea, faintness, and weakness. Symptoms come about as a result of sweating from exposure to heat, sunlight, exercise, etc.Papular urticaria, more commonly known as hives, is characterized by local elevated ridges (wheals) and redness (erythema) of the skin, usually caused by allergic reactions to insect bites, sensitivity to drugs or other environmental causes. (For more information on this disorder, choose “physical urticaria” as your search term in the Rare Disease Database.)Aquagenic urticaria is an itching condition caused by exposure to water. It is another physical urticaria. Contact urticaria refers to the non-allergic stinging reaction to certain plants, animals or medicines. Contact dermatitis is an acute or chronic inflammation of the skin, often sharply demarcated, produced by substances in contact with the skin to which a person is allergic. (For more information on this disorder, choose “Contact Dermatitis” as your search term in the Rare Disease Database.)
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Urticaria, Physical
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nord_1259_5
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Diagnosis of Urticaria, Physical
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The patient history and physical examination are the tools most often used to diagnose physical urticaria. If there is a history of reactions to physical triggers, the diagnosis may be confirmed with a challenge. The challenge is the application of the suspected agent, for example ice or light, to the skin, in hope of getting a response.
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Diagnosis of Urticaria, Physical. The patient history and physical examination are the tools most often used to diagnose physical urticaria. If there is a history of reactions to physical triggers, the diagnosis may be confirmed with a challenge. The challenge is the application of the suspected agent, for example ice or light, to the skin, in hope of getting a response.
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Urticaria, Physical
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nord_1259_6
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Therapies of Urticaria, Physical
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TreatmentProtection from and avoidance of the physical cause of the reaction is necessary. Symptoms such as itching and swelling can usually be relieved with an oral antihistamine. The more powerful systematic (intravenous) corticosteroids should be avoided unless they are vital.
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Therapies of Urticaria, Physical. TreatmentProtection from and avoidance of the physical cause of the reaction is necessary. Symptoms such as itching and swelling can usually be relieved with an oral antihistamine. The more powerful systematic (intravenous) corticosteroids should be avoided unless they are vital.
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Urticaria, Physical
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nord_1260_0
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Overview of Usher Syndrome
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Summary
Usher syndrome is a rare genetic disorder primarily characterized by deafness due to an impaired ability of the inner ear and auditory nerves to transmit sensory (sound) input to the brain (sensorineual hearing loss) accompanied by retinitis pigmentosa, a disorder that affects the retina and causes progressive loss of vision. Researchers have identified three clinical types of Usher syndrome. The age at which the symptoms appear and the severity of symptoms that distinguishes the different types of Usher syndrome are determined by the underlying genetic cause. Usher syndrome is inherited in an autosomal recessive pattern.Introduction
Usher syndrome was first described in 1858 by Albrecht Von Graefe, but was named for Charles Usher, a Scottish eye doctor who identified the disorder’s hereditary nature and recessive inheritance pattern.
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Overview of Usher Syndrome. Summary
Usher syndrome is a rare genetic disorder primarily characterized by deafness due to an impaired ability of the inner ear and auditory nerves to transmit sensory (sound) input to the brain (sensorineual hearing loss) accompanied by retinitis pigmentosa, a disorder that affects the retina and causes progressive loss of vision. Researchers have identified three clinical types of Usher syndrome. The age at which the symptoms appear and the severity of symptoms that distinguishes the different types of Usher syndrome are determined by the underlying genetic cause. Usher syndrome is inherited in an autosomal recessive pattern.Introduction
Usher syndrome was first described in 1858 by Albrecht Von Graefe, but was named for Charles Usher, a Scottish eye doctor who identified the disorder’s hereditary nature and recessive inheritance pattern.
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Usher Syndrome
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Symptoms of Usher Syndrome
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Usher syndrome is characterized by deafness due to an impaired ability of the inner ear and auditory nerves to transmit sensory (sound) input to the brain (sensorineural hearing loss) as well as abnormal accumulation of colored (pigmented) material on the nerve-rich membrane (the retina) lining the eyes (retinitis pigmentosa or RP). RP eventually causes retinal degeneration leading to progressive loss of vision and legal blindness. Sensorineural hearing loss may be profound or mild and may be progressive. The vision loss caused by RP may begin during childhood or later during life, and often first presents with difficulty seeing at night or in low light (“night blindness”). Studies show that clear central vision may be maintained for many years even while side (peripheral) vision decreases. These narrowed visual fields are also referred to as “tunnel vision.” Issues with balance are seen mainly in individuals with Usher syndrome types 1 and 3, although balance difficulties in Usher syndrome type 2 have been reported. Usher syndrome type 1 is characterized by severe to profound hearing loss in both ears at birth (congenital deafness) and balance problems. Many affected children do not learn to walk until 18 months of age or later. Vision problems usually begin at approximately ten years of age to early teens, although some parents report onset in children younger than 10. Usher syndrome type 2 is characterized by moderate to severe hearing loss in both ears at birth. In some people, hearing loss may worsen over time. Onset of night blindness occurs during the late teens or early twenties. Peripheral vision loss is ongoing, but central vision is usually retained into adulthood. Visual problems associated with Usher syndrome type 2 tend to progress more slowly than those associated with type 1.Usher syndrome type 3 is characterized by later onset hearing loss, variable vestibular (balance) dysfunction and RP that can present between the second and fourth decade of life. Balance issues occur in approximately 50% of individuals with Usher syndrome type 3.
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Symptoms of Usher Syndrome. Usher syndrome is characterized by deafness due to an impaired ability of the inner ear and auditory nerves to transmit sensory (sound) input to the brain (sensorineural hearing loss) as well as abnormal accumulation of colored (pigmented) material on the nerve-rich membrane (the retina) lining the eyes (retinitis pigmentosa or RP). RP eventually causes retinal degeneration leading to progressive loss of vision and legal blindness. Sensorineural hearing loss may be profound or mild and may be progressive. The vision loss caused by RP may begin during childhood or later during life, and often first presents with difficulty seeing at night or in low light (“night blindness”). Studies show that clear central vision may be maintained for many years even while side (peripheral) vision decreases. These narrowed visual fields are also referred to as “tunnel vision.” Issues with balance are seen mainly in individuals with Usher syndrome types 1 and 3, although balance difficulties in Usher syndrome type 2 have been reported. Usher syndrome type 1 is characterized by severe to profound hearing loss in both ears at birth (congenital deafness) and balance problems. Many affected children do not learn to walk until 18 months of age or later. Vision problems usually begin at approximately ten years of age to early teens, although some parents report onset in children younger than 10. Usher syndrome type 2 is characterized by moderate to severe hearing loss in both ears at birth. In some people, hearing loss may worsen over time. Onset of night blindness occurs during the late teens or early twenties. Peripheral vision loss is ongoing, but central vision is usually retained into adulthood. Visual problems associated with Usher syndrome type 2 tend to progress more slowly than those associated with type 1.Usher syndrome type 3 is characterized by later onset hearing loss, variable vestibular (balance) dysfunction and RP that can present between the second and fourth decade of life. Balance issues occur in approximately 50% of individuals with Usher syndrome type 3.
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Causes of Usher Syndrome
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Usher syndrome is caused by changes (variants or mutations) in specific genes. So far, Usher syndrome has been associated with variants in at least nine genes:Usher syndrome type 1: MYO7A (USH1B), USH1C, CDH23, PCDH15 (USH1F), and SANS (USH1G). CIB2, previously thought to be associated with USH1J, has been found to be a non-syndromic hearing loss gene, and likely not related to Usher syndrome. Usher syndrome type 2: USH2A, ADGRV1 (previously called VLGR1 and GPR98) and WHRN (DFNB31)Usher syndrome type 3: USH3A (CLRN1). HARS, originally reported to be associated with Usher type 3B, has no supporting evidence since the original paper in 2012. Therefore, it is likely not an Usher syndrome gene.These genes provide instructions for making proteins involved in normal hearing, vision and balance. Some of these proteins help specialized cells called hair cells, transmit sound from the inner ear to the brain and to sense light and color in the retina of the eye. The function of some of the proteins produced by genes associated with Usher syndrome is not known.Some people with a clinical diagnosis of Usher syndrome do not have variants in any of these genes, so there are probably other genes associated with the condition that have not yet been identified. There are also many other genes associated with hearing, vision and balance impairment that do not meet the clinical criteria for Usher syndrome.All types of Usher syndrome are inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a mutated gene from each parent. If an individual receives one normal gene and one mutated 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 mutated gene and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.Parents who are close biological relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
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Causes of Usher Syndrome. Usher syndrome is caused by changes (variants or mutations) in specific genes. So far, Usher syndrome has been associated with variants in at least nine genes:Usher syndrome type 1: MYO7A (USH1B), USH1C, CDH23, PCDH15 (USH1F), and SANS (USH1G). CIB2, previously thought to be associated with USH1J, has been found to be a non-syndromic hearing loss gene, and likely not related to Usher syndrome. Usher syndrome type 2: USH2A, ADGRV1 (previously called VLGR1 and GPR98) and WHRN (DFNB31)Usher syndrome type 3: USH3A (CLRN1). HARS, originally reported to be associated with Usher type 3B, has no supporting evidence since the original paper in 2012. Therefore, it is likely not an Usher syndrome gene.These genes provide instructions for making proteins involved in normal hearing, vision and balance. Some of these proteins help specialized cells called hair cells, transmit sound from the inner ear to the brain and to sense light and color in the retina of the eye. The function of some of the proteins produced by genes associated with Usher syndrome is not known.Some people with a clinical diagnosis of Usher syndrome do not have variants in any of these genes, so there are probably other genes associated with the condition that have not yet been identified. There are also many other genes associated with hearing, vision and balance impairment that do not meet the clinical criteria for Usher syndrome.All types of Usher syndrome are inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a mutated gene from each parent. If an individual receives one normal gene and one mutated 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 mutated gene and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.Parents who are close biological relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
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Affects of Usher Syndrome
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Usher syndrome is the most common genetic disorder involving both hearing and vision abnormalities and affects approximately three to ten in 100,000 people worldwide. Higher than average numbers of people with Usher syndrome have been found among Jewish people in Israel and Germany; French Canadians of Louisiana; Argentineans of Spanish descent and Nigerian Africans. USH3, the rarest form in most populations, comprises about 40% of Usher patients in Finland. Usher syndrome types 1 and 2 account for approximately 10 percent of all cases of bilateral (both ears) moderate to profound deafness in children.
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Affects of Usher Syndrome. Usher syndrome is the most common genetic disorder involving both hearing and vision abnormalities and affects approximately three to ten in 100,000 people worldwide. Higher than average numbers of people with Usher syndrome have been found among Jewish people in Israel and Germany; French Canadians of Louisiana; Argentineans of Spanish descent and Nigerian Africans. USH3, the rarest form in most populations, comprises about 40% of Usher patients in Finland. Usher syndrome types 1 and 2 account for approximately 10 percent of all cases of bilateral (both ears) moderate to profound deafness in children.
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Related disorders of Usher Syndrome
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Symptoms of the following disorders can be similar to those of Usher syndrome. Comparisons may be useful for a differential diagnosis:Alström syndrome is an inherited disorder characterized by retinal degeneration with nystagmus and loss of central vision. This disorder is associated with obesity in childhood. Sensorineural deafness and diabetes mellitus tend to develop after the age of ten years. (For more information on this condition, choose “Alström” as your search term in the Rare Disease Database.)Rubella (German measles) is an acute viral disorder that is of concern when contracted during the first three months of pregnancy because it can cause fetal abnormalities. These abnormalities may include hearing loss and/or vision disturbances as well as developmental malformations in the baby. (For more information on this disorder, choose “Rubella” as your search term in the Rare Disease Database.)Retinitis pigmentosa (RP) comprises a large group of inherited vision disorders that cause progressive degeneration of the retina. Peripheral (side) vision gradually decreases and eventually is lost in most cases. Central vision is usually preserved until late in these conditions. In addition to Usher syndrome, some forms of RP can be associated with deafness, obesity, kidney disease and various other general health problems, including central nervous system and metabolic disorders and occasionally chromosomal abnormalities (For more information on these disorders, choose “Retinitis Pigmentosa” as your search terms in the Rare Disease Database.)
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Related disorders of Usher Syndrome. Symptoms of the following disorders can be similar to those of Usher syndrome. Comparisons may be useful for a differential diagnosis:Alström syndrome is an inherited disorder characterized by retinal degeneration with nystagmus and loss of central vision. This disorder is associated with obesity in childhood. Sensorineural deafness and diabetes mellitus tend to develop after the age of ten years. (For more information on this condition, choose “Alström” as your search term in the Rare Disease Database.)Rubella (German measles) is an acute viral disorder that is of concern when contracted during the first three months of pregnancy because it can cause fetal abnormalities. These abnormalities may include hearing loss and/or vision disturbances as well as developmental malformations in the baby. (For more information on this disorder, choose “Rubella” as your search term in the Rare Disease Database.)Retinitis pigmentosa (RP) comprises a large group of inherited vision disorders that cause progressive degeneration of the retina. Peripheral (side) vision gradually decreases and eventually is lost in most cases. Central vision is usually preserved until late in these conditions. In addition to Usher syndrome, some forms of RP can be associated with deafness, obesity, kidney disease and various other general health problems, including central nervous system and metabolic disorders and occasionally chromosomal abnormalities (For more information on these disorders, choose “Retinitis Pigmentosa” as your search terms in the Rare Disease Database.)
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Diagnosis of Usher Syndrome
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Usher syndrome is diagnosed by hearing, balance and vision examinations. A hearing (audiologic) exam measures the frequency and loudness of sounds that a person can hear. A retinal exam is done to observe the retina and other structures in the back of the eye. An electroretinogram (ERG) measures the electrical response to light by the light-sensitive cells in the retina of the eyes. Vestibular (balance) function can be assessed by a variety of tests that evaluate different parts of the balance system. Genetic testing is clinically available for all known genes associated with Usher syndrome and should be performed to confirm the clinical diagnosis.
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Diagnosis of Usher Syndrome. Usher syndrome is diagnosed by hearing, balance and vision examinations. A hearing (audiologic) exam measures the frequency and loudness of sounds that a person can hear. A retinal exam is done to observe the retina and other structures in the back of the eye. An electroretinogram (ERG) measures the electrical response to light by the light-sensitive cells in the retina of the eyes. Vestibular (balance) function can be assessed by a variety of tests that evaluate different parts of the balance system. Genetic testing is clinically available for all known genes associated with Usher syndrome and should be performed to confirm the clinical diagnosis.
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Therapies of Usher Syndrome
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Treatment
The treatment of Usher syndrome is directed toward the specific symptoms that are apparent in each individual. Such treatment may require the coordinated efforts of a team of medical professionals, such as pediatricians or internists, specialists who assess and treat hearing and balance impairment (otolaryngologists and audiologists), physicians who specialize in diagnosing and treating eye disorders (ophthalmologists) and/or other health care professionals.Sensorineural hearing loss should be assessed, and communication options explored as early as possible to provide the child with a solid language base. Hearing aids or cochlear implants will benefit most infants and children with Usher syndrome. American Sign Language may be explored as a communication option. Individuals who sign visually often transfer to tactile sign as vision decreases. Early intervention is important in ensuring that children with Usher syndrome reach their potential. Services that may be beneficial may include special services for children with sensorineural deafness or deaf-blindness and other medical, social and/or vocational services.There is currently no known cure for RP, although researchers are working on genetic and other therapies to repair or reverse vision loss associated with RP as well as hearing loss. Some researchers have shown that taking a specific daily dose of vitamin A may slow the progression of retinal degeneration in some people with typical RP and Usher syndrome type 2. Some experts recommend that adult patients with common forms of RP take 15,000 IU daily of vitamin A palmitate under the care of an ophthalmologist, follow a regular balanced diet and avoid high-dose vitamin E supplementation. Because long-term high-dose vitamin A supplementation (e.g., exceeding 25,000 IU) may cause certain adverse effects such as liver disease, patients should be regularly monitored by their doctors when taking such supplementation. (The body’s reserves of vitamin A are primarily stored in the liver.) It is essential that any patients with RP considering such supplementation consult with their doctors for necessary evaluation to determine whether it is appropriate or inadvisable in their case.Individuals with RP in association with Usher syndrome may find low-vision aids to be helpful. Other treatment for Usher syndrome is symptomatic and supportive. Agencies that provide services to individuals with hearing and visual loss can be helpful.Genetic counseling is recommended for affected individuals and their families.
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Therapies of Usher Syndrome. Treatment
The treatment of Usher syndrome is directed toward the specific symptoms that are apparent in each individual. Such treatment may require the coordinated efforts of a team of medical professionals, such as pediatricians or internists, specialists who assess and treat hearing and balance impairment (otolaryngologists and audiologists), physicians who specialize in diagnosing and treating eye disorders (ophthalmologists) and/or other health care professionals.Sensorineural hearing loss should be assessed, and communication options explored as early as possible to provide the child with a solid language base. Hearing aids or cochlear implants will benefit most infants and children with Usher syndrome. American Sign Language may be explored as a communication option. Individuals who sign visually often transfer to tactile sign as vision decreases. Early intervention is important in ensuring that children with Usher syndrome reach their potential. Services that may be beneficial may include special services for children with sensorineural deafness or deaf-blindness and other medical, social and/or vocational services.There is currently no known cure for RP, although researchers are working on genetic and other therapies to repair or reverse vision loss associated with RP as well as hearing loss. Some researchers have shown that taking a specific daily dose of vitamin A may slow the progression of retinal degeneration in some people with typical RP and Usher syndrome type 2. Some experts recommend that adult patients with common forms of RP take 15,000 IU daily of vitamin A palmitate under the care of an ophthalmologist, follow a regular balanced diet and avoid high-dose vitamin E supplementation. Because long-term high-dose vitamin A supplementation (e.g., exceeding 25,000 IU) may cause certain adverse effects such as liver disease, patients should be regularly monitored by their doctors when taking such supplementation. (The body’s reserves of vitamin A are primarily stored in the liver.) It is essential that any patients with RP considering such supplementation consult with their doctors for necessary evaluation to determine whether it is appropriate or inadvisable in their case.Individuals with RP in association with Usher syndrome may find low-vision aids to be helpful. Other treatment for Usher syndrome is symptomatic and supportive. Agencies that provide services to individuals with hearing and visual loss can be helpful.Genetic counseling is recommended for affected individuals and their families.
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Overview of USP7-Related Diseases
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SummaryUSP7-related diseases are caused by changes (mutations) in a protein-coding gene called USP7. The clinical features in affected children include developmental delay/intellectual disability, autism spectrum disorder, increased prevalence of epilepsy, abnormal brain MRIs, and speech/motor impairments, with some patients being completely non-verbal.Individuals with USP7 mutations also show an increased prevalence of neonatal hypotonia, feeding problems, joint contractures, and hypogonadism. Additional clinical features include eye problems such as strabismus, myopia, or nystagmus, short stature, and difficulty gaining weight. Many patients experience gastrointestinal issues, such as reflux/GERD, chronic constipation, or chronic diarrhea. It is important to note that the clinical features (phenotypic spectrum) of USP7 mutations is still being uncovered, and that each individual case is unique. Currently, there are 25 individuals across the globe identified with USP7 mutations.
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Overview of USP7-Related Diseases. SummaryUSP7-related diseases are caused by changes (mutations) in a protein-coding gene called USP7. The clinical features in affected children include developmental delay/intellectual disability, autism spectrum disorder, increased prevalence of epilepsy, abnormal brain MRIs, and speech/motor impairments, with some patients being completely non-verbal.Individuals with USP7 mutations also show an increased prevalence of neonatal hypotonia, feeding problems, joint contractures, and hypogonadism. Additional clinical features include eye problems such as strabismus, myopia, or nystagmus, short stature, and difficulty gaining weight. Many patients experience gastrointestinal issues, such as reflux/GERD, chronic constipation, or chronic diarrhea. It is important to note that the clinical features (phenotypic spectrum) of USP7 mutations is still being uncovered, and that each individual case is unique. Currently, there are 25 individuals across the globe identified with USP7 mutations.
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Symptoms of USP7-Related Diseases
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The symptoms and severity of USP7-related diseases can vary from one person to another. Many features of the disorder are nonspecific and others may develop slowly over time or can be subtle. It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis. Often this requires input from a clinical geneticist or genetic counselor to supply the most recent and accurate information about the disorder and discuss genetic testing options or treatment plans.Initially, some affected infants (43%) may exhibit diminished muscle tone, known as hypotonia, which can cause a baby to feel “floppy” when held. Hypotonia can be associated with poor sucking ability, which may result in feeding difficulties (58%) and difficulty gaining weight (36%). Infants may also exhibit contractures of the joints (27%) and eye abnormalities (61%) such as strabismus (misalignment of the eyes), myopia (nearsightedness), or nystagmus (repetitive involuntary eye movements). In addition, individuals may exhibit hypogonadism (58%) in infancy. Hypogonadism refers to inadequate function of the sex organs, the testes in males and the ovaries in females. The sex organs in affected individuals fail to produce sufficient sex hormones, which can result in underdeveloped sex organs. Affected males may exhibit a small penis, underdeveloped scrotum, and small testes. Testes may not be descended into the scrotal sac at the time of birth (cryptorchidism). Affected females may exhibit an abnormally small clitoris or labia minor. Hypogonadism is also associated with delayed onset of puberty, incomplete development at puberty, and infertility.Dysmorphic facial features in affected individuals are generally variable and nonspecific, but can include deep-set eyes, straight eyebrows, and a deeper top fold on the ears with a straight edge on the bottom of the fold. These features can be noticeable shortly after birth or may develop slowly over time. Other common physical features include walking with the knees slightly bent and flat feet.As affected individuals grow older, the most commonly experienced clinical features include developmental delay/intellectual disability (94%), absence of language (25%) or speech impairment (100%), and autism spectrum disorder (58%), as well as short stature (33%).The most common gastrointestinal feature is gastroesophageal reflux disease (GERD), which occurs when the muscle at the end of the esophagus does not close properly, allowing stomach acid to flow back up into the esophagus and causing a burning sensation. Other common gastrointestinal features include chronic constipation (36%) and chronic diarrhea (20%).USP7-related diseases can also be accompanied by neurological features, including an abnormal brain MRI (90%), seizures (44%), and an abnormal gait (40%).
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Symptoms of USP7-Related Diseases. The symptoms and severity of USP7-related diseases can vary from one person to another. Many features of the disorder are nonspecific and others may develop slowly over time or can be subtle. It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis. Often this requires input from a clinical geneticist or genetic counselor to supply the most recent and accurate information about the disorder and discuss genetic testing options or treatment plans.Initially, some affected infants (43%) may exhibit diminished muscle tone, known as hypotonia, which can cause a baby to feel “floppy” when held. Hypotonia can be associated with poor sucking ability, which may result in feeding difficulties (58%) and difficulty gaining weight (36%). Infants may also exhibit contractures of the joints (27%) and eye abnormalities (61%) such as strabismus (misalignment of the eyes), myopia (nearsightedness), or nystagmus (repetitive involuntary eye movements). In addition, individuals may exhibit hypogonadism (58%) in infancy. Hypogonadism refers to inadequate function of the sex organs, the testes in males and the ovaries in females. The sex organs in affected individuals fail to produce sufficient sex hormones, which can result in underdeveloped sex organs. Affected males may exhibit a small penis, underdeveloped scrotum, and small testes. Testes may not be descended into the scrotal sac at the time of birth (cryptorchidism). Affected females may exhibit an abnormally small clitoris or labia minor. Hypogonadism is also associated with delayed onset of puberty, incomplete development at puberty, and infertility.Dysmorphic facial features in affected individuals are generally variable and nonspecific, but can include deep-set eyes, straight eyebrows, and a deeper top fold on the ears with a straight edge on the bottom of the fold. These features can be noticeable shortly after birth or may develop slowly over time. Other common physical features include walking with the knees slightly bent and flat feet.As affected individuals grow older, the most commonly experienced clinical features include developmental delay/intellectual disability (94%), absence of language (25%) or speech impairment (100%), and autism spectrum disorder (58%), as well as short stature (33%).The most common gastrointestinal feature is gastroesophageal reflux disease (GERD), which occurs when the muscle at the end of the esophagus does not close properly, allowing stomach acid to flow back up into the esophagus and causing a burning sensation. Other common gastrointestinal features include chronic constipation (36%) and chronic diarrhea (20%).USP7-related diseases can also be accompanied by neurological features, including an abnormal brain MRI (90%), seizures (44%), and an abnormal gait (40%).
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Causes of USP7-Related Diseases
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Overview
Our bodies are made up of trillions of cells. Within each cell is a nucleus, which contains X-shaped structures called chromosomes. These chromosomes are made up of tightly wound strands of DNA, our genetic material. Segments of DNA that provide instructions for the body to make proteins are called genes. Proteins play a critical role in many functions of the body. When a change (mutation) in a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain. The gene that is altered in patients with USP7-related diseases is the USP7 gene, located on the short (p) arm of chromosome 16.Human body cells normally have 46 chromosomes. Pairs of human chromosomes numbered from 1 through 22 are called autosomes and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 11p13” refers to band 13 on the short arm of chromosome 11. The numbered bands specify the location of the thousands of genes that are present on each chromosome. The specific location of the USP7 gene is chromosome 16p13.2.Inheritance Pattern
Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. The inheritance pattern of the disease caused by USP7 mutations is autosomal dominant, which means that only a single abnormal copy of the gene is necessary to cause the disease. Mutations in USP7 are either gene deletions, meaning the entire gene is missing, or point mutations, meaning just one letter in the DNA code is changed. Abnormal genes can either be inherited from a parent, or can result from de novo mutations, meaning that the parents are unaffected and the mutation arose spontaneously during the development of the parents' sperm and egg cells. The majority of documented cases of USP7 diseases are considered de novo mutations.If the parents of an affected child are considering having another baby, the risk of recurrence in a sibling depends on the type of mutation. If the child has a de novo mutation, the risk of a sibling also being affected is Underlying Mechanism
The USP7 gene contains instructions for producing (encoding) the USP7 protein, which plays a role in tumor suppression, control over the process of converting DNA into a protein (transcriptional regulation), immune response, and endosomal protein recycling. Endosomes are compartments within cells that transport molecules such as proteins. Endosomes direct proteins in three different directions: 1) towards the thin structure surrounding the surface of the cell (cell membrane) for recycling, 2) to a structure in cells called the Golgi apparatus, which helps modify and package proteins to leave the cell, or 3) to a structure called the lysosome to be broken down (degraded).Sometimes, endosomes mistakenly bring proteins inside the cell that are supposed to stay on the cell’s surface. When this happens, endosomes need to direct these proteins back to the cell membrane for recycling, and not to the lysosome where they would be broken down. In order for proteins to get back to the cell membrane, a protein called actin needs to be added to the endosome. It turns out that actin gets put on the endosome by a structure called WASH. For WASH to be working, it needs to be activated by a small protein mark, called ubiquitin. Ubiquitin gets added to WASH by a structure called the MUST complex, which is made up of 3 proteins including the USP7 protein. (In fact, USP7 actually stands for ubiquitin-specific protease 7). To put it all together, USP7 is a component of MUST, which uses ubiquitin to activate WASH, which adds actin to the endosome, which instructs the endosome to send important proteins back to the surface of the cell where they belong. When the USP7 gene has a mutation, this process doesn’t work, and the recycling and degradation of proteins in the cell will be changed, causing the symptoms seen in USP7-related diseases.Interestingly, USP7 actually has two functions on WASH: not only does it promote ubiquitination of WASH to activate it (which ultimately helps recycle proteins back to the membrane), but it also takes ubiquitin off of WASH to deactivate it (which would lead to proteins being degraded in the lysosome). Though these two functions seemingly oppose each other, this finding suggests that USP7 helps with precision control and fine-tuning of the protein recycling process.
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Causes of USP7-Related Diseases. Overview
Our bodies are made up of trillions of cells. Within each cell is a nucleus, which contains X-shaped structures called chromosomes. These chromosomes are made up of tightly wound strands of DNA, our genetic material. Segments of DNA that provide instructions for the body to make proteins are called genes. Proteins play a critical role in many functions of the body. When a change (mutation) in a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain. The gene that is altered in patients with USP7-related diseases is the USP7 gene, located on the short (p) arm of chromosome 16.Human body cells normally have 46 chromosomes. Pairs of human chromosomes numbered from 1 through 22 are called autosomes and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 11p13” refers to band 13 on the short arm of chromosome 11. The numbered bands specify the location of the thousands of genes that are present on each chromosome. The specific location of the USP7 gene is chromosome 16p13.2.Inheritance Pattern
Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. The inheritance pattern of the disease caused by USP7 mutations is autosomal dominant, which means that only a single abnormal copy of the gene is necessary to cause the disease. Mutations in USP7 are either gene deletions, meaning the entire gene is missing, or point mutations, meaning just one letter in the DNA code is changed. Abnormal genes can either be inherited from a parent, or can result from de novo mutations, meaning that the parents are unaffected and the mutation arose spontaneously during the development of the parents' sperm and egg cells. The majority of documented cases of USP7 diseases are considered de novo mutations.If the parents of an affected child are considering having another baby, the risk of recurrence in a sibling depends on the type of mutation. If the child has a de novo mutation, the risk of a sibling also being affected is Underlying Mechanism
The USP7 gene contains instructions for producing (encoding) the USP7 protein, which plays a role in tumor suppression, control over the process of converting DNA into a protein (transcriptional regulation), immune response, and endosomal protein recycling. Endosomes are compartments within cells that transport molecules such as proteins. Endosomes direct proteins in three different directions: 1) towards the thin structure surrounding the surface of the cell (cell membrane) for recycling, 2) to a structure in cells called the Golgi apparatus, which helps modify and package proteins to leave the cell, or 3) to a structure called the lysosome to be broken down (degraded).Sometimes, endosomes mistakenly bring proteins inside the cell that are supposed to stay on the cell’s surface. When this happens, endosomes need to direct these proteins back to the cell membrane for recycling, and not to the lysosome where they would be broken down. In order for proteins to get back to the cell membrane, a protein called actin needs to be added to the endosome. It turns out that actin gets put on the endosome by a structure called WASH. For WASH to be working, it needs to be activated by a small protein mark, called ubiquitin. Ubiquitin gets added to WASH by a structure called the MUST complex, which is made up of 3 proteins including the USP7 protein. (In fact, USP7 actually stands for ubiquitin-specific protease 7). To put it all together, USP7 is a component of MUST, which uses ubiquitin to activate WASH, which adds actin to the endosome, which instructs the endosome to send important proteins back to the surface of the cell where they belong. When the USP7 gene has a mutation, this process doesn’t work, and the recycling and degradation of proteins in the cell will be changed, causing the symptoms seen in USP7-related diseases.Interestingly, USP7 actually has two functions on WASH: not only does it promote ubiquitination of WASH to activate it (which ultimately helps recycle proteins back to the membrane), but it also takes ubiquitin off of WASH to deactivate it (which would lead to proteins being degraded in the lysosome). Though these two functions seemingly oppose each other, this finding suggests that USP7 helps with precision control and fine-tuning of the protein recycling process.
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Affects of USP7-Related Diseases
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USP7-related diseases are extremely rare disorders that have been described in only 25 families worldwide. The incidence and prevalence of the disorder is unknown. It is likely that people with these disorders go undiagnosed or misdiagnosed, making it difficult to determine the true frequency in the general population.
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Affects of USP7-Related Diseases. USP7-related diseases are extremely rare disorders that have been described in only 25 families worldwide. The incidence and prevalence of the disorder is unknown. It is likely that people with these disorders go undiagnosed or misdiagnosed, making it difficult to determine the true frequency in the general population.
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Related disorders of USP7-Related Diseases
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Prader-Willi syndrome (PWS) and Schaaf-Yang syndrome (SYS) are two other genetic multisystem disorders characterized by intellectual disability, hypotonia, and hypogonadism. USP7-related diseases and SYS also share an increased prevalence of autism; however, the prevalence of joint contractures is higher in SYS than in USP7¬-related diseases. In addition, though some families have described hyperphagia and lack of satiety in their children with USP7-related diseases, the prevalence is not known and these features are not as pronounced as what is seen in classic PWS. Furthermore, individuals with USP7-related diseases do not seem to manifest the corresponding morbid obesity typically present in PWS individuals.PWS occurs due to abnormalities affecting certain genes in a region of chromosome 15 called the Prader-Willi syndrome region (15q11-15q13). We have two copies of chromosome 15, but in the PWS region, only the paternal (father’s) copy is active, and the maternal copy is “imprinted” (silenced). PWS occurs when the PWS region of chromosome 15 is missing on the father’s chromosome, or when someone inherits two copies of chromosome 15 from their mother, and none from their father. (For more information on PWS, choose “Prader-Willi syndrome” as your search term in the Rare Disease Database.)Within the PWS region on chromosome 15 is the MAGEL2 gene. Sometimes, instead of the whole PWS region being deleted, the region is present but there is a mutation in the paternal copy of the MAGEL2 gene. This causes SYS.
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Related disorders of USP7-Related Diseases. Prader-Willi syndrome (PWS) and Schaaf-Yang syndrome (SYS) are two other genetic multisystem disorders characterized by intellectual disability, hypotonia, and hypogonadism. USP7-related diseases and SYS also share an increased prevalence of autism; however, the prevalence of joint contractures is higher in SYS than in USP7¬-related diseases. In addition, though some families have described hyperphagia and lack of satiety in their children with USP7-related diseases, the prevalence is not known and these features are not as pronounced as what is seen in classic PWS. Furthermore, individuals with USP7-related diseases do not seem to manifest the corresponding morbid obesity typically present in PWS individuals.PWS occurs due to abnormalities affecting certain genes in a region of chromosome 15 called the Prader-Willi syndrome region (15q11-15q13). We have two copies of chromosome 15, but in the PWS region, only the paternal (father’s) copy is active, and the maternal copy is “imprinted” (silenced). PWS occurs when the PWS region of chromosome 15 is missing on the father’s chromosome, or when someone inherits two copies of chromosome 15 from their mother, and none from their father. (For more information on PWS, choose “Prader-Willi syndrome” as your search term in the Rare Disease Database.)Within the PWS region on chromosome 15 is the MAGEL2 gene. Sometimes, instead of the whole PWS region being deleted, the region is present but there is a mutation in the paternal copy of the MAGEL2 gene. This causes SYS.
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Diagnosis of USP7-Related Diseases
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USP7 mutations are diagnosed through either whole exome sequencing, USP7 sequencing, or chromosome microarray analysis.Chromosome microarray analysis (CMA) studies can be compared to doing an inventory of books in a library – this type of testing checks 200,000 regions of chromosome material to see if there are extra or missing genes in an individual’s genome (a person’s complete set of DNA). Chromosome microarray testing can detect if the entire USP7 gene or pieces of the gene are missing (deleted), but misspellings within the USP7 gene will not be detected.Whole exome sequencing (WES) can be compared to checking for misspellings in books – this test examines 30,000,000 letters of DNA making up our genetic code. Specifically, whole exome sequencing looks for genetic changes (mutations) in a small portion of the human genome called the exome. While the human genome is a person’s complete set of DNA, including all of his or her genes, the exome is the part of the genome that contains the coding portions of the genes (exons) that code for the various amino acids that make up individual proteins. These proteins have wide and varied responsibilities in the body. Up to 84% of genetic disorders occur because of a change or alteration in these coding exons of the gene. Whole exome sequencing can identify a diagnosis of a USP7-related disorder by detecting even very small DNA mutations of a single letter (point mutations) in the USP7 gene.Sequencing of USP7 alone can make the diagnosis, but currently there appear to be no clinical laboratories offering this specific test. Clinical Testing and Work-UpOnce diagnosed, recommended tests include:
1. Measurement of IGF-1 and IGF-BP3 to screen for growth hormone deficiency
2. A brain MRI after 40 months of age to assess for abnormalities of white matter
3. Full assessment by a speech pathologist
4. Full assessment for physical and occupational therapy
5. Formal cognitive and behavioral testing by a licensed pediatric psychiatrist
6. A sleep apnea test/sleep study
7. An EEG test to test for abnormal electric activity that could cause/predispose seizures
8. A consultation with a gastroenterologist for any reflux, vomiting, or chronic constipation/diarrhea issues
9. An assessment by a pediatric ophthalmologist
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Diagnosis of USP7-Related Diseases. USP7 mutations are diagnosed through either whole exome sequencing, USP7 sequencing, or chromosome microarray analysis.Chromosome microarray analysis (CMA) studies can be compared to doing an inventory of books in a library – this type of testing checks 200,000 regions of chromosome material to see if there are extra or missing genes in an individual’s genome (a person’s complete set of DNA). Chromosome microarray testing can detect if the entire USP7 gene or pieces of the gene are missing (deleted), but misspellings within the USP7 gene will not be detected.Whole exome sequencing (WES) can be compared to checking for misspellings in books – this test examines 30,000,000 letters of DNA making up our genetic code. Specifically, whole exome sequencing looks for genetic changes (mutations) in a small portion of the human genome called the exome. While the human genome is a person’s complete set of DNA, including all of his or her genes, the exome is the part of the genome that contains the coding portions of the genes (exons) that code for the various amino acids that make up individual proteins. These proteins have wide and varied responsibilities in the body. Up to 84% of genetic disorders occur because of a change or alteration in these coding exons of the gene. Whole exome sequencing can identify a diagnosis of a USP7-related disorder by detecting even very small DNA mutations of a single letter (point mutations) in the USP7 gene.Sequencing of USP7 alone can make the diagnosis, but currently there appear to be no clinical laboratories offering this specific test. Clinical Testing and Work-UpOnce diagnosed, recommended tests include:
1. Measurement of IGF-1 and IGF-BP3 to screen for growth hormone deficiency
2. A brain MRI after 40 months of age to assess for abnormalities of white matter
3. Full assessment by a speech pathologist
4. Full assessment for physical and occupational therapy
5. Formal cognitive and behavioral testing by a licensed pediatric psychiatrist
6. A sleep apnea test/sleep study
7. An EEG test to test for abnormal electric activity that could cause/predispose seizures
8. A consultation with a gastroenterologist for any reflux, vomiting, or chronic constipation/diarrhea issues
9. An assessment by a pediatric ophthalmologist
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Therapies of USP7-Related Diseases
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Treatment
Treatment is directed toward the specific symptoms that are apparent in each individual. While at present a cure is not available for these diseases, early intervention and maintenance to treatment can greatly improve the overall health and quality of life for affected individuals and their families. Treatment may require the coordinated efforts of a team of specialists. Clinical geneticists, pediatricians, endocrinologists, speech therapists, psychologists, and other healthcare professionals may need to systematically and comprehensively plan an effective program for the child’s treatment. Genetic counseling may be of benefit for affected individuals and their families to further discuss the condition, provide information and to examine recurrence risks. Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease severity; the presence or absence of certain symptoms; an individual’s age and general health; and/or other elements. Decisions concerning the use of 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 family based upon the specifics of the patient’s case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors. In infants, special nipples or gavage feeding may be used to ensure adequate nutrition. Gavage feeding is a procedure in which a small, thin tube is passed through the nose and mouth to the stomach to directly feed a newborn who has feeding difficulties.In males, the treatment of hypogonadism with either testosterone or human chorionic gonadotropin may be beneficial during infancy, potentially increasing the size of the genitalia or prompting testicular descent into the scrotum when cryptorchidism is present. Although cryptorchidism may occasionally resolve spontaneously or with hormone therapy, most males may require surgical treatment.Individuals may also benefit from growth hormone (GH) therapy, which can help to increase height, improve lean body mass, and ultimately improve the quality of life. Children benefit from early intervention to assess and treat issues with motor skills, intellectual disability, and speech and language development. Early intervention may include physical and occupational therapy, special education, and speech therapy. An individualized education plan should be created at the start of school. Behavioral therapy may be beneficial to manage difficult behavior.Children should receive an ophthalmological exam to evaluate for eye abnormalities potentially associated with USP7-related diseases such as strabismus and to assess visual acuity.Sex hormones can be replaced at puberty as they can stimulate the development of secondary sexual characteristics and improve self-image. In males, the use of such therapy has been controversial because testosterone replacement by monthly injection may contribute to behavioral issues in males; use of a testosterone patch or gel will avert this problem. Sex hormone replacement therapy may increase the risk of stroke in females, as in the general population, and hygiene issues should also be considered. Sex education and consideration of contraception are important, particularly in females.
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Therapies of USP7-Related Diseases. Treatment
Treatment is directed toward the specific symptoms that are apparent in each individual. While at present a cure is not available for these diseases, early intervention and maintenance to treatment can greatly improve the overall health and quality of life for affected individuals and their families. Treatment may require the coordinated efforts of a team of specialists. Clinical geneticists, pediatricians, endocrinologists, speech therapists, psychologists, and other healthcare professionals may need to systematically and comprehensively plan an effective program for the child’s treatment. Genetic counseling may be of benefit for affected individuals and their families to further discuss the condition, provide information and to examine recurrence risks. Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease severity; the presence or absence of certain symptoms; an individual’s age and general health; and/or other elements. Decisions concerning the use of 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 family based upon the specifics of the patient’s case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors. In infants, special nipples or gavage feeding may be used to ensure adequate nutrition. Gavage feeding is a procedure in which a small, thin tube is passed through the nose and mouth to the stomach to directly feed a newborn who has feeding difficulties.In males, the treatment of hypogonadism with either testosterone or human chorionic gonadotropin may be beneficial during infancy, potentially increasing the size of the genitalia or prompting testicular descent into the scrotum when cryptorchidism is present. Although cryptorchidism may occasionally resolve spontaneously or with hormone therapy, most males may require surgical treatment.Individuals may also benefit from growth hormone (GH) therapy, which can help to increase height, improve lean body mass, and ultimately improve the quality of life. Children benefit from early intervention to assess and treat issues with motor skills, intellectual disability, and speech and language development. Early intervention may include physical and occupational therapy, special education, and speech therapy. An individualized education plan should be created at the start of school. Behavioral therapy may be beneficial to manage difficult behavior.Children should receive an ophthalmological exam to evaluate for eye abnormalities potentially associated with USP7-related diseases such as strabismus and to assess visual acuity.Sex hormones can be replaced at puberty as they can stimulate the development of secondary sexual characteristics and improve self-image. In males, the use of such therapy has been controversial because testosterone replacement by monthly injection may contribute to behavioral issues in males; use of a testosterone patch or gel will avert this problem. Sex hormone replacement therapy may increase the risk of stroke in females, as in the general population, and hygiene issues should also be considered. Sex education and consideration of contraception are important, particularly in females.
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Overview of Uterine Leiomyosarcoma
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A uterine leiomyosarcoma is a rare malignant (cancerous) tumor that arises from the smooth muscle lining the walls of the uterus (myometrium). There are essentially two types of muscles in the body: voluntary and involuntary. Smooth muscles are involuntary muscles; the brain has no conscious control over them. Smooth muscles react involuntarily in response to various stimuli. For example, the myometrium stretches during pregnancy to help accommodate the fetus and contracts during labor to help push out a baby during childbirth. Leiomyosarcoma is a form of cancer. The term “cancer” refers to a group of diseases characterized by abnormal, uncontrolled cellular growth that invades surrounding tissues and may spread (metastasize) to distant bodily tissues or organs via the bloodstream, the lymphatic system, or other means. Different forms of cancer, including leiomyosarcomas, may be classified based upon the cell type involved, the specific nature of the malignancy, and the disease's clinical course. Leiomyosarcoma is classified as a soft tissue sarcoma. Sarcomas are malignant tumors that arise from the connective tissue, which connects, supports and surrounds various structures and organs in the body. Soft tissue includes fat, muscle, never, tendons, tissue surrounding the joints (synovial tissue), and blood and lymph vessels. The exact cause of leiomyosarcoma, including uterine leiomyosarcoma, is unknown.
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Overview of Uterine Leiomyosarcoma. A uterine leiomyosarcoma is a rare malignant (cancerous) tumor that arises from the smooth muscle lining the walls of the uterus (myometrium). There are essentially two types of muscles in the body: voluntary and involuntary. Smooth muscles are involuntary muscles; the brain has no conscious control over them. Smooth muscles react involuntarily in response to various stimuli. For example, the myometrium stretches during pregnancy to help accommodate the fetus and contracts during labor to help push out a baby during childbirth. Leiomyosarcoma is a form of cancer. The term “cancer” refers to a group of diseases characterized by abnormal, uncontrolled cellular growth that invades surrounding tissues and may spread (metastasize) to distant bodily tissues or organs via the bloodstream, the lymphatic system, or other means. Different forms of cancer, including leiomyosarcomas, may be classified based upon the cell type involved, the specific nature of the malignancy, and the disease's clinical course. Leiomyosarcoma is classified as a soft tissue sarcoma. Sarcomas are malignant tumors that arise from the connective tissue, which connects, supports and surrounds various structures and organs in the body. Soft tissue includes fat, muscle, never, tendons, tissue surrounding the joints (synovial tissue), and blood and lymph vessels. The exact cause of leiomyosarcoma, including uterine leiomyosarcoma, is unknown.
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Symptoms of Uterine Leiomyosarcoma
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Symptoms of uterine leiomyosarcoma may vary from case to case depending upon the exact location, size and progression of the tumor. Many women will not have any apparent symptoms (asymptomatic). The most common symptom is abnormal bleeding from the vagina and the uterus. Postmenopausal bleeding is an important factor that may indicate a uterine leiomyosarcoma.Additional symptoms may occur including pressure or pain affecting the pelvis or stomach, abnormal vaginal discharge, and a change in bladder or bowel habits. General symptoms often associated with cancer include fatigue, fever, weight loss, and a general feeling of ill health (malaise).Uterine leiomyosarcomas are malignant and may spread (metastasize) locally and to other areas of the body, especially the lungs and liver often causing life-threatening complications. Leiomyosarcomas recur in more than half of the cases sometimes within eight to 16 months of the initial diagnosis and treatment.
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Symptoms of Uterine Leiomyosarcoma. Symptoms of uterine leiomyosarcoma may vary from case to case depending upon the exact location, size and progression of the tumor. Many women will not have any apparent symptoms (asymptomatic). The most common symptom is abnormal bleeding from the vagina and the uterus. Postmenopausal bleeding is an important factor that may indicate a uterine leiomyosarcoma.Additional symptoms may occur including pressure or pain affecting the pelvis or stomach, abnormal vaginal discharge, and a change in bladder or bowel habits. General symptoms often associated with cancer include fatigue, fever, weight loss, and a general feeling of ill health (malaise).Uterine leiomyosarcomas are malignant and may spread (metastasize) locally and to other areas of the body, especially the lungs and liver often causing life-threatening complications. Leiomyosarcomas recur in more than half of the cases sometimes within eight to 16 months of the initial diagnosis and treatment.
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Causes of Uterine Leiomyosarcoma
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The exact cause of uterine leiomyosarcoma is unknown. They often occur spontaneously, for no apparent reason. In extremely rare cases, some researchers believe they may signify a malignant change (transformation) of a benign (noncancerous) fibroid. However, other researchers argue that malignant transformation of fibroids is unproven. Fibroids are the most common tumors affecting women and often appear during childbearing years. Fibroids may also be known as leiomyomas or myomas. Most fibroids do not cause any symptoms or complications.Researchers speculate that genetic and immunologic abnormalities, environmental factors (e.g., exposure to ultraviolet rays, certain chemicals, ionizing radiation), diet, stress, and/or other factors may play contributing roles in causing specific types of cancer. Investigators are conducting ongoing basic research to learn more about the many factors that may result in cancer.In individuals with cancer, including leiomyosarcoma, malignancies may develop due to abnormal changes in the structure and orientation of certain cells known as oncogenes or tumor suppressor genes. Oncogenes control cell growth; tumor suppressor genes control cell division and ensure that cells die at the proper time. The specific cause of changes to these genes is unknown. However, current research suggests that abnormalities of DNA (deoxyribonucleic acid), which is the carrier of the body’s genetic code, are the underlying basis of cellular malignant transformation. These abnormal genetic changes may occur spontaneously for unknown reasons or, more rarely, may be inherited.Leiomyosarcomas are associated with specific genetic and environmental risk factors. Certain inherited conditions that run in families may increase the risk of developing a leiomyosarcoma. These disorders include Gardner syndrome, Li-Fraumeni syndrome, Werner syndrome, neurofibromatosis and several immune deficiency syndromes. The exact association between leiomyosarcoma and these disorders is not understood. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Researchers have speculated that exposure to high dose radiation and certain chemicals (e.g., herbicides) may be linked to an increased risk of developing leiomyosarcoma but no definitive link has been established.
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Causes of Uterine Leiomyosarcoma. The exact cause of uterine leiomyosarcoma is unknown. They often occur spontaneously, for no apparent reason. In extremely rare cases, some researchers believe they may signify a malignant change (transformation) of a benign (noncancerous) fibroid. However, other researchers argue that malignant transformation of fibroids is unproven. Fibroids are the most common tumors affecting women and often appear during childbearing years. Fibroids may also be known as leiomyomas or myomas. Most fibroids do not cause any symptoms or complications.Researchers speculate that genetic and immunologic abnormalities, environmental factors (e.g., exposure to ultraviolet rays, certain chemicals, ionizing radiation), diet, stress, and/or other factors may play contributing roles in causing specific types of cancer. Investigators are conducting ongoing basic research to learn more about the many factors that may result in cancer.In individuals with cancer, including leiomyosarcoma, malignancies may develop due to abnormal changes in the structure and orientation of certain cells known as oncogenes or tumor suppressor genes. Oncogenes control cell growth; tumor suppressor genes control cell division and ensure that cells die at the proper time. The specific cause of changes to these genes is unknown. However, current research suggests that abnormalities of DNA (deoxyribonucleic acid), which is the carrier of the body’s genetic code, are the underlying basis of cellular malignant transformation. These abnormal genetic changes may occur spontaneously for unknown reasons or, more rarely, may be inherited.Leiomyosarcomas are associated with specific genetic and environmental risk factors. Certain inherited conditions that run in families may increase the risk of developing a leiomyosarcoma. These disorders include Gardner syndrome, Li-Fraumeni syndrome, Werner syndrome, neurofibromatosis and several immune deficiency syndromes. The exact association between leiomyosarcoma and these disorders is not understood. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Researchers have speculated that exposure to high dose radiation and certain chemicals (e.g., herbicides) may be linked to an increased risk of developing leiomyosarcoma but no definitive link has been established.
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Affects of Uterine Leiomyosarcoma
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Uterine leiomyosarcoma is an extremely rare form of cancer, estimated to occur in 6 out of every 1,000,000 women in the United States each year. The average age at diagnosis is 51. Uterine leiomyosarcomas account for 1-2 percent of all malignant tumors of the uterus.Leiomyosarcoma is a form of soft tissue sarcoma. According to the American Cancer Society, 9,530 new cases of soft tissue sarcoma will occur in the United States in 2006. Soft tissue sarcomas affect men slightly more often than women and occur more often in adults than children and adolescents.
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Affects of Uterine Leiomyosarcoma. Uterine leiomyosarcoma is an extremely rare form of cancer, estimated to occur in 6 out of every 1,000,000 women in the United States each year. The average age at diagnosis is 51. Uterine leiomyosarcomas account for 1-2 percent of all malignant tumors of the uterus.Leiomyosarcoma is a form of soft tissue sarcoma. According to the American Cancer Society, 9,530 new cases of soft tissue sarcoma will occur in the United States in 2006. Soft tissue sarcomas affect men slightly more often than women and occur more often in adults than children and adolescents.
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Related disorders of Uterine Leiomyosarcoma
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Symptoms of the following disorders can be similar to those of uterine leiomyosarcoma. Comparisons may be useful for a differential diagnosis.Endometrial carcinoma refers to cancer of the inner membrane lining the uterus (endometrium). It is the most common type of gynecologic cancer in the United States and most cases occur after menopause. Endometrial carcinoma may cause postmenopausal bleeding. In women during their reproductive years, it may cause abnormalities with the menstrual cycle. The exact cause of endometrial carcinoma is unknown but factors known to increase risk are obesity, ingestion of unopposed estrogen, and certain hereditary cancer syndromes.Uterine fibroids, also known as leiomyomas, are benign smooth muscle tumors of the uterus. These common tumors affect approximately 20 percent of women by the age of 40. Most cases of uterine fibroids do not cause symptoms (asymptomatic) and do not require treatment. These tumors can grow in size to eventually cause heavy menstrual bleeding, prolonged menstrual bleeding, pressure or pain of the pelvis, and abnormalities of the urinary and gastrointestinal tracts. The exact cause of uterine fibroids is unknown.
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Related disorders of Uterine Leiomyosarcoma. Symptoms of the following disorders can be similar to those of uterine leiomyosarcoma. Comparisons may be useful for a differential diagnosis.Endometrial carcinoma refers to cancer of the inner membrane lining the uterus (endometrium). It is the most common type of gynecologic cancer in the United States and most cases occur after menopause. Endometrial carcinoma may cause postmenopausal bleeding. In women during their reproductive years, it may cause abnormalities with the menstrual cycle. The exact cause of endometrial carcinoma is unknown but factors known to increase risk are obesity, ingestion of unopposed estrogen, and certain hereditary cancer syndromes.Uterine fibroids, also known as leiomyomas, are benign smooth muscle tumors of the uterus. These common tumors affect approximately 20 percent of women by the age of 40. Most cases of uterine fibroids do not cause symptoms (asymptomatic) and do not require treatment. These tumors can grow in size to eventually cause heavy menstrual bleeding, prolonged menstrual bleeding, pressure or pain of the pelvis, and abnormalities of the urinary and gastrointestinal tracts. The exact cause of uterine fibroids is unknown.
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Diagnosis of Uterine Leiomyosarcoma
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The diagnosis of a uterine leiomyosarcoma is most commonly made incidentally when affected individuals are operated on for benign smooth muscle tumors of the uterus (leiomyomas or fibroids). The pathologic review of the fibroid surgery specimens may reveal certain characteristics under the microscope that are more characteristic of a leiomyosarcoma than a benign myoma. Thus, pathologic review is key diagnostic aspect is distinguishing malignant leiomyosarcoma from its benign counterpart, the leiomyoma.Specialized imaging techniques may be used to help evaluate the size, placement, and extension of the tumor and to serve as an aid for future surgical procedures, among individuals with uterine leiomyosarcomas. Such imaging techniques may include computerized tomography (CT) scanning, magnetic resonance imaging (MRI) and ultrasound. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. During an ultrasound reflected sound waves create an image of the uterus. Laboratory tests and specialized imaging tests may also be conducted to determine possible infiltration of regional lymph nodes and the presence of distant metastases.To confirm the diagnosis of metastatic leiomyosarcoma a fine-needle aspiration may be performed. Fine-need aspiration (FNA) is a diagnostic technique in which a thin, hollow needle is passed through the skin and inserted into the nodule or mass to withdraw small samples of tissue. The collected tissue is then studied under a microscope. In some cases, FNA may prove inconclusive and physicians may perform an incisional biopsy. During an incisional biopsy, a small sample tissue is surgically removed and sent to a pathology laboratory where it is processed and studied to determine its microscopic structure and makeup (histopathology).
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Diagnosis of Uterine Leiomyosarcoma. The diagnosis of a uterine leiomyosarcoma is most commonly made incidentally when affected individuals are operated on for benign smooth muscle tumors of the uterus (leiomyomas or fibroids). The pathologic review of the fibroid surgery specimens may reveal certain characteristics under the microscope that are more characteristic of a leiomyosarcoma than a benign myoma. Thus, pathologic review is key diagnostic aspect is distinguishing malignant leiomyosarcoma from its benign counterpart, the leiomyoma.Specialized imaging techniques may be used to help evaluate the size, placement, and extension of the tumor and to serve as an aid for future surgical procedures, among individuals with uterine leiomyosarcomas. Such imaging techniques may include computerized tomography (CT) scanning, magnetic resonance imaging (MRI) and ultrasound. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. During an ultrasound reflected sound waves create an image of the uterus. Laboratory tests and specialized imaging tests may also be conducted to determine possible infiltration of regional lymph nodes and the presence of distant metastases.To confirm the diagnosis of metastatic leiomyosarcoma a fine-needle aspiration may be performed. Fine-need aspiration (FNA) is a diagnostic technique in which a thin, hollow needle is passed through the skin and inserted into the nodule or mass to withdraw small samples of tissue. The collected tissue is then studied under a microscope. In some cases, FNA may prove inconclusive and physicians may perform an incisional biopsy. During an incisional biopsy, a small sample tissue is surgically removed and sent to a pathology laboratory where it is processed and studied to determine its microscopic structure and makeup (histopathology).
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Therapies of Uterine Leiomyosarcoma
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TreatmentThe therapeutic management of individuals with a uterine leiomyosarcoma may require the coordinated efforts of a team of medical professionals, such as physicians who specialize in the diagnosis and treatment of gynecologic cancers (gynecologic oncologists), specialists in the use of radiation to treat cancer (radiation oncologists), specialists in the use of chemotherapy to treat cancer (medical oncologists), oncology nurses, and other specialists.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as primary tumor location, extent of the primary tumor (stage), and degree of malignancy (grade); whether the tumor has spread to lymph nodes or distant sites; an individual’s age and general health; and/or other elements. Decisions concerning the use of particular interventions should be made by physicians and other members of the health care team in careful consultation with the patient, based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks; patient preference; and other appropriate factors.The primary form of treatment for a uterine leiomyosarcoma is surgical removal of the entire tumor and any affected tissue. Total surgical removal of the uterus (hysterectomy) is usually performed. Usually, surgical removal of the fallopian tubes and ovaries (bilateral salpingo-oophorectomy) may also be recommended, especially for women who are menopausal or have metastases.Anti-cancer drugs used alone or combination (chemotherapy) and radiation therapy have been used to treat individuals with leiomyosarcoma following surgery (adjuvant therapy) with limited benefit. Investigational therapies are underway to develop new chemotherapeutic combinations that may prove beneficial in treating leiomyosarcomas. In some cases, radiation therapy may be used before surgery to reduce the size of a tumor.Because leiomyosarcomas have a high risk of recurrence, individuals should be examined routinely after surgery.
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Therapies of Uterine Leiomyosarcoma. TreatmentThe therapeutic management of individuals with a uterine leiomyosarcoma may require the coordinated efforts of a team of medical professionals, such as physicians who specialize in the diagnosis and treatment of gynecologic cancers (gynecologic oncologists), specialists in the use of radiation to treat cancer (radiation oncologists), specialists in the use of chemotherapy to treat cancer (medical oncologists), oncology nurses, and other specialists.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as primary tumor location, extent of the primary tumor (stage), and degree of malignancy (grade); whether the tumor has spread to lymph nodes or distant sites; an individual’s age and general health; and/or other elements. Decisions concerning the use of particular interventions should be made by physicians and other members of the health care team in careful consultation with the patient, based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks; patient preference; and other appropriate factors.The primary form of treatment for a uterine leiomyosarcoma is surgical removal of the entire tumor and any affected tissue. Total surgical removal of the uterus (hysterectomy) is usually performed. Usually, surgical removal of the fallopian tubes and ovaries (bilateral salpingo-oophorectomy) may also be recommended, especially for women who are menopausal or have metastases.Anti-cancer drugs used alone or combination (chemotherapy) and radiation therapy have been used to treat individuals with leiomyosarcoma following surgery (adjuvant therapy) with limited benefit. Investigational therapies are underway to develop new chemotherapeutic combinations that may prove beneficial in treating leiomyosarcomas. In some cases, radiation therapy may be used before surgery to reduce the size of a tumor.Because leiomyosarcomas have a high risk of recurrence, individuals should be examined routinely after surgery.
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Overview of VACTERL Association
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VACTERL association is a nonrandom association of birth defects that affects multiple anatomical structures. The term VACTERL is an acronym with each letter representing the first letter of one of the more common findings seen in affected children:(V) = (costo-) vertebral abnormalities(A) = anal atresia(C) = cardiac (heart) defects(TE) = tracheal-esophageal abnormalities, including atresia, stenosis and fistula(R) = renal (kidney) and radial abnormalities(L) = limb abnormalities(S) = single umbilical arteryInitially, the acronym VATER included vertebral, anal, tracheoesophageal, radial and renal anomalies was used. The acronym was subsequently redefined with the addition of (C) for cardiac defects, (L) for limb defects other than radial anomalies, and (S) for single umbilical artery. VACTERL association is currently the most frequently used term to define this condition. The cause of VACTERL association remains unknown in most patients and is likely caused by a combination of different factors (multifactorial). It is not considered a hereditary disorder and usually occurs in a single individual in any given family.
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Overview of VACTERL Association. VACTERL association is a nonrandom association of birth defects that affects multiple anatomical structures. The term VACTERL is an acronym with each letter representing the first letter of one of the more common findings seen in affected children:(V) = (costo-) vertebral abnormalities(A) = anal atresia(C) = cardiac (heart) defects(TE) = tracheal-esophageal abnormalities, including atresia, stenosis and fistula(R) = renal (kidney) and radial abnormalities(L) = limb abnormalities(S) = single umbilical arteryInitially, the acronym VATER included vertebral, anal, tracheoesophageal, radial and renal anomalies was used. The acronym was subsequently redefined with the addition of (C) for cardiac defects, (L) for limb defects other than radial anomalies, and (S) for single umbilical artery. VACTERL association is currently the most frequently used term to define this condition. The cause of VACTERL association remains unknown in most patients and is likely caused by a combination of different factors (multifactorial). It is not considered a hereditary disorder and usually occurs in a single individual in any given family.
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Symptoms of VACTERL Association
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VACTERL association involves multiple anatomical defects. These defects are congenital and may be obvious at birth (e.g., anal atresia, tracheoesophageal fistula and esophageal atresia, radial defects) or not become recognized until later (e.g., cardiac, vertebral, and renal malformations). The combination of malformations may vary greatly from one child to another and an affected child will typically not have all of the malformations listed below.Vertebral AbnormalitiesVertebral abnormalities are defects of the spinal column. These defects include missing vertebrae, malformed vertebrae (half-formed vertebrae termed hemivertebrae, butterfly-shaped vertebrae, vertebral clefts and fusion of vertebrae), missing ribs, an increased number of ribs (supernumerary ribs), rib fusions and splitting of ribs. Side-to-side curvature of the spine (scoliosis) and absence of the tailbone, the lowest bone of the spinal column (sacral agenesis), may also occur. Anal AtresiaAnal atresia is a malformation in which the opening that connects the rectum through the anus to the exterior is closed. The closure may be a thin membrane of skin or a thicker blockage of skin and muscle. This condition, also termed imperforate anus, prevents the normal passage of bowel contents. Anal atresia may coexist with abnormalities in the lower urogenital tract. Cardiac (Heart) DefectsA number of different cardiac defects may occur in the VACTERL association, the most common being ventricular septal defects (VSDs). The normal heart has four chambers. The two upper chambers, known as atria, are separated from each other by a fibrous partition known as the atrial septum. The two lower chambers are known as ventricles and are separated from each other by the ventricular septum. Valves connect the atria (left and right) to their respective ventricles. The aorta, the main vessel of arterial circulation, carries blood away from the left ventricle to the rest of the body. A VSD is a hole in the ventricular septum and may occur anywhere in the septum. The size and location of the defect determine the severity of the symptoms. A small ventricular septal defect may close on its own (spontaneously) or become less significant as the child matures and grows. A moderately-sized defect may affect the ability of the heart to pump blood efficiently to the lungs and the rest of the body (congestive heart failure). Symptoms associated with heart failure include an abnormally rapid rate of breathing (tachypnea), wheezing, an unusually fast heartbeat (tachycardia), and failure to grow at the expected rate (failure to thrive). A large ventricular septal defect may cause life-threatening complications during infancy. Additional congenital heart defects that have occurred in the VACTERL association include atrial septal defects (ASDs); hypoplastic left heart syndrome (a life-treating condition in which there is underdevelopment of the left ventricle, the aortic and/or mitral valve, and the ascending aorta); transposition of the great arteries (a condition in which the aorta and pulmonary artery are switched in positions); a complex malformation known as tetralogy of Fallot; and patent ductus arteriosus [a condition in which the passage between the blood vessel that leads to the lungs (pulmonary arteries) and the major artery of the body (aorta) fails to close after birth]. (For more information on those conditions, choose the name of the disorder as your search term in the Rare Disease Database.)Tracheoesophageal Fistula and/or Esophageal AtresiaAn abnormal connection between the trachea and the esophagus (tracheoesophageal fistula) is the most common birth defect in the VACTERL association. The malformation potentially allows food to be inhaled (aspirated) into the lungs, which, in turn, may result in respiratory infections (e.g., pneumonia) and failure to thrive. Esophageal atresia, a malformation in which the esophagus narrows to a thin cord or ends in a blind pouch rather than providing passage to the stomach, may also be present. These two conditions may result in breathing, feeding and swallowing difficulties.Renal AbnormalitiesA variety of abnormalities affecting the kidneys and urinary tract including absence of development of one or both kidneys (renal aplasia), malformation of one or both kidneys (renal dysplasia), displaced or malpositioned kidneys (renal ectopia), abnormal backflow (reflux) of urine into the tube (ureter) that carries urine to the bladder (vesicoureteral reflux), resulting in abnormal accumulation of urine in the kidneys (hydronephrosis). In addition, affected children may experience frequent urinary tract infections and the urethral opening may be abnormally positioned at the end of the penis (hypospadias).Limb AnomaliesAnother major finding associated with VACTERL association is defects affecting the forearm on the thumb side (radius). These defects may include absence of the radius (radial aplasia), underdevelopment of the radius (radial hypoplasia), underdevelopment or absence of the thumb and/or the presence of an extra bone in the thumb (triphalangeal thumb). Other limb anomalies including extra digits (polydactyly), webbing of the digits (syndactyly), abnormal fusion of the two forearm bones (radioulnar synostosis) and lower limb malformations (such as clubfoot, and hypoplasia of the great toe and tibia) have been described in VACTERL association.Other Birth DefectsAdditional birth defects that have been reported to occur in a minority of affected individuals include facial asymmetry (hemifacial microsomia), abnormal shape and size of the ears, narrowing of the larynx (laryngeal stenosis), narrowing of the passages from the back of the nose to the throat that make it possible to breathe through the nose (choanal atresia), lung malformations , protrusion of part of the intestines through an abnormal opening in the muscular abdominal wall near the umbilical cord (omphalocele), intestinal misplacement and misalignment (malrotation), and tethered spinal cord. A single umbilical artery rather than the usual two arteries has been found in a minority of infants with VACTERL association. (For information on this condition, choose “tethered spinal cord” as your search term in the Rare Disease Database.)Some infants and young children with VACTERL association may grow slower than normal. In the vast majority of patients, VACTERL association does not affect mental functioning and intelligence.With the improvement of medical and surgical care, the patient outcomes (prognosis) of VACTERL association are much better than they were before. However, affected individuals may experience medical complications throughout life. For instance, vertebral malformations might lead to scoliosis and chronic back pain, anal atresia might be associated with incontinence and/or constipation, gastro-esophageal reflux might result from TE fistula and renal anomalies are associated with an increased risk of urinary tract infection (UTI) and renal stones (nephrolithiasis). In addition, individuals with limb abnormalities and malformation might have functional limitations.
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Symptoms of VACTERL Association. VACTERL association involves multiple anatomical defects. These defects are congenital and may be obvious at birth (e.g., anal atresia, tracheoesophageal fistula and esophageal atresia, radial defects) or not become recognized until later (e.g., cardiac, vertebral, and renal malformations). The combination of malformations may vary greatly from one child to another and an affected child will typically not have all of the malformations listed below.Vertebral AbnormalitiesVertebral abnormalities are defects of the spinal column. These defects include missing vertebrae, malformed vertebrae (half-formed vertebrae termed hemivertebrae, butterfly-shaped vertebrae, vertebral clefts and fusion of vertebrae), missing ribs, an increased number of ribs (supernumerary ribs), rib fusions and splitting of ribs. Side-to-side curvature of the spine (scoliosis) and absence of the tailbone, the lowest bone of the spinal column (sacral agenesis), may also occur. Anal AtresiaAnal atresia is a malformation in which the opening that connects the rectum through the anus to the exterior is closed. The closure may be a thin membrane of skin or a thicker blockage of skin and muscle. This condition, also termed imperforate anus, prevents the normal passage of bowel contents. Anal atresia may coexist with abnormalities in the lower urogenital tract. Cardiac (Heart) DefectsA number of different cardiac defects may occur in the VACTERL association, the most common being ventricular septal defects (VSDs). The normal heart has four chambers. The two upper chambers, known as atria, are separated from each other by a fibrous partition known as the atrial septum. The two lower chambers are known as ventricles and are separated from each other by the ventricular septum. Valves connect the atria (left and right) to their respective ventricles. The aorta, the main vessel of arterial circulation, carries blood away from the left ventricle to the rest of the body. A VSD is a hole in the ventricular septum and may occur anywhere in the septum. The size and location of the defect determine the severity of the symptoms. A small ventricular septal defect may close on its own (spontaneously) or become less significant as the child matures and grows. A moderately-sized defect may affect the ability of the heart to pump blood efficiently to the lungs and the rest of the body (congestive heart failure). Symptoms associated with heart failure include an abnormally rapid rate of breathing (tachypnea), wheezing, an unusually fast heartbeat (tachycardia), and failure to grow at the expected rate (failure to thrive). A large ventricular septal defect may cause life-threatening complications during infancy. Additional congenital heart defects that have occurred in the VACTERL association include atrial septal defects (ASDs); hypoplastic left heart syndrome (a life-treating condition in which there is underdevelopment of the left ventricle, the aortic and/or mitral valve, and the ascending aorta); transposition of the great arteries (a condition in which the aorta and pulmonary artery are switched in positions); a complex malformation known as tetralogy of Fallot; and patent ductus arteriosus [a condition in which the passage between the blood vessel that leads to the lungs (pulmonary arteries) and the major artery of the body (aorta) fails to close after birth]. (For more information on those conditions, choose the name of the disorder as your search term in the Rare Disease Database.)Tracheoesophageal Fistula and/or Esophageal AtresiaAn abnormal connection between the trachea and the esophagus (tracheoesophageal fistula) is the most common birth defect in the VACTERL association. The malformation potentially allows food to be inhaled (aspirated) into the lungs, which, in turn, may result in respiratory infections (e.g., pneumonia) and failure to thrive. Esophageal atresia, a malformation in which the esophagus narrows to a thin cord or ends in a blind pouch rather than providing passage to the stomach, may also be present. These two conditions may result in breathing, feeding and swallowing difficulties.Renal AbnormalitiesA variety of abnormalities affecting the kidneys and urinary tract including absence of development of one or both kidneys (renal aplasia), malformation of one or both kidneys (renal dysplasia), displaced or malpositioned kidneys (renal ectopia), abnormal backflow (reflux) of urine into the tube (ureter) that carries urine to the bladder (vesicoureteral reflux), resulting in abnormal accumulation of urine in the kidneys (hydronephrosis). In addition, affected children may experience frequent urinary tract infections and the urethral opening may be abnormally positioned at the end of the penis (hypospadias).Limb AnomaliesAnother major finding associated with VACTERL association is defects affecting the forearm on the thumb side (radius). These defects may include absence of the radius (radial aplasia), underdevelopment of the radius (radial hypoplasia), underdevelopment or absence of the thumb and/or the presence of an extra bone in the thumb (triphalangeal thumb). Other limb anomalies including extra digits (polydactyly), webbing of the digits (syndactyly), abnormal fusion of the two forearm bones (radioulnar synostosis) and lower limb malformations (such as clubfoot, and hypoplasia of the great toe and tibia) have been described in VACTERL association.Other Birth DefectsAdditional birth defects that have been reported to occur in a minority of affected individuals include facial asymmetry (hemifacial microsomia), abnormal shape and size of the ears, narrowing of the larynx (laryngeal stenosis), narrowing of the passages from the back of the nose to the throat that make it possible to breathe through the nose (choanal atresia), lung malformations , protrusion of part of the intestines through an abnormal opening in the muscular abdominal wall near the umbilical cord (omphalocele), intestinal misplacement and misalignment (malrotation), and tethered spinal cord. A single umbilical artery rather than the usual two arteries has been found in a minority of infants with VACTERL association. (For information on this condition, choose “tethered spinal cord” as your search term in the Rare Disease Database.)Some infants and young children with VACTERL association may grow slower than normal. In the vast majority of patients, VACTERL association does not affect mental functioning and intelligence.With the improvement of medical and surgical care, the patient outcomes (prognosis) of VACTERL association are much better than they were before. However, affected individuals may experience medical complications throughout life. For instance, vertebral malformations might lead to scoliosis and chronic back pain, anal atresia might be associated with incontinence and/or constipation, gastro-esophageal reflux might result from TE fistula and renal anomalies are associated with an increased risk of urinary tract infection (UTI) and renal stones (nephrolithiasis). In addition, individuals with limb abnormalities and malformation might have functional limitations.
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Causes of VACTERL Association
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The exact cause of VACTERL association is unknown. Clearly, the factors that lead to the widespread malformations must influence the very early stages of embryonic development. One or more VACTERL defects have occurred with greater frequency to women with diabetes than in the general population. Rarely, VACTERL association has been associated with gene alterations including duplications or deletions (copy number variation), and mitochondrial dysfunction (the mitochondria is a cellular structure responsible for energy production in the cell).
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Causes of VACTERL Association. The exact cause of VACTERL association is unknown. Clearly, the factors that lead to the widespread malformations must influence the very early stages of embryonic development. One or more VACTERL defects have occurred with greater frequency to women with diabetes than in the general population. Rarely, VACTERL association has been associated with gene alterations including duplications or deletions (copy number variation), and mitochondrial dysfunction (the mitochondria is a cellular structure responsible for energy production in the cell).
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Affects of VACTERL Association
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Estimates place the birth prevalence of VACTERL association at about 1 per 10,000 to 40,000 live births. The true frequency may be difficult to determine because different diagnostic criteria are used in different studies. In addition, VACTERL association is likely to be underdiagnosed, especially in children with fewer problems. Some studies have shown that males might be slightly more commonly affected than females, but no association with a specific geographic region or ethnic group has been determined. VACTERL association is generally not a heritable disease, and the risk of recurrence in another child from the same parents is low.
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Affects of VACTERL Association. Estimates place the birth prevalence of VACTERL association at about 1 per 10,000 to 40,000 live births. The true frequency may be difficult to determine because different diagnostic criteria are used in different studies. In addition, VACTERL association is likely to be underdiagnosed, especially in children with fewer problems. Some studies have shown that males might be slightly more commonly affected than females, but no association with a specific geographic region or ethnic group has been determined. VACTERL association is generally not a heritable disease, and the risk of recurrence in another child from the same parents is low.
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Related disorders of VACTERL Association
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The malformations that occur in VACTERL association can be seen in a number of other disorders. To avoid misdiagnosis, a complete evaluation is required to consider other possible causes of congenital malformations. Some of the disorders that can mimic VACTERL association are heritable and some occur sporadically. Examples of such conditions are described below.VACTERL with hydrocephalus is an extremely rare genetic disorder in which the multisystem features of VACTERL association occur in addition to hydrocephalus. Hydrocephalus is a condition in which excessive accumulation of cerebrospinal fluid in the skull causes pressure on the tissues of the brain and may result in abnormally enlarged head size (macrocephaly). Additional common symptoms associated with hydrocephalus include vomiting, irritability, seizures, and downward gaze of the eyes (sunsetting). Some affected infants may experience delays in reaching developmental milestones (developmental delays). The specific birth defects that occur in VACTERL with hydrocephalus vary from one child to another. Unlike VACTERL association, VACTERL with hydrocephalus is a genetic disorder and may be inherited in an autosomal recessive or X-linked pattern. (For more information on this disorder, choose VACTERL with hydrocephalus as your search term in the Rare Disease Database.)Fanconi anemia is an inherited anemia that leads to progressive, severe bone marrow failure, also known as aplastic anemia. The disorder is characterized by weakness, severe bleeding due to insufficient blood clotting and susceptibility to infection. Fanconi anemia may also be associated with heart (cardiac), kidney (renal), and/or skeletal abnormalities. Patients are also at increased risk for developing leukemia and other cancers. There are several different subtypes (complementation groups) of Fanconi anemia, each of which is thought to result from an abnormal change (mutation) to a different gene. Fanconi anemia follows autosomal recessive inheritance. (For more information on this disorder, choose “Fanconi” as your search term in the Rare Disease Database.)CHARGE syndrome is a rare pattern of malformations that may affect several organ systems of the body. CHARGE is an acronym that stands for (C)oloboma of the eye; (H)eart defects; (A)tresia of the Choanae, meaning bony or membranous blockage of the passageway between the nose and throat; (R)etardation of growth and development and/or mental deficiency; (G)enital anomalies; and (E)ar anomalies and/or deafness. Some affected individuals may also have other findings such as a small head (microcephaly), incomplete closure of the roof of the mouth (cleft palate), an abnormal groove in the upper lip (cleft lip), swallowing difficulties, paralysis of facial nerves (facial palsy), an abnormal connection between the windpipe and the tube that carries food from the throat to the stomach (tracheoesophageal fistula) and renal malformations. CHARGE syndrome is caused by alterations in the CHD7 gene. (For more information, choose “CHARGE” as your search term in the Rare Disease Database.)Holt-Oram syndrome is a rare genetic disorder characterized by distinctive malformations of the bones of the thumbs and forearms and the heart. Holt-Oram syndrome is an autosomal dominant disorder and as such may be inherited from an affected parent. In about 40 percent of patients, the disorder is the result of a spontaneous (i.e., de novo) genetic change (i.e., new gene alteration). The disorder is associated with alterations in the TBX5 gene. (For more information on this disorder, choose Holt-Oram as your search term in the Rare Disease Database.)Townes-Brocks syndrome is a rare inherited disorder that is apparent at birth (congenital). Although symptoms and physical characteristics associated with the disorder may vary greatly in range and severity from person to person, abnormalities tend to involve the face, ears, arms and legs (limbs), gastrointestinal system, and kidneys. Some affected individuals may also have abnormalities of the heart and the reproductive organs. Townes-Brocks syndrome follows autosomal dominant pattern of inheritance and in most patients is associated with alterations in the gene SALL1. (For more information on this disorder, choose “Townes Brocks” as your search term in the Rare Disease Database.)Trisomy 18 (Edwards syndrome) is a condition where affected individual have a third copy of chromosome 18 in their cells, compared to the normal two. It shows a significant overlap with VACTERL association, especially in the prenatal period and at birth. In fact, the combination of upper limb anomalies, congenital heart defects, renal malformations and growth retardation of prenatal onset is quite common in both conditions. Marked developmental delay easily differentiates the conditions later in infancy. (For more information on this disorder, choose “trisomy 18” as your search term in the Rare Disease Database.)
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Related disorders of VACTERL Association. The malformations that occur in VACTERL association can be seen in a number of other disorders. To avoid misdiagnosis, a complete evaluation is required to consider other possible causes of congenital malformations. Some of the disorders that can mimic VACTERL association are heritable and some occur sporadically. Examples of such conditions are described below.VACTERL with hydrocephalus is an extremely rare genetic disorder in which the multisystem features of VACTERL association occur in addition to hydrocephalus. Hydrocephalus is a condition in which excessive accumulation of cerebrospinal fluid in the skull causes pressure on the tissues of the brain and may result in abnormally enlarged head size (macrocephaly). Additional common symptoms associated with hydrocephalus include vomiting, irritability, seizures, and downward gaze of the eyes (sunsetting). Some affected infants may experience delays in reaching developmental milestones (developmental delays). The specific birth defects that occur in VACTERL with hydrocephalus vary from one child to another. Unlike VACTERL association, VACTERL with hydrocephalus is a genetic disorder and may be inherited in an autosomal recessive or X-linked pattern. (For more information on this disorder, choose VACTERL with hydrocephalus as your search term in the Rare Disease Database.)Fanconi anemia is an inherited anemia that leads to progressive, severe bone marrow failure, also known as aplastic anemia. The disorder is characterized by weakness, severe bleeding due to insufficient blood clotting and susceptibility to infection. Fanconi anemia may also be associated with heart (cardiac), kidney (renal), and/or skeletal abnormalities. Patients are also at increased risk for developing leukemia and other cancers. There are several different subtypes (complementation groups) of Fanconi anemia, each of which is thought to result from an abnormal change (mutation) to a different gene. Fanconi anemia follows autosomal recessive inheritance. (For more information on this disorder, choose “Fanconi” as your search term in the Rare Disease Database.)CHARGE syndrome is a rare pattern of malformations that may affect several organ systems of the body. CHARGE is an acronym that stands for (C)oloboma of the eye; (H)eart defects; (A)tresia of the Choanae, meaning bony or membranous blockage of the passageway between the nose and throat; (R)etardation of growth and development and/or mental deficiency; (G)enital anomalies; and (E)ar anomalies and/or deafness. Some affected individuals may also have other findings such as a small head (microcephaly), incomplete closure of the roof of the mouth (cleft palate), an abnormal groove in the upper lip (cleft lip), swallowing difficulties, paralysis of facial nerves (facial palsy), an abnormal connection between the windpipe and the tube that carries food from the throat to the stomach (tracheoesophageal fistula) and renal malformations. CHARGE syndrome is caused by alterations in the CHD7 gene. (For more information, choose “CHARGE” as your search term in the Rare Disease Database.)Holt-Oram syndrome is a rare genetic disorder characterized by distinctive malformations of the bones of the thumbs and forearms and the heart. Holt-Oram syndrome is an autosomal dominant disorder and as such may be inherited from an affected parent. In about 40 percent of patients, the disorder is the result of a spontaneous (i.e., de novo) genetic change (i.e., new gene alteration). The disorder is associated with alterations in the TBX5 gene. (For more information on this disorder, choose Holt-Oram as your search term in the Rare Disease Database.)Townes-Brocks syndrome is a rare inherited disorder that is apparent at birth (congenital). Although symptoms and physical characteristics associated with the disorder may vary greatly in range and severity from person to person, abnormalities tend to involve the face, ears, arms and legs (limbs), gastrointestinal system, and kidneys. Some affected individuals may also have abnormalities of the heart and the reproductive organs. Townes-Brocks syndrome follows autosomal dominant pattern of inheritance and in most patients is associated with alterations in the gene SALL1. (For more information on this disorder, choose “Townes Brocks” as your search term in the Rare Disease Database.)Trisomy 18 (Edwards syndrome) is a condition where affected individual have a third copy of chromosome 18 in their cells, compared to the normal two. It shows a significant overlap with VACTERL association, especially in the prenatal period and at birth. In fact, the combination of upper limb anomalies, congenital heart defects, renal malformations and growth retardation of prenatal onset is quite common in both conditions. Marked developmental delay easily differentiates the conditions later in infancy. (For more information on this disorder, choose “trisomy 18” as your search term in the Rare Disease Database.)
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Diagnosis of VACTERL Association
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VACTERL association is a diagnosis made when other possible causes of birth defects have been ruled out (diagnosis of exclusion). No clearly-established set or validated diagnostic criteria has been published to date, and no laboratory test exists that can diagnose or rule out VACTERL association. At the moment, the most stringent approach defines a “secure” designation of VACTERL association in presence of at least one anomaly in all three involved body parts (i.e. limbs, thorax and pelvis/lower abdomen), and “probable” in presence of two or more anomalies in two body parts. The diagnosis is a clinical diagnosis based on the defects present and therefore starts with a complete physical examination. Other tests performed will depend on the suspected birth defects. For example, X-ray imaging might be used to detect vertebral and limb anomalies and ultrasound imaging might identify cardiac or renal defects. Laboratory and genetic tests can be useful to rule out alternative diagnoses. Some malformations seen in VACTERL association might be identified before birth with imaging techniques such as prenatal ultrasound. Importantly, the presence of a single umbilical artery should prompt evaluation for VACTERL association and other birth defects.
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Diagnosis of VACTERL Association. VACTERL association is a diagnosis made when other possible causes of birth defects have been ruled out (diagnosis of exclusion). No clearly-established set or validated diagnostic criteria has been published to date, and no laboratory test exists that can diagnose or rule out VACTERL association. At the moment, the most stringent approach defines a “secure” designation of VACTERL association in presence of at least one anomaly in all three involved body parts (i.e. limbs, thorax and pelvis/lower abdomen), and “probable” in presence of two or more anomalies in two body parts. The diagnosis is a clinical diagnosis based on the defects present and therefore starts with a complete physical examination. Other tests performed will depend on the suspected birth defects. For example, X-ray imaging might be used to detect vertebral and limb anomalies and ultrasound imaging might identify cardiac or renal defects. Laboratory and genetic tests can be useful to rule out alternative diagnoses. Some malformations seen in VACTERL association might be identified before birth with imaging techniques such as prenatal ultrasound. Importantly, the presence of a single umbilical artery should prompt evaluation for VACTERL association and other birth defects.
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Therapies of VACTERL Association
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Treatment
Although children with VACTERL association may have many complications, their malformations are usually not life threatening. The treatment of VACTERL association is directed toward the specific malformations and related symptoms that occur in each individual, which often varies greatly. Many of the structural abnormalities (radial defects, heart defects, anal atresia, etc.) can be surgically corrected. In some individuals, surgery might be necessary as early as the neonatal period. Repeat surgeries might also be needed later in life to revise or further correct structural defects. A team approach is essential for optimal treatment of the condition. Individuals diagnosed with VACTERL association will need to be followed by a number of medical and developmental specialists depending on their individual needs. Some of the medical specialists who often follow individuals with VACTERL association include cardiologists, urologists, orthopedists, ear, nose and throat (ENT) physicians and clinical geneticists. Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.
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Therapies of VACTERL Association. Treatment
Although children with VACTERL association may have many complications, their malformations are usually not life threatening. The treatment of VACTERL association is directed toward the specific malformations and related symptoms that occur in each individual, which often varies greatly. Many of the structural abnormalities (radial defects, heart defects, anal atresia, etc.) can be surgically corrected. In some individuals, surgery might be necessary as early as the neonatal period. Repeat surgeries might also be needed later in life to revise or further correct structural defects. A team approach is essential for optimal treatment of the condition. Individuals diagnosed with VACTERL association will need to be followed by a number of medical and developmental specialists depending on their individual needs. Some of the medical specialists who often follow individuals with VACTERL association include cardiologists, urologists, orthopedists, ear, nose and throat (ENT) physicians and clinical geneticists. Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.
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Overview of VACTERL with Hydrocephalus
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VACTERL with hydrocephalus (VACTERL-H) is a rare genetic disorder in which the non-random congenital malformations of VACTERL association co-occur with hydrocephalus. The term VACTERL is an acronym with each letter representing the first letter of the associated malformation:(V) = vertebral abnormalities(A) = anal atresia(C) = cardiac (heart) defects(T) = tracheoesophageal fistula(E) = esophageal atresia(R) = renal (kidney) and radial abnormalities(L) = limb abnormalities(H)ydrocephalus is a condition in which accumulation of cerebrospinal fluid (CSF) in and around the brain and spinal cord causes increased pressure on the brain tissue.
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Overview of VACTERL with Hydrocephalus. VACTERL with hydrocephalus (VACTERL-H) is a rare genetic disorder in which the non-random congenital malformations of VACTERL association co-occur with hydrocephalus. The term VACTERL is an acronym with each letter representing the first letter of the associated malformation:(V) = vertebral abnormalities(A) = anal atresia(C) = cardiac (heart) defects(T) = tracheoesophageal fistula(E) = esophageal atresia(R) = renal (kidney) and radial abnormalities(L) = limb abnormalities(H)ydrocephalus is a condition in which accumulation of cerebrospinal fluid (CSF) in and around the brain and spinal cord causes increased pressure on the brain tissue.
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Symptoms of VACTERL with Hydrocephalus
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VACTERL with hydrocephalus (VACTERL-H) is a rare genetic disorder that affects multiple anatomical systems. Affected children typically present with a variety of congenital anomalies at birth, however, in some children core features of the disorder are not noted until later in life. The combination of congenital anomalies and the related symptoms may vary considerably in different affected individuals.Hydrocephalus is a condition in which excessive accumulation of cerebrospinal fluid causes increased pressure on the tissues of the brain. In infants and young children this finding may be associated with an abnormally enlarged head size (macrocephaly). Symptoms of acute hydrocephalus typically include vomiting, irritability, seizures, and in severe cases downward deviation of the eyes and eventually, if untreated, coma and death. Other important signs may include developmental delays evidenced by failure to achieve age appropriate developmental milestones and/or declining cognitive performance over time. VACTERL-H is clinically defined and typically at least three of the eight anatomical components of the disorder are considered necessary for diagnosis. Importantly, there must be no laboratory or clinical evidence of an alternative diagnosis. The defining features of the disorder are discussed individually below. Vertebral Anomalies
Vertebral anomalies typically include segmentation defects of the bones that comprise the spinal column. They are frequently associated with rib anomalies although this is not always the case. Commonly reported vertebral anomalies include hemivertebrae, “butterfly vertebrae,” and “wedge vertebrae” in which the bones of the spinal column have an abnormal shape or architecture. Additionally, vertebral fusions and supernumerary vertebrae have been described. These changes can result in the spine having an abnormal curvature, or scoliosis, which in some patients is the first sign that an underlying vertebral anomaly may be present. Anal Atresia
Imperforate anus/anal atresia is a malformation in which the anal opening or the passage that normally connects the anus and the lowest part of the large intestine (rectum) fails to develop. This condition prevents the normal passage of bowel contents and typically results in obstruction of bowel contents. While complete imperforate anus is typically noticed on the initial post-natal examination performed at birth, other less severe forms of stenosis or atresia may present later with signs and symptoms of intestinal obstruction. Signs and symptoms of anal atresia may include persistent nausea and vomiting, intestinal bloating and weight loss due to difficulties with feeding. Cardiac Defects
A wide range of congenital heart defects have been reported in children with VACTERL-H. The normal heart has four chambers. The two upper chambers, known as atria, are separated from each other by a fibrous partition known as the atrial septum. The two lower chambers are known as ventricles and are separated from each other by the ventricular septum. Valves connect the atria (left and right) to their respective ventricles. The aorta, the main vessel of arterial circulation, carries blood away from the left ventricle to the rest of the body. A ventricular septal defect (VSD) is caused by a hole or small perforation anywhere along the ventricular septum and can present with a variety of symptoms depending on the size and the location of the defect. A small ventricular septal defect may close on its own, however larger defects may affect the ability of the heart to pump blood efficiently to the lungs and the rest of the body and result in congestive heart failure. Signs and symptoms associated with heart failure may include increased respiratory rate (tachypnea), wheezing, increased heartrate (tachycardia), and growth delay in infants (failure to thrive). Additional congenital heart defects associated with VACTERL-H include atrial septal defects (ASDs); hypoplastic left heart syndrome (a life-treating condition in which there is underdevelopment of the left ventricle, the aortic and/or mitral valve, and the ascending aorta); a complex heart defect referred to as tetralogy of Fallot; transposition of the great arteries (a condition in which the aortic and pulmonary arteries are transposed); and patent ductus arteriosus [a condition in which the passage between the blood vessel that leads to the lungs (pulmonary arteries) and the major artery of the body (aorta) fails to close after birth]. (For more information on these conditions, choose the name of the disease as your search term in the Rare Disease Database.)Tracheoesophageal Fistula and/or Esophageal Atresia
A tracheoesophageal fistula is an abnormal connection between the trachea and the esophagus. This abnormal connection often leads to feeding problems and respiratory infections as a result of food being passed to the lungs inappropriately. Esophageal atresia is a condition in which the esophagus, which normally carries food from the mouth to the stomach, is narrowed or incompletely formed. This results in inability of contents of the esophagus such as food to pass to the stomach and intestines to be digested. Renal/Genitourinary Anomalies
A variety of abnormalities affecting the kidneys and urinary tract have been described in VACTERL-H. These include but are not limited to: lack of development of one or both kidneys (renal aplasia), malformation of one or both kidneys (renal dysplasia), displaced or malpositioned kidneys (renal ectopia), and abnormal backflow (reflux) of urine into the tube (ureter) that carries urine to the bladder (vesicoureteral reflux), and abnormal positioning of the urethral opening at the end of the penis (hypospadias). The presence of a renal or genitourinary anomaly can sometimes result in abnormal accumulation of urine in the kidneys (hydronephrosis) and/or frequent urinary tract infections. Limb Anomalies
Classically, anomalies of the forearm or thumb side of the forearm (radial side) have been reported in children with VACTERL-H. These include failure of the radius to grow (radial aplasia), underdevelopment of the radius (radial hypoplasia), underdevelopment or absence of the thumb and/or the presence of an extra bone in the thumb (triphalangeal tumb). However, other anomalies such as presence of extra digits (polydactyly) or missing digits (oligodactyly) of the hands, webbing of the fingers (syndactyly), and/or abnormal fusion of the two forearm bones (radioulnar synostosis) have also been described.Additionally, while not considered a core feature of VACTERL-H, the presence of a single umbilical artery (which is a vessel important for proper transport of blood and deoxygenated blood away from the fetus) is commonly reported. This finding, if present on prenatal ultrasound is important to identify as it may be the first sign an underlying disorder may be present and should prompt additional imaging testing to search for other anomalies associated with VACTERL-H. Prognosis
With the improvement of medical and surgical care, the long-term prognosis of patients with VACTERL-H has improved. However, even with early diagnosis and improvements in care, affected individuals often experience a number of medical complications as a result of the presence of specific congenital anomalies. Vertebral malformations often result in chronic back pain, anal atresia often results in incontinence and/or chronic constipation, gastro-esophageal reflux can be a consequence of tracheoesophageal fistulas, and renal anomalies are often associated with increased frequency of urinary tract infections (UTI) and the occurrence of renal stones (nephrolithiasis).
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Symptoms of VACTERL with Hydrocephalus. VACTERL with hydrocephalus (VACTERL-H) is a rare genetic disorder that affects multiple anatomical systems. Affected children typically present with a variety of congenital anomalies at birth, however, in some children core features of the disorder are not noted until later in life. The combination of congenital anomalies and the related symptoms may vary considerably in different affected individuals.Hydrocephalus is a condition in which excessive accumulation of cerebrospinal fluid causes increased pressure on the tissues of the brain. In infants and young children this finding may be associated with an abnormally enlarged head size (macrocephaly). Symptoms of acute hydrocephalus typically include vomiting, irritability, seizures, and in severe cases downward deviation of the eyes and eventually, if untreated, coma and death. Other important signs may include developmental delays evidenced by failure to achieve age appropriate developmental milestones and/or declining cognitive performance over time. VACTERL-H is clinically defined and typically at least three of the eight anatomical components of the disorder are considered necessary for diagnosis. Importantly, there must be no laboratory or clinical evidence of an alternative diagnosis. The defining features of the disorder are discussed individually below. Vertebral Anomalies
Vertebral anomalies typically include segmentation defects of the bones that comprise the spinal column. They are frequently associated with rib anomalies although this is not always the case. Commonly reported vertebral anomalies include hemivertebrae, “butterfly vertebrae,” and “wedge vertebrae” in which the bones of the spinal column have an abnormal shape or architecture. Additionally, vertebral fusions and supernumerary vertebrae have been described. These changes can result in the spine having an abnormal curvature, or scoliosis, which in some patients is the first sign that an underlying vertebral anomaly may be present. Anal Atresia
Imperforate anus/anal atresia is a malformation in which the anal opening or the passage that normally connects the anus and the lowest part of the large intestine (rectum) fails to develop. This condition prevents the normal passage of bowel contents and typically results in obstruction of bowel contents. While complete imperforate anus is typically noticed on the initial post-natal examination performed at birth, other less severe forms of stenosis or atresia may present later with signs and symptoms of intestinal obstruction. Signs and symptoms of anal atresia may include persistent nausea and vomiting, intestinal bloating and weight loss due to difficulties with feeding. Cardiac Defects
A wide range of congenital heart defects have been reported in children with VACTERL-H. The normal heart has four chambers. The two upper chambers, known as atria, are separated from each other by a fibrous partition known as the atrial septum. The two lower chambers are known as ventricles and are separated from each other by the ventricular septum. Valves connect the atria (left and right) to their respective ventricles. The aorta, the main vessel of arterial circulation, carries blood away from the left ventricle to the rest of the body. A ventricular septal defect (VSD) is caused by a hole or small perforation anywhere along the ventricular septum and can present with a variety of symptoms depending on the size and the location of the defect. A small ventricular septal defect may close on its own, however larger defects may affect the ability of the heart to pump blood efficiently to the lungs and the rest of the body and result in congestive heart failure. Signs and symptoms associated with heart failure may include increased respiratory rate (tachypnea), wheezing, increased heartrate (tachycardia), and growth delay in infants (failure to thrive). Additional congenital heart defects associated with VACTERL-H include atrial septal defects (ASDs); hypoplastic left heart syndrome (a life-treating condition in which there is underdevelopment of the left ventricle, the aortic and/or mitral valve, and the ascending aorta); a complex heart defect referred to as tetralogy of Fallot; transposition of the great arteries (a condition in which the aortic and pulmonary arteries are transposed); and patent ductus arteriosus [a condition in which the passage between the blood vessel that leads to the lungs (pulmonary arteries) and the major artery of the body (aorta) fails to close after birth]. (For more information on these conditions, choose the name of the disease as your search term in the Rare Disease Database.)Tracheoesophageal Fistula and/or Esophageal Atresia
A tracheoesophageal fistula is an abnormal connection between the trachea and the esophagus. This abnormal connection often leads to feeding problems and respiratory infections as a result of food being passed to the lungs inappropriately. Esophageal atresia is a condition in which the esophagus, which normally carries food from the mouth to the stomach, is narrowed or incompletely formed. This results in inability of contents of the esophagus such as food to pass to the stomach and intestines to be digested. Renal/Genitourinary Anomalies
A variety of abnormalities affecting the kidneys and urinary tract have been described in VACTERL-H. These include but are not limited to: lack of development of one or both kidneys (renal aplasia), malformation of one or both kidneys (renal dysplasia), displaced or malpositioned kidneys (renal ectopia), and abnormal backflow (reflux) of urine into the tube (ureter) that carries urine to the bladder (vesicoureteral reflux), and abnormal positioning of the urethral opening at the end of the penis (hypospadias). The presence of a renal or genitourinary anomaly can sometimes result in abnormal accumulation of urine in the kidneys (hydronephrosis) and/or frequent urinary tract infections. Limb Anomalies
Classically, anomalies of the forearm or thumb side of the forearm (radial side) have been reported in children with VACTERL-H. These include failure of the radius to grow (radial aplasia), underdevelopment of the radius (radial hypoplasia), underdevelopment or absence of the thumb and/or the presence of an extra bone in the thumb (triphalangeal tumb). However, other anomalies such as presence of extra digits (polydactyly) or missing digits (oligodactyly) of the hands, webbing of the fingers (syndactyly), and/or abnormal fusion of the two forearm bones (radioulnar synostosis) have also been described.Additionally, while not considered a core feature of VACTERL-H, the presence of a single umbilical artery (which is a vessel important for proper transport of blood and deoxygenated blood away from the fetus) is commonly reported. This finding, if present on prenatal ultrasound is important to identify as it may be the first sign an underlying disorder may be present and should prompt additional imaging testing to search for other anomalies associated with VACTERL-H. Prognosis
With the improvement of medical and surgical care, the long-term prognosis of patients with VACTERL-H has improved. However, even with early diagnosis and improvements in care, affected individuals often experience a number of medical complications as a result of the presence of specific congenital anomalies. Vertebral malformations often result in chronic back pain, anal atresia often results in incontinence and/or chronic constipation, gastro-esophageal reflux can be a consequence of tracheoesophageal fistulas, and renal anomalies are often associated with increased frequency of urinary tract infections (UTI) and the occurrence of renal stones (nephrolithiasis).
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VACTERL with Hydrocephalus
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Causes of VACTERL with Hydrocephalus
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VACTERL-H is generally considered to be a sporadic disorder, not passed down through families, and a consequence of defective differentiation of specific tissue types during early fetal development. However, in a subset of patients there is evidence for a familial or inherited component with some patients reporting multiple affected family members. In patients with a family history of VACTERL-H, the disorder is thought to show autosomal recessive or X-linked inheritance. Autosomal recessive disorders require that an individual inherits a disease-causing change from each parent. The inherited change results in the gene not to function properly. If an individual receives one working gene and one non-working gene associated with a particular disorder, the individual is said to be a carrier for that disorder, and typically does not have associated symptoms. The risk that two carrier parents will both pass their non-working/faulty gene and, therefore, have a child affected with the disorder is 25% with each pregnancy. There is a 50% risk that carriers will pass their faulty gene to each of their children. In autosomal recessive disorders the risk that a child will inherit a faulty or non-functioning gene is the same for both males and females. X-linked disorders are caused by inherited changes in genes located on the X chromosome. As males only have one X chromosome, inheriting a non-working copy of an X-linked gene is sufficient to cause disease. Females in contrast have two X chromosomes and so are considered carriers if they inherit one non-working copy of a gene. As would be expected, X-linked disorders are typically more common in males. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son. If a male with an X-linked disorder is able to reproduce, he will pass the non-working gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. For the majority of children for VACTERL-H a genetic diagnosis is never reached. However, several genes have recently been implicated in this disorder and in patients with a VACTERL-like presentation. The FANCB gene is located on the X chromosome and in addition to being reported in children with VACTERL-H, is a known cause of X-linked Fanconi anemia. Changes in FANCI, FANCL and BRCA2, and other Fanconi anemia-associated genes have also been repeatedly implicated in the disorder. It is important to rule out a diagnosis of Fanconi anemia in these children as Fanconi anemia is associated with increased risk for certain cancers. Additionally, changes in the ZIC3 and PTEN genes have been implicated in isolated cases.
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Causes of VACTERL with Hydrocephalus. VACTERL-H is generally considered to be a sporadic disorder, not passed down through families, and a consequence of defective differentiation of specific tissue types during early fetal development. However, in a subset of patients there is evidence for a familial or inherited component with some patients reporting multiple affected family members. In patients with a family history of VACTERL-H, the disorder is thought to show autosomal recessive or X-linked inheritance. Autosomal recessive disorders require that an individual inherits a disease-causing change from each parent. The inherited change results in the gene not to function properly. If an individual receives one working gene and one non-working gene associated with a particular disorder, the individual is said to be a carrier for that disorder, and typically does not have associated symptoms. The risk that two carrier parents will both pass their non-working/faulty gene and, therefore, have a child affected with the disorder is 25% with each pregnancy. There is a 50% risk that carriers will pass their faulty gene to each of their children. In autosomal recessive disorders the risk that a child will inherit a faulty or non-functioning gene is the same for both males and females. X-linked disorders are caused by inherited changes in genes located on the X chromosome. As males only have one X chromosome, inheriting a non-working copy of an X-linked gene is sufficient to cause disease. Females in contrast have two X chromosomes and so are considered carriers if they inherit one non-working copy of a gene. As would be expected, X-linked disorders are typically more common in males. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son. If a male with an X-linked disorder is able to reproduce, he will pass the non-working gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. For the majority of children for VACTERL-H a genetic diagnosis is never reached. However, several genes have recently been implicated in this disorder and in patients with a VACTERL-like presentation. The FANCB gene is located on the X chromosome and in addition to being reported in children with VACTERL-H, is a known cause of X-linked Fanconi anemia. Changes in FANCI, FANCL and BRCA2, and other Fanconi anemia-associated genes have also been repeatedly implicated in the disorder. It is important to rule out a diagnosis of Fanconi anemia in these children as Fanconi anemia is associated with increased risk for certain cancers. Additionally, changes in the ZIC3 and PTEN genes have been implicated in isolated cases.
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VACTERL with Hydrocephalus
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Affects of VACTERL with Hydrocephalus
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VACTERL with hydrocephalus is an extremely rare disorder that affects males and females in equal numbers. The exact prevalence of the disorder in the general population is unknown.
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Affects of VACTERL with Hydrocephalus. VACTERL with hydrocephalus is an extremely rare disorder that affects males and females in equal numbers. The exact prevalence of the disorder in the general population is unknown.
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VACTERL with Hydrocephalus
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Related disorders of VACTERL with Hydrocephalus
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The congenital malformations described in VACTERL-H can occur as isolated defects or as a component of other complex disorders. To avoid misdiagnosis, a complete evaluation including detailed clinical examinations and laboratory studies are often required to rule out other more common associated disorders. Some of the conditions often considered in the differential diagnosis of VACTERL-H are discussed below. Fanconi anemia is an inherited anemia that leads to progressive bone marrow failure, or aplastic anemia. Symptoms suggestive of the disorder are often severe and include weakness, increased bleeding due to inability of the body to form blood clots, and increased susceptibility to infection. Fanconi anemia is typically associated with heart (cardiac), kidney (renal), and/or skeletal anomalies often associated with VACTERL-H. However unlike children with VACTERL-H patients often have changes in skin coloring, small eyes, short stature and are at increased risk for leukemia and other cancers. There are several different subtypes (complementation groups) of Fanconi anemia, each of which is thought to result from an abnormal change (mutation) in a specific gene. Fanconi anemia follows autosomal recessive inheritance. (For more information on this disorder, choose “Fanconi” as your search term in the Rare Disease Database.)CHARGE syndrome is a rare pattern of malformations that may affect several organ systems of the body. CHARGE is an acronym that stands for (C)oloboma of the eye; (H)eart defects; (A)tresia of the choanae, or a bony or membranous blockage of the passageway between the nose and throat; (R)etardation of growth and development and/or mental deficiency; (G)enital anomalies; and (E)ar anomalies and/or deafness. Some affected individuals may also have other, variable symptoms and findings, such as a small head, incomplete closure of the roof of the mouth (cleft palate), an abnormal groove in the upper lip (cleft lip), swallowing difficulties, paralysis of facial nerves (facial palsy), an abnormal connection between the trachea and esophagus (tracheoesophageal fistula), renal malformations, and/or other features. CHARGE syndrome typically results from changes in the CHD7 gene. (For more information, choose “CHARGE” as your search term in the Rare Disease Database.)Baller-Gerold syndrome is a rare genetic disorder characterized by distinctive malformations of the skull and facial (craniofacial) area and bones of the forearms and hands. In affected infants, there is premature fusion of the fibrous joints (cranial sutures) between certain bones in the skull resulting in craniosynostosis. As a result, the head may appear unusually short and wide and/or pointed at the top (turribrachycephaly) or relatively triangular in shape (trigonocephaly). Baller-Gerold syndrome is also characterized by underdevelopment (hypoplasia) or absence (aplasia) of the bone on the outer side of the forearms (radii). In addition, the bone on the pinky side of the forearms (ulnae) can be unusually short and/or curved and the thumbs may be underdeveloped or absent. Some affected individuals also have congenital heart defects, kidney (renal) malformations, additional physical abnormalities, and/or intellectual disability. Baller-Gerold syndrome is thought to be inherited in an autosomal recessive pattern and is caused by changes in the RECQL4 gene. (For further information, choose “Baller-Gerold” as your search term in the Rare Disease Database.)
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Related disorders of VACTERL with Hydrocephalus. The congenital malformations described in VACTERL-H can occur as isolated defects or as a component of other complex disorders. To avoid misdiagnosis, a complete evaluation including detailed clinical examinations and laboratory studies are often required to rule out other more common associated disorders. Some of the conditions often considered in the differential diagnosis of VACTERL-H are discussed below. Fanconi anemia is an inherited anemia that leads to progressive bone marrow failure, or aplastic anemia. Symptoms suggestive of the disorder are often severe and include weakness, increased bleeding due to inability of the body to form blood clots, and increased susceptibility to infection. Fanconi anemia is typically associated with heart (cardiac), kidney (renal), and/or skeletal anomalies often associated with VACTERL-H. However unlike children with VACTERL-H patients often have changes in skin coloring, small eyes, short stature and are at increased risk for leukemia and other cancers. There are several different subtypes (complementation groups) of Fanconi anemia, each of which is thought to result from an abnormal change (mutation) in a specific gene. Fanconi anemia follows autosomal recessive inheritance. (For more information on this disorder, choose “Fanconi” as your search term in the Rare Disease Database.)CHARGE syndrome is a rare pattern of malformations that may affect several organ systems of the body. CHARGE is an acronym that stands for (C)oloboma of the eye; (H)eart defects; (A)tresia of the choanae, or a bony or membranous blockage of the passageway between the nose and throat; (R)etardation of growth and development and/or mental deficiency; (G)enital anomalies; and (E)ar anomalies and/or deafness. Some affected individuals may also have other, variable symptoms and findings, such as a small head, incomplete closure of the roof of the mouth (cleft palate), an abnormal groove in the upper lip (cleft lip), swallowing difficulties, paralysis of facial nerves (facial palsy), an abnormal connection between the trachea and esophagus (tracheoesophageal fistula), renal malformations, and/or other features. CHARGE syndrome typically results from changes in the CHD7 gene. (For more information, choose “CHARGE” as your search term in the Rare Disease Database.)Baller-Gerold syndrome is a rare genetic disorder characterized by distinctive malformations of the skull and facial (craniofacial) area and bones of the forearms and hands. In affected infants, there is premature fusion of the fibrous joints (cranial sutures) between certain bones in the skull resulting in craniosynostosis. As a result, the head may appear unusually short and wide and/or pointed at the top (turribrachycephaly) or relatively triangular in shape (trigonocephaly). Baller-Gerold syndrome is also characterized by underdevelopment (hypoplasia) or absence (aplasia) of the bone on the outer side of the forearms (radii). In addition, the bone on the pinky side of the forearms (ulnae) can be unusually short and/or curved and the thumbs may be underdeveloped or absent. Some affected individuals also have congenital heart defects, kidney (renal) malformations, additional physical abnormalities, and/or intellectual disability. Baller-Gerold syndrome is thought to be inherited in an autosomal recessive pattern and is caused by changes in the RECQL4 gene. (For further information, choose “Baller-Gerold” as your search term in the Rare Disease Database.)
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VACTERL with Hydrocephalus
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Diagnosis of VACTERL with Hydrocephalus
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The diagnosis of VACTERL-H is made clinically. Presence of at least three of the core features or the disorder, including presence of hydrocephalus, is usually typically considered sufficient for diagnosis. Other more common disorders should be ruled out with clinical and/or laboratory studies. Clinical diagnosis is based on the features seen and therefore starts with a complete physical examination. The diagnosis of VACTERL-H is usually made after birth, however, findings seen on prenatal imaging such as a single umbilical artery or radial aplasia may be suggestive of this diagnosis and prompt evaluation for other anomalies. Imaging studies, while not required are typically used to aid in diagnosis as milder anomalies may be difficult to diagnose on clinical examination alone.
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Diagnosis of VACTERL with Hydrocephalus. The diagnosis of VACTERL-H is made clinically. Presence of at least three of the core features or the disorder, including presence of hydrocephalus, is usually typically considered sufficient for diagnosis. Other more common disorders should be ruled out with clinical and/or laboratory studies. Clinical diagnosis is based on the features seen and therefore starts with a complete physical examination. The diagnosis of VACTERL-H is usually made after birth, however, findings seen on prenatal imaging such as a single umbilical artery or radial aplasia may be suggestive of this diagnosis and prompt evaluation for other anomalies. Imaging studies, while not required are typically used to aid in diagnosis as milder anomalies may be difficult to diagnose on clinical examination alone.
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VACTERL with Hydrocephalus
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Therapies of VACTERL with Hydrocephalus
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Treatment
The treatment of VACTERL with hydrocephalus is directed toward the specific findings in each individual so it usually differs from patient to patient. Many of the structural abnormalities (radial defects, heart defects, anal atresia, etc.) can be surgically corrected. Hydrocephalus may be treated by the insertion of a tube (shunt) to drain excess cerebrospinal fluid (CSF) away from the brain and into another part of the body, such as the abdomen where the CSF can be absorbed.A multidisciplinary approach is essential for optimal treatment given the complexity of anomalies and complications that can be associated with diagnosis. Individuals with VACTERL-H are typically followed by a number of medical and surgical specialists including cardiologists, urologists, neurosurgeons, orthopedists, and ear, nose and throat (ENT) physicians. Specific treatment and follow-up is dictated by the type and severity of the congenital anomaly. In sporadic and inherited forms of the disorder, genetic counseling is recommended for affected individuals and their families.
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Therapies of VACTERL with Hydrocephalus. Treatment
The treatment of VACTERL with hydrocephalus is directed toward the specific findings in each individual so it usually differs from patient to patient. Many of the structural abnormalities (radial defects, heart defects, anal atresia, etc.) can be surgically corrected. Hydrocephalus may be treated by the insertion of a tube (shunt) to drain excess cerebrospinal fluid (CSF) away from the brain and into another part of the body, such as the abdomen where the CSF can be absorbed.A multidisciplinary approach is essential for optimal treatment given the complexity of anomalies and complications that can be associated with diagnosis. Individuals with VACTERL-H are typically followed by a number of medical and surgical specialists including cardiologists, urologists, neurosurgeons, orthopedists, and ear, nose and throat (ENT) physicians. Specific treatment and follow-up is dictated by the type and severity of the congenital anomaly. In sporadic and inherited forms of the disorder, genetic counseling is recommended for affected individuals and their families.
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VACTERL with Hydrocephalus
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Overview of Valinemia
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Valinemia is a very rare metabolic disorder. It is characterized by elevated levels of the amino acid valine in the blood and urine caused by a deficiency of the enzyme valine transaminase. This enzyme is needed in the breakdown (metabolism) of valine. Infants with valinemia usually have a lack of appetite, vomit frequently, and fail to thrive. Low muscle tone (hypotonia) and hyperactivity also occur.The breakdown of valine involves at least seven stages and a deficiency of the appropriate enzyme at any of these stages leads to a disorder of varying severity and rarity.
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Overview of Valinemia. Valinemia is a very rare metabolic disorder. It is characterized by elevated levels of the amino acid valine in the blood and urine caused by a deficiency of the enzyme valine transaminase. This enzyme is needed in the breakdown (metabolism) of valine. Infants with valinemia usually have a lack of appetite, vomit frequently, and fail to thrive. Low muscle tone (hypotonia) and hyperactivity also occur.The breakdown of valine involves at least seven stages and a deficiency of the appropriate enzyme at any of these stages leads to a disorder of varying severity and rarity.
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Valinemia
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Symptoms of Valinemia
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Valinemia is usually present at birth. Symptoms in the newborn period include protein intolerance, metabolic acidosis, frequent vomiting, failure to thrive, and coma. The condition may become life-threatening. The levels of the amino acid valine in the blood and urine are elevated. Abnormally low muscle tone, excessive drowsiness, and/or hyperactivity can also occur.
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Symptoms of Valinemia. Valinemia is usually present at birth. Symptoms in the newborn period include protein intolerance, metabolic acidosis, frequent vomiting, failure to thrive, and coma. The condition may become life-threatening. The levels of the amino acid valine in the blood and urine are elevated. Abnormally low muscle tone, excessive drowsiness, and/or hyperactivity can also occur.
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Valinemia
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Causes of Valinemia
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Valinemia is a recessive genetic disorder. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
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Causes of Valinemia. Valinemia is a recessive genetic disorder. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
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Valinemia
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nord_1265_3
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Affects of Valinemia
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Valinemia is a rare disorder, occurring once in about 250,000 live births in the United States. It is present in affected infants at birth.
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Affects of Valinemia. Valinemia is a rare disorder, occurring once in about 250,000 live births in the United States. It is present in affected infants at birth.
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Valinemia
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nord_1265_4
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Related disorders of Valinemia
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Related disorders include maple syrup urine disease, propionic acidemia, methylmalonic acidemia, and multiple carboxylase deficiency. Maple syrup urine disease (MSUD) is an extremely rare inherited metabolic disorder characterized by a distinctive sweet odor of the urine and sweat. It is a serious disorder that, unless treated promptly and correctly, can be life threatening. Therapy must be started at the earliest possible age to achieve the best results. MSUD is manageable, just as diabetes is manageable, but care and attention must be given to diet and to the treatment of even minor illnesses. Symptoms develop because the body is unable to break down (metabolize) three of the essential amino acids, leucine, isoleucine, and valine. They are essential because they are used by the body to build proteins, and they are three of 11 amino acids that must be obtained as part of the daily diet since the body cannot synthesize them. These three amino aids share a common characteristic of chemical structure and are thus known as the branched chain amino acids (BCAAs). An affected newborn will present with abnormally high concentrations of acidic metabolic by-products of the BCAAs in the blood and other tissues (metabolic acidosis) that, if left untreated, may lead to seizures or coma, and may be life-threatening.Propionic acidemia is a rare metabolic disorder characterized by deficiency of propionyl CoA carboxylase, an enzyme involved in the breakdown (catabolism) of the chemical “building blocks” (amino acids) of certain proteins. Symptoms most commonly become apparent during the first weeks of life and may include abnormally diminished muscle tone (hypotonia), poor feeding, vomiting, listlessness (lethargy), excessive loss of fluids from bodily tissues (dehydration), and episodes of uncontrolled electrical activity in the brain (seizures). Without appropriate treatment, coma and potentially life-threatening complications may result. In rare cases, the condition may become apparent later during infancy and may be associated with less severe symptoms and findings. Propionic acidemia is inherited as an autosomal recessive trait.The methylmalonic acidemias are organic acidemias caused by an enzymatic defect in the metabolism of four amino acids (methionine, threonine, isoleucine and valine). This results in an abnormally high level of acid in the blood (academia) and body tissues. In the acute form, drowsiness, coma, and seizures may occur. Mental retardation is a long-term consequence. The disorder may be caused by a deficiency of one or more of the enzymes methylmalonyl CoA mutase, methylmalonyl racemase, or adenosylcobalamin synthetic enzymes. Excretion of methylmalonate, a product of amino acid metabolism, in the urine is abnormally high and therefore is a marker of the disorder. All known organic acidemias are inherited as autosomal recessive traits. Multiple carboxylase deficiency is a genetic metabolic disorder that leads to impaired activity of three enzymes that are dependent on the vitamin biotin: propionyl CoA carboxylase, beta-methylcrotonyl CoA carboxylase, and pyruvate carboxylase. This condition results from a defect in cellular biotin transport or metabolism. Symptoms of the disorder include acidity of the blood and body tissues (acidosis), a widespread red skin rash, baldness, and slowed physical development. The disorder occurs in both a neonatal and a late-onset form and is treatable.
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Related disorders of Valinemia. Related disorders include maple syrup urine disease, propionic acidemia, methylmalonic acidemia, and multiple carboxylase deficiency. Maple syrup urine disease (MSUD) is an extremely rare inherited metabolic disorder characterized by a distinctive sweet odor of the urine and sweat. It is a serious disorder that, unless treated promptly and correctly, can be life threatening. Therapy must be started at the earliest possible age to achieve the best results. MSUD is manageable, just as diabetes is manageable, but care and attention must be given to diet and to the treatment of even minor illnesses. Symptoms develop because the body is unable to break down (metabolize) three of the essential amino acids, leucine, isoleucine, and valine. They are essential because they are used by the body to build proteins, and they are three of 11 amino acids that must be obtained as part of the daily diet since the body cannot synthesize them. These three amino aids share a common characteristic of chemical structure and are thus known as the branched chain amino acids (BCAAs). An affected newborn will present with abnormally high concentrations of acidic metabolic by-products of the BCAAs in the blood and other tissues (metabolic acidosis) that, if left untreated, may lead to seizures or coma, and may be life-threatening.Propionic acidemia is a rare metabolic disorder characterized by deficiency of propionyl CoA carboxylase, an enzyme involved in the breakdown (catabolism) of the chemical “building blocks” (amino acids) of certain proteins. Symptoms most commonly become apparent during the first weeks of life and may include abnormally diminished muscle tone (hypotonia), poor feeding, vomiting, listlessness (lethargy), excessive loss of fluids from bodily tissues (dehydration), and episodes of uncontrolled electrical activity in the brain (seizures). Without appropriate treatment, coma and potentially life-threatening complications may result. In rare cases, the condition may become apparent later during infancy and may be associated with less severe symptoms and findings. Propionic acidemia is inherited as an autosomal recessive trait.The methylmalonic acidemias are organic acidemias caused by an enzymatic defect in the metabolism of four amino acids (methionine, threonine, isoleucine and valine). This results in an abnormally high level of acid in the blood (academia) and body tissues. In the acute form, drowsiness, coma, and seizures may occur. Mental retardation is a long-term consequence. The disorder may be caused by a deficiency of one or more of the enzymes methylmalonyl CoA mutase, methylmalonyl racemase, or adenosylcobalamin synthetic enzymes. Excretion of methylmalonate, a product of amino acid metabolism, in the urine is abnormally high and therefore is a marker of the disorder. All known organic acidemias are inherited as autosomal recessive traits. Multiple carboxylase deficiency is a genetic metabolic disorder that leads to impaired activity of three enzymes that are dependent on the vitamin biotin: propionyl CoA carboxylase, beta-methylcrotonyl CoA carboxylase, and pyruvate carboxylase. This condition results from a defect in cellular biotin transport or metabolism. Symptoms of the disorder include acidity of the blood and body tissues (acidosis), a widespread red skin rash, baldness, and slowed physical development. The disorder occurs in both a neonatal and a late-onset form and is treatable.
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Valinemia
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Diagnosis of Valinemia
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Diagnosis depends on the precise laboratory identification and measurement of metabolic products that accumulate in the blood and urine. Sophisticated chromatographic equipment is required to identify these metabolites.
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Diagnosis of Valinemia. Diagnosis depends on the precise laboratory identification and measurement of metabolic products that accumulate in the blood and urine. Sophisticated chromatographic equipment is required to identify these metabolites.
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Therapies of Valinemia
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TreatmentA diet low in valine introduced during early infancy usually improves symptoms of valinemia, and lowers the valine concentrations in the blood to normal levels.
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Therapies of Valinemia. TreatmentA diet low in valine introduced during early infancy usually improves symptoms of valinemia, and lowers the valine concentrations in the blood to normal levels.
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Valinemia
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Overview of Variegate Porphyria
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SummaryVariegate porphyria is a rare genetic metabolic disorder characterized by deficient function of the enzyme protoporphyrinogen oxidase (PPO or PPOX). This deficiency is caused by mutations in the PPOX gene, and leads to the accumulation of certain chemicals called porphyrins and porphyrin precursors in the body, which, in turn, can potentially result in a variety of symptoms. Specific symptoms can vary greatly from one person to another. Some affected individuals present with skin symptoms, some with neurological symptoms and some with both. Blistering and fragility of sun-exposed skin are the most common skin (cutaneous) symptoms. Common neurological symptoms include abdominal pain, nausea, vomiting, constipation, extremity pain and weakness, anxiety, restlessness and convulsions. Many different PPOX gene mutations have been identified in different families with variegate porphyria. The genetic mutation in a family is inherited as an autosomal dominant trait, but many individuals who inherit a PPOX gene mutation do not develop any symptoms (asymptomatic).IntroductionVariegate porphyria is one of a group of disorders known as the porphyrias. The porphyrias are characterized by abnormally high levels of porphyrins or porphyrin precursors in the body. Each porphyria is due to a deficiency of a different enzyme. There are eight enzymes in the pathway for making heme, which is a part of hemoglobin and other hemoproteins. There are at least eight types of porphyria. The symptoms associated with the various types of porphyria differ, depending upon the specific enzyme that is deficient. It is important to note that people who have one type of porphyria do not develop any of the other types. Porphyrias are generally classified into two groups: the “hepatic” and “erythropoietic” types. Porphyrins and porphyrin precursors originate in excess amounts from the liver in the hepatic types, and mostly from the bone marrow in the erythropoietic types. Variegate porphyria is a hepatic form of porphyria.Protoporphyrinogen and coproporphyrinogen accumulate in the liver in variegate porphyria because PPOX is deficient, and become oxidized to protoporphyrin and coproporphyrin, which are transported in the blood plasma and cause the skin to be sensitive to sunlight. The neurological symptoms are associated with accumulation of porphyrin precursors, namely, delta-aminolevulinic acid (ALA) and porphobilinogen (PBG).
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Overview of Variegate Porphyria. SummaryVariegate porphyria is a rare genetic metabolic disorder characterized by deficient function of the enzyme protoporphyrinogen oxidase (PPO or PPOX). This deficiency is caused by mutations in the PPOX gene, and leads to the accumulation of certain chemicals called porphyrins and porphyrin precursors in the body, which, in turn, can potentially result in a variety of symptoms. Specific symptoms can vary greatly from one person to another. Some affected individuals present with skin symptoms, some with neurological symptoms and some with both. Blistering and fragility of sun-exposed skin are the most common skin (cutaneous) symptoms. Common neurological symptoms include abdominal pain, nausea, vomiting, constipation, extremity pain and weakness, anxiety, restlessness and convulsions. Many different PPOX gene mutations have been identified in different families with variegate porphyria. The genetic mutation in a family is inherited as an autosomal dominant trait, but many individuals who inherit a PPOX gene mutation do not develop any symptoms (asymptomatic).IntroductionVariegate porphyria is one of a group of disorders known as the porphyrias. The porphyrias are characterized by abnormally high levels of porphyrins or porphyrin precursors in the body. Each porphyria is due to a deficiency of a different enzyme. There are eight enzymes in the pathway for making heme, which is a part of hemoglobin and other hemoproteins. There are at least eight types of porphyria. The symptoms associated with the various types of porphyria differ, depending upon the specific enzyme that is deficient. It is important to note that people who have one type of porphyria do not develop any of the other types. Porphyrias are generally classified into two groups: the “hepatic” and “erythropoietic” types. Porphyrins and porphyrin precursors originate in excess amounts from the liver in the hepatic types, and mostly from the bone marrow in the erythropoietic types. Variegate porphyria is a hepatic form of porphyria.Protoporphyrinogen and coproporphyrinogen accumulate in the liver in variegate porphyria because PPOX is deficient, and become oxidized to protoporphyrin and coproporphyrin, which are transported in the blood plasma and cause the skin to be sensitive to sunlight. The neurological symptoms are associated with accumulation of porphyrin precursors, namely, delta-aminolevulinic acid (ALA) and porphobilinogen (PBG).
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Variegate Porphyria
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Symptoms of Variegate Porphyria
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The symptoms and severity of variegate porphyria can vary greatly from one person to another. Symptoms are rarely apparent before puberty. Affected individuals often develop skin (cutaneous) or neurological abnormalities or both. It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their physicians about their specific clinical situations, associated symptoms and overall prognosis.Many individuals with variegate porphyria may not develop any notable symptoms (asymptomatic) for all or most of their lives. Other individuals can develop a variety of symptoms. Cutaneous symptoms, when they occur, are chronic and commonly last for months or years. Neurological symptoms usually occur as acute attacks lasting days or weeks and only occasionally become chronic. Acute attacks can be severe, and may occur in the absence of skin abnormalities.Symptoms during an attack may include intense abdominal discomfort or pain, which is usually constant, lasting hours to days, but may be cramping. Nausea, vomiting, constipation (occasionally diarrhea) and trouble urinating may also occur during acute attacks. These symptoms are due to effects on the nerves of the bowel and bladder. The central nervous system is often affected with insomnia, restlessness, agitation, confusion, hallucinations and convulsions. The level of sodium in the blood may decrease and cause convulsions. The peripheral nerves are affected, leading to severe pain in the extremities, back or chest and, especially with more prolonged attacks, paralysis of muscles. This may progress to involve all extremities and the muscles that control breathing. The urine may be reddish due to increased porphyrins, and dark due to porphobilin, which is a brownish degradation product of PBG.Increases in heart rate and blood pressure are very common on examination during attacks. Fever is usually absent or slight, because the neuropathy is not inflammatory. Reflexes may be increased initially and decreased or absent if motor neuropathy advances.A variety of triggers are known to set off an acute attack. These include a variety of drugs, steroid hormones alcohol, decreased intake of calories or carbohydrates, and metabolic or possibly psychological stress. Women may have attacks during the second half of the menstrual cycle when progesterone levels are highest. In some cases, no trigger can be identified.Chronic skin abnormalities result from photosensitivity, a condition in which the skin is abnormally sensitive to sunlight, causing blistering skin lesions. Symptoms include abnormally fragile skin, blisters (bullae), milia, which are tiny, white bumps or cysts, and excessive hair growth (hypertrichosis). Blisters are slow to heal and can scar leaving patches of skin that are abnormally dark (hyperpigmentation) or light (hypopigmentation). Skin symptoms may be less common in individuals who live in nontropical climates. Some individuals with variegate porphyria only develop skin abnormalities, others only develop neurological symptoms and some have both.Individuals with variegate porphyria are at an increased risk for developing a form of liver cancer known as hepatocellular carcinoma. There is also risk of developing chronic kidney disease.
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Symptoms of Variegate Porphyria. The symptoms and severity of variegate porphyria can vary greatly from one person to another. Symptoms are rarely apparent before puberty. Affected individuals often develop skin (cutaneous) or neurological abnormalities or both. It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their physicians about their specific clinical situations, associated symptoms and overall prognosis.Many individuals with variegate porphyria may not develop any notable symptoms (asymptomatic) for all or most of their lives. Other individuals can develop a variety of symptoms. Cutaneous symptoms, when they occur, are chronic and commonly last for months or years. Neurological symptoms usually occur as acute attacks lasting days or weeks and only occasionally become chronic. Acute attacks can be severe, and may occur in the absence of skin abnormalities.Symptoms during an attack may include intense abdominal discomfort or pain, which is usually constant, lasting hours to days, but may be cramping. Nausea, vomiting, constipation (occasionally diarrhea) and trouble urinating may also occur during acute attacks. These symptoms are due to effects on the nerves of the bowel and bladder. The central nervous system is often affected with insomnia, restlessness, agitation, confusion, hallucinations and convulsions. The level of sodium in the blood may decrease and cause convulsions. The peripheral nerves are affected, leading to severe pain in the extremities, back or chest and, especially with more prolonged attacks, paralysis of muscles. This may progress to involve all extremities and the muscles that control breathing. The urine may be reddish due to increased porphyrins, and dark due to porphobilin, which is a brownish degradation product of PBG.Increases in heart rate and blood pressure are very common on examination during attacks. Fever is usually absent or slight, because the neuropathy is not inflammatory. Reflexes may be increased initially and decreased or absent if motor neuropathy advances.A variety of triggers are known to set off an acute attack. These include a variety of drugs, steroid hormones alcohol, decreased intake of calories or carbohydrates, and metabolic or possibly psychological stress. Women may have attacks during the second half of the menstrual cycle when progesterone levels are highest. In some cases, no trigger can be identified.Chronic skin abnormalities result from photosensitivity, a condition in which the skin is abnormally sensitive to sunlight, causing blistering skin lesions. Symptoms include abnormally fragile skin, blisters (bullae), milia, which are tiny, white bumps or cysts, and excessive hair growth (hypertrichosis). Blisters are slow to heal and can scar leaving patches of skin that are abnormally dark (hyperpigmentation) or light (hypopigmentation). Skin symptoms may be less common in individuals who live in nontropical climates. Some individuals with variegate porphyria only develop skin abnormalities, others only develop neurological symptoms and some have both.Individuals with variegate porphyria are at an increased risk for developing a form of liver cancer known as hepatocellular carcinoma. There is also risk of developing chronic kidney disease.
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Variegate Porphyria
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Causes of Variegate Porphyria
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Variegate porphyria is caused by mutations of the PPOX gene. A PPOX mutation is inherited as an autosomal dominant trait within a family. Dominant genetic disorders occur when only a single copy of an altered gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the altered gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.In some individuals, the disorder is due to a spontaneous (de novo) genetic mutation that occurs in the egg or sperm cell. In such situations, the disorder is not inherited from the parents. The PPOX gene contains instructions for creating PPOX, one of the eight enzymes necessary for the production of heme. Heme is an iron-containing porphyrin (iron protoporphyrin) and is a part of many heme-containing proteins (hemoproteins) in the body. Hemoproteins interact with oxygen and some are involved in electron transport and energy metabolism. The best known hemoprotein is hemoglobin, which is made in the bone marrow, makes red blood cells red, and transports oxygen from the lungs to other tissues. However, the bone marrow and hemoglobin are not affected in variegate porphyria. In this condition the heme pathway in the liver, which makes heme for other important hemoproteins, is affected.Mutations of the PPOX gene result in deficient levels of PPOX, which, in turn, disrupts the biochemical process to create heme in the liver. This disruption causes porphyrins and porphyrin precursors to accumulate in the liver and these are then transported to other parts of the body to affect the nervous system and skin.A variety of different triggers are known to lead to attacks in individuals with variegate porphyria. Many of these triggers act by increasing heme synthesis in the liver, which makes the PPOX deficiency more significant and increases the accumulation of porphyrins and porphyrin precursors. As noted above, triggers include a variety of drugs, hormones (especially progesterone), reduced intake of calories and carbohydrate, alcohol, and stress induced by infection or other illness.
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Causes of Variegate Porphyria. Variegate porphyria is caused by mutations of the PPOX gene. A PPOX mutation is inherited as an autosomal dominant trait within a family. Dominant genetic disorders occur when only a single copy of an altered gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the altered gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.In some individuals, the disorder is due to a spontaneous (de novo) genetic mutation that occurs in the egg or sperm cell. In such situations, the disorder is not inherited from the parents. The PPOX gene contains instructions for creating PPOX, one of the eight enzymes necessary for the production of heme. Heme is an iron-containing porphyrin (iron protoporphyrin) and is a part of many heme-containing proteins (hemoproteins) in the body. Hemoproteins interact with oxygen and some are involved in electron transport and energy metabolism. The best known hemoprotein is hemoglobin, which is made in the bone marrow, makes red blood cells red, and transports oxygen from the lungs to other tissues. However, the bone marrow and hemoglobin are not affected in variegate porphyria. In this condition the heme pathway in the liver, which makes heme for other important hemoproteins, is affected.Mutations of the PPOX gene result in deficient levels of PPOX, which, in turn, disrupts the biochemical process to create heme in the liver. This disruption causes porphyrins and porphyrin precursors to accumulate in the liver and these are then transported to other parts of the body to affect the nervous system and skin.A variety of different triggers are known to lead to attacks in individuals with variegate porphyria. Many of these triggers act by increasing heme synthesis in the liver, which makes the PPOX deficiency more significant and increases the accumulation of porphyrins and porphyrin precursors. As noted above, triggers include a variety of drugs, hormones (especially progesterone), reduced intake of calories and carbohydrate, alcohol, and stress induced by infection or other illness.
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Variegate Porphyria
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Affects of Variegate Porphyria
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Some reports suggest that variegate porphyria affects more women than men. The incidence is estimated to occur in 1 in 100,000 individuals in the general population in European populations. The disorder occurs with the greatest frequency in South Africa in individuals of Dutch ancestry due to a founder effect. A founder effect is when a small isolated population of settlers (founders) expands over several generations leading to a high prevalence of a genetic trait. Most individuals with variegate porphyria in South Africa carry the same PPOX mutation and are descendants of a Dutch settler from the late 1600s. The incidence of variegate porphyria in South Africa among Caucasians is estimated to be 1 to 3 in 1,000 individuals.Although, in most cases, the symptoms of variegate porphyria occur after puberty or later, very rare cases have been described where symptoms developed during infancy or childhood. Most such cases are homozygous cases who have inherited a PPOX mutation from each parent. Homozygous cases may have impaired mental development and photosensitivity, but acute attacks are not prominent.
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Affects of Variegate Porphyria. Some reports suggest that variegate porphyria affects more women than men. The incidence is estimated to occur in 1 in 100,000 individuals in the general population in European populations. The disorder occurs with the greatest frequency in South Africa in individuals of Dutch ancestry due to a founder effect. A founder effect is when a small isolated population of settlers (founders) expands over several generations leading to a high prevalence of a genetic trait. Most individuals with variegate porphyria in South Africa carry the same PPOX mutation and are descendants of a Dutch settler from the late 1600s. The incidence of variegate porphyria in South Africa among Caucasians is estimated to be 1 to 3 in 1,000 individuals.Although, in most cases, the symptoms of variegate porphyria occur after puberty or later, very rare cases have been described where symptoms developed during infancy or childhood. Most such cases are homozygous cases who have inherited a PPOX mutation from each parent. Homozygous cases may have impaired mental development and photosensitivity, but acute attacks are not prominent.
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Variegate Porphyria
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Related disorders of Variegate Porphyria
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Acute attacks of variegate porphyria are identical to those that occur in three other porphyrias. Therefore, these are often classified as acute porphyrias based on these symptoms.Acute intermittent porphyria (AIP) is the most common of the acute porphyrias in countries other than South Africa, and is due to a deficiency of the enzyme porphobilinogen deaminase (PBGD), also known as hydroxymethylbilane synthase (HMBS) and formerly as uroporphyrinogen I-synthase. The factors that trigger acute attacks are the same as in variegate porphyria. Cutaneous symptoms do not occur in this condition. Hereditary coproporphyria also shares the same clinical features, and is due to a deficiency or coproporphyrinogen oxidase activity. Blistering skin lesions may occur, but much less commonly than in variegate porphyria. The fourth and least common acute porphyria is delta-aminolevulinic acid dehydratase porphyria (ALAD porphyria), which results from the deficiency of the second enzyme in the pathway to make heme. This disease, in contrast to the other three acute porphyrias, is autosomal recessive. Only six cases are documented in the literature. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)The skin lesions caused by variegate porphyria are identical to those in porphyria cutanea tarda, which is the most common of all the porphyrias. This disease does not cause neurological symptoms. It is caused by a deficiency of the uroporphyrinogen decarboxylase (UROD), the fifth enzyme in the heme pathway, in the liver. The severe deficiency of this enzyme in the liver is acquired and requires the presence of iron, but some patients have an inherited UROD gene mutation that acts as a predisposing susceptibility factor. Other susceptibility factors include alcohol, smoking, estrogens, hepatitis C, HIV and hemochromatosis (HFE) gene mutations. This porphyria responds to treatment by repeated phlebotomies to remove excess iron, or to a low-dose regimen of hydroxychloroquine (or chloroquine). (For more information on this disorder, choose “porphyria cutanea tarda” as your search term in the Rare Disease Database.)Congenital erythropoietic porphyria is a very rare inherited metabolic disorder resulting from the deficient function of the enzyme uroporphyrinogen III synthase (UROS), the fourth enzyme in the heme biosynthetic pathway. This is an autosomal recessive genetic disorder. The skin lesions in this disease are similar to those found in porphyria cutanea tarda and variegate porphyria, but are usually much more severe, reflecting much higher porphyrin levels. (For more information on this disorder, choose “congenital erythropoietic porphyria” as your search term in the Rare Disease Database.)Erythropoietic protoporphyria is the third most common porphyria and the most common in children. This disease is usually due to a deficiency of ferrochelatase, the last enzyme in the heme pathway. Some cases are due to gene mutations that increase production of delta-aminolevulinic acid synthase, the first enzyme in the pathway specifically in the marrow. Erythropoietic protoporphyria causes an acute nonblistering photosensitivity that is quite different from the skin manifestations of the other cutaneous porphyrias. (For more information on this disorder, choose “erythropoietic porphyria” as your search term in the Rare Disease Database.)
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Related disorders of Variegate Porphyria. Acute attacks of variegate porphyria are identical to those that occur in three other porphyrias. Therefore, these are often classified as acute porphyrias based on these symptoms.Acute intermittent porphyria (AIP) is the most common of the acute porphyrias in countries other than South Africa, and is due to a deficiency of the enzyme porphobilinogen deaminase (PBGD), also known as hydroxymethylbilane synthase (HMBS) and formerly as uroporphyrinogen I-synthase. The factors that trigger acute attacks are the same as in variegate porphyria. Cutaneous symptoms do not occur in this condition. Hereditary coproporphyria also shares the same clinical features, and is due to a deficiency or coproporphyrinogen oxidase activity. Blistering skin lesions may occur, but much less commonly than in variegate porphyria. The fourth and least common acute porphyria is delta-aminolevulinic acid dehydratase porphyria (ALAD porphyria), which results from the deficiency of the second enzyme in the pathway to make heme. This disease, in contrast to the other three acute porphyrias, is autosomal recessive. Only six cases are documented in the literature. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)The skin lesions caused by variegate porphyria are identical to those in porphyria cutanea tarda, which is the most common of all the porphyrias. This disease does not cause neurological symptoms. It is caused by a deficiency of the uroporphyrinogen decarboxylase (UROD), the fifth enzyme in the heme pathway, in the liver. The severe deficiency of this enzyme in the liver is acquired and requires the presence of iron, but some patients have an inherited UROD gene mutation that acts as a predisposing susceptibility factor. Other susceptibility factors include alcohol, smoking, estrogens, hepatitis C, HIV and hemochromatosis (HFE) gene mutations. This porphyria responds to treatment by repeated phlebotomies to remove excess iron, or to a low-dose regimen of hydroxychloroquine (or chloroquine). (For more information on this disorder, choose “porphyria cutanea tarda” as your search term in the Rare Disease Database.)Congenital erythropoietic porphyria is a very rare inherited metabolic disorder resulting from the deficient function of the enzyme uroporphyrinogen III synthase (UROS), the fourth enzyme in the heme biosynthetic pathway. This is an autosomal recessive genetic disorder. The skin lesions in this disease are similar to those found in porphyria cutanea tarda and variegate porphyria, but are usually much more severe, reflecting much higher porphyrin levels. (For more information on this disorder, choose “congenital erythropoietic porphyria” as your search term in the Rare Disease Database.)Erythropoietic protoporphyria is the third most common porphyria and the most common in children. This disease is usually due to a deficiency of ferrochelatase, the last enzyme in the heme pathway. Some cases are due to gene mutations that increase production of delta-aminolevulinic acid synthase, the first enzyme in the pathway specifically in the marrow. Erythropoietic protoporphyria causes an acute nonblistering photosensitivity that is quite different from the skin manifestations of the other cutaneous porphyrias. (For more information on this disorder, choose “erythropoietic porphyria” as your search term in the Rare Disease Database.)
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Variegate Porphyria
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Diagnosis of Variegate Porphyria
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A diagnosis of variegate porphyria is suspected based upon symptoms and examination of the skin. None of the symptoms are specific, so the diagnosis must be confirmed by biochemical testing. In the evaluation of neurological symptoms, the other acute porphyrias need to be considered. For initial screening, a spot urine sample should be obtained for measurement of PBG, ALA and total porphyrins. If none of these is elevated, acute porphyrias can be excluded as a cause of recent or concurrent symptoms. PBG measurement is most important and specific for acute porphyrias. However PBG and ALA may be less elevated and return to normal more quickly after an attack of variegate porphyria (or hereditary coproporphyria) than in acute intermittent porphyria. Therefore, measurement of total urine porphyrins is important, keeping in mind that an elevation of urine porphyrins can occur in many other medical conditions.When blistering skin manifestations are present, porphyria cutanea tarda, hereditary coproporphyria and even congenital erythropoietic porphyria are possibilities to differentiate. Measurement of plasma and fecal porphyrins and determining the wavelength of the fluorescence peak of plasma porphyrins is useful in differentiating these conditions.Molecular genetic testing to identify a PPOX mutation is recommended for all biochemically confirmed cases of variegate porphyria. Molecular testing is sometimes useful when symptoms have been absent for months or years and biochemical abnormalities are no longer present. Knowing the PPOX mutation is a family enables other family members to be tested reliably for the same mutation.
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Diagnosis of Variegate Porphyria. A diagnosis of variegate porphyria is suspected based upon symptoms and examination of the skin. None of the symptoms are specific, so the diagnosis must be confirmed by biochemical testing. In the evaluation of neurological symptoms, the other acute porphyrias need to be considered. For initial screening, a spot urine sample should be obtained for measurement of PBG, ALA and total porphyrins. If none of these is elevated, acute porphyrias can be excluded as a cause of recent or concurrent symptoms. PBG measurement is most important and specific for acute porphyrias. However PBG and ALA may be less elevated and return to normal more quickly after an attack of variegate porphyria (or hereditary coproporphyria) than in acute intermittent porphyria. Therefore, measurement of total urine porphyrins is important, keeping in mind that an elevation of urine porphyrins can occur in many other medical conditions.When blistering skin manifestations are present, porphyria cutanea tarda, hereditary coproporphyria and even congenital erythropoietic porphyria are possibilities to differentiate. Measurement of plasma and fecal porphyrins and determining the wavelength of the fluorescence peak of plasma porphyrins is useful in differentiating these conditions.Molecular genetic testing to identify a PPOX mutation is recommended for all biochemically confirmed cases of variegate porphyria. Molecular testing is sometimes useful when symptoms have been absent for months or years and biochemical abnormalities are no longer present. Knowing the PPOX mutation is a family enables other family members to be tested reliably for the same mutation.
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Variegate Porphyria
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Therapies of Variegate Porphyria
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TreatmentThe treatment of acute attacks of variegate porphyria is the same as for acute intermittent porphyria and hereditary coproporphyria. Hospitalization is usually indicated for pain control and treatment of other severe symptoms such as nausea and vomiting, electrolyte imbalances and convulsions. Monitoring for these manifestations as well and muscle weakness and respiratory embarrassment is also indicated in severe attacks. A narcotic analgesic is generally required for pain, and a phenothiazine, such as Compro (prochlorperazine) or Thorazine (chlorpromazine), or Zofran (ondansetron) for nausea and vomiting. Triggering factors should be identified and discontinued when possible. The American Porphyria Foundation’s website includes a database of safe and unsafe drugs (see Resources section of this report). Specific therapies are hemin for injection, which is available in the U.S. as Panhematin (lyophilized hematin), and glucose loading. Hemin represses the heme pathway in the liver and lowers ALA, PBG and porphyrins, and is associated with more rapid recovery from an attack. Glucose given intravenously has a similar effect, but because it is less potent is used only for mild attacks, or until hemin can be obtained from the manufacturer. In 2019, the Food and Drug Administration (FDA) approved Givlaari (givosiran) for the treatment of acute hepatic porphyria, including variegate porphyria, in adult patients. Givlaari aims to prevent attacks from occurring. Tagamet (cimetidine) has also been recommended based on little evidence and should not be used as a substitute for hemin or even glucose. Acute attacks are potentially life-threatening especially if not treated promptly, but most patients recover completely. Future attacks can be prevented by avoiding triggering factors. Frequent attacks that are cyclic can be prevented by administration of a GnRH analogue. Frequent noncyclic attacks are rare and can sometimes be prevented by prophylactic administration of hemin – perhaps a single dose weekly. Chronic skin manifestations may improve if triggering factors are avoided. Hemin and glucose have not been found to be useful for this and other chronic symptoms. Treatments that are effective in porphyria cutanea tarda, namely phlebotomies and low-dose Plaquenil (hydroxychloroquine) or Aralen (chloroquine), are not useful in variegate porphyria because, even though the skin abnormalities are the same, the underlying abnormalities in the liver are very different. Avoidance of exposure to sunlight is important and may lead to gradual improvement. The use of appropriate clothing (e.g., hats, long sleeved shirts) and opaque sunscreen products can be beneficial (regular sunscreen products are generally ineffective). More specific information on these preventive measures is available from the American Porphyria Foundation (see Resources section of this report). Individuals with variegate porphyria should carry Medic Alert bracelets or wallet cards. Individuals may also carry a list of drugs that they need to avoid, but such lists may not be up to date and it is best to refer to the American Porphyria Foundation’s website when needed. Genetic counseling may be of benefit for affected individuals and their families.
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Therapies of Variegate Porphyria. TreatmentThe treatment of acute attacks of variegate porphyria is the same as for acute intermittent porphyria and hereditary coproporphyria. Hospitalization is usually indicated for pain control and treatment of other severe symptoms such as nausea and vomiting, electrolyte imbalances and convulsions. Monitoring for these manifestations as well and muscle weakness and respiratory embarrassment is also indicated in severe attacks. A narcotic analgesic is generally required for pain, and a phenothiazine, such as Compro (prochlorperazine) or Thorazine (chlorpromazine), or Zofran (ondansetron) for nausea and vomiting. Triggering factors should be identified and discontinued when possible. The American Porphyria Foundation’s website includes a database of safe and unsafe drugs (see Resources section of this report). Specific therapies are hemin for injection, which is available in the U.S. as Panhematin (lyophilized hematin), and glucose loading. Hemin represses the heme pathway in the liver and lowers ALA, PBG and porphyrins, and is associated with more rapid recovery from an attack. Glucose given intravenously has a similar effect, but because it is less potent is used only for mild attacks, or until hemin can be obtained from the manufacturer. In 2019, the Food and Drug Administration (FDA) approved Givlaari (givosiran) for the treatment of acute hepatic porphyria, including variegate porphyria, in adult patients. Givlaari aims to prevent attacks from occurring. Tagamet (cimetidine) has also been recommended based on little evidence and should not be used as a substitute for hemin or even glucose. Acute attacks are potentially life-threatening especially if not treated promptly, but most patients recover completely. Future attacks can be prevented by avoiding triggering factors. Frequent attacks that are cyclic can be prevented by administration of a GnRH analogue. Frequent noncyclic attacks are rare and can sometimes be prevented by prophylactic administration of hemin – perhaps a single dose weekly. Chronic skin manifestations may improve if triggering factors are avoided. Hemin and glucose have not been found to be useful for this and other chronic symptoms. Treatments that are effective in porphyria cutanea tarda, namely phlebotomies and low-dose Plaquenil (hydroxychloroquine) or Aralen (chloroquine), are not useful in variegate porphyria because, even though the skin abnormalities are the same, the underlying abnormalities in the liver are very different. Avoidance of exposure to sunlight is important and may lead to gradual improvement. The use of appropriate clothing (e.g., hats, long sleeved shirts) and opaque sunscreen products can be beneficial (regular sunscreen products are generally ineffective). More specific information on these preventive measures is available from the American Porphyria Foundation (see Resources section of this report). Individuals with variegate porphyria should carry Medic Alert bracelets or wallet cards. Individuals may also carry a list of drugs that they need to avoid, but such lists may not be up to date and it is best to refer to the American Porphyria Foundation’s website when needed. Genetic counseling may be of benefit for affected individuals and their families.
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Overview of Vascular Malformations of the Brain
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As the name suggests, vascular malformations of the brain is an umbrella term for at least six conditions in which blood vessels of the brain are affected. Such malformations are classified into several types in which the symptoms, severity, and causes vary. These types of VMB are: (1) arteriovenous malformations (AVM), abnormal arteries and veins; (2) cavernous malformations (CM), enlarged blood-filled spaces; (3) venous angiomas (VA), abnormal veins; (4) telangiectasias (TA), enlarged capillary-sized vessels; (5) vein of Galen malformations (VGM); and (6) mixed malformations (MM).
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Overview of Vascular Malformations of the Brain. As the name suggests, vascular malformations of the brain is an umbrella term for at least six conditions in which blood vessels of the brain are affected. Such malformations are classified into several types in which the symptoms, severity, and causes vary. These types of VMB are: (1) arteriovenous malformations (AVM), abnormal arteries and veins; (2) cavernous malformations (CM), enlarged blood-filled spaces; (3) venous angiomas (VA), abnormal veins; (4) telangiectasias (TA), enlarged capillary-sized vessels; (5) vein of Galen malformations (VGM); and (6) mixed malformations (MM).
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Symptoms of Vascular Malformations of the Brain
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Vascular malformations of the brain may cause headaches, seizures, strokes, or bleeding in the brain (cerebral hemorrhage). Some researchers believe that the type of malformation determines the symptoms and progression of the disease. Other researchers believe that only the severity rather than the type of malformation is important. Arteriovenous malformations or AVMs affect arteries, veins, and middle- sized vessels but not capillaries. These blood vessels are enlarged, twisted, and tangled. Arteries and veins may be connected directly instead of being connected through fine capillaries for which reason they are often referred to as “shunt lesions” since the capillaries are by-passed. These abnormal “feeding” arteries progressively enlarge and as a result the “draining” veins dilate as well. The brain tissue between these vessels may be hardened or rigid (atrophied), full of a network of fine small fibers (fibrils) interspersed with flattened cells (gliotic), and sometimes may be calcified. Such malformations may, by drawing blood away from the brain, cause brain cell atrophy. Hemorrhages or seizures are commonly experienced with AVMs. (For more information on this disorder choose “Arteriovenous” for your search term in the Rare Disease Database.)Cavernous malformations, CMs (also called cavernous angiomas, or cavernous hemangiomas, or cavernomas) present as abnormally enlarged collections of blood-filled spaces. A cavernous hemangioma acts like a “blood sponge” soaking up blood that has found its way between capillaries, in the spaces between tissues (sinusoids) and “larger cavernous spaces.” These are “slow-flow lesions.” There is not usually any brain tissue in these spaces in contrast with symptoms of AVMs. Hemorrhages or seizures are also common with CMs. (For more information on this disorder choose “cavernous hemangioma” for your search term in the Rare Disease Database.)Venous angiomas (VAs) involve enlarged, tangled, and twisted veins that vary in size but do not involve the arteries. The site of these “growths” is most often just after the capillary stage of the vessel (post-capillary malformation). They may be isolated defects or associated with cavernous malformations. The defect shows itself as a “crown” of small veins (venules) that meet to form part of a larger vein (trunk). Telangiectasias are the malformations that arise as a result of the enlarging (dilation) of the tiny capillaries. These dilated capillaries make themselves known as small pink-red spots in various parts of the body such as the face, eyes, membranes that cover the brain (dura) and spinal cord (meninges), and mucous membranes (the thin moist layer lining the body's internal surfaces). (For more information on a disorder involving telangiectasias choose “hemorrhagic telangiectasia, hereditary” for your search term in the Rare Disease Database.)Vein of Galen malformations (VGMs begin while the embryo is developing. The vein of Galen is located under the cerebral hemispheres and drains the forward (anterior) and central regions of the brain into the proper sinuses. The malformations occur when the vein of Galen is not supported within the head by surrounding tissue and lacks the normal fibrous wall. Thus, the vein of Galen appears free-floating within the fluids of the cerebral spaces (sinuses). Should the pressure increase within the vein of Galen, its shape changes from a cylinder to that of a sphere. Such changes are accompanied by abnormal fetal blood circulation. In extreme cases, there may be cardiac failure or swelling of the brain (hydrocephalus).Mixed malformation is a phrase used to include any of several multiple-mixed malformations. Frequently, these malformations appear to be mixes of arteriovenous malformations with telangiectasias.
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Symptoms of Vascular Malformations of the Brain. Vascular malformations of the brain may cause headaches, seizures, strokes, or bleeding in the brain (cerebral hemorrhage). Some researchers believe that the type of malformation determines the symptoms and progression of the disease. Other researchers believe that only the severity rather than the type of malformation is important. Arteriovenous malformations or AVMs affect arteries, veins, and middle- sized vessels but not capillaries. These blood vessels are enlarged, twisted, and tangled. Arteries and veins may be connected directly instead of being connected through fine capillaries for which reason they are often referred to as “shunt lesions” since the capillaries are by-passed. These abnormal “feeding” arteries progressively enlarge and as a result the “draining” veins dilate as well. The brain tissue between these vessels may be hardened or rigid (atrophied), full of a network of fine small fibers (fibrils) interspersed with flattened cells (gliotic), and sometimes may be calcified. Such malformations may, by drawing blood away from the brain, cause brain cell atrophy. Hemorrhages or seizures are commonly experienced with AVMs. (For more information on this disorder choose “Arteriovenous” for your search term in the Rare Disease Database.)Cavernous malformations, CMs (also called cavernous angiomas, or cavernous hemangiomas, or cavernomas) present as abnormally enlarged collections of blood-filled spaces. A cavernous hemangioma acts like a “blood sponge” soaking up blood that has found its way between capillaries, in the spaces between tissues (sinusoids) and “larger cavernous spaces.” These are “slow-flow lesions.” There is not usually any brain tissue in these spaces in contrast with symptoms of AVMs. Hemorrhages or seizures are also common with CMs. (For more information on this disorder choose “cavernous hemangioma” for your search term in the Rare Disease Database.)Venous angiomas (VAs) involve enlarged, tangled, and twisted veins that vary in size but do not involve the arteries. The site of these “growths” is most often just after the capillary stage of the vessel (post-capillary malformation). They may be isolated defects or associated with cavernous malformations. The defect shows itself as a “crown” of small veins (venules) that meet to form part of a larger vein (trunk). Telangiectasias are the malformations that arise as a result of the enlarging (dilation) of the tiny capillaries. These dilated capillaries make themselves known as small pink-red spots in various parts of the body such as the face, eyes, membranes that cover the brain (dura) and spinal cord (meninges), and mucous membranes (the thin moist layer lining the body's internal surfaces). (For more information on a disorder involving telangiectasias choose “hemorrhagic telangiectasia, hereditary” for your search term in the Rare Disease Database.)Vein of Galen malformations (VGMs begin while the embryo is developing. The vein of Galen is located under the cerebral hemispheres and drains the forward (anterior) and central regions of the brain into the proper sinuses. The malformations occur when the vein of Galen is not supported within the head by surrounding tissue and lacks the normal fibrous wall. Thus, the vein of Galen appears free-floating within the fluids of the cerebral spaces (sinuses). Should the pressure increase within the vein of Galen, its shape changes from a cylinder to that of a sphere. Such changes are accompanied by abnormal fetal blood circulation. In extreme cases, there may be cardiac failure or swelling of the brain (hydrocephalus).Mixed malformation is a phrase used to include any of several multiple-mixed malformations. Frequently, these malformations appear to be mixes of arteriovenous malformations with telangiectasias.
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Causes of Vascular Malformations of the Brain
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Three types or forms of VMB have a genetic component. The evidence for a genetic cause is strong in the case of cavernous hemangiomas and telangiectasias. The case is much weaker for arteriovenous malformation of the brain (AVM). In each of these cases, the condition is transmitted as an autosomal dominant trait. The malfunctioning gene in the case of cavernous malformations has been tracked to gene map locus 7q11.2-q21, and in the case of telangiectasia to gene map locus 9q34.1.Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 9q34.1” refers to band 34.1 on the long arm of chromosome 7. The numbered bands specify the location of the thousands of genes that are present on each chromosome.To say that the abnormal gene is located at 7q11.2-q21 means that the gene in question is located in a region on the long arm of chromosome 7 between bands 11.2 and 21.Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females have two X chromosomes but one of the X chromosomes is “turned off” and all of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is “turned off”. A male has one X chromosome and if he inherits an X chromosome that contains a disease gene, he will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease, and a 25% chance to have an unaffected son. X-linked dominant disorders are also caused by an abnormal gene on the X chromosome, but in these rare conditions, females with an abnormal gene are affected with the disease. Males with an abnormal gene are more severely affected than females, and many of these males do not survive.
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Causes of Vascular Malformations of the Brain. Three types or forms of VMB have a genetic component. The evidence for a genetic cause is strong in the case of cavernous hemangiomas and telangiectasias. The case is much weaker for arteriovenous malformation of the brain (AVM). In each of these cases, the condition is transmitted as an autosomal dominant trait. The malfunctioning gene in the case of cavernous malformations has been tracked to gene map locus 7q11.2-q21, and in the case of telangiectasia to gene map locus 9q34.1.Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 9q34.1” refers to band 34.1 on the long arm of chromosome 7. The numbered bands specify the location of the thousands of genes that are present on each chromosome.To say that the abnormal gene is located at 7q11.2-q21 means that the gene in question is located in a region on the long arm of chromosome 7 between bands 11.2 and 21.Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females have two X chromosomes but one of the X chromosomes is “turned off” and all of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is “turned off”. A male has one X chromosome and if he inherits an X chromosome that contains a disease gene, he will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease, and a 25% chance to have an unaffected son. X-linked dominant disorders are also caused by an abnormal gene on the X chromosome, but in these rare conditions, females with an abnormal gene are affected with the disease. Males with an abnormal gene are more severely affected than females, and many of these males do not survive.
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Affects of Vascular Malformations of the Brain
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Vascular malformations of the brain affect males and females in equal numbers. A hereditary form of cavernous malformations tends to occur more frequently in Mexican-Americans. Arteriovenous malformations occur more frequently in males.
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Affects of Vascular Malformations of the Brain. Vascular malformations of the brain affect males and females in equal numbers. A hereditary form of cavernous malformations tends to occur more frequently in Mexican-Americans. Arteriovenous malformations occur more frequently in males.
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Related disorders of Vascular Malformations of the Brain
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Symptoms of the following disorders can be similar to those of vascular malformations of the brain. Comparisons may be useful for a differential diagnosis:Moyamoya diseaseMoyamoya disease is a progressive disease that effects blood vessels in the brain (cerebrovascular). It is characterized by narrowing and/or closing of the main artery to the brain (carotid) which decreases the blood supply. This lack of blood may cause semi- or complete paralysis of the feet, legs or the upper extremities. Cerebral bleeding, convulsions, headaches, various vision problems, mental deficiencies, and psychiatric problems may also occur. (For more information on this disorder, choose “Moyamoya” as your search term in the Rare Disease Database.Cerebral aneurysmA cerebral aneurysm is the dilation, bulging, or ballooning of part of the wall of a vein or artery in the brain. Cerebral aneurysms can occur at any age, although they are more common in adults than in children and are slightly more common in women than in men. The signs and symptoms of an unruptured cerebral aneurysm will partly depend on its size and its rate of growth. For example, a small, unchanging aneurysm will generally produce no symptoms, whereas a larger aneurysm that is steadily growing may produce symptoms such as loss of feeling in the face or problems with the eyes. Immediately before an aneurysm ruptures, an individual may experience such symptoms as a sudden and unusually severe headache, nausea, vision impairment, vomiting, and loss of consciousness. Cerebrovascular accident (stroke)Cerebrovascular accidents (strokes) occur because the blood supply to the brain has been cut off or decreased. Thrombotic strokes occur when a clot has narrowed or completely closed an artery in the neck or head. This is usually the result of the buildup of fat-containing materials and calcium (plaque) on the inner linings of the blood vessels (atherosclerosis or hardening of the arteries). Embolic strokes occur when a clot breaks away from a diseased artery in another part of the body or the heart and clogs a smaller artery in the brain. Hemorrhagic strokes occur when a blood vessel ruptures in or around the brain, depriving that area of circulating blood.Each type of stroke has its own symptoms, progression, and prognosis. Clumsiness, headaches, speech difficulties, weakness or paralysis of one or both sides of the body may occur. Stiff neck, nausea, vomiting, and loss of consciousness are also common symptoms.
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Related disorders of Vascular Malformations of the Brain. Symptoms of the following disorders can be similar to those of vascular malformations of the brain. Comparisons may be useful for a differential diagnosis:Moyamoya diseaseMoyamoya disease is a progressive disease that effects blood vessels in the brain (cerebrovascular). It is characterized by narrowing and/or closing of the main artery to the brain (carotid) which decreases the blood supply. This lack of blood may cause semi- or complete paralysis of the feet, legs or the upper extremities. Cerebral bleeding, convulsions, headaches, various vision problems, mental deficiencies, and psychiatric problems may also occur. (For more information on this disorder, choose “Moyamoya” as your search term in the Rare Disease Database.Cerebral aneurysmA cerebral aneurysm is the dilation, bulging, or ballooning of part of the wall of a vein or artery in the brain. Cerebral aneurysms can occur at any age, although they are more common in adults than in children and are slightly more common in women than in men. The signs and symptoms of an unruptured cerebral aneurysm will partly depend on its size and its rate of growth. For example, a small, unchanging aneurysm will generally produce no symptoms, whereas a larger aneurysm that is steadily growing may produce symptoms such as loss of feeling in the face or problems with the eyes. Immediately before an aneurysm ruptures, an individual may experience such symptoms as a sudden and unusually severe headache, nausea, vision impairment, vomiting, and loss of consciousness. Cerebrovascular accident (stroke)Cerebrovascular accidents (strokes) occur because the blood supply to the brain has been cut off or decreased. Thrombotic strokes occur when a clot has narrowed or completely closed an artery in the neck or head. This is usually the result of the buildup of fat-containing materials and calcium (plaque) on the inner linings of the blood vessels (atherosclerosis or hardening of the arteries). Embolic strokes occur when a clot breaks away from a diseased artery in another part of the body or the heart and clogs a smaller artery in the brain. Hemorrhagic strokes occur when a blood vessel ruptures in or around the brain, depriving that area of circulating blood.Each type of stroke has its own symptoms, progression, and prognosis. Clumsiness, headaches, speech difficulties, weakness or paralysis of one or both sides of the body may occur. Stiff neck, nausea, vomiting, and loss of consciousness are also common symptoms.
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Diagnosis of Vascular Malformations of the Brain
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Imaging apparatus, such as magnetic resonance imaging (MRI), computed tomography (CT) scans, venograms and/or digital intravenous or common angiography can take pictures of the brain's blood vessels to see if vascular malformations are present.
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Diagnosis of Vascular Malformations of the Brain. Imaging apparatus, such as magnetic resonance imaging (MRI), computed tomography (CT) scans, venograms and/or digital intravenous or common angiography can take pictures of the brain's blood vessels to see if vascular malformations are present.
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Therapies of Vascular Malformations of the Brain
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TreatmentCurrent treatment options vary according to the severity and location of the malformation. Surgical removal (resection), multiple embolization (an operation in which pellets are put into the circulatory system in order to block blood flow to and/or from the abnormal blood vessels), and irradiation are the treatments currently in use. In some cases, treatment may not be necessary. Recently introduced techniques involve particle beam and stereotaxic radio-surgery. Genetic counseling may be of benefit for patients and their families if they have a hereditary form of this disorder. Other treatment is symptomatic and supportive.
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Therapies of Vascular Malformations of the Brain. TreatmentCurrent treatment options vary according to the severity and location of the malformation. Surgical removal (resection), multiple embolization (an operation in which pellets are put into the circulatory system in order to block blood flow to and/or from the abnormal blood vessels), and irradiation are the treatments currently in use. In some cases, treatment may not be necessary. Recently introduced techniques involve particle beam and stereotaxic radio-surgery. Genetic counseling may be of benefit for patients and their families if they have a hereditary form of this disorder. Other treatment is symptomatic and supportive.
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Overview of Vasculitis
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Vasculitis is inflammation of blood vessels. In individuals with vasculitis, inflammation damages the lining of affected blood vessels, causing narrowing, the formation of blood clots (thrombosis), and/or blockage. As a result, there may be restriction of oxygenated blood supply to certain tissues (ischemia), potentially resulting in pain, tissue damage, and, in some cases, malfunction of certain affected organs. Vasculitis may affect veins and arteries of any type or size; may involve a single organ or many organs and tissues of the body; and may be a primary disease process or occur due to or in association with a number of different underlying disorders. Therefore, the range and severity of symptoms and findings associated with vasculitis may vary greatly. The specific underlying cause of vasculitis is not fully understood. However, in most cases, it is thought to be due to disturbances of the body's immune system.
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Overview of Vasculitis. Vasculitis is inflammation of blood vessels. In individuals with vasculitis, inflammation damages the lining of affected blood vessels, causing narrowing, the formation of blood clots (thrombosis), and/or blockage. As a result, there may be restriction of oxygenated blood supply to certain tissues (ischemia), potentially resulting in pain, tissue damage, and, in some cases, malfunction of certain affected organs. Vasculitis may affect veins and arteries of any type or size; may involve a single organ or many organs and tissues of the body; and may be a primary disease process or occur due to or in association with a number of different underlying disorders. Therefore, the range and severity of symptoms and findings associated with vasculitis may vary greatly. The specific underlying cause of vasculitis is not fully understood. However, in most cases, it is thought to be due to disturbances of the body's immune system.
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Symptoms of Vasculitis
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Vasculitis is a general term that means inflammation of blood vessels. This inflammation causes a narrowing of the inside of the vessel and can obstruct the flow of blood to the tissues (ischemia). The lack of blood may result in damage to nearby tissues (necrosis), formation of blood clots (thrombosis), and, in rare cases, a weakening or ballooning that may rupture of the vessel wall (aneurysm).Arteries and veins of all sizes and in all parts of the body may be affected. Vasculitis may be limited to only one location or certain organs (localized or isolated) such as the skin, brain, or specific internal organs. In other cases, vasculitis may affect multiple areas or organs of the body at the same time (systemic or generalized). It may occur alone or as a complication of many other disorders.The symptoms of vasculitis are many because of the wide variety of body systems it can affect. Depending on the system involved there may be muscle pain, joint pain, fever, weight loss, loss of appetite (anorexia), headache, or generalized weakness. There may also be ulcers of the mouth, hoarseness, night sweats, high blood pressure (hypertension), abdominal pain, diarrhea, blood in the urine (hematuria), or kidney (renal) failure. Eye inflammation and blurred vision are also symptomatic, and in very severe cases blindness can occur. When the respiratory system is involved there may be an inflammation of the sinuses, runny nose, asthma, a cough with or without bleeding (hemoptysis), shortness of breath (dyspnea), nosebleeds (epistaxis), or an inflammation of the membranes of the lungs.When vasculitis affects the skin there may be lesions that are flat and red (macules), nodules, and hemorrhages under the skin (purpura). These lesions may occur on any area of the body but are seen more frequently on the back, hands, buttocks, the inside area of the forearms and the lower extremities. These skin symptoms may occur only once or at regular intervals. They will usually last for several weeks and may leave darkened spots or scarring. In some cases of vasculitis there may be wheel-like lesions that cause intense itching (urticaria), or ring-shaped lesions and ulcers. Blister-like lesions (vesicles, bullae) may develop in severe cases.
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Symptoms of Vasculitis. Vasculitis is a general term that means inflammation of blood vessels. This inflammation causes a narrowing of the inside of the vessel and can obstruct the flow of blood to the tissues (ischemia). The lack of blood may result in damage to nearby tissues (necrosis), formation of blood clots (thrombosis), and, in rare cases, a weakening or ballooning that may rupture of the vessel wall (aneurysm).Arteries and veins of all sizes and in all parts of the body may be affected. Vasculitis may be limited to only one location or certain organs (localized or isolated) such as the skin, brain, or specific internal organs. In other cases, vasculitis may affect multiple areas or organs of the body at the same time (systemic or generalized). It may occur alone or as a complication of many other disorders.The symptoms of vasculitis are many because of the wide variety of body systems it can affect. Depending on the system involved there may be muscle pain, joint pain, fever, weight loss, loss of appetite (anorexia), headache, or generalized weakness. There may also be ulcers of the mouth, hoarseness, night sweats, high blood pressure (hypertension), abdominal pain, diarrhea, blood in the urine (hematuria), or kidney (renal) failure. Eye inflammation and blurred vision are also symptomatic, and in very severe cases blindness can occur. When the respiratory system is involved there may be an inflammation of the sinuses, runny nose, asthma, a cough with or without bleeding (hemoptysis), shortness of breath (dyspnea), nosebleeds (epistaxis), or an inflammation of the membranes of the lungs.When vasculitis affects the skin there may be lesions that are flat and red (macules), nodules, and hemorrhages under the skin (purpura). These lesions may occur on any area of the body but are seen more frequently on the back, hands, buttocks, the inside area of the forearms and the lower extremities. These skin symptoms may occur only once or at regular intervals. They will usually last for several weeks and may leave darkened spots or scarring. In some cases of vasculitis there may be wheel-like lesions that cause intense itching (urticaria), or ring-shaped lesions and ulcers. Blister-like lesions (vesicles, bullae) may develop in severe cases.
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Causes of Vasculitis
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The specific underlying cause of vasculitis is not fully understood. However, in most cases, vasculitis is thought to be due to disturbances of the body's immune system. Some forms of vasculitis may be due to allergic reactions or hypersensitivity to certain medications such as sulfur drugs, penicillin, propylthiouracil, other drugs, toxins, or other inhaled environmental irritants. Other forms may occur due to fungal, parasitic, or viral infections. In some instances, it is thought that vasculitis may be an autoimmune disorder. Autoimmune disorders are caused when the body's natural defenses against “foreign” or invading organisms (e.g., antibodies) begin to attack healthy tissue for unknown reasons.
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Causes of Vasculitis. The specific underlying cause of vasculitis is not fully understood. However, in most cases, vasculitis is thought to be due to disturbances of the body's immune system. Some forms of vasculitis may be due to allergic reactions or hypersensitivity to certain medications such as sulfur drugs, penicillin, propylthiouracil, other drugs, toxins, or other inhaled environmental irritants. Other forms may occur due to fungal, parasitic, or viral infections. In some instances, it is thought that vasculitis may be an autoimmune disorder. Autoimmune disorders are caused when the body's natural defenses against “foreign” or invading organisms (e.g., antibodies) begin to attack healthy tissue for unknown reasons.
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Affects of Vasculitis
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Vasculitis usually affects males and females in equal numbers. It is most commonly seen in the elderly.There are a large number of disorders that may be characterized by or associated with vasculitis. These disorders are often referred to as the Vasculitic syndromes or vasculitides. (For more information on these disorders, see the Related Disorders section below.)
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Affects of Vasculitis. Vasculitis usually affects males and females in equal numbers. It is most commonly seen in the elderly.There are a large number of disorders that may be characterized by or associated with vasculitis. These disorders are often referred to as the Vasculitic syndromes or vasculitides. (For more information on these disorders, see the Related Disorders section below.)
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Related disorders of Vasculitis
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The following are diseases that are associated with vasculitis:Polyarteritis nodosa is a rare multisystem disorder characterized by widespread inflammation, weakening, and degeneration of small- and medium-sized arteries. Blood vessels in any organ or organ system may be affected including arteries supplying the kidneys, heart, intestine, nervous system, and/or skeletal muscles. Damage to affected arteries may result in abnormally increased blood pressure (hypertension), “ballooning” (aneurysm) of an arterial wall, the formation of blood clots (thrombosis), obstruction of blood supply to certain tissues, and/or tissue damage and loss (necrosis) in certain affected areas. In many cases, affected individuals experience weight loss, fever, a general feeling of ill health (malaise), fatigue, weakness, headache, muscle aches (myalgias), and/or abdominal pain. Although the exact cause of polyarteritis nodosa is not known, many researchers suspect that the disorder is due to disturbances of the body's immune system. (For more information on this disorder, choose “polyarteritis nodosa” as your search term in the Rare Disease Database.)Hypersensitivity vasculitis includes a wide group of vasculitic syndromes that affect the upper and lower respiratory tract and kidneys. They are usually caused by an allergic reaction to an unknown antigen.Wegener's granulomatosis is an uncommon collagen vascular disorder that usually begins as a localized inflammation of the upper and lower respiratory tract mucosa, and usually progresses into generalized inflammation of the blood vessels (vasculitis) and kidney (glomerulonephritis). Other symptoms may include ulcerations of the mucous membranes in the nose with secondary bacterial infection, middle ear infection (otitis media) with hearing loss, cough, expectoration of blood (hemoptysis), and inflammation of the thin membrane lining the outside of the lungs and the inside of the chest cavity (pleuritis). The exact cause of Wegener's granulomatosis is not known. (For more information on this disorder choose “Wegener's granulomatosis” as your search term in the Rare Disease Database.)Lymphomatoid granulomatosis is a rare, progressive, vascular disease characterized by infiltration and destruction of the veins and arteries by lesions. These lesions can affect various parts of the body, especially the lungs. It can be a benign or malignant condition. (For more information on this disorder, choose “Lymphomatoid Granulomatosis” as your search term in the Rare Disease Database.)Buerger's disease, also known as thromboangiitis obliterans, is a rare disorder that, in most cases, affects young or middle-aged male cigarette smokers. It is characterized by narrowing or blockage (occlusion) of the veins and arteries of the extremities, resulting in reduced blood flow to these areas (peripheral vascular disease). The legs are more often affected than the arms. In most cases, the first symptom is extreme pain of the lower arms and legs while at rest. In addition, affected individuals may have sores (ulcers) on the extremities, numbness and tingling and a lack of normal blood flow to the fingers and/or toes when exposed to cold temperatures (Raynaud's phenomenon), and/or inflammation and clotting of certain veins (thrombophlebitis). The exact cause of Buerger's disease is not known; however, most affected individuals are smokers. (For more information on this disorder, choose “Buerger's” as your search term in the Rare Disease Database.)Churg-Strauss syndrome is a rare disorder that affects multiple organ systems and is characterized by the formation and accumulation of an abnormally large number of certain white blood cells (eosinophils), inflammation of blood vessels (angiitis or vasculitis), and inflammatory nodular lesions (granulomatosis). Other symptoms of Churg-Strauss syndrome include fever, a general feeling of weakness and fatigue (malaise), loss of appetite (anorexia) and weight loss. It is often preceded by asthma or allergies. The exact causes of Churg-Strauss syndrome is not known. (For more information on this disorder, choose “Churg Strauss” as your search term in the Rare Disease Database.)Henoch-Schonlein purpura is a rare inflammatory disease of the small blood vessels (capillaries) and is usually a self-limited disease. It is the most common form of childhood vascular inflammation (vasculitis) and results in inflammatory changes in small blood vessels. The symptoms of Henoch-Schonlein purpura usually begin suddenly and may include headache, fever, loss of appetite, cramping abdominal pain, and joint pain. Red or purple spots typically appear on the skin (petechial purpura). Inflammatory changes associated with this disorder can also develop in the joints, kidneys, digestive system, and, in rare cases, the brain and spinal cord (central nervous system). The exact cause of Henoch-Schonlein purpura is not fully understood, although research suggests that it may be an autoimmune disease or, in some cases, an extreme allergic reaction to certain 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.)Behcet's syndrome is a rare chronic relapsing inflammatory disorder characterized by inflammation of the eyes and ulcers of the mouth and genitals. The cause is unknown. Symptoms include areas of abnormal skin changes (ulcers or lesions) of the mouth and genitals that tend to recur spontaneously. Other systems of the body may also be effected including the joints, blood vessels, central nervous system, and/or digestive tract. (For more information on this disorder, choose “Behcet” as your search term in the Rare Disease Database.)Kawasaki syndrome, also known as mucocutaneous lymph node syndrome, is an inflammatory disease of childhood characterized by fever, skin rash, swollen lymph nodes (lymphadenopathy), inflammation of arteries (polyarteritis), and inflammation of the blood vessels (vasculitis). Inflammatory changes cause destructive lesions in blood vessels and may lead to complications involving the liver, gall bladder, and especially the heart. Kawasaki syndrome is the main cause of acquired heart disease in children. The exact cause of Kawasaki syndrome is unclear although it may be related to two previously unknown strains of staphylococcus and streptococcus bacteria. (For more information on this disorder, choose “Kawasaki” as your search term in the Rare Disease Database.)Hypocomplementemic urticarial vasculitis is a rare disorder characterized by recurrent episodes of vasculitis and (urticaria) associated with fever, arthritis, and abdominal pain. Other symptoms include swelling of (angioedema), ocular inflammation, and/or inflammation and degeneration of the clusters of capillaries (renal glomeruli) that filter the blood passing through the kidneys (glomerulonephritis). In some cases a chronic obstructive lung disease may develop. The exact cause of hypocomplementemic urticarial vasculitis is unknown.Primary angiitis of the central nervous system (CNS), also known as (isolated) vasculitis of the central nervous system, is an extremely rare disorder characterized by vasculitis of the CNS that occurs as a primary condition (i.e., not secondary to another disorder). Physical findings and symptoms associated with this disorder depend upon the specific blood vessels of the central nervous system that are affected.There are additional disorders that may be characterized by inflammation of certain blood vessels (vasculitis). These disorders include giant cell arteritis, polymyalgia rheumatica, lupus, essential mixed cryoglobulinemia, cutaneous necrotizing vasculitis, Cogan's syndrome type I, Takayasu's arteritis, and rheumatoid arthritis. (For more information on these disorders, choose the exact disease name in question as your search term in the Rare Disease Database.)
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Related disorders of Vasculitis. The following are diseases that are associated with vasculitis:Polyarteritis nodosa is a rare multisystem disorder characterized by widespread inflammation, weakening, and degeneration of small- and medium-sized arteries. Blood vessels in any organ or organ system may be affected including arteries supplying the kidneys, heart, intestine, nervous system, and/or skeletal muscles. Damage to affected arteries may result in abnormally increased blood pressure (hypertension), “ballooning” (aneurysm) of an arterial wall, the formation of blood clots (thrombosis), obstruction of blood supply to certain tissues, and/or tissue damage and loss (necrosis) in certain affected areas. In many cases, affected individuals experience weight loss, fever, a general feeling of ill health (malaise), fatigue, weakness, headache, muscle aches (myalgias), and/or abdominal pain. Although the exact cause of polyarteritis nodosa is not known, many researchers suspect that the disorder is due to disturbances of the body's immune system. (For more information on this disorder, choose “polyarteritis nodosa” as your search term in the Rare Disease Database.)Hypersensitivity vasculitis includes a wide group of vasculitic syndromes that affect the upper and lower respiratory tract and kidneys. They are usually caused by an allergic reaction to an unknown antigen.Wegener's granulomatosis is an uncommon collagen vascular disorder that usually begins as a localized inflammation of the upper and lower respiratory tract mucosa, and usually progresses into generalized inflammation of the blood vessels (vasculitis) and kidney (glomerulonephritis). Other symptoms may include ulcerations of the mucous membranes in the nose with secondary bacterial infection, middle ear infection (otitis media) with hearing loss, cough, expectoration of blood (hemoptysis), and inflammation of the thin membrane lining the outside of the lungs and the inside of the chest cavity (pleuritis). The exact cause of Wegener's granulomatosis is not known. (For more information on this disorder choose “Wegener's granulomatosis” as your search term in the Rare Disease Database.)Lymphomatoid granulomatosis is a rare, progressive, vascular disease characterized by infiltration and destruction of the veins and arteries by lesions. These lesions can affect various parts of the body, especially the lungs. It can be a benign or malignant condition. (For more information on this disorder, choose “Lymphomatoid Granulomatosis” as your search term in the Rare Disease Database.)Buerger's disease, also known as thromboangiitis obliterans, is a rare disorder that, in most cases, affects young or middle-aged male cigarette smokers. It is characterized by narrowing or blockage (occlusion) of the veins and arteries of the extremities, resulting in reduced blood flow to these areas (peripheral vascular disease). The legs are more often affected than the arms. In most cases, the first symptom is extreme pain of the lower arms and legs while at rest. In addition, affected individuals may have sores (ulcers) on the extremities, numbness and tingling and a lack of normal blood flow to the fingers and/or toes when exposed to cold temperatures (Raynaud's phenomenon), and/or inflammation and clotting of certain veins (thrombophlebitis). The exact cause of Buerger's disease is not known; however, most affected individuals are smokers. (For more information on this disorder, choose “Buerger's” as your search term in the Rare Disease Database.)Churg-Strauss syndrome is a rare disorder that affects multiple organ systems and is characterized by the formation and accumulation of an abnormally large number of certain white blood cells (eosinophils), inflammation of blood vessels (angiitis or vasculitis), and inflammatory nodular lesions (granulomatosis). Other symptoms of Churg-Strauss syndrome include fever, a general feeling of weakness and fatigue (malaise), loss of appetite (anorexia) and weight loss. It is often preceded by asthma or allergies. The exact causes of Churg-Strauss syndrome is not known. (For more information on this disorder, choose “Churg Strauss” as your search term in the Rare Disease Database.)Henoch-Schonlein purpura is a rare inflammatory disease of the small blood vessels (capillaries) and is usually a self-limited disease. It is the most common form of childhood vascular inflammation (vasculitis) and results in inflammatory changes in small blood vessels. The symptoms of Henoch-Schonlein purpura usually begin suddenly and may include headache, fever, loss of appetite, cramping abdominal pain, and joint pain. Red or purple spots typically appear on the skin (petechial purpura). Inflammatory changes associated with this disorder can also develop in the joints, kidneys, digestive system, and, in rare cases, the brain and spinal cord (central nervous system). The exact cause of Henoch-Schonlein purpura is not fully understood, although research suggests that it may be an autoimmune disease or, in some cases, an extreme allergic reaction to certain 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.)Behcet's syndrome is a rare chronic relapsing inflammatory disorder characterized by inflammation of the eyes and ulcers of the mouth and genitals. The cause is unknown. Symptoms include areas of abnormal skin changes (ulcers or lesions) of the mouth and genitals that tend to recur spontaneously. Other systems of the body may also be effected including the joints, blood vessels, central nervous system, and/or digestive tract. (For more information on this disorder, choose “Behcet” as your search term in the Rare Disease Database.)Kawasaki syndrome, also known as mucocutaneous lymph node syndrome, is an inflammatory disease of childhood characterized by fever, skin rash, swollen lymph nodes (lymphadenopathy), inflammation of arteries (polyarteritis), and inflammation of the blood vessels (vasculitis). Inflammatory changes cause destructive lesions in blood vessels and may lead to complications involving the liver, gall bladder, and especially the heart. Kawasaki syndrome is the main cause of acquired heart disease in children. The exact cause of Kawasaki syndrome is unclear although it may be related to two previously unknown strains of staphylococcus and streptococcus bacteria. (For more information on this disorder, choose “Kawasaki” as your search term in the Rare Disease Database.)Hypocomplementemic urticarial vasculitis is a rare disorder characterized by recurrent episodes of vasculitis and (urticaria) associated with fever, arthritis, and abdominal pain. Other symptoms include swelling of (angioedema), ocular inflammation, and/or inflammation and degeneration of the clusters of capillaries (renal glomeruli) that filter the blood passing through the kidneys (glomerulonephritis). In some cases a chronic obstructive lung disease may develop. The exact cause of hypocomplementemic urticarial vasculitis is unknown.Primary angiitis of the central nervous system (CNS), also known as (isolated) vasculitis of the central nervous system, is an extremely rare disorder characterized by vasculitis of the CNS that occurs as a primary condition (i.e., not secondary to another disorder). Physical findings and symptoms associated with this disorder depend upon the specific blood vessels of the central nervous system that are affected.There are additional disorders that may be characterized by inflammation of certain blood vessels (vasculitis). These disorders include giant cell arteritis, polymyalgia rheumatica, lupus, essential mixed cryoglobulinemia, cutaneous necrotizing vasculitis, Cogan's syndrome type I, Takayasu's arteritis, and rheumatoid arthritis. (For more information on these disorders, choose the exact disease name in question as your search term in the Rare Disease Database.)
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Diagnosis of Vasculitis
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Because of the wide range of symptoms and body systems involved, an extensive history and physical exam is needed before a clear diagnosis of the type of vasculitis can be made. In some cases, an x-ray of the blood vessels using dye (angiogram), or a biopsy of the affected organ may be recommended to give an accurate diagnosis and to insure proper treatment.
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Diagnosis of Vasculitis. Because of the wide range of symptoms and body systems involved, an extensive history and physical exam is needed before a clear diagnosis of the type of vasculitis can be made. In some cases, an x-ray of the blood vessels using dye (angiogram), or a biopsy of the affected organ may be recommended to give an accurate diagnosis and to insure proper treatment.
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Therapies of Vasculitis
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TreatmentTreatment of vasculitis depends on the cause and symptoms of the underlying disease and the specific organs of the body that are affected. The drugs prednisone, cyclophosphamide, methylprednisolone and pentoxifylline have proven to be successful in treating the autoimmune form of vasculitis. Other treatment is symptomatic and supportive.
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Therapies of Vasculitis. TreatmentTreatment of vasculitis depends on the cause and symptoms of the underlying disease and the specific organs of the body that are affected. The drugs prednisone, cyclophosphamide, methylprednisolone and pentoxifylline have proven to be successful in treating the autoimmune form of vasculitis. Other treatment is symptomatic and supportive.
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Overview of Ventricular Septal Defects
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Ventricular septal defects are heart defects that are present at birth (congenital). The normal heart has four chambers. The two upper chambers, known as atria, are separated from each other by a fibrous partition known as the atrial septum. The two lower chambers are known as ventricles and are separated from each other by the ventricular septum. Valves connect the atria (left and right) to their respective ventricles. The aorta, the main vessel of arterial circulation, carries blood from the left ventricle and away from the heart.Ventricular septal defects can occur in any portion of the ventricular septum. The size and location of the defect determine the severity of the symptoms. Small ventricular septal defects can close on their own; (spontaneously) or become less significant as the child matures and grows. Moderately-sized defects can cause congestive heart failure, which is characterized by an abnormally rapid rate of breathing (tachypnea), wheezing, unusually fast heartbeat (tachycardia), enlarged liver (hepatomegaly), and/or failure to thrive. Large ventricular septal defects can cause life-threatening complications during infancy. Persistent elevation of the pressure within the artery that carries blood away from the heart and to the lungs (pulmonary artery) can cause permanent damage to the lungs. The exact cause of ventricular septal defects is not fully understood.
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Overview of Ventricular Septal Defects. Ventricular septal defects are heart defects that are present at birth (congenital). The normal heart has four chambers. The two upper chambers, known as atria, are separated from each other by a fibrous partition known as the atrial septum. The two lower chambers are known as ventricles and are separated from each other by the ventricular septum. Valves connect the atria (left and right) to their respective ventricles. The aorta, the main vessel of arterial circulation, carries blood from the left ventricle and away from the heart.Ventricular septal defects can occur in any portion of the ventricular septum. The size and location of the defect determine the severity of the symptoms. Small ventricular septal defects can close on their own; (spontaneously) or become less significant as the child matures and grows. Moderately-sized defects can cause congestive heart failure, which is characterized by an abnormally rapid rate of breathing (tachypnea), wheezing, unusually fast heartbeat (tachycardia), enlarged liver (hepatomegaly), and/or failure to thrive. Large ventricular septal defects can cause life-threatening complications during infancy. Persistent elevation of the pressure within the artery that carries blood away from the heart and to the lungs (pulmonary artery) can cause permanent damage to the lungs. The exact cause of ventricular septal defects is not fully understood.
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Symptoms of Ventricular Septal Defects
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Infants with small ventricular septal defects may have no symptoms unless they experience infection that spreads to the lining of the heart and the valves (infective endocarditis). This form of the disease is known as Roger's disease.Infants with moderate ventricular septal defects may experience the symptoms of congestive heart failure. These may include excessive fatigue and difficulty breathing during feeding or periods of activity. Some infants may experience poor feeding; cold, grayish arms and legs; and/or rapid, shallow breathing. Ventricular septal defects of moderate size are also characterized by abnormal enlargement of the heart (cardiomegaly) and heart murmurs.A large ventricular septal defects can cause severe symptoms in infants. If the septum is entirely absent, the 2 ventricles come together to form a single chamber. This condition is known as common ventricle or cor triloculare biatriatum. In infants and children, large defects generally cause growth retardation and progressive heart failure. Other symptoms may include poor feeding; a slight bluish discoloration on the skin, lips, and mouth (cyanosis); rapid difficult breathing; excessive accumulation of fluid in the lungs and around the heart (pulmonary edema), and/or the elevation of pressure within the major artery that sends blood to the heart (pulmonary artery hypertension).Older children and adults with ventricular septal defects may develop Eisenmenger syndrome, which is characterized by the progressive impairment of the pulmonary blood vessels (vascular obstructive disease). Symptoms may include chest pain, difficulty breathing (dyspnea) after physical exertion, and episodes of fainting. Other symptoms may include the coughing up of blood from the lungs (hemoptysis) and abnormally low levels of oxygen in the circulating blood (hypoxia). Over time, hypoxia can result in clubbing of the fingers and the proliferation of red blood cells (polycythemia).Some infants with small or moderate sized ventricular septal defects may be at increased risk for acute inflammation of the valves and lining of the heart (infective endocarditis).
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Symptoms of Ventricular Septal Defects. Infants with small ventricular septal defects may have no symptoms unless they experience infection that spreads to the lining of the heart and the valves (infective endocarditis). This form of the disease is known as Roger's disease.Infants with moderate ventricular septal defects may experience the symptoms of congestive heart failure. These may include excessive fatigue and difficulty breathing during feeding or periods of activity. Some infants may experience poor feeding; cold, grayish arms and legs; and/or rapid, shallow breathing. Ventricular septal defects of moderate size are also characterized by abnormal enlargement of the heart (cardiomegaly) and heart murmurs.A large ventricular septal defects can cause severe symptoms in infants. If the septum is entirely absent, the 2 ventricles come together to form a single chamber. This condition is known as common ventricle or cor triloculare biatriatum. In infants and children, large defects generally cause growth retardation and progressive heart failure. Other symptoms may include poor feeding; a slight bluish discoloration on the skin, lips, and mouth (cyanosis); rapid difficult breathing; excessive accumulation of fluid in the lungs and around the heart (pulmonary edema), and/or the elevation of pressure within the major artery that sends blood to the heart (pulmonary artery hypertension).Older children and adults with ventricular septal defects may develop Eisenmenger syndrome, which is characterized by the progressive impairment of the pulmonary blood vessels (vascular obstructive disease). Symptoms may include chest pain, difficulty breathing (dyspnea) after physical exertion, and episodes of fainting. Other symptoms may include the coughing up of blood from the lungs (hemoptysis) and abnormally low levels of oxygen in the circulating blood (hypoxia). Over time, hypoxia can result in clubbing of the fingers and the proliferation of red blood cells (polycythemia).Some infants with small or moderate sized ventricular septal defects may be at increased risk for acute inflammation of the valves and lining of the heart (infective endocarditis).
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Causes of Ventricular Septal Defects
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The exact cause of VSDs is not known. These defects probably occur as the result of errors in the development of an embryo. During the early part of fetal development there is no wall (septum) to separate the left and right ventricles. As the fetus grows, so does a muscular wall that splits the lower chamber into two ventricles. If the muscle does not form a solid wall, a hole remains and is what is called the ventricular septal defect. The why and how of these developmental errors is not fully understood. However, research suggests that they may occur as the result of the complex interaction of many factors, both genetic and environmental (multifactorial).
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Causes of Ventricular Septal Defects. The exact cause of VSDs is not known. These defects probably occur as the result of errors in the development of an embryo. During the early part of fetal development there is no wall (septum) to separate the left and right ventricles. As the fetus grows, so does a muscular wall that splits the lower chamber into two ventricles. If the muscle does not form a solid wall, a hole remains and is what is called the ventricular septal defect. The why and how of these developmental errors is not fully understood. However, research suggests that they may occur as the result of the complex interaction of many factors, both genetic and environmental (multifactorial).
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Affects of Ventricular Septal Defects
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Ventricular septal defects are rare congenital malformations of the heart that occur more frequently in males than females. Approximately 1 percent of newborns have a congenital heart defect. About 25 to 30 percent of these infants are diagnosed with ventricular septal defects. Of the babies born with VSDs, 80 to 90 percent present with a small hole and mild symptoms.Most infants with ventricular septal defects have a single malformation that is not associated with any other disorder. Occasionally, infants may have ventricular septal defects in association with other malformation syndromes. These may include fetal alcohol syndrome, trisomy syndromes, fetal hydantoin syndrome (associated with a drug used to treat epilepsy), postrubella infection (German measles), maternal phenylketonuria (PKU), and other disorders.
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Affects of Ventricular Septal Defects. Ventricular septal defects are rare congenital malformations of the heart that occur more frequently in males than females. Approximately 1 percent of newborns have a congenital heart defect. About 25 to 30 percent of these infants are diagnosed with ventricular septal defects. Of the babies born with VSDs, 80 to 90 percent present with a small hole and mild symptoms.Most infants with ventricular septal defects have a single malformation that is not associated with any other disorder. Occasionally, infants may have ventricular septal defects in association with other malformation syndromes. These may include fetal alcohol syndrome, trisomy syndromes, fetal hydantoin syndrome (associated with a drug used to treat epilepsy), postrubella infection (German measles), maternal phenylketonuria (PKU), and other disorders.
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Related disorders of Ventricular Septal Defects
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Symptoms of the following disorders may be similar to those of ventricular septal defects. Comparisons may be useful for a differential diagnosis:Atrial septal defects are common congenital heart defects characterized by the presence of a small opening between the two atria of the heart. These defects lead to an increase in the workload on the right side of the heart as well as excessive blood flow to the lungs. The symptoms, which may become apparent during infancy, childhood, or adulthood, depend on the severity of the defect and can vary greatly. The symptoms tend to be mild at first and may include difficulty breathing (dyspnea), increased susceptibility to respiratory infections, and/or abnormal bluish discoloration of the skin and mucous membranes (cyanosis). Some people with atrial septal defects may be at increased risk for the formation of blood clots that can travel to the major arteries (embolism) and block blood circulation. (For more information on this disorder, choose “atrial septal defect” as your search term in the Rare Disease Database.)Atrioventricular septal defect is a rare heart defect that is present at birth (congenital) and characterized by the improper development of the septa and valves of the heart. Infants with the complete form of the defect usually develop congestive heart failure. Excessive fluid accumulates in other areas of the body, especially the lungs. Pulmonary congestion may lead to difficulty breathing (dyspnea). Other symptoms may include a bluish discoloration of the skin (cyanosis), poor feeding habits, abnormally rapid breathing (tachypnea) and heart rate (tachycardia), and/or excessive sweating (hyperhidrosis). Adults with atrioventricular septal defect may experience abnormally low blood pressure, irregular heartbeats, and/or a rapid heartbeat. (For more information on this disorder, choose “atrioventricular septal defect” as your search term in the Rare Disease Database.)Cor Triatriatum is an extremely rare congenital heart defect characterized by the presence of an extra chamber above the left atrium of the heart. The pulmonary veins, returning blood from the lungs, drain into this extra “third atrium.” The symptoms of Cor Triatriatum vary greatly and depend on the size of the opening between the chambers. Symptoms may include abnormally rapid breathing (tachypnea), wheezing, a bluish discoloration to the skin (cyanosis), coughing, and/or abnormal accumulation of fluid in the lungs (pulmonary congestion). (For more information on this disorder, choose “Cor Triatriatum” as your search term in the Rare Disease Database.)Mitral valve stenosis is a rare heart defect that may be present at birth (congenital) or acquired. It is characterized by the abnormal narrowing of the opening of the mitral valve. In the congenital form, the symptoms vary greatly and may include coughing, difficulty breathing, heart palpitations, and/or frequent respiratory infections. In acquired mitral valve stenosis, the symptoms may also include weakness, abdominal discomfort, chest pain (angina), and/or periodic loss of consciousness.Tetralogy of Fallot is the most common form of cyanotic congenital heart disease. Cyanosis is the abnormal bluish discoloration of the skin that occurs because of low levels of circulating oxygen in the blood. Tetralogy of Fallot consists of a combination of 4 different defects: a ventricular septal defect; obstructed outflow of blood from the right ventricle to the lungs (pulmonary stenosis); a displaced aorta, which causes blood to flow into the aorta from both the right and left ventricles (dextroposition or overriding aorta); and abnormal enlargement of the right ventricle (right ventricular hypertrophy). Symptoms may include difficulty breathing (dyspnea), fatigue, loss of appetite, slow weight gain, heart murmurs, an abnormal increase in the number of red blood cells (polycythemia), clubbing of the fingers and toes, and/or delayed physical growth. (For more information on this disorder, choose “Tetralogy of Fallot” as your search term in the Rare Disease Database.)Ventricular septal defects may occur in association with a variety of other disorders including Holt-Oram Syndrome, FG Syndrome, Genitopalatocardiac Syndrome, Fryns Syndrome, certain forms of Dandy-Walker Syndrome, Cardiomyopathy-Hypogonadism-Collagenoma Syndrome, Familial Idiopathic Cardiomyopathy, Simpson Dysmorphia Syndrome, Fetal Alcohol Syndrome, DiGeorge Syndrome, various Trisomy Syndromes, maternal alcoholism, maternal ingestion of phenylhydantoin, postrubella infection, and maternal Phenylketonuria. (For more information on these disorders choose “Holt- Oram,” “FG,” “Fryns,” “Dandy-Walker,” “Simpson Dysmorphia,” “Fetal Alcohol,” “DiGeorge,” “Trisomy,” and “Phenylketonuria” as your search terms in the Rare Disease Database.)
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Related disorders of Ventricular Septal Defects. Symptoms of the following disorders may be similar to those of ventricular septal defects. Comparisons may be useful for a differential diagnosis:Atrial septal defects are common congenital heart defects characterized by the presence of a small opening between the two atria of the heart. These defects lead to an increase in the workload on the right side of the heart as well as excessive blood flow to the lungs. The symptoms, which may become apparent during infancy, childhood, or adulthood, depend on the severity of the defect and can vary greatly. The symptoms tend to be mild at first and may include difficulty breathing (dyspnea), increased susceptibility to respiratory infections, and/or abnormal bluish discoloration of the skin and mucous membranes (cyanosis). Some people with atrial septal defects may be at increased risk for the formation of blood clots that can travel to the major arteries (embolism) and block blood circulation. (For more information on this disorder, choose “atrial septal defect” as your search term in the Rare Disease Database.)Atrioventricular septal defect is a rare heart defect that is present at birth (congenital) and characterized by the improper development of the septa and valves of the heart. Infants with the complete form of the defect usually develop congestive heart failure. Excessive fluid accumulates in other areas of the body, especially the lungs. Pulmonary congestion may lead to difficulty breathing (dyspnea). Other symptoms may include a bluish discoloration of the skin (cyanosis), poor feeding habits, abnormally rapid breathing (tachypnea) and heart rate (tachycardia), and/or excessive sweating (hyperhidrosis). Adults with atrioventricular septal defect may experience abnormally low blood pressure, irregular heartbeats, and/or a rapid heartbeat. (For more information on this disorder, choose “atrioventricular septal defect” as your search term in the Rare Disease Database.)Cor Triatriatum is an extremely rare congenital heart defect characterized by the presence of an extra chamber above the left atrium of the heart. The pulmonary veins, returning blood from the lungs, drain into this extra “third atrium.” The symptoms of Cor Triatriatum vary greatly and depend on the size of the opening between the chambers. Symptoms may include abnormally rapid breathing (tachypnea), wheezing, a bluish discoloration to the skin (cyanosis), coughing, and/or abnormal accumulation of fluid in the lungs (pulmonary congestion). (For more information on this disorder, choose “Cor Triatriatum” as your search term in the Rare Disease Database.)Mitral valve stenosis is a rare heart defect that may be present at birth (congenital) or acquired. It is characterized by the abnormal narrowing of the opening of the mitral valve. In the congenital form, the symptoms vary greatly and may include coughing, difficulty breathing, heart palpitations, and/or frequent respiratory infections. In acquired mitral valve stenosis, the symptoms may also include weakness, abdominal discomfort, chest pain (angina), and/or periodic loss of consciousness.Tetralogy of Fallot is the most common form of cyanotic congenital heart disease. Cyanosis is the abnormal bluish discoloration of the skin that occurs because of low levels of circulating oxygen in the blood. Tetralogy of Fallot consists of a combination of 4 different defects: a ventricular septal defect; obstructed outflow of blood from the right ventricle to the lungs (pulmonary stenosis); a displaced aorta, which causes blood to flow into the aorta from both the right and left ventricles (dextroposition or overriding aorta); and abnormal enlargement of the right ventricle (right ventricular hypertrophy). Symptoms may include difficulty breathing (dyspnea), fatigue, loss of appetite, slow weight gain, heart murmurs, an abnormal increase in the number of red blood cells (polycythemia), clubbing of the fingers and toes, and/or delayed physical growth. (For more information on this disorder, choose “Tetralogy of Fallot” as your search term in the Rare Disease Database.)Ventricular septal defects may occur in association with a variety of other disorders including Holt-Oram Syndrome, FG Syndrome, Genitopalatocardiac Syndrome, Fryns Syndrome, certain forms of Dandy-Walker Syndrome, Cardiomyopathy-Hypogonadism-Collagenoma Syndrome, Familial Idiopathic Cardiomyopathy, Simpson Dysmorphia Syndrome, Fetal Alcohol Syndrome, DiGeorge Syndrome, various Trisomy Syndromes, maternal alcoholism, maternal ingestion of phenylhydantoin, postrubella infection, and maternal Phenylketonuria. (For more information on these disorders choose “Holt- Oram,” “FG,” “Fryns,” “Dandy-Walker,” “Simpson Dysmorphia,” “Fetal Alcohol,” “DiGeorge,” “Trisomy,” and “Phenylketonuria” as your search terms in the Rare Disease Database.)
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Diagnosis of Ventricular Septal Defects
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Diagnosis of Ventricular Septal Defects.
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Therapies of Ventricular Septal Defects
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The diagnosis of ventricular septal defects is confirmed by a thorough clinical evaluation and specialized tests that allow physicians to evaluate the structure and function of the heart as well as the exact nature of the defect. X-ray studies and electrocardiogram (EKG) results may help to confirm the diagnosis. In one procedure, ultrasonic waves are directed toward the heart (Doppler echocardiogram), enabling physicians to study the motion and function of the heart and the surrounding vessels. During cardiac catheterization, a small hollow tube (catheter) is inserted into a large vein and threaded through the blood vessels that lead to the heart. This procedure allows physicians to determine the rate of blood flow through the heart, measure pressure within the heart, and thoroughly identify anatomical abnormalities.Although surgery is the definitive treatment for ventricular septal defects, it may not be recommended for all infants with these defects. Surgery is not indicated for infants with small ventricular septal defects that may close on their own or become less significant as the child matures and grows. Conservative treatment may include careful monitoring of symptoms and heart function.Medical management of infants with ventricular septal defects before surgery includes treatment of the symptoms related to congestive heart failure. Drugs such as digoxin may help to prevent irregular heartbeats and excessively rapid heartbeats (tachycardia). Restriction of salt in the diet, drugs that help to eliminate excessive fluid from the body (diuretics), and bed rest may also be effective therapies for congestive heart failure. Nutritional considerations are also important in infants with ventricular septal defects. Respiratory infections should be treated vigorously and early. Because of the risk of bacterial infection of the lining of the heart and the valves (endocarditis), individuals with ventricular septal defects should be given antibiotic drugs before any surgical procedure, including dental procedures such as tooth extractions.If symptoms persist after conservative treatment, open heart surgery is usually recommended to repair ventricular septal defects. Surgery during infancy or childhood has a high rate of success and it can prevent pulmonary vascular disease. One of several surgical procedures may be considered for the repair of the defect. The exact procedure is selected based upon the severity and location of the defect. Surgery may consist of closure of the hole in the septum with stitches (sutures) or with a patch (dacron or allograft).Other indications for surgical repair in infants with ventricular septal defects include congestive heart failure that is not responsive to medical management, poor weight gain, and/or significant pulmonary artery hypertension. Surgery is also suggested when the heart is abnormally enlarged (cardiomegaly) or there is significant exchange of blood from the left to right side of the heart (shunting), with resistance to the entry of blood into the lungs.
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Therapies of Ventricular Septal Defects. The diagnosis of ventricular septal defects is confirmed by a thorough clinical evaluation and specialized tests that allow physicians to evaluate the structure and function of the heart as well as the exact nature of the defect. X-ray studies and electrocardiogram (EKG) results may help to confirm the diagnosis. In one procedure, ultrasonic waves are directed toward the heart (Doppler echocardiogram), enabling physicians to study the motion and function of the heart and the surrounding vessels. During cardiac catheterization, a small hollow tube (catheter) is inserted into a large vein and threaded through the blood vessels that lead to the heart. This procedure allows physicians to determine the rate of blood flow through the heart, measure pressure within the heart, and thoroughly identify anatomical abnormalities.Although surgery is the definitive treatment for ventricular septal defects, it may not be recommended for all infants with these defects. Surgery is not indicated for infants with small ventricular septal defects that may close on their own or become less significant as the child matures and grows. Conservative treatment may include careful monitoring of symptoms and heart function.Medical management of infants with ventricular septal defects before surgery includes treatment of the symptoms related to congestive heart failure. Drugs such as digoxin may help to prevent irregular heartbeats and excessively rapid heartbeats (tachycardia). Restriction of salt in the diet, drugs that help to eliminate excessive fluid from the body (diuretics), and bed rest may also be effective therapies for congestive heart failure. Nutritional considerations are also important in infants with ventricular septal defects. Respiratory infections should be treated vigorously and early. Because of the risk of bacterial infection of the lining of the heart and the valves (endocarditis), individuals with ventricular septal defects should be given antibiotic drugs before any surgical procedure, including dental procedures such as tooth extractions.If symptoms persist after conservative treatment, open heart surgery is usually recommended to repair ventricular septal defects. Surgery during infancy or childhood has a high rate of success and it can prevent pulmonary vascular disease. One of several surgical procedures may be considered for the repair of the defect. The exact procedure is selected based upon the severity and location of the defect. Surgery may consist of closure of the hole in the septum with stitches (sutures) or with a patch (dacron or allograft).Other indications for surgical repair in infants with ventricular septal defects include congestive heart failure that is not responsive to medical management, poor weight gain, and/or significant pulmonary artery hypertension. Surgery is also suggested when the heart is abnormally enlarged (cardiomegaly) or there is significant exchange of blood from the left to right side of the heart (shunting), with resistance to the entry of blood into the lungs.
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Overview of Vernal Keratonconjunctivitis
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Vernal keratoconjunctivitis (VKC) is a chronic, non-contagious allergic disorder with seasonal recurrences usually appearing during the spring or warm weather. VKC is caused by a hypersensitivity to airborne-allergens. It usually affects younger members of the population, ages 3-25 and most patients are males. Major symptoms include itching, sensitivity to light (photophobia) and redness. Signs consist of inflammation of the mucous membrane lining the inside of the eyelid (conjunctiva) and the outer coat of the eyeball (sclera); hard, cobblestone-like bumps (papillae) on the upper eyelid; and stringy or mucous discharge.
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Overview of Vernal Keratonconjunctivitis. Vernal keratoconjunctivitis (VKC) is a chronic, non-contagious allergic disorder with seasonal recurrences usually appearing during the spring or warm weather. VKC is caused by a hypersensitivity to airborne-allergens. It usually affects younger members of the population, ages 3-25 and most patients are males. Major symptoms include itching, sensitivity to light (photophobia) and redness. Signs consist of inflammation of the mucous membrane lining the inside of the eyelid (conjunctiva) and the outer coat of the eyeball (sclera); hard, cobblestone-like bumps (papillae) on the upper eyelid; and stringy or mucous discharge.
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Symptoms of Vernal Keratonconjunctivitis
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VKC symptoms include inflammation of the outer membrane of the eye. This causes the eyes to become red and may cause blurred vision. The eyes become sensitive to light and itch intensely. Usually both eyes are affected, and cobblestone-like changes appear in the upper eyelid linings (palpebral conjunctiva). In other patients, a gelatinous nodule may develop in the tissue adjacent to the cornea (limbus). In very severe cases, the corneas may scar (shield ulcers) or clouding of the lens (cataract) may occur, leading to temporarily or permanently reduced vision.
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Symptoms of Vernal Keratonconjunctivitis. VKC symptoms include inflammation of the outer membrane of the eye. This causes the eyes to become red and may cause blurred vision. The eyes become sensitive to light and itch intensely. Usually both eyes are affected, and cobblestone-like changes appear in the upper eyelid linings (palpebral conjunctiva). In other patients, a gelatinous nodule may develop in the tissue adjacent to the cornea (limbus). In very severe cases, the corneas may scar (shield ulcers) or clouding of the lens (cataract) may occur, leading to temporarily or permanently reduced vision.
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Causes of Vernal Keratonconjunctivitis
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The cause of VKC is a hypersensitivity or allergic reaction of the eyes to airborne allergens. The pathogenesis of ocular allergies is related to a complex exchange of information between tissues through cell-to-cell communications, chemical mediators, cytokines, and adhesion molecules. It is also possible that the neural and endocrine systems may influence ocular allergic responses.The longer a patient suffers from seasonal VKC, the more likely he or she is to develop the disease chronically. That is why it is important to obtain a swift diagnosis and treat the disease as soon as possible.
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Causes of Vernal Keratonconjunctivitis. The cause of VKC is a hypersensitivity or allergic reaction of the eyes to airborne allergens. The pathogenesis of ocular allergies is related to a complex exchange of information between tissues through cell-to-cell communications, chemical mediators, cytokines, and adhesion molecules. It is also possible that the neural and endocrine systems may influence ocular allergic responses.The longer a patient suffers from seasonal VKC, the more likely he or she is to develop the disease chronically. That is why it is important to obtain a swift diagnosis and treat the disease as soon as possible.
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Affects of Vernal Keratonconjunctivitis
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Onset of VKC typically occurs at about 11 years of age, but onset can be between 3 and 25 years of age. The disorder appears to affect more males than females. Usually patients with VKC have a family history of atopic diseases, such as asthma, eczema, or rhinitis. It occurs most often during the spring or summer but up to 60% of patients experience recurrences in the winter periodically. It is more present in climates that are dry and warm.
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Affects of Vernal Keratonconjunctivitis. Onset of VKC typically occurs at about 11 years of age, but onset can be between 3 and 25 years of age. The disorder appears to affect more males than females. Usually patients with VKC have a family history of atopic diseases, such as asthma, eczema, or rhinitis. It occurs most often during the spring or summer but up to 60% of patients experience recurrences in the winter periodically. It is more present in climates that are dry and warm.
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Related disorders of Vernal Keratonconjunctivitis
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Symptoms of the following disorder can be similar to those of vernal keratoconjunctivitis. Comparisons may be useful for a differential diagnosis.Conjunctivitis or “pink eye” is caused by an infection of the outer lining of the eye and eyelids from bacteria or viruses. The eyes become red and irritated with a sandy or burning feeling. The disease may follow a cold or sore throat, and is most common in children. Sticky pus is visible in the eye and can cause the eyelids to stick together. Pink eye is highly contagious.
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Related disorders of Vernal Keratonconjunctivitis. Symptoms of the following disorder can be similar to those of vernal keratoconjunctivitis. Comparisons may be useful for a differential diagnosis.Conjunctivitis or “pink eye” is caused by an infection of the outer lining of the eye and eyelids from bacteria or viruses. The eyes become red and irritated with a sandy or burning feeling. The disease may follow a cold or sore throat, and is most common in children. Sticky pus is visible in the eye and can cause the eyelids to stick together. Pink eye is highly contagious.
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Diagnosis of Vernal Keratonconjunctivitis
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The diagnosis of VKC is usually straightforward and can almost always be diagnosed based on signs and symptoms. However, atypical presentations or patients that experience incomplete forms of VKC may have a more difficult time obtaining a diagnosis. Having asthma or dermatitis also helps support the diagnosis of VKC.Clinical Testing and Work-UpDifficult cases of VKC can be diagnosed and treated by conjunctival scraping, demonstrating the presence of infiltrating eosinophils.
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Diagnosis of Vernal Keratonconjunctivitis. The diagnosis of VKC is usually straightforward and can almost always be diagnosed based on signs and symptoms. However, atypical presentations or patients that experience incomplete forms of VKC may have a more difficult time obtaining a diagnosis. Having asthma or dermatitis also helps support the diagnosis of VKC.Clinical Testing and Work-UpDifficult cases of VKC can be diagnosed and treated by conjunctival scraping, demonstrating the presence of infiltrating eosinophils.
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Therapies of Vernal Keratonconjunctivitis
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TreatmentVKC usually subsides at the onset of puberty, and treatment is both preventive and therapeutic. To prevent flare-ups, the agent that causes the allergy should be avoided if possible. Wearing dark sunglasses in the daytime, avoiding dust, and not going out on hot afternoons are also recommended. Mast cell stabilizer eye drops can be used at the beginning of the season or the first sign of a flare-up to prevent severe symptoms.Topical eye drops are generally preferred as the first source of treatment. Cold compresses and artificial tears and ointments also may soothe, lubricate and dilute the antigen. Topical antihistamines producing constriction of the blood vessels and ducts may help. Mast-cell stabilizers may prevent further flare-ups of the disorder or may help control a flare-up but do little to reduce the symptoms of VKC. Non-steroid anti-inflammatories (NSAIDS) may relieve symptoms in moderate cases, but topical steroids should be reserved for more severe cases.
Topical steroid preparations are the most effective therapy for moderate to severe forms of VKC; however, their use should be carefully monitored because long-term use can cause glaucoma. Cyclosporine eye drops can also be useful.It is important to begin treatment of VKC immediately upon receiving a diagnosis because the longer a patient suffers with the disease, there is a decrease in visual function and the chances of developing cataracts or permanent blindness increases.A few prescription drugs have been approved by the U.S. Food and Drug Administration (FDA) for treatment of VKC including cromolyn sodium (Opticrom), lodoxamide tromethamine (Alomide) and levocabastine (Livostin).In 2021, cyclosporine ophthalmic emulsion (Verkazia) was approved to treat VKC in children and adults.Oral administration of montelukast (Singulair), a drug usually prescribed for asthma, has also been shown to be an effective treatment of VKC.
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Therapies of Vernal Keratonconjunctivitis. TreatmentVKC usually subsides at the onset of puberty, and treatment is both preventive and therapeutic. To prevent flare-ups, the agent that causes the allergy should be avoided if possible. Wearing dark sunglasses in the daytime, avoiding dust, and not going out on hot afternoons are also recommended. Mast cell stabilizer eye drops can be used at the beginning of the season or the first sign of a flare-up to prevent severe symptoms.Topical eye drops are generally preferred as the first source of treatment. Cold compresses and artificial tears and ointments also may soothe, lubricate and dilute the antigen. Topical antihistamines producing constriction of the blood vessels and ducts may help. Mast-cell stabilizers may prevent further flare-ups of the disorder or may help control a flare-up but do little to reduce the symptoms of VKC. Non-steroid anti-inflammatories (NSAIDS) may relieve symptoms in moderate cases, but topical steroids should be reserved for more severe cases.
Topical steroid preparations are the most effective therapy for moderate to severe forms of VKC; however, their use should be carefully monitored because long-term use can cause glaucoma. Cyclosporine eye drops can also be useful.It is important to begin treatment of VKC immediately upon receiving a diagnosis because the longer a patient suffers with the disease, there is a decrease in visual function and the chances of developing cataracts or permanent blindness increases.A few prescription drugs have been approved by the U.S. Food and Drug Administration (FDA) for treatment of VKC including cromolyn sodium (Opticrom), lodoxamide tromethamine (Alomide) and levocabastine (Livostin).In 2021, cyclosporine ophthalmic emulsion (Verkazia) was approved to treat VKC in children and adults.Oral administration of montelukast (Singulair), a drug usually prescribed for asthma, has also been shown to be an effective treatment of VKC.
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Overview of Very Long Chain Acyl CoA Dehydrogenase Deficiency (LCAD)
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Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a rare genetic disorder of fatty acid metabolism that is transmitted in an autosomal recessive pattern. It occurs when an enzyme needed to break down certain very long-chain fatty acids is missing or not working properly. VLCADD is one of the metabolic diseases known as fatty acid oxidation (FOD) diseases. In the past, the name long-chain acyl-CoA dehydrogenase deficiency (LCADD) was applied to one such disease, but today it is clear that all cases once thought to be LCADD are actually VLCADD.The breakdown of fatty acids takes place in the mitochondria found in each cell. The mitochondria are small, well-defined structures that are found in the cytoplasm of cells and in which energy is generated from the breakdown of complex substances into simpler ones (mitochondrial oxidation). Classically, two forms of VLCADD have been described: an early-onset, severe form which, if unrecognized and undiagnosed, can lead to extreme weakness of the heart muscles (cardiomyopathy) and be life-threatening, and a later-onset, milder form that is characterized by repeated bouts of low blood sugar (hypoglycemia). In reality, patients can present with a combination of symptoms and the disease is best thought of as being a continuum. Since the advent of expanded newborn screening programs using tandem mass spectrometry technology, most VLCADD infants in the United States are being detected neonatal period.
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Overview of Very Long Chain Acyl CoA Dehydrogenase Deficiency (LCAD). Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a rare genetic disorder of fatty acid metabolism that is transmitted in an autosomal recessive pattern. It occurs when an enzyme needed to break down certain very long-chain fatty acids is missing or not working properly. VLCADD is one of the metabolic diseases known as fatty acid oxidation (FOD) diseases. In the past, the name long-chain acyl-CoA dehydrogenase deficiency (LCADD) was applied to one such disease, but today it is clear that all cases once thought to be LCADD are actually VLCADD.The breakdown of fatty acids takes place in the mitochondria found in each cell. The mitochondria are small, well-defined structures that are found in the cytoplasm of cells and in which energy is generated from the breakdown of complex substances into simpler ones (mitochondrial oxidation). Classically, two forms of VLCADD have been described: an early-onset, severe form which, if unrecognized and undiagnosed, can lead to extreme weakness of the heart muscles (cardiomyopathy) and be life-threatening, and a later-onset, milder form that is characterized by repeated bouts of low blood sugar (hypoglycemia). In reality, patients can present with a combination of symptoms and the disease is best thought of as being a continuum. Since the advent of expanded newborn screening programs using tandem mass spectrometry technology, most VLCADD infants in the United States are being detected neonatal period.
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Symptoms of Very Long Chain Acyl CoA Dehydrogenase Deficiency (LCAD)
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Children with early-onset VLCADD present with symptoms within days or weeks after birth. These infants show signs of low blood sugar (hypoglycemia), irritability and listlessness (lethargy). Blood ammonia levels also may be high. Infants also are at risk for weakness of the heart muscles (cardiomyopathy), abnormal heart rhythms and cardiorespiratory failure. Similar symptoms may occur any time in the first few months of life. Cardiomyopathy is uncommon in infancy but may be life threatening when present. The incidence of hypoglycemia decreases with age and is uncommon after about age 6. After this age, muscle symptoms predominate including periodic attacks of pain, fatigue, and/or muscle breakdown (rhabdomyolysis) with activity or otherwise mild illnesses. Some patients may show their first symptoms in early adolescence. Cardiomyopathy and cardiac arrhythmias can occur at any age. The hypoglycemia associated with VLCADD occurs with little or no accumulation of ketone bodies (hypoketotic hypoglycemia) in the blood. (Ketone bodies are chemical substances normally produced by fatty acid metabolism in the liver.) There are very complicated patterns of blood chemicals and concentrations of unusual acids in the blood. A patient’s blood or urine will be examined for these patterns if VLCADD is suspected. However, because hypoglycemia usually occurs well after other symptoms, home glucose monitoring is not typically useful. Affected individuals of any age are at risk to experience recurrent increased acid levels in blood and body tissues (metabolic acidosis); sudden cessation of breathing (respiratory arrest) and even cardiac arrest. Without prompt, appropriate treatment, such acute episodes may lead to potentially life-threatening complications. (For further information, please see Standard Therapies below.)Individuals with VLCADD deficiency may have fat deposits (fatty infiltration) and abnormal enlargement of the liver (hepatomegaly); poor muscle tone (hypotonia); and/or evidence of cardiomyopathy. For example, there may be abnormal thickening (hypertrophy) or stretching and enlargement (dilation) of the the heart (i.e., hypertrophic or dilated cardiomyopathy). Cardiomyopathy may lead to weakening in the force of heart contractions, decreased efficiency in the circulation of blood through the lungs and to the rest of the body (heart failure), and various associated symptoms will depend upon the nature and severity of the condition, patient age, and other factors.
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Symptoms of Very Long Chain Acyl CoA Dehydrogenase Deficiency (LCAD). Children with early-onset VLCADD present with symptoms within days or weeks after birth. These infants show signs of low blood sugar (hypoglycemia), irritability and listlessness (lethargy). Blood ammonia levels also may be high. Infants also are at risk for weakness of the heart muscles (cardiomyopathy), abnormal heart rhythms and cardiorespiratory failure. Similar symptoms may occur any time in the first few months of life. Cardiomyopathy is uncommon in infancy but may be life threatening when present. The incidence of hypoglycemia decreases with age and is uncommon after about age 6. After this age, muscle symptoms predominate including periodic attacks of pain, fatigue, and/or muscle breakdown (rhabdomyolysis) with activity or otherwise mild illnesses. Some patients may show their first symptoms in early adolescence. Cardiomyopathy and cardiac arrhythmias can occur at any age. The hypoglycemia associated with VLCADD occurs with little or no accumulation of ketone bodies (hypoketotic hypoglycemia) in the blood. (Ketone bodies are chemical substances normally produced by fatty acid metabolism in the liver.) There are very complicated patterns of blood chemicals and concentrations of unusual acids in the blood. A patient’s blood or urine will be examined for these patterns if VLCADD is suspected. However, because hypoglycemia usually occurs well after other symptoms, home glucose monitoring is not typically useful. Affected individuals of any age are at risk to experience recurrent increased acid levels in blood and body tissues (metabolic acidosis); sudden cessation of breathing (respiratory arrest) and even cardiac arrest. Without prompt, appropriate treatment, such acute episodes may lead to potentially life-threatening complications. (For further information, please see Standard Therapies below.)Individuals with VLCADD deficiency may have fat deposits (fatty infiltration) and abnormal enlargement of the liver (hepatomegaly); poor muscle tone (hypotonia); and/or evidence of cardiomyopathy. For example, there may be abnormal thickening (hypertrophy) or stretching and enlargement (dilation) of the the heart (i.e., hypertrophic or dilated cardiomyopathy). Cardiomyopathy may lead to weakening in the force of heart contractions, decreased efficiency in the circulation of blood through the lungs and to the rest of the body (heart failure), and various associated symptoms will depend upon the nature and severity of the condition, patient age, and other factors.
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Causes of Very Long Chain Acyl CoA Dehydrogenase Deficiency (LCAD)
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VLCADD deficiency is inherited in an autosomal recessive fashion. Original reports of long chain Acyl-CoA dehydrogenase deficiency (LCAD) in the literature were in error and all previously published cases of LCAD deficiency have been shown to be VLCAD deficiency.Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.Recessive genetic disorders occur when an individual inherits one copy of a gene that does not function properly from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.As noted above, VLCADD is a genetic disorder of fatty acid metabolism. Metabolic disorders result from abnormal structure and functioning of a specific protein known as an enzyme. Enzymes are proteins that speed up the chemical reactions of the body. Enzymes are complicated proteins that must be folded in very precise ways in order to do their job of speeding up specific chemical reactions so that metabolism may proceed.
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Causes of Very Long Chain Acyl CoA Dehydrogenase Deficiency (LCAD). VLCADD deficiency is inherited in an autosomal recessive fashion. Original reports of long chain Acyl-CoA dehydrogenase deficiency (LCAD) in the literature were in error and all previously published cases of LCAD deficiency have been shown to be VLCAD deficiency.Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.Recessive genetic disorders occur when an individual inherits one copy of a gene that does not function properly from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.As noted above, VLCADD is a genetic disorder of fatty acid metabolism. Metabolic disorders result from abnormal structure and functioning of a specific protein known as an enzyme. Enzymes are proteins that speed up the chemical reactions of the body. Enzymes are complicated proteins that must be folded in very precise ways in order to do their job of speeding up specific chemical reactions so that metabolism may proceed.
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Very Long Chain Acyl CoA Dehydrogenase Deficiency (LCAD)
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