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nord_185_5 | Diagnosis of Budd Chiari Syndrome | A diagnosis of Budd-Chiari syndrome is made based upon a thorough clinical evaluation, a detailed patient history, and a variety of specialized tests. A procedure in which a radiographic dye is administered into the body to allow for x-rays of the blood vessels (angiography) is often used to aid diagnosis. Magnetic resonance imagining (MRI) and ultrasound are also used as diagnostic procedures. During MRI, a magnetic field and radio waves are used to create cross-sectional images of organs and structures in the body. Surgical removal and microscopic evaluation of liver tissue (biopsy) may be helpful in diagnosis of Budd-Chiari syndrome. | Diagnosis of Budd Chiari Syndrome. A diagnosis of Budd-Chiari syndrome is made based upon a thorough clinical evaluation, a detailed patient history, and a variety of specialized tests. A procedure in which a radiographic dye is administered into the body to allow for x-rays of the blood vessels (angiography) is often used to aid diagnosis. Magnetic resonance imagining (MRI) and ultrasound are also used as diagnostic procedures. During MRI, a magnetic field and radio waves are used to create cross-sectional images of organs and structures in the body. Surgical removal and microscopic evaluation of liver tissue (biopsy) may be helpful in diagnosis of Budd-Chiari syndrome. | 185 | Budd Chiari Syndrome |
nord_185_6 | Therapies of Budd Chiari Syndrome | TreatmentTreatment of Budd-Chiari syndrome is most successful if the disorder is diagnosed early. There are also various methods of treatment. The use of high doses of the corticosteroid drug, prednisone, may also be administered. Drugs that hinder blood clotting (anticoagulants) such as heparin may be beneficial for treatment of individuals with Budd-Chiari syndrome.Surgical widening (dilation) of affected veins (angioplasty) may ease high pressure in the vessel walls. In some cases, Budd-Chiari syndrome may be treated surgically by diverting blood flow from one vein to another (shunting). In other cases, a blocked vein may be cleared out and then a slender rod (stent) may be inserted into the vein to maintain blood flow. In serious cases of Budd-Chiari syndrome, liver transplantation may be necessary. | Therapies of Budd Chiari Syndrome. TreatmentTreatment of Budd-Chiari syndrome is most successful if the disorder is diagnosed early. There are also various methods of treatment. The use of high doses of the corticosteroid drug, prednisone, may also be administered. Drugs that hinder blood clotting (anticoagulants) such as heparin may be beneficial for treatment of individuals with Budd-Chiari syndrome.Surgical widening (dilation) of affected veins (angioplasty) may ease high pressure in the vessel walls. In some cases, Budd-Chiari syndrome may be treated surgically by diverting blood flow from one vein to another (shunting). In other cases, a blocked vein may be cleared out and then a slender rod (stent) may be inserted into the vein to maintain blood flow. In serious cases of Budd-Chiari syndrome, liver transplantation may be necessary. | 185 | Budd Chiari Syndrome |
nord_186_0 | Overview of Buerger’s Disease | 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 affected more often than the arms. In most cases, the first symptom is extreme pain of the lower arms and legs while at rest. Affected individuals may also experience cramping in the legs when they walk that, in rare cases, may cause limping (claudication). 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). In severe cases, individuals with Buerger's disease may exhibit tissue death (gangrene) of affected limbs. The exact cause of Buerger's disease is not known; however, most affected individuals are heavy tobacco users. | Overview of Buerger’s Disease. 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 affected more often than the arms. In most cases, the first symptom is extreme pain of the lower arms and legs while at rest. Affected individuals may also experience cramping in the legs when they walk that, in rare cases, may cause limping (claudication). 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). In severe cases, individuals with Buerger's disease may exhibit tissue death (gangrene) of affected limbs. The exact cause of Buerger's disease is not known; however, most affected individuals are heavy tobacco users. | 186 | Buerger’s Disease |
nord_186_1 | Symptoms of Buerger’s Disease | Buerger's disease is characterized by narrowing or blockage (occlusion) of the intermediate and/or small sized arteries and veins of the extremities, resulting in reduced blood flow to these areas (peripheral vascular disease). Buerger's disease tends to occur in sudden (acute) episodes that may last from one to four weeks. The disorder runs a recurrent course.In most cases, the first sign of Buerger's disease is extreme pain in the lower arms and/or legs while at rest. Affected individuals may also experience cramping in the legs when they walk that, in rare cases, may cause affected individuals to limp (claudication). Other physical features associated with Buerger's disease may include sores (ulcers) on the arms and legs, pale discoloration of the hands, 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 inflammation and clotting of certain veins (thrombophlebitis). Dry dark ulcerations that often form on the tips of the fingers or toes may be extremely painful. Pain associated with these ulcers may worsen with elevation. In severe cases, individuals with Buerger's disease may exhibit tissue death (gangrene) of the affected areas. In some cases, arteries and veins of the intestines may also be affected. This may result in extreme heaviness or pain (angina) in the abdomen and weight loss. In extremely rare cases (i.e., fewer than 2 percent), affected individuals have exhibited neurological abnormalities. | Symptoms of Buerger’s Disease. Buerger's disease is characterized by narrowing or blockage (occlusion) of the intermediate and/or small sized arteries and veins of the extremities, resulting in reduced blood flow to these areas (peripheral vascular disease). Buerger's disease tends to occur in sudden (acute) episodes that may last from one to four weeks. The disorder runs a recurrent course.In most cases, the first sign of Buerger's disease is extreme pain in the lower arms and/or legs while at rest. Affected individuals may also experience cramping in the legs when they walk that, in rare cases, may cause affected individuals to limp (claudication). Other physical features associated with Buerger's disease may include sores (ulcers) on the arms and legs, pale discoloration of the hands, 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 inflammation and clotting of certain veins (thrombophlebitis). Dry dark ulcerations that often form on the tips of the fingers or toes may be extremely painful. Pain associated with these ulcers may worsen with elevation. In severe cases, individuals with Buerger's disease may exhibit tissue death (gangrene) of the affected areas. In some cases, arteries and veins of the intestines may also be affected. This may result in extreme heaviness or pain (angina) in the abdomen and weight loss. In extremely rare cases (i.e., fewer than 2 percent), affected individuals have exhibited neurological abnormalities. | 186 | Buerger’s Disease |
nord_186_2 | Causes of Buerger’s Disease | The exact cause of Buerger's disease is unknown. However, the use of tobacco is associated with the development of the disorder. In fact, most researchers believe that past or present use of tobacco products by an individual is a requirement for the diagnosis of Buerger's disease. The exact relationship tobacco products have with Buerger's disease is not completely understood.Some scientists believe that Buerger's disease may be an autoimmune disorder. In some cases, trauma to the hands and feet may contribute to the 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.Genetic factors may play a role in the development or severity of Buerger's disease because the prevalence varies significantly between ethic groups. More research is necessary to determine the exact role, if any, that genetics plays in the development of the disorder. The symptoms of Buerger's disease develop because of impaired blood flow (ischemia) to certain areas of the body most often the arms and legs. | Causes of Buerger’s Disease. The exact cause of Buerger's disease is unknown. However, the use of tobacco is associated with the development of the disorder. In fact, most researchers believe that past or present use of tobacco products by an individual is a requirement for the diagnosis of Buerger's disease. The exact relationship tobacco products have with Buerger's disease is not completely understood.Some scientists believe that Buerger's disease may be an autoimmune disorder. In some cases, trauma to the hands and feet may contribute to the 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.Genetic factors may play a role in the development or severity of Buerger's disease because the prevalence varies significantly between ethic groups. More research is necessary to determine the exact role, if any, that genetics plays in the development of the disorder. The symptoms of Buerger's disease develop because of impaired blood flow (ischemia) to certain areas of the body most often the arms and legs. | 186 | Buerger’s Disease |
nord_186_3 | Affects of Buerger’s Disease | Buerger's disease is a very rare disorder that, in most cases, affects young or middle-aged male cigarette smokers with onset of symptoms before 40-45 years of age. In recent years, more affected women have been reported in the medical literature. Some scientists have speculated that this is due to an increase in the amount of women who smoke. At one time the ratio of affected men to women was 100:1, recent articles in the medical literature have speculated that ratio may be 10:1 or closer. In extremely rare cases, individuals who do not smoke have developed Buerger's disease. Buerger's disease is extremely rare in the United States and Europe, but more common in other parts of the world, especially in parts of Asia and the Far and Middle East. The incidence in the United States has been estimated at 12.6-20 per 100,000 people in the general population. Buerger's disease occurs with greater frequency in countries that have heavy tobacco use. Although most cases are associated with cigarette smoking, the disorder has also developed in individuals who did not smoke but used smokeless tobacco (e.g., chewing tobacco). | Affects of Buerger’s Disease. Buerger's disease is a very rare disorder that, in most cases, affects young or middle-aged male cigarette smokers with onset of symptoms before 40-45 years of age. In recent years, more affected women have been reported in the medical literature. Some scientists have speculated that this is due to an increase in the amount of women who smoke. At one time the ratio of affected men to women was 100:1, recent articles in the medical literature have speculated that ratio may be 10:1 or closer. In extremely rare cases, individuals who do not smoke have developed Buerger's disease. Buerger's disease is extremely rare in the United States and Europe, but more common in other parts of the world, especially in parts of Asia and the Far and Middle East. The incidence in the United States has been estimated at 12.6-20 per 100,000 people in the general population. Buerger's disease occurs with greater frequency in countries that have heavy tobacco use. Although most cases are associated with cigarette smoking, the disorder has also developed in individuals who did not smoke but used smokeless tobacco (e.g., chewing tobacco). | 186 | Buerger’s Disease |
nord_186_4 | Related disorders of Buerger’s Disease | Symptoms of the following disorders can be similar to those of Buerger's disease. Comparisons may be useful for a differential diagnosis: 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. (For more information on this disorder, choose “Vasculitis” as your search term in the Rare Disease Database.)Scleroderma is a rare connective tissue disorder characterized by abnormal thickening of the skin. Connective tissue is composed of collagen, which supports and binds other body tissues. There are several types of scleroderma. Some types affect certain, specific parts of the body, while other types can affect the whole body and internal organs (systemic). The exact cause of scleroderma is unknown. The immune system and vascular system as well as connective tissue metabolism are known to play some role in the disease process. (For more information on this disorder, choose “scleroderma” as your search term in the Rare Disease Database.)Takayasu arteritis is a rare disorder characterized by inflammation of the large elastic arteries. The main artery of the heart (aorta) and the pulmonary (lung) artery are affected. This disorder causes progressive inflammation of many arteries in the body (polyarteritis), resulting in the reduction of blood flow. Arteries in the head and arms may be affected, and this can result in the loss of the major pulse points in the body. Some people with takayasu arteritis have irregular narrowing of portions of the large arteries (segmental stenosis) and abnormal backward flow of blood from the aorta into the left ventricle of the heart (aortic regurgitation). (For more information on this disorder, choose “Takayasu” as your search term in the Rare Disease Database.) | Related disorders of Buerger’s Disease. Symptoms of the following disorders can be similar to those of Buerger's disease. Comparisons may be useful for a differential diagnosis: 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. (For more information on this disorder, choose “Vasculitis” as your search term in the Rare Disease Database.)Scleroderma is a rare connective tissue disorder characterized by abnormal thickening of the skin. Connective tissue is composed of collagen, which supports and binds other body tissues. There are several types of scleroderma. Some types affect certain, specific parts of the body, while other types can affect the whole body and internal organs (systemic). The exact cause of scleroderma is unknown. The immune system and vascular system as well as connective tissue metabolism are known to play some role in the disease process. (For more information on this disorder, choose “scleroderma” as your search term in the Rare Disease Database.)Takayasu arteritis is a rare disorder characterized by inflammation of the large elastic arteries. The main artery of the heart (aorta) and the pulmonary (lung) artery are affected. This disorder causes progressive inflammation of many arteries in the body (polyarteritis), resulting in the reduction of blood flow. Arteries in the head and arms may be affected, and this can result in the loss of the major pulse points in the body. Some people with takayasu arteritis have irregular narrowing of portions of the large arteries (segmental stenosis) and abnormal backward flow of blood from the aorta into the left ventricle of the heart (aortic regurgitation). (For more information on this disorder, choose “Takayasu” as your search term in the Rare Disease Database.) | 186 | Buerger’s Disease |
nord_186_5 | Diagnosis of Buerger’s Disease | A diagnosis of Buerger's disease may be made based upon the identification of characteristic physical features and symptoms. Many physicians require a history of recent or current tobacco use in a diagnosis of Buerger's disease. A test such as an angiography or noninvasive techniques may be used to confirm a diagnosis. During an angiography, injection of a specialized dye is used to make the blood vessels visible on x-rays. | Diagnosis of Buerger’s Disease. A diagnosis of Buerger's disease may be made based upon the identification of characteristic physical features and symptoms. Many physicians require a history of recent or current tobacco use in a diagnosis of Buerger's disease. A test such as an angiography or noninvasive techniques may be used to confirm a diagnosis. During an angiography, injection of a specialized dye is used to make the blood vessels visible on x-rays. | 186 | Buerger’s Disease |
nord_186_6 | Therapies of Buerger’s Disease | TreatmentThe treatment of Buerger's disease is symptomatic and supportive. Symptoms usually improve if affected individuals stop smoking. In some cases, when individuals stop smoking complete remission of the disorder may occur.If an affected individual does not stop smoking, treatment options for Buerger's disease should avoid premature or unnecessary surgery. Conservative treatment may include drugs that prevent the blood from clotting (anticoagulants), drugs that increase the diameter of blood vessels (vasodilators), drugs that prevent inflammation (antiinflammatories), antibiotics, and/or drugs that relieve pain (analgesics).In some cases surgery may become necessary. Affected individuals have been treated with an operation in which nerve terminals (ganglia) are destroyed to interrupt the nerve pathway and improve blood supply to the affected limb (sympathectomay). In some cases, surgeons may try bypass procedures to get around the blocked or narrow (occluded) veins and/or arteries. In severe cases, surgeons may be forced to remove (amputate) a finger or toe or part of an arm or leg. | Therapies of Buerger’s Disease. TreatmentThe treatment of Buerger's disease is symptomatic and supportive. Symptoms usually improve if affected individuals stop smoking. In some cases, when individuals stop smoking complete remission of the disorder may occur.If an affected individual does not stop smoking, treatment options for Buerger's disease should avoid premature or unnecessary surgery. Conservative treatment may include drugs that prevent the blood from clotting (anticoagulants), drugs that increase the diameter of blood vessels (vasodilators), drugs that prevent inflammation (antiinflammatories), antibiotics, and/or drugs that relieve pain (analgesics).In some cases surgery may become necessary. Affected individuals have been treated with an operation in which nerve terminals (ganglia) are destroyed to interrupt the nerve pathway and improve blood supply to the affected limb (sympathectomay). In some cases, surgeons may try bypass procedures to get around the blocked or narrow (occluded) veins and/or arteries. In severe cases, surgeons may be forced to remove (amputate) a finger or toe or part of an arm or leg. | 186 | Buerger’s Disease |
nord_187_0 | Overview of Bullous Pemphigoid | Bullous pemphigoid (BP) is a rare, autoimmune, chronic skin disorder characterized by blistering, urticarial lesions (hives) and itching. Less commonly these blisters can involve the mucous membranes including the eyes, oral mucosa, esophagus and genital mucosa. It typically presents in older adults as a generalized intensely itchy blistering skin condition. | Overview of Bullous Pemphigoid. Bullous pemphigoid (BP) is a rare, autoimmune, chronic skin disorder characterized by blistering, urticarial lesions (hives) and itching. Less commonly these blisters can involve the mucous membranes including the eyes, oral mucosa, esophagus and genital mucosa. It typically presents in older adults as a generalized intensely itchy blistering skin condition. | 187 | Bullous Pemphigoid |
nord_187_1 | Symptoms of Bullous Pemphigoid | The first symptom of BP is usually redness and itching of the skin. Within weeks to months, thin-walled, tense blisters with clear fluid centers (bullae) appear on the arms and legs (flexor surfaces), in the armpits (axillae), on the abdomen, and/or in the skinfolds of the groin. Mucous membranes may also be involved but are less commonly seen than skin blisters. The blisters are usually tense (tight), and contain clear or blood-tinged fluid; they do not rupture easily with gentle contact. If the blisters do rupture, pain may occur but healing is usually rapid and resolves without scarring. Bullous pemphigoid usually itches and in its early phase urticarial (hives) lesions may be present before blisters are noted. | Symptoms of Bullous Pemphigoid. The first symptom of BP is usually redness and itching of the skin. Within weeks to months, thin-walled, tense blisters with clear fluid centers (bullae) appear on the arms and legs (flexor surfaces), in the armpits (axillae), on the abdomen, and/or in the skinfolds of the groin. Mucous membranes may also be involved but are less commonly seen than skin blisters. The blisters are usually tense (tight), and contain clear or blood-tinged fluid; they do not rupture easily with gentle contact. If the blisters do rupture, pain may occur but healing is usually rapid and resolves without scarring. Bullous pemphigoid usually itches and in its early phase urticarial (hives) lesions may be present before blisters are noted. | 187 | Bullous Pemphigoid |
nord_187_2 | Causes of Bullous Pemphigoid | Bullous pemphigoid is an autoimmune blistering disease. Autoimmune disorders are generated when the body’s natural defenses against “foreign” or invading organisms, attack healthy tissue for unknown reasons. In BP, an autoantibody binds to a component of the skin that holds the dermis and epidermis together, causing separation of these two layers, thus forming a blister. The autoantibodies recognize components of the basement membrane zone called BP antigen 1 and 2 (and in some cases other basement membrane zone antigens). These proteins are part of complexes that hold the skin together, called hemidesmosomes, and provide structural support to the skin. When the body “attacks” these proteins, the skin becomes more fragile and the clinical manifestations of BP become apparent. Certain drug reactions can produce skin lesions that are very similar to BP. It is essential to determine whether the patient’s symptoms are adverse reactions to the pharmaceuticals, or whether the blisters are the result of an autoimmune reaction. | Causes of Bullous Pemphigoid. Bullous pemphigoid is an autoimmune blistering disease. Autoimmune disorders are generated when the body’s natural defenses against “foreign” or invading organisms, attack healthy tissue for unknown reasons. In BP, an autoantibody binds to a component of the skin that holds the dermis and epidermis together, causing separation of these two layers, thus forming a blister. The autoantibodies recognize components of the basement membrane zone called BP antigen 1 and 2 (and in some cases other basement membrane zone antigens). These proteins are part of complexes that hold the skin together, called hemidesmosomes, and provide structural support to the skin. When the body “attacks” these proteins, the skin becomes more fragile and the clinical manifestations of BP become apparent. Certain drug reactions can produce skin lesions that are very similar to BP. It is essential to determine whether the patient’s symptoms are adverse reactions to the pharmaceuticals, or whether the blisters are the result of an autoimmune reaction. | 187 | Bullous Pemphigoid |
nord_187_3 | Affects of Bullous Pemphigoid | BP is a rare disorder that affects males and females in equal numbers. This disorder primarily affects the elderly, with an average age around 80 years old. Rare cases have been reported in infants and adolescents. Recently, researchers have learned of an association between BP and neurological disorders. It is reported that between a third to a half of all BP patients have neurological diseases, such as dementia, Parkinson’s disease, stroke, epilepsy, and multiple sclerosis. These conditions normally occur before the onset of BP. | Affects of Bullous Pemphigoid. BP is a rare disorder that affects males and females in equal numbers. This disorder primarily affects the elderly, with an average age around 80 years old. Rare cases have been reported in infants and adolescents. Recently, researchers have learned of an association between BP and neurological disorders. It is reported that between a third to a half of all BP patients have neurological diseases, such as dementia, Parkinson’s disease, stroke, epilepsy, and multiple sclerosis. These conditions normally occur before the onset of BP. | 187 | Bullous Pemphigoid |
nord_187_4 | Related disorders of Bullous Pemphigoid | Symptoms of the following disorders can be similar to those of BP. Comparisons may be useful for a differential diagnosis:Pemphigus is a general term for a group of rare autoimmune blistering skin disorders. All forms of pemphigus are characterized by the development of blistering eruptions on the outer layer of the skin (epidermis). The blisters that occur in pemphigus may be referred to as flaccid bullae because they are not firm and break open (rupture) easily. In pemphigus vulgaris, lesions develop on the mucous membranes such as those lining the inside the mouth. Mucous membranes are the thin, moist coverings of many of the body's internal surfaces. Pemphigus is also an autoimmune blistering condition similar to BP but with different target antigens in the skin (desmoglein 1 and 3) (For more information on this disorder, choose “pemphigus” as your search term on the Rare Disease Database.)Erythema multiforme (EM) is an inflammatory skin disorder characterized by target-shaped lesions on the skin and/or mucous membranes. EM is most often triggered by an infection or medications. The early symptoms of this disorder may include red, elevated spots (erythematous macules or papules) that often have a targetoid appearance on the skin that may have fluid filled centers and that eventually grow into larger blisters. Affected areas generally include the hands, forearms, feet, and/or mucous membranes of the mouth, nose, and/or genitals. The skin lesions and blisters caused by erythema multiforme generally appear on both sides of the body and tend to heal in approximately 2 to 3 weeks. Erythema multiforme may also cause fever, joint pain, muscle stiffness, and fatigue. (For more information on this disorder, choose “erythema multiforme” as your search term in the Rare Disease Database.)Mucous membrane pemphigoid (MMP) is a rare chronic disease characterized by blistering and scarring of the mucous membranes particularly in the mouth and membranes that surround the eyes (conjunctiva). Initial symptoms include redness and inflammation of these areas and scarring may occur on the membranes, including the eyes. Blisters may also develop in the mucous membranes of the pharynx, esophagus, nose, urethra and/or vulva. If MMP involves the skin, it typically affects the face, scalp, and upper body. (For more information on this disorder, choose “mucous membrane pemphigoid” as your search term in the Rare Disease Database.)Dermatitis herpetiformis (DH) is a rare, chronic, autoimmune skin condition characterized by the presence of groups of severely itchy blisters and raised red skin lesions. These are most commonly located on the elbows, knees, buttocks, lower back and scalp. The most common age of onset of DH is 30-40 years of age but individuals of all ages can be affected. DH is rare in children. DH is a skin manifestation of celiac disease. DH is treated with a gluten free diet and frequently a medication called dapsone. (For more information on this disorder, choose “dermatitis herpetiformis” as your search term in the Rare Disease Database.)Epidermolysis bullosa (EB) is a genetic skin disorder characterized clinically by blister formation from mechanical trauma. EB ranges from being a minor inconvenience requiring modification of some activities, to being completely disabling and, in some cases, fatal. Friction causes blister formation. Blisters can form anywhere on the surface of the skin, within the oral cavity and in more severe forms may also involve the external surface of the eye, as well as the respiratory, gastrointestinal and genitourinary tracts. In some forms of the disease, disfiguring scars and disabling musculoskeletal deformities occur. Currently, there is no cure for EB. Supportive care includes daily wound care, bandaging, and pain management as needed. Most types of EB are inherited, and usually first appear during childhood. (For more information on these disorders, choose “epidermolysis bullosa” as your search term in the Rare Disease Database.)Epidermolysis bullosa acquista (EBA) is a rare autoimmune disorder of the skin that typically affects middle-aged and elderly people. The most common locations for lesions to occur are areas that are exposed to repeated minor trauma, such as the hands, feet, knees, and elbows. Mucosal involvement is also common. After the blisters heal, scars usually remain. EBA is similar clinically to BP and difficult to differentiate without specific immunofluorescent testing. | Related disorders of Bullous Pemphigoid. Symptoms of the following disorders can be similar to those of BP. Comparisons may be useful for a differential diagnosis:Pemphigus is a general term for a group of rare autoimmune blistering skin disorders. All forms of pemphigus are characterized by the development of blistering eruptions on the outer layer of the skin (epidermis). The blisters that occur in pemphigus may be referred to as flaccid bullae because they are not firm and break open (rupture) easily. In pemphigus vulgaris, lesions develop on the mucous membranes such as those lining the inside the mouth. Mucous membranes are the thin, moist coverings of many of the body's internal surfaces. Pemphigus is also an autoimmune blistering condition similar to BP but with different target antigens in the skin (desmoglein 1 and 3) (For more information on this disorder, choose “pemphigus” as your search term on the Rare Disease Database.)Erythema multiforme (EM) is an inflammatory skin disorder characterized by target-shaped lesions on the skin and/or mucous membranes. EM is most often triggered by an infection or medications. The early symptoms of this disorder may include red, elevated spots (erythematous macules or papules) that often have a targetoid appearance on the skin that may have fluid filled centers and that eventually grow into larger blisters. Affected areas generally include the hands, forearms, feet, and/or mucous membranes of the mouth, nose, and/or genitals. The skin lesions and blisters caused by erythema multiforme generally appear on both sides of the body and tend to heal in approximately 2 to 3 weeks. Erythema multiforme may also cause fever, joint pain, muscle stiffness, and fatigue. (For more information on this disorder, choose “erythema multiforme” as your search term in the Rare Disease Database.)Mucous membrane pemphigoid (MMP) is a rare chronic disease characterized by blistering and scarring of the mucous membranes particularly in the mouth and membranes that surround the eyes (conjunctiva). Initial symptoms include redness and inflammation of these areas and scarring may occur on the membranes, including the eyes. Blisters may also develop in the mucous membranes of the pharynx, esophagus, nose, urethra and/or vulva. If MMP involves the skin, it typically affects the face, scalp, and upper body. (For more information on this disorder, choose “mucous membrane pemphigoid” as your search term in the Rare Disease Database.)Dermatitis herpetiformis (DH) is a rare, chronic, autoimmune skin condition characterized by the presence of groups of severely itchy blisters and raised red skin lesions. These are most commonly located on the elbows, knees, buttocks, lower back and scalp. The most common age of onset of DH is 30-40 years of age but individuals of all ages can be affected. DH is rare in children. DH is a skin manifestation of celiac disease. DH is treated with a gluten free diet and frequently a medication called dapsone. (For more information on this disorder, choose “dermatitis herpetiformis” as your search term in the Rare Disease Database.)Epidermolysis bullosa (EB) is a genetic skin disorder characterized clinically by blister formation from mechanical trauma. EB ranges from being a minor inconvenience requiring modification of some activities, to being completely disabling and, in some cases, fatal. Friction causes blister formation. Blisters can form anywhere on the surface of the skin, within the oral cavity and in more severe forms may also involve the external surface of the eye, as well as the respiratory, gastrointestinal and genitourinary tracts. In some forms of the disease, disfiguring scars and disabling musculoskeletal deformities occur. Currently, there is no cure for EB. Supportive care includes daily wound care, bandaging, and pain management as needed. Most types of EB are inherited, and usually first appear during childhood. (For more information on these disorders, choose “epidermolysis bullosa” as your search term in the Rare Disease Database.)Epidermolysis bullosa acquista (EBA) is a rare autoimmune disorder of the skin that typically affects middle-aged and elderly people. The most common locations for lesions to occur are areas that are exposed to repeated minor trauma, such as the hands, feet, knees, and elbows. Mucosal involvement is also common. After the blisters heal, scars usually remain. EBA is similar clinically to BP and difficult to differentiate without specific immunofluorescent testing. | 187 | Bullous Pemphigoid |
nord_187_5 | Diagnosis of Bullous Pemphigoid | Diagnosis is made based on a combination of clinical interpretation and laboratory findings. | Diagnosis of Bullous Pemphigoid. Diagnosis is made based on a combination of clinical interpretation and laboratory findings. | 187 | Bullous Pemphigoid |
nord_187_6 | Therapies of Bullous Pemphigoid | Treatment
The goal of therapy is to reduce symptoms (itching and formation of new blisters). Local skin care with antibacterial ointment to cover eroded blisters is recommended for all patients to decrease the likelihood of developing a secondary bacterial infection. High potency topical corticosteroid creams are typically used as first-line treatment. If topical application is not an appropriate option (for example, the patient is unable to apply ointment), oral corticosteroids, such as prednisone, may be considered. Since the cumulative effects of long-term corticosteroid therapy are undesirable, treatment aims at the lowest dose over the shortest period of time. A 2010 Cochrane review summarized the available treatment data for BP and concluded that very potent topical steroids are effective and safe treatments for BP, but their use in extensive disease may be limited by side effects and practical factors, such as the need to cover large areas with ointment. Initial doses of prednisolone greater than 0.75 mg per kg per day do not give additional benefit and could cause more adverse reactions. Doses lower than 0.75 mg per kg per day may be adequate to control disease and reduce likelihood and severity of potential side effects. An anti-inflammatory antibiotic, doxycycline, has been studied to treat BP. The benefit of using non-steroidal agents is their superior safety profile. This is often combined with a B vitamin called niacinamide. In more severe cases, patients will often be treated with medications that suppress the immune system. Examples of these medications include mycophenolate mofetil, azathioprine, methotrexate, rituximab and others.Because many patients with BP are elderly, decisions about whether to treat with drugs that alter the immune system (such as corticosteroids) must be individualized because it may make patients more susceptible to infections. | Therapies of Bullous Pemphigoid. Treatment
The goal of therapy is to reduce symptoms (itching and formation of new blisters). Local skin care with antibacterial ointment to cover eroded blisters is recommended for all patients to decrease the likelihood of developing a secondary bacterial infection. High potency topical corticosteroid creams are typically used as first-line treatment. If topical application is not an appropriate option (for example, the patient is unable to apply ointment), oral corticosteroids, such as prednisone, may be considered. Since the cumulative effects of long-term corticosteroid therapy are undesirable, treatment aims at the lowest dose over the shortest period of time. A 2010 Cochrane review summarized the available treatment data for BP and concluded that very potent topical steroids are effective and safe treatments for BP, but their use in extensive disease may be limited by side effects and practical factors, such as the need to cover large areas with ointment. Initial doses of prednisolone greater than 0.75 mg per kg per day do not give additional benefit and could cause more adverse reactions. Doses lower than 0.75 mg per kg per day may be adequate to control disease and reduce likelihood and severity of potential side effects. An anti-inflammatory antibiotic, doxycycline, has been studied to treat BP. The benefit of using non-steroidal agents is their superior safety profile. This is often combined with a B vitamin called niacinamide. In more severe cases, patients will often be treated with medications that suppress the immune system. Examples of these medications include mycophenolate mofetil, azathioprine, methotrexate, rituximab and others.Because many patients with BP are elderly, decisions about whether to treat with drugs that alter the immune system (such as corticosteroids) must be individualized because it may make patients more susceptible to infections. | 187 | Bullous Pemphigoid |
nord_188_0 | Overview of C Syndrome | SummaryC syndrome, also known as Opitz trigonocephaly syndrome (OTCS), is a complex condition defined by a broad group of clinical features and abnormalities. Children may be given this preliminary diagnosis and later diagnosed with a specific genetic condition. Affected children are born with a malformation in which the head is a triangular shape due to premature union of the skull bones (trigonocephaly), a narrow pointed forehead, a flat broad nasal bridge with a short nose, vertical folds over the inner corners of the eyes, an abnormal palate that is deeply furrowed, abnormalities of the ear, crossed eyes (strabismus), joints that are bent or in a fixed position, and loose skin. Developmental and learning disabilities are common. These signs and symptoms can vary significantly from one patient to another.OTCS is a heterogeneous disorder, which means that it does not have a single cause. Changes (mutations) in multiple and distinct genes, combinations of genes and chromosomal abnormalities may be the underlying cause this condition.IntroductionIn 1969, John Marius Opitz, a German-American medical geneticist, was treating two siblings, one brother and one sister. He noticed similar features: trigonocephaly, facial dysmorphia and severe mental delay. The syndrome was first named “C syndrome of multiple congenital abnormalities”, where the “C” stood for this family’s surname. Then, it was renamed C syndrome, Opitz C syndrome or Opitz trigonocephaly syndrome. | Overview of C Syndrome. SummaryC syndrome, also known as Opitz trigonocephaly syndrome (OTCS), is a complex condition defined by a broad group of clinical features and abnormalities. Children may be given this preliminary diagnosis and later diagnosed with a specific genetic condition. Affected children are born with a malformation in which the head is a triangular shape due to premature union of the skull bones (trigonocephaly), a narrow pointed forehead, a flat broad nasal bridge with a short nose, vertical folds over the inner corners of the eyes, an abnormal palate that is deeply furrowed, abnormalities of the ear, crossed eyes (strabismus), joints that are bent or in a fixed position, and loose skin. Developmental and learning disabilities are common. These signs and symptoms can vary significantly from one patient to another.OTCS is a heterogeneous disorder, which means that it does not have a single cause. Changes (mutations) in multiple and distinct genes, combinations of genes and chromosomal abnormalities may be the underlying cause this condition.IntroductionIn 1969, John Marius Opitz, a German-American medical geneticist, was treating two siblings, one brother and one sister. He noticed similar features: trigonocephaly, facial dysmorphia and severe mental delay. The syndrome was first named “C syndrome of multiple congenital abnormalities”, where the “C” stood for this family’s surname. Then, it was renamed C syndrome, Opitz C syndrome or Opitz trigonocephaly syndrome. | 188 | C Syndrome |
nord_188_1 | Symptoms of C Syndrome | One of the major features of OTCS is a condition in which the skull is a triangular shape. This occurs due to premature closure of the bones (trigonocephaly or prominent metopic suture due to its premature fusion). Patients with this disorder also have a distinct face in which the nasal bridge is broad with a short nose, there are vertical folds over the inner corners of the eyes (epicanthus) and paralysis of facial muscles (facial palsy). These children may have abnormalities of the outer ear, crossed eyes (strabismus), thin upper lip, smooth vertical groove between the base of the nose and the border of the upper lip (philtrum),an undersized jaw (micrognathia), a short neck and loose skin. Additional characteristics can include abnormalities of the breastbone (sternum), webbed fingers and/or toes (syndactyly), short limbs, heart, pancreas, kidney and lung abnormalities and failure of one or both testicles to move down into the scrotum (cryptorchidism). Feeding difficulties may occur because of a deeply furrowed palate in the mouth and malposition of teeth. Additional characteristics can include loss of muscle tone and joints in the hands bent in a fixed position or dislocated.Affected children may have central nervous system malformations and seizures. Developmental delay (motor, mental or global) and speech delay are common and children with C syndrome have intellectual disability that can vary from mild to severe. | Symptoms of C Syndrome. One of the major features of OTCS is a condition in which the skull is a triangular shape. This occurs due to premature closure of the bones (trigonocephaly or prominent metopic suture due to its premature fusion). Patients with this disorder also have a distinct face in which the nasal bridge is broad with a short nose, there are vertical folds over the inner corners of the eyes (epicanthus) and paralysis of facial muscles (facial palsy). These children may have abnormalities of the outer ear, crossed eyes (strabismus), thin upper lip, smooth vertical groove between the base of the nose and the border of the upper lip (philtrum),an undersized jaw (micrognathia), a short neck and loose skin. Additional characteristics can include abnormalities of the breastbone (sternum), webbed fingers and/or toes (syndactyly), short limbs, heart, pancreas, kidney and lung abnormalities and failure of one or both testicles to move down into the scrotum (cryptorchidism). Feeding difficulties may occur because of a deeply furrowed palate in the mouth and malposition of teeth. Additional characteristics can include loss of muscle tone and joints in the hands bent in a fixed position or dislocated.Affected children may have central nervous system malformations and seizures. Developmental delay (motor, mental or global) and speech delay are common and children with C syndrome have intellectual disability that can vary from mild to severe. | 188 | C Syndrome |
nord_188_2 | Causes of C Syndrome | There is no common genetic cause for OTCS. Recent research has found that changes (mutations) in specific genes could be associated with this condition: MAGEL2, FOXP1, IFT140 and ASXL3. Until recently, OTCS was thought to follow an autosomal recessive pattern of inheritance. However, it is now believed that the disorder occurs as a result of de novo dominant heritance or gonadal mosaicism. Mosaicism refers to a condition in which a person has cells that differ from each other in genetic makeup. Dominant genetic disorders occur when only a single copy of an altered gene is necessary to cause a particular disease. The altered gene can be inherited from an affected parent or can be the result of a new change (mutation) 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. | Causes of C Syndrome. There is no common genetic cause for OTCS. Recent research has found that changes (mutations) in specific genes could be associated with this condition: MAGEL2, FOXP1, IFT140 and ASXL3. Until recently, OTCS was thought to follow an autosomal recessive pattern of inheritance. However, it is now believed that the disorder occurs as a result of de novo dominant heritance or gonadal mosaicism. Mosaicism refers to a condition in which a person has cells that differ from each other in genetic makeup. Dominant genetic disorders occur when only a single copy of an altered gene is necessary to cause a particular disease. The altered gene can be inherited from an affected parent or can be the result of a new change (mutation) 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. | 188 | C Syndrome |
nord_188_3 | Affects of C Syndrome | Only about 60 patients with OTCS have been reported in the world’s medical literature. OTCS is a very rare disorder that seems to affect males and females in equal numbers. The prevalence is between 1/800,000 and 1/1,000,000. | Affects of C Syndrome. Only about 60 patients with OTCS have been reported in the world’s medical literature. OTCS is a very rare disorder that seems to affect males and females in equal numbers. The prevalence is between 1/800,000 and 1/1,000,000. | 188 | C Syndrome |
nord_188_4 | Related disorders of C Syndrome | Symptoms of the following condition can be similar to those of OTCS. Comparisons may be useful for a differential diagnosis:Bohring-Opitz syndrome (BOS) is a rare, multiple anomaly syndrome that affects growth, development, and variable organ-systems. Individuals with BOS often have severe growth restriction and are therefore quite small; they may have feeding difficulties, characteristic facial features, and the presence of a red or pink birthmark (nevus flammeus) on the forehead or eyelids. Individuals may also have seizures, heart anomalies, and a characteristic ‘BOS posture’ where the elbows are bent and wrists angle outwards. Additional abnormalities may include a smaller than average head size (microcephaly), a visible ridge over the forehead (metopic ridge), a cleft lip and/or palate, eye abnormalities, recurrent infections, and pauses during breathing while asleep (sleep apnea), as well as sleep difficulties. Children with BOS may have varying degrees of learning differences, but these are generally severe, and most children do not learn to talk or walk. BOS is caused by mutations in the ASXL1, ASXL2, and KLHL7 genes. (For more information, search for Bohring-Opitz syndrome in the Rare Disease Database.) | Related disorders of C Syndrome. Symptoms of the following condition can be similar to those of OTCS. Comparisons may be useful for a differential diagnosis:Bohring-Opitz syndrome (BOS) is a rare, multiple anomaly syndrome that affects growth, development, and variable organ-systems. Individuals with BOS often have severe growth restriction and are therefore quite small; they may have feeding difficulties, characteristic facial features, and the presence of a red or pink birthmark (nevus flammeus) on the forehead or eyelids. Individuals may also have seizures, heart anomalies, and a characteristic ‘BOS posture’ where the elbows are bent and wrists angle outwards. Additional abnormalities may include a smaller than average head size (microcephaly), a visible ridge over the forehead (metopic ridge), a cleft lip and/or palate, eye abnormalities, recurrent infections, and pauses during breathing while asleep (sleep apnea), as well as sleep difficulties. Children with BOS may have varying degrees of learning differences, but these are generally severe, and most children do not learn to talk or walk. BOS is caused by mutations in the ASXL1, ASXL2, and KLHL7 genes. (For more information, search for Bohring-Opitz syndrome in the Rare Disease Database.) | 188 | C Syndrome |
nord_188_5 | Diagnosis of C Syndrome | OTCS is a clinical diagnosis based on the features mentioned earlier. Since multiple genes (and chromosomal abnormalities) may be associated with this condition, whole exome sequencing (WES) can be used to identify the underlying molecular cause in some patients clinically diagnosed with this condition. | Diagnosis of C Syndrome. OTCS is a clinical diagnosis based on the features mentioned earlier. Since multiple genes (and chromosomal abnormalities) may be associated with this condition, whole exome sequencing (WES) can be used to identify the underlying molecular cause in some patients clinically diagnosed with this condition. | 188 | C Syndrome |
nord_188_6 | Therapies of C Syndrome | Treatment
There is no specific treatment for OTCS but treatment for some symptoms is possible. When trigonocephaly is severe, surgery may be performed to relieve the pressure on the brain and improve facial appearance. Other surgical procedures may be indicated for heart and other malformations. Supportive therapies such as speech therapy and interdisciplinary rehabilitation may be helpful in some patients. Genetic counseling is recommended for patients and their families. | Therapies of C Syndrome. Treatment
There is no specific treatment for OTCS but treatment for some symptoms is possible. When trigonocephaly is severe, surgery may be performed to relieve the pressure on the brain and improve facial appearance. Other surgical procedures may be indicated for heart and other malformations. Supportive therapies such as speech therapy and interdisciplinary rehabilitation may be helpful in some patients. Genetic counseling is recommended for patients and their families. | 188 | C Syndrome |
nord_189_0 | Overview of C3 Glomerulopathy: Dense Deposit Disease and C3 Glomerulonephritis | Over the past decade, important advances in our understanding of complement-mediated renal diseases have led to the adoption of new names or ‘disease categories’ to more precisely group diseases that appear to share a similar cause. Consider, for example, dense deposit disease (DDD), a very rare kidney disease characterized on a renal biopsy test called ‘immunofluorescence’ by an abundance of a protein called C3 in the renal glomeruli and named for the extremely dense ‘sausage-like’ deposits that are seen in the glomerular basement membrane (GBM) using electron microscopy. In 2013, after a consensus meeting, scientists recommended that DDD be sub-grouped under a new heading – C3 Glomerulopathy, abbreviated C3G. The adoption of this new term was driven by the recognition that there is another group of patients with glomerular disease whose kidney biopsy is reminiscent of DDD. On electron microscopy, the deposits in these patients are lighter in color and more widespread in location, but on immunofluorescence, as with DDD there is an abundance of C3 in the renal glomeruli. These patients are said to have C3 glomerulonephritis or C3GN. In recognition of shared similarities, both DDD and C3GN are now classified as sub-types of C3G. C3G, itself, falls under the category of C3 dominant glomerulopathy, which also includes monoclonal gammopathy of renal significance (MGRS) and post-infectious glomerulonephritis (PIGN), two diseases that can mimic C3G but are distinct in their causality, natural history and treatment. What happens in C3G? The glomeruli are the filtering units of the kidney, where blood gets filtered under pressure through the GBM into another space, called Bowman’s space, as urine. About 1-2 million glomeruli in each kidney do the filtering, creating a filtrate of water, sodium, potassium, chloride, glucose and small proteins. In both DDD and C3GN, deposits of C3 and other proteins in the GBM disrupt kidney function. Progressive damage to the glomeruli occurs and after about 10 years, enough damage has occurred so that about half of all persons with C3G have kidney failure. When kidney failure occurs, dialysis must be started, or transplantation must be performed. The rate of progression to end-stage kidney failure and dialysis appears to be similar for both DDD and C3GN.In addition to dense deposits in the kidney, persons with DDD can develop deposits in their eyes in an area called Bruch’s membrane. This occurs because the ‘choriocapillaris-Bruch’s membrane-retinal pigment epithelium’ interface in the eye is very similar to the capillary-GBM interface in the kidney. The eye deposits are called drusen. Whether they occur more or less frequently in patients with C3GN is not clear. | Overview of C3 Glomerulopathy: Dense Deposit Disease and C3 Glomerulonephritis. Over the past decade, important advances in our understanding of complement-mediated renal diseases have led to the adoption of new names or ‘disease categories’ to more precisely group diseases that appear to share a similar cause. Consider, for example, dense deposit disease (DDD), a very rare kidney disease characterized on a renal biopsy test called ‘immunofluorescence’ by an abundance of a protein called C3 in the renal glomeruli and named for the extremely dense ‘sausage-like’ deposits that are seen in the glomerular basement membrane (GBM) using electron microscopy. In 2013, after a consensus meeting, scientists recommended that DDD be sub-grouped under a new heading – C3 Glomerulopathy, abbreviated C3G. The adoption of this new term was driven by the recognition that there is another group of patients with glomerular disease whose kidney biopsy is reminiscent of DDD. On electron microscopy, the deposits in these patients are lighter in color and more widespread in location, but on immunofluorescence, as with DDD there is an abundance of C3 in the renal glomeruli. These patients are said to have C3 glomerulonephritis or C3GN. In recognition of shared similarities, both DDD and C3GN are now classified as sub-types of C3G. C3G, itself, falls under the category of C3 dominant glomerulopathy, which also includes monoclonal gammopathy of renal significance (MGRS) and post-infectious glomerulonephritis (PIGN), two diseases that can mimic C3G but are distinct in their causality, natural history and treatment. What happens in C3G? The glomeruli are the filtering units of the kidney, where blood gets filtered under pressure through the GBM into another space, called Bowman’s space, as urine. About 1-2 million glomeruli in each kidney do the filtering, creating a filtrate of water, sodium, potassium, chloride, glucose and small proteins. In both DDD and C3GN, deposits of C3 and other proteins in the GBM disrupt kidney function. Progressive damage to the glomeruli occurs and after about 10 years, enough damage has occurred so that about half of all persons with C3G have kidney failure. When kidney failure occurs, dialysis must be started, or transplantation must be performed. The rate of progression to end-stage kidney failure and dialysis appears to be similar for both DDD and C3GN.In addition to dense deposits in the kidney, persons with DDD can develop deposits in their eyes in an area called Bruch’s membrane. This occurs because the ‘choriocapillaris-Bruch’s membrane-retinal pigment epithelium’ interface in the eye is very similar to the capillary-GBM interface in the kidney. The eye deposits are called drusen. Whether they occur more or less frequently in patients with C3GN is not clear. | 189 | C3 Glomerulopathy: Dense Deposit Disease and C3 Glomerulonephritis |
nord_189_1 | Symptoms of C3 Glomerulopathy: Dense Deposit Disease and C3 Glomerulonephritis | The signs and symptoms of DDD and C3GN are similar. They include blood in the urine, which is called hematuria; dark foamy urine, which signifies the presence of protein or ‘proteinuria’; cloudiness of the urine, reflecting the presence of white blood cells; swelling or ‘edema’, initially of the legs although any part of the body can be affected; high blood pressure; decreased urine output; and decreased alertness.As mentioned earlier, when a kidney biopsy is done in a person with the above signs and symptoms if C3G (either DDD or C3GN) is suspected, the immunofluorescence analysis must show abundant C3 in the glomerular capillaries. This finding is a requirement and in its absence the diagnosis of C3G can be excluded. Sophisticated studies have been done to determine the precise composition of the electron-dense deposits in DDD and C3GN, and in addition to C3 and its breakdown fragments, glomeruli contain many other proteins that belong to a system called the complement system. Proteins from both the alternative pathway of complement and the terminal pathway of the complement are found. This finding agrees with our understanding of the pathophysiology of DDD and C3GN.As might be expected, since complement proteins are typically in the blood stream, if they become trapped in the kidneys, blood stream levels will often be correspondingly reduced; and in fact, in persons with both DDD and C3GN several complement proteins in the blood stream circulate at lower-than-expected levels. The most notable is the decrease in C3, which tends to be reduced to a greater extent in persons with DDD as compared to C3GN. Studies are currently being done to measure the levels of many different complement proteins in persons with DDD and C3GN and to compare these levels to persons without any kidney disease to determine whether the ‘profile’ for DDD and C3GN is unique. This technique is called ‘complement biomarker profiling’. This type of information provides clinicians with insight into what is happening at the level of the complement system in their patients with DDD and C3GN and can help to drive treatment decisions. | Symptoms of C3 Glomerulopathy: Dense Deposit Disease and C3 Glomerulonephritis. The signs and symptoms of DDD and C3GN are similar. They include blood in the urine, which is called hematuria; dark foamy urine, which signifies the presence of protein or ‘proteinuria’; cloudiness of the urine, reflecting the presence of white blood cells; swelling or ‘edema’, initially of the legs although any part of the body can be affected; high blood pressure; decreased urine output; and decreased alertness.As mentioned earlier, when a kidney biopsy is done in a person with the above signs and symptoms if C3G (either DDD or C3GN) is suspected, the immunofluorescence analysis must show abundant C3 in the glomerular capillaries. This finding is a requirement and in its absence the diagnosis of C3G can be excluded. Sophisticated studies have been done to determine the precise composition of the electron-dense deposits in DDD and C3GN, and in addition to C3 and its breakdown fragments, glomeruli contain many other proteins that belong to a system called the complement system. Proteins from both the alternative pathway of complement and the terminal pathway of the complement are found. This finding agrees with our understanding of the pathophysiology of DDD and C3GN.As might be expected, since complement proteins are typically in the blood stream, if they become trapped in the kidneys, blood stream levels will often be correspondingly reduced; and in fact, in persons with both DDD and C3GN several complement proteins in the blood stream circulate at lower-than-expected levels. The most notable is the decrease in C3, which tends to be reduced to a greater extent in persons with DDD as compared to C3GN. Studies are currently being done to measure the levels of many different complement proteins in persons with DDD and C3GN and to compare these levels to persons without any kidney disease to determine whether the ‘profile’ for DDD and C3GN is unique. This technique is called ‘complement biomarker profiling’. This type of information provides clinicians with insight into what is happening at the level of the complement system in their patients with DDD and C3GN and can help to drive treatment decisions. | 189 | C3 Glomerulopathy: Dense Deposit Disease and C3 Glomerulonephritis |
nord_189_2 | Causes of C3 Glomerulopathy: Dense Deposit Disease and C3 Glomerulonephritis | The immediate cause of the symptoms of C3G is the change in the filtering mechanism of the kidney. The damaged glomeruli (the filters) permit protein and red and white blood cells to pass into the urine-containing space.The most abundant protein in the blood stream is albumin. As albumin passes into the urine and is lost from the blood stream, hypoalbuminemia or ‘low albumin in the blood stream’ develops. One consequence of hypoalbuminemia is that water leaks out of the circulation and accumulates in the surrounding tissues. This process leads to edema or swelling. Because of gravity and hydrostatic pressure (water pressure), the effects of fluid leakage are most apparent in the feet and ankles, which become swollen. As kidney function further deteriorates and urine output decreases, sodium and water are retained, and the swelling becomes magnified. High blood pressure also develops.The specific cause of C3G is lack of regulation of the complement system. The causes of complement dysregulation can be divided into genetic and acquired factors. Amongst the former are changes in many of the complement genes, and amongst the latter are specific antibodies called C3 nephritic factors or C3Nefs that impair normal regulation of the complement system. It appears that patients with DDD are more likely to have C3Nefs, while patients with C3GN are more likely to have abnormalities in a group of proteins called the ‘complement factor H related’ proteins. Identifying drivers of complement dysregulation in C3G remains an active area of research because in about 30% of patients, a precise cause for complement dysregulation cannot be found. | Causes of C3 Glomerulopathy: Dense Deposit Disease and C3 Glomerulonephritis. The immediate cause of the symptoms of C3G is the change in the filtering mechanism of the kidney. The damaged glomeruli (the filters) permit protein and red and white blood cells to pass into the urine-containing space.The most abundant protein in the blood stream is albumin. As albumin passes into the urine and is lost from the blood stream, hypoalbuminemia or ‘low albumin in the blood stream’ develops. One consequence of hypoalbuminemia is that water leaks out of the circulation and accumulates in the surrounding tissues. This process leads to edema or swelling. Because of gravity and hydrostatic pressure (water pressure), the effects of fluid leakage are most apparent in the feet and ankles, which become swollen. As kidney function further deteriorates and urine output decreases, sodium and water are retained, and the swelling becomes magnified. High blood pressure also develops.The specific cause of C3G is lack of regulation of the complement system. The causes of complement dysregulation can be divided into genetic and acquired factors. Amongst the former are changes in many of the complement genes, and amongst the latter are specific antibodies called C3 nephritic factors or C3Nefs that impair normal regulation of the complement system. It appears that patients with DDD are more likely to have C3Nefs, while patients with C3GN are more likely to have abnormalities in a group of proteins called the ‘complement factor H related’ proteins. Identifying drivers of complement dysregulation in C3G remains an active area of research because in about 30% of patients, a precise cause for complement dysregulation cannot be found. | 189 | C3 Glomerulopathy: Dense Deposit Disease and C3 Glomerulonephritis |
nord_189_3 | Affects of C3 Glomerulopathy: Dense Deposit Disease and C3 Glomerulonephritis | C3G affects persons of all ages, although the mean age appears to be lower in DDD patients as compared to C3GN patients. The prevalence of C3G is estimated at 2-3 per 1,000,000 people. Persons over the age of 50 who present with a biopsy consistent with C3G should be evaluated for MGRS. | Affects of C3 Glomerulopathy: Dense Deposit Disease and C3 Glomerulonephritis. C3G affects persons of all ages, although the mean age appears to be lower in DDD patients as compared to C3GN patients. The prevalence of C3G is estimated at 2-3 per 1,000,000 people. Persons over the age of 50 who present with a biopsy consistent with C3G should be evaluated for MGRS. | 189 | C3 Glomerulopathy: Dense Deposit Disease and C3 Glomerulonephritis |
nord_189_4 | Related disorders of C3 Glomerulopathy: Dense Deposit Disease and C3 Glomerulonephritis | Many types of glomerular injury mimic C3G and cause signs and symptoms of acute glomerulonephritis. For example, amongst children, acute glomerulonephritis may reflect underlying IgA nephropathy, Henoch-Schonlein purpura, hemolytic uremic syndrome or PIGN. Amongst adults, the list of disorders that trigger acute glomerulonephritis is longer and more varied, and includes Goodpasture’s syndrome, viral diseases such as mononucleosis, measles, or mumps, infective endocarditis, and sexually transmitted diseases. As mentioned above, the elderly who present with a C3G picture on renal biopsy should be evaluated for MGRS.PIGN deserves special mention. It typically follows an infection at a site other than the kidneys, such as a skin or throat infection, usually with a specific type of bacterium known as ‘group A hemolytic streptococcus bacterium’. Because of the streptococcal infection, the glomeruli may become plugged and inflamed, leading to inefficient filtering by the kidneys. Protein and blood will be present in the urine, and edema may develop throughout the body. Hypertension will occur. Fortunately, PIGN is rare because of the common use of antibiotics for infections that trigger this disease. However, it still occurs and affects people of any age, especially children 6-10 years old. The onset of renal problems is about 1-2 weeks after a throat infection and about 3-4 weeks after a skin infection. Most frequently, PIGN resolves without the need for renal biopsy. Occasional cases of PIGN never get better but instead ‘evolve’ into DDD or C3GN. | Related disorders of C3 Glomerulopathy: Dense Deposit Disease and C3 Glomerulonephritis. Many types of glomerular injury mimic C3G and cause signs and symptoms of acute glomerulonephritis. For example, amongst children, acute glomerulonephritis may reflect underlying IgA nephropathy, Henoch-Schonlein purpura, hemolytic uremic syndrome or PIGN. Amongst adults, the list of disorders that trigger acute glomerulonephritis is longer and more varied, and includes Goodpasture’s syndrome, viral diseases such as mononucleosis, measles, or mumps, infective endocarditis, and sexually transmitted diseases. As mentioned above, the elderly who present with a C3G picture on renal biopsy should be evaluated for MGRS.PIGN deserves special mention. It typically follows an infection at a site other than the kidneys, such as a skin or throat infection, usually with a specific type of bacterium known as ‘group A hemolytic streptococcus bacterium’. Because of the streptococcal infection, the glomeruli may become plugged and inflamed, leading to inefficient filtering by the kidneys. Protein and blood will be present in the urine, and edema may develop throughout the body. Hypertension will occur. Fortunately, PIGN is rare because of the common use of antibiotics for infections that trigger this disease. However, it still occurs and affects people of any age, especially children 6-10 years old. The onset of renal problems is about 1-2 weeks after a throat infection and about 3-4 weeks after a skin infection. Most frequently, PIGN resolves without the need for renal biopsy. Occasional cases of PIGN never get better but instead ‘evolve’ into DDD or C3GN. | 189 | C3 Glomerulopathy: Dense Deposit Disease and C3 Glomerulonephritis |
nord_189_5 | Diagnosis of C3 Glomerulopathy: Dense Deposit Disease and C3 Glomerulonephritis | C3G can only be diagnosed by a kidney biopsy. The kidney deposits stain for the complement protein C3 and when examined under an electron microscope, dense deposits are present. | Diagnosis of C3 Glomerulopathy: Dense Deposit Disease and C3 Glomerulonephritis. C3G can only be diagnosed by a kidney biopsy. The kidney deposits stain for the complement protein C3 and when examined under an electron microscope, dense deposits are present. | 189 | C3 Glomerulopathy: Dense Deposit Disease and C3 Glomerulonephritis |
nord_189_6 | Therapies of C3 Glomerulopathy: Dense Deposit Disease and C3 Glomerulonephritis | There is currently no specific therapy for C3G, however several non-specific treatments are appropriate. These treatments slow progression of chronic glomerular diseases through aggressive blood pressure control and reduction of proteinuria. Both angiotensin-converting enzyme (ACE) inhibitors and angiotensin II type-1 receptor blockers (ARBs) are first-line drugs to decrease spillage of protein into the urine and to improve kidney hemodynamics. These drugs may also limit the infiltration of white blood cells into the kidney. If hyperlipidemia (increased lipid in the blood stream) is present, lipid-lowering drugs can be used to reduce long-term atherosclerotic risks. These drugs may also delay progression of kidney disease.Although widely used at one point, long steroid therapy should be avoided in C3G. It is, however, effective in a form of glomerulonephritis called juvenile acute non-proliferative glomerulonephritis (JANG), which can be confused with DDD. JANG can be distinguished from DDD because: 1) DDD is associated with low C3 levels; and 2) persons with DDD often have nephrotic syndrome (greater than 3.5 gm of protein in the urine over 24 hours; hypoalbuminemia; edema). In JANG, C3 levels remain at the lower limit of normal.Some studies suggest that mycophenolate mofetil (MMF, +/- a short course of steroids) may be beneficial in patients with C3G by decreasing the rate of progression to end-stage kidney failure. MMF inhibits inosine monophosphate dehydrogenase, the enzyme that controls the rate of synthesis of guanine monophosphate. One class of anti-complement drugs is widely available. Known as eculizumab or ravulizumab, these two drugs are humanized monoclonal antibodies against C5 that block activity of the terminal pathway of complement. Eculizumab requires dosing every two weeks while ravulizumab can be given every eight weeks. In studies that have looked at the effect of eculizumab in patients with C3G, it appears that eculizumab is effective in decreasing proteinuria and the rate of progression of kidney disease in some but not all patients. Identifying those patients who are likely to respond to eculizumab is difficult, but elevated levels of soluble C5b-9 may be indicative of a good response. Soluble C5b-9 is one of the biomarkers of complement activity that is regularly measured when complement biomarker profiling is done, as was mentioned earlier. However, because eculizumab blocks generation of a small cleavage product of C5 called C5a, eculizumab has a potent anti-inflammatory effect, which may contribute to some of its observed effect.Persons with C3G who progress to end-stage kidney failure must receive dialysis – either peritoneal dialysis or hemodialysis – or a kidney transplantation. Transplantation is associated with a high rate of disease recurrence in the allograft and about half of transplants ultimately fail. There is some indication that pre-transplant complement biomarkers can predict which patients are more likely to develop clinically significant recurrence of C3G. | Therapies of C3 Glomerulopathy: Dense Deposit Disease and C3 Glomerulonephritis. There is currently no specific therapy for C3G, however several non-specific treatments are appropriate. These treatments slow progression of chronic glomerular diseases through aggressive blood pressure control and reduction of proteinuria. Both angiotensin-converting enzyme (ACE) inhibitors and angiotensin II type-1 receptor blockers (ARBs) are first-line drugs to decrease spillage of protein into the urine and to improve kidney hemodynamics. These drugs may also limit the infiltration of white blood cells into the kidney. If hyperlipidemia (increased lipid in the blood stream) is present, lipid-lowering drugs can be used to reduce long-term atherosclerotic risks. These drugs may also delay progression of kidney disease.Although widely used at one point, long steroid therapy should be avoided in C3G. It is, however, effective in a form of glomerulonephritis called juvenile acute non-proliferative glomerulonephritis (JANG), which can be confused with DDD. JANG can be distinguished from DDD because: 1) DDD is associated with low C3 levels; and 2) persons with DDD often have nephrotic syndrome (greater than 3.5 gm of protein in the urine over 24 hours; hypoalbuminemia; edema). In JANG, C3 levels remain at the lower limit of normal.Some studies suggest that mycophenolate mofetil (MMF, +/- a short course of steroids) may be beneficial in patients with C3G by decreasing the rate of progression to end-stage kidney failure. MMF inhibits inosine monophosphate dehydrogenase, the enzyme that controls the rate of synthesis of guanine monophosphate. One class of anti-complement drugs is widely available. Known as eculizumab or ravulizumab, these two drugs are humanized monoclonal antibodies against C5 that block activity of the terminal pathway of complement. Eculizumab requires dosing every two weeks while ravulizumab can be given every eight weeks. In studies that have looked at the effect of eculizumab in patients with C3G, it appears that eculizumab is effective in decreasing proteinuria and the rate of progression of kidney disease in some but not all patients. Identifying those patients who are likely to respond to eculizumab is difficult, but elevated levels of soluble C5b-9 may be indicative of a good response. Soluble C5b-9 is one of the biomarkers of complement activity that is regularly measured when complement biomarker profiling is done, as was mentioned earlier. However, because eculizumab blocks generation of a small cleavage product of C5 called C5a, eculizumab has a potent anti-inflammatory effect, which may contribute to some of its observed effect.Persons with C3G who progress to end-stage kidney failure must receive dialysis – either peritoneal dialysis or hemodialysis – or a kidney transplantation. Transplantation is associated with a high rate of disease recurrence in the allograft and about half of transplants ultimately fail. There is some indication that pre-transplant complement biomarkers can predict which patients are more likely to develop clinically significant recurrence of C3G. | 189 | C3 Glomerulopathy: Dense Deposit Disease and C3 Glomerulonephritis |
nord_190_0 | Overview of CADASIL | CADASIL is a rare genetic disorder affecting the small blood vessels in the brain. The term CADASIL was first coined in 1993. The age of onset, severity, specific symptoms and disease progression varies greatly from one person to another, even among members of the same family. CADASIL is an acronym that stands for:(C)erebral – relating to the brain(A)utosomal(D)ominant – a form of inheritance in which one copy of an abnormal gene is necessary for the development of a disorder(A)rteriopathy – disease of the arteries (blood vessels that carry blood away from the heart)(S)ubcortical – relating to specific areas of the brain supplied by deep small blood vessels(I)nfarcts – tissue loss in the brain caused by lack of blood flow to the brain, which occurs when circulation through the small arteries is severely reduced or interrupted(L)eukoencephalopathy – lesions in the brain white matter caused by the disease and observed on MRI | Overview of CADASIL. CADASIL is a rare genetic disorder affecting the small blood vessels in the brain. The term CADASIL was first coined in 1993. The age of onset, severity, specific symptoms and disease progression varies greatly from one person to another, even among members of the same family. CADASIL is an acronym that stands for:(C)erebral – relating to the brain(A)utosomal(D)ominant – a form of inheritance in which one copy of an abnormal gene is necessary for the development of a disorder(A)rteriopathy – disease of the arteries (blood vessels that carry blood away from the heart)(S)ubcortical – relating to specific areas of the brain supplied by deep small blood vessels(I)nfarcts – tissue loss in the brain caused by lack of blood flow to the brain, which occurs when circulation through the small arteries is severely reduced or interrupted(L)eukoencephalopathy – lesions in the brain white matter caused by the disease and observed on MRI | 190 | CADASIL |
nord_190_1 | Symptoms of CADASIL | Hallmark symptoms of CADASIL may include: 1) recurrent strokes, 2) cognitive impairment, 3) migraine with aura, and 4) psychiatric disturbances. These symptoms are caused by damage to small blood vessels, especially those within the brain. The specific symptoms and severity of the disorder can vary greatly among affected individuals, even among members of the same family.Despite this variability, most individuals (approximately three out of four patients) experience recurrent stroke or transient ischemic attacks (TIAs), beginning at 40-50 years of age. Strokes cause weakness and/or loss of feeling of one part of the body, speech difficulties, visual loss or lack of coordination. TIAs result in similar symptoms as strokes but resolve in less than 24 hours. Repeated strokes can cause progression of symptoms listed above and also cause cognitive disturbances, loss of bladder control (urinary incontinence) or loss of balance.Although strokes are the most common symptom associated with CADASIL, some affected individuals never have strokes. It is not uncommon for CADASIL patients to have evidence of stroke on MRI without any history of stroke-like symptoms (silent strokes).Cognitive impairment eventually develops in many affected individuals on average between the ages of 50-60, although the progression of the disease will vary. Symptoms may include slowly progressive difficulty with concentration, deficits in attention span or memory dysfunction, difficulty making decisions or solving problems, and general loss of interest (apathy). With age, continued cognitive decline may result in dementia, a progressive loss of memory and decline in intellectual abilities that interferes with performing routine tasks of daily life.Migraine with aura may be a predominant symptom in some affected individuals, occurring in at least half of CADASIL patients. Migraines are severe headaches that often cause excruciating pain and can be disabling. In individuals with CADASIL, abnormal feelings or warning signs called “aura” often precede these headaches. These additional symptoms usually affect vision and may consist of the sudden appearance of a bright light in the center of the field of vision (scintillating scotoma) or, less frequently, disturbances in all or part of the field of vision. The auras preceding the migraine usually last 20 to 30 minutes but are sometimes longer. Some patients suffer from severe attacks with unusual symptoms such as confusion, fever or coma in very rare situations. Finally, many individuals with CADASIL develop psychiatric abnormalities ranging from personality and behavioral changes to severe anxiety and depression. | Symptoms of CADASIL. Hallmark symptoms of CADASIL may include: 1) recurrent strokes, 2) cognitive impairment, 3) migraine with aura, and 4) psychiatric disturbances. These symptoms are caused by damage to small blood vessels, especially those within the brain. The specific symptoms and severity of the disorder can vary greatly among affected individuals, even among members of the same family.Despite this variability, most individuals (approximately three out of four patients) experience recurrent stroke or transient ischemic attacks (TIAs), beginning at 40-50 years of age. Strokes cause weakness and/or loss of feeling of one part of the body, speech difficulties, visual loss or lack of coordination. TIAs result in similar symptoms as strokes but resolve in less than 24 hours. Repeated strokes can cause progression of symptoms listed above and also cause cognitive disturbances, loss of bladder control (urinary incontinence) or loss of balance.Although strokes are the most common symptom associated with CADASIL, some affected individuals never have strokes. It is not uncommon for CADASIL patients to have evidence of stroke on MRI without any history of stroke-like symptoms (silent strokes).Cognitive impairment eventually develops in many affected individuals on average between the ages of 50-60, although the progression of the disease will vary. Symptoms may include slowly progressive difficulty with concentration, deficits in attention span or memory dysfunction, difficulty making decisions or solving problems, and general loss of interest (apathy). With age, continued cognitive decline may result in dementia, a progressive loss of memory and decline in intellectual abilities that interferes with performing routine tasks of daily life.Migraine with aura may be a predominant symptom in some affected individuals, occurring in at least half of CADASIL patients. Migraines are severe headaches that often cause excruciating pain and can be disabling. In individuals with CADASIL, abnormal feelings or warning signs called “aura” often precede these headaches. These additional symptoms usually affect vision and may consist of the sudden appearance of a bright light in the center of the field of vision (scintillating scotoma) or, less frequently, disturbances in all or part of the field of vision. The auras preceding the migraine usually last 20 to 30 minutes but are sometimes longer. Some patients suffer from severe attacks with unusual symptoms such as confusion, fever or coma in very rare situations. Finally, many individuals with CADASIL develop psychiatric abnormalities ranging from personality and behavioral changes to severe anxiety and depression. | 190 | CADASIL |
nord_190_2 | Causes of CADASIL | CADASIL is caused by changes (mutations) in the NOTCH3 gene. The NOTCH3 gene contains instructions to create a protein that is predominantly expressed in smooth muscle cells in the walls of small arteries. Mutations in the NOTCH3 gene result in abnormal accumulation of this protein at the surface of smooth muscle cells. Ultimately, NOTCH3 mutations lead to progressive damage to the small blood vessels in the brain, premature destruction of smooth muscle cells, and narrowing of the lumen and thickening the vessel wall of the small blood vessels. Microscopic protein accumulations of debris called granular osmiophilic material (GOM) accumulate in blood vessels of CADASIL patients. As a consequence of these changes, there is reduction of blood flow to the brain causing small strokes (or lacunes), small bleeds (microbleeds), dilated spaces surrounded the vessels (dilated perivascular spaces) and tissue loss in the surface of the brain (cortex) as well underneath the cortex (subcortical region).CADASIL is inherited in an autosomal dominant fashion. 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. Most individuals with CADASIL have a parent with the disorder, but CADASIL can be due to a spontaneous genetic mutation that occurs for unknown reasons (de novo mutation). In these rare cases, there is no previous family history of the disorder. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy. The risk is the same for males and females. | Causes of CADASIL. CADASIL is caused by changes (mutations) in the NOTCH3 gene. The NOTCH3 gene contains instructions to create a protein that is predominantly expressed in smooth muscle cells in the walls of small arteries. Mutations in the NOTCH3 gene result in abnormal accumulation of this protein at the surface of smooth muscle cells. Ultimately, NOTCH3 mutations lead to progressive damage to the small blood vessels in the brain, premature destruction of smooth muscle cells, and narrowing of the lumen and thickening the vessel wall of the small blood vessels. Microscopic protein accumulations of debris called granular osmiophilic material (GOM) accumulate in blood vessels of CADASIL patients. As a consequence of these changes, there is reduction of blood flow to the brain causing small strokes (or lacunes), small bleeds (microbleeds), dilated spaces surrounded the vessels (dilated perivascular spaces) and tissue loss in the surface of the brain (cortex) as well underneath the cortex (subcortical region).CADASIL is inherited in an autosomal dominant fashion. 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. Most individuals with CADASIL have a parent with the disorder, but CADASIL can be due to a spontaneous genetic mutation that occurs for unknown reasons (de novo mutation). In these rare cases, there is no previous family history of the disorder. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy. The risk is the same for males and females. | 190 | CADASIL |
nord_190_3 | Affects of CADASIL | CADASIL affects males and females in equal numbers. The disorder is found worldwide and affects all races. The disease affects approximately 2 to 5 of 100,000 people. Research suggests that the disorder often goes undiagnosed or misdiagnosed making it difficult to determine the true frequency of CADASIL in the general population. | Affects of CADASIL. CADASIL affects males and females in equal numbers. The disorder is found worldwide and affects all races. The disease affects approximately 2 to 5 of 100,000 people. Research suggests that the disorder often goes undiagnosed or misdiagnosed making it difficult to determine the true frequency of CADASIL in the general population. | 190 | CADASIL |
nord_190_4 | Related disorders of CADASIL | Symptoms of the following disorders can be similar to those of CADASIL. Comparisons may be useful for a differential diagnosis.Sporadic cerebral small vessel disease (SVD) related to age and hypertension is a progressive and common neurological disorder characterized by dysfunction of blood vessels supplying the white-matter and deep structures of the brain. As in CADASIL, patients can experience progressive memory loss, deterioration of intellectual abilities and loss of balance with a progressive worsening of these symptoms, but symptoms are usually less severe and occur later in life. This condition is not inherited.A variety of rare genetic disorders may have symptoms similar to those found in CADASIL. These disorders include cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL); mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS); Fabry disease, and a variety of leukodystrophies, rare progressive metabolic disorders that affect the brain, spinal cord and often the peripheral nerves. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Multiple sclerosis is a prevalent chronic neuroimmune (both the nervous system and the immunological system are involved) disorder of the central nervous system involving the brain, spinal cord and optic nerves. By means of a mechanism not clearly understood, the protective fatty, insulating substance called myelin sheath that covers the nerve is destroyed. The inflammatory attacks that produce the characteristic scarring (plaques or patches) of the myelin sheath occur randomly at multiple sites and vary in intensity. The course of the disease may advance, relapse, remit, or stabilize. The randomness of the location of plaques or patches causes a wide range of neurological symptoms, which may vary from person to person. (For more information on this disorder, choose “multiple sclerosis” as your search term in the Rare Disease Database.) | Related disorders of CADASIL. Symptoms of the following disorders can be similar to those of CADASIL. Comparisons may be useful for a differential diagnosis.Sporadic cerebral small vessel disease (SVD) related to age and hypertension is a progressive and common neurological disorder characterized by dysfunction of blood vessels supplying the white-matter and deep structures of the brain. As in CADASIL, patients can experience progressive memory loss, deterioration of intellectual abilities and loss of balance with a progressive worsening of these symptoms, but symptoms are usually less severe and occur later in life. This condition is not inherited.A variety of rare genetic disorders may have symptoms similar to those found in CADASIL. These disorders include cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL); mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS); Fabry disease, and a variety of leukodystrophies, rare progressive metabolic disorders that affect the brain, spinal cord and often the peripheral nerves. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Multiple sclerosis is a prevalent chronic neuroimmune (both the nervous system and the immunological system are involved) disorder of the central nervous system involving the brain, spinal cord and optic nerves. By means of a mechanism not clearly understood, the protective fatty, insulating substance called myelin sheath that covers the nerve is destroyed. The inflammatory attacks that produce the characteristic scarring (plaques or patches) of the myelin sheath occur randomly at multiple sites and vary in intensity. The course of the disease may advance, relapse, remit, or stabilize. The randomness of the location of plaques or patches causes a wide range of neurological symptoms, which may vary from person to person. (For more information on this disorder, choose “multiple sclerosis” as your search term in the Rare Disease Database.) | 190 | CADASIL |
nord_190_5 | Diagnosis of CADASIL | CADASIL is suspected based on symptoms, family history, and brain MRI lesions compatible with the disease. Although MRI can identify characteristic changes in the brains of individuals with CADASIL, such changes are not unique to CADASIL and can occur with other disorders. As such, the CADASIL diagnosis can only be confirmed by DNA testing of blood samples for characteristic mutations in the NOTCH3 gene or by identifying granular osmiophilic material (GOM) inclusions on a skin biopsy. | Diagnosis of CADASIL. CADASIL is suspected based on symptoms, family history, and brain MRI lesions compatible with the disease. Although MRI can identify characteristic changes in the brains of individuals with CADASIL, such changes are not unique to CADASIL and can occur with other disorders. As such, the CADASIL diagnosis can only be confirmed by DNA testing of blood samples for characteristic mutations in the NOTCH3 gene or by identifying granular osmiophilic material (GOM) inclusions on a skin biopsy. | 190 | CADASIL |
nord_190_6 | Therapies of CADASIL | Treatment
At the present, there is no treatment that can cure the disease or prevent its onset. Patients should be treated for factors that can further damage blood vessels, such as hypertension, and should be encouraged to abstain from smoking. The efficacy of tPA for treatment of acute strokes in CADASIL patients is uncertain; although no contraindication to tPA has been established for this specific population, careful evaluation of prior microbleeds is suggested. Migraines can be treated with traditional analgesics such as acetaminophen or NSAIDs. Other medicines commonly used to treat acute migraine attack such as vasoconstrictors: especially triptans or ergot derivates, are not recommended for patients with CADASIL. Medications such as anti-hypertensive, anti-convulsants, and anti-depressants may be used for prevention of migraines in CADASIL patients. Drug therapy for depression or other psychiatric abnormalities are sometimes needed. Psychological support is often essential, and genetic counseling is recommended for affected individuals and their families. | Therapies of CADASIL. Treatment
At the present, there is no treatment that can cure the disease or prevent its onset. Patients should be treated for factors that can further damage blood vessels, such as hypertension, and should be encouraged to abstain from smoking. The efficacy of tPA for treatment of acute strokes in CADASIL patients is uncertain; although no contraindication to tPA has been established for this specific population, careful evaluation of prior microbleeds is suggested. Migraines can be treated with traditional analgesics such as acetaminophen or NSAIDs. Other medicines commonly used to treat acute migraine attack such as vasoconstrictors: especially triptans or ergot derivates, are not recommended for patients with CADASIL. Medications such as anti-hypertensive, anti-convulsants, and anti-depressants may be used for prevention of migraines in CADASIL patients. Drug therapy for depression or other psychiatric abnormalities are sometimes needed. Psychological support is often essential, and genetic counseling is recommended for affected individuals and their families. | 190 | CADASIL |
nord_191_0 | Overview of Campomelic Syndrome | Campomelic syndrome is a rare congenital disorder in which multiple anomalies are present. It is characterized by bowing and angular shape of the long bones of the legs, especially the tibia; multiple minor anomalies of the face; cleft palate; other skeletal anomalies such as abnormalities of the shoulder and pelvic area and eleven pairs of ribs instead of the usual twelve; underdevelopment of the trachea; developmental delay in some cases and incomplete development of genitalia in males such that they appear to be females. | Overview of Campomelic Syndrome. Campomelic syndrome is a rare congenital disorder in which multiple anomalies are present. It is characterized by bowing and angular shape of the long bones of the legs, especially the tibia; multiple minor anomalies of the face; cleft palate; other skeletal anomalies such as abnormalities of the shoulder and pelvic area and eleven pairs of ribs instead of the usual twelve; underdevelopment of the trachea; developmental delay in some cases and incomplete development of genitalia in males such that they appear to be females. | 191 | Campomelic Syndrome |
nord_191_1 | Symptoms of Campomelic Syndrome | Campomelic syndrome is a rare form of skeletal dysplasia characterized by bowing and an angular shape of the long bones of the legs. Eleven sets of ribs instead of the usual twelve may be present. The pelvis and shoulder blade may be underdeveloped. The skull may be large, long and narrow. The face may appear flat with forward tilting nostrils, high forehead, small chin, and cleft palate. Babies may regurgitate formula through the nose, are susceptible to middle ear infections and frequently experience respiratory distress. Respiratory distress due to an underdeveloped ribcage is the most serious symptom of campomelic syndrome. The lungs may not have sufficient space to grow properly due to the underdeveloped ribcage.Other symptoms that may occur in some patients with campomelic syndrome are dislocated hips, clubfoot, underdeveloped lungs, abnormal cervical and thoracic vertebrae,and heart and kidney abnormalities.Some individuals with campomelic syndrome have sex reversal in which they are chromosomally male but have female genitalia and reproductive system. | Symptoms of Campomelic Syndrome. Campomelic syndrome is a rare form of skeletal dysplasia characterized by bowing and an angular shape of the long bones of the legs. Eleven sets of ribs instead of the usual twelve may be present. The pelvis and shoulder blade may be underdeveloped. The skull may be large, long and narrow. The face may appear flat with forward tilting nostrils, high forehead, small chin, and cleft palate. Babies may regurgitate formula through the nose, are susceptible to middle ear infections and frequently experience respiratory distress. Respiratory distress due to an underdeveloped ribcage is the most serious symptom of campomelic syndrome. The lungs may not have sufficient space to grow properly due to the underdeveloped ribcage.Other symptoms that may occur in some patients with campomelic syndrome are dislocated hips, clubfoot, underdeveloped lungs, abnormal cervical and thoracic vertebrae,and heart and kidney abnormalities.Some individuals with campomelic syndrome have sex reversal in which they are chromosomally male but have female genitalia and reproductive system. | 191 | Campomelic Syndrome |
nord_191_2 | Causes of Campomelic Syndrome | Campomelic syndrome was once thought to be inherited as an autosomal recessive genetic trait but this is no longer thought to be true. Molecular genetic research has shown that a change (mutation) in a single copy of the SOX9 gene on chromosome 17 or disturbance in the regulation of this gene causes campomelic syndrome. The regulation of the SOX9 gene is sometimes disturbed by a rearrangement of genes on chromosome 17 (translocation). It is now believed that campomelic syndrome is inherited as an autosomal dominant trait. Some families have been reported in which multiple children are affected but both parents are unaffected. This may be due to one parent having a mixture of sperm or egg cells with normal and abnormal SOX9 genes (gonadal mosaicism). As a result, one or more of this parent's children may inherit the gene mutation and exhibit the disorder even though the parent has no apparent symptoms.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 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. 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. | Causes of Campomelic Syndrome. Campomelic syndrome was once thought to be inherited as an autosomal recessive genetic trait but this is no longer thought to be true. Molecular genetic research has shown that a change (mutation) in a single copy of the SOX9 gene on chromosome 17 or disturbance in the regulation of this gene causes campomelic syndrome. The regulation of the SOX9 gene is sometimes disturbed by a rearrangement of genes on chromosome 17 (translocation). It is now believed that campomelic syndrome is inherited as an autosomal dominant trait. Some families have been reported in which multiple children are affected but both parents are unaffected. This may be due to one parent having a mixture of sperm or egg cells with normal and abnormal SOX9 genes (gonadal mosaicism). As a result, one or more of this parent's children may inherit the gene mutation and exhibit the disorder even though the parent has no apparent symptoms.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 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. 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. | 191 | Campomelic Syndrome |
nord_191_3 | Affects of Campomelic Syndrome | Campomelic syndrome is a rare disorder that is thought to affect females twice as often as males. These numbers may not be accurate as some patients with this disorder have associated sex reversal and have been mistakenly identified as the opposite sex. Approximately one hundred cases of this disorder have been reported in the medical literature. | Affects of Campomelic Syndrome. Campomelic syndrome is a rare disorder that is thought to affect females twice as often as males. These numbers may not be accurate as some patients with this disorder have associated sex reversal and have been mistakenly identified as the opposite sex. Approximately one hundred cases of this disorder have been reported in the medical literature. | 191 | Campomelic Syndrome |
nord_191_4 | Related disorders of Campomelic Syndrome | Symptoms of the following disorders can be similar to those of campomelic syndrome. Comparisons may be useful for a differential diagnosis:Achondroplasia is a rare musculoskeletal disorder belonging to a group of congenital abnormalities known as the chondrodystrophies. The chondrodystrophies are disorders that affect the manner in which cartilage is converted into bone. Acondroplasia is characterized by short-limbed dwarfism along with curvature of the spine and abnormalities of the skull. (For more information on this disorder, choose “Achondroplasia” as your search term in the Rare Disease Database.)Hypophosphatasia is a rare genetic metabolic bone disorder characterized by skeletal defects due to failure of bone mineral to be deposited in uncalcified bone and cartilage at the end of the long bones. Infants affected with this form of the disorder often have increased pressure inside the skull which may result in bulging eyes. The bones usually become weak and bent and kidney failure may occur. (For more information on this disorder, choose “Hypophosphatasia” as your search term in the Rare Disease Database.)Osteogenesis imperfecta is a rare hereditary connective tissue disorder. Symptoms of this disorder may include: frequent fractures of the bones, poor or delayed growth, bowed legs, spinal deformities, and a triangular shaped face. Osteogenesis imperfecta is grouped into syndromes according to the combination and severity of symptoms accompanying the basic bone disorder, and according to the apparent mode of inheritance. (For more information on this disorder, choose “Osteogenesis Imperfecta” as your search term in the Rare Disease Database.)Non-syndromal congenital bowing of legs is a condition in which the long bones of the legs are bowed but no other abnormalities are present. | Related disorders of Campomelic Syndrome. Symptoms of the following disorders can be similar to those of campomelic syndrome. Comparisons may be useful for a differential diagnosis:Achondroplasia is a rare musculoskeletal disorder belonging to a group of congenital abnormalities known as the chondrodystrophies. The chondrodystrophies are disorders that affect the manner in which cartilage is converted into bone. Acondroplasia is characterized by short-limbed dwarfism along with curvature of the spine and abnormalities of the skull. (For more information on this disorder, choose “Achondroplasia” as your search term in the Rare Disease Database.)Hypophosphatasia is a rare genetic metabolic bone disorder characterized by skeletal defects due to failure of bone mineral to be deposited in uncalcified bone and cartilage at the end of the long bones. Infants affected with this form of the disorder often have increased pressure inside the skull which may result in bulging eyes. The bones usually become weak and bent and kidney failure may occur. (For more information on this disorder, choose “Hypophosphatasia” as your search term in the Rare Disease Database.)Osteogenesis imperfecta is a rare hereditary connective tissue disorder. Symptoms of this disorder may include: frequent fractures of the bones, poor or delayed growth, bowed legs, spinal deformities, and a triangular shaped face. Osteogenesis imperfecta is grouped into syndromes according to the combination and severity of symptoms accompanying the basic bone disorder, and according to the apparent mode of inheritance. (For more information on this disorder, choose “Osteogenesis Imperfecta” as your search term in the Rare Disease Database.)Non-syndromal congenital bowing of legs is a condition in which the long bones of the legs are bowed but no other abnormalities are present. | 191 | Campomelic Syndrome |
nord_191_5 | Diagnosis of Campomelic Syndrome | Diagnosis is based on clinical examination, x-rays of vertebrae, hips, chest, legs and feet, ultrasound of kidneys and echocardiogram of the heart. DNA analysis of blood can confirm a mutation in the SOX9 gene. | Diagnosis of Campomelic Syndrome. Diagnosis is based on clinical examination, x-rays of vertebrae, hips, chest, legs and feet, ultrasound of kidneys and echocardiogram of the heart. DNA analysis of blood can confirm a mutation in the SOX9 gene. | 191 | Campomelic Syndrome |
nord_191_6 | Therapies of Campomelic Syndrome | TreatmentTreatment of respiratory problems consists of mechanical or physical breathing assistance such as positive end expiratory pressure (PEEP). Orthopedic medical care including surgery may help alleviate some of the more serious bone deformities. The bowed tibiae usually straighten spontaneously.It may be appropriate to reassign the sex of a male with female genitalia to be female.Genetic counseling may be of benefit for patients and their families. Other treatment is symptomatic and supportive.The Vertical Expandable Prosthetic Titanium Rib (VEPTR) was approved by the FDA in 2004 as a treatment for thoracic insufficiency syndrome (TIS) in pediatric patients. TIS is a congenital condition where severe deformities of the chest, spine, and ribs prevent normal breathing and lung development. The VEPTR is an implanted, expandable device that helps straighten the spine and separate ribs so that the lungs can grow and fill with enough air to breathe. The length of the device can be adjusted as the patient grows. The titanium rib was developed at the University of Texas Health Science Center in San Antonio. It is manufactured by Synthes Spine Co.. http://www.synthes.com/sites/NA/Products/Spine/Screw_Hook_Rod_and_Clamp_System/Pages/VEPTR_and_VEPTR_II.aspxFor more information, please contact:Synthes, Inc.1302 Wrights Lane EastWest Chester, PA 19380800-523-0322 | Therapies of Campomelic Syndrome. TreatmentTreatment of respiratory problems consists of mechanical or physical breathing assistance such as positive end expiratory pressure (PEEP). Orthopedic medical care including surgery may help alleviate some of the more serious bone deformities. The bowed tibiae usually straighten spontaneously.It may be appropriate to reassign the sex of a male with female genitalia to be female.Genetic counseling may be of benefit for patients and their families. Other treatment is symptomatic and supportive.The Vertical Expandable Prosthetic Titanium Rib (VEPTR) was approved by the FDA in 2004 as a treatment for thoracic insufficiency syndrome (TIS) in pediatric patients. TIS is a congenital condition where severe deformities of the chest, spine, and ribs prevent normal breathing and lung development. The VEPTR is an implanted, expandable device that helps straighten the spine and separate ribs so that the lungs can grow and fill with enough air to breathe. The length of the device can be adjusted as the patient grows. The titanium rib was developed at the University of Texas Health Science Center in San Antonio. It is manufactured by Synthes Spine Co.. http://www.synthes.com/sites/NA/Products/Spine/Screw_Hook_Rod_and_Clamp_System/Pages/VEPTR_and_VEPTR_II.aspxFor more information, please contact:Synthes, Inc.1302 Wrights Lane EastWest Chester, PA 19380800-523-0322 | 191 | Campomelic Syndrome |
nord_192_0 | Overview of Camurati-Engelmann Disease | SummaryCamurati-Engelmann disease (CED) is characterized by increased bone density primarily affecting the long bones of the arms and legs and the skull. The thickening of these bones leads to pain, a waddling gait, muscle weakness, and extreme fatigue. Increased density of the skull can cause a variety of neurological deficits such as headaches, hearing loss, vision problems, dizziness (vertigo), ringing in the ears (tinnitus), and even facial paralysis. The first symptoms of the condition can appear at varying ages, but usually during childhood, with pain and proximal muscle weakness developing by adolescence. CED is often diagnosed based on a physical exam and radiographic findings (X-rays). CED is inherited in an autosomal dominant manner and is caused by changes (mutations) in the TGFB1 gene. | Overview of Camurati-Engelmann Disease. SummaryCamurati-Engelmann disease (CED) is characterized by increased bone density primarily affecting the long bones of the arms and legs and the skull. The thickening of these bones leads to pain, a waddling gait, muscle weakness, and extreme fatigue. Increased density of the skull can cause a variety of neurological deficits such as headaches, hearing loss, vision problems, dizziness (vertigo), ringing in the ears (tinnitus), and even facial paralysis. The first symptoms of the condition can appear at varying ages, but usually during childhood, with pain and proximal muscle weakness developing by adolescence. CED is often diagnosed based on a physical exam and radiographic findings (X-rays). CED is inherited in an autosomal dominant manner and is caused by changes (mutations) in the TGFB1 gene. | 192 | Camurati-Engelmann Disease |
nord_192_1 | Symptoms of Camurati-Engelmann Disease | The first signs and symptoms of CED are usually limb pain, a waddling gait, muscle weakness, and extreme tiredness. If the bones at the base of the skull are affected, the individual may experience headaches, hearing loss, vision problems, vertigo, tinnitus, and even facial paralysis. Additional musculoskeletal features include scoliosis, joint contractures, knock knees, and flat feet. The individual may also present with abnormally long limbs in proportion to the height of their body, a decrease in muscle mass and body fat, visible prominence of the long bones in the legs, and rarely delayed puberty. While the first signs and symptoms can appear at varying ages, most appear during childhood or adolescence. The signs and symptoms of CED can be extremely variable even among affected family members. Some individuals with a TGFB1 mutation do not develop signs or symptoms of the disease or evidence of increased bone density on X-ray examination (i.e., reduced penetrance). | Symptoms of Camurati-Engelmann Disease. The first signs and symptoms of CED are usually limb pain, a waddling gait, muscle weakness, and extreme tiredness. If the bones at the base of the skull are affected, the individual may experience headaches, hearing loss, vision problems, vertigo, tinnitus, and even facial paralysis. Additional musculoskeletal features include scoliosis, joint contractures, knock knees, and flat feet. The individual may also present with abnormally long limbs in proportion to the height of their body, a decrease in muscle mass and body fat, visible prominence of the long bones in the legs, and rarely delayed puberty. While the first signs and symptoms can appear at varying ages, most appear during childhood or adolescence. The signs and symptoms of CED can be extremely variable even among affected family members. Some individuals with a TGFB1 mutation do not develop signs or symptoms of the disease or evidence of increased bone density on X-ray examination (i.e., reduced penetrance). | 192 | Camurati-Engelmann Disease |
nord_192_2 | Causes of Camurati-Engelmann Disease | CED is caused by mutations in TGFB1 which encodes transforming growth factor beta-1 protein. This protein helps control the growth and proliferation of cells, the process by which the cells mature and begin to specify (differentiate), cell movement, and cell directed self-destruction (apoptosis). The specific protein plays a huge role during prenatal development in the formation of blood vessels, the regulation of muscle tissue and body fat development, wound healing, and immune system function. The protein is most abundant in skeletal tissue and the extracellular matrix that provides structural support and nutrients to the surrounding cells.Normally, TGFB1 is inactive until a chemical signal is sent to turn it on. TGFB1 mutations that cause CED result in the gene being always turned on and active. This leads to increased bone density and decreased fat and muscle tissue, contributing to the symptoms listed above. Most individuals with CED have a TGFB1 mutation identified on molecular genetic testing, but some affected individuals do not. CED is inherited as an autosomal dominant condition. This occurs when only a single copy of the mutated gene is needed to cause a specific disorder. The altered gene can be inherited from either parent, or can be a new mutation in the affected individual. The risk of transmitting the disease to the offspring of an affected parent is 50%, and is the same for males and females. Rarely, the disease can come from a spontaneous genetic mutation in the egg or sperm cell. In these people, the disease isn’t inherited from the one of the parents, but the individual can still pass it to their offspring. | Causes of Camurati-Engelmann Disease. CED is caused by mutations in TGFB1 which encodes transforming growth factor beta-1 protein. This protein helps control the growth and proliferation of cells, the process by which the cells mature and begin to specify (differentiate), cell movement, and cell directed self-destruction (apoptosis). The specific protein plays a huge role during prenatal development in the formation of blood vessels, the regulation of muscle tissue and body fat development, wound healing, and immune system function. The protein is most abundant in skeletal tissue and the extracellular matrix that provides structural support and nutrients to the surrounding cells.Normally, TGFB1 is inactive until a chemical signal is sent to turn it on. TGFB1 mutations that cause CED result in the gene being always turned on and active. This leads to increased bone density and decreased fat and muscle tissue, contributing to the symptoms listed above. Most individuals with CED have a TGFB1 mutation identified on molecular genetic testing, but some affected individuals do not. CED is inherited as an autosomal dominant condition. This occurs when only a single copy of the mutated gene is needed to cause a specific disorder. The altered gene can be inherited from either parent, or can be a new mutation in the affected individual. The risk of transmitting the disease to the offspring of an affected parent is 50%, and is the same for males and females. Rarely, the disease can come from a spontaneous genetic mutation in the egg or sperm cell. In these people, the disease isn’t inherited from the one of the parents, but the individual can still pass it to their offspring. | 192 | Camurati-Engelmann Disease |
nord_192_3 | Affects of Camurati-Engelmann Disease | The prevalence of CED is unknown; more than 300affected people have been reported worldwide. | Affects of Camurati-Engelmann Disease. The prevalence of CED is unknown; more than 300affected people have been reported worldwide. | 192 | Camurati-Engelmann Disease |
nord_192_4 | Related disorders of Camurati-Engelmann Disease | Symptoms of the following disorders can be similar to those of CED. For more information on these disorders, enter the disease name as your search term in the Rare Disease Database.Kenny-Caffey syndrome type 2Juvenile Paget disease | Related disorders of Camurati-Engelmann Disease. Symptoms of the following disorders can be similar to those of CED. For more information on these disorders, enter the disease name as your search term in the Rare Disease Database.Kenny-Caffey syndrome type 2Juvenile Paget disease | 192 | Camurati-Engelmann Disease |
nord_192_5 | Diagnosis of Camurati-Engelmann Disease | The diagnosis of CED is based on a physical examination after an individual presents with limb pain and weakness. Imaging studies such as X-rays show thickening of the long bones which can initially be asymmetric, but progresses to become bilateral and symmetric. The bones involved are usually the femur, tibia, fibula, humerus, radius, ulna, and the skull base. Molecular genetic testing for mutations in TGFB1 is available to confirm the diagnosis. | Diagnosis of Camurati-Engelmann Disease. The diagnosis of CED is based on a physical examination after an individual presents with limb pain and weakness. Imaging studies such as X-rays show thickening of the long bones which can initially be asymmetric, but progresses to become bilateral and symmetric. The bones involved are usually the femur, tibia, fibula, humerus, radius, ulna, and the skull base. Molecular genetic testing for mutations in TGFB1 is available to confirm the diagnosis. | 192 | Camurati-Engelmann Disease |
nord_192_6 | Therapies of Camurati-Engelmann Disease | TreatmentTreatment for CED consists of management of symptoms. To manage the pain caused by the thickening of the bones, individuals may be treated with corticosteroids, and non-steroidal anti-inflammatory drugs (NSAIDs). Corticosteroids have shown benefits in affected individuals. Although they are helpful to improve walking, the major side effects of taking corticosteroids long term may outweigh the benefits of the drugs. Some of these side effects include high blood sugar, increased risk of infections, and suppressed adrenal hormone production. Losartan has been reported to reduce limb pain and increase muscle strength in some individuals. No formal studies have been completed on the efficacy of losartan and data are limited on the long term effects and benefits of this drug.For those with hearing problems caused by the thickening of the bones of the base of the skull, decompression surgery in which a small piece of the base of the skull is removed has been done in some individuals with mixed results. This procedure can result in an increased risk of complications as well as the possibility for bone to re-grow after the surgery. | Therapies of Camurati-Engelmann Disease. TreatmentTreatment for CED consists of management of symptoms. To manage the pain caused by the thickening of the bones, individuals may be treated with corticosteroids, and non-steroidal anti-inflammatory drugs (NSAIDs). Corticosteroids have shown benefits in affected individuals. Although they are helpful to improve walking, the major side effects of taking corticosteroids long term may outweigh the benefits of the drugs. Some of these side effects include high blood sugar, increased risk of infections, and suppressed adrenal hormone production. Losartan has been reported to reduce limb pain and increase muscle strength in some individuals. No formal studies have been completed on the efficacy of losartan and data are limited on the long term effects and benefits of this drug.For those with hearing problems caused by the thickening of the bones of the base of the skull, decompression surgery in which a small piece of the base of the skull is removed has been done in some individuals with mixed results. This procedure can result in an increased risk of complications as well as the possibility for bone to re-grow after the surgery. | 192 | Camurati-Engelmann Disease |
nord_193_0 | Overview of Canavan Disease | Canavan disease is rare genetic neurological disorder characterized by the spongy degeneration of the white matter in the brain. Affected infants may appear normal at birth, but usually develop symptoms between 3-6 months of age. Symptoms may include an abnormally large head (macrocephaly), lack of head control, severely diminished muscle tone resulting in “floppiness,” and delays in reaching developmental milestones such as independent sitting and walking. Most affected children develop life-threatening complications by 10 years of age. Canavan disease occurs because of mutations in the aspartoacylase (ASPA) gene that affects the breakdown (metabolism) of the N-acetylaspartic acid (NNA). It is inherited as an autosomal recessive condition.Canavan disease belongs to a group of disorders known as the leukodystrophies. The leukodystrophies are a group of rare, progressive, metabolic, genetic disorders that can affect the brain, spinal cord and often the nerves outside the central nervous system (peripheral nerves). Each type of leukodystrophy is caused by an abnormality affecting a specific gene that results in abnormal development of one of at least 10 different chemicals that make up the white matter of the brain. The white matter is tissue composed of nerve fibers. Many of these nerve fibers are covered by a collection of fats (lipids) and proteins known as myelin. Myelin, which collectively may be referred to as the myelin sheath, protects the nerve fibers, acts as an insulator and increases the speed of transmission of nerve signals. Each type of leukodystrophy affects a different part of the myelin sheath, leading a range of different neurological problems. | Overview of Canavan Disease. Canavan disease is rare genetic neurological disorder characterized by the spongy degeneration of the white matter in the brain. Affected infants may appear normal at birth, but usually develop symptoms between 3-6 months of age. Symptoms may include an abnormally large head (macrocephaly), lack of head control, severely diminished muscle tone resulting in “floppiness,” and delays in reaching developmental milestones such as independent sitting and walking. Most affected children develop life-threatening complications by 10 years of age. Canavan disease occurs because of mutations in the aspartoacylase (ASPA) gene that affects the breakdown (metabolism) of the N-acetylaspartic acid (NNA). It is inherited as an autosomal recessive condition.Canavan disease belongs to a group of disorders known as the leukodystrophies. The leukodystrophies are a group of rare, progressive, metabolic, genetic disorders that can affect the brain, spinal cord and often the nerves outside the central nervous system (peripheral nerves). Each type of leukodystrophy is caused by an abnormality affecting a specific gene that results in abnormal development of one of at least 10 different chemicals that make up the white matter of the brain. The white matter is tissue composed of nerve fibers. Many of these nerve fibers are covered by a collection of fats (lipids) and proteins known as myelin. Myelin, which collectively may be referred to as the myelin sheath, protects the nerve fibers, acts as an insulator and increases the speed of transmission of nerve signals. Each type of leukodystrophy affects a different part of the myelin sheath, leading a range of different neurological problems. | 193 | Canavan Disease |
nord_193_1 | Symptoms of Canavan Disease | The symptoms and progression of Canavan disease varies from case to case. The disorder usually becomes apparent between 3 and 6 months of age and the initial symptoms usually include extremely poor head control, an abnormally large head (macrocepahly), and severely diminished muscle tone (hypotonia) resulting in “floppiness.” Affected infants may be generally unresponsive (apathetic), lethargic or irritable. Some infants may experience difficulty swallowing (dysphagia), which contributes to feeding difficulties.Affected infants also show delays in reaching developmental milestones (e.g., sitting or standing unassisted) and most never walk independently. The progressive loss of abilities requiring the coordination of mental and muscular activity (psychomotor regression) and mental retardation also become apparent during infancy. Most affected infants do learn to smile, laugh, raise their heads and interact socially.Additional symptoms that affect children with Canavan disease include seizures, sleep disorders, feeding difficulties, nasal regurgitation, backflow of acid from the stomach to the esophagus (reflux) sometimes associated with vomiting, and deterioration of the nerves of the eyes (optic nerves) that transmit impulses from the nerve-rich membrane lining the eyes (retina) to the brain (optic atrophy). Optic atrophy may cause reduced visual responsiveness. In most case, hearing is unaffected, but hearing loss can occur.As affected infants age, hypotonia may eventually develop into spasticity, a condition characterized by involuntary muscle spasms that result in slow, stiff movements of the legs. Affected individuals may eventually exhibit uncontrolled rigid extensions and rotations of the arms, legs, fingers, and toes (decerebrate rigidity) or paralysis. Canavan disease eventually progresses to cause life-threatening complications; however, the severity and progression of the disease varies. Some individuals develop life-threatening complications in infancy; others live beyond their teen-age years.In the last few years, a mild form of Canavan disease has been recognized, with characteristic mutations of the ASPA gene and only slightly increased NAA in the urine. These children may be only slightly delayed, can learn and go to school. The head may be somewhat enlarged, but the typical white matter changes associated with Canavan may be absent. The prognosis is certainly much better. | Symptoms of Canavan Disease. The symptoms and progression of Canavan disease varies from case to case. The disorder usually becomes apparent between 3 and 6 months of age and the initial symptoms usually include extremely poor head control, an abnormally large head (macrocepahly), and severely diminished muscle tone (hypotonia) resulting in “floppiness.” Affected infants may be generally unresponsive (apathetic), lethargic or irritable. Some infants may experience difficulty swallowing (dysphagia), which contributes to feeding difficulties.Affected infants also show delays in reaching developmental milestones (e.g., sitting or standing unassisted) and most never walk independently. The progressive loss of abilities requiring the coordination of mental and muscular activity (psychomotor regression) and mental retardation also become apparent during infancy. Most affected infants do learn to smile, laugh, raise their heads and interact socially.Additional symptoms that affect children with Canavan disease include seizures, sleep disorders, feeding difficulties, nasal regurgitation, backflow of acid from the stomach to the esophagus (reflux) sometimes associated with vomiting, and deterioration of the nerves of the eyes (optic nerves) that transmit impulses from the nerve-rich membrane lining the eyes (retina) to the brain (optic atrophy). Optic atrophy may cause reduced visual responsiveness. In most case, hearing is unaffected, but hearing loss can occur.As affected infants age, hypotonia may eventually develop into spasticity, a condition characterized by involuntary muscle spasms that result in slow, stiff movements of the legs. Affected individuals may eventually exhibit uncontrolled rigid extensions and rotations of the arms, legs, fingers, and toes (decerebrate rigidity) or paralysis. Canavan disease eventually progresses to cause life-threatening complications; however, the severity and progression of the disease varies. Some individuals develop life-threatening complications in infancy; others live beyond their teen-age years.In the last few years, a mild form of Canavan disease has been recognized, with characteristic mutations of the ASPA gene and only slightly increased NAA in the urine. These children may be only slightly delayed, can learn and go to school. The head may be somewhat enlarged, but the typical white matter changes associated with Canavan may be absent. The prognosis is certainly much better. | 193 | Canavan Disease |
nord_193_2 | Causes of Canavan Disease | Canavan disease is caused by disruptions or changes (mutations) to the aspartoacylase (ASPA) gene. This mutation is inherited as an autosomal recessive trait. 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 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.The defective gene responsible for Canavan disease has been mapped to chromosome 17 (17pter-p13). 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 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 ASPA contains instructions for developing (encoding) aspartoacylase, an enzyme that breaks down (metabolizes) N-acetylaspartic acid (NAA). NAA is a compound that researchers believe plays a vital role in maintaining the brain's white matter. Deficient or inactive aspartoacylase results in the accumulation of NAA in brain tissue. The symptoms of Canavan disease result from damage to the white matter from the abnormally high levels of NAA. | Causes of Canavan Disease. Canavan disease is caused by disruptions or changes (mutations) to the aspartoacylase (ASPA) gene. This mutation is inherited as an autosomal recessive trait. 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 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.The defective gene responsible for Canavan disease has been mapped to chromosome 17 (17pter-p13). 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 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 ASPA contains instructions for developing (encoding) aspartoacylase, an enzyme that breaks down (metabolizes) N-acetylaspartic acid (NAA). NAA is a compound that researchers believe plays a vital role in maintaining the brain's white matter. Deficient or inactive aspartoacylase results in the accumulation of NAA in brain tissue. The symptoms of Canavan disease result from damage to the white matter from the abnormally high levels of NAA. | 193 | Canavan Disease |
nord_193_3 | Affects of Canavan Disease | Canavan disease affects males and females in equal numbers. It affects all ethnic groups, but occurs with greater frequency in individuals of Ashkenazi Jewish descent. In this population, the carrier frequency is estimated to be as high as one in 40-58 people. The risk for an affected child born to Ashkenazi Jewish parents is between 1 and 6,400 and 1 in 13,456. The carrier frequency in other populations is not known, but most likely far lower. The overall incidence of Canavan disease in the general population is unknown. | Affects of Canavan Disease. Canavan disease affects males and females in equal numbers. It affects all ethnic groups, but occurs with greater frequency in individuals of Ashkenazi Jewish descent. In this population, the carrier frequency is estimated to be as high as one in 40-58 people. The risk for an affected child born to Ashkenazi Jewish parents is between 1 and 6,400 and 1 in 13,456. The carrier frequency in other populations is not known, but most likely far lower. The overall incidence of Canavan disease in the general population is unknown. | 193 | Canavan Disease |
nord_193_4 | Related disorders of Canavan Disease | Symptoms of the following disorders can be similar to those of Canavan disease. Comparisons may be useful for a differential diagnosis.Leukodystrophies are a group of very rare, progressive, metabolic, genetic diseases that affect the brain, spinal cord and often the peripheral nerves. Each type of leukodystrophy is caused by a specific gene abnormality that leads to abnormal development of one of at least 10 different chemicals that make up the white matter (myelin sheath) of the brain. The myelin sheath is the protective covering of the nerve and nerves can't function normally with out it. Each type of leukodystrophy affects a different part of the myelin sheath, leading to a range of neurological problems. (For more information on this disorder, choose “leukodystrophy” as your search term in the Rare Disease Database.)Metachromatic leukodystrophy, the most common form of leukodystrophy, is a rare inherited neurometabolic disorder affecting the white matter of the brain (leukoencephalopathy). It is characterized by the accumulation of a fatty substance known as sulfatide (a sphingolipid) in the brain and other areas of the body (i.e., liver, gall bladder, kidneys, and/or spleen). The fatty protective covering on the nerve fibers (myelin) is lost from areas of the central nervous system (CNS) due to the buildup of sulfatide. Symptoms of metachromatic leukodystrophy may include convulsions, seizures, personality changes, spasticity, progressive dementia, motor disturbances progressing to paralysis, and/or visual impairment leading to blindness. Metachromatic leukodystrophy is inherited as an autosomal recessive trait. (For more information on this disorder, choose “metachromatic leukodystrophy” as your search term in the Rare Disease Database.)Tay-Sachs disease is a rare, neurodegenerative disorder in which deficiency of an enzyme (hexosaminidase A) results in excessive accumulation of certain fats (lipids) known as gangliosides in the brain and nerve cells. This abnormal accumulation of gangliosides leads to progressive dysfunction of the central nervous system. This disorder is categorized as a lysosomal storage disease. Lysosomes are the major digestive units in cells. Enzymes within lysosomes break down or “digest” nutrients, including certain complex carbohydrates and fats. Symptoms associated with Tay-Sachs disease may include an exaggerated startle response to sudden noises, listlessness, loss of previously acquired skills (i.e., psychomotor regression), and severely diminished muscle tone (hypotonia). With disease progression, affected infants and children may develop cherry-red spots within the middle layer of the eyes, gradual loss of vision, and deafness, increasing muscle stiffness and restricted movements (spasticity), eventual paralysis, uncontrolled electrical disturbances in the brain (seizures), and deterioration of cognitive processes (dementia). Tay-Sachs disease is inherited as an autosomal recessive trait.Certain mitochondrial disorders, such as Leigh's disease, may be associated with spongy degeneration of the central nervous system. Mitochondrial disorders are characterized by mutations affecting the parts of the cell that release energy (mitochondria). Mitochondrial diseases often hamper the ability of affected cells to break down food and oxygen and produce energy. In most mitochondrial disorders, abnormally high numbers of defective mitochondria are present in the cells of the body. Mitochondrial diseases often affect more than one organ system of the body. (For more information on this disorder, choose the specific disorder name as your search term in the Rare Disease Database.) | Related disorders of Canavan Disease. Symptoms of the following disorders can be similar to those of Canavan disease. Comparisons may be useful for a differential diagnosis.Leukodystrophies are a group of very rare, progressive, metabolic, genetic diseases that affect the brain, spinal cord and often the peripheral nerves. Each type of leukodystrophy is caused by a specific gene abnormality that leads to abnormal development of one of at least 10 different chemicals that make up the white matter (myelin sheath) of the brain. The myelin sheath is the protective covering of the nerve and nerves can't function normally with out it. Each type of leukodystrophy affects a different part of the myelin sheath, leading to a range of neurological problems. (For more information on this disorder, choose “leukodystrophy” as your search term in the Rare Disease Database.)Metachromatic leukodystrophy, the most common form of leukodystrophy, is a rare inherited neurometabolic disorder affecting the white matter of the brain (leukoencephalopathy). It is characterized by the accumulation of a fatty substance known as sulfatide (a sphingolipid) in the brain and other areas of the body (i.e., liver, gall bladder, kidneys, and/or spleen). The fatty protective covering on the nerve fibers (myelin) is lost from areas of the central nervous system (CNS) due to the buildup of sulfatide. Symptoms of metachromatic leukodystrophy may include convulsions, seizures, personality changes, spasticity, progressive dementia, motor disturbances progressing to paralysis, and/or visual impairment leading to blindness. Metachromatic leukodystrophy is inherited as an autosomal recessive trait. (For more information on this disorder, choose “metachromatic leukodystrophy” as your search term in the Rare Disease Database.)Tay-Sachs disease is a rare, neurodegenerative disorder in which deficiency of an enzyme (hexosaminidase A) results in excessive accumulation of certain fats (lipids) known as gangliosides in the brain and nerve cells. This abnormal accumulation of gangliosides leads to progressive dysfunction of the central nervous system. This disorder is categorized as a lysosomal storage disease. Lysosomes are the major digestive units in cells. Enzymes within lysosomes break down or “digest” nutrients, including certain complex carbohydrates and fats. Symptoms associated with Tay-Sachs disease may include an exaggerated startle response to sudden noises, listlessness, loss of previously acquired skills (i.e., psychomotor regression), and severely diminished muscle tone (hypotonia). With disease progression, affected infants and children may develop cherry-red spots within the middle layer of the eyes, gradual loss of vision, and deafness, increasing muscle stiffness and restricted movements (spasticity), eventual paralysis, uncontrolled electrical disturbances in the brain (seizures), and deterioration of cognitive processes (dementia). Tay-Sachs disease is inherited as an autosomal recessive trait.Certain mitochondrial disorders, such as Leigh's disease, may be associated with spongy degeneration of the central nervous system. Mitochondrial disorders are characterized by mutations affecting the parts of the cell that release energy (mitochondria). Mitochondrial diseases often hamper the ability of affected cells to break down food and oxygen and produce energy. In most mitochondrial disorders, abnormally high numbers of defective mitochondria are present in the cells of the body. Mitochondrial diseases often affect more than one organ system of the body. (For more information on this disorder, choose the specific disorder name as your search term in the Rare Disease Database.) | 193 | Canavan Disease |
nord_193_5 | Diagnosis of Canavan Disease | A diagnosis of Canavan disease may be suspected in infants with the characteristic findings of the disorder (e.g., poor head control, macrocephaly, etc.). A diagnosis may be confirmed by a thorough clinical evaluation, a detailed patient history, and a variety of specialized tests. Such tests may include may include gas chromatography-mass spectrometry, a device that can detect elevated levels of NAA in the urine. Elevated levels of NAA can also be detected in the blood and cerebrospinal fluid (CSF). Examination of certain connective tissue cells from the skin (cultured fibroblasts) can reveal deficiency of the enzyme aspartoacylase. Aspartoacylase activity is also absent in white blood cells.Prenatal diagnosis of Canavan disease is available through amniocentesis by measuring the level of NAA in the fluid that surrounds the developing fetus (amniotic fluid) at 16-18 weeks of gestation. If both parents have known ASPA gene mutations, prenatal diagnosis is available using chorionic villus sampling (CVS) in which a sample of placental cells is removed at 10-12 weeks gestation for mutation analysis. | Diagnosis of Canavan Disease. A diagnosis of Canavan disease may be suspected in infants with the characteristic findings of the disorder (e.g., poor head control, macrocephaly, etc.). A diagnosis may be confirmed by a thorough clinical evaluation, a detailed patient history, and a variety of specialized tests. Such tests may include may include gas chromatography-mass spectrometry, a device that can detect elevated levels of NAA in the urine. Elevated levels of NAA can also be detected in the blood and cerebrospinal fluid (CSF). Examination of certain connective tissue cells from the skin (cultured fibroblasts) can reveal deficiency of the enzyme aspartoacylase. Aspartoacylase activity is also absent in white blood cells.Prenatal diagnosis of Canavan disease is available through amniocentesis by measuring the level of NAA in the fluid that surrounds the developing fetus (amniotic fluid) at 16-18 weeks of gestation. If both parents have known ASPA gene mutations, prenatal diagnosis is available using chorionic villus sampling (CVS) in which a sample of placental cells is removed at 10-12 weeks gestation for mutation analysis. | 193 | Canavan Disease |
nord_193_6 | Therapies of Canavan Disease | TreatmentThe treatment of Canavan disease is directed toward the specific symptoms that are apparent in each individual. Supportive care may alleviate some discomfort. Physical therapy and early intervention may help to improve posture and communication skills, respectively. If swallowing difficulties occur, feeding tubes may be useful to ensure proper nutrition and hydration. Seizures may be treated with anti-seizure (anti-convulsant) medications.Genetic counseling and carrier testing will benefit families in which this disease occurs. | Therapies of Canavan Disease. TreatmentThe treatment of Canavan disease is directed toward the specific symptoms that are apparent in each individual. Supportive care may alleviate some discomfort. Physical therapy and early intervention may help to improve posture and communication skills, respectively. If swallowing difficulties occur, feeding tubes may be useful to ensure proper nutrition and hydration. Seizures may be treated with anti-seizure (anti-convulsant) medications.Genetic counseling and carrier testing will benefit families in which this disease occurs. | 193 | Canavan Disease |
nord_194_0 | Overview of CARASIL | Classic CARASIL is a rare genetic disorder that is characterized by damage to the small blood vessels in the brain. Individuals with CARASIL are at risk of developing multiple strokes, even if they do not have cardiovascular risk factors. The symptoms of CARASIL result from damage to various small blood vessels, especially those within the brain. Individuals with CARASIL may develop a variety of symptoms relating to white matter involvement or changes in deep white matter in the brain (leukoaraiosis), which are observed on MRI or CT). Such symptoms include an increasing muscle tone (spasticity), pyramidal signs and pseudobulbar palsy. Pseudobulbar palsy is a group of neurologic symptoms that includes difficulty with chewing, swallowing and speech. Eventually, gait disturbance and dementia may result. About a third of patients have stroke-like episodes. The age of onset is between 20 to 50 years old. CARASIL is an acronym that stands for:(C)erebral – relating to the brain or the cerebellum, which is part of the brain that controls balance and muscular coordination(A)utosomal (R)ecessive – a form of inheritance in which two copies (one from each parent) of an abnormal gene is necessary for the development of a disorder(A)rteriopathy – disease of the small arteries (blood vessels that carry blood away from the heart)(S)ubcortical – relating to a specific area of the deep brain that is involved in higher functioning (e.g., voluntary movements, reasoning, memory)(I)nfarcts – tissue loss in the brain caused by lack of oxygen to the brain, which occurs when blood flow in the small arteries is blocked or abnorma.(L)eukoencephalopathy – destruction of the myelin, an oily substance that covers and protects nerve fibers in the central nervous systemOther characteristics of classic CARASIL include early sparse hair (alopecia) and degenerative changes in the spine (spondylolisthesis). Spondylolisthesis begins between 10 and 30 years, causing back pain and herniated discs in the cervical and lumbar areas. However, patients without these symptoms have also been reported.Recently, certain changes (pathogenic variants or mutations) in the HTRA1 gene have been shown to cause cerebral small vessel disease (CSVD) even in people with only one gene variant (heterozygotes) and this is called HTRA1-related cerebral small vessel disease (or CARASIL 2). These patients have neurologic symptoms and small vessel disease similar to CARASIL, but the onset is often later, and symptoms such as alopecia and spondylolisthesis are not present. | Overview of CARASIL. Classic CARASIL is a rare genetic disorder that is characterized by damage to the small blood vessels in the brain. Individuals with CARASIL are at risk of developing multiple strokes, even if they do not have cardiovascular risk factors. The symptoms of CARASIL result from damage to various small blood vessels, especially those within the brain. Individuals with CARASIL may develop a variety of symptoms relating to white matter involvement or changes in deep white matter in the brain (leukoaraiosis), which are observed on MRI or CT). Such symptoms include an increasing muscle tone (spasticity), pyramidal signs and pseudobulbar palsy. Pseudobulbar palsy is a group of neurologic symptoms that includes difficulty with chewing, swallowing and speech. Eventually, gait disturbance and dementia may result. About a third of patients have stroke-like episodes. The age of onset is between 20 to 50 years old. CARASIL is an acronym that stands for:(C)erebral – relating to the brain or the cerebellum, which is part of the brain that controls balance and muscular coordination(A)utosomal (R)ecessive – a form of inheritance in which two copies (one from each parent) of an abnormal gene is necessary for the development of a disorder(A)rteriopathy – disease of the small arteries (blood vessels that carry blood away from the heart)(S)ubcortical – relating to a specific area of the deep brain that is involved in higher functioning (e.g., voluntary movements, reasoning, memory)(I)nfarcts – tissue loss in the brain caused by lack of oxygen to the brain, which occurs when blood flow in the small arteries is blocked or abnorma.(L)eukoencephalopathy – destruction of the myelin, an oily substance that covers and protects nerve fibers in the central nervous systemOther characteristics of classic CARASIL include early sparse hair (alopecia) and degenerative changes in the spine (spondylolisthesis). Spondylolisthesis begins between 10 and 30 years, causing back pain and herniated discs in the cervical and lumbar areas. However, patients without these symptoms have also been reported.Recently, certain changes (pathogenic variants or mutations) in the HTRA1 gene have been shown to cause cerebral small vessel disease (CSVD) even in people with only one gene variant (heterozygotes) and this is called HTRA1-related cerebral small vessel disease (or CARASIL 2). These patients have neurologic symptoms and small vessel disease similar to CARASIL, but the onset is often later, and symptoms such as alopecia and spondylolisthesis are not present. | 194 | CARASIL |
nord_194_1 | Symptoms of CARASIL | The cerebral symptoms of CARASIL are caused by damage to cerebral small blood vessels. The specific symptoms and severity of the disorder can vary greatly among affected individuals. Onset of the disorder is usually in early adulthood but may range from the early 20s to the mid-40s. CARASIL is often rapidly progressive.Damage to the small blood vessels of the brain and reduce or cut off blood flow to the brain (stroke). Reduced blood flow to the brain can cause damage to brain tissue, which may cause a variety of different symptoms. Symptoms that may occur in individuals with CARASIL include increasing muscle tone, slurred speech, stiff movements of the legs (spasticity), gait disturbances, loss of bladder control (urinary incontinence) and problems with swallowing Most affected individuals experience progressive brain damage, especially to the white matter, which is the portion of the brain that contains myelinated nerve fibers. Eventually the disorder causes cognitive impairment which may include memory problems, difficulties making decisions or solving problems, speech difficulties, deficits in attention span and general loss of interest (apathy). Continued cognitive decline ultimately results in dementia. Dementia is defined as the progressive loss of memory and decline in intellectual abilities that interferes with performing routine tasks of daily life.Additional important symptoms that have been associated with CARASIL include sparse hair (alopecia) and degenerative change of the spinal column (spondylosis). Spondylosis begins between 10 to 30 years and causes back pain and a herniated disc in the cervical and the lumbar region. Although alopecia occurs in most cases and develops before the onset of neurological symptoms, some cases without alopecia have been reported.Individuals with only one pathogenic variant (mutation) in the HTRA1 gene can have neurological symptoms and small vessel damage similar to those of CARASIL. However, the onset tends to be later and symptoms such as alopecia and spondylosis are usually not present. | Symptoms of CARASIL. The cerebral symptoms of CARASIL are caused by damage to cerebral small blood vessels. The specific symptoms and severity of the disorder can vary greatly among affected individuals. Onset of the disorder is usually in early adulthood but may range from the early 20s to the mid-40s. CARASIL is often rapidly progressive.Damage to the small blood vessels of the brain and reduce or cut off blood flow to the brain (stroke). Reduced blood flow to the brain can cause damage to brain tissue, which may cause a variety of different symptoms. Symptoms that may occur in individuals with CARASIL include increasing muscle tone, slurred speech, stiff movements of the legs (spasticity), gait disturbances, loss of bladder control (urinary incontinence) and problems with swallowing Most affected individuals experience progressive brain damage, especially to the white matter, which is the portion of the brain that contains myelinated nerve fibers. Eventually the disorder causes cognitive impairment which may include memory problems, difficulties making decisions or solving problems, speech difficulties, deficits in attention span and general loss of interest (apathy). Continued cognitive decline ultimately results in dementia. Dementia is defined as the progressive loss of memory and decline in intellectual abilities that interferes with performing routine tasks of daily life.Additional important symptoms that have been associated with CARASIL include sparse hair (alopecia) and degenerative change of the spinal column (spondylosis). Spondylosis begins between 10 to 30 years and causes back pain and a herniated disc in the cervical and the lumbar region. Although alopecia occurs in most cases and develops before the onset of neurological symptoms, some cases without alopecia have been reported.Individuals with only one pathogenic variant (mutation) in the HTRA1 gene can have neurological symptoms and small vessel damage similar to those of CARASIL. However, the onset tends to be later and symptoms such as alopecia and spondylosis are usually not present. | 194 | CARASIL |
nord_194_2 | Causes of CARASIL | CARASIL is caused by changes (pathogenic variants or mutations) of the HTRA1 gene. CARASIL is inherited as 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. However, with variants in HTRA1, depending on the type, even carriers may exhibit symptoms. Symptoms in carriers are usually milder than in patients with classic CARASIL. When this is the case, the condition may follow autosomal dominant inheritance. Dominant genetic disorders occur when only a single copy of an abnormal 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. In some individuals, the disorder is due to spontaneous (de novo) genetic mutations that occur in the egg or sperm cell. In such situations, the disorder is not inherited from the parents. | Causes of CARASIL. CARASIL is caused by changes (pathogenic variants or mutations) of the HTRA1 gene. CARASIL is inherited as 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. However, with variants in HTRA1, depending on the type, even carriers may exhibit symptoms. Symptoms in carriers are usually milder than in patients with classic CARASIL. When this is the case, the condition may follow autosomal dominant inheritance. Dominant genetic disorders occur when only a single copy of an abnormal 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. In some individuals, the disorder is due to spontaneous (de novo) genetic mutations that occur in the egg or sperm cell. In such situations, the disorder is not inherited from the parents. | 194 | CARASIL |
nord_194_3 | Affects of CARASIL | Classic CARASIL is extremely rare and is more common in Asians but has also been reported in Caucasian populations. Equal numbers of males and females are affected.The incidence of classic CARASIL is unknown.
A rare HTRA1 gene variant (in the protease domain) has been reported in the UK biobank in 1 in 450 individuals. It is difficult to determine the frequency of HTRA1-related cerebral small vessel disease in the general population, but disease related to HTRA1 gene variants may be more common than initially thought. | Affects of CARASIL. Classic CARASIL is extremely rare and is more common in Asians but has also been reported in Caucasian populations. Equal numbers of males and females are affected.The incidence of classic CARASIL is unknown.
A rare HTRA1 gene variant (in the protease domain) has been reported in the UK biobank in 1 in 450 individuals. It is difficult to determine the frequency of HTRA1-related cerebral small vessel disease in the general population, but disease related to HTRA1 gene variants may be more common than initially thought. | 194 | CARASIL |
nord_194_4 | Related disorders of CARASIL | Symptoms of the following disorders can be similar to those of CARASIL. Comparisons may be useful for a differential diagnosis.Binswanger’s disease is a progressive neurological disorder characterized by atherosclerotic blood vessels supplying the white-matter and deep structures of the brain (basal ganglia and thalamus). Most patients experience progressive memory loss and deterioration of intellectual abilities (dementia), urinary urgency or incontinence and an abnormally slow, shuffling, unsteady pattern of walking, usually over a 5–10-year period. Due to their vascular etiology, the symptoms and physical findings associated with Binswanger’s disease may suddenly worsen due to stroke, stabilize and then improve for a brief time, but the patient’s overall condition continues to progress as the blood vessels become increasingly obstructed. (For more information on this disorder, choose “Binswanger’s disease” as your search term in the Rare Disease Database.)Multiple sclerosis (MS) is a chronic neuroimmunologic (both the nervous system and the immunological system are involved) disorder of the central nervous system involving the brain, spinal cord and optic nerves. By means of a mechanism not clearly understood, the protective fatty, insulating substance called myelin sheath that covers the nerve is destroyed. The inflammatory attacks that produce the characteristic scarring (plaques or patches) of the myelin sheath occur unpredictability, vary in intensity, and at many sites thus the name, multiple sclerosis. During the course of the disease, patients may have attacks (relapses or exacerbations), gradually worsen (progression), or stabilize. The randomness of the location of damage can result in a wide range of neurological symptoms, which may vary from person to person. Recently it has been learned that the nerve fibers themselves (axons), in addition to the myelin sheaths, are also affected early in the MS disease process (For more information on this disorder, choose “multiple sclerosis” as your search term in the Rare Disease Database.)A variety of rare genetic disorders may have symptoms similar to those found in CARASIL. These disorders include cerebral autosomal dominant arteriopathy with subcortical infarcts and leukodystrophy (CADASIL), mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), Fabry disease, and some of the leukodystrophies, which are a rare group of progressive metabolic disorders that affect the brain, spinal cord and often the peripheral nerves. (For more information on this disorder, choose the specific disorder name as your search term in the Rare Disease Database.) | Related disorders of CARASIL. Symptoms of the following disorders can be similar to those of CARASIL. Comparisons may be useful for a differential diagnosis.Binswanger’s disease is a progressive neurological disorder characterized by atherosclerotic blood vessels supplying the white-matter and deep structures of the brain (basal ganglia and thalamus). Most patients experience progressive memory loss and deterioration of intellectual abilities (dementia), urinary urgency or incontinence and an abnormally slow, shuffling, unsteady pattern of walking, usually over a 5–10-year period. Due to their vascular etiology, the symptoms and physical findings associated with Binswanger’s disease may suddenly worsen due to stroke, stabilize and then improve for a brief time, but the patient’s overall condition continues to progress as the blood vessels become increasingly obstructed. (For more information on this disorder, choose “Binswanger’s disease” as your search term in the Rare Disease Database.)Multiple sclerosis (MS) is a chronic neuroimmunologic (both the nervous system and the immunological system are involved) disorder of the central nervous system involving the brain, spinal cord and optic nerves. By means of a mechanism not clearly understood, the protective fatty, insulating substance called myelin sheath that covers the nerve is destroyed. The inflammatory attacks that produce the characteristic scarring (plaques or patches) of the myelin sheath occur unpredictability, vary in intensity, and at many sites thus the name, multiple sclerosis. During the course of the disease, patients may have attacks (relapses or exacerbations), gradually worsen (progression), or stabilize. The randomness of the location of damage can result in a wide range of neurological symptoms, which may vary from person to person. Recently it has been learned that the nerve fibers themselves (axons), in addition to the myelin sheaths, are also affected early in the MS disease process (For more information on this disorder, choose “multiple sclerosis” as your search term in the Rare Disease Database.)A variety of rare genetic disorders may have symptoms similar to those found in CARASIL. These disorders include cerebral autosomal dominant arteriopathy with subcortical infarcts and leukodystrophy (CADASIL), mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), Fabry disease, and some of the leukodystrophies, which are a rare group of progressive metabolic disorders that affect the brain, spinal cord and often the peripheral nerves. (For more information on this disorder, choose the specific disorder name as your search term in the Rare Disease Database.) | 194 | CARASIL |
nord_194_5 | Diagnosis of CARASIL | CARASIL should be suspected in individuals with early onset changes in deep white matter in the brain (leukoaraiosis), alopecia in the teens or the twenties and acute lower back pain (lumbago) with spondylosis. However, some patients do not have these symptoms. Diagnosis of CARASIL is based on these characteristic symptoms, a detailed history, thorough clinical evaluation and a variety of tests, including special imaging techniques. Imaging may include magnetic resonance imaging (MRI), which uses magnetic fields and radio waves to produce cross-sectional images of specific organs and body tissues, including the brain MRI can identify characteristic changes in the brain of CARASIL patients with CADASIL, including bilateral lesions in the anterior temporal regions, external capsule, and spinocerebellar tract CARASIL patients may have a characteristic change in the brainstem called the Ark sign.The diagnosis of CARASIL can be confirmed by molecular genetic testing that identifies variants in the HTRA1 gene. | Diagnosis of CARASIL. CARASIL should be suspected in individuals with early onset changes in deep white matter in the brain (leukoaraiosis), alopecia in the teens or the twenties and acute lower back pain (lumbago) with spondylosis. However, some patients do not have these symptoms. Diagnosis of CARASIL is based on these characteristic symptoms, a detailed history, thorough clinical evaluation and a variety of tests, including special imaging techniques. Imaging may include magnetic resonance imaging (MRI), which uses magnetic fields and radio waves to produce cross-sectional images of specific organs and body tissues, including the brain MRI can identify characteristic changes in the brain of CARASIL patients with CADASIL, including bilateral lesions in the anterior temporal regions, external capsule, and spinocerebellar tract CARASIL patients may have a characteristic change in the brainstem called the Ark sign.The diagnosis of CARASIL can be confirmed by molecular genetic testing that identifies variants in the HTRA1 gene. | 194 | CARASIL |
nord_194_6 | Therapies of CARASIL | TreatmentThere is no specific therapy for CARASIL. Treatment is directed toward the specific symptoms that are apparent in each individual. Patients with one HTRA1 gene variant have an increased risk for cerebrovascular disease and should be treated appropriately.Genetic counseling is recommended for affected individuals and their families. | Therapies of CARASIL. TreatmentThere is no specific therapy for CARASIL. Treatment is directed toward the specific symptoms that are apparent in each individual. Patients with one HTRA1 gene variant have an increased risk for cerebrovascular disease and should be treated appropriately.Genetic counseling is recommended for affected individuals and their families. | 194 | CARASIL |
nord_195_0 | Overview of Carbamoyl Phosphate Synthetase 1 Deficiency | Carbamoyl phosphate synthetase 1 deficiency (CPSID) is a rare inherited disorder characterized by complete or partial lack of the carbamoyl phosphate synthetase (CPS) enzyme. This is one of five enzymes that play a role in the breakdown and removal of nitrogen from the body, a process known as the urea cycle. The lack of the CPSI enzyme results in excessive accumulation of nitrogen, in the form of ammonia (hyperammonemia), in the blood. Affected children may experience vomiting, refusal to eat, progressive lethargy, and coma. CPSID is inherited as an autosomal recessive genetic disorder.The urea cycle disorders are a group of rare disorders affecting the urea cycle, a series of biochemical processes in which nitrogen is converted into urea and removed from the body through the urine. Nitrogen is a waste product of protein metabolism. Failure to break down nitrogen results in the abnormal accumulation of nitrogen, in the form of ammonia, in the blood. | Overview of Carbamoyl Phosphate Synthetase 1 Deficiency. Carbamoyl phosphate synthetase 1 deficiency (CPSID) is a rare inherited disorder characterized by complete or partial lack of the carbamoyl phosphate synthetase (CPS) enzyme. This is one of five enzymes that play a role in the breakdown and removal of nitrogen from the body, a process known as the urea cycle. The lack of the CPSI enzyme results in excessive accumulation of nitrogen, in the form of ammonia (hyperammonemia), in the blood. Affected children may experience vomiting, refusal to eat, progressive lethargy, and coma. CPSID is inherited as an autosomal recessive genetic disorder.The urea cycle disorders are a group of rare disorders affecting the urea cycle, a series of biochemical processes in which nitrogen is converted into urea and removed from the body through the urine. Nitrogen is a waste product of protein metabolism. Failure to break down nitrogen results in the abnormal accumulation of nitrogen, in the form of ammonia, in the blood. | 195 | Carbamoyl Phosphate Synthetase 1 Deficiency |
nord_195_1 | Symptoms of Carbamoyl Phosphate Synthetase 1 Deficiency | CPSID may be associated with complete or partial absence of the CPS enzyme. Complete lack of the CPS enzyme results in the severe form of the disorder, in which symptoms occur shortly after birth (neonatal period). Partial lack of the CPS enzyme results in a milder form of the disorder that can occur at any time during the life of the patient. The symptoms of CPSID are caused by the accumulation of ammonia in the blood. The severe form of CPSID occurs within 24-72 hours after birth, regardless of exposure to dietary protein. This form of CPSID is initially characterized by refusal to eat, lethargy, lack of appetite, vomiting, and irritability. Shortly thereafter, affected infants may also experience seizures, respiratory distress, and abnormal movements and postures, The symptoms are mostly attributable to the swelling of the brain (cerebral edema) caused by hyperammonemia.In neonatal cases, untreated CPSID progresses to coma due to high levels of ammonia in the blood (hyperammonemic coma). In such cases and even with effective treatment, the disorder may potentially result in neurological abnormalities, including developmental delays and intellectual disability. The neurological abnormalities are more severe in infants who are in hyperammonemic coma for a prolonged period (days). If left untreated, the disorder will typically results in death of the patient.Those with the milder form of CPSID show symptoms later during infancy, childhood, or adulthood. Symptoms are often triggered by a secondary illness such as a viral infection or other stress. Symptoms may include failure to grow and gain weight at the expected rate (failure to thrive), avoidance of protein from the diet, inability to coordinate voluntary movements (ataxia), lethargy, vomiting, and/or diminished muscle tone (hypotonia). Patients with the milder form of CPSID may still experience hyperammonemic coma and life-threatening complications. | Symptoms of Carbamoyl Phosphate Synthetase 1 Deficiency. CPSID may be associated with complete or partial absence of the CPS enzyme. Complete lack of the CPS enzyme results in the severe form of the disorder, in which symptoms occur shortly after birth (neonatal period). Partial lack of the CPS enzyme results in a milder form of the disorder that can occur at any time during the life of the patient. The symptoms of CPSID are caused by the accumulation of ammonia in the blood. The severe form of CPSID occurs within 24-72 hours after birth, regardless of exposure to dietary protein. This form of CPSID is initially characterized by refusal to eat, lethargy, lack of appetite, vomiting, and irritability. Shortly thereafter, affected infants may also experience seizures, respiratory distress, and abnormal movements and postures, The symptoms are mostly attributable to the swelling of the brain (cerebral edema) caused by hyperammonemia.In neonatal cases, untreated CPSID progresses to coma due to high levels of ammonia in the blood (hyperammonemic coma). In such cases and even with effective treatment, the disorder may potentially result in neurological abnormalities, including developmental delays and intellectual disability. The neurological abnormalities are more severe in infants who are in hyperammonemic coma for a prolonged period (days). If left untreated, the disorder will typically results in death of the patient.Those with the milder form of CPSID show symptoms later during infancy, childhood, or adulthood. Symptoms are often triggered by a secondary illness such as a viral infection or other stress. Symptoms may include failure to grow and gain weight at the expected rate (failure to thrive), avoidance of protein from the diet, inability to coordinate voluntary movements (ataxia), lethargy, vomiting, and/or diminished muscle tone (hypotonia). Patients with the milder form of CPSID may still experience hyperammonemic coma and life-threatening complications. | 195 | Carbamoyl Phosphate Synthetase 1 Deficiency |
nord_195_2 | Causes of Carbamoyl Phosphate Synthetase 1 Deficiency | CPSID is inherited as an autosomal recessive genetic disorder and is caused by mutations in the CPSI gene. Mutations in the CPSI gene result in production of an abnormal carbamoyl phosphate synthetase enzyme. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. | Causes of Carbamoyl Phosphate Synthetase 1 Deficiency. CPSID is inherited as an autosomal recessive genetic disorder and is caused by mutations in the CPSI gene. Mutations in the CPSI gene result in production of an abnormal carbamoyl phosphate synthetase enzyme. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. | 195 | Carbamoyl Phosphate Synthetase 1 Deficiency |
nord_195_3 | Affects of Carbamoyl Phosphate Synthetase 1 Deficiency | The estimated frequency of CPSID is 1 in 150-200,000 births. The estimated frequency of urea cycle disorders collectively is one in 30,000. However, because urea cycle disorders like CPSID often go unrecognized, these disorders are under-diagnosed, making it difficult to determine the true frequency of urea cycle disorders in the general population. | Affects of Carbamoyl Phosphate Synthetase 1 Deficiency. The estimated frequency of CPSID is 1 in 150-200,000 births. The estimated frequency of urea cycle disorders collectively is one in 30,000. However, because urea cycle disorders like CPSID often go unrecognized, these disorders are under-diagnosed, making it difficult to determine the true frequency of urea cycle disorders in the general population. | 195 | Carbamoyl Phosphate Synthetase 1 Deficiency |
nord_195_4 | Related disorders of Carbamoyl Phosphate Synthetase 1 Deficiency | Symptoms of the following disorders may be similar to those of CPSID Comparisons may be useful for a differential diagnosis:The urea cycle disorders are a group of rare disorders affecting the urea cycle, a series of biochemical processes in which nitrogen is converted into urea and removed from the body through the urine. Nitrogen is a waste product of protein metabolism. The symptoms of all urea cycle disorders vary in severity and result from the excessive accumulation of ammonia in the blood and body tissues (hyperammonemia). Common symptoms include lack of appetite, vomiting, drowsiness, seizures, and/or coma. The liver may be abnormally enlarged (hepatomegaly). In some cases, life-threatening complications may result. In addition to CPS deficiency, the other urea cycle disorders are: argininosuccinic acid synthetase deficiency (citrullinemia type 1); argininosuccinase acid lyase deficiency; ornithine transcarbamylase (OTC) deficiency; arginase deficiency and N-acetylglutamate synthetase (NAGS) deficiency. Disorders in transport in the urea cycle (citrin deficiency or citrullinemia type 2 and ornithine transport) will also present with similar symptoms in severe forms(For more information on these disorders, choose the specific disorder name as your search terms in the Rare Disease Database.)Organic acidemias are a rare group of inherited metabolic disorders characterized by deficiency of certain enzymes that are necessary to breakdown (metabolize) chemical “building blocks” (amino acids) of certain proteins. Failure to break down amino acids results in the excessive accumulation of acids in the blood. Symptoms may include abnormally diminished muscle tone (hypotonia), poor feeding, vomiting, lethargy, and seizures. If left untreated, organic acidemias may progress to coma and life-threatening complications. These disorders are of a genetic origin and affect the urea cycle as a secondary phenomenon.Reye syndrome is a rare childhood disease characterized by liver failure, abnormal brain function (encephalopathy), abnormally low levels of glucose (hypoglycemia), and high levels of ammonia in the blood. This disorder usually follows a viral infection. It may be triggered by the use of aspirin in children recovering from chicken pox or influenza. (For more information on this disorder, choose “Reye” as your search term in the Rare Disease Database.) | Related disorders of Carbamoyl Phosphate Synthetase 1 Deficiency. Symptoms of the following disorders may be similar to those of CPSID Comparisons may be useful for a differential diagnosis:The urea cycle disorders are a group of rare disorders affecting the urea cycle, a series of biochemical processes in which nitrogen is converted into urea and removed from the body through the urine. Nitrogen is a waste product of protein metabolism. The symptoms of all urea cycle disorders vary in severity and result from the excessive accumulation of ammonia in the blood and body tissues (hyperammonemia). Common symptoms include lack of appetite, vomiting, drowsiness, seizures, and/or coma. The liver may be abnormally enlarged (hepatomegaly). In some cases, life-threatening complications may result. In addition to CPS deficiency, the other urea cycle disorders are: argininosuccinic acid synthetase deficiency (citrullinemia type 1); argininosuccinase acid lyase deficiency; ornithine transcarbamylase (OTC) deficiency; arginase deficiency and N-acetylglutamate synthetase (NAGS) deficiency. Disorders in transport in the urea cycle (citrin deficiency or citrullinemia type 2 and ornithine transport) will also present with similar symptoms in severe forms(For more information on these disorders, choose the specific disorder name as your search terms in the Rare Disease Database.)Organic acidemias are a rare group of inherited metabolic disorders characterized by deficiency of certain enzymes that are necessary to breakdown (metabolize) chemical “building blocks” (amino acids) of certain proteins. Failure to break down amino acids results in the excessive accumulation of acids in the blood. Symptoms may include abnormally diminished muscle tone (hypotonia), poor feeding, vomiting, lethargy, and seizures. If left untreated, organic acidemias may progress to coma and life-threatening complications. These disorders are of a genetic origin and affect the urea cycle as a secondary phenomenon.Reye syndrome is a rare childhood disease characterized by liver failure, abnormal brain function (encephalopathy), abnormally low levels of glucose (hypoglycemia), and high levels of ammonia in the blood. This disorder usually follows a viral infection. It may be triggered by the use of aspirin in children recovering from chicken pox or influenza. (For more information on this disorder, choose “Reye” as your search term in the Rare Disease Database.) | 195 | Carbamoyl Phosphate Synthetase 1 Deficiency |
nord_195_5 | Diagnosis of Carbamoyl Phosphate Synthetase 1 Deficiency | A diagnosis of a urea cycle disorder, such as CPSID, should be considered in any newborn who has an undiagnosed illness characterized by vomiting, progressive lethargy, and irritability.A diagnosis of CPSID involves a detailed patient/family history, identification of characteristic findings, and a variety of specialized tests. Blood tests may reveal excessive amounts of ammonia in the blood, which is the main criterion for a diagnosis of urea cycle disorders including CPSID. However, high levels of ammonia in the blood may characterize other disorders such as the organic acidemias, congenital lactic acidosis, liver disease, and fatty acid oxidation disorders. Urea cycle disorders can be differentiated from these disorders through the examination of urine for elevated levels of, or abnormal, organic acids. In urea cycle disorders, urinary organic acids are normal except for the presence of orotic acid in OTCD. Genetic sequencing of the CPSI gene is the main form of diagnosis at this time (typically combined with sequence of the other urea cycle enzymes). Measurement of CPSID1 enzyme activity on cells obtained from a liver biopsy can confirm the diagnosis but is rarely employed currently. | Diagnosis of Carbamoyl Phosphate Synthetase 1 Deficiency. A diagnosis of a urea cycle disorder, such as CPSID, should be considered in any newborn who has an undiagnosed illness characterized by vomiting, progressive lethargy, and irritability.A diagnosis of CPSID involves a detailed patient/family history, identification of characteristic findings, and a variety of specialized tests. Blood tests may reveal excessive amounts of ammonia in the blood, which is the main criterion for a diagnosis of urea cycle disorders including CPSID. However, high levels of ammonia in the blood may characterize other disorders such as the organic acidemias, congenital lactic acidosis, liver disease, and fatty acid oxidation disorders. Urea cycle disorders can be differentiated from these disorders through the examination of urine for elevated levels of, or abnormal, organic acids. In urea cycle disorders, urinary organic acids are normal except for the presence of orotic acid in OTCD. Genetic sequencing of the CPSI gene is the main form of diagnosis at this time (typically combined with sequence of the other urea cycle enzymes). Measurement of CPSID1 enzyme activity on cells obtained from a liver biopsy can confirm the diagnosis but is rarely employed currently. | 195 | Carbamoyl Phosphate Synthetase 1 Deficiency |
nord_195_6 | Therapies of Carbamoyl Phosphate Synthetase 1 Deficiency | Treatment
Treatment is very complex and should be coordinated by a metabolic specialist at a center experienced in the care of urea cycle patients. Therapy is based on reducing plasma ammonia concentration, preventing excess ammonia from being formed, and reducing the amount of nitrogen in the diet while supplying enough for growth.Reduction of plasma ammonia concentration is accomplished by dialysis and several different methods are available.The nitrogen scavenger drugs sodium phenylacetate and sodium benzoate provide an alternative pathway for removing excess nitrogen. Intravenous and oral forms of these medications are available (Ammonul and Ucephan). Phenylbutyrate (Buphenyl) has a less offensive odor than the other medications but is available as oral therapy only.Dietary restrictions in individuals with CPSID are aimed at limiting the amount of protein intake. Children with CPSID are placed on a low-protein, high calorie diet, supplemented by essential amino acids. Treatment may also include citrulline or arginine, to maintain a normal rate of protein formation (synthesis).Prompt treatment is necessary when individuals have extremely high ammonia levels (severe hyperammonemic episode). Prompt treatment can sometimes prevent coma and severe neurological symptoms. However, in some cases, especially those with complete enzyme deficiency, prompt treatment will not prevent recurrent episodes of hyperammonemia and the potential development of serious complications. In many centers liver transplantation is offered as a more permanent solution to severe CPSID.Consensus treatment guidelines are available online at the NIH sponsored urea cycle disorders consortium website.http://rarediseasesnetwork.epi.usf.edu/ucdc/Seizures are treated with phenobarbital or carbamazepine. Valproic acid and intravenous steroids should be avoided, as it can increase blood ammonia levels. Prednisone and other similar steroid compounds should also be avoided because they will trigger a protein catabolic state and hyperammonemia. Inhaled steroids are somewhat safer if necessary.Of note, the chemotherapy drug cyclophosphamide appears to directly inhibit CPSI.Affected individuals should receive periodic blood tests to determine the levels of ammonia in the blood. Excessive levels of ammonia should be promptly treated.Genetic counseling is recommended for affected individuals and their families. | Therapies of Carbamoyl Phosphate Synthetase 1 Deficiency. Treatment
Treatment is very complex and should be coordinated by a metabolic specialist at a center experienced in the care of urea cycle patients. Therapy is based on reducing plasma ammonia concentration, preventing excess ammonia from being formed, and reducing the amount of nitrogen in the diet while supplying enough for growth.Reduction of plasma ammonia concentration is accomplished by dialysis and several different methods are available.The nitrogen scavenger drugs sodium phenylacetate and sodium benzoate provide an alternative pathway for removing excess nitrogen. Intravenous and oral forms of these medications are available (Ammonul and Ucephan). Phenylbutyrate (Buphenyl) has a less offensive odor than the other medications but is available as oral therapy only.Dietary restrictions in individuals with CPSID are aimed at limiting the amount of protein intake. Children with CPSID are placed on a low-protein, high calorie diet, supplemented by essential amino acids. Treatment may also include citrulline or arginine, to maintain a normal rate of protein formation (synthesis).Prompt treatment is necessary when individuals have extremely high ammonia levels (severe hyperammonemic episode). Prompt treatment can sometimes prevent coma and severe neurological symptoms. However, in some cases, especially those with complete enzyme deficiency, prompt treatment will not prevent recurrent episodes of hyperammonemia and the potential development of serious complications. In many centers liver transplantation is offered as a more permanent solution to severe CPSID.Consensus treatment guidelines are available online at the NIH sponsored urea cycle disorders consortium website.http://rarediseasesnetwork.epi.usf.edu/ucdc/Seizures are treated with phenobarbital or carbamazepine. Valproic acid and intravenous steroids should be avoided, as it can increase blood ammonia levels. Prednisone and other similar steroid compounds should also be avoided because they will trigger a protein catabolic state and hyperammonemia. Inhaled steroids are somewhat safer if necessary.Of note, the chemotherapy drug cyclophosphamide appears to directly inhibit CPSI.Affected individuals should receive periodic blood tests to determine the levels of ammonia in the blood. Excessive levels of ammonia should be promptly treated.Genetic counseling is recommended for affected individuals and their families. | 195 | Carbamoyl Phosphate Synthetase 1 Deficiency |
nord_196_0 | Overview of Carcinoid Syndrome | Carcinoid syndrome is a disease consisting of a combination of symptoms, physical manifestations, and abnormal laboratory findings. Carcinoid syndrome is seen in individuals who have an underlying carcinoid tumour with spread to the liver. Carcinoid tumors are well-differentiated neuroendocrine tumours with secretory properties, releasing serotonin, along with a number of other active peptides. These tumors can arise anywhere along the primitive gut and are therefore found in the bronchial tree (airways) and along the gastrointestinal tract. The tumor cells can also migrate (metastasize) to the liver.Carcinoid tumors most commonly occur in the small intestine and appendix, but 10% originate in the lung. Other affected areas include the rectum, colon, pancreas, stomach, ovary, thymus, kidney, prostate, breast and elsewhere. These slow-growing malignancies tend to spread to lymph nodes and the liver but can also metastasize to lung, bone, brain, and skin.Only about 10% of the people with a carcinoid tumor will develop carcinoid syndrome. Major symptoms of this syndrome include hot, red facial flushing, diarrhea and wheezing. Carcinoid syndrome occurs when the tumor produces excessive amounts of serotonin in an individual with liver metastases. In patients who have no spread to the liver, the serotonin released by an intestinal tumor will be broken down to an inactive substance; thus, carcinoid syndrome does not occur. | Overview of Carcinoid Syndrome. Carcinoid syndrome is a disease consisting of a combination of symptoms, physical manifestations, and abnormal laboratory findings. Carcinoid syndrome is seen in individuals who have an underlying carcinoid tumour with spread to the liver. Carcinoid tumors are well-differentiated neuroendocrine tumours with secretory properties, releasing serotonin, along with a number of other active peptides. These tumors can arise anywhere along the primitive gut and are therefore found in the bronchial tree (airways) and along the gastrointestinal tract. The tumor cells can also migrate (metastasize) to the liver.Carcinoid tumors most commonly occur in the small intestine and appendix, but 10% originate in the lung. Other affected areas include the rectum, colon, pancreas, stomach, ovary, thymus, kidney, prostate, breast and elsewhere. These slow-growing malignancies tend to spread to lymph nodes and the liver but can also metastasize to lung, bone, brain, and skin.Only about 10% of the people with a carcinoid tumor will develop carcinoid syndrome. Major symptoms of this syndrome include hot, red facial flushing, diarrhea and wheezing. Carcinoid syndrome occurs when the tumor produces excessive amounts of serotonin in an individual with liver metastases. In patients who have no spread to the liver, the serotonin released by an intestinal tumor will be broken down to an inactive substance; thus, carcinoid syndrome does not occur. | 196 | Carcinoid Syndrome |
nord_196_1 | Symptoms of Carcinoid Syndrome | Symptoms may be non-hormonal, secondary to tumor bulk and therefore depend on location; or hormonal as a result of carcinoid syndrome. Those caused by the tumour may include abdominal pain, anemia, pneumonia, cough and haemoptysis (cough productive of blood). Carcinoid tumors can also be present without producing any symptoms and may often go undetected for a long period of time.The symptoms of carcinoid syndrome include episodes of warmth and redness of the face, head and upper chest; diarrhea; marked changes in blood pressure (usually hypotension, a decrease in blood pressure); asthmatic-like wheezing; weight loss or gain; malnutrition; dehydration; weakness; muscle and joint aching; and peptic ulcer.In later stages, carcinoid syndrome may damage the heart valves, resulting in symptoms of congestive heart failure. The diarrhea may be so severe that vital nutrients of the body, such as potassium and water, are depleted creating life-threatening electrolyte imbalance. The syndrome may also be accompanied by stomach pain, blockage of the arteries in the liver, heart palpitations and excessive peptide excretion in the urine. In extremely rare cases, the acute occurrence of flushing, blood pressure changes, weakness, palpitations, faintness and wheezing constitutes a carcinoid crisis that can be life-threatening. Not all of these features need be present in a carcinoid crisis or for a diagnosis of carcinoid syndrome. | Symptoms of Carcinoid Syndrome. Symptoms may be non-hormonal, secondary to tumor bulk and therefore depend on location; or hormonal as a result of carcinoid syndrome. Those caused by the tumour may include abdominal pain, anemia, pneumonia, cough and haemoptysis (cough productive of blood). Carcinoid tumors can also be present without producing any symptoms and may often go undetected for a long period of time.The symptoms of carcinoid syndrome include episodes of warmth and redness of the face, head and upper chest; diarrhea; marked changes in blood pressure (usually hypotension, a decrease in blood pressure); asthmatic-like wheezing; weight loss or gain; malnutrition; dehydration; weakness; muscle and joint aching; and peptic ulcer.In later stages, carcinoid syndrome may damage the heart valves, resulting in symptoms of congestive heart failure. The diarrhea may be so severe that vital nutrients of the body, such as potassium and water, are depleted creating life-threatening electrolyte imbalance. The syndrome may also be accompanied by stomach pain, blockage of the arteries in the liver, heart palpitations and excessive peptide excretion in the urine. In extremely rare cases, the acute occurrence of flushing, blood pressure changes, weakness, palpitations, faintness and wheezing constitutes a carcinoid crisis that can be life-threatening. Not all of these features need be present in a carcinoid crisis or for a diagnosis of carcinoid syndrome. | 196 | Carcinoid Syndrome |
nord_196_2 | Causes of Carcinoid Syndrome | The underlying cause of carcinoid tumors remains unclear. Some studies have suggested risk factors such as smoking and dietary intake, however, further research is needed to confirm these findings. In the majority of cases tumors are slow-growing and can produce hormonal chemical substances such as serotonin, bradykinins, tachykinins and prostaglandins. If the original carcinoid cells spread (metastasize) to the liver, these substances are no longer broken down to their inactive form and are released into the systemic (main) circulation, causing the signs and symptoms of carcinoid syndrome. When tumors affect organs other than the gastrointestinal tract, such as the ovaries, carcinoid syndrome can occur in the absence of liver metastases. | Causes of Carcinoid Syndrome. The underlying cause of carcinoid tumors remains unclear. Some studies have suggested risk factors such as smoking and dietary intake, however, further research is needed to confirm these findings. In the majority of cases tumors are slow-growing and can produce hormonal chemical substances such as serotonin, bradykinins, tachykinins and prostaglandins. If the original carcinoid cells spread (metastasize) to the liver, these substances are no longer broken down to their inactive form and are released into the systemic (main) circulation, causing the signs and symptoms of carcinoid syndrome. When tumors affect organs other than the gastrointestinal tract, such as the ovaries, carcinoid syndrome can occur in the absence of liver metastases. | 196 | Carcinoid Syndrome |
nord_196_3 | Affects of Carcinoid Syndrome | Carcinoid tumors are rare, with only 27 new cases per million diagnosed in the U.S. per year. Of these, only about 10% will develop carcinoid syndrome. The syndrome affects males and females in equal numbers. All races can be affected though there is a slightly increased prevalence in black African males. All ages can be affected but most gastrointestinal cases occur in middle-age. Bronchial (airway) tumors are most often seen in the fifth decade but can affect people at any age. Carcinoid syndrome may be more prevalent than suspected because diagnosis is difficult and sometimes overlooked; some patients may not exhibit all three of the hallmark symptoms of flushing, wheezing, and diarrhea. | Affects of Carcinoid Syndrome. Carcinoid tumors are rare, with only 27 new cases per million diagnosed in the U.S. per year. Of these, only about 10% will develop carcinoid syndrome. The syndrome affects males and females in equal numbers. All races can be affected though there is a slightly increased prevalence in black African males. All ages can be affected but most gastrointestinal cases occur in middle-age. Bronchial (airway) tumors are most often seen in the fifth decade but can affect people at any age. Carcinoid syndrome may be more prevalent than suspected because diagnosis is difficult and sometimes overlooked; some patients may not exhibit all three of the hallmark symptoms of flushing, wheezing, and diarrhea. | 196 | Carcinoid Syndrome |
nord_196_4 | Related disorders of Carcinoid Syndrome | Symptoms of the following disorders can be similar to those of carcinoid syndrome. Comparisons may be useful for a differential diagnosis:Multiple endocrine neoplasia (MEN) type 1 is a rare genetic disorder in which benign (noncancerous) tumors arise from the cells of various glands of the endocrine system. The endocrine system is the network of glands that secrete hormones into the bloodstream where they travel to various areas of the body. These hormones regulate the chemical processes (metabolism) that influence the function of various organs and activities within the body. Hormones are involved in numerous vital processes including regulating heart rate, body temperature and blood pressure as well as cell differentiation and growth and also in modulation of several metabolic processes. In individuals with MEN type 1, benign tumors develop in multiple endocrine glands, most often the parathyroid, pancreas and pituitary glands. These affected glands secrete excessive amounts of hormones into the bloodstream, which can result in a variety of symptoms. Some benign tumors associated with MEN type 1 can become malignant (cancerous). MEN type 1 can run in families or can occur as the result of a spontaneous new gene mutation in the affected person.Pancreatic cholera or VIPoma is characterized by watery diarrhea, the loss of potassium through the urine (hypokalemia) and acidosis. In most cases this disorder is due to a non-B-islet-cell tumor of the pancreas that secretes vasoactive intestinal polypeptide (VIP) and peptide histidine isoleucine. The episodes of diarrhea in association with profound loss of potassium, hypochlorhydria, and metabolic acidosis can be a life-threatening situation due to the excessive fluid and electrolyte loss.Zollinger-Ellison syndrome is an unusual condition characterized by small tumors (usually of the pancreas) that secrete a hormone that produces excess amounts of stomach (gastric) juices and resultant peptic ulcers (gastrinoma). These tumors can also appear in the lower stomach wall, spleen or lymph nodes close to the stomach. Large amounts of gastric acid can be found in lower stomach areas where ulcers can form. Pain from these persistent ulcers may be severe. Diarrhea and excretion of fat in the feces (steatorrhea) commonly occurs. This can result in a decrease of potassium levels in the blood. (For more information on this disorder, choose “Zollinger” as your search term in the Rare Disease Database.)Cushing syndrome consists of a group of symptoms attributable to an excess of cortisol and other hormones from the cortex of the adrenal gland. Cushing syndrome patients may have a chronically flushed face, high blood pressure (hypertension), edema, kidney stones, and severe metabolic disturbances. This syndrome is characterized by significant weight gain with fat deposits in particular parts of the body, such as the trunk, while other parts of the body, such as the arms and legs, remain slender. (For more information on this disorder, choose “Cushing” as your search term in the Rare Disease Database.)Hyperthyroidism is a condition resulting from overproduction of thyroid hormones. Symptoms may include anxiety, fatigue, marked protrusion of the eyeballs (exophthalmos), sweating, heart palpitations, diarrhea, weight loss, and/or heat intolerance. Hyperthyroidism may result from any of a number of different underlying causes.Systemic mast cell disease (mastocytosis) is a rare disorder characterized by abnormal accumulations of specific cells (mast cells) normally found in connective tissue. The liver, spleen, lungs, bone, skin, and sometimes the membrane surrounding the brain and spine (meninges) may be affected. Cases beginning during adulthood tend to involve the inner organs more than the skin, whereas during childhood, the condition is often marked by skin manifestations with minimal organ involvement. Mastocytosis is initially characterized by a vague feeling of discomfort or ill health, weakness, nausea, vomiting, heart beat irregularities, weight loss, and/or diarrhea. (For more information on this disorder, choose “mastocytosis” as your search term in the Rare Disease Database.)Pheochromocytoma is a rare type of tumor that arises from certain cells known as chromaffin cells, which produce hormones necessary for the body to function properly. Most pheochromocytomas originate in one of the two adrenal glands located above the kidneys in the back of the upper abdomen. (For more information on this disorder, choose “pheochromocytoma” as your search term in the Rare Disease Database.)Pancreatic islet cell tumors may be nonfunctioning or functioning tumors. Nonfunctioning tumors may cause obstruction in the shortest part of the small intestine (duodenum) or in the biliary tract, which connects the liver to the duodenum and includes the gall bladder. These nonfunctioning tumors may erode and bleed into the stomach and/or the intestines, or they may cause an abdominal mass. Functioning tumors secrete excessive amounts of hormones, which may lead to various syndromes including low blood sugar (hypoglycemia), multiple bleeding ulcers (Zollinger-Ellison Syndrome), pancreatic cholera (Verner-Morrison Syndrome), carcinoid syndrome or diabetes. (For more information on this condition, choose “pancreatic islet cell tumor” as your search term in the Rare Disease Database.)Frequently, carcinoid syndrome may be misdiagnosed as Crohn’s disease, irritable bowel syndrome, or in women, menopause. | Related disorders of Carcinoid Syndrome. Symptoms of the following disorders can be similar to those of carcinoid syndrome. Comparisons may be useful for a differential diagnosis:Multiple endocrine neoplasia (MEN) type 1 is a rare genetic disorder in which benign (noncancerous) tumors arise from the cells of various glands of the endocrine system. The endocrine system is the network of glands that secrete hormones into the bloodstream where they travel to various areas of the body. These hormones regulate the chemical processes (metabolism) that influence the function of various organs and activities within the body. Hormones are involved in numerous vital processes including regulating heart rate, body temperature and blood pressure as well as cell differentiation and growth and also in modulation of several metabolic processes. In individuals with MEN type 1, benign tumors develop in multiple endocrine glands, most often the parathyroid, pancreas and pituitary glands. These affected glands secrete excessive amounts of hormones into the bloodstream, which can result in a variety of symptoms. Some benign tumors associated with MEN type 1 can become malignant (cancerous). MEN type 1 can run in families or can occur as the result of a spontaneous new gene mutation in the affected person.Pancreatic cholera or VIPoma is characterized by watery diarrhea, the loss of potassium through the urine (hypokalemia) and acidosis. In most cases this disorder is due to a non-B-islet-cell tumor of the pancreas that secretes vasoactive intestinal polypeptide (VIP) and peptide histidine isoleucine. The episodes of diarrhea in association with profound loss of potassium, hypochlorhydria, and metabolic acidosis can be a life-threatening situation due to the excessive fluid and electrolyte loss.Zollinger-Ellison syndrome is an unusual condition characterized by small tumors (usually of the pancreas) that secrete a hormone that produces excess amounts of stomach (gastric) juices and resultant peptic ulcers (gastrinoma). These tumors can also appear in the lower stomach wall, spleen or lymph nodes close to the stomach. Large amounts of gastric acid can be found in lower stomach areas where ulcers can form. Pain from these persistent ulcers may be severe. Diarrhea and excretion of fat in the feces (steatorrhea) commonly occurs. This can result in a decrease of potassium levels in the blood. (For more information on this disorder, choose “Zollinger” as your search term in the Rare Disease Database.)Cushing syndrome consists of a group of symptoms attributable to an excess of cortisol and other hormones from the cortex of the adrenal gland. Cushing syndrome patients may have a chronically flushed face, high blood pressure (hypertension), edema, kidney stones, and severe metabolic disturbances. This syndrome is characterized by significant weight gain with fat deposits in particular parts of the body, such as the trunk, while other parts of the body, such as the arms and legs, remain slender. (For more information on this disorder, choose “Cushing” as your search term in the Rare Disease Database.)Hyperthyroidism is a condition resulting from overproduction of thyroid hormones. Symptoms may include anxiety, fatigue, marked protrusion of the eyeballs (exophthalmos), sweating, heart palpitations, diarrhea, weight loss, and/or heat intolerance. Hyperthyroidism may result from any of a number of different underlying causes.Systemic mast cell disease (mastocytosis) is a rare disorder characterized by abnormal accumulations of specific cells (mast cells) normally found in connective tissue. The liver, spleen, lungs, bone, skin, and sometimes the membrane surrounding the brain and spine (meninges) may be affected. Cases beginning during adulthood tend to involve the inner organs more than the skin, whereas during childhood, the condition is often marked by skin manifestations with minimal organ involvement. Mastocytosis is initially characterized by a vague feeling of discomfort or ill health, weakness, nausea, vomiting, heart beat irregularities, weight loss, and/or diarrhea. (For more information on this disorder, choose “mastocytosis” as your search term in the Rare Disease Database.)Pheochromocytoma is a rare type of tumor that arises from certain cells known as chromaffin cells, which produce hormones necessary for the body to function properly. Most pheochromocytomas originate in one of the two adrenal glands located above the kidneys in the back of the upper abdomen. (For more information on this disorder, choose “pheochromocytoma” as your search term in the Rare Disease Database.)Pancreatic islet cell tumors may be nonfunctioning or functioning tumors. Nonfunctioning tumors may cause obstruction in the shortest part of the small intestine (duodenum) or in the biliary tract, which connects the liver to the duodenum and includes the gall bladder. These nonfunctioning tumors may erode and bleed into the stomach and/or the intestines, or they may cause an abdominal mass. Functioning tumors secrete excessive amounts of hormones, which may lead to various syndromes including low blood sugar (hypoglycemia), multiple bleeding ulcers (Zollinger-Ellison Syndrome), pancreatic cholera (Verner-Morrison Syndrome), carcinoid syndrome or diabetes. (For more information on this condition, choose “pancreatic islet cell tumor” as your search term in the Rare Disease Database.)Frequently, carcinoid syndrome may be misdiagnosed as Crohn’s disease, irritable bowel syndrome, or in women, menopause. | 196 | Carcinoid Syndrome |
nord_196_5 | Diagnosis of Carcinoid Syndrome | Diagnosis is best achieved with a multimodality approach including biochemical investigation, radiological and nuclear imaging, and finally histological (tissue biopsy) confirmation where possible. The occurrence of episodic facial flushing and/or chronic diarrhea not diagnosed by standard tests as being a result of more common causes should lead to suspicion of carcinoid syndrome. In the past, measurement of 24-hour urinary excretion of 5-hydroxyendolacetic acid (5-HIAA), a product of the breakdown (metabolism) of serotonin, in a patient on a low serotonin diet was the main lab test used. It is still useful and the level of 5-HIAA will be clearly elevated in 50% of the cases. However, there are also blood tests available, the most useful being chromogranin-A, often in combination with an imaging technique known as octreoscan, that may confirm the diagnosis of carcinoid syndrome even when urinary 5-HIAA is normal. This technique may also be helpful in indicating the presence of carcinoid tumors when the full spectrum of symptoms is not apparent. Other investigations that may be helpful, depending on the location of the primary tumor, include CT scan, ultrasound, MRI and endoscopy. Sometimes the diagnosis is established incidentally at the time of surgery for another suspected condition such as intestinal obstruction or appendicitis. | Diagnosis of Carcinoid Syndrome. Diagnosis is best achieved with a multimodality approach including biochemical investigation, radiological and nuclear imaging, and finally histological (tissue biopsy) confirmation where possible. The occurrence of episodic facial flushing and/or chronic diarrhea not diagnosed by standard tests as being a result of more common causes should lead to suspicion of carcinoid syndrome. In the past, measurement of 24-hour urinary excretion of 5-hydroxyendolacetic acid (5-HIAA), a product of the breakdown (metabolism) of serotonin, in a patient on a low serotonin diet was the main lab test used. It is still useful and the level of 5-HIAA will be clearly elevated in 50% of the cases. However, there are also blood tests available, the most useful being chromogranin-A, often in combination with an imaging technique known as octreoscan, that may confirm the diagnosis of carcinoid syndrome even when urinary 5-HIAA is normal. This technique may also be helpful in indicating the presence of carcinoid tumors when the full spectrum of symptoms is not apparent. Other investigations that may be helpful, depending on the location of the primary tumor, include CT scan, ultrasound, MRI and endoscopy. Sometimes the diagnosis is established incidentally at the time of surgery for another suspected condition such as intestinal obstruction or appendicitis. | 196 | Carcinoid Syndrome |
nord_196_6 | Therapies of Carcinoid Syndrome | Treatment
Standard treatment is surgery to remove the entire tumor where possible and reduce (debulk) any metastases. In gastrointestinal tumors this will involve resection of the affected area. For bronchial (airway) lesions, procedures such as lobectomy, sleeve resection or pneumonectomy may be required depending on the location of the mass. Debulking of liver metastases can be done by surgical excision or by newer techniques such as cryoablation and radiofrequency ablation. Hepatic artery catheterization with injection of embolic inert particles alone or mixed with chemotherapy has been very effective in many patients with liver metastases. The chemotherapeutic drugs injected in this treatment are cisplatin, mitomycin, and doxorubicin. Systemic chemotherapy is also used with an overall beneficial response in approximately one third of the patients. Drugs used for this purpose include dacarbazine, VP-16 (etoposide), cisplatin, doxorubicin, 5-fluorouracil, streptozotocin and cyclophosphamide. Some newer agents are currently being investigated. Once the tumors have been removed, periodic long-term surveillance is required.Octreotide (Sandostatin) injections are the mainstay for symptomatic management of carcinoid syndrome. Octreotide is a synthetic form of the pancreatic hormone, somatostatin, and it may be administered in three to four subcutaneous injections per day, one long-acting intramuscular injection every three or four weeks, or by continuous infusion with a sub-cutaneous pump. Sometimes, it is combined with injection of low-dose alpha interferon, which enhances the body’s response.In 2017, Xermelo (telotriastat ethyl) tablets in combination with somatostatin analog (SSA) therapy was FDA approved for the treatment of adults with carcinoid syndrome diarrhea that SSA therapy alone inadequately controls. Xermelo is manufactured by Lexicon Pharmaceuticals, Inc.Various nutritional products are available and may be useful, as may anti-diarrheal and anti-cholinergic medications. Patients are often advised to avoid certain substances such as alcohol and foods with a high concentration of tyramine, as these may make symptoms worse. | Therapies of Carcinoid Syndrome. Treatment
Standard treatment is surgery to remove the entire tumor where possible and reduce (debulk) any metastases. In gastrointestinal tumors this will involve resection of the affected area. For bronchial (airway) lesions, procedures such as lobectomy, sleeve resection or pneumonectomy may be required depending on the location of the mass. Debulking of liver metastases can be done by surgical excision or by newer techniques such as cryoablation and radiofrequency ablation. Hepatic artery catheterization with injection of embolic inert particles alone or mixed with chemotherapy has been very effective in many patients with liver metastases. The chemotherapeutic drugs injected in this treatment are cisplatin, mitomycin, and doxorubicin. Systemic chemotherapy is also used with an overall beneficial response in approximately one third of the patients. Drugs used for this purpose include dacarbazine, VP-16 (etoposide), cisplatin, doxorubicin, 5-fluorouracil, streptozotocin and cyclophosphamide. Some newer agents are currently being investigated. Once the tumors have been removed, periodic long-term surveillance is required.Octreotide (Sandostatin) injections are the mainstay for symptomatic management of carcinoid syndrome. Octreotide is a synthetic form of the pancreatic hormone, somatostatin, and it may be administered in three to four subcutaneous injections per day, one long-acting intramuscular injection every three or four weeks, or by continuous infusion with a sub-cutaneous pump. Sometimes, it is combined with injection of low-dose alpha interferon, which enhances the body’s response.In 2017, Xermelo (telotriastat ethyl) tablets in combination with somatostatin analog (SSA) therapy was FDA approved for the treatment of adults with carcinoid syndrome diarrhea that SSA therapy alone inadequately controls. Xermelo is manufactured by Lexicon Pharmaceuticals, Inc.Various nutritional products are available and may be useful, as may anti-diarrheal and anti-cholinergic medications. Patients are often advised to avoid certain substances such as alcohol and foods with a high concentration of tyramine, as these may make symptoms worse. | 196 | Carcinoid Syndrome |
nord_197_0 | Overview of CARD9 Deficiency | SummaryCARD9 deficiency is a rare disorder of the immune system caused by changes (mutations) in the gene called caspase recruitment domain family member 9 (CARD9). CARD9 deficiency leads to increased susceptibility to certain fungal infections. Generally speaking, the term “fungi” includes two broad categories, yeasts and molds that can be accurately identified in a hospital diagnostic microbiology laboratory. CARD9 deficiency can render affected individuals susceptible particularly to the yeast called Candida (causing “candidiasis”), as well as to certain types of molds (those called “dermatophytes”, which usually cause infections like “ringworm” and “athlete’s foot”, as well as those called “black molds” or “pheohyphomycetes”). However, current knowledge suggests that people with CARD9 deficiency are at increased risk for disease with only one of these types of fungus. As well, people with CARD9 deficiency do not seem to be at increased risk for infections caused by other microbes, such as bacteria, viruses, or parasites.IntroductionCARD9 deficiency is a type of primary immunodeficiency. Primary immunodeficiency diseases (also called “inborn errors of immunity”) are a group of more than 420 rare, chronic disorders in which part of the body’s immune system is missing or functions improperly. These diseases are caused by a mutation in a gene or genes, and, although some disorders present at birth or in early childhood, the disorders can affect anyone, regardless of age or gender. Some affect a single part of the immune system; others may affect one or more components of the system. | Overview of CARD9 Deficiency. SummaryCARD9 deficiency is a rare disorder of the immune system caused by changes (mutations) in the gene called caspase recruitment domain family member 9 (CARD9). CARD9 deficiency leads to increased susceptibility to certain fungal infections. Generally speaking, the term “fungi” includes two broad categories, yeasts and molds that can be accurately identified in a hospital diagnostic microbiology laboratory. CARD9 deficiency can render affected individuals susceptible particularly to the yeast called Candida (causing “candidiasis”), as well as to certain types of molds (those called “dermatophytes”, which usually cause infections like “ringworm” and “athlete’s foot”, as well as those called “black molds” or “pheohyphomycetes”). However, current knowledge suggests that people with CARD9 deficiency are at increased risk for disease with only one of these types of fungus. As well, people with CARD9 deficiency do not seem to be at increased risk for infections caused by other microbes, such as bacteria, viruses, or parasites.IntroductionCARD9 deficiency is a type of primary immunodeficiency. Primary immunodeficiency diseases (also called “inborn errors of immunity”) are a group of more than 420 rare, chronic disorders in which part of the body’s immune system is missing or functions improperly. These diseases are caused by a mutation in a gene or genes, and, although some disorders present at birth or in early childhood, the disorders can affect anyone, regardless of age or gender. Some affect a single part of the immune system; others may affect one or more components of the system. | 197 | CARD9 Deficiency |
nord_197_1 | Symptoms of CARD9 Deficiency | The signs and symptoms (or manifestations) of CARD9 deficiency appear quite varied.As mentioned above, some persons develop infection only with Candida, while others develop infection only with dermatophytes, and others develop infection only with “black molds”.The following conditions can be caused by CARD9 deficiency:
• invasive fungal disease
• mycosis
• Candida infection (candidiasis)
• chronic mucocutaneous candidiasis (CMC)
• invasive candidiasis
• spontaneous central nervous system candidiasis (brain candidiasis)
• Candidal endophthalmitis (eye candidiasis)
• Candidal osteomyelitis (bone candidiasis)
• deep dermatophytosis
• chronic invasive dermatophyte infection (tinea profunda)
• pheohyphomycosis (black mold disease)Infections with Candida can be superficial and chronic (termed “chronic mucocutaneous candidiasis” or CMC). In distinction to the majority of other primary immunodeficiency disorders that cause CMC, CARD9 deficiency distinctly predisposes to invasive infection with Candida (termed “invasive candidiasis”), where the Candida can invade beyond the skin to go to other parts of the body. A very distinct manifestation is Candida involving the brain or the meninges (the protective layer of the brain, resulting in meningitis). In some cases of CARD9 deficiency where Candida infects the brain, the affected patients have radiologic brain imaging (for example, by CT or MRI) and are found to have mass(es) that resemble brain cancers; however, on biopsy, there is no cancer and only Candida infection is found. CARD9 deficiency can also lead to candida infection of the eye (leading to loss of vision) or of bone (leading to pain in the affected area). In all of these cases of invasive candidiasis, there is no risk factor for the fungus to reach these organs (the usual risk factors include things such as leukemia, chemotherapy, intravenous lines, all of which are absent in affected individuals).The invasive candidiasis may appear to be successfully treated with antifungal drugs that target Candida, although the infection may recur (relapse), when the antifungal drug is stopped; in some instances, it may recur even when the person is currently taking the right antifungal drug.Infections with dermatophytes and “black molds” tend be chronic and difficult to treat, responding partially or poorly to antifungal drugs. They can be disfiguring and they can also spread from the skin to lymph nodes and deep organs, including the brain.There has been a report of other fungal infections associated with CARD9 deficiency, although the evidence has been less conclusive.Although CARD9 deficiency is a genetic disorder, the invasive fungal infection can occur at any age. In fact, most of the reported cases have been in adults. Males and females are equally affected. | Symptoms of CARD9 Deficiency. The signs and symptoms (or manifestations) of CARD9 deficiency appear quite varied.As mentioned above, some persons develop infection only with Candida, while others develop infection only with dermatophytes, and others develop infection only with “black molds”.The following conditions can be caused by CARD9 deficiency:
• invasive fungal disease
• mycosis
• Candida infection (candidiasis)
• chronic mucocutaneous candidiasis (CMC)
• invasive candidiasis
• spontaneous central nervous system candidiasis (brain candidiasis)
• Candidal endophthalmitis (eye candidiasis)
• Candidal osteomyelitis (bone candidiasis)
• deep dermatophytosis
• chronic invasive dermatophyte infection (tinea profunda)
• pheohyphomycosis (black mold disease)Infections with Candida can be superficial and chronic (termed “chronic mucocutaneous candidiasis” or CMC). In distinction to the majority of other primary immunodeficiency disorders that cause CMC, CARD9 deficiency distinctly predisposes to invasive infection with Candida (termed “invasive candidiasis”), where the Candida can invade beyond the skin to go to other parts of the body. A very distinct manifestation is Candida involving the brain or the meninges (the protective layer of the brain, resulting in meningitis). In some cases of CARD9 deficiency where Candida infects the brain, the affected patients have radiologic brain imaging (for example, by CT or MRI) and are found to have mass(es) that resemble brain cancers; however, on biopsy, there is no cancer and only Candida infection is found. CARD9 deficiency can also lead to candida infection of the eye (leading to loss of vision) or of bone (leading to pain in the affected area). In all of these cases of invasive candidiasis, there is no risk factor for the fungus to reach these organs (the usual risk factors include things such as leukemia, chemotherapy, intravenous lines, all of which are absent in affected individuals).The invasive candidiasis may appear to be successfully treated with antifungal drugs that target Candida, although the infection may recur (relapse), when the antifungal drug is stopped; in some instances, it may recur even when the person is currently taking the right antifungal drug.Infections with dermatophytes and “black molds” tend be chronic and difficult to treat, responding partially or poorly to antifungal drugs. They can be disfiguring and they can also spread from the skin to lymph nodes and deep organs, including the brain.There has been a report of other fungal infections associated with CARD9 deficiency, although the evidence has been less conclusive.Although CARD9 deficiency is a genetic disorder, the invasive fungal infection can occur at any age. In fact, most of the reported cases have been in adults. Males and females are equally affected. | 197 | CARD9 Deficiency |
nord_197_2 | Causes of CARD9 Deficiency | CARD9 deficiency is caused by mutations in the CARD9 gene. This gene is responsible for production of the CARD9 protein which is normally expressed by only two specific types of white blood cells: neutrophils and monocytes (monocytes in the blood become macrophages once they go into tissues). In CARD9 deficiency, the CARD9 protein is abnormal, and both of these types of cells (neutrophils and monocytes/macrophages) have difficulty responding to fungus, which allows one of the above fungal diseases to develop.CARD9 deficiency is inherited in an autosomal recessive fashion, which means that both copies of the gene, one inherited from each parent, have to have a mutation in order for a person to develop this condition. If only one copy of the gene has a mutation, then the person is considered to be a “carrier”; to date, carriers are not thought to be at increased risk for fungal infections. However, the risk for two carrier parents to pass the gene mutation and, consequently, to have an affected child is 25 percent with each pregnancy. | Causes of CARD9 Deficiency. CARD9 deficiency is caused by mutations in the CARD9 gene. This gene is responsible for production of the CARD9 protein which is normally expressed by only two specific types of white blood cells: neutrophils and monocytes (monocytes in the blood become macrophages once they go into tissues). In CARD9 deficiency, the CARD9 protein is abnormal, and both of these types of cells (neutrophils and monocytes/macrophages) have difficulty responding to fungus, which allows one of the above fungal diseases to develop.CARD9 deficiency is inherited in an autosomal recessive fashion, which means that both copies of the gene, one inherited from each parent, have to have a mutation in order for a person to develop this condition. If only one copy of the gene has a mutation, then the person is considered to be a “carrier”; to date, carriers are not thought to be at increased risk for fungal infections. However, the risk for two carrier parents to pass the gene mutation and, consequently, to have an affected child is 25 percent with each pregnancy. | 197 | CARD9 Deficiency |
nord_197_3 | Affects of CARD9 Deficiency | CARD9 deficiency affects males and females in apparently equal numbers and has been reported all over the world. However, the exact frequency of this condition in the general population is unknown. It may be relatively more frequently found in some parts of the world because of a local “founder effect”. A “founder effect” occurs in history when a new population is established by a very small number of individuals; over generations, carriers may become more common, allowing two carriers to have children, who are then affected. | Affects of CARD9 Deficiency. CARD9 deficiency affects males and females in apparently equal numbers and has been reported all over the world. However, the exact frequency of this condition in the general population is unknown. It may be relatively more frequently found in some parts of the world because of a local “founder effect”. A “founder effect” occurs in history when a new population is established by a very small number of individuals; over generations, carriers may become more common, allowing two carriers to have children, who are then affected. | 197 | CARD9 Deficiency |
nord_197_4 | Related disorders of CARD9 Deficiency | The invasive fungal disease that is seen in CARD9 deficiency can also occur in other primary immunodeficiencies. For example, in chronic granulomatous disease (CGD), where the ability of white blood cells to produce a “respiratory burst” does not work properly, those patients can get infections with certain fungi. Also, patients with genetic mutations in the pathway that control the interleukin(IL)-12/Interferon-gamma pathway can also get invasive infections with certain molds.CARD9 deficiency can also predispose to chronic mucocutaneous candidiasis (CMC). CMC can be seen in many other primary immunodeficiencies, including those in which special subsets of lymphocytes (called T helper cells that produce IL-17 or Th17) do not function properly. | Related disorders of CARD9 Deficiency. The invasive fungal disease that is seen in CARD9 deficiency can also occur in other primary immunodeficiencies. For example, in chronic granulomatous disease (CGD), where the ability of white blood cells to produce a “respiratory burst” does not work properly, those patients can get infections with certain fungi. Also, patients with genetic mutations in the pathway that control the interleukin(IL)-12/Interferon-gamma pathway can also get invasive infections with certain molds.CARD9 deficiency can also predispose to chronic mucocutaneous candidiasis (CMC). CMC can be seen in many other primary immunodeficiencies, including those in which special subsets of lymphocytes (called T helper cells that produce IL-17 or Th17) do not function properly. | 197 | CARD9 Deficiency |
nord_197_5 | Diagnosis of CARD9 Deficiency | A diagnosis of CARD9 deficiency is suspected based upon a thorough clinical evaluation, a detailed patient history, particularly one in which there is invasive fungal infection without any of the typical risk factors listed above, and a variety of blood tests.A diagnosis of CARD9 deficiency can be confirmed through molecular genetic testing for mutations in the CARD9 gene. | Diagnosis of CARD9 Deficiency. A diagnosis of CARD9 deficiency is suspected based upon a thorough clinical evaluation, a detailed patient history, particularly one in which there is invasive fungal infection without any of the typical risk factors listed above, and a variety of blood tests.A diagnosis of CARD9 deficiency can be confirmed through molecular genetic testing for mutations in the CARD9 gene. | 197 | CARD9 Deficiency |
nord_197_6 | Therapies of CARD9 Deficiency | TreatmentAs CARD9 deficiency presents with invasive fungal disease, the treatment is directed toward the fungus causing the infection, with anti-fungal drugs. There are many different types of antifungal drugs, some exist for oral consumption and some require intravenous administration. The optimal duration of antifungal treatment has not been established. In some instances, prompt antifungal therapy is required until there has been a good clinical response, followed by maintenance (prophylactic) dosing (using lower doses) for a certain period of time.In some people, despite seemingly-appropriate antifungal therapy, the fungus recurs to cause disease. In those situations, an alternative antifungal drug (or combination of antifungal drugs) may be necessary. In some recurrences, surgical removal of the main fungal focus of infection may be necessary.Other treatment is symptomatic and supportive. | Therapies of CARD9 Deficiency. TreatmentAs CARD9 deficiency presents with invasive fungal disease, the treatment is directed toward the fungus causing the infection, with anti-fungal drugs. There are many different types of antifungal drugs, some exist for oral consumption and some require intravenous administration. The optimal duration of antifungal treatment has not been established. In some instances, prompt antifungal therapy is required until there has been a good clinical response, followed by maintenance (prophylactic) dosing (using lower doses) for a certain period of time.In some people, despite seemingly-appropriate antifungal therapy, the fungus recurs to cause disease. In those situations, an alternative antifungal drug (or combination of antifungal drugs) may be necessary. In some recurrences, surgical removal of the main fungal focus of infection may be necessary.Other treatment is symptomatic and supportive. | 197 | CARD9 Deficiency |
nord_198_0 | Overview of Cardiofaciocutaneous Syndrome | Summary Cardiofaciocutaneous (CFC) syndrome is one of the RASopathies and is a rare genetic disorder is typically characterized by unusually sparse, brittle, curly hair; relatively large head (relative macrocephaly); a prominent forehead and abnormal narrowing of the sides of the forehead (bi-temporal narrowing); intellectual disability; failure to thrive; heart defects that are present at birth (congenital) or acquired later; short stature and skin abnormalities. CFC syndrome is a dominant disorder often caused by de novo (new) mutations in one of four genes called BRAF, MAP2K1 (MEK1), MAP2K2 (MEK2), and KRAS. Some affected individuals do not have a mutation in one of these genes, suggesting that other genes are also associated with CFC syndrome. Introduction CFC syndrome was first described in 1986, based on the observation of eight unrelated patients who had intellectual disability and similar abnormalities in facial appearance, skin, hair, nails and heart. | Overview of Cardiofaciocutaneous Syndrome. Summary Cardiofaciocutaneous (CFC) syndrome is one of the RASopathies and is a rare genetic disorder is typically characterized by unusually sparse, brittle, curly hair; relatively large head (relative macrocephaly); a prominent forehead and abnormal narrowing of the sides of the forehead (bi-temporal narrowing); intellectual disability; failure to thrive; heart defects that are present at birth (congenital) or acquired later; short stature and skin abnormalities. CFC syndrome is a dominant disorder often caused by de novo (new) mutations in one of four genes called BRAF, MAP2K1 (MEK1), MAP2K2 (MEK2), and KRAS. Some affected individuals do not have a mutation in one of these genes, suggesting that other genes are also associated with CFC syndrome. Introduction CFC syndrome was first described in 1986, based on the observation of eight unrelated patients who had intellectual disability and similar abnormalities in facial appearance, skin, hair, nails and heart. | 198 | Cardiofaciocutaneous Syndrome |
nord_198_1 | Symptoms of Cardiofaciocutaneous Syndrome | Most individuals are initially referred because of feeding difficulties (poor suck) and failure to thrive. Later, cognitive developmental delay and other clinical manifestations may be observed.Facial AppearanceAffected individuals may have a relatively large head (macrocephaly) when compared to their height, a high forehead and abnormal narrowing of the sides of the forehead (bitemporal narrowing), causing the head to appear “box-like” in shape. The ears are abnormally angulated towards the back of the head and low set (posteriorly angulated) with the ear lobes occasionally having creasing. The nose is short, bulbous and with anteverted nostrils and a depressed bridge. There is also an underdevelopment (hypoplasia) of the ridges of the bone above the eyes (supraorbital ridges); widely spaced eyes (ocular hypertelorism); downslant of eyelid openings and drooping of one or both upperlids (ptosis).Skin, hair and nailsMost patients have some kind of ectodermal abnormality, either of skin, hair or nails. Children with CFC Syndrome usually have sparse, slow growing, fine or thick, curly scalp hair that is abnormally dry and brittle. They also have absent or sparse eyebrows and eyelashes. In some children, the nails are dystrophic, with broad flat nails, and/or fast growing. Skin involvement ranges from dry skin to the skin disease known as hyperkeratosis. Pigmented nevi are very distinct to CFC syndrome and help define the syndrome. Other typical skin manifestations include small hard bumps (keratosis pilaris), facial skin lesions around the eyebrows (ulerythema ophryogenes), and benign vascular tumors (infantile hemangiomas).HeartCongenital heart defects are present in over 75% of patients, with the most common heart defects being pulmonic stenosis and atrial or ventricular septal defects. There may also be hypertrophic cardiomyopathy (thickening of the heart muscle) and rhythm disturbances. These defects may be diagnosed at birth or later in life.Intellectual DisabilityThere is some form of cognitive or neurologic delay in nearly all patients with CFC syndrome. Most individuals fall in the range of moderate intellectual disability. Global developmental delay including gross motor and language delay is very common. Autism and other sensory behavioral issues have been reported in some individuals with CFC syndrome.OcularSymptoms affecting the eyes can effect both their appearance: ocular hypertelorism (increased distance between eyes), strabismus (uneven alignment of the eyes) and their function; involuntary eye movements, astigmatism, nearsightedness and/or farsightedness. Optic nerve hypoplasia, cortical blindness, and cataracts have been described. Although most individuals with CFC syndrome have ocular symptoms, some have a normal ophthalmologic examination.Feeding/gastrointestinalSevere feeding problems manifest as gastroesophageal reflux (GER), aspiration, vomiting, and affected individuals will avoid eating (avoidance of eating can lead to growth delays). Often individuals with gastrointestinal symptoms will require a feeding tube that may persist into early childhood. Other GI problems include dysmotility, intestinal malrotation (abnormal development of the intestine), hernia, and/or constipation. Some individuals have inflammation of the spleen and/or liver. Most children have malnutrition secondary to avoidance of eating. Fatty liver and anal stenosis (tightening of the anal sphincter) have also been reported.Endocrine AbnormalitiesAffected individuals can have growth hormone deficiency and early onset puberty.Growth DelaysGrowth may be normal with appropriate birth weight and length; however, weight and length may drop to below the fifth percentile during early infancy while head circumference remains within the normal range, which gives the appearance of macrocephaly.Additional AbnormalitiesAdditional abnormalities that are present in some but not all patients include short stature; webbed neck; abnormal shape of the thorax (pectus carinatum); joint hyperextension; hypotonia (reduced muscle tone), neoplasia (typically lymphyoblastic leukemia), especially during the first years of life; urogenital anomalies; seizures; and undescended testes (cryptorchidism) of boys. | Symptoms of Cardiofaciocutaneous Syndrome. Most individuals are initially referred because of feeding difficulties (poor suck) and failure to thrive. Later, cognitive developmental delay and other clinical manifestations may be observed.Facial AppearanceAffected individuals may have a relatively large head (macrocephaly) when compared to their height, a high forehead and abnormal narrowing of the sides of the forehead (bitemporal narrowing), causing the head to appear “box-like” in shape. The ears are abnormally angulated towards the back of the head and low set (posteriorly angulated) with the ear lobes occasionally having creasing. The nose is short, bulbous and with anteverted nostrils and a depressed bridge. There is also an underdevelopment (hypoplasia) of the ridges of the bone above the eyes (supraorbital ridges); widely spaced eyes (ocular hypertelorism); downslant of eyelid openings and drooping of one or both upperlids (ptosis).Skin, hair and nailsMost patients have some kind of ectodermal abnormality, either of skin, hair or nails. Children with CFC Syndrome usually have sparse, slow growing, fine or thick, curly scalp hair that is abnormally dry and brittle. They also have absent or sparse eyebrows and eyelashes. In some children, the nails are dystrophic, with broad flat nails, and/or fast growing. Skin involvement ranges from dry skin to the skin disease known as hyperkeratosis. Pigmented nevi are very distinct to CFC syndrome and help define the syndrome. Other typical skin manifestations include small hard bumps (keratosis pilaris), facial skin lesions around the eyebrows (ulerythema ophryogenes), and benign vascular tumors (infantile hemangiomas).HeartCongenital heart defects are present in over 75% of patients, with the most common heart defects being pulmonic stenosis and atrial or ventricular septal defects. There may also be hypertrophic cardiomyopathy (thickening of the heart muscle) and rhythm disturbances. These defects may be diagnosed at birth or later in life.Intellectual DisabilityThere is some form of cognitive or neurologic delay in nearly all patients with CFC syndrome. Most individuals fall in the range of moderate intellectual disability. Global developmental delay including gross motor and language delay is very common. Autism and other sensory behavioral issues have been reported in some individuals with CFC syndrome.OcularSymptoms affecting the eyes can effect both their appearance: ocular hypertelorism (increased distance between eyes), strabismus (uneven alignment of the eyes) and their function; involuntary eye movements, astigmatism, nearsightedness and/or farsightedness. Optic nerve hypoplasia, cortical blindness, and cataracts have been described. Although most individuals with CFC syndrome have ocular symptoms, some have a normal ophthalmologic examination.Feeding/gastrointestinalSevere feeding problems manifest as gastroesophageal reflux (GER), aspiration, vomiting, and affected individuals will avoid eating (avoidance of eating can lead to growth delays). Often individuals with gastrointestinal symptoms will require a feeding tube that may persist into early childhood. Other GI problems include dysmotility, intestinal malrotation (abnormal development of the intestine), hernia, and/or constipation. Some individuals have inflammation of the spleen and/or liver. Most children have malnutrition secondary to avoidance of eating. Fatty liver and anal stenosis (tightening of the anal sphincter) have also been reported.Endocrine AbnormalitiesAffected individuals can have growth hormone deficiency and early onset puberty.Growth DelaysGrowth may be normal with appropriate birth weight and length; however, weight and length may drop to below the fifth percentile during early infancy while head circumference remains within the normal range, which gives the appearance of macrocephaly.Additional AbnormalitiesAdditional abnormalities that are present in some but not all patients include short stature; webbed neck; abnormal shape of the thorax (pectus carinatum); joint hyperextension; hypotonia (reduced muscle tone), neoplasia (typically lymphyoblastic leukemia), especially during the first years of life; urogenital anomalies; seizures; and undescended testes (cryptorchidism) of boys. | 198 | Cardiofaciocutaneous Syndrome |
nord_198_2 | Causes of Cardiofaciocutaneous Syndrome | CFC syndrome is a dominant genetic disorder caused by an abnormality (mutation) in one of four genes: BRAF (~75%), MAP2K1 (MEK1), MAP2K2 (MEK2) (~25%) and KRAS (<2%). These genes are part of a pathway called Ras/Mitogen-activated protein kinase (MAPK) that is important in cell growth and cell division. Some affected individuals do not have a mutation in one of these genes, suggesting that other genes are also associated with CFC.Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene in CFC syndrome is usually the result of a sporadic gene abnormality (mutation) not inherited from either parent. Therefore, risk to the siblings of an affected individual is small. The theoretical risk of passing the abnormal gene from an affected person to their child is 50% for each pregnancy. However, there have been a few families documented in the literature of a mutated gene being passed through generations. | Causes of Cardiofaciocutaneous Syndrome. CFC syndrome is a dominant genetic disorder caused by an abnormality (mutation) in one of four genes: BRAF (~75%), MAP2K1 (MEK1), MAP2K2 (MEK2) (~25%) and KRAS (<2%). These genes are part of a pathway called Ras/Mitogen-activated protein kinase (MAPK) that is important in cell growth and cell division. Some affected individuals do not have a mutation in one of these genes, suggesting that other genes are also associated with CFC.Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene in CFC syndrome is usually the result of a sporadic gene abnormality (mutation) not inherited from either parent. Therefore, risk to the siblings of an affected individual is small. The theoretical risk of passing the abnormal gene from an affected person to their child is 50% for each pregnancy. However, there have been a few families documented in the literature of a mutated gene being passed through generations. | 198 | Cardiofaciocutaneous Syndrome |
nord_198_3 | Affects of Cardiofaciocutaneous Syndrome | Currently, there is no study providing an accurate estimate of the population prevalence of CFC syndrome. However one study in Japan, reported the incidence to be approximately 1 in 810,000. It is thought that males and females are affected equally. There are patients are reported from all continents. The number of affected individuals reported in the medical literature is now close to 400 and the total number worldwide is estimated to be more than this. This may be an underestimate, however, because mildly affected adults may go undiagnosed. | Affects of Cardiofaciocutaneous Syndrome. Currently, there is no study providing an accurate estimate of the population prevalence of CFC syndrome. However one study in Japan, reported the incidence to be approximately 1 in 810,000. It is thought that males and females are affected equally. There are patients are reported from all continents. The number of affected individuals reported in the medical literature is now close to 400 and the total number worldwide is estimated to be more than this. This may be an underestimate, however, because mildly affected adults may go undiagnosed. | 198 | Cardiofaciocutaneous Syndrome |
nord_198_4 | Related disorders of Cardiofaciocutaneous Syndrome | Symptoms of the following disorders may be similar to those of Cardiofaciocutaneous syndrome. Comparisons may be useful for a differential diagnosis:Noonan syndrome, a common genetic disorder occurring in approximately 1 in 2500 individuals, is another RASopathy. It is characterized by a distinctive facial appearance similar to that seen in children with CFC syndrome, such as webbing of the neck, short stature, characteristic abnormalities of the chest, congenital heart defects, and/or other abnormalities. In individuals with the disorder, malformations of the head and facial (craniofacial) area may include widely set eyes (ocular hypertelorism); downwardly slanting eyelid folds (palpebral fissures); drooping of the upper eyelids (ptosis) or unusually thick, “hooded” eyelids; a prominent upper lip; and/or low-set, prominent external ears (pinnae) that are abnormally rotated toward the back of the head (posteriorly angulated).Individuals with Noonan syndrome may also have wispy scalp hair during infancy that becomes unusually wooly or curly during later childhood. In addition, in most cases, affected individuals have a distinctive chest malformation characterized by abnormal protrusion of the upper (superior) portion of the bone forming the center of the chest (sternum) and/or abnormal depression of the lower (inferior) portion of the sternum (pectus carinatum and/or pectus excavatum, respectively).In many males with Noonan syndrome, one or both testes may have failed to descend into the scrotum (cryptorchidism). In addition, affected individuals often have congenital heart defects, particularly obstruction of the normal flow of blood from the lower right chamber (ventricle) of the heart to the lungs (valvar pulmonary stenosis). Additional abnormalities associated with Noonan syndrome may include low levels of circulating platelets in the blood (thrombocytopenia) and/or other blood clotting abnormalities (coagulation factor deficiencies), potentially causing abnormal bruising and bleeding.Noonan syndrome has autosomal dominant inheritance. Cases in which a positive family history has not been found are thought to represent new genetic changes (mutations) that occur randomly, with no apparent cause (sporadic). There are now more than 10 genes known to cause Noonan syndrome, with more likely to be reported in the coming years. (For more information on this disorder, choose “Noonan” as your search term in the Rare Disease Database.)Costello syndrome is another RASopathy related to Noonan syndrome and CFC syndrome. It is a very rare genetic disorder characterized by growth delay after birth (postnatal), leading to short stature; a distinctive facial appearance; excessive, loose skin on the neck, palms of the hands, fingers, and soles of the feet; development of benign (non-cancerous) growths (papillomata) around the mouth (perioral) and nostrils (nares); and/or intellectual disability.Characteristic craniofacial abnormalities may include an unusually large head (macrocephaly); a large, depressed nasal bridge; abnormally wide nostrils; low-set ears with large, thick lobes; and/or unusually thick lips.
Other physical features may include the development of dry, hardened, thickened skin on the palms of the hands and the soles of the feet (palmoplantar hyperkeratosis) and/or abnormally deep creases on the palms and soles. In addition, some affected individuals may also have congenital heart defects. Most cases of Costello syndrome occur sporadically, with no family history of the disorder. Such cases are thought to represent new dominant gene mutations. (For more information on this disorder, choose “Costello” as your search term in the Rare Disease Database.)There may be additional congenital disorders that are characterized by craniofacial malformations, hair abnormalities, skin changes, congenital heart defects, intellectual disability, and/or other symptoms and findings similar to those associated with CFC syndrome. (For information on such disorders, choose the exact disease name in question as your search term in the Rare Disease Database.) | Related disorders of Cardiofaciocutaneous Syndrome. Symptoms of the following disorders may be similar to those of Cardiofaciocutaneous syndrome. Comparisons may be useful for a differential diagnosis:Noonan syndrome, a common genetic disorder occurring in approximately 1 in 2500 individuals, is another RASopathy. It is characterized by a distinctive facial appearance similar to that seen in children with CFC syndrome, such as webbing of the neck, short stature, characteristic abnormalities of the chest, congenital heart defects, and/or other abnormalities. In individuals with the disorder, malformations of the head and facial (craniofacial) area may include widely set eyes (ocular hypertelorism); downwardly slanting eyelid folds (palpebral fissures); drooping of the upper eyelids (ptosis) or unusually thick, “hooded” eyelids; a prominent upper lip; and/or low-set, prominent external ears (pinnae) that are abnormally rotated toward the back of the head (posteriorly angulated).Individuals with Noonan syndrome may also have wispy scalp hair during infancy that becomes unusually wooly or curly during later childhood. In addition, in most cases, affected individuals have a distinctive chest malformation characterized by abnormal protrusion of the upper (superior) portion of the bone forming the center of the chest (sternum) and/or abnormal depression of the lower (inferior) portion of the sternum (pectus carinatum and/or pectus excavatum, respectively).In many males with Noonan syndrome, one or both testes may have failed to descend into the scrotum (cryptorchidism). In addition, affected individuals often have congenital heart defects, particularly obstruction of the normal flow of blood from the lower right chamber (ventricle) of the heart to the lungs (valvar pulmonary stenosis). Additional abnormalities associated with Noonan syndrome may include low levels of circulating platelets in the blood (thrombocytopenia) and/or other blood clotting abnormalities (coagulation factor deficiencies), potentially causing abnormal bruising and bleeding.Noonan syndrome has autosomal dominant inheritance. Cases in which a positive family history has not been found are thought to represent new genetic changes (mutations) that occur randomly, with no apparent cause (sporadic). There are now more than 10 genes known to cause Noonan syndrome, with more likely to be reported in the coming years. (For more information on this disorder, choose “Noonan” as your search term in the Rare Disease Database.)Costello syndrome is another RASopathy related to Noonan syndrome and CFC syndrome. It is a very rare genetic disorder characterized by growth delay after birth (postnatal), leading to short stature; a distinctive facial appearance; excessive, loose skin on the neck, palms of the hands, fingers, and soles of the feet; development of benign (non-cancerous) growths (papillomata) around the mouth (perioral) and nostrils (nares); and/or intellectual disability.Characteristic craniofacial abnormalities may include an unusually large head (macrocephaly); a large, depressed nasal bridge; abnormally wide nostrils; low-set ears with large, thick lobes; and/or unusually thick lips.
Other physical features may include the development of dry, hardened, thickened skin on the palms of the hands and the soles of the feet (palmoplantar hyperkeratosis) and/or abnormally deep creases on the palms and soles. In addition, some affected individuals may also have congenital heart defects. Most cases of Costello syndrome occur sporadically, with no family history of the disorder. Such cases are thought to represent new dominant gene mutations. (For more information on this disorder, choose “Costello” as your search term in the Rare Disease Database.)There may be additional congenital disorders that are characterized by craniofacial malformations, hair abnormalities, skin changes, congenital heart defects, intellectual disability, and/or other symptoms and findings similar to those associated with CFC syndrome. (For information on such disorders, choose the exact disease name in question as your search term in the Rare Disease Database.) | 198 | Cardiofaciocutaneous Syndrome |
nord_198_5 | Diagnosis of Cardiofaciocutaneous Syndrome | In most cases, CFC syndrome is diagnosed during infancy based upon a thorough clinical evaluation, characteristic physical findings, and specialized tests. Congenital heart defects that may occur in association with CFC syndrome (e.g., pulmonary stenosis and/or atrial septal defects) may be detected and/or confirmed by a thorough clinical examination and specialized tests that allow physicians to evaluate the structure and function of the heart.Clinical examination may include a physician's evaluation of heart and lung sounds through use of a stethoscope. For example, in mild asymptomatic cases of pulmonary stenosis, the condition may initially be detected through an abnormal heart murmur heard during such stethoscopic evaluation.Specialized cardiac tests may include x-ray studies, electrocardiography (EKG), echocardiography, and/or cardiac catheterization. X-ray studies may reveal abnormal enlargement of the heart (cardiomegaly) or malformation of certain heart structures. An EKG, which records the electrical activities of the heart muscle, may reveal abnormal electrical patterns. During an echocardiogram, sound waves are directed toward the heart, enabling physicians to study cardiac function and motion. During cardiac catheterization, a small hollow tube (catheter) is inserted into a large vein and threaded through the blood vessels leading to the heart. This procedure allows physicians to determine the rate of blood flow through the heart, measure the pressure within the heart, and/or thoroughly identify anatomical abnormalities.Physicians may also closely evaluate the respiratory (ventilatory) capabilities of affected individuals with pulmonary stenosis and/or other heart abnormalities since associated cardiac defects may result in inadequate blood supply to the lungs and breathlessness.Additional specialized tests may also be conducted to help identify and/or confirm the presence of other abnormalities that may occur in some cases of CFC syndrome. For example, according to the medical literature, computerized tomography (CT) scanning may help confirm the presence of hydrocephalus or, in some cases, degeneration of the outer layer of the brain (cortical atrophy) in some individuals with the disorder. During CT scanning, a computer and X-rays are used to create a film showing cross-sectional images of an organ's tissue structure. In addition, electroencephalography (EEG), which records the brain's electrical impulses, may reveal brain wave patterns that are characteristic of certain types of seizure activity. Examination with an instrument that visualizes the interior of the eye (ophthalmoscopy), other specialized imaging techniques, and/or other tests may also be used to diagnose and/or confirm certain eye abnormalities that may be associated with CFC syndrome.Molecular genetic testing is available for mutations in the four genes known to cause CFC syndrome. Testing can be done by using a multi-gene panel that screens all of the genes currently known to cause a RASopathy since there is a considerable overlap among them or whole exome sequencing can be considered.Clinical Testing and Work-Up
Individuals known to have or suspected to have CFC syndrome may have the following evaluations. a complete physical examination including measurement growth parameters; cardiac evaluation including echocardiogram and electrocardiogram; neurologic evaluation; MRI of the brain to detect any structural changes; electroencephalogram if seizures are suspected; full abdominal ultrasound examination to evaluate for renal and urogenital anomalies; psychomotor developmental evaluation; endocrine evaluation if growth delay is suspected; ophthalmologic examination; audiologic examination; nutrition and feeding evaluation, consider swallow study; and dermatologic evaluation. Consensus guidelines for the management of individuals with CFC were published in 2012 and should be referenced in the care of any patient with this diagnosis. | Diagnosis of Cardiofaciocutaneous Syndrome. In most cases, CFC syndrome is diagnosed during infancy based upon a thorough clinical evaluation, characteristic physical findings, and specialized tests. Congenital heart defects that may occur in association with CFC syndrome (e.g., pulmonary stenosis and/or atrial septal defects) may be detected and/or confirmed by a thorough clinical examination and specialized tests that allow physicians to evaluate the structure and function of the heart.Clinical examination may include a physician's evaluation of heart and lung sounds through use of a stethoscope. For example, in mild asymptomatic cases of pulmonary stenosis, the condition may initially be detected through an abnormal heart murmur heard during such stethoscopic evaluation.Specialized cardiac tests may include x-ray studies, electrocardiography (EKG), echocardiography, and/or cardiac catheterization. X-ray studies may reveal abnormal enlargement of the heart (cardiomegaly) or malformation of certain heart structures. An EKG, which records the electrical activities of the heart muscle, may reveal abnormal electrical patterns. During an echocardiogram, sound waves are directed toward the heart, enabling physicians to study cardiac function and motion. During cardiac catheterization, a small hollow tube (catheter) is inserted into a large vein and threaded through the blood vessels leading to the heart. This procedure allows physicians to determine the rate of blood flow through the heart, measure the pressure within the heart, and/or thoroughly identify anatomical abnormalities.Physicians may also closely evaluate the respiratory (ventilatory) capabilities of affected individuals with pulmonary stenosis and/or other heart abnormalities since associated cardiac defects may result in inadequate blood supply to the lungs and breathlessness.Additional specialized tests may also be conducted to help identify and/or confirm the presence of other abnormalities that may occur in some cases of CFC syndrome. For example, according to the medical literature, computerized tomography (CT) scanning may help confirm the presence of hydrocephalus or, in some cases, degeneration of the outer layer of the brain (cortical atrophy) in some individuals with the disorder. During CT scanning, a computer and X-rays are used to create a film showing cross-sectional images of an organ's tissue structure. In addition, electroencephalography (EEG), which records the brain's electrical impulses, may reveal brain wave patterns that are characteristic of certain types of seizure activity. Examination with an instrument that visualizes the interior of the eye (ophthalmoscopy), other specialized imaging techniques, and/or other tests may also be used to diagnose and/or confirm certain eye abnormalities that may be associated with CFC syndrome.Molecular genetic testing is available for mutations in the four genes known to cause CFC syndrome. Testing can be done by using a multi-gene panel that screens all of the genes currently known to cause a RASopathy since there is a considerable overlap among them or whole exome sequencing can be considered.Clinical Testing and Work-Up
Individuals known to have or suspected to have CFC syndrome may have the following evaluations. a complete physical examination including measurement growth parameters; cardiac evaluation including echocardiogram and electrocardiogram; neurologic evaluation; MRI of the brain to detect any structural changes; electroencephalogram if seizures are suspected; full abdominal ultrasound examination to evaluate for renal and urogenital anomalies; psychomotor developmental evaluation; endocrine evaluation if growth delay is suspected; ophthalmologic examination; audiologic examination; nutrition and feeding evaluation, consider swallow study; and dermatologic evaluation. Consensus guidelines for the management of individuals with CFC were published in 2012 and should be referenced in the care of any patient with this diagnosis. | 198 | Cardiofaciocutaneous Syndrome |
nord_198_6 | Therapies of Cardiofaciocutaneous Syndrome | Treatment
The treatment of CFC syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians; physicians who diagnose and treat skin disorders (dermatologists), heart abnormalities (cardiologists), eye disorders (ophthalmologists), and/or neurological abnormalities (neurologists); and/or other health care professionals may need to systematically and comprehensively plan an affected child's treatment.Specific therapies for CFC syndrome are symptomatic and supportive. In some individuals with congenital heart defects such as pulmonary stenosis and/or atrial septal defects, treatment with certain medications, surgical intervention, and/or other techniques may be necessary. In such cases, the surgical procedures performed will depend upon the location, severity, and/or combination of anatomical abnormalities and their associated symptoms.In individuals with CFC syndrome, respiratory infections should be treated promptly and vigorously. Because of the potentially increased risk of bacterial infection of the lining of the heart (endocarditis) and the heart valves, individuals with atrial septal defects may be given antibiotic drugs before any surgical procedure, including dental procedures such as tooth extractions.In affected individuals with hydrocephalus, shunts may be implanted to drain excess cerebrospinal fluid away from the brain, relieving pressure. In addition, in some cases, treatment with anticonvulsant drugs may help prevent, reduce, or control seizures.In individuals affected by certain ocular abnormalities, corrective glasses, contact lenses, and/or surgery may be used to help improve vision.Oftentimes, children who are failing to thrive will require a nasogastic or gastrostomy tube (feeding tubes). An increased caloric intake may also be beneficial in conjunction with increase fiber if the affected individual suffers from constipation.In addition, to help alleviate skin abnormalities, physicians may recommend certain lubricating lotions or ointments, such as petroleum jelly. Applying such lubricants may be particularly effective after bathing while the skin is moist. In affected individuals with hemangiomas, treatment may not be required in some cases. In other cases, physicians may recommend removal of hemangiomas, depending upon severity, location, the occurrence of associated bleeding, and/or other associated symptoms or difficulties (e.g., obstruction of vision due to location on an eyelid). Various removal techniques may be used (e.g., laser surgery, cryosurgery, plastic surgery).Early intervention may be beneficial in helping children with CFC syndrome reach their potential. Special services that may be of assistance may include special remedial education, speech therapy, occupational therapy, physical therapy, and/or other medical, social, and/or vocational services.Genetic counseling is recommended for affected individuals and their families. Other treatment for the disorder is symptomatic and supportive. | Therapies of Cardiofaciocutaneous Syndrome. Treatment
The treatment of CFC syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians; physicians who diagnose and treat skin disorders (dermatologists), heart abnormalities (cardiologists), eye disorders (ophthalmologists), and/or neurological abnormalities (neurologists); and/or other health care professionals may need to systematically and comprehensively plan an affected child's treatment.Specific therapies for CFC syndrome are symptomatic and supportive. In some individuals with congenital heart defects such as pulmonary stenosis and/or atrial septal defects, treatment with certain medications, surgical intervention, and/or other techniques may be necessary. In such cases, the surgical procedures performed will depend upon the location, severity, and/or combination of anatomical abnormalities and their associated symptoms.In individuals with CFC syndrome, respiratory infections should be treated promptly and vigorously. Because of the potentially increased risk of bacterial infection of the lining of the heart (endocarditis) and the heart valves, individuals with atrial septal defects may be given antibiotic drugs before any surgical procedure, including dental procedures such as tooth extractions.In affected individuals with hydrocephalus, shunts may be implanted to drain excess cerebrospinal fluid away from the brain, relieving pressure. In addition, in some cases, treatment with anticonvulsant drugs may help prevent, reduce, or control seizures.In individuals affected by certain ocular abnormalities, corrective glasses, contact lenses, and/or surgery may be used to help improve vision.Oftentimes, children who are failing to thrive will require a nasogastic or gastrostomy tube (feeding tubes). An increased caloric intake may also be beneficial in conjunction with increase fiber if the affected individual suffers from constipation.In addition, to help alleviate skin abnormalities, physicians may recommend certain lubricating lotions or ointments, such as petroleum jelly. Applying such lubricants may be particularly effective after bathing while the skin is moist. In affected individuals with hemangiomas, treatment may not be required in some cases. In other cases, physicians may recommend removal of hemangiomas, depending upon severity, location, the occurrence of associated bleeding, and/or other associated symptoms or difficulties (e.g., obstruction of vision due to location on an eyelid). Various removal techniques may be used (e.g., laser surgery, cryosurgery, plastic surgery).Early intervention may be beneficial in helping children with CFC syndrome reach their potential. Special services that may be of assistance may include special remedial education, speech therapy, occupational therapy, physical therapy, and/or other medical, social, and/or vocational services.Genetic counseling is recommended for affected individuals and their families. Other treatment for the disorder is symptomatic and supportive. | 198 | Cardiofaciocutaneous Syndrome |
nord_199_0 | Overview of Carney Complex | Carney complex is a rare genetic disorder characterized by multiple benign tumors (multiple neoplasia) most often affecting the heart, skin and endocrine system and abnormalities in skin coloring (pigment) resulting in a spotty appearance to the skin of affected areas. Benign tumors of connective tissue (myxomas) are common in individuals with Carney complex and, most often, are found in the heart where they can potentially cause serious, life-threatening complications including stroke, valvular obstruction or heart failure. A wide variety of endocrine abnormalities potentially can occur in Carney complex affecting a variety of glands. Additional tumors include myxomas affecting the skin and nerve sheath tumors (schwannomas). Skin pigment abnormalities include tiny flat (freckle-like) black or brown spots (multiple lentigines) and small, blue or bluish-black spots (blue nevi). The specific symptoms and severity of Carney complex can vary greatly from one person to another. In many cases, Carney complex is due to mutations of the PRKAR1A gene. The mutation can occur randomly for no apparent reason (i.e., new mutation) or be inherited as an autosomal dominant trait.Carney complex is a different disorder from Carney triad. Carney triad encompasses three types of tumors: a gastric stromal sarcoma; functioning extra-adrenal paragangliomas; and pulmonary chondromas. Although these two disorders are completely unrelated, both have sometimes been referred to as Carney syndrome, causing confusion. This report deals solely with Carney complex. | Overview of Carney Complex. Carney complex is a rare genetic disorder characterized by multiple benign tumors (multiple neoplasia) most often affecting the heart, skin and endocrine system and abnormalities in skin coloring (pigment) resulting in a spotty appearance to the skin of affected areas. Benign tumors of connective tissue (myxomas) are common in individuals with Carney complex and, most often, are found in the heart where they can potentially cause serious, life-threatening complications including stroke, valvular obstruction or heart failure. A wide variety of endocrine abnormalities potentially can occur in Carney complex affecting a variety of glands. Additional tumors include myxomas affecting the skin and nerve sheath tumors (schwannomas). Skin pigment abnormalities include tiny flat (freckle-like) black or brown spots (multiple lentigines) and small, blue or bluish-black spots (blue nevi). The specific symptoms and severity of Carney complex can vary greatly from one person to another. In many cases, Carney complex is due to mutations of the PRKAR1A gene. The mutation can occur randomly for no apparent reason (i.e., new mutation) or be inherited as an autosomal dominant trait.Carney complex is a different disorder from Carney triad. Carney triad encompasses three types of tumors: a gastric stromal sarcoma; functioning extra-adrenal paragangliomas; and pulmonary chondromas. Although these two disorders are completely unrelated, both have sometimes been referred to as Carney syndrome, causing confusion. This report deals solely with Carney complex. | 199 | Carney Complex |
nord_199_1 | Symptoms of Carney Complex | The symptoms and severity of Carney complex can vary greatly from one person to another, even among members of the same family. The disorder may be evident at birth, but the median age of diagnosis is 20. Many of the signs and symptoms of Carney complex become apparent during the teen-age years or during early adulthood.It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals or parents of affected children should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.The presenting sign of Carney complex is often numerous tiny (freckle-like) black or brown spots on the skin (multiple lentigines). Although these tiny, flat discolorations resemble freckles, they tend to be darker and usually range between 2 and 10 millimeters in size. Lentigines are most often found around the upper and lower lips (pink part), on the eyelids, the membrane lining the eyes and the inside of the eyelids (conjunctiva), the ears and the genital area. Lentigines can be apparent at birth. In most cases, lentigines increase in number around puberty. Lentigines tend to fade in the 40s.Another type of skin abnormality associated with Carney complex are blue nevi. Blue nevi are raised, small, blue or bluish-black spots on the skin. Less frequently, affected individuals may develop areas of light brown discoloration with irregular or jagged borders (café au lait spots) and white patches of skin due to loss of pigment (depigmented lesions).Individuals with Carney complex are prone to developing a type of tumor known as a myxoma. Myxomas are small benign tumors consisting of connective tissue. Myxomas can affect any area of the body except the hands and feet and, in Carney complex, are most commonly seen in the heart (cardiac myxomas). One myxoma or multiple myxomas may be present. Myxomas may develop in any or all of the chambers of the heart. 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 valves allow for blood to be pumped through the chambers. Blood travels from the right ventricle through the pulmonary artery to the lungs where it receives oxygen. The blood returns to the heart through pulmonary veins and enters the left ventricle. The left ventricle sends the now oxygen-filled blood into the main artery of the body (aorta).Cardiac myxomas can potentially cause serious life-threatening complications usually due to the obstruction of blood flow. Specific complications can include stroke due to blockage of an artery (embolism) in the brain by a piece of detached cardiac myxoma or the inability of the heart to pump blood to the rest of the body, causing fluid buildup in the heart, lungs and various body tissues (congestive heart failure). Complete blockage (occlusion) of a valvular opening potentially can cause sudden death. Additional heart abnormalities that may occur in individuals with Carney complex include palpitations, diastolic heart murmurs and “tumor plop”, which is a distinctive sound related to the movement of a tumor within the heart. Cardiac myxomas may also cause general, nonspecific symptoms including fatigue, fever, muscle pain (myalgia), difficulty breathing (dyspnea) and unintended weight loss.Less often, myxomas can be found in other areas of the body in addition to or instead of the heart. These areas include the eyelids, nipples and the external ear canal. Any area of the body can be affected except the hands and feet. Cutaneous myxomas may present as white, pink or flesh-colored papules or small nodules just under the surface of the skin. They generally do not cause any symptoms and can appear at any time from birth through the fourth decade. They are generally 1 cm or less in diameter. Myxomas may also occur in the oropharynx area, which encompasses the tongue, hard palate and the back wall of the throat (pharynx). In women, myxomas can also occur in the breasts after puberty. In addition, women may develop myxomas in the genital tract including the vagina, uterus and cervix. In rare cases, affected individuals may develop an osteochondromyxoma, a rare bone tumor predominantly affecting the nasal sinuses or the long bones of the arms and legs.Individuals with Carney complex can develop a wide variety of abnormalities affecting the endocrine system including the development of multiple benign tumors. The endocrine system is the network of glands that secrete hormones into the bloodstream where they travel to various areas of the body. These hormones regulate the chemical processes (metabolism) that influence the function of various organs and activities within the body. Hormones are involved in numerous vital processes including regulating heart rate, body temperature and blood pressure as well as cell differentiation and growth and also in modulation of several metabolic processes.The most common endocrine tumor associated with Carney complex is known as primary pigmented nodular adrenocortical disease (PPNAD). PPNAD affects approximately 25 percent of individuals with Carney complex. The condition is characterized by multiple tiny nodules affecting the adrenal glands. The adrenal glands are situated atop the kidneys and produce cortisol, which is a hormone that is involved in certain metabolic and cardiovascular processes and helps the body respond to stress. PPNAD is a rare disorder that predominantly occurs in individuals with Carney complex. Elevated cortisol levels due to PPNAD can cause a disorder known as Cushing’s syndrome.Cushing’s syndrome is a disorder that occurs because of abnormally high levels of cortisol in the body. The symptoms develop slowly over time. Affected children may experience weight gain and growth delays. Adults may experience progressive weight gain resulting in extra fat in the midsection, between the shoulder blades, around the neck and in the face, giving the face a rounded appearance. Additional symptoms include high blood pressure (hypertension), fatigue, purple or red stretch marks (striae) on the abdomen, excessive thirst, weakness of the muscles closest to the body (proximal muscle weakness) and psychological disturbances. Some affected women may experience disturbances of their menstrual cycles and a male pattern of hair growth (hirsutism). Some affected individuals may have progressive thinning and loss of protein of bones (osteoporosis) because of prolonged mild elevation of cortisol.Some individuals with Carney complex may have a benign tumor (adenoma) of the pituitary gland. The pituitary gland is a small gland located near the base of the skull that produces several hormones and releases them into the bloodstream as needed by the body. Infrequently, individuals with Carney complex can develop a condition known as acromegaly. Acromegaly occurs when a pituitary adenoma causes increased production of growth hormone. Symptoms include abnormal enlargement of the bones of the arms, legs and head. The bones in the jaws and in the front of the skull are typically most often affected. Consequently, affected individuals may exhibit abnormal enlargement of the hands, feet, jaws and face. Acromegaly may also cause thickening of the soft tissues of the body, particularly the heart and accelerated growth leading to tall stature. Acromegaly is a slowly progressive condition.Some individuals with Carney complex may have multiple tumors (nodules) affecting the thyroid. The thyroid is a butterfly-shaped gland at the base of the neck that secretes hormones that help to regulate growth and development in the body. In most cases, these nodules are benign nonfunctioning adenomas. Nonfunctioning means that the adenoma does not produce excess hormones. Some affected individuals may have papillary or follicular thyroid carcinoma. In rare cases, thyroid carcinoma has developed in individuals with a longstanding history of multiple thyroid nodules.In males, an endocrine tumor known as a large-cell calcifying Sertoli cell tumor (LCCSCT) may develop. This tumor is found in the testes as tiny areas of calcification and sometimes can be associated with early development of secondary sexual characteristics (precocious puberty). This tumor can potentially cause breast development in males (gynecomastia). LCCSCTs are almost always benign; only one case has ever been reported of malignant transformation. Approximately one-third of males with Carney complex have these tumors present when first diagnosed with the disorder, usually during the first decade of life. Virtually all adult males develop LCCSCTs at some point. Less frequently, two other testicular tumors can also occur in males with Carney complex, specifically Leydig cell tumors and pigmented nodular adrenocortical rest tumors. Leydig cell tumors potentially can become malignant. Pigmented nodular adrenocortical rest tumors are benign, but can cause Cushing’s syndrome.In some cases, testicular tumors can affect fertility due to replacement and obstruction of the tiny tubes in which sperm is formed (seminiferous tubules) and decreased sperm motility (oligoasthenospermia). The presence of these tumors can cause the testes to become abnormally large (macroorchidism) as well.Although not a frequent finding, some females with Carney complex have developed ovarian cysts. In approximately 10 percent of cases, individuals with Carney complex may develop a psammomatous melanotic schwannoma, which is a rare tumor of the peripheral nerve sheath. They can occur anywhere along the central and peripheral nervous system, but most often affect the gastrointestinal tract (including the esophagus) or the network of nerves adjacent to the spine (paraspinal sympathetic chain). Depending upon their location psammomatous melanotic schwannomas can cause pain or discomfort as well as damage to one or more nerves (radiculopathy). In rare cases, these tumors can become malignant. | Symptoms of Carney Complex. The symptoms and severity of Carney complex can vary greatly from one person to another, even among members of the same family. The disorder may be evident at birth, but the median age of diagnosis is 20. Many of the signs and symptoms of Carney complex become apparent during the teen-age years or during early adulthood.It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals or parents of affected children should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.The presenting sign of Carney complex is often numerous tiny (freckle-like) black or brown spots on the skin (multiple lentigines). Although these tiny, flat discolorations resemble freckles, they tend to be darker and usually range between 2 and 10 millimeters in size. Lentigines are most often found around the upper and lower lips (pink part), on the eyelids, the membrane lining the eyes and the inside of the eyelids (conjunctiva), the ears and the genital area. Lentigines can be apparent at birth. In most cases, lentigines increase in number around puberty. Lentigines tend to fade in the 40s.Another type of skin abnormality associated with Carney complex are blue nevi. Blue nevi are raised, small, blue or bluish-black spots on the skin. Less frequently, affected individuals may develop areas of light brown discoloration with irregular or jagged borders (café au lait spots) and white patches of skin due to loss of pigment (depigmented lesions).Individuals with Carney complex are prone to developing a type of tumor known as a myxoma. Myxomas are small benign tumors consisting of connective tissue. Myxomas can affect any area of the body except the hands and feet and, in Carney complex, are most commonly seen in the heart (cardiac myxomas). One myxoma or multiple myxomas may be present. Myxomas may develop in any or all of the chambers of the heart. 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 valves allow for blood to be pumped through the chambers. Blood travels from the right ventricle through the pulmonary artery to the lungs where it receives oxygen. The blood returns to the heart through pulmonary veins and enters the left ventricle. The left ventricle sends the now oxygen-filled blood into the main artery of the body (aorta).Cardiac myxomas can potentially cause serious life-threatening complications usually due to the obstruction of blood flow. Specific complications can include stroke due to blockage of an artery (embolism) in the brain by a piece of detached cardiac myxoma or the inability of the heart to pump blood to the rest of the body, causing fluid buildup in the heart, lungs and various body tissues (congestive heart failure). Complete blockage (occlusion) of a valvular opening potentially can cause sudden death. Additional heart abnormalities that may occur in individuals with Carney complex include palpitations, diastolic heart murmurs and “tumor plop”, which is a distinctive sound related to the movement of a tumor within the heart. Cardiac myxomas may also cause general, nonspecific symptoms including fatigue, fever, muscle pain (myalgia), difficulty breathing (dyspnea) and unintended weight loss.Less often, myxomas can be found in other areas of the body in addition to or instead of the heart. These areas include the eyelids, nipples and the external ear canal. Any area of the body can be affected except the hands and feet. Cutaneous myxomas may present as white, pink or flesh-colored papules or small nodules just under the surface of the skin. They generally do not cause any symptoms and can appear at any time from birth through the fourth decade. They are generally 1 cm or less in diameter. Myxomas may also occur in the oropharynx area, which encompasses the tongue, hard palate and the back wall of the throat (pharynx). In women, myxomas can also occur in the breasts after puberty. In addition, women may develop myxomas in the genital tract including the vagina, uterus and cervix. In rare cases, affected individuals may develop an osteochondromyxoma, a rare bone tumor predominantly affecting the nasal sinuses or the long bones of the arms and legs.Individuals with Carney complex can develop a wide variety of abnormalities affecting the endocrine system including the development of multiple benign tumors. The endocrine system is the network of glands that secrete hormones into the bloodstream where they travel to various areas of the body. These hormones regulate the chemical processes (metabolism) that influence the function of various organs and activities within the body. Hormones are involved in numerous vital processes including regulating heart rate, body temperature and blood pressure as well as cell differentiation and growth and also in modulation of several metabolic processes.The most common endocrine tumor associated with Carney complex is known as primary pigmented nodular adrenocortical disease (PPNAD). PPNAD affects approximately 25 percent of individuals with Carney complex. The condition is characterized by multiple tiny nodules affecting the adrenal glands. The adrenal glands are situated atop the kidneys and produce cortisol, which is a hormone that is involved in certain metabolic and cardiovascular processes and helps the body respond to stress. PPNAD is a rare disorder that predominantly occurs in individuals with Carney complex. Elevated cortisol levels due to PPNAD can cause a disorder known as Cushing’s syndrome.Cushing’s syndrome is a disorder that occurs because of abnormally high levels of cortisol in the body. The symptoms develop slowly over time. Affected children may experience weight gain and growth delays. Adults may experience progressive weight gain resulting in extra fat in the midsection, between the shoulder blades, around the neck and in the face, giving the face a rounded appearance. Additional symptoms include high blood pressure (hypertension), fatigue, purple or red stretch marks (striae) on the abdomen, excessive thirst, weakness of the muscles closest to the body (proximal muscle weakness) and psychological disturbances. Some affected women may experience disturbances of their menstrual cycles and a male pattern of hair growth (hirsutism). Some affected individuals may have progressive thinning and loss of protein of bones (osteoporosis) because of prolonged mild elevation of cortisol.Some individuals with Carney complex may have a benign tumor (adenoma) of the pituitary gland. The pituitary gland is a small gland located near the base of the skull that produces several hormones and releases them into the bloodstream as needed by the body. Infrequently, individuals with Carney complex can develop a condition known as acromegaly. Acromegaly occurs when a pituitary adenoma causes increased production of growth hormone. Symptoms include abnormal enlargement of the bones of the arms, legs and head. The bones in the jaws and in the front of the skull are typically most often affected. Consequently, affected individuals may exhibit abnormal enlargement of the hands, feet, jaws and face. Acromegaly may also cause thickening of the soft tissues of the body, particularly the heart and accelerated growth leading to tall stature. Acromegaly is a slowly progressive condition.Some individuals with Carney complex may have multiple tumors (nodules) affecting the thyroid. The thyroid is a butterfly-shaped gland at the base of the neck that secretes hormones that help to regulate growth and development in the body. In most cases, these nodules are benign nonfunctioning adenomas. Nonfunctioning means that the adenoma does not produce excess hormones. Some affected individuals may have papillary or follicular thyroid carcinoma. In rare cases, thyroid carcinoma has developed in individuals with a longstanding history of multiple thyroid nodules.In males, an endocrine tumor known as a large-cell calcifying Sertoli cell tumor (LCCSCT) may develop. This tumor is found in the testes as tiny areas of calcification and sometimes can be associated with early development of secondary sexual characteristics (precocious puberty). This tumor can potentially cause breast development in males (gynecomastia). LCCSCTs are almost always benign; only one case has ever been reported of malignant transformation. Approximately one-third of males with Carney complex have these tumors present when first diagnosed with the disorder, usually during the first decade of life. Virtually all adult males develop LCCSCTs at some point. Less frequently, two other testicular tumors can also occur in males with Carney complex, specifically Leydig cell tumors and pigmented nodular adrenocortical rest tumors. Leydig cell tumors potentially can become malignant. Pigmented nodular adrenocortical rest tumors are benign, but can cause Cushing’s syndrome.In some cases, testicular tumors can affect fertility due to replacement and obstruction of the tiny tubes in which sperm is formed (seminiferous tubules) and decreased sperm motility (oligoasthenospermia). The presence of these tumors can cause the testes to become abnormally large (macroorchidism) as well.Although not a frequent finding, some females with Carney complex have developed ovarian cysts. In approximately 10 percent of cases, individuals with Carney complex may develop a psammomatous melanotic schwannoma, which is a rare tumor of the peripheral nerve sheath. They can occur anywhere along the central and peripheral nervous system, but most often affect the gastrointestinal tract (including the esophagus) or the network of nerves adjacent to the spine (paraspinal sympathetic chain). Depending upon their location psammomatous melanotic schwannomas can cause pain or discomfort as well as damage to one or more nerves (radiculopathy). In rare cases, these tumors can become malignant. | 199 | Carney Complex |
nord_199_2 | Causes of Carney Complex | Some cases of Carney complex occur due to mutations of the PRKAR1A gene. This mutation may occur randomly for no apparent reason (i.e., new mutation) with no family history or be inherited as an autosomal dominant trait. The majority of cases of Carney complex have occurred in individuals with a family history of the disorder.Genetic diseases are determined by the combination of abnormal 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 percent for each pregnancy regardless of the sex of the resulting child.Some individuals with Carney complex do not have an identifiable mutation of the PRKAR1A gene. Researchers believe that additional, as yet unidentified, genes may cause the disorder in these cases (genetic heterogeneity). Investigators have determined that an as yet unidentified gene on the short arm (p) of chromosome 2 is involved in some cases of Carney complex. These cases are sometimes referred to as Carney complex type II. More research is necessary to determine the gene on this region of chromosome 2 that causes certain cases of Carney complex.Investigators have determined that the PRKAR1A gene is located on the long arm (q) of chromosome 17 (17q22-q24). 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 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 PRKAR1A gene is believed to be a tumor suppressor gene. A tumor suppressor is a gene that slows down cell division, repairs damage to the DNA of cells, and tells cells when to die, a normal process called apoptosis. The PRKAR1A gene creates (encodes) a protein known as protein kinase A (PKA) R1alpha regulatory subunit. A mutation of the PRKAR1A gene leads to increased PKA signaling in affected tissues. It is believed that PKA can suppress or stimulate cell growth and proliferation. However, the exact function of this protein and how mutations of the PRKAR1A gene ultimately lead to the symptoms of Carney complex are not fully understood. | Causes of Carney Complex. Some cases of Carney complex occur due to mutations of the PRKAR1A gene. This mutation may occur randomly for no apparent reason (i.e., new mutation) with no family history or be inherited as an autosomal dominant trait. The majority of cases of Carney complex have occurred in individuals with a family history of the disorder.Genetic diseases are determined by the combination of abnormal 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 percent for each pregnancy regardless of the sex of the resulting child.Some individuals with Carney complex do not have an identifiable mutation of the PRKAR1A gene. Researchers believe that additional, as yet unidentified, genes may cause the disorder in these cases (genetic heterogeneity). Investigators have determined that an as yet unidentified gene on the short arm (p) of chromosome 2 is involved in some cases of Carney complex. These cases are sometimes referred to as Carney complex type II. More research is necessary to determine the gene on this region of chromosome 2 that causes certain cases of Carney complex.Investigators have determined that the PRKAR1A gene is located on the long arm (q) of chromosome 17 (17q22-q24). 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 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 PRKAR1A gene is believed to be a tumor suppressor gene. A tumor suppressor is a gene that slows down cell division, repairs damage to the DNA of cells, and tells cells when to die, a normal process called apoptosis. The PRKAR1A gene creates (encodes) a protein known as protein kinase A (PKA) R1alpha regulatory subunit. A mutation of the PRKAR1A gene leads to increased PKA signaling in affected tissues. It is believed that PKA can suppress or stimulate cell growth and proliferation. However, the exact function of this protein and how mutations of the PRKAR1A gene ultimately lead to the symptoms of Carney complex are not fully understood. | 199 | Carney Complex |
nord_199_3 | Affects of Carney Complex | Carney complex affects males and females in equal numbers. Approximately 600 affected individuals have been reported since the disorder was first described in the medical literature in 1985. The disorder can present at any age, but the mean age at diagnosis is 20. | Affects of Carney Complex. Carney complex affects males and females in equal numbers. Approximately 600 affected individuals have been reported since the disorder was first described in the medical literature in 1985. The disorder can present at any age, but the mean age at diagnosis is 20. | 199 | Carney Complex |
nord_199_4 | Related disorders of Carney Complex | Symptoms of the following disorders can be similar to those of Carney complex. Comparisons may be useful for a differential diagnosis.Peutz-Jeghers syndrome is a rare, genetic gastrointestinal disorder characterized by the development of polyps on the mucous lining of the small intestines and dark discolorations on the skin and mucous membranes. Polyps can also be found in the stomach, large intestines and nasal passages. Common symptoms include nausea, vomiting, and abdominal pain that occurs because of a form of intestinal obstruction (intussusception). Additional symptoms include bleeding from the rectum and dark skin discolorations around the lips, eyes, anus, inside the cheeks, and on the arms. Severe intestinal bleeding can cause anemia and episodes of recurring, severe abdominal pain. Individuals with Peutz-Jeghers syndrome have an increased risk of developing certain types of cancer including tumors of the gastrointestinal tract, pancreas, cervix, ovaries and breast. The specific symptoms and severity of Peutz-Jeghers syndrome can vary greatly from one person to another. Peutz-Jeghers syndrome is inherited as an autosomal dominant trait and occurs due to mutations of a gene located on chromosome 19. (For more information on this disorder, choose “Peutz-Jeghers” as your search term in the Rare Disease Database.)Multiple endocrine neoplasia (MEN) type 1 is a rare genetic disorder in which benign (noncancerous) tumors arise from the cells of various glands of the endocrine system. As mentioned earlier, the endocrine system is the network of glands that secrete hormones into the bloodstream where they travel to various areas of the body. These hormones regulate the chemical processes (metabolism) that influence the function of various organs and activities within the body. Hormones are involved in numerous vital processes including regulating heart rate, body temperature and blood pressure as well as cell differentiation and growth and also in modulation of several metabolic processes. In individuals with MEN type 1, benign tumors develop in multiple endocrine glands, most often the parathyroid, pancreas and pituitary glands. These affected glands secrete excessive amounts of hormones into the bloodstream, which can result in a variety of symptoms. Some benign tumors associated with MEN type 1 can become malignant (cancerous). MEN type 1 can run in families or can occur as the result of a new gene mutation in the affected person. (For more information on this disorder, choose “multiple endocrine neoplasia” as your search term in the Rare Disease Database.)There are several disorders that may be associated with certain symptoms that are also found in individuals with Carney complex. Such disorders include PTEN hamartoma syndrome, Noonan syndrome, LEOPARD syndrome, Bannayan-Riley-Ruvalcaba syndrome, Watson syndrome, McCune-Albright syndrome, neurofibromatosis type I, neurofibromatosis type II, Beckwith-Wiedemann syndrome, and Li Fraumeni syndrome. Many symptoms of Carney complex can occur as isolated findings including primary pigmented nodular adrenocortical disease, isolated familial cardiac myxomas, isolated familial schwannomatosis and thyroid cancer. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | Related disorders of Carney Complex. Symptoms of the following disorders can be similar to those of Carney complex. Comparisons may be useful for a differential diagnosis.Peutz-Jeghers syndrome is a rare, genetic gastrointestinal disorder characterized by the development of polyps on the mucous lining of the small intestines and dark discolorations on the skin and mucous membranes. Polyps can also be found in the stomach, large intestines and nasal passages. Common symptoms include nausea, vomiting, and abdominal pain that occurs because of a form of intestinal obstruction (intussusception). Additional symptoms include bleeding from the rectum and dark skin discolorations around the lips, eyes, anus, inside the cheeks, and on the arms. Severe intestinal bleeding can cause anemia and episodes of recurring, severe abdominal pain. Individuals with Peutz-Jeghers syndrome have an increased risk of developing certain types of cancer including tumors of the gastrointestinal tract, pancreas, cervix, ovaries and breast. The specific symptoms and severity of Peutz-Jeghers syndrome can vary greatly from one person to another. Peutz-Jeghers syndrome is inherited as an autosomal dominant trait and occurs due to mutations of a gene located on chromosome 19. (For more information on this disorder, choose “Peutz-Jeghers” as your search term in the Rare Disease Database.)Multiple endocrine neoplasia (MEN) type 1 is a rare genetic disorder in which benign (noncancerous) tumors arise from the cells of various glands of the endocrine system. As mentioned earlier, the endocrine system is the network of glands that secrete hormones into the bloodstream where they travel to various areas of the body. These hormones regulate the chemical processes (metabolism) that influence the function of various organs and activities within the body. Hormones are involved in numerous vital processes including regulating heart rate, body temperature and blood pressure as well as cell differentiation and growth and also in modulation of several metabolic processes. In individuals with MEN type 1, benign tumors develop in multiple endocrine glands, most often the parathyroid, pancreas and pituitary glands. These affected glands secrete excessive amounts of hormones into the bloodstream, which can result in a variety of symptoms. Some benign tumors associated with MEN type 1 can become malignant (cancerous). MEN type 1 can run in families or can occur as the result of a new gene mutation in the affected person. (For more information on this disorder, choose “multiple endocrine neoplasia” as your search term in the Rare Disease Database.)There are several disorders that may be associated with certain symptoms that are also found in individuals with Carney complex. Such disorders include PTEN hamartoma syndrome, Noonan syndrome, LEOPARD syndrome, Bannayan-Riley-Ruvalcaba syndrome, Watson syndrome, McCune-Albright syndrome, neurofibromatosis type I, neurofibromatosis type II, Beckwith-Wiedemann syndrome, and Li Fraumeni syndrome. Many symptoms of Carney complex can occur as isolated findings including primary pigmented nodular adrenocortical disease, isolated familial cardiac myxomas, isolated familial schwannomatosis and thyroid cancer. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | 199 | Carney Complex |
nord_199_5 | Diagnosis of Carney Complex | A diagnosis of Carney complex is made based upon a detailed patient history, a thorough clinical evaluation, a variety of specialized tests and identification of characteristic symptoms. According to the medical literature, identification of two or more of the following symptoms in typical fashion is indicative of Carney complex: cardiac myxoma: skin myxoma; lentiginosis; multiple blue nevi; primary pigmented nodular adrenocortical disease (PPNAD); testicular tumors; acromegaly; thyroid tumors, melanotic schwannoma; or an osteochondromyxoma.Tests that may performed to help obtain a diagnosis of Carney complex include surgical removal and microscopic study of affected skin (skin biopsy), urine analysis to detect elevated levels of cortisol (indicative of Cushing's disease), an echocardiogram to detect the presence of cardiac myxomas, and blood tests to detect abnormal high levels of certain hormones such as insulin-like growth factor, cortisol and prolactin due to the presence of endocrine tumors.A diagnosis of Carney complex can be confirmed in some cases through molecular genetic testing, which can reveal the characteristic mutation of the PRKAR1A gene that causes the disorder in many cases. Molecular genetic testing is available on a clinical basis. | Diagnosis of Carney Complex. A diagnosis of Carney complex is made based upon a detailed patient history, a thorough clinical evaluation, a variety of specialized tests and identification of characteristic symptoms. According to the medical literature, identification of two or more of the following symptoms in typical fashion is indicative of Carney complex: cardiac myxoma: skin myxoma; lentiginosis; multiple blue nevi; primary pigmented nodular adrenocortical disease (PPNAD); testicular tumors; acromegaly; thyroid tumors, melanotic schwannoma; or an osteochondromyxoma.Tests that may performed to help obtain a diagnosis of Carney complex include surgical removal and microscopic study of affected skin (skin biopsy), urine analysis to detect elevated levels of cortisol (indicative of Cushing's disease), an echocardiogram to detect the presence of cardiac myxomas, and blood tests to detect abnormal high levels of certain hormones such as insulin-like growth factor, cortisol and prolactin due to the presence of endocrine tumors.A diagnosis of Carney complex can be confirmed in some cases through molecular genetic testing, which can reveal the characteristic mutation of the PRKAR1A gene that causes the disorder in many cases. Molecular genetic testing is available on a clinical basis. | 199 | Carney Complex |
nord_199_6 | Therapies of Carney Complex | TreatmentThe treatment of Carney complex is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, cardiologists, cardiothoracic surgeons, endocrinologists, dermatologists and other healthcare professionals may need to systematically and comprehensively plan an affected child's treatment.Affected individuals should receive regular screening for the various potential symptoms associated with Carney complex. No specific guidelines have been agreed upon in the medical literature, but most sources recommend yearly screening for cardiac myxoma.The specific therapeutic procedures and interventions for individuals with Carney complex will vary, depending upon numerous factors including the specific symptoms present, the extent of the disorder, an individual's age and overall health, tolerance of certain medications or procedures, personal preference and other factors. Decisions concerning the use of particular therapeutic interventions should be made by physicians and other members of the healthcare team in careful consultation with the patient and/or parents based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.Cardiac myxomas require open-heart surgical removal. Despite surgery, cardiac myxomas can recur. Cutaneous and mammary myxomas also require surgical removal. Surgical removal of the adrenal glands (adrenalectomy) may be required in individuals who develop Cushing's syndrome.A pituitary adenoma may be treated by transsphenoidal surgery; a procedure in which all or part of a pituitary tumor is removed. In some cases, surgery results in a rapid therapeutic response, and lowering growth hormone levels.Although rare, cancerous tumors may occur in Carney complex including thyroid carcinoma and malignant psammomatous melanotic schwannoma. Surgical removal of the primary tumor and any metastatic lesions is necessary. Individuals who have their thyroid removed will require lifelong supplementation of the hormones normally produced by the thyroid.Surgical removal of one or both testes (orchiectomy) may be recommended to avoid or cope with the adverse effects (e.g., gynecomastia) of excessive hormone production that can occur in males with LCCSCT. However, because these tumors are benign, some physicians prefer surgery that spares fertility. In some cases, surgery that spares the testicles combined with strict monitoring of growth and puberty milestones has been performed. The administration of antiestrogen drugs may be necessary in the case of recurrence. Leydig cell tumors, because of the potential of malignant transformation, are usually treated by orchiectomy.Genetic counseling should be offered to affected individuals and their families. Other treatment is symptomatic and supportive. | Therapies of Carney Complex. TreatmentThe treatment of Carney complex is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, cardiologists, cardiothoracic surgeons, endocrinologists, dermatologists and other healthcare professionals may need to systematically and comprehensively plan an affected child's treatment.Affected individuals should receive regular screening for the various potential symptoms associated with Carney complex. No specific guidelines have been agreed upon in the medical literature, but most sources recommend yearly screening for cardiac myxoma.The specific therapeutic procedures and interventions for individuals with Carney complex will vary, depending upon numerous factors including the specific symptoms present, the extent of the disorder, an individual's age and overall health, tolerance of certain medications or procedures, personal preference and other factors. Decisions concerning the use of particular therapeutic interventions should be made by physicians and other members of the healthcare team in careful consultation with the patient and/or parents based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.Cardiac myxomas require open-heart surgical removal. Despite surgery, cardiac myxomas can recur. Cutaneous and mammary myxomas also require surgical removal. Surgical removal of the adrenal glands (adrenalectomy) may be required in individuals who develop Cushing's syndrome.A pituitary adenoma may be treated by transsphenoidal surgery; a procedure in which all or part of a pituitary tumor is removed. In some cases, surgery results in a rapid therapeutic response, and lowering growth hormone levels.Although rare, cancerous tumors may occur in Carney complex including thyroid carcinoma and malignant psammomatous melanotic schwannoma. Surgical removal of the primary tumor and any metastatic lesions is necessary. Individuals who have their thyroid removed will require lifelong supplementation of the hormones normally produced by the thyroid.Surgical removal of one or both testes (orchiectomy) may be recommended to avoid or cope with the adverse effects (e.g., gynecomastia) of excessive hormone production that can occur in males with LCCSCT. However, because these tumors are benign, some physicians prefer surgery that spares fertility. In some cases, surgery that spares the testicles combined with strict monitoring of growth and puberty milestones has been performed. The administration of antiestrogen drugs may be necessary in the case of recurrence. Leydig cell tumors, because of the potential of malignant transformation, are usually treated by orchiectomy.Genetic counseling should be offered to affected individuals and their families. Other treatment is symptomatic and supportive. | 199 | Carney Complex |
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