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Overview of Mesenchymal Chondrosarcoma
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Mesenchymal chondrosarcoma is an extremely rare, often aggressive form of cancer. It is an uncommon type of chondrosarcoma. Conventional chondrosarcoma is a form of bone cancer that arises from cartilage cells. Cartilage is the specialized tissue that serves as a buffer or cushion at joints. Most of the skeleton of an embryo consists of cartilage, which is slowly converted into bone. Approximately two-thirds of cases of mesenchymal chondrosarcoma affect the bones, especially the spine, ribs or jaws. The remaining cases occur in areas of the body other than bone (extraskeletal, that is, occurring in soft tissues like muscle and fat). Unlike conventional chondrosarcomas, mesenchymal chondrosarcomas occur with greater frequency in young adults. This form of cancer often spreads (metastasizes) to other areas of the body and can cause life-threatening complications.
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Overview of Mesenchymal Chondrosarcoma. Mesenchymal chondrosarcoma is an extremely rare, often aggressive form of cancer. It is an uncommon type of chondrosarcoma. Conventional chondrosarcoma is a form of bone cancer that arises from cartilage cells. Cartilage is the specialized tissue that serves as a buffer or cushion at joints. Most of the skeleton of an embryo consists of cartilage, which is slowly converted into bone. Approximately two-thirds of cases of mesenchymal chondrosarcoma affect the bones, especially the spine, ribs or jaws. The remaining cases occur in areas of the body other than bone (extraskeletal, that is, occurring in soft tissues like muscle and fat). Unlike conventional chondrosarcomas, mesenchymal chondrosarcomas occur with greater frequency in young adults. This form of cancer often spreads (metastasizes) to other areas of the body and can cause life-threatening complications.
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Symptoms of Mesenchymal Chondrosarcoma
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The symptoms of mesenchymal chondrosarcoma may vary depending upon the exact location and progression of the tumor. Most mesenchymal chondrosarcomas arise in the bones of the jaw, spine or the ribs. However, the tumor can arise almost anywhere within the body. The arms and legs are also frequent sites of tumor development, especially the main bone of the thigh (femur). Approximately one-third of cases occur outside of bone, appearing as soft tissue masses and can affect the muscle or central nervous systemThe specific symptoms associated with mesenchymal chondrosarcoma may be vague and nonspecific. Many individuals may develop pain and swelling in the affected area. Such vague symptoms can be present for a long time before a diagnosis is made. If a tumor grows large enough it can compress nearby structures and cause additional symptoms. For example, a tumor that compresses the spinal cord can cause paralysis, while a mesenchymal chondrosarcoma in the eye socket (orbit) can cause pain, swelling, visual disturbances and protrusion of the eyeball (exophthalmos).Mesenchymal chondrosarcomas are an aggressive form of cancer that can spread (metastasize) to other areas of the body, especially the lungs, liver, lymph nodes and other bones and may cause life-threatening complications.
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Symptoms of Mesenchymal Chondrosarcoma. The symptoms of mesenchymal chondrosarcoma may vary depending upon the exact location and progression of the tumor. Most mesenchymal chondrosarcomas arise in the bones of the jaw, spine or the ribs. However, the tumor can arise almost anywhere within the body. The arms and legs are also frequent sites of tumor development, especially the main bone of the thigh (femur). Approximately one-third of cases occur outside of bone, appearing as soft tissue masses and can affect the muscle or central nervous systemThe specific symptoms associated with mesenchymal chondrosarcoma may be vague and nonspecific. Many individuals may develop pain and swelling in the affected area. Such vague symptoms can be present for a long time before a diagnosis is made. If a tumor grows large enough it can compress nearby structures and cause additional symptoms. For example, a tumor that compresses the spinal cord can cause paralysis, while a mesenchymal chondrosarcoma in the eye socket (orbit) can cause pain, swelling, visual disturbances and protrusion of the eyeball (exophthalmos).Mesenchymal chondrosarcomas are an aggressive form of cancer that can spread (metastasize) to other areas of the body, especially the lungs, liver, lymph nodes and other bones and may cause life-threatening complications.
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Causes of Mesenchymal Chondrosarcoma
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The exact cause of mesenchymal chondrosarcoma is unknown. Investigators are conducting ongoing basic research to learn more about the many factors that may result in cancer. No identifiable risk factors for the development of mesenchymal chondrosarcoma have been discovered.In individuals with cancer, including mesenchymal chondrosarcoma, malignancies may develop due to abnormal changes in the structure and orientation of certain cells known as oncogenes or tumor suppressor genes. Oncogenes control cell growth; tumor suppressor genes control cell division and ensure that cells die at the proper time. Current research has shown that abnormalities of DNA (deoxyribonucleic acid), which is the carrier of the body's genetic code, are the underlying basis of cellular malignant transformation. The characteristic DNA change in mesenchymal chondrosarcoma is the deletion of a part of chromosome 8 that ends up linking to DNA genes together in a new way. The genes are termed HEY1 and NCOA2. These abnormal genetic changes appear to occur spontaneously for unknown reasons. Mesenchymal chondrosarcomas are thought to arise from early, immature cartilage cells called chondroblasts. Chondroblasts eventually develop into chondrocytes, the main cell that makes up cartilage.
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Causes of Mesenchymal Chondrosarcoma. The exact cause of mesenchymal chondrosarcoma is unknown. Investigators are conducting ongoing basic research to learn more about the many factors that may result in cancer. No identifiable risk factors for the development of mesenchymal chondrosarcoma have been discovered.In individuals with cancer, including mesenchymal chondrosarcoma, malignancies may develop due to abnormal changes in the structure and orientation of certain cells known as oncogenes or tumor suppressor genes. Oncogenes control cell growth; tumor suppressor genes control cell division and ensure that cells die at the proper time. Current research has shown that abnormalities of DNA (deoxyribonucleic acid), which is the carrier of the body's genetic code, are the underlying basis of cellular malignant transformation. The characteristic DNA change in mesenchymal chondrosarcoma is the deletion of a part of chromosome 8 that ends up linking to DNA genes together in a new way. The genes are termed HEY1 and NCOA2. These abnormal genetic changes appear to occur spontaneously for unknown reasons. Mesenchymal chondrosarcomas are thought to arise from early, immature cartilage cells called chondroblasts. Chondroblasts eventually develop into chondrocytes, the main cell that makes up cartilage.
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Affects of Mesenchymal Chondrosarcoma
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Mesenchymal chondrosarcoma was first described in the medical literature in 1959. It is an extremely rare form of cancer; fewer than 800 cancers have been reported in the medical literature. This tumor is most common in children and young adults (aged 10-30), but can affect individuals of any age including young children and older adults. Females are affected slightly more often than males. Mesenchymal chondrosarcoma is more likely to occur outside the bone in young adults or children and to affect bone in older adults. Mesenchymal chondrosarcomas account for approximately 5-10 percent of all cases of chondrosarcoma.
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Affects of Mesenchymal Chondrosarcoma. Mesenchymal chondrosarcoma was first described in the medical literature in 1959. It is an extremely rare form of cancer; fewer than 800 cancers have been reported in the medical literature. This tumor is most common in children and young adults (aged 10-30), but can affect individuals of any age including young children and older adults. Females are affected slightly more often than males. Mesenchymal chondrosarcoma is more likely to occur outside the bone in young adults or children and to affect bone in older adults. Mesenchymal chondrosarcomas account for approximately 5-10 percent of all cases of chondrosarcoma.
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Related disorders of Mesenchymal Chondrosarcoma
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Symptoms of the following disorders can be similar to those of mesenchymal chondrosarcoma. Comparisons to other sarcomas of bone or soft tissue may be useful to understand the place of this diagnosis better.Extraskeletal myxoid chondrosarcoma is rather different from mesenchymal chondrosarcoma. Extraskeletal myxoid chondrosarcoma is a sarcoma arising in soft tissue with relatively slow growth and frequent local recurrence as well as innumerable metastatic sites in the lungs, a diagnosis that is usually less chemotherapy sensitive than mesenchymal chondrosarcoma.Ewing sarcoma is a rare bone tumor that occurs most often in adolescents. It may also arise outside of the bone in soft tissue (extraosseous Ewing sarcoma). Ewing sarcoma is related to another type of tumor known as primitive neuroectodermal tumor (PNET). Researchers have learned that both of these tumors arise from the same primitive cell and now refer to these tumors as the Ewing family of tumors (EFT). This general term encompasses Ewing's sarcoma of bone, extraosseous Ewing's sarcoma, primitive neuroectodermal tumor, and Askin tumor (a tumor of the chest wall). Ewing sarcoma of bone accounts for the majority of the tumors in this family. Ewing sarcoma of bone most often affects the long bone of the legs (femur) and flat bones such as those found in the pelvis and chest well. Ewing sarcoma is an aggressive cancer that may spread (metastasize) to the lungs, other bones, and bone marrow potentially causing life-threatening complications. The exact cause of these tumors is unknown. (For more information on this disorder, choose “Ewing sarcoma” as your search term in the Rare Disease Database.)Osteosarcoma is a tumor affecting the bones. It is the most common form of bone cancer. Approximately 60 percent of cases occur in children and adolescents during the second decade of life. Osteosarcomas affect males twice as often as females. The bones most commonly affected are the long bones of the arms and legs. Symptoms may vary depending upon the location and extent of the disease. Pain, swelling, tenderness and eventually the formation of a lump may occur in the affected area. General symptoms may include fever, weight loss, anemia, and lack of energy. Osteosarcomas may weaken the surrounding bone resulting in fractures. Osteosarcomas may spread (metastasize) to other areas of the body. The exact cause of osteosarcoma is unknown. (For more information on this disorder, choose “osteosarcoma” as your search term in the Rare Disease Database.)Additional tumors must also be differentiated from mesenchymal chondrosarcoma including osteochondromas, primary tumors of bone. (For more information on these tumors, choose the specific tumor name as your search term in the Rare Disease Database.)
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Related disorders of Mesenchymal Chondrosarcoma. Symptoms of the following disorders can be similar to those of mesenchymal chondrosarcoma. Comparisons to other sarcomas of bone or soft tissue may be useful to understand the place of this diagnosis better.Extraskeletal myxoid chondrosarcoma is rather different from mesenchymal chondrosarcoma. Extraskeletal myxoid chondrosarcoma is a sarcoma arising in soft tissue with relatively slow growth and frequent local recurrence as well as innumerable metastatic sites in the lungs, a diagnosis that is usually less chemotherapy sensitive than mesenchymal chondrosarcoma.Ewing sarcoma is a rare bone tumor that occurs most often in adolescents. It may also arise outside of the bone in soft tissue (extraosseous Ewing sarcoma). Ewing sarcoma is related to another type of tumor known as primitive neuroectodermal tumor (PNET). Researchers have learned that both of these tumors arise from the same primitive cell and now refer to these tumors as the Ewing family of tumors (EFT). This general term encompasses Ewing's sarcoma of bone, extraosseous Ewing's sarcoma, primitive neuroectodermal tumor, and Askin tumor (a tumor of the chest wall). Ewing sarcoma of bone accounts for the majority of the tumors in this family. Ewing sarcoma of bone most often affects the long bone of the legs (femur) and flat bones such as those found in the pelvis and chest well. Ewing sarcoma is an aggressive cancer that may spread (metastasize) to the lungs, other bones, and bone marrow potentially causing life-threatening complications. The exact cause of these tumors is unknown. (For more information on this disorder, choose “Ewing sarcoma” as your search term in the Rare Disease Database.)Osteosarcoma is a tumor affecting the bones. It is the most common form of bone cancer. Approximately 60 percent of cases occur in children and adolescents during the second decade of life. Osteosarcomas affect males twice as often as females. The bones most commonly affected are the long bones of the arms and legs. Symptoms may vary depending upon the location and extent of the disease. Pain, swelling, tenderness and eventually the formation of a lump may occur in the affected area. General symptoms may include fever, weight loss, anemia, and lack of energy. Osteosarcomas may weaken the surrounding bone resulting in fractures. Osteosarcomas may spread (metastasize) to other areas of the body. The exact cause of osteosarcoma is unknown. (For more information on this disorder, choose “osteosarcoma” as your search term in the Rare Disease Database.)Additional tumors must also be differentiated from mesenchymal chondrosarcoma including osteochondromas, primary tumors of bone. (For more information on these tumors, choose the specific tumor name as your search term in the Rare Disease Database.)
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Diagnosis of Mesenchymal Chondrosarcoma
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A diagnosis of mesenchymal chondrosarcoma may be difficult. Some individuals may seek attention because of pain and swelling. A diagnosis may be made based upon a thorough clinical examination, a detailed patient history and a variety of specialized tests including x-ray studies and a procedure in which a small sample of tissue is removed and studied under a microscope (biopsy). A biopsy of a tumor or mass determines what type of cancer is present by identifying the cell type that makes up the tumor. In individuals suspected of a mesenchymal chondrosarcoma an open biopsy or a needle-guided biopsy is recommended.Specialized imaging techniques may be used to help evaluate the size, placement, and extension of the tumor and to serve as an aid for future surgical procedures, among individuals with mesenchymal chondrosarcoma. Such imaging techniques may include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. Because of the risk of a mesenchymal chondrosarcoma spreading the lungs, a CT scan of the lungs is often performed. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. Bone scans, tests that can detect areas of increased or decreased bone activity, may be performed to determine whether a mesenchymal chondrosarcoma has spread to affect other bones.
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Diagnosis of Mesenchymal Chondrosarcoma. A diagnosis of mesenchymal chondrosarcoma may be difficult. Some individuals may seek attention because of pain and swelling. A diagnosis may be made based upon a thorough clinical examination, a detailed patient history and a variety of specialized tests including x-ray studies and a procedure in which a small sample of tissue is removed and studied under a microscope (biopsy). A biopsy of a tumor or mass determines what type of cancer is present by identifying the cell type that makes up the tumor. In individuals suspected of a mesenchymal chondrosarcoma an open biopsy or a needle-guided biopsy is recommended.Specialized imaging techniques may be used to help evaluate the size, placement, and extension of the tumor and to serve as an aid for future surgical procedures, among individuals with mesenchymal chondrosarcoma. Such imaging techniques may include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. Because of the risk of a mesenchymal chondrosarcoma spreading the lungs, a CT scan of the lungs is often performed. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. Bone scans, tests that can detect areas of increased or decreased bone activity, may be performed to determine whether a mesenchymal chondrosarcoma has spread to affect other bones.
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Therapies of Mesenchymal Chondrosarcoma
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TreatmentThere are implications for future treatment even in terms of placement of a biopsy incision. As a result, treatment by a multidisciplinary group of health professionals even at the time of suspicion of a bone sarcoma his highly recommended to optimize treatment. The therapeutic management of individuals with a mesenchymal chondrosarcoma typically requires the coordinated efforts of a team of medical professionals, such as physicians who specialize in the diagnosis and treatment of cancer (pediatric or medical oncologists), specialists in the use of radiation to treat cancer (radiation oncologists), surgeons, oncology nurses, and other specialists.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as primary tumor location, extent of the primary tumor (stage); whether the tumor has spread to distant sites; an individual's age and general health; and/or other elements. Decisions concerning the use of particular interventions should be made by physicians and other members of the health care team in careful consultation with the patient, based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks; patient preference; and other appropriate factors.After a carefully placed biopsy to determine the diagnosis, the primary initial form of treatment for a mesenchymal chondrosarcoma is usually surgery or chemotherapy. Often times chemotherapy will be given first, followed by surgical removal of the entire tumor and any affected tissue. Radiation may or may not be employed in the treatment of mesenchymal chondrosarcoma, depending on how large the tumor is and where it is situated. Many medical oncologists advocate a chemotherapy treatment plan similar to that of a related bone cancer called Ewing's sarcoma. Radiation therapy after surgery is also typically standard practice for larger tumors.Because mesenchymal chondrosarcomas can recur even after optimal therapy, individuals should be examined routinely after surgery (follow-up care). The specifics of follow-up care are different for each person. In some cases, the return of cancer (relapse) has not occurred until many years after treatment.
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Therapies of Mesenchymal Chondrosarcoma. TreatmentThere are implications for future treatment even in terms of placement of a biopsy incision. As a result, treatment by a multidisciplinary group of health professionals even at the time of suspicion of a bone sarcoma his highly recommended to optimize treatment. The therapeutic management of individuals with a mesenchymal chondrosarcoma typically requires the coordinated efforts of a team of medical professionals, such as physicians who specialize in the diagnosis and treatment of cancer (pediatric or medical oncologists), specialists in the use of radiation to treat cancer (radiation oncologists), surgeons, oncology nurses, and other specialists.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as primary tumor location, extent of the primary tumor (stage); whether the tumor has spread to distant sites; an individual's age and general health; and/or other elements. Decisions concerning the use of particular interventions should be made by physicians and other members of the health care team in careful consultation with the patient, based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks; patient preference; and other appropriate factors.After a carefully placed biopsy to determine the diagnosis, the primary initial form of treatment for a mesenchymal chondrosarcoma is usually surgery or chemotherapy. Often times chemotherapy will be given first, followed by surgical removal of the entire tumor and any affected tissue. Radiation may or may not be employed in the treatment of mesenchymal chondrosarcoma, depending on how large the tumor is and where it is situated. Many medical oncologists advocate a chemotherapy treatment plan similar to that of a related bone cancer called Ewing's sarcoma. Radiation therapy after surgery is also typically standard practice for larger tumors.Because mesenchymal chondrosarcomas can recur even after optimal therapy, individuals should be examined routinely after surgery (follow-up care). The specifics of follow-up care are different for each person. In some cases, the return of cancer (relapse) has not occurred until many years after treatment.
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Overview of Mesenteric Panniculitis
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SummaryMesenteric panniculitis, also known as sclerosing mesenteritis, belongs to a spectrum of rare diseases of the fatty (adipose) tissue of the mesentery. Mesenteric panniculitis is characterized by fat degeneration and necrosis, chronic inflammation, and at times, scarring and fibrosis of fatty tissue within the mesentery. This inflammatory and at times progressive condition is most consistent with autoimmune disorders. There is currently limited understanding of the progression of events that lead to the development of mesenteric panniculitis.The mesentery is a fold of tissue within the peritoneum that supports and attaches the small and large intestines to the walls of the abdomen. The mesentery contains fat, blood vessels, lymphatic tissue, lymphatic vessels and other forms of connective tissue. Anatomists previously considered it to be a fragmented collection of intra-abdominal connective tissue. Recently, the anatomy of the mesentery has been clarified and the mesentery has been found to represent a continuous organ that extends from the duodenojejunal flexure to the mesorectum. The portion of the mesentery that is adjacent to the small intestine is most often affected in mesenteric panniculitis. Although the exact cause of mesenteric panniculitis remains unknown, the disease has been associated with a variety of other conditions, including neoplasms, other autoimmune diseases and abdominal trauma.Clinical symptoms of mesenteric panniculitis are highly variable. Some individuals have few or no noticeable symptoms; others may be greatly affected by a variety of complaints including abdominal pain, nausea/vomiting, bloating, early satiety, loss of appetite and diarrhea or constipation. Systemic symptoms, especially fatigue, commonly occur in patients with mesenteric panniculitis. A computerized tomogram (CT) or other imaging of the abdomen shows thickening of the mesentery, sometimes with lymph node enlargement. Due to its variable clinical presentation and rarity, the diagnosis of mesenteric panniculitis is often delayed. Tissue biopsy is required to secure the diagnosis of mesenteric panniculitis and rule out neoplastic infiltration of the mesentery. However, not every patient suspected of having the disease will require a biopsy. There is limited information on the natural history of mesenteric panniculitis, but a stable clinical course is generally anticipated. Due to the rarity of mesenteric panniculitis, there is little prospective data available on its treatment. Nonetheless, corticosteroids and other medications directed at lowering the degree of inflammation and other medications that improve symptoms are felt to be the mainstay of treatment for mesenteric panniculitis.IntroductionMesenteric panniculitis is a rare disorder that is part of a spectrum of diseases affecting the mesentery, a continuous organ that extends from the duodenojejunal flexure to the mesorectum that supports and attaches the intestines to the abdominal wall. Individuals with mesenteric panniculitis develop inflammation and necrosis of the fatty tissue of the mesentery, especially in the area of the small bowel. The condition progresses to cause chronic inflammation of the mesentery. In some patients, ongoing inflammation can result in scarring (fibrosis) of the mesentery.Mesenteric panniculitis was first described in the medical literature in 1924 as “retractile mesenteritis”. Since that time, alternative names have been used to describe the condition including mesenteric panniculitis, retractile mesenteritis and mesenteric lipodystrophy. These names denote the predominant features of the disease process in the mesentery. Mesenteric panniculitis refers to the manifestation of the disease with a predominance of inflammation, sclerosing mesenteritis (or retractile mesenteritis) is the term that refers to a form of the disease with a predominance of fibrosis; and mesenteric lipodystrophy refers to disease with a histologic predominance of fat necrosis.Emory et al. examined three entities (sclerosing mesenteritis, mesenteric panniculitis, and mesenteric lipodystrophy) and confirmed that there was a great deal of histologic overlap between the three entities and suggested that they are all manifestations of the same condition. The authors of this historic study also concluded that the most appropriate term for the process was “sclerosing mesenteritis” based on the presence of some degree of fibrosis. The authors also hypothesized that the condition might be a progressive process moving from lipodystrophy to mesenteric panniculitis to retractile mesenteritis. At present, mesenteric panniculitis is the most commonly used and recommended name for the condition. Overall, additional names that have been used for this disorder include mesenteric fibrosis, mesenteric sclerosis, liposclerotic mesenteritis, mesenteric Pfeifer-Weber-Christian disease, mesenteric lipogranuloma, xanthogranulomatous mesenteritis, inflammatory pseudotumor, retroperitoneal xanthogranuloma and isolated lipodystrophy.
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Overview of Mesenteric Panniculitis. SummaryMesenteric panniculitis, also known as sclerosing mesenteritis, belongs to a spectrum of rare diseases of the fatty (adipose) tissue of the mesentery. Mesenteric panniculitis is characterized by fat degeneration and necrosis, chronic inflammation, and at times, scarring and fibrosis of fatty tissue within the mesentery. This inflammatory and at times progressive condition is most consistent with autoimmune disorders. There is currently limited understanding of the progression of events that lead to the development of mesenteric panniculitis.The mesentery is a fold of tissue within the peritoneum that supports and attaches the small and large intestines to the walls of the abdomen. The mesentery contains fat, blood vessels, lymphatic tissue, lymphatic vessels and other forms of connective tissue. Anatomists previously considered it to be a fragmented collection of intra-abdominal connective tissue. Recently, the anatomy of the mesentery has been clarified and the mesentery has been found to represent a continuous organ that extends from the duodenojejunal flexure to the mesorectum. The portion of the mesentery that is adjacent to the small intestine is most often affected in mesenteric panniculitis. Although the exact cause of mesenteric panniculitis remains unknown, the disease has been associated with a variety of other conditions, including neoplasms, other autoimmune diseases and abdominal trauma.Clinical symptoms of mesenteric panniculitis are highly variable. Some individuals have few or no noticeable symptoms; others may be greatly affected by a variety of complaints including abdominal pain, nausea/vomiting, bloating, early satiety, loss of appetite and diarrhea or constipation. Systemic symptoms, especially fatigue, commonly occur in patients with mesenteric panniculitis. A computerized tomogram (CT) or other imaging of the abdomen shows thickening of the mesentery, sometimes with lymph node enlargement. Due to its variable clinical presentation and rarity, the diagnosis of mesenteric panniculitis is often delayed. Tissue biopsy is required to secure the diagnosis of mesenteric panniculitis and rule out neoplastic infiltration of the mesentery. However, not every patient suspected of having the disease will require a biopsy. There is limited information on the natural history of mesenteric panniculitis, but a stable clinical course is generally anticipated. Due to the rarity of mesenteric panniculitis, there is little prospective data available on its treatment. Nonetheless, corticosteroids and other medications directed at lowering the degree of inflammation and other medications that improve symptoms are felt to be the mainstay of treatment for mesenteric panniculitis.IntroductionMesenteric panniculitis is a rare disorder that is part of a spectrum of diseases affecting the mesentery, a continuous organ that extends from the duodenojejunal flexure to the mesorectum that supports and attaches the intestines to the abdominal wall. Individuals with mesenteric panniculitis develop inflammation and necrosis of the fatty tissue of the mesentery, especially in the area of the small bowel. The condition progresses to cause chronic inflammation of the mesentery. In some patients, ongoing inflammation can result in scarring (fibrosis) of the mesentery.Mesenteric panniculitis was first described in the medical literature in 1924 as “retractile mesenteritis”. Since that time, alternative names have been used to describe the condition including mesenteric panniculitis, retractile mesenteritis and mesenteric lipodystrophy. These names denote the predominant features of the disease process in the mesentery. Mesenteric panniculitis refers to the manifestation of the disease with a predominance of inflammation, sclerosing mesenteritis (or retractile mesenteritis) is the term that refers to a form of the disease with a predominance of fibrosis; and mesenteric lipodystrophy refers to disease with a histologic predominance of fat necrosis.Emory et al. examined three entities (sclerosing mesenteritis, mesenteric panniculitis, and mesenteric lipodystrophy) and confirmed that there was a great deal of histologic overlap between the three entities and suggested that they are all manifestations of the same condition. The authors of this historic study also concluded that the most appropriate term for the process was “sclerosing mesenteritis” based on the presence of some degree of fibrosis. The authors also hypothesized that the condition might be a progressive process moving from lipodystrophy to mesenteric panniculitis to retractile mesenteritis. At present, mesenteric panniculitis is the most commonly used and recommended name for the condition. Overall, additional names that have been used for this disorder include mesenteric fibrosis, mesenteric sclerosis, liposclerotic mesenteritis, mesenteric Pfeifer-Weber-Christian disease, mesenteric lipogranuloma, xanthogranulomatous mesenteritis, inflammatory pseudotumor, retroperitoneal xanthogranuloma and isolated lipodystrophy.
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Symptoms of Mesenteric Panniculitis
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In general, mesenteric panniculitis is a chronic, benign disorder with a favorable prognosis that occasionally resolves on its own (spontaneous regression). Nonetheless, symptoms of mesenteric panniculitis may be severe in some patients and can result in significant effects on quality of life. The clinical presentation of mesenteric panniculitis is highly variable. Some patients have few or no noticeable symptoms. The diagnosis of mesenteric panniculitis may be made incidentally following a CT scan of the abdomen, generally for the evaluation of abdominal pain. Symptoms of mesenteric panniculitis fall into two categories. Some symptoms, such as abdominal pain, are due to the mass-like effect of mesenteric inflammation, and potentially involvement of adjacent structures including the small intestine. The second group of symptoms occurs in the presence of chronic inflammation and may include weight loss, fever, and fatigue. Some affected individuals may develop complications such as small bowel obstruction or acute abdomen. Small bowel obstruction prevents the passage of food through the intestines and can cause a variety of nonspecific gastrointestinal symptoms as well as a nutrient malabsorption.The most common symptom of mesenteric panniculitis is abdominal pain. The pain is generally located in the middle portion of the abdomen but can be present in other areas of the abdomen or pelvis as well. Other common symptoms include nausea, vomiting, early satiety, anorexia, fatigue, fever, unintended weight loss and altered bowel habits (either constipation or diarrhea). In some patients a tender mass may be detected in the middle portion of the abdomen mass. Abdominal distension from chylous ascites has also been described. A thorough examination to rule out peripheral lymphadenopathy or other signs of neoplasm is necessary in all patients.
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Symptoms of Mesenteric Panniculitis. In general, mesenteric panniculitis is a chronic, benign disorder with a favorable prognosis that occasionally resolves on its own (spontaneous regression). Nonetheless, symptoms of mesenteric panniculitis may be severe in some patients and can result in significant effects on quality of life. The clinical presentation of mesenteric panniculitis is highly variable. Some patients have few or no noticeable symptoms. The diagnosis of mesenteric panniculitis may be made incidentally following a CT scan of the abdomen, generally for the evaluation of abdominal pain. Symptoms of mesenteric panniculitis fall into two categories. Some symptoms, such as abdominal pain, are due to the mass-like effect of mesenteric inflammation, and potentially involvement of adjacent structures including the small intestine. The second group of symptoms occurs in the presence of chronic inflammation and may include weight loss, fever, and fatigue. Some affected individuals may develop complications such as small bowel obstruction or acute abdomen. Small bowel obstruction prevents the passage of food through the intestines and can cause a variety of nonspecific gastrointestinal symptoms as well as a nutrient malabsorption.The most common symptom of mesenteric panniculitis is abdominal pain. The pain is generally located in the middle portion of the abdomen but can be present in other areas of the abdomen or pelvis as well. Other common symptoms include nausea, vomiting, early satiety, anorexia, fatigue, fever, unintended weight loss and altered bowel habits (either constipation or diarrhea). In some patients a tender mass may be detected in the middle portion of the abdomen mass. Abdominal distension from chylous ascites has also been described. A thorough examination to rule out peripheral lymphadenopathy or other signs of neoplasm is necessary in all patients.
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Causes of Mesenteric Panniculitis
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There is little information available on the cause of mesenteric panniculitis. Many autoimmune diseases are believed to occur when patients with genetic predisposition to the diseases are exposed to an environmental factor that triggers an inappropriate immunologic response. This response ultimately leads to chronic inflammation. To this end, many conditions have been associated with and possibly predispose to the development of mesenteric panniculitis. These include surgery, acute pancreatitis, other autoimmune conditions and trauma.Surgery Multiple papers have cited a relationship between mesenteric panniculitis and abdominal trauma or surgery. A review of the literature suggests a relatively low rate of association (4.76%). InfectionsMultiple case reports of mesenteric panniculitis have detailed the history of chronic infections including tuberculosis, histoplasmosis, Whipple's disease, typhoid fever, cholera and syphilis that have possibly led to the development of sclerosing mesenteritis. Autoimmune DiseasesEvidence suggests that mesenteric panniculitis is an autoimmune disorder. Autoimmune diseases occur when the body’s natural defense mechanisms such as antibodies and lymphocytes, (that are normally in place for prevention of infectious diseases and cancer), instead cause a reaction and damage to the patient’s own healthy tissue. In general, genetic and environmental factors play a role in the development of autoimmune diseases. A number of factors support the hypothesis that mesenteric panniculitis is an autoimmune disease. These include the fact that biopsies of affected areas show chronic, ongoing inflammation, (although inflammation is not specific for autoimmune processes). Additionally, systemic symptoms that are characteristic of other autoimmune diseases such as rheumatoid arthritis and Crohn’s disease including fever and fatigue can occur in patients with mesenteric panniculitis. Patients with mesenteric panniculitis also frequently often have a strong family history of autoimmune diseases. Finally, elevation of inflammatory markers that are measured in the blood, such as the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are often found in patients with mesenteric panniculitis. Because mesenteric panniculitis occurs in some patients after certain medications, infections, abdominal surgery or trauma, other theories have been proposed to explain this disorder including post inflammatory reactions to acute inflammation or infection, or a deficient blood supply (ischemia) to the mesentery. However, these conditions probably develop secondary to an autoimmune reaction. Neoplastic DiseasesA significant number of patients with radiographically diagnosed “mesenteric panniculitis” have a variety of known or soon to be diagnosed cancers. A case control study from 2013 suggested that the appearance of “mesenteric panniculitis” often represents a paraneoplastic process. A significant number of patients having mesenteric abnormalities consistent with mesenteric panniculitis on CT scan will have an underlying form of cancer. The most common cancers with mesenteric panniculitis like abnormalities on CT scan are lymphomas. Other cancers associated with this finding include carcinoid tumor, colon, renal and prostate cancers. Mesenteric thickening and inflammation often appeared to represent a paraneoplastic syndrome that was not due to the physical presence of cancerous tissue in the affected area. In one study, few of the areas owed increased uptake in positron emission scanning and these abnormalities were generally stable in patients with cancer.Other Fibrosing ConditionsThere is also a known association between mesenteric panniculitis and other fibro-sclerotic disorders. This suggests that mesenteric panniculitis belongs to a larger spectrum of diseases in which inflammation and fibrosis affect multiple organ systems of the body. Fibro-sclerotic disorders that have been reported to occur with mesenteric panniculitis include retroperitoneal fibrosis, Sjögren’s syndrome and sclerosing pancreatitis.
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Causes of Mesenteric Panniculitis. There is little information available on the cause of mesenteric panniculitis. Many autoimmune diseases are believed to occur when patients with genetic predisposition to the diseases are exposed to an environmental factor that triggers an inappropriate immunologic response. This response ultimately leads to chronic inflammation. To this end, many conditions have been associated with and possibly predispose to the development of mesenteric panniculitis. These include surgery, acute pancreatitis, other autoimmune conditions and trauma.Surgery Multiple papers have cited a relationship between mesenteric panniculitis and abdominal trauma or surgery. A review of the literature suggests a relatively low rate of association (4.76%). InfectionsMultiple case reports of mesenteric panniculitis have detailed the history of chronic infections including tuberculosis, histoplasmosis, Whipple's disease, typhoid fever, cholera and syphilis that have possibly led to the development of sclerosing mesenteritis. Autoimmune DiseasesEvidence suggests that mesenteric panniculitis is an autoimmune disorder. Autoimmune diseases occur when the body’s natural defense mechanisms such as antibodies and lymphocytes, (that are normally in place for prevention of infectious diseases and cancer), instead cause a reaction and damage to the patient’s own healthy tissue. In general, genetic and environmental factors play a role in the development of autoimmune diseases. A number of factors support the hypothesis that mesenteric panniculitis is an autoimmune disease. These include the fact that biopsies of affected areas show chronic, ongoing inflammation, (although inflammation is not specific for autoimmune processes). Additionally, systemic symptoms that are characteristic of other autoimmune diseases such as rheumatoid arthritis and Crohn’s disease including fever and fatigue can occur in patients with mesenteric panniculitis. Patients with mesenteric panniculitis also frequently often have a strong family history of autoimmune diseases. Finally, elevation of inflammatory markers that are measured in the blood, such as the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are often found in patients with mesenteric panniculitis. Because mesenteric panniculitis occurs in some patients after certain medications, infections, abdominal surgery or trauma, other theories have been proposed to explain this disorder including post inflammatory reactions to acute inflammation or infection, or a deficient blood supply (ischemia) to the mesentery. However, these conditions probably develop secondary to an autoimmune reaction. Neoplastic DiseasesA significant number of patients with radiographically diagnosed “mesenteric panniculitis” have a variety of known or soon to be diagnosed cancers. A case control study from 2013 suggested that the appearance of “mesenteric panniculitis” often represents a paraneoplastic process. A significant number of patients having mesenteric abnormalities consistent with mesenteric panniculitis on CT scan will have an underlying form of cancer. The most common cancers with mesenteric panniculitis like abnormalities on CT scan are lymphomas. Other cancers associated with this finding include carcinoid tumor, colon, renal and prostate cancers. Mesenteric thickening and inflammation often appeared to represent a paraneoplastic syndrome that was not due to the physical presence of cancerous tissue in the affected area. In one study, few of the areas owed increased uptake in positron emission scanning and these abnormalities were generally stable in patients with cancer.Other Fibrosing ConditionsThere is also a known association between mesenteric panniculitis and other fibro-sclerotic disorders. This suggests that mesenteric panniculitis belongs to a larger spectrum of diseases in which inflammation and fibrosis affect multiple organ systems of the body. Fibro-sclerotic disorders that have been reported to occur with mesenteric panniculitis include retroperitoneal fibrosis, Sjögren’s syndrome and sclerosing pancreatitis.
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Affects of Mesenteric Panniculitis
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The epidemiology of mesenteric panniculitis has not been fully defined. One study reported that findings consistent with mesenteric panniculitis occurred in 359 patients (0.24%) from a total of 147,794 abdominal computed tomography (CT) examinations undertaken for over a 5-year period in a large community based medical system. Of these, 100 patients (28%) had known malignancy or were later diagnosed with cancer. The incidence of mesenteric panniculitis from recent studies has shown a range from 0.16% – 3.4%. This range is dependent on the method of diagnosis and whether it is histologic versus radiologically diagnosed. In some reports, mesenteric panniculitis has a male predominance of 2:1. Mesenteric panniculitis most often appears during the sixth and seventh decade of life, and its incidence appears to increase with age. Children and adolescents are rarely affected, possibly related to a lesser amount of fat in their mesentery, but more importantly because of specific characteristics of this form of autoimmunity.
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Affects of Mesenteric Panniculitis. The epidemiology of mesenteric panniculitis has not been fully defined. One study reported that findings consistent with mesenteric panniculitis occurred in 359 patients (0.24%) from a total of 147,794 abdominal computed tomography (CT) examinations undertaken for over a 5-year period in a large community based medical system. Of these, 100 patients (28%) had known malignancy or were later diagnosed with cancer. The incidence of mesenteric panniculitis from recent studies has shown a range from 0.16% – 3.4%. This range is dependent on the method of diagnosis and whether it is histologic versus radiologically diagnosed. In some reports, mesenteric panniculitis has a male predominance of 2:1. Mesenteric panniculitis most often appears during the sixth and seventh decade of life, and its incidence appears to increase with age. Children and adolescents are rarely affected, possibly related to a lesser amount of fat in their mesentery, but more importantly because of specific characteristics of this form of autoimmunity.
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Related disorders of Mesenteric Panniculitis
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Symptoms of mesenteric panniculitis mimic those of a number of other benign and malignant conditions. Because of this, it is important to rule out other diseases prior to confirming the diagnosis of mesenteric panniculitis. Infectious causes range from viral, bacterial (including V. cholerae) and parasitic infections. There are also a variety of diseases that are associated with mesenteric abnormalities on abdominal imaging. Such conditions include primary or metastatic mesentery cancer, gastrointestinal lymphoma, desmoid tumors, inflammation of the pancreas (pancreatitis), Crohn’s disease, idiopathic nodular panniculitis, locally advanced pancreatic adenocarcinoma, retroperitoneal fibrosis and other sclerotic diseases as mentioned above.
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Related disorders of Mesenteric Panniculitis. Symptoms of mesenteric panniculitis mimic those of a number of other benign and malignant conditions. Because of this, it is important to rule out other diseases prior to confirming the diagnosis of mesenteric panniculitis. Infectious causes range from viral, bacterial (including V. cholerae) and parasitic infections. There are also a variety of diseases that are associated with mesenteric abnormalities on abdominal imaging. Such conditions include primary or metastatic mesentery cancer, gastrointestinal lymphoma, desmoid tumors, inflammation of the pancreas (pancreatitis), Crohn’s disease, idiopathic nodular panniculitis, locally advanced pancreatic adenocarcinoma, retroperitoneal fibrosis and other sclerotic diseases as mentioned above.
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Diagnosis of Mesenteric Panniculitis
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The diagnosis of mesenteric panniculitis is made based upon identification of suggestive symptoms, a detailed patient history, and a thorough clinical evaluation. Clinical Testing and Work-Up
Affected individuals may have non-specific laboratory abnormalities such as reduced red blood cell counts (anemia). Laboratory markers of inflammation such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) can also be elevated. Radiographic Diagnosis
These five diagnostic signs that have been felt to be specific for mesenteric panniculitis and separate it from other causes of abdominal masses include the presence of a well-defined “mass effect” on neighboring structures (sign 1) constituted by mesenteric fat tissue of inhomogeneous higher attenuation than adjacent retroperitoneal or meso-colonic fat (sign 2) and containing small soft tissue nodes (sign 3). It may typically be surrounded by a hypo-attenuated fatty “halo sign” (sign 4) and a hyperattenuating pseudo-capsule may also surround the entity (sign 5). However, these diagnostic criteria were not histologically verified, but they have overall come to represent the closest general standards available.Radiographic studies such as computerized tomography (CT) scanning or magnetic resonance imaging (MRI) reveal characteristic findings in the abdominal or pelvic mesentery. Imaging reveals characteristic thickening, fat necrosis and calcification of the mesentery. Mild cases are referred to a “misty mesentery”. Enlargement and calcification of mesenteric and pelvic lymph nodes are commonly present. Because mesenteric panniculitis is not an invasive disorder, blood vessels within the mesentery appear to be spared from the inflammatory mass. This is referred to as the “halo sign” and is highly characteristic of mesenteric panniculitis as opposed to malignancy of the mesentery. Surgical biopsy and microscopic study of affected tissue is required to completely rule out other conditions and to confirm a diagnosis of mesenteric panniculitis.
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Diagnosis of Mesenteric Panniculitis. The diagnosis of mesenteric panniculitis is made based upon identification of suggestive symptoms, a detailed patient history, and a thorough clinical evaluation. Clinical Testing and Work-Up
Affected individuals may have non-specific laboratory abnormalities such as reduced red blood cell counts (anemia). Laboratory markers of inflammation such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) can also be elevated. Radiographic Diagnosis
These five diagnostic signs that have been felt to be specific for mesenteric panniculitis and separate it from other causes of abdominal masses include the presence of a well-defined “mass effect” on neighboring structures (sign 1) constituted by mesenteric fat tissue of inhomogeneous higher attenuation than adjacent retroperitoneal or meso-colonic fat (sign 2) and containing small soft tissue nodes (sign 3). It may typically be surrounded by a hypo-attenuated fatty “halo sign” (sign 4) and a hyperattenuating pseudo-capsule may also surround the entity (sign 5). However, these diagnostic criteria were not histologically verified, but they have overall come to represent the closest general standards available.Radiographic studies such as computerized tomography (CT) scanning or magnetic resonance imaging (MRI) reveal characteristic findings in the abdominal or pelvic mesentery. Imaging reveals characteristic thickening, fat necrosis and calcification of the mesentery. Mild cases are referred to a “misty mesentery”. Enlargement and calcification of mesenteric and pelvic lymph nodes are commonly present. Because mesenteric panniculitis is not an invasive disorder, blood vessels within the mesentery appear to be spared from the inflammatory mass. This is referred to as the “halo sign” and is highly characteristic of mesenteric panniculitis as opposed to malignancy of the mesentery. Surgical biopsy and microscopic study of affected tissue is required to completely rule out other conditions and to confirm a diagnosis of mesenteric panniculitis.
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Therapies of Mesenteric Panniculitis
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Treatment
Most treatment recommendations are based on case reports or small case series. The only clinical prospective study of a treatment for mesenteric panniculitis has been performed using the drug thalidomide. The goals of treatment for mesenteric panniculitis are reduction of mesenteric inflammation and the control of symptoms of the disease.Generally, individuals with no symptoms are not treated, but are regularly monitored to see whether the disorder progresses on abdominal imaging (watch and wait approach). A decision regarding biopsy is made during this time. In most patients, the disease remains asymptomatic. The mesenteric mass is generally stable or even regresses on its own.For patients with symptoms related to chronic mesenteric inflammation, anti-inflammatory agents, especially corticosteroids are the initial treatment of choice. Additional anti-inflammatory drugs that have been used to treat mesenteric panniculitis include colchicine, azathioprine, cyclophosphamide, infliximab and pentoxifylline. A prospective clinical trial has demonstrated that the drug thalidomide improves symptoms and reduces blood levels of ESR and CRP in patients with mesenteric panniculitis. Low dose naltrexone (LDN) is also a promising new therapy for mesenteric panniculitis. LDN appears to work by modulating the immune system and by increasing blood levels of enkephalins and endorphins. Tamoxifen and other hormonal therapies have been proposed to treat patients with mesenteric fibrosis due to their anti-fibrotic effects. Unfortunately, serious side effects may occur with these medications including the development of thromboembolic phenomena and secondary malignancies. Because of the rarity of mesenteric panniculitis, few controlled clinical studies of medical therapies for this condition are likely to be performed in the future.When individuals with mesenteric panniculitis develop small intestinal obstruction, surgery may be required. In general, surgery should be avoided in patients with mesenteric panniculitis and there should never be an attempt to surgically remove the mesenteric mass for the purpose of curing the disease.
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Therapies of Mesenteric Panniculitis. Treatment
Most treatment recommendations are based on case reports or small case series. The only clinical prospective study of a treatment for mesenteric panniculitis has been performed using the drug thalidomide. The goals of treatment for mesenteric panniculitis are reduction of mesenteric inflammation and the control of symptoms of the disease.Generally, individuals with no symptoms are not treated, but are regularly monitored to see whether the disorder progresses on abdominal imaging (watch and wait approach). A decision regarding biopsy is made during this time. In most patients, the disease remains asymptomatic. The mesenteric mass is generally stable or even regresses on its own.For patients with symptoms related to chronic mesenteric inflammation, anti-inflammatory agents, especially corticosteroids are the initial treatment of choice. Additional anti-inflammatory drugs that have been used to treat mesenteric panniculitis include colchicine, azathioprine, cyclophosphamide, infliximab and pentoxifylline. A prospective clinical trial has demonstrated that the drug thalidomide improves symptoms and reduces blood levels of ESR and CRP in patients with mesenteric panniculitis. Low dose naltrexone (LDN) is also a promising new therapy for mesenteric panniculitis. LDN appears to work by modulating the immune system and by increasing blood levels of enkephalins and endorphins. Tamoxifen and other hormonal therapies have been proposed to treat patients with mesenteric fibrosis due to their anti-fibrotic effects. Unfortunately, serious side effects may occur with these medications including the development of thromboembolic phenomena and secondary malignancies. Because of the rarity of mesenteric panniculitis, few controlled clinical studies of medical therapies for this condition are likely to be performed in the future.When individuals with mesenteric panniculitis develop small intestinal obstruction, surgery may be required. In general, surgery should be avoided in patients with mesenteric panniculitis and there should never be an attempt to surgically remove the mesenteric mass for the purpose of curing the disease.
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Overview of Mesothelioma
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SummaryMesothelioma is a rare form of cancer that affects the cells that make up the mesothelium. The mesothelium is the lining or membrane that covers and protects various internal organs of the body. The mesothelium is composed of two layers of specialized cells known as mesothelial cells. One layer directly surrounds the internal organs; the other forms a protective sac around thoracic and peritoneal organs. The most common form of mesothelioma affects the pleura, which is the membrane or sac that lines the lungs and chest cavity. Other common sites include the peritoneum, which is the membrane lining the abdominal cavity, and the pericardium, which is the membrane lining the heart (heart sac). Mesothelial tissue is also found in other areas of the body including the membrane covering the testicles (tunica vaginalis). The disorder most often occurs in older adults. Mesothelioma is often an aggressive form of cancer with a poor prognosis, with pleural mesothelioma patients having a median survival of only about 12-14 months with current therapies. Treatments are available, but are not effective for everyone.IntroductionThe term “cancer” refers to a group of diseases characterized by abnormal, uncontrolled cellular growth (e.g., mesothelial cells) that invades surrounding tissues and may spread (metastasize) to distant bodily tissues or organs via the bloodstream, the lymphatic system, or other means. Different forms of cancer, including mesothelioma, may be classified based upon the cell type involved, the specific nature of the malignancy, the tissues or organs affected, and the disease's clinical course. Symptoms of mesothelioma vary depending upon the location, type and stage of the cancer. Approximately 70 to 80% of cases of mesothelioma result from exposure to asbestos. Symptoms of mesothelioma may not appear until up to 30 to 50 years after initial exposure to asbestos. However, after symptoms become apparent, mesothelioma may rapidly progress to cause life-threatening complications.
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Overview of Mesothelioma. SummaryMesothelioma is a rare form of cancer that affects the cells that make up the mesothelium. The mesothelium is the lining or membrane that covers and protects various internal organs of the body. The mesothelium is composed of two layers of specialized cells known as mesothelial cells. One layer directly surrounds the internal organs; the other forms a protective sac around thoracic and peritoneal organs. The most common form of mesothelioma affects the pleura, which is the membrane or sac that lines the lungs and chest cavity. Other common sites include the peritoneum, which is the membrane lining the abdominal cavity, and the pericardium, which is the membrane lining the heart (heart sac). Mesothelial tissue is also found in other areas of the body including the membrane covering the testicles (tunica vaginalis). The disorder most often occurs in older adults. Mesothelioma is often an aggressive form of cancer with a poor prognosis, with pleural mesothelioma patients having a median survival of only about 12-14 months with current therapies. Treatments are available, but are not effective for everyone.IntroductionThe term “cancer” refers to a group of diseases characterized by abnormal, uncontrolled cellular growth (e.g., mesothelial cells) that invades surrounding tissues and may spread (metastasize) to distant bodily tissues or organs via the bloodstream, the lymphatic system, or other means. Different forms of cancer, including mesothelioma, may be classified based upon the cell type involved, the specific nature of the malignancy, the tissues or organs affected, and the disease's clinical course. Symptoms of mesothelioma vary depending upon the location, type and stage of the cancer. Approximately 70 to 80% of cases of mesothelioma result from exposure to asbestos. Symptoms of mesothelioma may not appear until up to 30 to 50 years after initial exposure to asbestos. However, after symptoms become apparent, mesothelioma may rapidly progress to cause life-threatening complications.
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Symptoms of Mesothelioma
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The symptoms of mesothelioma vary depending upon the location, type and stage of the cancer. Unfortunately, early in the course of the disease, many people have no symptoms, and the tumor can be difficult to see on X-ray examination.In approximately 85% of patients, mesothelioma arises in the membranes surrounding the lungs (malignant pleural mesothelioma). A collection of fluid around the lung, termed a pleural effusion, may be present. Symptoms may include shortness of breath or difficulty breathing (dyspnea), chest pain, or a chronic cough due to pleural effusion. Difficulty swallowing (dysphagia) can also occur, but is usually a late complication. A mass in the chest wall or unusual lumps of tissue under the skin of the chest may develop in some cases.When the membrane surrounding the stomach is affected (peritoneal mesothelioma), symptoms may include unexplained weight loss, abdominal pain, nausea, vomiting, diarrhea, loss of appetite, low levels of circulating red blood cells (anemia), and abnormal accumulation of fluid (ascites) in the space (peritoneal cavity) between the two layers of the membrane (peritoneum) that lines the abdomen. Small bowel obstruction may occur, usually as a late complication of the disorder.When the membrane surrounding the heart is affected (pericardial mesothelioma), heart rhythm abnormalities or low blood pressure may occur. Chest pain and breathing difficulties can also occur with pericardial mesothelioma.Individuals with mesothelioma may also experience general symptoms including fever, weakness, night sweats, unexplained weight loss, and a general feeling of ill health (malaise).In extremely rare cases, mesothelial tissue lining the testicles can give rise to mesothelioma. This tissue is part of the peritoneal mesothelium that extends into the scrotum.
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Symptoms of Mesothelioma. The symptoms of mesothelioma vary depending upon the location, type and stage of the cancer. Unfortunately, early in the course of the disease, many people have no symptoms, and the tumor can be difficult to see on X-ray examination.In approximately 85% of patients, mesothelioma arises in the membranes surrounding the lungs (malignant pleural mesothelioma). A collection of fluid around the lung, termed a pleural effusion, may be present. Symptoms may include shortness of breath or difficulty breathing (dyspnea), chest pain, or a chronic cough due to pleural effusion. Difficulty swallowing (dysphagia) can also occur, but is usually a late complication. A mass in the chest wall or unusual lumps of tissue under the skin of the chest may develop in some cases.When the membrane surrounding the stomach is affected (peritoneal mesothelioma), symptoms may include unexplained weight loss, abdominal pain, nausea, vomiting, diarrhea, loss of appetite, low levels of circulating red blood cells (anemia), and abnormal accumulation of fluid (ascites) in the space (peritoneal cavity) between the two layers of the membrane (peritoneum) that lines the abdomen. Small bowel obstruction may occur, usually as a late complication of the disorder.When the membrane surrounding the heart is affected (pericardial mesothelioma), heart rhythm abnormalities or low blood pressure may occur. Chest pain and breathing difficulties can also occur with pericardial mesothelioma.Individuals with mesothelioma may also experience general symptoms including fever, weakness, night sweats, unexplained weight loss, and a general feeling of ill health (malaise).In extremely rare cases, mesothelial tissue lining the testicles can give rise to mesothelioma. This tissue is part of the peritoneal mesothelium that extends into the scrotum.
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Causes of Mesothelioma
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Researchers speculate that genetic and immunologic abnormalities, environmental exposures, and/or other factors may play contributing roles in causing specific types of cancer such as mesothelioma.Approximately 70 to 80% of affected individuals have a significant history of asbestos exposure making it the major associated risk factor for the development of mesothelioma. Asbestos is a fibrous material that is resistant to fire, resulting in its use as insulation and in fire safety products. Asbestos was also used in the production of a wide variety of products including brake linings, roofing products, floor tiles, and cement. Asbestos production and use peaked in the United States during the 1930s-1960s and slowly tapered off during the 1970s. Most use of asbestos in the United States stopped after 1989. Asbestos is associated with the development of mesothelioma when asbestos fibers are inhaled or swallowed and then attach to tissues lining the respiratory and/or digestive tracts.There are different types of asbestos fibers such as serpentine fibers, which are long and curvy, and amphibole fibers, which are straight and needle-like. Serpentine fibers, due to their shape, are more easily cleared from the lungs. Crocidolite fibers, which are a subtype of amphibole fibers, are most commonly associated with mesothelioma in humans.The most common form of asbestos exposure is occupational, in which a person is exposed because of their job. The list of potential jobs is long and extensive because of the widespread use of asbestos in the past. In addition to occupational exposure, both para-occupational and non-occupational exposure has been linked to mesothelioma. Para-occupational exposure occurs when a person is exposed to asbestos from another person who is exposed through their work. For example, people who are exposed to asbestos at work may bring the fibers home on their clothes, thereby exposing their family. After such secondary exposure, there is an increased risk of the spouse and/or children developing mesothelioma.Although asbestos is the major risk factor for developing mesothelioma, asbestos exposure alone does not account for every affected individual. Causes of non-asbestos related mesothelioma have been suggested. A volcanic mineral, known as erionite, can also cause mesothelioma. Erionite was first linked to the disorder because of a greatly increased incidence of mesothelioma in Cappadocia, in the central Anatoli region of Turkey. Researchers believe that genetic factors in the native population may also play a significant role in the increased prevalence of the disorder in this region. However, to date, a genetic factor has not been identified in Cappadocia. Erionite is a fibrous material that belongs to a group of minerals called zeolites. Zeolites are chemically related to asbestos. Erionite is found in the United States, particularly in North Dakota, Western states and often in gravel quarries or road development projects.In rare cases, individuals develop mesothelioma without any obvious asbestos or erionite exposure. The cause in such cases is unknown (idiopathic or spontaneous mesothelioma). In such cases, it is possible that individuals experienced unknown exposure to asbestos or erionite. It is also possible that other causative agents exist that result in the development of mesothelioma such as radiation and possibly certain chemicals or viruses.One such example, according to some researchers, is the simian virus 40 (SV40). The SV40 virus was proposed to play a role in the development of some cases of mesothelioma, although this was controversial and is now largely discredited. Recent studies failed to establish a link, and most researchers in the field have concluded that a causal role does not exist. Much of the evidence for S40 in mesothelioma was derived using polymerase chain reaction (PCR) technique, and newer evidence has shown a high risk of false-positive PCR results owing to the presence of SV40 sequences in common laboratory plasmids.The exact manner in which exposure to asbestos and other causative agents result in the development of mesothelioma is not well understood. Some individuals with heavy exposure to asbestos never develop mesothelioma. Other individuals with limited exposure to asbestos have developed the disease. According to the medical literature, some individuals have developed mesothelioma after only a single exposure to asbestos.Overall, only a small fraction of individuals exposed to asbestos or other causative agents of mesothelioma actually develop the disorder. Genetics may explain, in part, why some people develop mesothelioma and others do not. Inherited mutations of certain genes, such as the tumor suppressor gene BAP1, may result in a genetic predisposition to developing the disease. A person who is genetically predisposed to a disorder carries a mutated gene (or genes) that increases his or her susceptibility to the disease, but may not occur unless there is loss of the second (normal) copy of the gene. The latter may be triggered under certain circumstances, such as due to a particular environmental factor such as those described above. People without a genetic predisposition to a disease can still develop the disease, but the risk is much lower.Specific genes that have been linked to predisposition and/or progression of mesothelioma include the tumor suppressor genes BAP1, CDKN2A, and NF2. Inheritance of a mutant copy of the BAP1 gene, which encodes the BRCA1-associated protein 1, in particular has been shown to convey a greatly increased risk of developing mesothelioma as well as ocular (uveal) and skin melanomas, carcinomas of the kidney, skin (basal cell) and other organs, and benign melanocytic skin tumors. Somatic (acquired) mutations of BAP1, NF2 and CDKN2A (which encodes both p16INK4A and p14ARF) occur frequently in both sporadic (non-hereditary) and hereditary forms of mesothelioma.However, not everyone who has an inherited mutation of BAP1 will develop mesothelioma. Some individuals who carry a germline BAP1 mutation develop one of more of the other tumor types connected with the BAP1 syndrome. Some BAP1 mutation carriers have developed only benign skin tumors, and others have developed no tumors to date. Long-term studies of such individuals are needed to assess cancer susceptibility over a lifetime. Notably, a mouse model carrying a germline Bap1 mutation was reported to be much more susceptible to the development of asbestos-induced mesotheliomas than similarly exposed siblings that did not carry the mutation. Long-term follow-up of unexposed mice revealed two spontaneous mesotheliomas among 93 Bap1-mutant mice (~2%), whereas none were found in any of more than 40 siblings lacking the mutation, although this difference was not statistically significant (p > 0.05).Importantly, in humans, the vast majority of all mesotheliomas (>99%) occur in individuals who do not have a germline BAP1 mutation. Whether any other genetic factor(s) make certain individuals more susceptible to the carcinogenic effects of asbestos via a gene–environment interaction, or to the development of idiopathic mesothelioma, is an area of growing research interest.
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Causes of Mesothelioma. Researchers speculate that genetic and immunologic abnormalities, environmental exposures, and/or other factors may play contributing roles in causing specific types of cancer such as mesothelioma.Approximately 70 to 80% of affected individuals have a significant history of asbestos exposure making it the major associated risk factor for the development of mesothelioma. Asbestos is a fibrous material that is resistant to fire, resulting in its use as insulation and in fire safety products. Asbestos was also used in the production of a wide variety of products including brake linings, roofing products, floor tiles, and cement. Asbestos production and use peaked in the United States during the 1930s-1960s and slowly tapered off during the 1970s. Most use of asbestos in the United States stopped after 1989. Asbestos is associated with the development of mesothelioma when asbestos fibers are inhaled or swallowed and then attach to tissues lining the respiratory and/or digestive tracts.There are different types of asbestos fibers such as serpentine fibers, which are long and curvy, and amphibole fibers, which are straight and needle-like. Serpentine fibers, due to their shape, are more easily cleared from the lungs. Crocidolite fibers, which are a subtype of amphibole fibers, are most commonly associated with mesothelioma in humans.The most common form of asbestos exposure is occupational, in which a person is exposed because of their job. The list of potential jobs is long and extensive because of the widespread use of asbestos in the past. In addition to occupational exposure, both para-occupational and non-occupational exposure has been linked to mesothelioma. Para-occupational exposure occurs when a person is exposed to asbestos from another person who is exposed through their work. For example, people who are exposed to asbestos at work may bring the fibers home on their clothes, thereby exposing their family. After such secondary exposure, there is an increased risk of the spouse and/or children developing mesothelioma.Although asbestos is the major risk factor for developing mesothelioma, asbestos exposure alone does not account for every affected individual. Causes of non-asbestos related mesothelioma have been suggested. A volcanic mineral, known as erionite, can also cause mesothelioma. Erionite was first linked to the disorder because of a greatly increased incidence of mesothelioma in Cappadocia, in the central Anatoli region of Turkey. Researchers believe that genetic factors in the native population may also play a significant role in the increased prevalence of the disorder in this region. However, to date, a genetic factor has not been identified in Cappadocia. Erionite is a fibrous material that belongs to a group of minerals called zeolites. Zeolites are chemically related to asbestos. Erionite is found in the United States, particularly in North Dakota, Western states and often in gravel quarries or road development projects.In rare cases, individuals develop mesothelioma without any obvious asbestos or erionite exposure. The cause in such cases is unknown (idiopathic or spontaneous mesothelioma). In such cases, it is possible that individuals experienced unknown exposure to asbestos or erionite. It is also possible that other causative agents exist that result in the development of mesothelioma such as radiation and possibly certain chemicals or viruses.One such example, according to some researchers, is the simian virus 40 (SV40). The SV40 virus was proposed to play a role in the development of some cases of mesothelioma, although this was controversial and is now largely discredited. Recent studies failed to establish a link, and most researchers in the field have concluded that a causal role does not exist. Much of the evidence for S40 in mesothelioma was derived using polymerase chain reaction (PCR) technique, and newer evidence has shown a high risk of false-positive PCR results owing to the presence of SV40 sequences in common laboratory plasmids.The exact manner in which exposure to asbestos and other causative agents result in the development of mesothelioma is not well understood. Some individuals with heavy exposure to asbestos never develop mesothelioma. Other individuals with limited exposure to asbestos have developed the disease. According to the medical literature, some individuals have developed mesothelioma after only a single exposure to asbestos.Overall, only a small fraction of individuals exposed to asbestos or other causative agents of mesothelioma actually develop the disorder. Genetics may explain, in part, why some people develop mesothelioma and others do not. Inherited mutations of certain genes, such as the tumor suppressor gene BAP1, may result in a genetic predisposition to developing the disease. A person who is genetically predisposed to a disorder carries a mutated gene (or genes) that increases his or her susceptibility to the disease, but may not occur unless there is loss of the second (normal) copy of the gene. The latter may be triggered under certain circumstances, such as due to a particular environmental factor such as those described above. People without a genetic predisposition to a disease can still develop the disease, but the risk is much lower.Specific genes that have been linked to predisposition and/or progression of mesothelioma include the tumor suppressor genes BAP1, CDKN2A, and NF2. Inheritance of a mutant copy of the BAP1 gene, which encodes the BRCA1-associated protein 1, in particular has been shown to convey a greatly increased risk of developing mesothelioma as well as ocular (uveal) and skin melanomas, carcinomas of the kidney, skin (basal cell) and other organs, and benign melanocytic skin tumors. Somatic (acquired) mutations of BAP1, NF2 and CDKN2A (which encodes both p16INK4A and p14ARF) occur frequently in both sporadic (non-hereditary) and hereditary forms of mesothelioma.However, not everyone who has an inherited mutation of BAP1 will develop mesothelioma. Some individuals who carry a germline BAP1 mutation develop one of more of the other tumor types connected with the BAP1 syndrome. Some BAP1 mutation carriers have developed only benign skin tumors, and others have developed no tumors to date. Long-term studies of such individuals are needed to assess cancer susceptibility over a lifetime. Notably, a mouse model carrying a germline Bap1 mutation was reported to be much more susceptible to the development of asbestos-induced mesotheliomas than similarly exposed siblings that did not carry the mutation. Long-term follow-up of unexposed mice revealed two spontaneous mesotheliomas among 93 Bap1-mutant mice (~2%), whereas none were found in any of more than 40 siblings lacking the mutation, although this difference was not statistically significant (p > 0.05).Importantly, in humans, the vast majority of all mesotheliomas (>99%) occur in individuals who do not have a germline BAP1 mutation. Whether any other genetic factor(s) make certain individuals more susceptible to the carcinogenic effects of asbestos via a gene–environment interaction, or to the development of idiopathic mesothelioma, is an area of growing research interest.
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Mesothelioma
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Affects of Mesothelioma
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Mesothelioma can affect individuals of any age although it occurs most often in individuals 50 years or older. According to data compiled from the U.S. Surveillance Epidemiology and End Results (SEER) program between the years 1973-1992, there has been a consistently higher rate of mesothelioma in men than in women. Approximately 3,000 new patients of mesothelioma are diagnosed each year in the United States, and many more may be misdiagnosed or under-reported. As stated above, individuals with a history of asbestos exposure are at greatest risk for this disease.The lining of the chest cavity and lungs (pleura) is the most common site for mesothelioma, accounting for more than 85% of cases. The lining of the abdomen (peritoneum) is the second most common site and accounts for approximately 10% of all cases. Approximately 250 new cases of peritoneal mesothelioma occur every year in the United States.The exact incidence or prevalence of mesothelioma is unknown, but the disorder certainly accounts for less than 1% of all forms of cancer. The incidence of mesothelioma that develops without known exposure to asbestos is approximately 1 in 1,000,000 in the general population.
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Affects of Mesothelioma. Mesothelioma can affect individuals of any age although it occurs most often in individuals 50 years or older. According to data compiled from the U.S. Surveillance Epidemiology and End Results (SEER) program between the years 1973-1992, there has been a consistently higher rate of mesothelioma in men than in women. Approximately 3,000 new patients of mesothelioma are diagnosed each year in the United States, and many more may be misdiagnosed or under-reported. As stated above, individuals with a history of asbestos exposure are at greatest risk for this disease.The lining of the chest cavity and lungs (pleura) is the most common site for mesothelioma, accounting for more than 85% of cases. The lining of the abdomen (peritoneum) is the second most common site and accounts for approximately 10% of all cases. Approximately 250 new cases of peritoneal mesothelioma occur every year in the United States.The exact incidence or prevalence of mesothelioma is unknown, but the disorder certainly accounts for less than 1% of all forms of cancer. The incidence of mesothelioma that develops without known exposure to asbestos is approximately 1 in 1,000,000 in the general population.
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Mesothelioma
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Related disorders of Mesothelioma
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Symptoms of the following disorders can be similar to those of mesothelioma. Comparisons may be useful for a differential diagnosis:Other malignant forms of cancer may be confused with mesothelioma including adenocarcinoma, which may arise in the lungs or other areas and spread to the lining of the chest (pleura). Forms of lymphoma, myeloma, thymoma, and leukemia may also have similar symptoms to mesothelioma. Pneumonia may mimic some of the early signs of mesothelioma. Pulmonary fibrosis, pulmonary embolism, lung infections and other lung diseases may need to be differentiated from mesothelioma.
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Related disorders of Mesothelioma. Symptoms of the following disorders can be similar to those of mesothelioma. Comparisons may be useful for a differential diagnosis:Other malignant forms of cancer may be confused with mesothelioma including adenocarcinoma, which may arise in the lungs or other areas and spread to the lining of the chest (pleura). Forms of lymphoma, myeloma, thymoma, and leukemia may also have similar symptoms to mesothelioma. Pneumonia may mimic some of the early signs of mesothelioma. Pulmonary fibrosis, pulmonary embolism, lung infections and other lung diseases may need to be differentiated from mesothelioma.
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Mesothelioma
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Diagnosis of Mesothelioma
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A diagnosis of mesothelioma is made based upon a thorough clinical evaluation, a detailed patient history, characteristic symptoms and physical findings, as well as a variety of specialized tests including chest X-rays, blood tests, and tests that determine lung function. Specialized imaging techniques may also be used to help evaluate the size, placement, and extension of the mesothelioma.Clinical Testing and Work Up
Specialized imaging techniques may include computerized tomography (CT) scanning and positron emission tomography (PET) scanning. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures and can reveal the entire pleural surface. During a PET scan, three-dimensional images are produced that reflect the brain’s chemical activity.Less often, magnetic resonance imaging (MRI) may be used. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. An MRI can provide additional information about mesothelioma in individuals who are candidates for surgery.A diagnosis of mesothelioma will usually need to be confirmed by the surgical removal and microscopic examination (biopsy) of affected tissue. Different types of biopsies (e.g., transthoracic needle biopsy, needle-assisted thoracoscopy) may be performed. Needle biopsy of mesothelioma may be performed by a radiologist using either ultrasound or a CT scan to guide placement of the needle. During video thoracoscopy, a thin tube with a built-in camera (thoracoscope) is inserted into the chest through a small surgical cut (incision) allowing a physician to view the lungs and obtain tissue samples. This is usually a formal operative procedure performed in an operating room, or similar setting, and may require a general anesthetic with a temporary breathing tube. A similar procedure called a laparoscopy may be performed to view the peritoneum lining the inside of the abdomen. Only in rare cases will a needle biopsy, a thoracoscopy, or laparoscopy not obtain enough tissue for diagnosis. In these cases, more invasive techniques such as a thoracotomy or laparotomy (operative procedures with larger incisions), may be performed to assist in the diagnosis of mesothelioma.Staging
When an individual is diagnosed with mesothelioma, assessment is also required to determine the extent or “stage” of the disease. Staging is important to help determine how far the disease has spread, characterize the potential disease course, and determine appropriate treatment approaches. Some of the same diagnostic tests described above may be used in staging mesothelioma. In addition, even when the disease is limited to the chest, a physician may need to perform a procedure called a mediastinoscopy (similar to other techniques above) to take biopsies of lymph nodes in the central region (mediastinum) of the chest, or laparoscopy to rule out spread into the abdomen, as radiographic tests may miss disease in these areas. There is no consensus staging system for mesothelioma; at least six different staging systems have been proposed in the medical literature.
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Diagnosis of Mesothelioma. A diagnosis of mesothelioma is made based upon a thorough clinical evaluation, a detailed patient history, characteristic symptoms and physical findings, as well as a variety of specialized tests including chest X-rays, blood tests, and tests that determine lung function. Specialized imaging techniques may also be used to help evaluate the size, placement, and extension of the mesothelioma.Clinical Testing and Work Up
Specialized imaging techniques may include computerized tomography (CT) scanning and positron emission tomography (PET) scanning. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures and can reveal the entire pleural surface. During a PET scan, three-dimensional images are produced that reflect the brain’s chemical activity.Less often, magnetic resonance imaging (MRI) may be used. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. An MRI can provide additional information about mesothelioma in individuals who are candidates for surgery.A diagnosis of mesothelioma will usually need to be confirmed by the surgical removal and microscopic examination (biopsy) of affected tissue. Different types of biopsies (e.g., transthoracic needle biopsy, needle-assisted thoracoscopy) may be performed. Needle biopsy of mesothelioma may be performed by a radiologist using either ultrasound or a CT scan to guide placement of the needle. During video thoracoscopy, a thin tube with a built-in camera (thoracoscope) is inserted into the chest through a small surgical cut (incision) allowing a physician to view the lungs and obtain tissue samples. This is usually a formal operative procedure performed in an operating room, or similar setting, and may require a general anesthetic with a temporary breathing tube. A similar procedure called a laparoscopy may be performed to view the peritoneum lining the inside of the abdomen. Only in rare cases will a needle biopsy, a thoracoscopy, or laparoscopy not obtain enough tissue for diagnosis. In these cases, more invasive techniques such as a thoracotomy or laparotomy (operative procedures with larger incisions), may be performed to assist in the diagnosis of mesothelioma.Staging
When an individual is diagnosed with mesothelioma, assessment is also required to determine the extent or “stage” of the disease. Staging is important to help determine how far the disease has spread, characterize the potential disease course, and determine appropriate treatment approaches. Some of the same diagnostic tests described above may be used in staging mesothelioma. In addition, even when the disease is limited to the chest, a physician may need to perform a procedure called a mediastinoscopy (similar to other techniques above) to take biopsies of lymph nodes in the central region (mediastinum) of the chest, or laparoscopy to rule out spread into the abdomen, as radiographic tests may miss disease in these areas. There is no consensus staging system for mesothelioma; at least six different staging systems have been proposed in the medical literature.
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Mesothelioma
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Therapies of Mesothelioma
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Treatment The therapeutic management of individuals with mesothelioma may require the coordinated efforts of a team of medical professionals, such as physicians who specialize in the diagnosis and chemotherapy of cancer (medical oncologists), specialists in the use of radiation to treat cancer (radiation oncologists), surgeons, oncology nurses, and other specialists (depending upon the primary tumor site). Psychosocial support for the entire family is essential as well. Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as primary tumor location, extent of the primary tumor (stage), and degree of malignancy (grade); whether the tumor has spread to lymph nodes or distant sites; individual’s age and general health; and/or other elements. Decisions concerning the use of particular interventions should be made by physicians and other members of the health care team in careful consultation with the patient and family, based upon the specifics of his or her case, a thorough discussion of the potential benefits and risks, patient preference, and other appropriate factors. As this is an unusual disease, patients should consider seeking the care of a highly experienced specialist in this area, preferably at a major medical center that has extensive experience treating this very challenging disease. In many individuals with mesothelioma, standard therapy includes surgical removal of all or a portion of the malignancy and affected tissues. Surgical removal of the lining of the chest (pleura) may be performed in some cases of pleural mesothelioma (pleurectomy). Another procedure, known as an extrapleural pneumonectomy involves surgical removal of the pleura, pericardium, diaphragm, and the entire affected lung. Surgical removal of the peritoneum and surrounding tissue may be performed in cases of peritoneal mesothelioma. Surgery may also be performed to remove fluid accumulation from the chest or abdomen in order to relieve pain and other symptoms. In addition, based upon primary tumor site, size, and other factors, recommended therapy may often include postoperative radiation to help treat known or possible residual disease. If initial surgery is not an option due to the specific location and/or progression of the malignancy, therapy may include radiation alone. Radiation therapy preferentially destroys or injures rapidly dividing cells, primarily cancerous cells. However, some healthy cells (e.g., hair follicles, bone marrow, etc.) may also be damaged, leading to certain side effects. Thus, during such therapy, the radiation is passed through diseased tissue in carefully calculated dosages to destroy cancer cells while minimizing exposure and damage to normal cells. Radiation therapy works to destroy cancer cells by depositing energy that damages their genetic material, preventing or slowing their growth and replication. Various types of radiation may be used–again, depending on cancer type, location, stage and grade, prior treatments. For some affected individuals, particularly those who have locally advanced, metastatic, or recurrent disease, or those unable to tolerate more aggressive approaches, therapy with certain anticancer drugs (chemotherapy) may also be recommended. Combination chemotherapy is generally more effective than treatment with a single agent, and physicians may recommend combination therapy with multiple chemotherapeutic drugs that have different modes of action in destroying tumor cells and/or preventing them from multiplying. For some patients, some combination of two or all three treatment modalities (surgery, radiation, chemotherapy) may be considered. This is known as the multimodal approach. In 2004, the U.S. Food and Drug Administration (FDA) approved the orphan drug Alimta (pemetrexed disodium) used in combination with Platinol (cisplatin) for the treatment of individuals with malignant pleural mesothelioma when surgery is not an option. More recently, in 2020, FDA approved the combination of Opdivo (nivolumab) plus Yervoy (ipilimumab) as first-line treatment for adult patients with unresectable malignant pleural mesothelioma. Some treatment for individuals with mesothelioma may help to reduce symptoms and ease pain. Such therapies include procedures known as thoracentesis and paracentesis to drain fluid that may accumulate in the chest or stomach. During a thoracentesis, a needle or small tube (catheter) is inserted into the chest cavity to remove excessive fluid. During a paracentesis, a small, thin tube is inserted into the abdomen.
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Therapies of Mesothelioma. Treatment The therapeutic management of individuals with mesothelioma may require the coordinated efforts of a team of medical professionals, such as physicians who specialize in the diagnosis and chemotherapy of cancer (medical oncologists), specialists in the use of radiation to treat cancer (radiation oncologists), surgeons, oncology nurses, and other specialists (depending upon the primary tumor site). Psychosocial support for the entire family is essential as well. Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as primary tumor location, extent of the primary tumor (stage), and degree of malignancy (grade); whether the tumor has spread to lymph nodes or distant sites; individual’s age and general health; and/or other elements. Decisions concerning the use of particular interventions should be made by physicians and other members of the health care team in careful consultation with the patient and family, based upon the specifics of his or her case, a thorough discussion of the potential benefits and risks, patient preference, and other appropriate factors. As this is an unusual disease, patients should consider seeking the care of a highly experienced specialist in this area, preferably at a major medical center that has extensive experience treating this very challenging disease. In many individuals with mesothelioma, standard therapy includes surgical removal of all or a portion of the malignancy and affected tissues. Surgical removal of the lining of the chest (pleura) may be performed in some cases of pleural mesothelioma (pleurectomy). Another procedure, known as an extrapleural pneumonectomy involves surgical removal of the pleura, pericardium, diaphragm, and the entire affected lung. Surgical removal of the peritoneum and surrounding tissue may be performed in cases of peritoneal mesothelioma. Surgery may also be performed to remove fluid accumulation from the chest or abdomen in order to relieve pain and other symptoms. In addition, based upon primary tumor site, size, and other factors, recommended therapy may often include postoperative radiation to help treat known or possible residual disease. If initial surgery is not an option due to the specific location and/or progression of the malignancy, therapy may include radiation alone. Radiation therapy preferentially destroys or injures rapidly dividing cells, primarily cancerous cells. However, some healthy cells (e.g., hair follicles, bone marrow, etc.) may also be damaged, leading to certain side effects. Thus, during such therapy, the radiation is passed through diseased tissue in carefully calculated dosages to destroy cancer cells while minimizing exposure and damage to normal cells. Radiation therapy works to destroy cancer cells by depositing energy that damages their genetic material, preventing or slowing their growth and replication. Various types of radiation may be used–again, depending on cancer type, location, stage and grade, prior treatments. For some affected individuals, particularly those who have locally advanced, metastatic, or recurrent disease, or those unable to tolerate more aggressive approaches, therapy with certain anticancer drugs (chemotherapy) may also be recommended. Combination chemotherapy is generally more effective than treatment with a single agent, and physicians may recommend combination therapy with multiple chemotherapeutic drugs that have different modes of action in destroying tumor cells and/or preventing them from multiplying. For some patients, some combination of two or all three treatment modalities (surgery, radiation, chemotherapy) may be considered. This is known as the multimodal approach. In 2004, the U.S. Food and Drug Administration (FDA) approved the orphan drug Alimta (pemetrexed disodium) used in combination with Platinol (cisplatin) for the treatment of individuals with malignant pleural mesothelioma when surgery is not an option. More recently, in 2020, FDA approved the combination of Opdivo (nivolumab) plus Yervoy (ipilimumab) as first-line treatment for adult patients with unresectable malignant pleural mesothelioma. Some treatment for individuals with mesothelioma may help to reduce symptoms and ease pain. Such therapies include procedures known as thoracentesis and paracentesis to drain fluid that may accumulate in the chest or stomach. During a thoracentesis, a needle or small tube (catheter) is inserted into the chest cavity to remove excessive fluid. During a paracentesis, a small, thin tube is inserted into the abdomen.
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Mesothelioma
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nord_803_0
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Overview of Metachromatic Leukodystrophy
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SummaryMetachromatic leukodystrophy (MLD) is a rare hereditary disease characterized by accumulation of fats called sulfatides. This causes the destruction of the protective fatty layer (myelin sheath) surrounding the nerves in both the central nervous system and the peripheral nervous system. There are three types of MLD based on the age symptoms appear: late-infantile MLD, juvenile MLD, and adult MLD. All subtypes ultimately affect both intellectual and motor function. Symptoms vary by type but can include difficulty talking, seizures, difficulty walking, personality changes, and behavior and personality changes. MLD is caused by changes (mutations) in the ARSA gene and, in rare cases, the PSAP gene.IntroductionThis condition is called metachromatic leukodystrophy because when viewed under a microscope, sulfatide accumulation in cells appears as granules that are colored differently than other cellular material (metachromatic). A leukodystrophy is a genetic disorder that disrupts myelination in the brain.
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Overview of Metachromatic Leukodystrophy. SummaryMetachromatic leukodystrophy (MLD) is a rare hereditary disease characterized by accumulation of fats called sulfatides. This causes the destruction of the protective fatty layer (myelin sheath) surrounding the nerves in both the central nervous system and the peripheral nervous system. There are three types of MLD based on the age symptoms appear: late-infantile MLD, juvenile MLD, and adult MLD. All subtypes ultimately affect both intellectual and motor function. Symptoms vary by type but can include difficulty talking, seizures, difficulty walking, personality changes, and behavior and personality changes. MLD is caused by changes (mutations) in the ARSA gene and, in rare cases, the PSAP gene.IntroductionThis condition is called metachromatic leukodystrophy because when viewed under a microscope, sulfatide accumulation in cells appears as granules that are colored differently than other cellular material (metachromatic). A leukodystrophy is a genetic disorder that disrupts myelination in the brain.
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Metachromatic Leukodystrophy
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Symptoms of Metachromatic Leukodystrophy
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Each MLD subtype has specific symptoms and rate of progression. Each subtype is based on age of onset.Over half of the children affected by MLD show symptoms in the first 3 years of life. This form is called late-infantile MLD. Often the first signs of disease are from demyelination of the peripheral nervous system and include difficulty walking.Juvenile MLD (J-MLD) is less common and occurs in 20-30% of people with MLD. Onset is between 4 years old and sexual maturity, usually between 12 and 14 years of age. Often with J-MLD, the first signs include behavioral problems or new difficulty in school.All forms of MLD are progressive. In late-infantile MLD, within months of the first symptoms, most children lose the ability to talk and walk. The progression in the juvenile and adult forms can occur over years to decades. Regardless of the subtype, last stage of the disease is often characterized by blindness, inability to move, unresponsiveness, and an inability to speak.
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Symptoms of Metachromatic Leukodystrophy. Each MLD subtype has specific symptoms and rate of progression. Each subtype is based on age of onset.Over half of the children affected by MLD show symptoms in the first 3 years of life. This form is called late-infantile MLD. Often the first signs of disease are from demyelination of the peripheral nervous system and include difficulty walking.Juvenile MLD (J-MLD) is less common and occurs in 20-30% of people with MLD. Onset is between 4 years old and sexual maturity, usually between 12 and 14 years of age. Often with J-MLD, the first signs include behavioral problems or new difficulty in school.All forms of MLD are progressive. In late-infantile MLD, within months of the first symptoms, most children lose the ability to talk and walk. The progression in the juvenile and adult forms can occur over years to decades. Regardless of the subtype, last stage of the disease is often characterized by blindness, inability to move, unresponsiveness, and an inability to speak.
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Metachromatic Leukodystrophy
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Causes of Metachromatic Leukodystrophy
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MLD is an autosomal recessive genetic disorder. Recessive genetic disorders occur when both copies of the gene are affected. If a child is affected, most of the time, their parents are carriers, meaning each parent will have one changed (mutated) copy and one normal copy of the ARSA gene, but will not have symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25%. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. The ARSA gene encodes the protein arylsulfatase A. There is some association with specific mutations and the subtype of MLD (genotype-phenotype correlation). Rarely, children with MLD have working copies of the ARSA gene, but abnormalities in PSAP gene, which encodes several saposin proteins, including saposin B, an activator of arylsulfatase A.Abnormalities in these proteins result in the inability of the body to breakdown fats (lipids) that contain sulfate (sulfatides). Accumulation of sulfatides then occurs in the nervous system, kidneys, testes, and brain, and interferes with the production of myelin, the substance that insulates and protects the nerves. When the sulfatides build up within the nervous system, the myelin breaks down and nerves connecting the brain and spinal cord do not function properly. This leads to problems with brain function that results in the mental and physical problems present in those who have MLD. The symptoms vary depending on which parts of the brain are affected.
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Causes of Metachromatic Leukodystrophy. MLD is an autosomal recessive genetic disorder. Recessive genetic disorders occur when both copies of the gene are affected. If a child is affected, most of the time, their parents are carriers, meaning each parent will have one changed (mutated) copy and one normal copy of the ARSA gene, but will not have symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25%. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. The ARSA gene encodes the protein arylsulfatase A. There is some association with specific mutations and the subtype of MLD (genotype-phenotype correlation). Rarely, children with MLD have working copies of the ARSA gene, but abnormalities in PSAP gene, which encodes several saposin proteins, including saposin B, an activator of arylsulfatase A.Abnormalities in these proteins result in the inability of the body to breakdown fats (lipids) that contain sulfate (sulfatides). Accumulation of sulfatides then occurs in the nervous system, kidneys, testes, and brain, and interferes with the production of myelin, the substance that insulates and protects the nerves. When the sulfatides build up within the nervous system, the myelin breaks down and nerves connecting the brain and spinal cord do not function properly. This leads to problems with brain function that results in the mental and physical problems present in those who have MLD. The symptoms vary depending on which parts of the brain are affected.
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Metachromatic Leukodystrophy
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Affects of Metachromatic Leukodystrophy
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The true prevalence rate of MLD is unknown, but is estimated to be between 1 in 40,000 and 1 in 160,000. The Navajo also have a higher prevalence rate of 1 in every 2,500 people. In certain populations in the Middle East, these numbers may be even higher.
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Affects of Metachromatic Leukodystrophy. The true prevalence rate of MLD is unknown, but is estimated to be between 1 in 40,000 and 1 in 160,000. The Navajo also have a higher prevalence rate of 1 in every 2,500 people. In certain populations in the Middle East, these numbers may be even higher.
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Metachromatic Leukodystrophy
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Related disorders of Metachromatic Leukodystrophy
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There are multiple related disorders that have been identified with similar causes or symptoms, including other leukodystrophies, which can have a similar initial presentation in early childhood.Arylsulfatase A pseudodeficiency involves low arylsulfatase A enzyme activity (less than 15% of normal), but no symptoms.Multiple sulfatase deficiency is caused by the loss (partial or complete) of all sulfatases, including arylsulfatase A. Children affected by MSD will have low enzymatic activity of multiple sulfatases, not just arylsulfatase A. For more information on this disorder, choose “multiple sulfatase deficiency” as your search term in the Rare Disease Database.Acquired conditions, such as inflammatory demyelinating polyneuropathy, can look similar on initial electrophysiological testing. MLD should be considered in the differential in young children diagnosed with chronic inflammatory demyelinating polyneuropathy (CIDP) or Guillain–Barré syndrome (GBS). These diagnoses can be easily distinguished with sulfatase testing.
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Related disorders of Metachromatic Leukodystrophy. There are multiple related disorders that have been identified with similar causes or symptoms, including other leukodystrophies, which can have a similar initial presentation in early childhood.Arylsulfatase A pseudodeficiency involves low arylsulfatase A enzyme activity (less than 15% of normal), but no symptoms.Multiple sulfatase deficiency is caused by the loss (partial or complete) of all sulfatases, including arylsulfatase A. Children affected by MSD will have low enzymatic activity of multiple sulfatases, not just arylsulfatase A. For more information on this disorder, choose “multiple sulfatase deficiency” as your search term in the Rare Disease Database.Acquired conditions, such as inflammatory demyelinating polyneuropathy, can look similar on initial electrophysiological testing. MLD should be considered in the differential in young children diagnosed with chronic inflammatory demyelinating polyneuropathy (CIDP) or Guillain–Barré syndrome (GBS). These diagnoses can be easily distinguished with sulfatase testing.
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Metachromatic Leukodystrophy
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Diagnosis of Metachromatic Leukodystrophy
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MLD is first suspected by recognizing the characteristic pattern of progressive impairment. In the late-infantile form, the first signs are often difficult walking, which can present as new inability to fully lift the feet while walking (foot drop) or by toe walking. For adult MLD, the first signs are slurred speech and behavioral issues that include difficulty in school, behavior changes, and decreased ability in school. Individuals with juvenile MLD can present with motor or cognitive symptoms.Clinical Testing and Work-Up
The diagnosis of MLD is made through both genetic and biochemical testing. Genetic testing can identify mutations in the ARSA and PSAP genes. Biochemical testing includes sulfatase enzyme activity and urinary sulfatide excretion.An MRI can confirm a diagnosis of MLD. An MRI shows imaging of a person’s brain and can show the presence and absence of myelin. There is a classic pattern of myelin loss in the brains of individuals affected by MLD. As the disease progresses, imaging shows accumulating injury to the brain. Of note, in young children, the initial brain imaging can be normal.
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Diagnosis of Metachromatic Leukodystrophy. MLD is first suspected by recognizing the characteristic pattern of progressive impairment. In the late-infantile form, the first signs are often difficult walking, which can present as new inability to fully lift the feet while walking (foot drop) or by toe walking. For adult MLD, the first signs are slurred speech and behavioral issues that include difficulty in school, behavior changes, and decreased ability in school. Individuals with juvenile MLD can present with motor or cognitive symptoms.Clinical Testing and Work-Up
The diagnosis of MLD is made through both genetic and biochemical testing. Genetic testing can identify mutations in the ARSA and PSAP genes. Biochemical testing includes sulfatase enzyme activity and urinary sulfatide excretion.An MRI can confirm a diagnosis of MLD. An MRI shows imaging of a person’s brain and can show the presence and absence of myelin. There is a classic pattern of myelin loss in the brains of individuals affected by MLD. As the disease progresses, imaging shows accumulating injury to the brain. Of note, in young children, the initial brain imaging can be normal.
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Metachromatic Leukodystrophy
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nord_803_6
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Therapies of Metachromatic Leukodystrophy
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Treatment
In pre- or minimally symptomatic children, stem cell transplantation can be considered. Otherwise, the main treatment is supportive and focused on symptomatic relief.
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Therapies of Metachromatic Leukodystrophy. Treatment
In pre- or minimally symptomatic children, stem cell transplantation can be considered. Otherwise, the main treatment is supportive and focused on symptomatic relief.
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Metachromatic Leukodystrophy
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nord_804_0
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Overview of Metaphyseal Chondrodysplasia, Schmid Type
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Metaphyseal chondrodysplasia, Schmid type (MCDS), is a very rare inherited disorder characterized by short stature with abnormally short arms and legs (short-limbed dwarfism) and bowed legs (genu varum). Other physical characteristics may include outward “flaring” of the bones of the lower rib cage, lumbar lordosis, pain in the legs, and/or hip deformities in which the thigh bone is angled toward the center of the body (coxa vara). Such abnormalities of the legs and hips typically result in an unusual “waddling” walk (gait). MCDS is transmitted as an autosomal dominant trait.
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Overview of Metaphyseal Chondrodysplasia, Schmid Type. Metaphyseal chondrodysplasia, Schmid type (MCDS), is a very rare inherited disorder characterized by short stature with abnormally short arms and legs (short-limbed dwarfism) and bowed legs (genu varum). Other physical characteristics may include outward “flaring” of the bones of the lower rib cage, lumbar lordosis, pain in the legs, and/or hip deformities in which the thigh bone is angled toward the center of the body (coxa vara). Such abnormalities of the legs and hips typically result in an unusual “waddling” walk (gait). MCDS is transmitted as an autosomal dominant trait.
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Metaphyseal Chondrodysplasia, Schmid Type
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Symptoms of Metaphyseal Chondrodysplasia, Schmid Type
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In MCDS, portions of the bones of the arms and legs develop abnormally with unusual cartilage formations and subsequent abnormal bone formation at the large end portions (metaphyses) of the long bones. Bone growth normally takes place at the metaphyses, but in individuals with MCDS, the growth plate does not function as well as normal and the bones of the leg bow. Consequently, affected individuals exhibit unusually short arms and legs and short stature (short-limbed dwarfism) that usually become apparent by the second year of life.Symptoms of MCDS are usually noticed for the first time when an infant begins walking. The legs are bowed (genu varum) and a waddling gait is present. Moderate short stature becomes apparent as the child grows. Affected children may also exhibit a hip deformity in which the thigh bone is angled toward the center of the body (coxa vara), flaring of the bones of the lower rib cage, and/or a small chest (thorax).Some affected children may experience pain in the legs, pain of the joints (arthritis), and joint stiffness. Joint pain may worsen with age.
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Symptoms of Metaphyseal Chondrodysplasia, Schmid Type. In MCDS, portions of the bones of the arms and legs develop abnormally with unusual cartilage formations and subsequent abnormal bone formation at the large end portions (metaphyses) of the long bones. Bone growth normally takes place at the metaphyses, but in individuals with MCDS, the growth plate does not function as well as normal and the bones of the leg bow. Consequently, affected individuals exhibit unusually short arms and legs and short stature (short-limbed dwarfism) that usually become apparent by the second year of life.Symptoms of MCDS are usually noticed for the first time when an infant begins walking. The legs are bowed (genu varum) and a waddling gait is present. Moderate short stature becomes apparent as the child grows. Affected children may also exhibit a hip deformity in which the thigh bone is angled toward the center of the body (coxa vara), flaring of the bones of the lower rib cage, and/or a small chest (thorax).Some affected children may experience pain in the legs, pain of the joints (arthritis), and joint stiffness. Joint pain may worsen with age.
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Metaphyseal Chondrodysplasia, Schmid Type
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nord_804_2
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Causes of Metaphyseal Chondrodysplasia, Schmid Type
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MCDS is caused by a mutation of the gene for type X collagen called COL10A1. This gene has been mapped to chromosome 6q21-22.3. MCDS is transmitted as an autosomal dominant trait.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 6q21-22.3” refers to band 21-22.3 on the long arm of chromosome 6. The numbered bands specify the location of the thousands of genes that are present on each chromosome.Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.
Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.
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Causes of Metaphyseal Chondrodysplasia, Schmid Type. MCDS is caused by a mutation of the gene for type X collagen called COL10A1. This gene has been mapped to chromosome 6q21-22.3. MCDS is transmitted as an autosomal dominant trait.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 6q21-22.3” refers to band 21-22.3 on the long arm of chromosome 6. The numbered bands specify the location of the thousands of genes that are present on each chromosome.Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.
Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.
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Metaphyseal Chondrodysplasia, Schmid Type
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Affects of Metaphyseal Chondrodysplasia, Schmid Type
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Metaphyseal chondrodysplasia Schmid type is a very rare bone disorder that affects males and females in equal numbers. Individuals of several large families (kindred) have been documented in the medical literature.
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Affects of Metaphyseal Chondrodysplasia, Schmid Type. Metaphyseal chondrodysplasia Schmid type is a very rare bone disorder that affects males and females in equal numbers. Individuals of several large families (kindred) have been documented in the medical literature.
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Metaphyseal Chondrodysplasia, Schmid Type
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Related disorders of Metaphyseal Chondrodysplasia, Schmid Type
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Symptoms of the following disorders can be similar to those of Schmid type metaphyseal chondrodysplasia. Comparisons may be useful for differential diagnosis:McKusick type metaphyseal chondrodysplasia, also known as cartilage-hair hypoplasia, is an extremely rare inherited disorder characterized by unusually fine, sparse hair and abnormal development of the cartilage and subsequent bone formation in the long bones of the arms and legs (metaphyseal chondrodysplasia), resulting in unusually short arms and legs and short stature (short-limbed dwarfism). Most affected individuals exhibit impairment of certain white blood cells (T-cells) that play an important role in helping the body’s immune system fight certain infections (cellular immunodeficiency). In addition, affected individuals may also exhibit impaired absorption of certain necessary nutrients (malabsorption); abnormally low levels of certain white blood cells in the body (neutropenia and lymphocytopenia); low levels of circulating red blood cells (anemia); increased susceptibility to repeated infections, such as chickenpox; abnormalities of the teeth; and/or other physical findings. The range and severity of symptoms vary widely from person to person. McKusick type metaphyseal chondrodysplasia is inherited as an autosomal recessive genetic trait. (For more information on this disorder, choose “McKusick type metaphyseal chondrodysplasia” as your search term in the Rare Disease Database.)Jansen type metaphyseal chondrodysplasia is an extremely rare inherited disorder characterized by severe short stature with abnormally short arms and legs (short-limbed dwarfism). Abnormally short arms and legs result from the improper formation of the cartilage at the end portions (metaphyses) of the long bones (metaphyseal chondrodysplasia). Improper cartilage development may also occur in the metaphyses of other bones of the body, particularly those of the hands and feet (i.e., metacarpals and metatarsals). Affected children may also exhibit malformation of certain bones of the skull; deformities of certain joints including swelling, pain, and stiffness; abnormally short fingers (brachydactyly); and/or abnormal front-to-back and side-to-side curvature of the spine (kyphoscoliosis). In addition, affected children may have abnormally high levels of calcium in the blood (hypercalcemia). Jansen type metaphyseal chondrodysplasia is thought to be inherited as an autosomal dominant genetic trait. (For more information on this disorder choose, “Jansen yype metaphyseal chondrodysplasia” as your search term in the Rare Disease Database.)Spahr type metaphyseal chondrodysplasia is an extremely rare inherited disorder characterized by abnormal development of the cartilage and subsequent bone formation in the long bones of the arms and legs (metaphyseal chondrodysplasia), resulting in severely bowed legs and short stature (short-limbed dwarfism). This disorder is very similar to Schmid type metaphyseal chondrodysplasia except Spahr type metaphyseal chondrodysplasia is thought to be inherited as an autosomal recessive genetic trait.Vitamin D deficiency rickets is a rare inherited disorder characterized by skeletal abnormalities due, in most cases, to a deficiency in vitamin D levels (Type I) or inability to properly utilize vitamin D (Type II). Skeletal abnormalities may include bowed legs; abnormal front-to-back and side-to-side curvature of the spine (kyphoscoliosis); malformations of the bones of the spine, pelvis, and legs; and/or, in severe cases, abnormal side-to-side (horizontal) depression of the lower portion of the chest cavity (Harrison Groove). In most cases, affected infants will exhibit abnormally low levels of calcium in the blood (hypocalcemia). (For more information on this disorder, choose “rickets, vitamin D deficiency” as your search term in the Rare Disease Database.)
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Related disorders of Metaphyseal Chondrodysplasia, Schmid Type. Symptoms of the following disorders can be similar to those of Schmid type metaphyseal chondrodysplasia. Comparisons may be useful for differential diagnosis:McKusick type metaphyseal chondrodysplasia, also known as cartilage-hair hypoplasia, is an extremely rare inherited disorder characterized by unusually fine, sparse hair and abnormal development of the cartilage and subsequent bone formation in the long bones of the arms and legs (metaphyseal chondrodysplasia), resulting in unusually short arms and legs and short stature (short-limbed dwarfism). Most affected individuals exhibit impairment of certain white blood cells (T-cells) that play an important role in helping the body’s immune system fight certain infections (cellular immunodeficiency). In addition, affected individuals may also exhibit impaired absorption of certain necessary nutrients (malabsorption); abnormally low levels of certain white blood cells in the body (neutropenia and lymphocytopenia); low levels of circulating red blood cells (anemia); increased susceptibility to repeated infections, such as chickenpox; abnormalities of the teeth; and/or other physical findings. The range and severity of symptoms vary widely from person to person. McKusick type metaphyseal chondrodysplasia is inherited as an autosomal recessive genetic trait. (For more information on this disorder, choose “McKusick type metaphyseal chondrodysplasia” as your search term in the Rare Disease Database.)Jansen type metaphyseal chondrodysplasia is an extremely rare inherited disorder characterized by severe short stature with abnormally short arms and legs (short-limbed dwarfism). Abnormally short arms and legs result from the improper formation of the cartilage at the end portions (metaphyses) of the long bones (metaphyseal chondrodysplasia). Improper cartilage development may also occur in the metaphyses of other bones of the body, particularly those of the hands and feet (i.e., metacarpals and metatarsals). Affected children may also exhibit malformation of certain bones of the skull; deformities of certain joints including swelling, pain, and stiffness; abnormally short fingers (brachydactyly); and/or abnormal front-to-back and side-to-side curvature of the spine (kyphoscoliosis). In addition, affected children may have abnormally high levels of calcium in the blood (hypercalcemia). Jansen type metaphyseal chondrodysplasia is thought to be inherited as an autosomal dominant genetic trait. (For more information on this disorder choose, “Jansen yype metaphyseal chondrodysplasia” as your search term in the Rare Disease Database.)Spahr type metaphyseal chondrodysplasia is an extremely rare inherited disorder characterized by abnormal development of the cartilage and subsequent bone formation in the long bones of the arms and legs (metaphyseal chondrodysplasia), resulting in severely bowed legs and short stature (short-limbed dwarfism). This disorder is very similar to Schmid type metaphyseal chondrodysplasia except Spahr type metaphyseal chondrodysplasia is thought to be inherited as an autosomal recessive genetic trait.Vitamin D deficiency rickets is a rare inherited disorder characterized by skeletal abnormalities due, in most cases, to a deficiency in vitamin D levels (Type I) or inability to properly utilize vitamin D (Type II). Skeletal abnormalities may include bowed legs; abnormal front-to-back and side-to-side curvature of the spine (kyphoscoliosis); malformations of the bones of the spine, pelvis, and legs; and/or, in severe cases, abnormal side-to-side (horizontal) depression of the lower portion of the chest cavity (Harrison Groove). In most cases, affected infants will exhibit abnormally low levels of calcium in the blood (hypocalcemia). (For more information on this disorder, choose “rickets, vitamin D deficiency” as your search term in the Rare Disease Database.)
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Metaphyseal Chondrodysplasia, Schmid Type
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Diagnosis of Metaphyseal Chondrodysplasia, Schmid Type
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In most cases, the diagnosis of MCDS is suspected during early childhood, usually by the second or third year of life. The diagnosis may be confirmed by a thorough clinical evaluation, identification of characteristic physical findings, and a variety of specialized tests, particularly advanced imaging techniques. These techniques include x-ray studies that may reveal abnormal development of the large (bulbous) ends (metaphyses) of certain bones of the body, particularly those of the arms and legs, abnormal enlargement of the growing end of the upper portion of the thigh bone (capital femoral epiphysis).Molecular genetic testing for the COL10A1 gene is available to confirm the diagnosis. This test involves sequence of DNA from the COL10A1 gene and should detect any disease causing mutations. Prenatal diagnosis is available if the specific COL10A1 mutation has been identified in the family.MCDS is often mistaken for vitamin D deficiency rickets. It is important that proper diagnosis is made as to avoid unnecessary and potentially harmful vitamin D therapy.
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Diagnosis of Metaphyseal Chondrodysplasia, Schmid Type. In most cases, the diagnosis of MCDS is suspected during early childhood, usually by the second or third year of life. The diagnosis may be confirmed by a thorough clinical evaluation, identification of characteristic physical findings, and a variety of specialized tests, particularly advanced imaging techniques. These techniques include x-ray studies that may reveal abnormal development of the large (bulbous) ends (metaphyses) of certain bones of the body, particularly those of the arms and legs, abnormal enlargement of the growing end of the upper portion of the thigh bone (capital femoral epiphysis).Molecular genetic testing for the COL10A1 gene is available to confirm the diagnosis. This test involves sequence of DNA from the COL10A1 gene and should detect any disease causing mutations. Prenatal diagnosis is available if the specific COL10A1 mutation has been identified in the family.MCDS is often mistaken for vitamin D deficiency rickets. It is important that proper diagnosis is made as to avoid unnecessary and potentially harmful vitamin D therapy.
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Metaphyseal Chondrodysplasia, Schmid Type
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nord_804_6
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Therapies of Metaphyseal Chondrodysplasia, Schmid Type
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TreatmentThe treatment of MCDS is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, orthopedic surgeons, physical therapists, and other health care professionals may need to systematically and comprehensively plan an affected child's treatment.Physical therapy and/or orthopedic surgery may help correct certain specific findings associated with metaphyseal chondrodysplasia, Schmid type, such as deformity of the hip.Early intervention is important to ensure that children with MCDS reach their potential. Special services that may be beneficial to affected children may include speech therapy, special social support, physical therapy, and other medical, social, and/or vocational services.Growth hormone therapy is not effective to increase final adult height.Genetic counseling will be of benefit for affected individuals and their families. Other treatment for this disorder is symptomatic and supportive.
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Therapies of Metaphyseal Chondrodysplasia, Schmid Type. TreatmentThe treatment of MCDS is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, orthopedic surgeons, physical therapists, and other health care professionals may need to systematically and comprehensively plan an affected child's treatment.Physical therapy and/or orthopedic surgery may help correct certain specific findings associated with metaphyseal chondrodysplasia, Schmid type, such as deformity of the hip.Early intervention is important to ensure that children with MCDS reach their potential. Special services that may be beneficial to affected children may include speech therapy, special social support, physical therapy, and other medical, social, and/or vocational services.Growth hormone therapy is not effective to increase final adult height.Genetic counseling will be of benefit for affected individuals and their families. Other treatment for this disorder is symptomatic and supportive.
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Metaphyseal Chondrodysplasia, Schmid Type
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nord_805_0
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Overview of Metatropic Dysplasia I
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Metatropic Dysplasia I is a rare genetic disorder characterized by extremely small stature, with short arms and legs. Other characteristics of this disorder are a narrow thorax, short ribs, and kyphoscoliosis (backward and sideways curvature of the spinal column) which develops into short trunk dwarfism.
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Overview of Metatropic Dysplasia I. Metatropic Dysplasia I is a rare genetic disorder characterized by extremely small stature, with short arms and legs. Other characteristics of this disorder are a narrow thorax, short ribs, and kyphoscoliosis (backward and sideways curvature of the spinal column) which develops into short trunk dwarfism.
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Metatropic Dysplasia I
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Symptoms of Metatropic Dysplasia I
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Metatropic Dysplasia I is characterized by abnormal skeletal development. Patients with this disorder typically have short ribs, short deformed arms and legs, kyphoscoliosis (abnormal curvature of the spine) and extremely short stature. A long narrow thorax, bulging joints with limited mobility of the knees and hips, and unusual increased extension of the finger joints are typical features.An unusually long torso, which later develops into short trunk dwarfism due to curvature of the spine, is an early feature of Metatropic Dysplasia I. The spine develops a forward hump-like curvature causing a humpback.X-rays show growth insufficiency of the vertebral column with flattening of vertebrae and often growth insufficiency in the arm and leg bones at the hip and shoulder joints. A crescent-like iliac causing a hump at the end of the spine is also apparent.
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Symptoms of Metatropic Dysplasia I. Metatropic Dysplasia I is characterized by abnormal skeletal development. Patients with this disorder typically have short ribs, short deformed arms and legs, kyphoscoliosis (abnormal curvature of the spine) and extremely short stature. A long narrow thorax, bulging joints with limited mobility of the knees and hips, and unusual increased extension of the finger joints are typical features.An unusually long torso, which later develops into short trunk dwarfism due to curvature of the spine, is an early feature of Metatropic Dysplasia I. The spine develops a forward hump-like curvature causing a humpback.X-rays show growth insufficiency of the vertebral column with flattening of vertebrae and often growth insufficiency in the arm and leg bones at the hip and shoulder joints. A crescent-like iliac causing a hump at the end of the spine is also apparent.
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Metatropic Dysplasia I
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Causes of Metatropic Dysplasia I
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Metatropic Dysplasia I can be inherited as an autosomal dominant or autosomal recessive trait.Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother.In dominant disorders, a single copy of the disease gene (received from either the mother or father) will be expressed “dominating” the other normal gene and resulting in the appearance of the disease. The risk of transmitting the disorder from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child. In recessive disorders, the condition does not appear unless a person inherits the same defective gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease, but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy.
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Causes of Metatropic Dysplasia I. Metatropic Dysplasia I can be inherited as an autosomal dominant or autosomal recessive trait.Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother.In dominant disorders, a single copy of the disease gene (received from either the mother or father) will be expressed “dominating” the other normal gene and resulting in the appearance of the disease. The risk of transmitting the disorder from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child. In recessive disorders, the condition does not appear unless a person inherits the same defective gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease, but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy.
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Metatropic Dysplasia I
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Affects of Metatropic Dysplasia I
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Metatropic Dysplasia I is a very rare disorder that affects males and females in equal numbers.
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Affects of Metatropic Dysplasia I. Metatropic Dysplasia I is a very rare disorder that affects males and females in equal numbers.
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Metatropic Dysplasia I
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Related disorders of Metatropic Dysplasia I
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Symptoms of the following disorders can be similar to those of Metatropic Dysplasia I. Comparisons may be useful for a differential diagnosis:Kniest Syndrome is a rare type of dwarfism that is characterized by unusually short arms and legs, a round face with hollow or depressed areas, swelling and stiffness of the joints, and a stiff drawing up (contractures) of the fingers. A cleft palate, curvature of the spine (scoliosis), vision and hearing problems may also occur. (For more information on this disorder, choose “Kniest” as your search term in the Rare Disease Database.)Morquio Syndrome is a metabolic disorder characterized by an accumulation of keratan sulfate. Bony abnormalities of the head, chest, hands, knees, and spine may occur as a result of this defect. Intelligence is usually normal. The bony abnormalities of the spine can result in spinal cord compression. There also may be enlargement of the liver, curvature of the spine, a back flow of blood from the aortic valve of the heart into the left ventricle of the heart, as well as a loss of hearing. (For more information on this disorder, choose “Morquio” as your search term in the Rare Disease Database.)
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Related disorders of Metatropic Dysplasia I. Symptoms of the following disorders can be similar to those of Metatropic Dysplasia I. Comparisons may be useful for a differential diagnosis:Kniest Syndrome is a rare type of dwarfism that is characterized by unusually short arms and legs, a round face with hollow or depressed areas, swelling and stiffness of the joints, and a stiff drawing up (contractures) of the fingers. A cleft palate, curvature of the spine (scoliosis), vision and hearing problems may also occur. (For more information on this disorder, choose “Kniest” as your search term in the Rare Disease Database.)Morquio Syndrome is a metabolic disorder characterized by an accumulation of keratan sulfate. Bony abnormalities of the head, chest, hands, knees, and spine may occur as a result of this defect. Intelligence is usually normal. The bony abnormalities of the spine can result in spinal cord compression. There also may be enlargement of the liver, curvature of the spine, a back flow of blood from the aortic valve of the heart into the left ventricle of the heart, as well as a loss of hearing. (For more information on this disorder, choose “Morquio” as your search term in the Rare Disease Database.)
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Metatropic Dysplasia I
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Diagnosis of Metatropic Dysplasia I
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Diagnosis of Metatropic Dysplasia I.
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Metatropic Dysplasia I
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Therapies of Metatropic Dysplasia I
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Treatment of Metatropic Dysplasia I is symptomatic and supportive. When partial dislocation of the segments of the spinal column at the top of the spine (cervical vertebrae) is present, the joint between the two vertebrae can be fused together. This procedure should be done in order to prevent damage to the cervical part of the spinal cord.Genetic counseling may be of benefit for patients and their families.
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Therapies of Metatropic Dysplasia I. Treatment of Metatropic Dysplasia I is symptomatic and supportive. When partial dislocation of the segments of the spinal column at the top of the spine (cervical vertebrae) is present, the joint between the two vertebrae can be fused together. This procedure should be done in order to prevent damage to the cervical part of the spinal cord.Genetic counseling may be of benefit for patients and their families.
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Metatropic Dysplasia I
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nord_806_0
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Overview of Mevalonate Kinase Deficiency
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Mevalonate kinase deficiency (MKD) is a rare genetic autoinflammatory disorder. Autoinflammatory syndromes are a group of disorders characterized by seemingly random or unprovoked episodes of inflammation generally due to an abnormality of the innate immune system. They are not the same as autoimmune disorders, in which the adaptive immune system malfunctions and mistakenly attacks healthy tissue.Mevalonate kinase deficiency is a spectrum of disease, ranging from more mild to severe complications. Hyper IgD syndrome (HIDS) is part of this spectrum and is characterized by episodes or “attacks” of fever associated with other symptoms including joint pain (arthralgia), muscle pain (myalgia), skin rash and abdominal pain. Most episodes last several days and can repeat throughout life. The frequency of episodes and their severity vary greatly from one person to another. Mevalonate aciduria is a more severe form. In addition to symptoms associated with HIDS, mevalonate aciduria can cause growth deficiency before and after birth, neurological abnormalities and ocular problems. Sometimes, mevalonate aciduria can cause life-threatening complications in childhood. Mevalonate kinase deficiency is caused by changes (mutations) in the MVK gene.
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Overview of Mevalonate Kinase Deficiency. Mevalonate kinase deficiency (MKD) is a rare genetic autoinflammatory disorder. Autoinflammatory syndromes are a group of disorders characterized by seemingly random or unprovoked episodes of inflammation generally due to an abnormality of the innate immune system. They are not the same as autoimmune disorders, in which the adaptive immune system malfunctions and mistakenly attacks healthy tissue.Mevalonate kinase deficiency is a spectrum of disease, ranging from more mild to severe complications. Hyper IgD syndrome (HIDS) is part of this spectrum and is characterized by episodes or “attacks” of fever associated with other symptoms including joint pain (arthralgia), muscle pain (myalgia), skin rash and abdominal pain. Most episodes last several days and can repeat throughout life. The frequency of episodes and their severity vary greatly from one person to another. Mevalonate aciduria is a more severe form. In addition to symptoms associated with HIDS, mevalonate aciduria can cause growth deficiency before and after birth, neurological abnormalities and ocular problems. Sometimes, mevalonate aciduria can cause life-threatening complications in childhood. Mevalonate kinase deficiency is caused by changes (mutations) in the MVK gene.
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Mevalonate Kinase Deficiency
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Symptoms of Mevalonate Kinase Deficiency
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Mevalonate kinase deficiency is a spectrum of disease that can range from milder symptoms to severe, even life-threatening complications. Affected individuals can fall anywhere along this spectrum and it is important to remember every person is unique and the disorder may affect them differently from how it affects another person.The milder end of the spectrum, also known as hyper IgD syndrome, is more common and is characterized by recurrent episodes of unexplained fever. There is often an abrupt onset of fever with no associated infection. These episodes are accompanied by fatigue, chills, abdominal pain, swelling of affected lymph nodes (lymphadenopathy), a rash, joint inflammation (arthritis) and pain (arthralgia). Additional symptoms include nausea, diarrhea, vomiting, headaches, small ulcers in the mouth and abnormal enlargement of the liver and spleen (hepatosplenomegaly). The rash consists of reddish (erythematous) spots (macules) or bumps (papules). Some individuals have a cough and inflammation of the back of the throat (pharyngitis).The specific symptoms present during an episode and their severity vary from person to person. For an affected individual, the severity of individual episodes also varies. Episodes usually last for three to seven days, but can be shorter or longer. The frequency of episodes varies greatly. Some individuals have an episode every month, some more frequently and others less frequently. The frequency of episodes may also increase or decrease during a person’s life. Between episodes, individuals with mevalonate kinase deficiency may not display symptoms, while others may experience fatigue, headaches or ulcers in the mouth. Joint and skin problems may persist for a short time after an episode ends.Mevalonate kinase deficiency is often more severe in children. Affected children often have a high spiking fever that, in rare instances, can cause seizures. Children are also more likely to have an abnormally enlarged spleen (splenomegaly). Episodes occur more frequently in children than adults. Episodes of fever may be set off by minor “triggers” such as emotional or physical stress. In children, episodes can follow vaccination. Adults may have mood and psychiatric features including depression.Less common symptoms include inflammation of conjunctiva, which is the mucous membrane that covers the front of the eye and lines the inside of the eyelids (conjunctivitis), inflammation of the middle layer of the eye (uveitis), and inflammation of the main nerve of the eye that sends impulses from the brain to the retina (optic neuritis). In rare instances, kidney (renal) problems may develop including benign (non-cancerous) tumors of the kidney called angiomyolipomas. Some people may be prone to developing infection, particularly pneumococcal infection. Additional findings that have been associated with this disorder include retinitis pigmentosum, an eye disorder in which abnormal pigmented materials builds up in the retina causing a decline in vision; inflammation of the lining of the colon (colitis), which can cause abdominal bloating and pain, a constant urge to have a bowel movement, dehydration, diarrhea, bloody stools, and fever; and disseminated superficial actinic porokeratosis (DSAP), which is a skin disorder causing dry patches of skin and small growths (papules), mainly on the arms and legs.In rare instances, people with mevalonate kinase deficiency develop long-term complications including AA amyloidosis, joint contractures, and abdominal adhesions. AA amyloidosis can occur in many chronic inflammatory disorders and is characterized by the accumulation of amyloid proteins in the kidneys. This can lead to progressive damage and dysfunction of the kidneys. Joint contractures occur when a joint becomes fixed in a bent or extended position, completely or partially restricting the movement of the joint. Abdominal adhesions are abnormal bands of fibrous tissues that form in the abdomen and cause abdominal organs and tissue to stick together. They may not cause symptoms or can cause chronic abdominal pain.The severe end of the spectrum, known as mevalonate aciduria, is characterized by episodes or fever and accompanying symptoms as described for the milder end of the spectrum. These episodes are usually more frequent and more severe. Affected infants and children may also have growth deficiency before and after birth, failure to grow and gain weight (failure to thrive), and distinctive facial features including widely spaced eyes (hypertelorism), a large forehead (frontal bossing), long eyelashes, and a triangularly-shaped face. Some infants may have microcephaly, a condition where the circumference of the head is smaller than would be expected. They may also experience delays in reaching developmental milestones (developmental delays), delays in reaching milestones that require the coordination of muscular and mental activity (psychomotor delays), intellectual disability, problems with voluntary muscle control leading to poor coordination (ataxia), and seizures. Some infants have diminished muscle tone (hypotonia). Cataracts have also been reported. Children may be prone to developing infections. The severe end of the spectrum of mevalonate kinase deficiency can be severe enough to cause life-threatening complications in some instances.
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Symptoms of Mevalonate Kinase Deficiency. Mevalonate kinase deficiency is a spectrum of disease that can range from milder symptoms to severe, even life-threatening complications. Affected individuals can fall anywhere along this spectrum and it is important to remember every person is unique and the disorder may affect them differently from how it affects another person.The milder end of the spectrum, also known as hyper IgD syndrome, is more common and is characterized by recurrent episodes of unexplained fever. There is often an abrupt onset of fever with no associated infection. These episodes are accompanied by fatigue, chills, abdominal pain, swelling of affected lymph nodes (lymphadenopathy), a rash, joint inflammation (arthritis) and pain (arthralgia). Additional symptoms include nausea, diarrhea, vomiting, headaches, small ulcers in the mouth and abnormal enlargement of the liver and spleen (hepatosplenomegaly). The rash consists of reddish (erythematous) spots (macules) or bumps (papules). Some individuals have a cough and inflammation of the back of the throat (pharyngitis).The specific symptoms present during an episode and their severity vary from person to person. For an affected individual, the severity of individual episodes also varies. Episodes usually last for three to seven days, but can be shorter or longer. The frequency of episodes varies greatly. Some individuals have an episode every month, some more frequently and others less frequently. The frequency of episodes may also increase or decrease during a person’s life. Between episodes, individuals with mevalonate kinase deficiency may not display symptoms, while others may experience fatigue, headaches or ulcers in the mouth. Joint and skin problems may persist for a short time after an episode ends.Mevalonate kinase deficiency is often more severe in children. Affected children often have a high spiking fever that, in rare instances, can cause seizures. Children are also more likely to have an abnormally enlarged spleen (splenomegaly). Episodes occur more frequently in children than adults. Episodes of fever may be set off by minor “triggers” such as emotional or physical stress. In children, episodes can follow vaccination. Adults may have mood and psychiatric features including depression.Less common symptoms include inflammation of conjunctiva, which is the mucous membrane that covers the front of the eye and lines the inside of the eyelids (conjunctivitis), inflammation of the middle layer of the eye (uveitis), and inflammation of the main nerve of the eye that sends impulses from the brain to the retina (optic neuritis). In rare instances, kidney (renal) problems may develop including benign (non-cancerous) tumors of the kidney called angiomyolipomas. Some people may be prone to developing infection, particularly pneumococcal infection. Additional findings that have been associated with this disorder include retinitis pigmentosum, an eye disorder in which abnormal pigmented materials builds up in the retina causing a decline in vision; inflammation of the lining of the colon (colitis), which can cause abdominal bloating and pain, a constant urge to have a bowel movement, dehydration, diarrhea, bloody stools, and fever; and disseminated superficial actinic porokeratosis (DSAP), which is a skin disorder causing dry patches of skin and small growths (papules), mainly on the arms and legs.In rare instances, people with mevalonate kinase deficiency develop long-term complications including AA amyloidosis, joint contractures, and abdominal adhesions. AA amyloidosis can occur in many chronic inflammatory disorders and is characterized by the accumulation of amyloid proteins in the kidneys. This can lead to progressive damage and dysfunction of the kidneys. Joint contractures occur when a joint becomes fixed in a bent or extended position, completely or partially restricting the movement of the joint. Abdominal adhesions are abnormal bands of fibrous tissues that form in the abdomen and cause abdominal organs and tissue to stick together. They may not cause symptoms or can cause chronic abdominal pain.The severe end of the spectrum, known as mevalonate aciduria, is characterized by episodes or fever and accompanying symptoms as described for the milder end of the spectrum. These episodes are usually more frequent and more severe. Affected infants and children may also have growth deficiency before and after birth, failure to grow and gain weight (failure to thrive), and distinctive facial features including widely spaced eyes (hypertelorism), a large forehead (frontal bossing), long eyelashes, and a triangularly-shaped face. Some infants may have microcephaly, a condition where the circumference of the head is smaller than would be expected. They may also experience delays in reaching developmental milestones (developmental delays), delays in reaching milestones that require the coordination of muscular and mental activity (psychomotor delays), intellectual disability, problems with voluntary muscle control leading to poor coordination (ataxia), and seizures. Some infants have diminished muscle tone (hypotonia). Cataracts have also been reported. Children may be prone to developing infections. The severe end of the spectrum of mevalonate kinase deficiency can be severe enough to cause life-threatening complications in some instances.
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Mevalonate Kinase Deficiency
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nord_806_2
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Causes of Mevalonate Kinase Deficiency
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Mevalonate kinase deficiency is caused by changes (mutations) in the MKV gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the specific protein, this can affect many organ systems of the body.The MKV gene contains instructions (encodes) for creating the mevalonate kinase enzyme. This enzyme is important in the mevalonate pathway. A pathway is a series of chemical reactions in the body that produce a substance or substances essential for the proper function and health of the body. The mevalonate pathway produces cholesterol and unsaturated lipid (fat) chains called nonsterol isoprenoids. Because of changes in the MKV gene, people with mevalonate kinase deficiency have reduced levels and/or activity of the mevalonate kinase enzyme. People with HIDS have between 1.8% and 28% of residual enzyme activity. People with mevalonate aciduria have less than .5% of residual enzyme activity. This causes a lack of cholesterol and isoprenoids in the body. It also causes mevalonate acid to build up in the body and high levels of this acid will be found in the urine. The immune system makes higher levels of interleukin 1b, which contributes to episodes of hyperinflammation. An interleukin is a type of cytokine. Cytokines are specialized proteins secreted from certain immune system cells that either stimulate or inhibit the function of other immune system cells. The complete effects in the body of reduced levels of mevalonate kinase enzyme and the exact underlying reasons that symptoms develop in mevalonate kinase deficiency are not fully understood. Less residual enzyme is generally associated with more severe symptoms.Researchers believe that additional factors influence the severity of mevalonate kinase deficiency including modifier genes. Modifier genes, unlike the gene that causes the disorder, affect the clinical severity of the disorder. More research is necessary to discover the various modifier genes associated with mevalonate kinase deficiency and their exact role in the development of the disorder. Sometimes, episodes are caused or “triggered” by an event including trauma, surgery, stress or vaccination. However, many times an episode occurs without an identified trigger.In most instances, mevalonate kinase deficiency is inherited in an autosomal recessive manner. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits two copies of an altered gene for the same trait, one from each parent. If an individual inherits 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 altered 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 is 25%. The risk is the same for males and females.Sometimes, individuals develop mevalonate kinase deficiency but only one altered MKV gene can be found. Some individuals with mevalonate kinase deficiency can have abnormally high levels of immunoglobulin IgD in the fluid portion (serum) of the blood (thus, the term hyper IgD). Immunoglobulins or antibodies are proteins produced by certain white blood cells. There are five classes of immunoglobulins known as IgA, IgD, IgE, IgG, and IgM. Immunoglobulins play a role in defending the body against foreign substances or microorganisms by destroying them or coating them so they are more easily destroyed by white blood cells. While the specific function of other immunoglobulins is well-known, the specific function of IgD within the immune system is unknown. Some people can also have elevated levels of IgD without having HIDS or mevalonate kinase deficiency.
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Causes of Mevalonate Kinase Deficiency. Mevalonate kinase deficiency is caused by changes (mutations) in the MKV gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the specific protein, this can affect many organ systems of the body.The MKV gene contains instructions (encodes) for creating the mevalonate kinase enzyme. This enzyme is important in the mevalonate pathway. A pathway is a series of chemical reactions in the body that produce a substance or substances essential for the proper function and health of the body. The mevalonate pathway produces cholesterol and unsaturated lipid (fat) chains called nonsterol isoprenoids. Because of changes in the MKV gene, people with mevalonate kinase deficiency have reduced levels and/or activity of the mevalonate kinase enzyme. People with HIDS have between 1.8% and 28% of residual enzyme activity. People with mevalonate aciduria have less than .5% of residual enzyme activity. This causes a lack of cholesterol and isoprenoids in the body. It also causes mevalonate acid to build up in the body and high levels of this acid will be found in the urine. The immune system makes higher levels of interleukin 1b, which contributes to episodes of hyperinflammation. An interleukin is a type of cytokine. Cytokines are specialized proteins secreted from certain immune system cells that either stimulate or inhibit the function of other immune system cells. The complete effects in the body of reduced levels of mevalonate kinase enzyme and the exact underlying reasons that symptoms develop in mevalonate kinase deficiency are not fully understood. Less residual enzyme is generally associated with more severe symptoms.Researchers believe that additional factors influence the severity of mevalonate kinase deficiency including modifier genes. Modifier genes, unlike the gene that causes the disorder, affect the clinical severity of the disorder. More research is necessary to discover the various modifier genes associated with mevalonate kinase deficiency and their exact role in the development of the disorder. Sometimes, episodes are caused or “triggered” by an event including trauma, surgery, stress or vaccination. However, many times an episode occurs without an identified trigger.In most instances, mevalonate kinase deficiency is inherited in an autosomal recessive manner. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits two copies of an altered gene for the same trait, one from each parent. If an individual inherits 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 altered 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 is 25%. The risk is the same for males and females.Sometimes, individuals develop mevalonate kinase deficiency but only one altered MKV gene can be found. Some individuals with mevalonate kinase deficiency can have abnormally high levels of immunoglobulin IgD in the fluid portion (serum) of the blood (thus, the term hyper IgD). Immunoglobulins or antibodies are proteins produced by certain white blood cells. There are five classes of immunoglobulins known as IgA, IgD, IgE, IgG, and IgM. Immunoglobulins play a role in defending the body against foreign substances or microorganisms by destroying them or coating them so they are more easily destroyed by white blood cells. While the specific function of other immunoglobulins is well-known, the specific function of IgD within the immune system is unknown. Some people can also have elevated levels of IgD without having HIDS or mevalonate kinase deficiency.
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Mevalonate Kinase Deficiency
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nord_806_3
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Affects of Mevalonate Kinase Deficiency
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Mevalonate kinase deficiency affects males and females in equal numbers. More than 300 individuals worldwide are known to have the disorder, but the true number is likely greater. Most people with the disorder are individuals of western European heritage with approximately 60% occurring in Dutch or French individuals. The exact incidence and prevalence is unknown and it is likely that the disorder goes misdiagnosed or undiagnosed. This makes it difficult to determine the exact incidence or prevalence of mevalonate kinase deficiency in the general population.
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Affects of Mevalonate Kinase Deficiency. Mevalonate kinase deficiency affects males and females in equal numbers. More than 300 individuals worldwide are known to have the disorder, but the true number is likely greater. Most people with the disorder are individuals of western European heritage with approximately 60% occurring in Dutch or French individuals. The exact incidence and prevalence is unknown and it is likely that the disorder goes misdiagnosed or undiagnosed. This makes it difficult to determine the exact incidence or prevalence of mevalonate kinase deficiency in the general population.
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Mevalonate Kinase Deficiency
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nord_806_4
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Related disorders of Mevalonate Kinase Deficiency
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Symptoms of the following disorders can be similar to those of mevalonate kinase deficiency. Comparisons may be useful for a differential diagnosis.Mevalonate kinase deficiency belongs to a group of disorders known as the periodic fever syndromes or hereditary autoinflammatory syndromes. This group includes familial Mediterranean fever, tumor necrosis factor TNF-receptor associated periodic syndrome (TRAPS), familial cold urticaria and Muckle-Wells syndrome. NORD has other reports on these disorders. Choose the specific disorder name as your search term in the Rare Disease Database.Familial Mediterranean fever (FMF) is a rare, inherited, inflammatory disease characterized by recurrent attacks of fever and acute inflammation of the membranes that line the abdominal cavity (peritonitis) and/or the lungs (pleuritis); pain and swelling of the joints (arthritis); and/or the heart (pericarditis) and, in some cases, skin rashes. In addition, some affected individuals may experience a serious complication known as amyloidosis, which is characterized by abnormal accumulation of a fatty-like substance (amyloid) in various parts of the body. If amyloid accumulates in the kidneys (renal amyloidosis), it may impair kidney function potentially resulting in life-threatening complications. In most instances, but not exclusively, FMF affects persons of Mediterranean origin such as Sephardic Jews, Arabs, Armenians, and Turks. FMF is inherited in an autosomal recessive pattern and caused by mutations in the gene encoding pyrin. (For more information on this disorder, choose “familial Mediterranean fever” as your search term in the Rare Disease Database.)Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) is a rare disorder characterized by recurrent episodes of fever. Fever usually occurs along with canker sores of the mouth (aphthous stomatitis), a sore, reddened throat (pharyngitis) and inflammation of glands in the neck (cervical adenitis). Episodes start suddenly and usually last for about 3-7 days. The period of time between episodes can vary, but is often about 3-8 weeks. In between episodes, affected children are unaffected and grow normally. PFAPA usually occurs during childhood, and typically goes away during adolescence or adulthood. The exact cause of PFAPA is unknown.
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Related disorders of Mevalonate Kinase Deficiency. Symptoms of the following disorders can be similar to those of mevalonate kinase deficiency. Comparisons may be useful for a differential diagnosis.Mevalonate kinase deficiency belongs to a group of disorders known as the periodic fever syndromes or hereditary autoinflammatory syndromes. This group includes familial Mediterranean fever, tumor necrosis factor TNF-receptor associated periodic syndrome (TRAPS), familial cold urticaria and Muckle-Wells syndrome. NORD has other reports on these disorders. Choose the specific disorder name as your search term in the Rare Disease Database.Familial Mediterranean fever (FMF) is a rare, inherited, inflammatory disease characterized by recurrent attacks of fever and acute inflammation of the membranes that line the abdominal cavity (peritonitis) and/or the lungs (pleuritis); pain and swelling of the joints (arthritis); and/or the heart (pericarditis) and, in some cases, skin rashes. In addition, some affected individuals may experience a serious complication known as amyloidosis, which is characterized by abnormal accumulation of a fatty-like substance (amyloid) in various parts of the body. If amyloid accumulates in the kidneys (renal amyloidosis), it may impair kidney function potentially resulting in life-threatening complications. In most instances, but not exclusively, FMF affects persons of Mediterranean origin such as Sephardic Jews, Arabs, Armenians, and Turks. FMF is inherited in an autosomal recessive pattern and caused by mutations in the gene encoding pyrin. (For more information on this disorder, choose “familial Mediterranean fever” as your search term in the Rare Disease Database.)Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) is a rare disorder characterized by recurrent episodes of fever. Fever usually occurs along with canker sores of the mouth (aphthous stomatitis), a sore, reddened throat (pharyngitis) and inflammation of glands in the neck (cervical adenitis). Episodes start suddenly and usually last for about 3-7 days. The period of time between episodes can vary, but is often about 3-8 weeks. In between episodes, affected children are unaffected and grow normally. PFAPA usually occurs during childhood, and typically goes away during adolescence or adulthood. The exact cause of PFAPA is unknown.
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Mevalonate Kinase Deficiency
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nord_806_5
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Diagnosis of Mevalonate Kinase Deficiency
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A diagnosis of a mevalonate kinase deficiency is made based upon a thorough clinical evaluation, identification of characteristic symptoms (e.g., lifelong recurrent fevers not due to infection), and a variety of tests including blood tests to determine the levels of immunoglobulin D (IgD) in the blood, urine tests to detect the presence of mevalonate kinase, and DNA analysis to detect the genetic mutation associated with the disorder.A high level of immunoglobulin D (IgD) is indicative of mevalonate kinase deficiency, but does not confirm a diagnosis. Some individuals do not show this finding and their IgD levels may be normal. Also, other periodic fever syndromes may have high levels of IgD in the blood. Further testing is required to determine whether a person has mevalonate kinase deficiency.A urine test can reveal high levels of mevalonate acid. This is indicative of mevalonate kinase deficiency. However, many people with this disorder have normal levels of mevalonate acid in the urine, making this test unreliable on its own to diagnose mevalonate kinase deficiency.A diagnosis of mevalonate kinase deficiency can be confirmed through molecular genetic testing. This type of testing identifies changes in the MKV gene that causes the disorder. This type of testing is available only as a diagnostic service at specialized laboratories.There are new classification criteria that have been proposed for mevalonate kinase deficiency and other hereditary periodic fever syndromes. A person would be classified as having mevalonate kinase deficiency if they have genetic testing showing mutations in the MVK gene and either GI symptoms, enlarged lymph nodes in the neck, or mouth sores.
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Diagnosis of Mevalonate Kinase Deficiency. A diagnosis of a mevalonate kinase deficiency is made based upon a thorough clinical evaluation, identification of characteristic symptoms (e.g., lifelong recurrent fevers not due to infection), and a variety of tests including blood tests to determine the levels of immunoglobulin D (IgD) in the blood, urine tests to detect the presence of mevalonate kinase, and DNA analysis to detect the genetic mutation associated with the disorder.A high level of immunoglobulin D (IgD) is indicative of mevalonate kinase deficiency, but does not confirm a diagnosis. Some individuals do not show this finding and their IgD levels may be normal. Also, other periodic fever syndromes may have high levels of IgD in the blood. Further testing is required to determine whether a person has mevalonate kinase deficiency.A urine test can reveal high levels of mevalonate acid. This is indicative of mevalonate kinase deficiency. However, many people with this disorder have normal levels of mevalonate acid in the urine, making this test unreliable on its own to diagnose mevalonate kinase deficiency.A diagnosis of mevalonate kinase deficiency can be confirmed through molecular genetic testing. This type of testing identifies changes in the MKV gene that causes the disorder. This type of testing is available only as a diagnostic service at specialized laboratories.There are new classification criteria that have been proposed for mevalonate kinase deficiency and other hereditary periodic fever syndromes. A person would be classified as having mevalonate kinase deficiency if they have genetic testing showing mutations in the MVK gene and either GI symptoms, enlarged lymph nodes in the neck, or mouth sores.
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Mevalonate Kinase Deficiency
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nord_806_6
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Therapies of Mevalonate Kinase Deficiency
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Treatment is directed toward the specific symptoms that are apparent in each individual. Various drugs including paracetamol (acetaminophen) have been used to treat affected individuals. Corticosteroids, such as prednisone, have been used to treat some individuals. Nonsteroidal anti-inflammatories and pain medications (analgesics) have also been tried. These drugs have led to complete or partial remissions during a fever episode but success is inconsistent and temporary. They are generally considered best for people with mild symptoms and only a few episodes.Several other medications have been used in people with mevalonate kinase deficiency. Colchicine is a medication that reduces inflammation and has been effective in other periodic fever syndromes, but has, generally, been ineffective in mevalonate kinase deficiency. Statins are another medication that has been tried in affected individuals, but similarly have not proven to be effective.In 2016, the U.S. Food and Drug Administration (FDA) approved canakinumab (Ilaris) for the treatment of individuals with mevalonate kinase deficiency. Canakinumab is a fully-humanized protein which blocks the cytokine interleukin-1 beta, which contributes to fever episodes. In a recent clinical trial, significantly more people with mevalonate kinase deficiency had complete resolution of symptoms when treated with cankinumab than with placebo. However, more research is necessary to determine the long-term safety and efficacy of canakinumab for people with mevalonate kinase deficiency.Some affected individuals have been treated with anakinra. Anakinra is an interleukin-1 receptor antagonist; it blocks the activity of interleukin-1. Initial reports suggest that this drug is safe and has shown some benefit in treating individuals with mevalonate kinase deficiency. More research is necessary to determine the long-term safety and effectiveness of anakinra for this disorder.Some people have been treated with drugs that block the activity of tumor necrosis factor, a specialized protein (cytokine) that is helps to protect the body and is involved in inflammation. These TNF-inhibitors are called etanercept and adalimumab. More research is necessary to determine the long-term safety and effectiveness of these therapies for people with mevalonate kinase deficiency.Tocilizumab is a drug that suppresses the immune system by blocking a different cytokine called interleukin-6. Tocilizumab has been tried as a treatment for people with mevalonate kinase deficiency. This drug has shown benefit in reducing the frequency and duration of fever episodes. More research is necessary to determine the long-term safety and effectiveness of this therapy.Genetic counseling is recommended for affected individuals and their families.
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Therapies of Mevalonate Kinase Deficiency. Treatment is directed toward the specific symptoms that are apparent in each individual. Various drugs including paracetamol (acetaminophen) have been used to treat affected individuals. Corticosteroids, such as prednisone, have been used to treat some individuals. Nonsteroidal anti-inflammatories and pain medications (analgesics) have also been tried. These drugs have led to complete or partial remissions during a fever episode but success is inconsistent and temporary. They are generally considered best for people with mild symptoms and only a few episodes.Several other medications have been used in people with mevalonate kinase deficiency. Colchicine is a medication that reduces inflammation and has been effective in other periodic fever syndromes, but has, generally, been ineffective in mevalonate kinase deficiency. Statins are another medication that has been tried in affected individuals, but similarly have not proven to be effective.In 2016, the U.S. Food and Drug Administration (FDA) approved canakinumab (Ilaris) for the treatment of individuals with mevalonate kinase deficiency. Canakinumab is a fully-humanized protein which blocks the cytokine interleukin-1 beta, which contributes to fever episodes. In a recent clinical trial, significantly more people with mevalonate kinase deficiency had complete resolution of symptoms when treated with cankinumab than with placebo. However, more research is necessary to determine the long-term safety and efficacy of canakinumab for people with mevalonate kinase deficiency.Some affected individuals have been treated with anakinra. Anakinra is an interleukin-1 receptor antagonist; it blocks the activity of interleukin-1. Initial reports suggest that this drug is safe and has shown some benefit in treating individuals with mevalonate kinase deficiency. More research is necessary to determine the long-term safety and effectiveness of anakinra for this disorder.Some people have been treated with drugs that block the activity of tumor necrosis factor, a specialized protein (cytokine) that is helps to protect the body and is involved in inflammation. These TNF-inhibitors are called etanercept and adalimumab. More research is necessary to determine the long-term safety and effectiveness of these therapies for people with mevalonate kinase deficiency.Tocilizumab is a drug that suppresses the immune system by blocking a different cytokine called interleukin-6. Tocilizumab has been tried as a treatment for people with mevalonate kinase deficiency. This drug has shown benefit in reducing the frequency and duration of fever episodes. More research is necessary to determine the long-term safety and effectiveness of this therapy.Genetic counseling is recommended for affected individuals and their families.
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Mevalonate Kinase Deficiency
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nord_807_0
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Overview of Microvillus Inclusion Disease
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SummaryMicrovillus inclusion disease (MVID) is an extremely rare inherited intestinal disorder (enteropathy) that is typically apparent within hours or days after birth. The disorder is characterized by chronic, severe, watery diarrhea and insufficient absorption (malabsorption) of necessary nutrients due to incomplete development (hypoplasia) and/or degeneration (atrophy) of surface cells of the wall of the small intestine (e.g., hypoplastic villus atrophy, defective brush-border assembly and differentiation). Infants with MVID may have chronic diarrhea and malabsorption may result in severe dehydration, deficiency of necessary nutrients (malnutrition), a failure to grow and gain weight at the expected rate (failure to thrive), and/or disturbance of the body's balance of acids and bases, which is essential in regulating the body's composition of bodily fluids (acidosis). MVID is inherited in an autosomal recessive pattern.IntroductionMVID was first described in the medical literature in 1978.
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Overview of Microvillus Inclusion Disease. SummaryMicrovillus inclusion disease (MVID) is an extremely rare inherited intestinal disorder (enteropathy) that is typically apparent within hours or days after birth. The disorder is characterized by chronic, severe, watery diarrhea and insufficient absorption (malabsorption) of necessary nutrients due to incomplete development (hypoplasia) and/or degeneration (atrophy) of surface cells of the wall of the small intestine (e.g., hypoplastic villus atrophy, defective brush-border assembly and differentiation). Infants with MVID may have chronic diarrhea and malabsorption may result in severe dehydration, deficiency of necessary nutrients (malnutrition), a failure to grow and gain weight at the expected rate (failure to thrive), and/or disturbance of the body's balance of acids and bases, which is essential in regulating the body's composition of bodily fluids (acidosis). MVID is inherited in an autosomal recessive pattern.IntroductionMVID was first described in the medical literature in 1978.
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Microvillus Inclusion Disease
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nord_807_1
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Symptoms of Microvillus Inclusion Disease
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MVID is characterized by severe, large amounts of watery diarrhea appearing at birth or within seventy-two hours. Symptoms of a rare late onset form may not occur until two or three months after birth. Diarrhea persists even after oral feeding is stopped and does not decrease with age. Diarrhea often worsens after feeding because of malabsorption of necessary nutrients. The diarrhea often results in life-threatening complications, specifically severe dehydration and metabolic acidosis, which may cause kidney failure, requiring the infant to be hospitalized. There may also be related weight loss, growth retardation and developmental delay.Infants affected by this disorder require total intravenous hydration and total parenteral nutrition (TPN). TPN may be associated with an increased risk of developing blockage of the liver or bile ducts preventing the normal flow of bile (cholestasis) and liver failure. Liver disease and cholestatis can also occur independent of TPN due to the genetic defect in bile duct cells.
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Symptoms of Microvillus Inclusion Disease. MVID is characterized by severe, large amounts of watery diarrhea appearing at birth or within seventy-two hours. Symptoms of a rare late onset form may not occur until two or three months after birth. Diarrhea persists even after oral feeding is stopped and does not decrease with age. Diarrhea often worsens after feeding because of malabsorption of necessary nutrients. The diarrhea often results in life-threatening complications, specifically severe dehydration and metabolic acidosis, which may cause kidney failure, requiring the infant to be hospitalized. There may also be related weight loss, growth retardation and developmental delay.Infants affected by this disorder require total intravenous hydration and total parenteral nutrition (TPN). TPN may be associated with an increased risk of developing blockage of the liver or bile ducts preventing the normal flow of bile (cholestasis) and liver failure. Liver disease and cholestatis can also occur independent of TPN due to the genetic defect in bile duct cells.
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Microvillus Inclusion Disease
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nord_807_2
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Causes of Microvillus Inclusion Disease
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MVID is caused by loss of function changes (mutations) in myosin Vb (Myo5b) gene, a molecular motor gene that is responsible for traffic of proteins into the brush border of epithelial cells. Most cases of MVID are caused by mutations in Myo5b. However, some patients with MVID with late presentation and milder disease have been reported to have mutations in syntaxin 3, a gene for a SNARE protein that is responsible for vesicle fusion with the membrane. MVID follows an autosomal recessive pattern of inheritance. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females. All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. MVID has been reported in consanguineous families.
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Causes of Microvillus Inclusion Disease. MVID is caused by loss of function changes (mutations) in myosin Vb (Myo5b) gene, a molecular motor gene that is responsible for traffic of proteins into the brush border of epithelial cells. Most cases of MVID are caused by mutations in Myo5b. However, some patients with MVID with late presentation and milder disease have been reported to have mutations in syntaxin 3, a gene for a SNARE protein that is responsible for vesicle fusion with the membrane. MVID follows an autosomal recessive pattern of inheritance. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females. All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. MVID has been reported in consanguineous families.
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Affects of Microvillus Inclusion Disease
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Fewer than 100 cases of MVID have been reported in the medical literature. The true prevalence of this disorder is unknown. Most cases become apparent soon after birth, but it is also believed by some that there is a later-onset form that becomes apparent six to eight weeks after birth in infants that, until then, have appeared healthy. MVID affects more females than males with a sex ratio of about 2:1.
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Affects of Microvillus Inclusion Disease. Fewer than 100 cases of MVID have been reported in the medical literature. The true prevalence of this disorder is unknown. Most cases become apparent soon after birth, but it is also believed by some that there is a later-onset form that becomes apparent six to eight weeks after birth in infants that, until then, have appeared healthy. MVID affects more females than males with a sex ratio of about 2:1.
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Microvillus Inclusion Disease
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Related disorders of Microvillus Inclusion Disease
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Symptoms of the following disorders can be similar to those of microvillus inclusion disease. Comparisons may be useful for a differential diagnosis:Lactose intolerance is a malabsorption syndrome that results from impaired absorption of a sugar found in milk (lactose). This nutrient is normally absorbed in the small bowel. Lactose intolerance is characterized by diarrhea and abdominal distention causing stomach pain and gas (flatulence) that occurs after drinking milk. A lack of one or more intestinal enzymes results in an inability to digest certain carbohydrates. Lactase, maltase, isomaltase, and sucrase usually split complex sugars into simple sugars. In patients with lactose intolerance, the enzyme, lactase, which digests this sugar in the small bowel, is lacking. Patients with MVID also display carbohydrate malabsorption because of lack of development of the intestinal brush border. Familial chloride diarrhea or congenital chloride diarrhea (CCD) is a malabsorption syndrome with autosomal recessive inheritance. This disease is caused by mutations in the DRA gene and affects absorption of chloride in the distal small intestine and colon. This disorder is apparent during the first few weeks of life and is characterized by an abnormally large number of watery stools containing an excess of chloride. Infants born with this disorder are often premature. Infantile diarrhea with abnormal hair is another malabsorption syndrome with autosomal recessive inheritance. The disorder usually develops around the third week of life with a rapidly progressive course. It is characterized by severe unexplained diarrhea, low birth weight and large, low-set, simple ears, flat nasal bridge, and large mouth. Black, kinky hair that easily falls out and a lack of normal amino acids is another feature of this syndrome.Soy protein intolerant infants are allergic to soy proteins. Often, they are allergic, not only to soy, but to many other foods. They have complex nutritional problems and should be distinguished from those with sensitivity to common food proteins such as cow’s milk, egg and peanuts.Congenital sodium diarrhea is inherited in an autosomal recessive pattern. It occurs as a result of a defective sodium exchange in the small intestine and kidney due to mutations in the NHE3 ion transporter gene. The disorder is usually present at birth and is characterized by profuse watery diarrhea and a swollen abdomen.
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Related disorders of Microvillus Inclusion Disease. Symptoms of the following disorders can be similar to those of microvillus inclusion disease. Comparisons may be useful for a differential diagnosis:Lactose intolerance is a malabsorption syndrome that results from impaired absorption of a sugar found in milk (lactose). This nutrient is normally absorbed in the small bowel. Lactose intolerance is characterized by diarrhea and abdominal distention causing stomach pain and gas (flatulence) that occurs after drinking milk. A lack of one or more intestinal enzymes results in an inability to digest certain carbohydrates. Lactase, maltase, isomaltase, and sucrase usually split complex sugars into simple sugars. In patients with lactose intolerance, the enzyme, lactase, which digests this sugar in the small bowel, is lacking. Patients with MVID also display carbohydrate malabsorption because of lack of development of the intestinal brush border. Familial chloride diarrhea or congenital chloride diarrhea (CCD) is a malabsorption syndrome with autosomal recessive inheritance. This disease is caused by mutations in the DRA gene and affects absorption of chloride in the distal small intestine and colon. This disorder is apparent during the first few weeks of life and is characterized by an abnormally large number of watery stools containing an excess of chloride. Infants born with this disorder are often premature. Infantile diarrhea with abnormal hair is another malabsorption syndrome with autosomal recessive inheritance. The disorder usually develops around the third week of life with a rapidly progressive course. It is characterized by severe unexplained diarrhea, low birth weight and large, low-set, simple ears, flat nasal bridge, and large mouth. Black, kinky hair that easily falls out and a lack of normal amino acids is another feature of this syndrome.Soy protein intolerant infants are allergic to soy proteins. Often, they are allergic, not only to soy, but to many other foods. They have complex nutritional problems and should be distinguished from those with sensitivity to common food proteins such as cow’s milk, egg and peanuts.Congenital sodium diarrhea is inherited in an autosomal recessive pattern. It occurs as a result of a defective sodium exchange in the small intestine and kidney due to mutations in the NHE3 ion transporter gene. The disorder is usually present at birth and is characterized by profuse watery diarrhea and a swollen abdomen.
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Microvillus Inclusion Disease
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Diagnosis of Microvillus Inclusion Disease
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The diagnosis of MVID may be based upon electron microscopy of a tissue sample (biopsy) from the intestine of an ailing child, which depicts microscopic findings of brush border defects in the villus in association with microvillus inclusions (MIs) usually in villus enterocytes characteristic of the disorder. Genetic testing is available and can confirm the diagnosis. Before a biopsy is performed, other causes of dehydration and diarrhea in infants are ruled out.
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Diagnosis of Microvillus Inclusion Disease. The diagnosis of MVID may be based upon electron microscopy of a tissue sample (biopsy) from the intestine of an ailing child, which depicts microscopic findings of brush border defects in the villus in association with microvillus inclusions (MIs) usually in villus enterocytes characteristic of the disorder. Genetic testing is available and can confirm the diagnosis. Before a biopsy is performed, other causes of dehydration and diarrhea in infants are ruled out.
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Microvillus Inclusion Disease
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Therapies of Microvillus Inclusion Disease
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TreatmentNo effective drug treatment is available. Treatment of MVID is accomplished through intravenous feeding called total parenteral nutrition (TPN).However, chronic TPN carries with it high risks of infection (sepsis), liver damage and other organ disorders. Therefore, the affected child must be carefully monitored by a physician.Some children with severe disease have been treated with transplantation of a part of the small intestine.Other treatment is symptomatic and supportive. Genetic counseling is recommended for affected individuals and their families.
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Therapies of Microvillus Inclusion Disease. TreatmentNo effective drug treatment is available. Treatment of MVID is accomplished through intravenous feeding called total parenteral nutrition (TPN).However, chronic TPN carries with it high risks of infection (sepsis), liver damage and other organ disorders. Therefore, the affected child must be carefully monitored by a physician.Some children with severe disease have been treated with transplantation of a part of the small intestine.Other treatment is symptomatic and supportive. Genetic counseling is recommended for affected individuals and their families.
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Overview of Mikulicz Syndrome
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Mikulicz syndrome is a chronic condition characterized by the abnormal enlargement of glands in the head and neck, including those near the ears (parotids) and those around the eyes (lacrimal) and mouth (salivary). The tonsils and other glands in the soft tissue of the face and neck may also be involved. Although the disorder is almost always described as benign, it always occurs in association with another underlying disorder such as tuberculosis, leukemia, syphilis, Hodgkin's disease, lymphosarcoma, Sjögren syndrome, or lupus (SLE). People who have Mikulicz syndrome are at heightened risk for developing lymphomas.Some people with Mikulicz syndrome may experience recurring fevers. The fever may be accompanied by dry eyes, diminished tear production (lacrimation), and inflammation of various parts of the eyes (uveitis). Lacrimal gland enlargement, parotid gland enlargement, dry mouth and dry eyes are the classic signs.The exact cause of Mikulicz syndrome is not known. Some scientists believe that Mikulicz syndrome should be considered a form of Sjögren syndrome.
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Overview of Mikulicz Syndrome. Mikulicz syndrome is a chronic condition characterized by the abnormal enlargement of glands in the head and neck, including those near the ears (parotids) and those around the eyes (lacrimal) and mouth (salivary). The tonsils and other glands in the soft tissue of the face and neck may also be involved. Although the disorder is almost always described as benign, it always occurs in association with another underlying disorder such as tuberculosis, leukemia, syphilis, Hodgkin's disease, lymphosarcoma, Sjögren syndrome, or lupus (SLE). People who have Mikulicz syndrome are at heightened risk for developing lymphomas.Some people with Mikulicz syndrome may experience recurring fevers. The fever may be accompanied by dry eyes, diminished tear production (lacrimation), and inflammation of various parts of the eyes (uveitis). Lacrimal gland enlargement, parotid gland enlargement, dry mouth and dry eyes are the classic signs.The exact cause of Mikulicz syndrome is not known. Some scientists believe that Mikulicz syndrome should be considered a form of Sjögren syndrome.
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Mikulicz Syndrome
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Symptoms of Mikulicz Syndrome
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Mikulicz syndrome is characterized by the sudden onset of extreme dryness in the mouth (xerostomia) that may lead to difficulty swallowing and tooth decay. Other symptoms include enlarged tear glands (lacrimal glands), leading to absent or decreased tears; enlarged glands in the neck (parotid glands); hard, painless swellings (tumefactions) of the saliva glands (salivary glands) of the mouth and those near the ears (parotid). Glands near the jaw (submaxillary) may also become swollen. Symptoms may persist for long periods of time or come and go with frequent recurrences. The symptoms of Mikulicz syndrome are very similar to those of Sjögren syndrome and some researchers suspect that they may be the same disorder (see Related Disorders section of this report).
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Symptoms of Mikulicz Syndrome. Mikulicz syndrome is characterized by the sudden onset of extreme dryness in the mouth (xerostomia) that may lead to difficulty swallowing and tooth decay. Other symptoms include enlarged tear glands (lacrimal glands), leading to absent or decreased tears; enlarged glands in the neck (parotid glands); hard, painless swellings (tumefactions) of the saliva glands (salivary glands) of the mouth and those near the ears (parotid). Glands near the jaw (submaxillary) may also become swollen. Symptoms may persist for long periods of time or come and go with frequent recurrences. The symptoms of Mikulicz syndrome are very similar to those of Sjögren syndrome and some researchers suspect that they may be the same disorder (see Related Disorders section of this report).
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Mikulicz Syndrome
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Causes of Mikulicz Syndrome
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The exact cause of Mikulicz syndrome is not known, although it is suspected to be an autoimmune disorder. Autoimmune disorders are caused when the body's natural defenses against “foreign” or invading organisms (e.g., antibodies) begin to attack healthy tissue for unknown reasons.The symptoms of Mikulicz syndrome may occur due to the excessive accumulation of certain white blood cells (lymphocytes) into many glands of the face, mouth, and/or neck.
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Causes of Mikulicz Syndrome. The exact cause of Mikulicz syndrome is not known, although it is suspected to be an autoimmune disorder. Autoimmune disorders are caused when the body's natural defenses against “foreign” or invading organisms (e.g., antibodies) begin to attack healthy tissue for unknown reasons.The symptoms of Mikulicz syndrome may occur due to the excessive accumulation of certain white blood cells (lymphocytes) into many glands of the face, mouth, and/or neck.
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Mikulicz Syndrome
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Affects of Mikulicz Syndrome
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Mikulicz syndrome affects more females than males and most often presents during the middle adult years. It often occurs in combination with Sjögren syndrome. Some scientists have speculated that Mikulicz Syndrome and Sjögren Syndrome may actually be the same disorder.
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Affects of Mikulicz Syndrome. Mikulicz syndrome affects more females than males and most often presents during the middle adult years. It often occurs in combination with Sjögren syndrome. Some scientists have speculated that Mikulicz Syndrome and Sjögren Syndrome may actually be the same disorder.
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Mikulicz Syndrome
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Related disorders of Mikulicz Syndrome
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Symptoms of the following disorders can be similar to those of Mikulicz Syndrome. Comparisons may be useful for a differential diagnosis:Mumps is an acute viral illness that causes painful inflammation and swelling of the salivary glands, including the parotid, submaxillary, sublingual, and buccal glands. At one time, Mumps was a common infectious disease of childhood. However, a vaccine against this disease was developed in 1967. The onset of the illness is marked by headache, loss of appetite, a general feeling of ill health (malaise), and a low to moderate fever. Within 24 hours, the temperature rises to approximately 104.0F and is usually associated with pain and swelling of the glands in front of the ears (parotid) and under the jaw (submaxillary). (For more information on this disorder, choose “Mumps” as your search term in the Rare Disease Database.)Heerfordt's Syndrome, also known as Uveoparotid fever, is similar to Mikulicz Syndrome and is sometimes the first symptom of another disease, Sarcoidosis. Heerfordt's Syndrome is characterized by swelling of the glands in front of the ears (parotids) and paralysis of one or more of the cranial nerves. The nerves of the face are most commonly affected.Sjögren Syndrome is an autoimmune disorder characterized by the progressive degeneration of mucous secreting glands, especially those of the mouth (salivary) and eyes (lacrimal). The symptoms of Sjögren Syndrome usually begin suddenly and may include inflammation of the membranes that surround the eyes and the corneas (keratoconjunctivitis). Varying degrees of dryness in the mouth (sicca xerostomia) may cause difficulty swallowing and/or dental disease. (For more information on this disorder, choose “Sjögren” as your search term in the Rare Disease Database.)Swelling of the glands in front of the ears (parotid swelling) may occur for many different reasons. Painless swelling on both sides of the face may occur without fever and in association with other disorders such as Laennec's Cirrhosis, chronic alcoholism, malnutrition, diabetes mellitus, pregnancy, lactation, and/or Hypertriglyceridemia. Malignant and benign salivary gland tumors can also cause swelling of the salivary glands. Parotid gland enlargement may also be related to the use of certain drugs (e.g., guanethidine or iodine). Obstruction of the duct from the parotid gland to the mouth (Stensen's duct) by a stone (calcification) can also cause swelling of the parotid gland.
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Related disorders of Mikulicz Syndrome. Symptoms of the following disorders can be similar to those of Mikulicz Syndrome. Comparisons may be useful for a differential diagnosis:Mumps is an acute viral illness that causes painful inflammation and swelling of the salivary glands, including the parotid, submaxillary, sublingual, and buccal glands. At one time, Mumps was a common infectious disease of childhood. However, a vaccine against this disease was developed in 1967. The onset of the illness is marked by headache, loss of appetite, a general feeling of ill health (malaise), and a low to moderate fever. Within 24 hours, the temperature rises to approximately 104.0F and is usually associated with pain and swelling of the glands in front of the ears (parotid) and under the jaw (submaxillary). (For more information on this disorder, choose “Mumps” as your search term in the Rare Disease Database.)Heerfordt's Syndrome, also known as Uveoparotid fever, is similar to Mikulicz Syndrome and is sometimes the first symptom of another disease, Sarcoidosis. Heerfordt's Syndrome is characterized by swelling of the glands in front of the ears (parotids) and paralysis of one or more of the cranial nerves. The nerves of the face are most commonly affected.Sjögren Syndrome is an autoimmune disorder characterized by the progressive degeneration of mucous secreting glands, especially those of the mouth (salivary) and eyes (lacrimal). The symptoms of Sjögren Syndrome usually begin suddenly and may include inflammation of the membranes that surround the eyes and the corneas (keratoconjunctivitis). Varying degrees of dryness in the mouth (sicca xerostomia) may cause difficulty swallowing and/or dental disease. (For more information on this disorder, choose “Sjögren” as your search term in the Rare Disease Database.)Swelling of the glands in front of the ears (parotid swelling) may occur for many different reasons. Painless swelling on both sides of the face may occur without fever and in association with other disorders such as Laennec's Cirrhosis, chronic alcoholism, malnutrition, diabetes mellitus, pregnancy, lactation, and/or Hypertriglyceridemia. Malignant and benign salivary gland tumors can also cause swelling of the salivary glands. Parotid gland enlargement may also be related to the use of certain drugs (e.g., guanethidine or iodine). Obstruction of the duct from the parotid gland to the mouth (Stensen's duct) by a stone (calcification) can also cause swelling of the parotid gland.
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Mikulicz Syndrome
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Diagnosis of Mikulicz Syndrome
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Diagnosis of Mikulicz Syndrome.
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Mikulicz Syndrome
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Therapies of Mikulicz Syndrome
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Biopsy of one of the swollen glands is key to the diagnosis of Mikulicz syndrome. An ultrasound examination of the area may help to rule out other reasons for gland swelling. Treatment of this disorder is symptomatic. Medical therapies are more productively directed toward the treatment of any underlying disease. Artificial tears may be used to maintain moisture in the eyes, and artificial saliva may be used to treat oral symptoms.Some individuals with Mikulicz syndrome may be instructed to follow a soft moist diet. This may help to reduce the pain caused by chewing and swallowing. Other treatment is symptomatic and supportive.
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Therapies of Mikulicz Syndrome. Biopsy of one of the swollen glands is key to the diagnosis of Mikulicz syndrome. An ultrasound examination of the area may help to rule out other reasons for gland swelling. Treatment of this disorder is symptomatic. Medical therapies are more productively directed toward the treatment of any underlying disease. Artificial tears may be used to maintain moisture in the eyes, and artificial saliva may be used to treat oral symptoms.Some individuals with Mikulicz syndrome may be instructed to follow a soft moist diet. This may help to reduce the pain caused by chewing and swallowing. Other treatment is symptomatic and supportive.
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Mikulicz Syndrome
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Overview of Miller Fisher Syndrome
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SummaryMiller Fisher syndrome (MFS) is a rare acquired nerve disease related to Guillain-Barré syndrome (GBS). Features include weakness of the eye muscles causing difficulty moving the eyes; impaired limb coordination and unsteadiness; and absent tendon reflexes. Other symptoms may include facial, swallowing and limb weakness, as well as respiratory failure. MFS can affect both children and adults. It often occurs several days (up to four weeks) after a bacterial or viral illness. MFS is rare, affecting one to two people per million each year. It is an autoimmune disease, in which the immune system attacks the nerves. Specific treatment is available but most patients recover within six months even without treatment. Very few patients have permanent neurological problems or relapse. Death is very rare.IntroductionMFS is named after Dr. Charles Miller Fisher, a Canadian neurologist working at Massachusetts General Hospital. In 1956, he described three patients with ophthalmoplegia (eye muscle weakness), ataxia (incoordination), and areflexia (absence of tendon reflexes). He deduced that their disease shared features with Guillain-Barré syndrome (GBS) to which it is related. (For more information on GBS, see https://rarediseases.org/rare-diseases/guillain-barre-syndrome/)
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Overview of Miller Fisher Syndrome. SummaryMiller Fisher syndrome (MFS) is a rare acquired nerve disease related to Guillain-Barré syndrome (GBS). Features include weakness of the eye muscles causing difficulty moving the eyes; impaired limb coordination and unsteadiness; and absent tendon reflexes. Other symptoms may include facial, swallowing and limb weakness, as well as respiratory failure. MFS can affect both children and adults. It often occurs several days (up to four weeks) after a bacterial or viral illness. MFS is rare, affecting one to two people per million each year. It is an autoimmune disease, in which the immune system attacks the nerves. Specific treatment is available but most patients recover within six months even without treatment. Very few patients have permanent neurological problems or relapse. Death is very rare.IntroductionMFS is named after Dr. Charles Miller Fisher, a Canadian neurologist working at Massachusetts General Hospital. In 1956, he described three patients with ophthalmoplegia (eye muscle weakness), ataxia (incoordination), and areflexia (absence of tendon reflexes). He deduced that their disease shared features with Guillain-Barré syndrome (GBS) to which it is related. (For more information on GBS, see https://rarediseases.org/rare-diseases/guillain-barre-syndrome/)
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Miller Fisher Syndrome
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Symptoms of Miller Fisher Syndrome
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MFS has three defining features:These symptoms typically develop rapidly over a few days. Some patients have weakness of the face, tongue and swallowing muscles as well. Others also develop weakness of the limbs and breathing muscles and are then considered to have GBS-MFS overlap syndrome. MFS often occurs several days or up to four weeks after an infective illness (especially Campylobacter jejuni, a diarrheal illness, or Haemophilus influenzae, a respiratory infection).
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Symptoms of Miller Fisher Syndrome. MFS has three defining features:These symptoms typically develop rapidly over a few days. Some patients have weakness of the face, tongue and swallowing muscles as well. Others also develop weakness of the limbs and breathing muscles and are then considered to have GBS-MFS overlap syndrome. MFS often occurs several days or up to four weeks after an infective illness (especially Campylobacter jejuni, a diarrheal illness, or Haemophilus influenzae, a respiratory infection).
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Miller Fisher Syndrome
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Causes of Miller Fisher Syndrome
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MFS is an autoimmune disease in which antibodies against a bacterial or viral infection cross-react with and attack the nerves. The site of attack may be the myelin sheaths, which insulate and protect the nerve fibers (axons), or the axons themselves. The principal autoantibody is directed against a molecule called ganglioside GQ1b, which is especially present on the nerves affected. The antibody is present in the blood of at least 80% of people with MFS and can be used to confirm the diagnosis.MFS does not usually affect more than one person in the same family. There are very rare reports of siblings or identical twins being affected. It is thus possible that there is a hereditary predisposition to develop the disease. It is not infectious.
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Causes of Miller Fisher Syndrome. MFS is an autoimmune disease in which antibodies against a bacterial or viral infection cross-react with and attack the nerves. The site of attack may be the myelin sheaths, which insulate and protect the nerve fibers (axons), or the axons themselves. The principal autoantibody is directed against a molecule called ganglioside GQ1b, which is especially present on the nerves affected. The antibody is present in the blood of at least 80% of people with MFS and can be used to confirm the diagnosis.MFS does not usually affect more than one person in the same family. There are very rare reports of siblings or identical twins being affected. It is thus possible that there is a hereditary predisposition to develop the disease. It is not infectious.
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Miller Fisher Syndrome
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Affects of Miller Fisher Syndrome
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MFS is rare, affecting only one to two people per million each year in most parts of the world. It is more common in East Asia. It affects both children and adults. It is more common in men than women and in the young than the old. The average age of onset is 45 years.
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Affects of Miller Fisher Syndrome. MFS is rare, affecting only one to two people per million each year in most parts of the world. It is more common in East Asia. It affects both children and adults. It is more common in men than women and in the young than the old. The average age of onset is 45 years.
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Miller Fisher Syndrome
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Related disorders of Miller Fisher Syndrome
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Rarely, patients only have components of MFS such as ophthalmoplegia (paralysis of eye movements) or ataxia (incoordination). On the other hand, MFS can progress to involve the limb and respiratory muscles and this is called the MFS-GBS overlap syndrome. Researchers have not yet found a way to predict which patients will progress from MFS into more severe disease, but in one series such progression always occurred during the first week. Bickerstaff brainstem encephalitis resembles MFS or MFS-GBS overlap syndrome but also includes altered consciousness and extensor plantar responses and reflex changes, which indicate central nervous system involvement. Like MFS, most patients with Bickerstaff brainstem encephalitis have antibodies to ganglioside GQ1b.
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Related disorders of Miller Fisher Syndrome. Rarely, patients only have components of MFS such as ophthalmoplegia (paralysis of eye movements) or ataxia (incoordination). On the other hand, MFS can progress to involve the limb and respiratory muscles and this is called the MFS-GBS overlap syndrome. Researchers have not yet found a way to predict which patients will progress from MFS into more severe disease, but in one series such progression always occurred during the first week. Bickerstaff brainstem encephalitis resembles MFS or MFS-GBS overlap syndrome but also includes altered consciousness and extensor plantar responses and reflex changes, which indicate central nervous system involvement. Like MFS, most patients with Bickerstaff brainstem encephalitis have antibodies to ganglioside GQ1b.
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Miller Fisher Syndrome
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Diagnosis of Miller Fisher Syndrome
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MFS is often hard to diagnose because it can mimic other neurologic diseases such as myasthenia gravis, botulism, diphtheria, brain stem stroke, brain stem encephalitis and basal meningitis. Physicians should have a high index of suspension, rule out similar diseases and consider testing for anti-GQ1b antibody to help diagnose Miller Fisher syndrome.Clinical Testing and Work-Up
The diagnosis of MFS is clinical. It depends on identifying the characteristic features from the symptoms and physical examination. There is no definitive diagnostic test. Antibodies against ganglioside GQ1b support the diagnosis but also occur in Bickerstaff brainstem encephalitis. As in GBS, the cerebrospinal fluid often shows a high protein while the cell count remains normal. The sample of cerebrospinal fluid is collected by a spinal tap (lumbar puncture). In a third of patients with Bickerstaff brainstem encephalitis the cell count is increased.Nerve conduction tests (electromyography) are often done to support the diagnosis. In MFS, the tests on the motor nerves are usually normal but the sensory nerve action potentials are absent and there are abnormalities of the sensory nerves which produce the tendon reflexes. The tests involve recording of the muscle or sensory nerve fiber activity following small electric shocks to the nerves. Magnetic resonance imaging (MRI) of the brain may be done as part of the diagnostic work up. It is usually normal in MFS but may show abnormalities in the brain stem in Bickerstaff brainstem encephalitis. In GBS, it usually shows enhancement (increased signal) in the spinal nerve roots following injection of a radio-opaque dye.
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Diagnosis of Miller Fisher Syndrome. MFS is often hard to diagnose because it can mimic other neurologic diseases such as myasthenia gravis, botulism, diphtheria, brain stem stroke, brain stem encephalitis and basal meningitis. Physicians should have a high index of suspension, rule out similar diseases and consider testing for anti-GQ1b antibody to help diagnose Miller Fisher syndrome.Clinical Testing and Work-Up
The diagnosis of MFS is clinical. It depends on identifying the characteristic features from the symptoms and physical examination. There is no definitive diagnostic test. Antibodies against ganglioside GQ1b support the diagnosis but also occur in Bickerstaff brainstem encephalitis. As in GBS, the cerebrospinal fluid often shows a high protein while the cell count remains normal. The sample of cerebrospinal fluid is collected by a spinal tap (lumbar puncture). In a third of patients with Bickerstaff brainstem encephalitis the cell count is increased.Nerve conduction tests (electromyography) are often done to support the diagnosis. In MFS, the tests on the motor nerves are usually normal but the sensory nerve action potentials are absent and there are abnormalities of the sensory nerves which produce the tendon reflexes. The tests involve recording of the muscle or sensory nerve fiber activity following small electric shocks to the nerves. Magnetic resonance imaging (MRI) of the brain may be done as part of the diagnostic work up. It is usually normal in MFS but may show abnormalities in the brain stem in Bickerstaff brainstem encephalitis. In GBS, it usually shows enhancement (increased signal) in the spinal nerve roots following injection of a radio-opaque dye.
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Miller Fisher Syndrome
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Therapies of Miller Fisher Syndrome
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Treatment
Most patients recover within six months. The average recovery time is 8 to 12 weeks. The disease rarely causes permanent neurological problems. Relapse occurs in less than 3 percent of patients. Death is very rare. Supportive care to manage the physical and emotional challenges of the disease is needed. Good nursing, physical therapy, occupational therapy and psychological support are important.Because the prognosis is so good and clinical trials have not been done, it is not known whether specific treatment helps. However, because MFS is related to GBS and may progress to MFS-GBS overlap syndrome, the usual treatments for GBS are often given. These are intravenous immunoglobulin (IVIg) or plasmapheresis (plasma exchange). Steroids are not used since they are not beneficial in GBS. The initial treatment is usually IVIg. IVIg consists of infusions of high doses of immune globulin (the antibodies in the blood) into a vein. It is usually given daily for five days. The immune globulin comes from highly purified, pooled plasma from thousands of healthy people. It is believed to work by blocking the effects of the antibody that causes the disease. Plasmapheresis is a procedure that removes antibodies from the blood. One vein is connected via a thin plastic tube to a machine which separates the plasma (the liquid portion of the blood) from the red blood cells and returns the red blood cells with a plasma substitute into another vein. It is usually done five times over about two weeks. IVIg is more convenient and widely available than plasmapheresis.
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Therapies of Miller Fisher Syndrome. Treatment
Most patients recover within six months. The average recovery time is 8 to 12 weeks. The disease rarely causes permanent neurological problems. Relapse occurs in less than 3 percent of patients. Death is very rare. Supportive care to manage the physical and emotional challenges of the disease is needed. Good nursing, physical therapy, occupational therapy and psychological support are important.Because the prognosis is so good and clinical trials have not been done, it is not known whether specific treatment helps. However, because MFS is related to GBS and may progress to MFS-GBS overlap syndrome, the usual treatments for GBS are often given. These are intravenous immunoglobulin (IVIg) or plasmapheresis (plasma exchange). Steroids are not used since they are not beneficial in GBS. The initial treatment is usually IVIg. IVIg consists of infusions of high doses of immune globulin (the antibodies in the blood) into a vein. It is usually given daily for five days. The immune globulin comes from highly purified, pooled plasma from thousands of healthy people. It is believed to work by blocking the effects of the antibody that causes the disease. Plasmapheresis is a procedure that removes antibodies from the blood. One vein is connected via a thin plastic tube to a machine which separates the plasma (the liquid portion of the blood) from the red blood cells and returns the red blood cells with a plasma substitute into another vein. It is usually done five times over about two weeks. IVIg is more convenient and widely available than plasmapheresis.
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Miller Fisher Syndrome
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Overview of Miller Syndrome
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SummaryMiller syndrome, also known as postaxial acrofacial dysostosis, is a rare genetic disorder characterized by craniofacial malformations occurring along with abnormalities of the arms, hands and/or feet. Craniofacial abnormalities include underdevelopment of the cheekbones (malar hypoplasia); an abnormally small lower jaw (micrognathia); incomplete closure of the roof of the mouth (cleft palate); small, protruding, “cup-shaped” ears; and/or absence of tissue (colobomas) from the lower eyelids. Limb abnormalities may include incomplete development, webbing (syndactyly), and/or closure or absence of certain fingers and/or toes; and/or improper development and/or abnormal fusion of bones in the forearms (radioulnar synostosis), causing the forearms to appear unusually short. Additional physical abnormalities can occur in some cases. Intelligence is not affected. Miller syndrome is inherited in an autosomal recessive pattern caused by mutations in the DHODH gene.IntroductionMiller syndrome was first described in the medical field between 1969 and 1979 through several independent reports. The disorder is refereed by several names derived from some of the physicians who first reported the disorder including M. Miller, H.R. Wiedemann, and E. Genee. Some researchers believe that Miller syndrome represents a distinct entity under the broader term of “postaxial acrofacial dysostosis,” which would include other disorders with similar and overlapping craniofacial and limb abnormalities, but ultimately distinct symptoms.
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Overview of Miller Syndrome. SummaryMiller syndrome, also known as postaxial acrofacial dysostosis, is a rare genetic disorder characterized by craniofacial malformations occurring along with abnormalities of the arms, hands and/or feet. Craniofacial abnormalities include underdevelopment of the cheekbones (malar hypoplasia); an abnormally small lower jaw (micrognathia); incomplete closure of the roof of the mouth (cleft palate); small, protruding, “cup-shaped” ears; and/or absence of tissue (colobomas) from the lower eyelids. Limb abnormalities may include incomplete development, webbing (syndactyly), and/or closure or absence of certain fingers and/or toes; and/or improper development and/or abnormal fusion of bones in the forearms (radioulnar synostosis), causing the forearms to appear unusually short. Additional physical abnormalities can occur in some cases. Intelligence is not affected. Miller syndrome is inherited in an autosomal recessive pattern caused by mutations in the DHODH gene.IntroductionMiller syndrome was first described in the medical field between 1969 and 1979 through several independent reports. The disorder is refereed by several names derived from some of the physicians who first reported the disorder including M. Miller, H.R. Wiedemann, and E. Genee. Some researchers believe that Miller syndrome represents a distinct entity under the broader term of “postaxial acrofacial dysostosis,” which would include other disorders with similar and overlapping craniofacial and limb abnormalities, but ultimately distinct symptoms.
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Miller Syndrome
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Symptoms of Miller Syndrome
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The specific symptoms associated with Miller syndrome may vary from one person to another. Affected individuals may develop a variety of craniofacial and limb abnormalities. Most abnormalities are noticeable at birth.Common craniofacial abnormalities include underdevelopment of the cheekbones (malar hypoplasia); an abnormally small lower jaw (micrognathia); incomplete closure of the roof of the mouth (cleft palate); narrowing of the back of the nasal cavity (choanal atresia); small, protruding, “cup-shaped” ears; and/or absence of tissue (colobomas) from the lower eyelids. Additional craniofacial findings can include a gap of missing tissue in the upper lip (cleft lip), a broad bridge of the nose, downward-slanting palpebral fissures (which means that the opening between the eyelids slants downward), partial or total absence of the eyelashes of the lower eyelids, and lower eyelids that are turned (inverted) outwards so that the inner surface is exposed (ectropion).Micrognathia and choanal atresia may contribute to difficulty breathing and/or feeding difficulties. Some affected individuals develop hearing loss due to improper conduction of sound from the outer or middle ear to the inner ear (conductive hearing loss). Hearing impairment may cause speech development to be delayed when not treated.Individuals with Miller syndrome also have various abnormalities affecting the arms and legs including absence or abnormality of either the fifth or both the fourth and fifth fingers of the hands and toes of the feet and, in some cases, the ulna and/or the fibula may be underdeveloped. The ulna is the forearm bone on the pinky side of the arm; the fibula is the outer and narrower long bone of the lower legs, thus the medical term “postaxial” which refers to fourth and fifth fingers or toes; as well as the ulna and fibula. This can cause the forearms and/or the lower legs to appear short. Additional symptoms can occur including webbing (syndactyly) of the fingers and toes, underdevelopment of the thumbs, and the formation of an abnormal bone or soft tissue connection between the ulna and the radius, two main bones of the forearm (radioulnar synostosis).In some cases, additional symptoms develop including growth deficiency after birth (postnatal growth deficiency), a sunken breastbone so that the chest appears ‘scooped out’ (pectus excavatum), rib defects, and extra (accessory) nipples. Affected infants may have hips that dislocate easily and may potentially be dislocated at birth. Affected male infants may have undescended testicles (cryptorchidism).Some individuals have kidney, gastrointestinal or heart abnormalities. Kidney abnormalities may include the backflow of urine from the bladder to the kidneys (kidney reflux). Gastrointestinal abnormalities can include abnormal positioning of the intestines (midgut malrotation) and narrowing of the opening that connects the stomach to the duodenum, the first part of the small intestine (pyloric stenosis). Heart defects can include ventricular septal defects (VSDs), which are also known as a ‘hole in the heart’. VSDs are characterized by an abnormal opening in the wall (septum) that separates the lower chambers of the heart (ventricles).
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Symptoms of Miller Syndrome. The specific symptoms associated with Miller syndrome may vary from one person to another. Affected individuals may develop a variety of craniofacial and limb abnormalities. Most abnormalities are noticeable at birth.Common craniofacial abnormalities include underdevelopment of the cheekbones (malar hypoplasia); an abnormally small lower jaw (micrognathia); incomplete closure of the roof of the mouth (cleft palate); narrowing of the back of the nasal cavity (choanal atresia); small, protruding, “cup-shaped” ears; and/or absence of tissue (colobomas) from the lower eyelids. Additional craniofacial findings can include a gap of missing tissue in the upper lip (cleft lip), a broad bridge of the nose, downward-slanting palpebral fissures (which means that the opening between the eyelids slants downward), partial or total absence of the eyelashes of the lower eyelids, and lower eyelids that are turned (inverted) outwards so that the inner surface is exposed (ectropion).Micrognathia and choanal atresia may contribute to difficulty breathing and/or feeding difficulties. Some affected individuals develop hearing loss due to improper conduction of sound from the outer or middle ear to the inner ear (conductive hearing loss). Hearing impairment may cause speech development to be delayed when not treated.Individuals with Miller syndrome also have various abnormalities affecting the arms and legs including absence or abnormality of either the fifth or both the fourth and fifth fingers of the hands and toes of the feet and, in some cases, the ulna and/or the fibula may be underdeveloped. The ulna is the forearm bone on the pinky side of the arm; the fibula is the outer and narrower long bone of the lower legs, thus the medical term “postaxial” which refers to fourth and fifth fingers or toes; as well as the ulna and fibula. This can cause the forearms and/or the lower legs to appear short. Additional symptoms can occur including webbing (syndactyly) of the fingers and toes, underdevelopment of the thumbs, and the formation of an abnormal bone or soft tissue connection between the ulna and the radius, two main bones of the forearm (radioulnar synostosis).In some cases, additional symptoms develop including growth deficiency after birth (postnatal growth deficiency), a sunken breastbone so that the chest appears ‘scooped out’ (pectus excavatum), rib defects, and extra (accessory) nipples. Affected infants may have hips that dislocate easily and may potentially be dislocated at birth. Affected male infants may have undescended testicles (cryptorchidism).Some individuals have kidney, gastrointestinal or heart abnormalities. Kidney abnormalities may include the backflow of urine from the bladder to the kidneys (kidney reflux). Gastrointestinal abnormalities can include abnormal positioning of the intestines (midgut malrotation) and narrowing of the opening that connects the stomach to the duodenum, the first part of the small intestine (pyloric stenosis). Heart defects can include ventricular septal defects (VSDs), which are also known as a ‘hole in the heart’. VSDs are characterized by an abnormal opening in the wall (septum) that separates the lower chambers of the heart (ventricles).
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Miller Syndrome
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Causes of Miller Syndrome
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Miller syndrome is caused by mutations in the dihydroorotate dehydrogenase (DHODH) gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.The DHODH gene contains instructions for creating (encoding) the enzyme dihydroorotate dehydrogenase. Mutations in this gene result in a deficiency of functional dihydroorotate dehydrogenase. This enzyme plays a role in the production (biosynthesis) of pyrimidine, which are compounds found in deoxyribonucleic acid (DNA), ribonucleic acid (RNA) and certain molecules within the body. The exact underlying manner that decreased levels of functional dihydroorotate dehydrogenase contributes to the specific symptoms associated with Miller syndrome is not fully understood. Research into the underlying causes and genetic aspects of this disorder is ongoing.Miller syndrome is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits an abnormal gene from each parent. If an individual receives one normal gene and one abnormal gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the abnormal gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
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Causes of Miller Syndrome. Miller syndrome is caused by mutations in the dihydroorotate dehydrogenase (DHODH) gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.The DHODH gene contains instructions for creating (encoding) the enzyme dihydroorotate dehydrogenase. Mutations in this gene result in a deficiency of functional dihydroorotate dehydrogenase. This enzyme plays a role in the production (biosynthesis) of pyrimidine, which are compounds found in deoxyribonucleic acid (DNA), ribonucleic acid (RNA) and certain molecules within the body. The exact underlying manner that decreased levels of functional dihydroorotate dehydrogenase contributes to the specific symptoms associated with Miller syndrome is not fully understood. Research into the underlying causes and genetic aspects of this disorder is ongoing.Miller syndrome is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits an abnormal gene from each parent. If an individual receives one normal gene and one abnormal gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the abnormal gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
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Miller Syndrome
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Affects of Miller Syndrome
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Miller syndrome is a rare disorder with an estimated prevalence of approximately 1 case per 1 million newborns. Because cases may go undiagnosed or misdiagnosed, determining the true frequency in the general population is difficult. Fewer than 75 cases have been described in the medical literature. Males and females are affected in equal numbers.
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Affects of Miller Syndrome. Miller syndrome is a rare disorder with an estimated prevalence of approximately 1 case per 1 million newborns. Because cases may go undiagnosed or misdiagnosed, determining the true frequency in the general population is difficult. Fewer than 75 cases have been described in the medical literature. Males and females are affected in equal numbers.
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Related disorders of Miller Syndrome
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Symptoms of the following disorders can be similar to those of Miller syndrome. Comparisons may be useful for a differential diagnosis.Nager syndrome (also known as preaxial acrofacial dysostosis) is a rare inherited disorder characterized by craniofacial malformations similar to those in Miller syndrome occurring in association with abnormalities of the arms, hands, and/or feet. Craniofacial malformations include underdevelopment of the cheekbones (malar hypoplasia); incomplete development of the lower jaw (mandibular hypoplasia), causing the jaw to appear abnormally small (micrognathia); hypoplastic and/or malformed (dysplastic) external ears (pinnae) and blind ending or absent external ear canals (microtia), resulting in hearing impairment (conductive hearing loss); and/or downwardly slanted palpebral fissures, lack or absence of the lower eyelashes, and/or drooping upper eyelids (ptosis). Limb abnormalities include underdevelopment or absence of the thumbs, absence of one of the bones in the forearms (radius), abnormal fusion of bones in the forearms (radioulnar synostosis), permanent flexion of certain fingers (camptodactyly), and/or webbing of the toes (syndactyly). Nager syndrome is typically inherited as an autosomal dominant trait cause by a mutation in the SF3B4. In most cases, Nager syndrome appears to occur randomly and newly in the family (sporadic) yet autosomal recessive inheritance has been previously described. The mainly anterior (radius) forearm abnormalities (as opposed to posterior-ulna) and the general lack of abnormalities in the lower limbs might help distinguish Nager syndrome from Miller syndrome (For more information on this disorder, choose “Nager” as your search term in the Rare Disease Database.)Treacher Collins syndrome (TCS) is a rare genetic disorder characterized by distinctive abnormalities of the head and face area resulting from underdevelopment (hypoplasia) of certain facial structures including the jaw, cheekbones and nearby structures (zygomatic complex). Craniofacial abnormalities tend to involve the cheekbones, jaws, mouth, ears, and/or eyes. In addition to the various facial abnormalities, affected individuals may have malformations of the external ears and middle ear structures and eye (ocular) abnormalities including an abnormal downward slant to the opening between the upper and lower eyelids (palpebral fissures). Affected individuals may develop hearing loss and breathing (respiratory) difficulties. Furthermore, brain and behavioral anomalies such as microcephaly and psychomotor delay have also been occasionally reported as part of the condition. The specific symptoms and physical characteristics associated with TCS can vary greatly from one individual to another. Some individuals may have mild symptoms and go undiagnosed, while others may develop serious, life-threatening respiratory complications. TCS is caused by a mutation in the TCOF1, POLR1C or POLR1D genes. In the case of TCOF1 or POLR1D, the mode of inheritance is autosomal dominant, while in the case of POLR1C it is autosomal recessive. (For more information on this disorder, choose “Treacher Collins” as your search term in the Rare Disease Database.)A variety of rare disorders include postaxial acrofacial dysostosis as a finding including acrofacial dysostosis syndrome of Rodriguez, Weyers acrofacial dysostosis, Catania acrofacial dysostosis, Palagonia acrofacial dysostosis, and Cincinnati acrofacial dysostosis. Other disorders that may have symptoms or physical findings that overlap with Miller syndrome include ophthalmo-acromelic syndrome, Pallister-Hall syndrome, madibulofacial dysostosis type Guion-Almeida, Burn-McKeown syndrome, and oculo-auriculo-vertebral syndrome.
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Related disorders of Miller Syndrome. Symptoms of the following disorders can be similar to those of Miller syndrome. Comparisons may be useful for a differential diagnosis.Nager syndrome (also known as preaxial acrofacial dysostosis) is a rare inherited disorder characterized by craniofacial malformations similar to those in Miller syndrome occurring in association with abnormalities of the arms, hands, and/or feet. Craniofacial malformations include underdevelopment of the cheekbones (malar hypoplasia); incomplete development of the lower jaw (mandibular hypoplasia), causing the jaw to appear abnormally small (micrognathia); hypoplastic and/or malformed (dysplastic) external ears (pinnae) and blind ending or absent external ear canals (microtia), resulting in hearing impairment (conductive hearing loss); and/or downwardly slanted palpebral fissures, lack or absence of the lower eyelashes, and/or drooping upper eyelids (ptosis). Limb abnormalities include underdevelopment or absence of the thumbs, absence of one of the bones in the forearms (radius), abnormal fusion of bones in the forearms (radioulnar synostosis), permanent flexion of certain fingers (camptodactyly), and/or webbing of the toes (syndactyly). Nager syndrome is typically inherited as an autosomal dominant trait cause by a mutation in the SF3B4. In most cases, Nager syndrome appears to occur randomly and newly in the family (sporadic) yet autosomal recessive inheritance has been previously described. The mainly anterior (radius) forearm abnormalities (as opposed to posterior-ulna) and the general lack of abnormalities in the lower limbs might help distinguish Nager syndrome from Miller syndrome (For more information on this disorder, choose “Nager” as your search term in the Rare Disease Database.)Treacher Collins syndrome (TCS) is a rare genetic disorder characterized by distinctive abnormalities of the head and face area resulting from underdevelopment (hypoplasia) of certain facial structures including the jaw, cheekbones and nearby structures (zygomatic complex). Craniofacial abnormalities tend to involve the cheekbones, jaws, mouth, ears, and/or eyes. In addition to the various facial abnormalities, affected individuals may have malformations of the external ears and middle ear structures and eye (ocular) abnormalities including an abnormal downward slant to the opening between the upper and lower eyelids (palpebral fissures). Affected individuals may develop hearing loss and breathing (respiratory) difficulties. Furthermore, brain and behavioral anomalies such as microcephaly and psychomotor delay have also been occasionally reported as part of the condition. The specific symptoms and physical characteristics associated with TCS can vary greatly from one individual to another. Some individuals may have mild symptoms and go undiagnosed, while others may develop serious, life-threatening respiratory complications. TCS is caused by a mutation in the TCOF1, POLR1C or POLR1D genes. In the case of TCOF1 or POLR1D, the mode of inheritance is autosomal dominant, while in the case of POLR1C it is autosomal recessive. (For more information on this disorder, choose “Treacher Collins” as your search term in the Rare Disease Database.)A variety of rare disorders include postaxial acrofacial dysostosis as a finding including acrofacial dysostosis syndrome of Rodriguez, Weyers acrofacial dysostosis, Catania acrofacial dysostosis, Palagonia acrofacial dysostosis, and Cincinnati acrofacial dysostosis. Other disorders that may have symptoms or physical findings that overlap with Miller syndrome include ophthalmo-acromelic syndrome, Pallister-Hall syndrome, madibulofacial dysostosis type Guion-Almeida, Burn-McKeown syndrome, and oculo-auriculo-vertebral syndrome.
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Miller Syndrome
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Diagnosis of Miller Syndrome
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A diagnosis of Miller syndrome is based upon a thorough clinical evaluation, a detailed patient history, and identification of characteristic physical findings. Many of the associated abnormalities are present at birth (congenital).Specialized x-ray studies will confirm the presence and/or extent of certain observed craniofacial abnormalities. For example, such imaging tests show the abnormal smallness of the jaw (micrognathia) due to underdevelopment of the lower jaw bone (mandibular hypoplasia).Molecular genetic testing can confirm a diagnosis of Miller syndrome. Molecular genetic testing can detect a mutation the DHODH gene, but is available only as a diagnostic service at specialized laboratories.
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Diagnosis of Miller Syndrome. A diagnosis of Miller syndrome is based upon a thorough clinical evaluation, a detailed patient history, and identification of characteristic physical findings. Many of the associated abnormalities are present at birth (congenital).Specialized x-ray studies will confirm the presence and/or extent of certain observed craniofacial abnormalities. For example, such imaging tests show the abnormal smallness of the jaw (micrognathia) due to underdevelopment of the lower jaw bone (mandibular hypoplasia).Molecular genetic testing can confirm a diagnosis of Miller syndrome. Molecular genetic testing can detect a mutation the DHODH gene, but is available only as a diagnostic service at specialized laboratories.
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Miller Syndrome
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Therapies of Miller Syndrome
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TreatmentThe treatment of Miller 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, oral surgeons, plastic surgeons, pediatric ear, nose and throat specialists (pediatric otolaryngologists), specialists in diagnosing and treating eye disorders (ophthalmologists), specialists in diagnosing and treating ear disorders (otologists), specialists in treating hearing loss (audiologists), specialists in treating kidney disorders (nephrologists), psychologists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Affected individuals may benefit from referral to a craniofacial center where a team of experienced specialists will coordinate care.Specific treatment may consist of surgery to create a small opening in the throat, through which a small tube is inserted to assist with breathing. Additional jaw surgery may also be necessary to improve breathing. In addition, it might be also necessary to create a small opening in the stomach to allow the insertion of a feeding tube in infants experiencing difficulty eating in order to maintain proper nutrition.Surgery may be required to correct abnormalities of the limbs, and eyes. Surgery and/or speech therapy may be necessary when cleft palate or cleft lip is present. Congenital heart defects often require surgical intervention.Early intervention with appropriate physical, occupational, and speech therapy services is important in ensuring that affected children reach their full potential. Physical and occupational therapy may be necessary to aid in walking and using one’s hands. Speech therapy may be of benefit for individuals with speech development delays due to hearing loss. Hearing loss may require the use of a hearing aid.Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well.
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Therapies of Miller Syndrome. TreatmentThe treatment of Miller 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, oral surgeons, plastic surgeons, pediatric ear, nose and throat specialists (pediatric otolaryngologists), specialists in diagnosing and treating eye disorders (ophthalmologists), specialists in diagnosing and treating ear disorders (otologists), specialists in treating hearing loss (audiologists), specialists in treating kidney disorders (nephrologists), psychologists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Affected individuals may benefit from referral to a craniofacial center where a team of experienced specialists will coordinate care.Specific treatment may consist of surgery to create a small opening in the throat, through which a small tube is inserted to assist with breathing. Additional jaw surgery may also be necessary to improve breathing. In addition, it might be also necessary to create a small opening in the stomach to allow the insertion of a feeding tube in infants experiencing difficulty eating in order to maintain proper nutrition.Surgery may be required to correct abnormalities of the limbs, and eyes. Surgery and/or speech therapy may be necessary when cleft palate or cleft lip is present. Congenital heart defects often require surgical intervention.Early intervention with appropriate physical, occupational, and speech therapy services is important in ensuring that affected children reach their full potential. Physical and occupational therapy may be necessary to aid in walking and using one’s hands. Speech therapy may be of benefit for individuals with speech development delays due to hearing loss. Hearing loss may require the use of a hearing aid.Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well.
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Miller Syndrome
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Overview of Mitochondrial Neurogastrointestinal Encephalopathy
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Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare multisystem disorder characterized by progressive degeneration of the muscles of the gastrointestinal tract causing gastrointestinal dysmotility, weakness of extra-ocular muscles causing drooping of the eyelids (ptosis) and restricted eye movements (ophthalmoparesis), degeneration of peripheral nerves causing altered sensation and weakness the distal arms and legs, and general wasting (cachexia). The specific symptoms associated with MNGIE vary from case to case and may include vomiting, nausea, diarrhea, abdominal pain, and numbness or sensations of pins and needles in the hands and feet. . Additional findings may occur in some cases. MNGIE is caused by changes (mutations) in the TYMP gene encoding thymidine phosphorylase (TP) and is inherited as an autosomal recessive trait.MNGIE patients also show changes (e.g. depletions, deletions, or point mutations) in the genetic material (DNA) of the mitochondria. Mitochondria, found by the hundreds within virtually every cell of the body, generate most of the cellular energy through the respiratory chain enzymes (complexes I-V), which convert electrons derived from sugars and fats into ATP, the energy currency of the cell. The genetic blueprints for essential components of the respiratory chain are mitochondrial DNA (mtDNA). Disorders due to mitochondrial dysfunction, often defects of the respiratory chain, are called mitochondrial disease. Because energy is essential for many tissue functions, mitochondrial diseases typically affect multiple organs of the body.
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Overview of Mitochondrial Neurogastrointestinal Encephalopathy. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare multisystem disorder characterized by progressive degeneration of the muscles of the gastrointestinal tract causing gastrointestinal dysmotility, weakness of extra-ocular muscles causing drooping of the eyelids (ptosis) and restricted eye movements (ophthalmoparesis), degeneration of peripheral nerves causing altered sensation and weakness the distal arms and legs, and general wasting (cachexia). The specific symptoms associated with MNGIE vary from case to case and may include vomiting, nausea, diarrhea, abdominal pain, and numbness or sensations of pins and needles in the hands and feet. . Additional findings may occur in some cases. MNGIE is caused by changes (mutations) in the TYMP gene encoding thymidine phosphorylase (TP) and is inherited as an autosomal recessive trait.MNGIE patients also show changes (e.g. depletions, deletions, or point mutations) in the genetic material (DNA) of the mitochondria. Mitochondria, found by the hundreds within virtually every cell of the body, generate most of the cellular energy through the respiratory chain enzymes (complexes I-V), which convert electrons derived from sugars and fats into ATP, the energy currency of the cell. The genetic blueprints for essential components of the respiratory chain are mitochondrial DNA (mtDNA). Disorders due to mitochondrial dysfunction, often defects of the respiratory chain, are called mitochondrial disease. Because energy is essential for many tissue functions, mitochondrial diseases typically affect multiple organs of the body.
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Mitochondrial Neurogastrointestinal Encephalopathy
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Symptoms of Mitochondrial Neurogastrointestinal Encephalopathy
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The symptoms and severity of MNGIE vary from case to case. Onset of symptoms is usually before 20 years of age, but may range from 5-60 years of age. MNGIE is characterized by a variety of gastrointestinal and neurological findings. The most prominent symptom of MNGIE is progressive dysfunction of the muscles of the gastrointestinal tract (gastrointestinal dysmotility). Any portion of the gastrointestinal tract from the back of the throat (oropharynx) to the large intestine may be affected. The most common form of gastrointestinal dysmotility associated with MNGIE is small intestine hypomotility, in which the muscles of the intestinal walls fail to contract normally and generate the wave-like (peristaltic) motions required to push food through the digestive tract. Failure to push food through the intestines although no physical blockage is present is known as intestinal pseudoobstruction. When the muscles of the wall of the stomach are involved the condition is known as gastroparesis. Individuals with MNGIE may develop a variety of gastrointestinal symptoms. The specific symptoms will vary from case to case, but may include vomiting, nausea, diarrhea, abdominal pain, a feeling of early fullness (premature satiety), stomach rumblings (borborygmi), and difficulty swallowing (dysphagia). Some affected individuals may also develop small sac-like protrusions (diverticula) of inner intestinal layer through the outer muscular wall of the small intestine. The gastrointestinal symptoms associated with MNGIE may result in a variety of complications including bacterial overgrowth in the intestines and, less frequently, failure of the intestines to absorb nutrients during digestion (malabsorption). Consequently, affected individuals may develop weight loss, and the loss of tissue and muscle mass (cachexia). Most individuals with MNGIE are extremely thin and some individuals may have short statute. The most common neurological symptoms associated with MNGIE are drooping of the upper eyelid (ptosis) because of weakness of muscles of the eyelid, weakness of additional muscles around the eye gradually restricting the movements of the eyes (ophthalmoplegia), hearing loss, and peripheral neuropathy, a condition in which there is damage or malfunction of the peripheral nervous system (i.e., the nerves outside the central nervous system). The symptoms of peripheral neuropathy vary greatly, but may include weakness of the muscles of the distal arms or legs or abnormal sensations such as tingling (paresthesias), burning or numbness. The legs are affected more often and earlier than the arms. Individuals with MNGIE often exhibit destruction of the myelin sheath that covers nerve fibers in the brain (leukoencephalopathy). This clinical finding is usually not associated with symptoms (asymptomatic).
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Symptoms of Mitochondrial Neurogastrointestinal Encephalopathy. The symptoms and severity of MNGIE vary from case to case. Onset of symptoms is usually before 20 years of age, but may range from 5-60 years of age. MNGIE is characterized by a variety of gastrointestinal and neurological findings. The most prominent symptom of MNGIE is progressive dysfunction of the muscles of the gastrointestinal tract (gastrointestinal dysmotility). Any portion of the gastrointestinal tract from the back of the throat (oropharynx) to the large intestine may be affected. The most common form of gastrointestinal dysmotility associated with MNGIE is small intestine hypomotility, in which the muscles of the intestinal walls fail to contract normally and generate the wave-like (peristaltic) motions required to push food through the digestive tract. Failure to push food through the intestines although no physical blockage is present is known as intestinal pseudoobstruction. When the muscles of the wall of the stomach are involved the condition is known as gastroparesis. Individuals with MNGIE may develop a variety of gastrointestinal symptoms. The specific symptoms will vary from case to case, but may include vomiting, nausea, diarrhea, abdominal pain, a feeling of early fullness (premature satiety), stomach rumblings (borborygmi), and difficulty swallowing (dysphagia). Some affected individuals may also develop small sac-like protrusions (diverticula) of inner intestinal layer through the outer muscular wall of the small intestine. The gastrointestinal symptoms associated with MNGIE may result in a variety of complications including bacterial overgrowth in the intestines and, less frequently, failure of the intestines to absorb nutrients during digestion (malabsorption). Consequently, affected individuals may develop weight loss, and the loss of tissue and muscle mass (cachexia). Most individuals with MNGIE are extremely thin and some individuals may have short statute. The most common neurological symptoms associated with MNGIE are drooping of the upper eyelid (ptosis) because of weakness of muscles of the eyelid, weakness of additional muscles around the eye gradually restricting the movements of the eyes (ophthalmoplegia), hearing loss, and peripheral neuropathy, a condition in which there is damage or malfunction of the peripheral nervous system (i.e., the nerves outside the central nervous system). The symptoms of peripheral neuropathy vary greatly, but may include weakness of the muscles of the distal arms or legs or abnormal sensations such as tingling (paresthesias), burning or numbness. The legs are affected more often and earlier than the arms. Individuals with MNGIE often exhibit destruction of the myelin sheath that covers nerve fibers in the brain (leukoencephalopathy). This clinical finding is usually not associated with symptoms (asymptomatic).
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Mitochondrial Neurogastrointestinal Encephalopathy
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Causes of Mitochondrial Neurogastrointestinal Encephalopathy
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MNGIE 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. MNGIE is caused by mutations of the TYMP gene encoding thymidine phosphorylase (TP); the gene is located near the end (telomere) of the long arm (q) of chromosome 22 (22q13.32-qter). 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 22q13.32-qter” refers to bands 13 to the end portion (ter) of the long arm of chromosome 22. The numbered bands specify the location of the thousands of genes that are present on each chromosome. The TYMP gene contains instructions (encodes) for the production of thymidine phosphorylase, an enzyme necessary for the breakdown and conversion of certain chemical compounds (nucleosides) in the body. Mutations of the TP gene cause very low activity of thymidine phosphorylase in the cells and tissues of the body. Deficiency of TP enzyme results in abnormally elevated levels of nucleosides, deoxyuridine and thymidine, in the body. Researchers believe that elevated levels of thymidine damage or impair mitochondrial DNA replication, repair, or both. Individuals with MNGIE have mitochondrial DNA defects (e.g., depletions, deletions, duplications). Mitochondrial DNA continually repairs and replicates throughout life so affected individuals are believed to accumulate additional abnormalities of mitochondrial DNA as they age.
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Causes of Mitochondrial Neurogastrointestinal Encephalopathy. MNGIE 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. MNGIE is caused by mutations of the TYMP gene encoding thymidine phosphorylase (TP); the gene is located near the end (telomere) of the long arm (q) of chromosome 22 (22q13.32-qter). 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 22q13.32-qter” refers to bands 13 to the end portion (ter) of the long arm of chromosome 22. The numbered bands specify the location of the thousands of genes that are present on each chromosome. The TYMP gene contains instructions (encodes) for the production of thymidine phosphorylase, an enzyme necessary for the breakdown and conversion of certain chemical compounds (nucleosides) in the body. Mutations of the TP gene cause very low activity of thymidine phosphorylase in the cells and tissues of the body. Deficiency of TP enzyme results in abnormally elevated levels of nucleosides, deoxyuridine and thymidine, in the body. Researchers believe that elevated levels of thymidine damage or impair mitochondrial DNA replication, repair, or both. Individuals with MNGIE have mitochondrial DNA defects (e.g., depletions, deletions, duplications). Mitochondrial DNA continually repairs and replicates throughout life so affected individuals are believed to accumulate additional abnormalities of mitochondrial DNA as they age.
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Affects of Mitochondrial Neurogastrointestinal Encephalopathy
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MNGIE is an extremely rare disorder that affects males and females in equal numbers. The prevalence is unknown and as of 2011 fewer than 200 cases have been reported in the medical literature. Researchers believe that the disorder often goes unrecognized or misdiagnosed, making it difficult to determine its true frequency in the general population. MNGIE was first described in the medical literature in 1976 as congenital oculoskeletal myopathy with abnormal muscle and liver mitochondria. Since then, it has been reported under a variety of different names including mitochondrial encephalomyopathy with sensorimotor polyneuropathy, ophthalmoplegia and pseudo-obstruction (MEPOP); myoneurogastrointestinal encephalopathy syndrome; oculogastrointestinal muscular dystrophy; and polyneuropathy, ophthalmoplegia, leukoencephalopathy, and intestinal pseudo-obstruction (POLIP).
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Affects of Mitochondrial Neurogastrointestinal Encephalopathy. MNGIE is an extremely rare disorder that affects males and females in equal numbers. The prevalence is unknown and as of 2011 fewer than 200 cases have been reported in the medical literature. Researchers believe that the disorder often goes unrecognized or misdiagnosed, making it difficult to determine its true frequency in the general population. MNGIE was first described in the medical literature in 1976 as congenital oculoskeletal myopathy with abnormal muscle and liver mitochondria. Since then, it has been reported under a variety of different names including mitochondrial encephalomyopathy with sensorimotor polyneuropathy, ophthalmoplegia and pseudo-obstruction (MEPOP); myoneurogastrointestinal encephalopathy syndrome; oculogastrointestinal muscular dystrophy; and polyneuropathy, ophthalmoplegia, leukoencephalopathy, and intestinal pseudo-obstruction (POLIP).
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Related disorders of Mitochondrial Neurogastrointestinal Encephalopathy
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Symptoms of the following disorders can be similar to those of MNGIE. Comparisons may be useful for a differential diagnosis. Mitochondrial disorders are a group of related disorders characterized by mutations affecting the parts of the cell that release energy (mitochondria). Mitochondrial disorders often hamper the ability of affected cells to combine food with oxygen to 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. Common symptoms associated with mitochondrial disorders include muscle weakness, stroke-like episodes, and seizures. Exercise intolerance is another common symptom. Some forms are associated with disease of the heart muscle (cardiomyopathy). Mitochondrial disorders include Kearns-Sayre syndrome, MELAS syndrome, MERRF syndrome, NARP, and Leber hereditary optic neuropathy. (For more information on this disorder, choose the specific disorder name as your search term in the Rare Disease Database.) 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 cannot function normally with out it. Each type of leukodystrophy affects a different part of the myelin sheath, leading to a range of neurological problems. Leukodystrophy can cause problems with movement, vision, hearing, balance, ability to eat, memory, behavior, and thought. Leukodystrophies are progressive diseases meaning that the symptoms of the disease tend to get worse over time. (For more information on this disorder, choose “leukodystrophy” as your search term in the Rare Disease Database.) Many disorders have gastrointestinal symptoms that are similar to those found in MNGIE including Crohn's disease. Crohn's disease is an inflammatory bowel disease characterized by severe, chronic inflammation of the intestinal wall or any portion of the gastrointestinal tract. The lower portion of the small intestine (ileum) and the rectum are most commonly affected by this disorder. Symptoms may include watery diarrhea, abdominal pain, fever, and weight loss. The symptoms of Crohn's disease can be difficult to manage and proper diagnosis is often delayed. The exact cause of Crohn's disease is unknown. (For more information on this disorder, choose “Crohn's” as your search term in the Rare Disease Database.)
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Related disorders of Mitochondrial Neurogastrointestinal Encephalopathy. Symptoms of the following disorders can be similar to those of MNGIE. Comparisons may be useful for a differential diagnosis. Mitochondrial disorders are a group of related disorders characterized by mutations affecting the parts of the cell that release energy (mitochondria). Mitochondrial disorders often hamper the ability of affected cells to combine food with oxygen to 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. Common symptoms associated with mitochondrial disorders include muscle weakness, stroke-like episodes, and seizures. Exercise intolerance is another common symptom. Some forms are associated with disease of the heart muscle (cardiomyopathy). Mitochondrial disorders include Kearns-Sayre syndrome, MELAS syndrome, MERRF syndrome, NARP, and Leber hereditary optic neuropathy. (For more information on this disorder, choose the specific disorder name as your search term in the Rare Disease Database.) 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 cannot function normally with out it. Each type of leukodystrophy affects a different part of the myelin sheath, leading to a range of neurological problems. Leukodystrophy can cause problems with movement, vision, hearing, balance, ability to eat, memory, behavior, and thought. Leukodystrophies are progressive diseases meaning that the symptoms of the disease tend to get worse over time. (For more information on this disorder, choose “leukodystrophy” as your search term in the Rare Disease Database.) Many disorders have gastrointestinal symptoms that are similar to those found in MNGIE including Crohn's disease. Crohn's disease is an inflammatory bowel disease characterized by severe, chronic inflammation of the intestinal wall or any portion of the gastrointestinal tract. The lower portion of the small intestine (ileum) and the rectum are most commonly affected by this disorder. Symptoms may include watery diarrhea, abdominal pain, fever, and weight loss. The symptoms of Crohn's disease can be difficult to manage and proper diagnosis is often delayed. The exact cause of Crohn's disease is unknown. (For more information on this disorder, choose “Crohn's” as your search term in the Rare Disease Database.)
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Diagnosis of Mitochondrial Neurogastrointestinal Encephalopathy
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A diagnosis of MNGIE is suspected based upon a detailed patient history, a thorough clinical evaluation, identification of characteristic findings, and a variety of specialized tests such as blood tests or magnetic resonance imaging (MRI). Blood tests may reveal elevated lactic acid. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. In individuals with MNGIE, it is used to demonstrate asymptomatic leukoencephalopathy.A diagnosis of MNGIE may be confirmed biochemically by demonstrating low TP enzyme activity in the buffy coat containing white blood cells (leukocytes) and platelets or by detecting elevated plasma levels of the nucleosides thymidine and deoxyuridine. Alternatively, the diagnosis can be confirmed through molecular genetic testing, in which examination of deoxyribonucleic acid (DNA) reveals specific genetic mutations associated with MNGIE.
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Diagnosis of Mitochondrial Neurogastrointestinal Encephalopathy. A diagnosis of MNGIE is suspected based upon a detailed patient history, a thorough clinical evaluation, identification of characteristic findings, and a variety of specialized tests such as blood tests or magnetic resonance imaging (MRI). Blood tests may reveal elevated lactic acid. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. In individuals with MNGIE, it is used to demonstrate asymptomatic leukoencephalopathy.A diagnosis of MNGIE may be confirmed biochemically by demonstrating low TP enzyme activity in the buffy coat containing white blood cells (leukocytes) and platelets or by detecting elevated plasma levels of the nucleosides thymidine and deoxyuridine. Alternatively, the diagnosis can be confirmed through molecular genetic testing, in which examination of deoxyribonucleic acid (DNA) reveals specific genetic mutations associated with MNGIE.
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Therapies of Mitochondrial Neurogastrointestinal Encephalopathy
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TreatmentThe treatment of MNGIE is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, internists, gastroenterologists, neurologists, surgeons, cardiologists, dental specialists, speech pathologists, specialists who assess and treat hearing problems (audiologists), eye specialists and others may need to systematically and comprehensively plan an affected patient's treatment.Specific treatments may include drug therapies for nausea and vomiting and for symptoms secondary to nerve dysfunction (neuropathy) such as pain. Pain affecting certain organs of the gastrointestinal tract (abdominal viscera) may be treated by a procedure known as celiac plexus neurolysis. During this procedure, nerve impulses are temporarily disrupted thereby lessening pain.Affected individuals may need to be evaluated for swallowing difficulties to prevent aspiration.Nutritional supplementation may become necessary and may be provided through parenteral feedings or a gastrostomy tube. Parenteral feeding is being fed through any pathway that does not involve the gastrointestinal tract or lungs, i.e., feeding through a tube directly into the veins (intravenous). Gastrostomy refers to creating a surgical opening in the stomach through which a tube is inserted to provide direct nutritional support.Individuals with MNGIE should avoid drugs that interfere or hamper mitochondrial function. Such drugs include valproate, phenytoin, chloramphenicol, linezolid, aminoglycosides, and tetracycline.Some affected individuals may benefit from occupational and physical therapy. Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
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Therapies of Mitochondrial Neurogastrointestinal Encephalopathy. TreatmentThe treatment of MNGIE is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, internists, gastroenterologists, neurologists, surgeons, cardiologists, dental specialists, speech pathologists, specialists who assess and treat hearing problems (audiologists), eye specialists and others may need to systematically and comprehensively plan an affected patient's treatment.Specific treatments may include drug therapies for nausea and vomiting and for symptoms secondary to nerve dysfunction (neuropathy) such as pain. Pain affecting certain organs of the gastrointestinal tract (abdominal viscera) may be treated by a procedure known as celiac plexus neurolysis. During this procedure, nerve impulses are temporarily disrupted thereby lessening pain.Affected individuals may need to be evaluated for swallowing difficulties to prevent aspiration.Nutritional supplementation may become necessary and may be provided through parenteral feedings or a gastrostomy tube. Parenteral feeding is being fed through any pathway that does not involve the gastrointestinal tract or lungs, i.e., feeding through a tube directly into the veins (intravenous). Gastrostomy refers to creating a surgical opening in the stomach through which a tube is inserted to provide direct nutritional support.Individuals with MNGIE should avoid drugs that interfere or hamper mitochondrial function. Such drugs include valproate, phenytoin, chloramphenicol, linezolid, aminoglycosides, and tetracycline.Some affected individuals may benefit from occupational and physical therapy. Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
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Overview of Mitral Valve Prolapse Syndrome
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The mitral valve is the valve between the left upper and left lower chambers (left atrium and left ventricle) of the heart. Mitral valve prolapse syndrome (MVP) is a common condition in which one or both of the flaps (cusps) of the mitral valve bulge or collapse backward (prolapse) into the left atrium during ventricular contraction (systole). In some cases, this may allow leakage or the backward flow of blood from the left ventricle back into the left atrium (mitral regurgitation).The exact underlying mechanism responsible for MVP remains unknown. In many affected individuals, the condition appears to occur in the absence of an associated disorder or syndrome (idiopathic). Evidence indicates that the condition is sometimes familial, suggesting autosomal dominant inheritance. In other cases, MVP occurs in association with certain inherited connective tissue diseases, other heart abnormalities, or other underlying conditions, disorders, or syndromes.In many individuals with MVP, no associated symptoms are apparent (asymptomatic). However, in other cases, the condition may result in chest pain, abnormal heart rhythms (arrhythmias), fatigue, dizziness, and/or other symptoms and signs. MVP is often associated with a characteristic click and/or a subsequent delayed murmur that may be detected through use of a stethoscope during physical examination.
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Overview of Mitral Valve Prolapse Syndrome. The mitral valve is the valve between the left upper and left lower chambers (left atrium and left ventricle) of the heart. Mitral valve prolapse syndrome (MVP) is a common condition in which one or both of the flaps (cusps) of the mitral valve bulge or collapse backward (prolapse) into the left atrium during ventricular contraction (systole). In some cases, this may allow leakage or the backward flow of blood from the left ventricle back into the left atrium (mitral regurgitation).The exact underlying mechanism responsible for MVP remains unknown. In many affected individuals, the condition appears to occur in the absence of an associated disorder or syndrome (idiopathic). Evidence indicates that the condition is sometimes familial, suggesting autosomal dominant inheritance. In other cases, MVP occurs in association with certain inherited connective tissue diseases, other heart abnormalities, or other underlying conditions, disorders, or syndromes.In many individuals with MVP, no associated symptoms are apparent (asymptomatic). However, in other cases, the condition may result in chest pain, abnormal heart rhythms (arrhythmias), fatigue, dizziness, and/or other symptoms and signs. MVP is often associated with a characteristic click and/or a subsequent delayed murmur that may be detected through use of a stethoscope during physical examination.
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Symptoms of Mitral Valve Prolapse Syndrome
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In many individuals with mitral valve prolapse syndrome (MVP), no symptoms are apparent (asymptomatic) and the condition is often nonprogressive. However, others with MVP may develop fatigue, difficulty breathing (dyspnea) with exertion, awareness of the heart beat and a “pounding” or racing of the heart (palpitations), and abnormal heart rhythms (arrhythmias). Additional signs may include lightheadedness, fainting episodes (syncope), abnormally low blood pressure upon standing (orthostatic hypotension), headaches, chest pain, and/or other symptoms and findings. In rare cases, MVP may lead to heart failure or impaired ability of the heart to pump blood effectively to the lungs and on to the rest of the body due to severe mitral regurgitation; the formation of blood clots; transient ischemic attacks (TIAs) or stroke; and/or sudden potentially life-threatening complications. (TIAs are characterized by temporary impairment of brain function due to brief interruptions of blood supply. A stroke refers to localized death of brain tissue [cerebral infarction] due to lack of blood flow and insufficient oxygen supply to the brain. TIAs or stroke may result from interruption of the brain's blood supply by a blood clot carried in the bloodstream [embolism].) Individuals with MVP associated with mitral regurgitation may have an increased risk of developing bacterial infections of the heart lining and valves (bacterial endocarditis). (For further information, please see the “Standard Therapies” section of this report below.)
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Symptoms of Mitral Valve Prolapse Syndrome. In many individuals with mitral valve prolapse syndrome (MVP), no symptoms are apparent (asymptomatic) and the condition is often nonprogressive. However, others with MVP may develop fatigue, difficulty breathing (dyspnea) with exertion, awareness of the heart beat and a “pounding” or racing of the heart (palpitations), and abnormal heart rhythms (arrhythmias). Additional signs may include lightheadedness, fainting episodes (syncope), abnormally low blood pressure upon standing (orthostatic hypotension), headaches, chest pain, and/or other symptoms and findings. In rare cases, MVP may lead to heart failure or impaired ability of the heart to pump blood effectively to the lungs and on to the rest of the body due to severe mitral regurgitation; the formation of blood clots; transient ischemic attacks (TIAs) or stroke; and/or sudden potentially life-threatening complications. (TIAs are characterized by temporary impairment of brain function due to brief interruptions of blood supply. A stroke refers to localized death of brain tissue [cerebral infarction] due to lack of blood flow and insufficient oxygen supply to the brain. TIAs or stroke may result from interruption of the brain's blood supply by a blood clot carried in the bloodstream [embolism].) Individuals with MVP associated with mitral regurgitation may have an increased risk of developing bacterial infections of the heart lining and valves (bacterial endocarditis). (For further information, please see the “Standard Therapies” section of this report below.)
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Causes of Mitral Valve Prolapse Syndrome
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The specific underlying mechanism responsible for mitral valve prolapse syndrome (MVP) is unknown. However, evidence indicates that various changes of the mitral valve or the lower left chamber of the heart (left ventricle) may lead to MVP. Such abnormalities may include excessive or redundant mitral valve flap (cusp) tissue and/or elongation of the strands of tendon (chordae tendinea) that anchor the cusps to certain muscles (papillary muscles) of the ventricle.In many affected individuals, MVP appears to occur as an isolated condition in the absence of an associated disorder or syndrome (idiopathic). In addition, according to experts, there appears to be an increased frequency of the condition in some families, suggesting an autosomal dominant mode of inheritance. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother. In autosomal dominant disorders, a single copy of the disease gene (received from either the mother or father) may be expressed “dominating” the other normal gene and resulting in the appearance of the disease. The risk of transmitting the disorder from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child. The risk is the same for each pregnancy.In other affected individuals, the changes associated with MVP may occur with various underlying conditions or syndromes, including certain inherited connective tissue disorders, such as Marfan syndrome, Ehlers-Danlos syndrome (EDS), or osteogenesis imperfecta (OI); particular heart (cardiac) abnormalities; or other disorders. Marfan syndrome, an autosomal dominant disorder, may be characterized by cardiac, blood vessel, musculoskeletal, and eye abnormalities. EDS refers to a group of genetic disorders characterized by abnormally flexible, easily dislocated joints; unusually loose, thin, “stretchy” (elastic) skin; and excessive tissue fragility. OI is an autosomal dominant disorder in which defective development of connective tissue may result in abnormally brittle, fragile bones; recurrent fractures; abnormal thinness of the white outer coat of the eyes, causing them to appear blue (blue sclerae); and other associated findings. (For further information on these disorders, choose “Marfan,” “Ehlers Danlos,” or “osteogenesis imperfecta” as your search term in the Rare Disease Database.)Cardiac abnormalities potentially associated with MVP may include disease of heart muscle (cardiomyopathy); heart malfunction or damage due to narrowing or blockage of the arteries supplying heart muscle (coronary artery disease); an abnormal opening in the fibrous partition (septum) that normally separates the two upper heart chambers (i.e., certain atrial septal defects); rheumatic heart disease; or other conditions. Rheumatic heart disease is damage to heart muscle and heart valves caused by acute rheumatic fever, an inflammatory disease that may occur as a delayed reaction to infection with streptococcal bacteria (i.e., group A beta-hemolytic streptococci). (For further information, please choose “rheumatic fever” as your search term in the Rare Disease Database.)
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Causes of Mitral Valve Prolapse Syndrome. The specific underlying mechanism responsible for mitral valve prolapse syndrome (MVP) is unknown. However, evidence indicates that various changes of the mitral valve or the lower left chamber of the heart (left ventricle) may lead to MVP. Such abnormalities may include excessive or redundant mitral valve flap (cusp) tissue and/or elongation of the strands of tendon (chordae tendinea) that anchor the cusps to certain muscles (papillary muscles) of the ventricle.In many affected individuals, MVP appears to occur as an isolated condition in the absence of an associated disorder or syndrome (idiopathic). In addition, according to experts, there appears to be an increased frequency of the condition in some families, suggesting an autosomal dominant mode of inheritance. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother. In autosomal dominant disorders, a single copy of the disease gene (received from either the mother or father) may be expressed “dominating” the other normal gene and resulting in the appearance of the disease. The risk of transmitting the disorder from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child. The risk is the same for each pregnancy.In other affected individuals, the changes associated with MVP may occur with various underlying conditions or syndromes, including certain inherited connective tissue disorders, such as Marfan syndrome, Ehlers-Danlos syndrome (EDS), or osteogenesis imperfecta (OI); particular heart (cardiac) abnormalities; or other disorders. Marfan syndrome, an autosomal dominant disorder, may be characterized by cardiac, blood vessel, musculoskeletal, and eye abnormalities. EDS refers to a group of genetic disorders characterized by abnormally flexible, easily dislocated joints; unusually loose, thin, “stretchy” (elastic) skin; and excessive tissue fragility. OI is an autosomal dominant disorder in which defective development of connective tissue may result in abnormally brittle, fragile bones; recurrent fractures; abnormal thinness of the white outer coat of the eyes, causing them to appear blue (blue sclerae); and other associated findings. (For further information on these disorders, choose “Marfan,” “Ehlers Danlos,” or “osteogenesis imperfecta” as your search term in the Rare Disease Database.)Cardiac abnormalities potentially associated with MVP may include disease of heart muscle (cardiomyopathy); heart malfunction or damage due to narrowing or blockage of the arteries supplying heart muscle (coronary artery disease); an abnormal opening in the fibrous partition (septum) that normally separates the two upper heart chambers (i.e., certain atrial septal defects); rheumatic heart disease; or other conditions. Rheumatic heart disease is damage to heart muscle and heart valves caused by acute rheumatic fever, an inflammatory disease that may occur as a delayed reaction to infection with streptococcal bacteria (i.e., group A beta-hemolytic streptococci). (For further information, please choose “rheumatic fever” as your search term in the Rare Disease Database.)
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Affects of Mitral Valve Prolapse Syndrome
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Although mitral valve prolapse syndrome (MVP) has been reported in individuals of various ages, it is most commonly noted in young adults. Estimates indicate that MVP affects approximately four to eight percent of young adults in the general population, with females affected more commonly than males.
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Affects of Mitral Valve Prolapse Syndrome. Although mitral valve prolapse syndrome (MVP) has been reported in individuals of various ages, it is most commonly noted in young adults. Estimates indicate that MVP affects approximately four to eight percent of young adults in the general population, with females affected more commonly than males.
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Related disorders of Mitral Valve Prolapse Syndrome
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As noted above, mitral valve prolapse syndrome may occur as an isolated condition or in association with various underlying disorders or syndromes. For further information, please see the “Causes” section above or use the disease name in question as your search term in the Rare Disease Database.
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Related disorders of Mitral Valve Prolapse Syndrome. As noted above, mitral valve prolapse syndrome may occur as an isolated condition or in association with various underlying disorders or syndromes. For further information, please see the “Causes” section above or use the disease name in question as your search term in the Rare Disease Database.
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Diagnosis of Mitral Valve Prolapse Syndrome
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Mitral valve prolapse syndrome (MVP) may be diagnosed based upon thorough clinical examination, a complete patient and family history, and various tests. The condition is often recognized through use of a stethoscope during routine physical examination, based upon detection of a characteristic clicking sound or sounds (systolic clicks) and/or a subsequent, delayed, high-pitched murmur (late systolic regurgitation murmur). The diagnosis may be confirmed based upon specialized imaging techniques, particularly echocardiography, during which sound waves are directed toward the heart, enabling physicians to identify abnormal positioning and prolapse of the mitral valve flaps. In some cases, additional cardiac and other diagnostic studies may be recommended to help confirm and assess the severity of potentially associated abnormalities, such as accompanying regurgitation.
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Diagnosis of Mitral Valve Prolapse Syndrome. Mitral valve prolapse syndrome (MVP) may be diagnosed based upon thorough clinical examination, a complete patient and family history, and various tests. The condition is often recognized through use of a stethoscope during routine physical examination, based upon detection of a characteristic clicking sound or sounds (systolic clicks) and/or a subsequent, delayed, high-pitched murmur (late systolic regurgitation murmur). The diagnosis may be confirmed based upon specialized imaging techniques, particularly echocardiography, during which sound waves are directed toward the heart, enabling physicians to identify abnormal positioning and prolapse of the mitral valve flaps. In some cases, additional cardiac and other diagnostic studies may be recommended to help confirm and assess the severity of potentially associated abnormalities, such as accompanying regurgitation.
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Therapies of Mitral Valve Prolapse Syndrome
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TreatmentThe treatment of MVP is directed toward the specific symptoms that are apparent. Most individuals with MVP have no associated symptoms and require no treatment. However, as mentioned above, those with associated mitral regurgitation may have an increased risk of developing bacterial infections of the heart lining and valves (bacterial endocarditis). Therefore, appropriate antibiotic therapy (antibiotic prophylaxis) is required prior to dental procedures, surgical procedures, and certain diagnostic techniques to help prevent such infection.In some cases, treatment with certain medications (e.g., beta blockers) may be recommended for those with associated chest pain, headaches, dizziness, or certain other findings. In addition, antiarrhythmic agents may be administered for those with symptoms due to abnormal heart rhythms.In rare cases, if affected individuals have severe mitral regurgitation, surgical mitral valve repair or replacement may be required. For those who experience transient ischemic attacks, disease management may include the use of aspirin or appropriate anticlotting (anticoagulant) agents. Other treatment for this disorder is symptomatic and supportive.
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Therapies of Mitral Valve Prolapse Syndrome. TreatmentThe treatment of MVP is directed toward the specific symptoms that are apparent. Most individuals with MVP have no associated symptoms and require no treatment. However, as mentioned above, those with associated mitral regurgitation may have an increased risk of developing bacterial infections of the heart lining and valves (bacterial endocarditis). Therefore, appropriate antibiotic therapy (antibiotic prophylaxis) is required prior to dental procedures, surgical procedures, and certain diagnostic techniques to help prevent such infection.In some cases, treatment with certain medications (e.g., beta blockers) may be recommended for those with associated chest pain, headaches, dizziness, or certain other findings. In addition, antiarrhythmic agents may be administered for those with symptoms due to abnormal heart rhythms.In rare cases, if affected individuals have severe mitral regurgitation, surgical mitral valve repair or replacement may be required. For those who experience transient ischemic attacks, disease management may include the use of aspirin or appropriate anticlotting (anticoagulant) agents. Other treatment for this disorder is symptomatic and supportive.
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Overview of Mixed Connective Tissue Disease
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Mixed connective tissue disease (MTCD) is an uncommon systemic inflammatory rheumatic condition. MCTD is a specific subset of the broader category of rheumatic “overlap syndromes”, a term used to describe when a patient has features of more than one classic inflammatory rheumatic disease. These classic rheumatic diseases include systemic lupus erythematosus, polymyositis, scleroderma and rheumatoid arthritis. Individuals with an overlap syndrome may, but need not meet, complete diagnostic criteria for one (or more than one) classic rheumatic disease. MCTD is distinguished from other overlap syndromes by a laboratory result: MCTD patients have rheumatic overlap syndrome plus anti-RNP antibodies. Additionally, it has been proposed that the term “MCTD” be reserved for patients with clinical features that include at least one of the following “common manifestations”: Raynaud’s phenomenon, puffy fingers or swollen hands.
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Overview of Mixed Connective Tissue Disease. Mixed connective tissue disease (MTCD) is an uncommon systemic inflammatory rheumatic condition. MCTD is a specific subset of the broader category of rheumatic “overlap syndromes”, a term used to describe when a patient has features of more than one classic inflammatory rheumatic disease. These classic rheumatic diseases include systemic lupus erythematosus, polymyositis, scleroderma and rheumatoid arthritis. Individuals with an overlap syndrome may, but need not meet, complete diagnostic criteria for one (or more than one) classic rheumatic disease. MCTD is distinguished from other overlap syndromes by a laboratory result: MCTD patients have rheumatic overlap syndrome plus anti-RNP antibodies. Additionally, it has been proposed that the term “MCTD” be reserved for patients with clinical features that include at least one of the following “common manifestations”: Raynaud’s phenomenon, puffy fingers or swollen hands.
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Symptoms of Mixed Connective Tissue Disease
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Individuals with MCTD have symptoms that overlap with those of two or more inflammatory rheumatic diseases. These diseases, in which autoimmunity, excess immune activation and inflammation are hallmarks, include systemic lupus erythematosus, polymyositis, scleroderma and rheumatoid arthritis. (For more information on these disorders, see the Related Disorders section of this report.) While inflammatory rheumatic diseases have at times been referred to as “connective tissue diseases”, this can cause confusion with other conditions which are characterized by biochemically abnormal connective tissues (such as Ehlers-Danlos syndrome or Marfan syndrome) in which autoimmunity, excess immune reactions and inflammation need not occur, and which are not part of MCTD.A condition known as Raynaud’s phenomenon may precede the development of additional symptoms of MCTD. Raynaud’s phenomenon, which is seen also in over 95% of patients with scleroderma, is characterized by painfully cold fingers and toes with blue and/or white color changes caused by spasm of blood vessels in the hands and feet in response to cold or stress. It also occurs in approximately 90 percent of individuals with MCTD.Pain in multiple joints (polyarthralgia) or inflammation of joints (arthritis) also occurs in the majority of affected individuals. Lupus-like skin inflammation in sun-exposed areas and hair loss are common, as are skin thickening changes on the fingers and face like those seen in scleroderma. Muscle weakness due to inflammation (myositis) of the muscles can also occur, typically primarily affecting large centrally-located muscle groups. Additional frequent symptoms include hand swelling and fatigue.Dysfunction of the esophagus occurs in at least half of individuals with MCTD. The esophagus is the tube that carries food from the mouth to the stomach. Esophageal trouble most often manifests as heartburn (gastroesophageal reflux) and difficulty swallowing solid foods. Nearly half of individuals with MCTD may develop clinically significant lung involvement, typically with a delay of months to years after the condition first emerges. MCTD lung disease may lead to breathing (respiratory) difficulties caused either by high blood pressure in the lungs (pulmonary hypertension) or by causing lung inflammation and scarring in and around the lung air sacs (interstitial lung disease).Heart (cardiac) involvement is less common in MCTD than lung problems, but can be serious when it occurs.Kidney (renal) disease occurs much less often in MCTD than in lupus (10 percent of individuals with MCTD) and is often mild in MCTD.Neurologic abnormalities are noted in approximately 10 percent of individuals with MCTD. The neurologic findings of aseptic meningitis (an inflammation of the lining surfaces that surround the brain and spinal cord, without an associated infection) or trigeminal neuralgia (an impairment in the function of one of the major cranial nerves that supplies sensory and motor functions to parts of the face) have been observed to occur with increased frequency in MCTD.Low levels of circulating red blood cells (anemia) and a reduction in the white blood cell count (leukopenia) occur in 30 to 40 percent of patients. Enlargement of the lymph nodes (lymphadenopathy), enlargement of the spleen (splenomegaly), enlargement of the liver (hepatomegaly) and intestinal involvement may also occur in some patients.Although medications may be required to help control MCTD, the condition has been reported to eventually enter spontaneous sustained remission in as many as 40% of patients.Patterns of organ targeting have been reported that suggest disease subtypes. Some patients have more vascular manifestations, and have higher risk for pulmonary hypertension. Some patients have more myositis manifestations and have higher risk for interstitial lung disease. Some patients with more classic rheumatoid arthritis manifestations may have a lower risk of major internal organ damage.
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Symptoms of Mixed Connective Tissue Disease. Individuals with MCTD have symptoms that overlap with those of two or more inflammatory rheumatic diseases. These diseases, in which autoimmunity, excess immune activation and inflammation are hallmarks, include systemic lupus erythematosus, polymyositis, scleroderma and rheumatoid arthritis. (For more information on these disorders, see the Related Disorders section of this report.) While inflammatory rheumatic diseases have at times been referred to as “connective tissue diseases”, this can cause confusion with other conditions which are characterized by biochemically abnormal connective tissues (such as Ehlers-Danlos syndrome or Marfan syndrome) in which autoimmunity, excess immune reactions and inflammation need not occur, and which are not part of MCTD.A condition known as Raynaud’s phenomenon may precede the development of additional symptoms of MCTD. Raynaud’s phenomenon, which is seen also in over 95% of patients with scleroderma, is characterized by painfully cold fingers and toes with blue and/or white color changes caused by spasm of blood vessels in the hands and feet in response to cold or stress. It also occurs in approximately 90 percent of individuals with MCTD.Pain in multiple joints (polyarthralgia) or inflammation of joints (arthritis) also occurs in the majority of affected individuals. Lupus-like skin inflammation in sun-exposed areas and hair loss are common, as are skin thickening changes on the fingers and face like those seen in scleroderma. Muscle weakness due to inflammation (myositis) of the muscles can also occur, typically primarily affecting large centrally-located muscle groups. Additional frequent symptoms include hand swelling and fatigue.Dysfunction of the esophagus occurs in at least half of individuals with MCTD. The esophagus is the tube that carries food from the mouth to the stomach. Esophageal trouble most often manifests as heartburn (gastroesophageal reflux) and difficulty swallowing solid foods. Nearly half of individuals with MCTD may develop clinically significant lung involvement, typically with a delay of months to years after the condition first emerges. MCTD lung disease may lead to breathing (respiratory) difficulties caused either by high blood pressure in the lungs (pulmonary hypertension) or by causing lung inflammation and scarring in and around the lung air sacs (interstitial lung disease).Heart (cardiac) involvement is less common in MCTD than lung problems, but can be serious when it occurs.Kidney (renal) disease occurs much less often in MCTD than in lupus (10 percent of individuals with MCTD) and is often mild in MCTD.Neurologic abnormalities are noted in approximately 10 percent of individuals with MCTD. The neurologic findings of aseptic meningitis (an inflammation of the lining surfaces that surround the brain and spinal cord, without an associated infection) or trigeminal neuralgia (an impairment in the function of one of the major cranial nerves that supplies sensory and motor functions to parts of the face) have been observed to occur with increased frequency in MCTD.Low levels of circulating red blood cells (anemia) and a reduction in the white blood cell count (leukopenia) occur in 30 to 40 percent of patients. Enlargement of the lymph nodes (lymphadenopathy), enlargement of the spleen (splenomegaly), enlargement of the liver (hepatomegaly) and intestinal involvement may also occur in some patients.Although medications may be required to help control MCTD, the condition has been reported to eventually enter spontaneous sustained remission in as many as 40% of patients.Patterns of organ targeting have been reported that suggest disease subtypes. Some patients have more vascular manifestations, and have higher risk for pulmonary hypertension. Some patients have more myositis manifestations and have higher risk for interstitial lung disease. Some patients with more classic rheumatoid arthritis manifestations may have a lower risk of major internal organ damage.
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Mixed Connective Tissue Disease
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Causes of Mixed Connective Tissue Disease
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MCTD is caused by immune reactions against self (autoimmunity). The anti-RNP immune response that helps define the disease also appears to mediate some of the damage it induces. The RNP molecules are usually in the nucleus of all human cells, where they help to manufacture messenger RNA, and where the immune system cannot find them. However, in dead or dying cells, RNP molecules can become exposed to the immune system. Since RNP molecules are nearly identical in humans to their counterparts in single celled organisms without immune systems, the human immune system can be fooled into responding to RNP as if it were from a dangerous invader.Several genes that control the immune system’s responsiveness to invaders and the ability to hide or destroy dead cell debris influence the risk of developing MCTD. Prior immune exposures to other things that look like RNP (such as with prior viral infections) may also increase the risk. Additional effects of heredity and the environment on the risk for developing MCTD and on its manifestations and severity are likely.
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Causes of Mixed Connective Tissue Disease. MCTD is caused by immune reactions against self (autoimmunity). The anti-RNP immune response that helps define the disease also appears to mediate some of the damage it induces. The RNP molecules are usually in the nucleus of all human cells, where they help to manufacture messenger RNA, and where the immune system cannot find them. However, in dead or dying cells, RNP molecules can become exposed to the immune system. Since RNP molecules are nearly identical in humans to their counterparts in single celled organisms without immune systems, the human immune system can be fooled into responding to RNP as if it were from a dangerous invader.Several genes that control the immune system’s responsiveness to invaders and the ability to hide or destroy dead cell debris influence the risk of developing MCTD. Prior immune exposures to other things that look like RNP (such as with prior viral infections) may also increase the risk. Additional effects of heredity and the environment on the risk for developing MCTD and on its manifestations and severity are likely.
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Mixed Connective Tissue Disease
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Affects of Mixed Connective Tissue Disease
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The onset of MCTD can occur anytime from early childhood to elderly adulthood, but the average age of onset is 37 years. Approximately 75 percent of patients are female. The point prevalence of MCTD has been found to be 3.8 per 100,000 adults in Norway, and is thought to be similar in many other parts of the world, though much higher prevalence of MCTD has been noted in some countries, notably in Japan.Debate exists in the medical literature as to whether MCTD is a distinct syndrome or should be considered either as a subset of lupus or as instances of undifferentiated autoimmune rheumatic disease.
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Affects of Mixed Connective Tissue Disease. The onset of MCTD can occur anytime from early childhood to elderly adulthood, but the average age of onset is 37 years. Approximately 75 percent of patients are female. The point prevalence of MCTD has been found to be 3.8 per 100,000 adults in Norway, and is thought to be similar in many other parts of the world, though much higher prevalence of MCTD has been noted in some countries, notably in Japan.Debate exists in the medical literature as to whether MCTD is a distinct syndrome or should be considered either as a subset of lupus or as instances of undifferentiated autoimmune rheumatic disease.
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Mixed Connective Tissue Disease
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Related disorders of Mixed Connective Tissue Disease
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The symptoms of the following disorders can be similar to those of MCTD. Comparisons may be useful for a differential diagnosis:Systemic lupus erythematosus (lupus) is a chronic, autoimmune disorder in which multiple targets are attacked, typically including dead cell debris and connective tissue structures. In autoimmune disorders, the body’s own immune system attacks cells and tissues causing inflammation and malfunction of various organ systems. In lupus, organ systems often involved include the skin, kidneys, blood and joints. Many different symptoms can be associated with lupus, but most affected individuals do not experience all of the symptoms. In many patients, lupus may be a mild disorder affecting only a few organ systems. In other patients, it may result in serious complications.Systemic scleroderma is an uncommon autoimmune disease characterized by abnormally increased production and accumulation of collagen, the body’s major structural protein, in skin and other organs of the body, in combination with abnormal blood vessel function leading to Raynaud’s phenomenon. Major targets of the autoimmune response in scleroderma include self-proteins that can become more likely to provoke an immune reaction under conditions of erratic blood flow (leading to “ischemia-reperfusion injury”). Associated symptoms, which may vary widely from person to person, may include Raynaud’s phenomenon, abnormal tightness, thickening, “waxiness”, and loss of elasticity of the skin; shortness of breath; difficulty swallowing; muscle weakness; joint pain; heart abnormalities including irregular heartbeats (palpitations), kidney (renal) abnormalities, and/or other symptoms and findings. (For more information on this disorder, choose “systemic scleroderma” as your search term in the Rare Disease Database.)Polymyositis is a rare autoimmune disease characterized by inflammatory damage in muscle fibers. The major symptom of this disorder is muscle weakness, usually in the neck, trunk, shoulders and thighs. Eventually, it may become difficult for patients to rise from a sitting position, climb stairs, lift objects and/or reach overhead. Other tissues can also develop inflammation in cases of myositis, including the skin (in which case the term dermatomyositis rather than polymyositis is used), the joints, the lungs (interstitial pneumonitis), and the heart. (For more information on this disorder, choose “polymyositis” as your search term in the Rare Disease Database.)Rheumatoid arthritis (RA) is a chronic progressive form of inflammatory arthritis that can lead to joint destruction. Rheumatoid arthritis is characterized by inflammation of the joints (arthritis) on both sides of the body (symmetrical) leading to swelling, pain and decreased mobility. The course of the disease is highly variable.
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Related disorders of Mixed Connective Tissue Disease. The symptoms of the following disorders can be similar to those of MCTD. Comparisons may be useful for a differential diagnosis:Systemic lupus erythematosus (lupus) is a chronic, autoimmune disorder in which multiple targets are attacked, typically including dead cell debris and connective tissue structures. In autoimmune disorders, the body’s own immune system attacks cells and tissues causing inflammation and malfunction of various organ systems. In lupus, organ systems often involved include the skin, kidneys, blood and joints. Many different symptoms can be associated with lupus, but most affected individuals do not experience all of the symptoms. In many patients, lupus may be a mild disorder affecting only a few organ systems. In other patients, it may result in serious complications.Systemic scleroderma is an uncommon autoimmune disease characterized by abnormally increased production and accumulation of collagen, the body’s major structural protein, in skin and other organs of the body, in combination with abnormal blood vessel function leading to Raynaud’s phenomenon. Major targets of the autoimmune response in scleroderma include self-proteins that can become more likely to provoke an immune reaction under conditions of erratic blood flow (leading to “ischemia-reperfusion injury”). Associated symptoms, which may vary widely from person to person, may include Raynaud’s phenomenon, abnormal tightness, thickening, “waxiness”, and loss of elasticity of the skin; shortness of breath; difficulty swallowing; muscle weakness; joint pain; heart abnormalities including irregular heartbeats (palpitations), kidney (renal) abnormalities, and/or other symptoms and findings. (For more information on this disorder, choose “systemic scleroderma” as your search term in the Rare Disease Database.)Polymyositis is a rare autoimmune disease characterized by inflammatory damage in muscle fibers. The major symptom of this disorder is muscle weakness, usually in the neck, trunk, shoulders and thighs. Eventually, it may become difficult for patients to rise from a sitting position, climb stairs, lift objects and/or reach overhead. Other tissues can also develop inflammation in cases of myositis, including the skin (in which case the term dermatomyositis rather than polymyositis is used), the joints, the lungs (interstitial pneumonitis), and the heart. (For more information on this disorder, choose “polymyositis” as your search term in the Rare Disease Database.)Rheumatoid arthritis (RA) is a chronic progressive form of inflammatory arthritis that can lead to joint destruction. Rheumatoid arthritis is characterized by inflammation of the joints (arthritis) on both sides of the body (symmetrical) leading to swelling, pain and decreased mobility. The course of the disease is highly variable.
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Mixed Connective Tissue Disease
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Diagnosis of Mixed Connective Tissue Disease
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MCTD may be diagnosed based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic findings and specialized tests such as blood tests that reveal abnormally high levels of antibodies to the U1 small nuclear ribonucleoprotein (anti-RNP). Several sets of diagnostic criteria for MCTD have been published that have similar performance characteristics. After diagnosis, ongoing surveillance for the potential for late-emerging lung disease is typically performed; serial pulmonary function testing is often an aspect of this assessment.
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Diagnosis of Mixed Connective Tissue Disease. MCTD may be diagnosed based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic findings and specialized tests such as blood tests that reveal abnormally high levels of antibodies to the U1 small nuclear ribonucleoprotein (anti-RNP). Several sets of diagnostic criteria for MCTD have been published that have similar performance characteristics. After diagnosis, ongoing surveillance for the potential for late-emerging lung disease is typically performed; serial pulmonary function testing is often an aspect of this assessment.
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Mixed Connective Tissue Disease
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Therapies of Mixed Connective Tissue Disease
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TreatmentThe treatment of MCTD is based upon the specific symptoms that present in each person. Although no controlled treatment studies have been performed in MCTD itself, some patients with MCTD have been included in previous trials of lupus, scleroderma, myositis and rheumatoid arthritis. In general, it appears that these MCTD subgroups respond similarly to treatments as have been reported in larger classical rheumatic disease-specific patient cohorts. These observations and accumulated clinical experience by MCTD experts supports the use of antimalarials for potential lupus-like disease modifying effects, the use of vasodilators to treat Raynaud’s phenomenon, the use of proton pump inhibitors for GERD, the use of additional disease-modifying anti-rheumatic drugs (DMARDs) for rheumatoid arthritis-like polyarthritis, the use of anti-fibrotics approved for use in other forms of pulmonary fibrosis for the treatment of MCTD-associated pulmonary fibrosis, and the use of treatments approved for other forms of pulmonary hypertension for MCTD-associated pulmonary hypertension.Cohort studies of MCTD patients with pulmonary hypertension or other lung disease have suggested that these patients may be more likely to respond well to a course of aggressive immunosuppression than is typical for patients with similar lung disease stemming from other causes.Low-to-moderate doses of corticosteroids are often effective for rapid control of disease flares, and may be used as part of long-term therapy in some patients, despite their substantial long-term drug toxicities. Scleroderma renal crisis, a serious complication of scleroderma that is more likely after the use of high dose corticosteroids, can occur in MCTD.Nonsteroidal anti-inflammatory drugs (NSAIDs) are sometimes used to help control mild inflammatory symptoms, though their use must be balanced with their risk for gastrointestinal, renal and other complications. Rarely, NSAIDs can cause asepticmeningitis in some individuals; this seems to occur more often in patients with MCTD compared to other groups.
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Therapies of Mixed Connective Tissue Disease. TreatmentThe treatment of MCTD is based upon the specific symptoms that present in each person. Although no controlled treatment studies have been performed in MCTD itself, some patients with MCTD have been included in previous trials of lupus, scleroderma, myositis and rheumatoid arthritis. In general, it appears that these MCTD subgroups respond similarly to treatments as have been reported in larger classical rheumatic disease-specific patient cohorts. These observations and accumulated clinical experience by MCTD experts supports the use of antimalarials for potential lupus-like disease modifying effects, the use of vasodilators to treat Raynaud’s phenomenon, the use of proton pump inhibitors for GERD, the use of additional disease-modifying anti-rheumatic drugs (DMARDs) for rheumatoid arthritis-like polyarthritis, the use of anti-fibrotics approved for use in other forms of pulmonary fibrosis for the treatment of MCTD-associated pulmonary fibrosis, and the use of treatments approved for other forms of pulmonary hypertension for MCTD-associated pulmonary hypertension.Cohort studies of MCTD patients with pulmonary hypertension or other lung disease have suggested that these patients may be more likely to respond well to a course of aggressive immunosuppression than is typical for patients with similar lung disease stemming from other causes.Low-to-moderate doses of corticosteroids are often effective for rapid control of disease flares, and may be used as part of long-term therapy in some patients, despite their substantial long-term drug toxicities. Scleroderma renal crisis, a serious complication of scleroderma that is more likely after the use of high dose corticosteroids, can occur in MCTD.Nonsteroidal anti-inflammatory drugs (NSAIDs) are sometimes used to help control mild inflammatory symptoms, though their use must be balanced with their risk for gastrointestinal, renal and other complications. Rarely, NSAIDs can cause asepticmeningitis in some individuals; this seems to occur more often in patients with MCTD compared to other groups.
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Overview of Mixed Cryoglobulinemia
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SummaryMixed cryoglobulinemia is a rare disorder characterized by the presence of cryoglobulins in the blood. Cryoglobulins are abnormal proteins that thicken and clump together at cold temperatures, usually below 98.6 degrees Fahrenheit (the average human body temperature). However, the exact temperature at which this occurs may vary from one person to another. When these proteins clump together, they can restrict blood flow to joints, muscles, and organs. Eventually, damage or inflammation of affected blood vessels and surrounding tissue can develop, a condition known as vasculitis. Small blood vessels are usually affected, but occasionally larger blood vessels are involved. Common symptoms include skin lesions, joint pain (arthralgia), and weakness, but specific symptoms can vary greatly from one person to another and can potentially involve multiple organ systems. Mixed cryoglobulinemia is believed to be an immune-mediated disorder (in which the immune system response to chronic infection causes damage to various tissues) or an autoimmune disorder (in which the immune system mistakenly attacks the body’s own tissue). Many cases of mixed cryoglobulinemia are associated with chronic infection with the hepatitis C virus. In rare cases, no underlying cause for the disorder can be identified (essential mixed cryoglobulinemia).IntroductionCryoglobulinemia involves dysfunction of the immune system. The immune system is divided into several components, the combined actions of which are responsible for defending against infectious agents. The T cell system (cell-mediated immune response) contributes to fighting several viruses, some bacteria and yeast and fungi. The B cell system (humoral immune response) fights infection caused by other viruses and bacteria. It does so by secreting immune factors called antibodies (also known as immunoglobulins) into the fluid portion of the blood (serum) and body secretions (e.g. saliva). There are five classes of immunoglobulins (Ig) known as IgA, IgD, IgE, IgG, and IgM. Antibodies can directly kill microorganisms or coat them so they are more easily destroyed by white blood cells. Any substance that triggers a response by the immune system is known as an antigen. Cryoglobulinemia is generally broken down in three subtypes. In type I cryoglobulinemia, cryoglobulins are made up of a specific immunoglobulin, usually IgM. Type I cryoglobulinemia is usually associated with an underlying disorder, specifically certain types of cancer. Type II and type III cryoglobulinemia are known as mixed cryoglobulinemia. In these disorders, cryoglobulins are abnormal immune complexes. An immune complex is formed when an antibody attaches to an antigen. Unlike type I cryoglobulinemia, the cryoglobulins in type II and type III contain rheumatoid factor, which is an autoantibody (i.e. an antibody that attacks the body own tissue). The distinction between type II and type III cryoglobulinemia is mostly technical and deals with whether the rheumatoid factor is monoclonal or polyclonal. The clinical pictures of type II and III cryoglobulinemia are similar. This report primarily deals with mixed cryoglobulinemia.
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Overview of Mixed Cryoglobulinemia. SummaryMixed cryoglobulinemia is a rare disorder characterized by the presence of cryoglobulins in the blood. Cryoglobulins are abnormal proteins that thicken and clump together at cold temperatures, usually below 98.6 degrees Fahrenheit (the average human body temperature). However, the exact temperature at which this occurs may vary from one person to another. When these proteins clump together, they can restrict blood flow to joints, muscles, and organs. Eventually, damage or inflammation of affected blood vessels and surrounding tissue can develop, a condition known as vasculitis. Small blood vessels are usually affected, but occasionally larger blood vessels are involved. Common symptoms include skin lesions, joint pain (arthralgia), and weakness, but specific symptoms can vary greatly from one person to another and can potentially involve multiple organ systems. Mixed cryoglobulinemia is believed to be an immune-mediated disorder (in which the immune system response to chronic infection causes damage to various tissues) or an autoimmune disorder (in which the immune system mistakenly attacks the body’s own tissue). Many cases of mixed cryoglobulinemia are associated with chronic infection with the hepatitis C virus. In rare cases, no underlying cause for the disorder can be identified (essential mixed cryoglobulinemia).IntroductionCryoglobulinemia involves dysfunction of the immune system. The immune system is divided into several components, the combined actions of which are responsible for defending against infectious agents. The T cell system (cell-mediated immune response) contributes to fighting several viruses, some bacteria and yeast and fungi. The B cell system (humoral immune response) fights infection caused by other viruses and bacteria. It does so by secreting immune factors called antibodies (also known as immunoglobulins) into the fluid portion of the blood (serum) and body secretions (e.g. saliva). There are five classes of immunoglobulins (Ig) known as IgA, IgD, IgE, IgG, and IgM. Antibodies can directly kill microorganisms or coat them so they are more easily destroyed by white blood cells. Any substance that triggers a response by the immune system is known as an antigen. Cryoglobulinemia is generally broken down in three subtypes. In type I cryoglobulinemia, cryoglobulins are made up of a specific immunoglobulin, usually IgM. Type I cryoglobulinemia is usually associated with an underlying disorder, specifically certain types of cancer. Type II and type III cryoglobulinemia are known as mixed cryoglobulinemia. In these disorders, cryoglobulins are abnormal immune complexes. An immune complex is formed when an antibody attaches to an antigen. Unlike type I cryoglobulinemia, the cryoglobulins in type II and type III contain rheumatoid factor, which is an autoantibody (i.e. an antibody that attacks the body own tissue). The distinction between type II and type III cryoglobulinemia is mostly technical and deals with whether the rheumatoid factor is monoclonal or polyclonal. The clinical pictures of type II and III cryoglobulinemia are similar. This report primarily deals with mixed cryoglobulinemia.
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Mixed Cryoglobulinemia
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Symptoms of Mixed Cryoglobulinemia
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The symptoms and physical findings of mixed cryoglobulinemia can vary greatly from one individual to another. Many different organ symptoms can be potentially become involved. Some individuals will only exhibit one manifestation of the disorder; others will exhibit symptoms of multiple organ systems.Most affected individuals develop purplish discoloration of the skin due to bleeding underneath the skin from small blood vessels (purpura). Numerous small lesions the size of pinpricks (petechaie) may develop. Larger lesions or bruising (ecchymoses) can also occur. The lower extremities are most often affected. Purpuric lesions are most common after an affected individual has been standing or sitting for long periods of time (orthostatic purpura). In some cases, open sores (ulceration) and hives (urticarial) may also develop. Loss of tissue (necrosis) on the extremities (e.g. fingers and toes) can also occur.Although joint pain (arthralgia) is very common in individuals with cryoglobulinemia, joint inflammation (arthritis) occurs far less frequently. Additional nonspecific symptoms are common including mild to severe itching, mild to severe pain, abdominal pain, muscle weakness, muscle pain (myalgia), and abnormal enlargement of the lymph nodes (lymphadenopathy). In some cases, abnormal enlargement of the liver and/or spleen (hepatosplenomegaly) may occur.Cryoglobulinemia can be associated with a kidney (renal) disease known as membranoproliferative glomerulonephritis (MPGN) type I characterized by a specific pattern of injury to the kidney most likely caused by deposition of cryoglobulins in the kidney. MPGN type I can be a severe complication, eventually leading to kidney failure.Affected individuals may experience damage to the nerves outside the central nervous system (peripheral neuropathy). Peripheral neuropathy is characterized by numbness or tingling and painful or burning sensations that usually begin in the feet and sometimes the arms. These sensations may worsen at night (nocturnal exacerbation). Peripheral neuropathy may cause muscles weakness in legs and arms.Affected individuals may also develop an abnormally dry mouth (xerostomia) and abnormally dry eyes (xerophthalmia), a combination which is sometimes referred to as Sicca syndrome. Numbness and tingling and a lack of blood flow to the fingers/or toes when exposed to cold temperatures (Raynaud’s phenomenon) may also occur. Internal bleeding and abnormal blood clot formation has also been reported.Chronic inflammation of the liver (hepatitis) can occur in affected individuals, particularly those with hepatitis C-associated mixed cryoglobulinemia. Chronic hepatitis is often mild or moderate and may not cause any symptoms. Symptoms that can occur include fatigue and aching muscles or joints. Chronic hepatitis can eventually progress to cause scarring (cirrhosis) of the liver.Less often, additional symptoms have been reported in individuals with mixed cryoglobulinemia including lung disease, widespread (diffuse) vasculitis, and certain endocrine disorders such as disorders of affecting the thyroid including autoimmune thyroiditis, hypothyroidism and thyroid cancer. Diffuse vasculitis is a severe, potentially life-threatening complication. When the gastrointestinal tract is involved, sudden, severe abdominal pain (acute abdomen) may be the initial symptom.Diabetes mellitus type 2 occurs with greater frequency in individuals with hepatitis C infection with and without mixed cryoglobulinemia than it does in the general population. Whether individuals with mixed cryoglobulinemia have a higher risk of developing diabetes is not known. Some individuals with mixed cryoglobulinemia may develop cancer as a late complication of the disorder, specifically a type of B-cell lymphoma or a form of liver cancer known as hepatocellular carcinoma.
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Symptoms of Mixed Cryoglobulinemia. The symptoms and physical findings of mixed cryoglobulinemia can vary greatly from one individual to another. Many different organ symptoms can be potentially become involved. Some individuals will only exhibit one manifestation of the disorder; others will exhibit symptoms of multiple organ systems.Most affected individuals develop purplish discoloration of the skin due to bleeding underneath the skin from small blood vessels (purpura). Numerous small lesions the size of pinpricks (petechaie) may develop. Larger lesions or bruising (ecchymoses) can also occur. The lower extremities are most often affected. Purpuric lesions are most common after an affected individual has been standing or sitting for long periods of time (orthostatic purpura). In some cases, open sores (ulceration) and hives (urticarial) may also develop. Loss of tissue (necrosis) on the extremities (e.g. fingers and toes) can also occur.Although joint pain (arthralgia) is very common in individuals with cryoglobulinemia, joint inflammation (arthritis) occurs far less frequently. Additional nonspecific symptoms are common including mild to severe itching, mild to severe pain, abdominal pain, muscle weakness, muscle pain (myalgia), and abnormal enlargement of the lymph nodes (lymphadenopathy). In some cases, abnormal enlargement of the liver and/or spleen (hepatosplenomegaly) may occur.Cryoglobulinemia can be associated with a kidney (renal) disease known as membranoproliferative glomerulonephritis (MPGN) type I characterized by a specific pattern of injury to the kidney most likely caused by deposition of cryoglobulins in the kidney. MPGN type I can be a severe complication, eventually leading to kidney failure.Affected individuals may experience damage to the nerves outside the central nervous system (peripheral neuropathy). Peripheral neuropathy is characterized by numbness or tingling and painful or burning sensations that usually begin in the feet and sometimes the arms. These sensations may worsen at night (nocturnal exacerbation). Peripheral neuropathy may cause muscles weakness in legs and arms.Affected individuals may also develop an abnormally dry mouth (xerostomia) and abnormally dry eyes (xerophthalmia), a combination which is sometimes referred to as Sicca syndrome. Numbness and tingling and a lack of blood flow to the fingers/or toes when exposed to cold temperatures (Raynaud’s phenomenon) may also occur. Internal bleeding and abnormal blood clot formation has also been reported.Chronic inflammation of the liver (hepatitis) can occur in affected individuals, particularly those with hepatitis C-associated mixed cryoglobulinemia. Chronic hepatitis is often mild or moderate and may not cause any symptoms. Symptoms that can occur include fatigue and aching muscles or joints. Chronic hepatitis can eventually progress to cause scarring (cirrhosis) of the liver.Less often, additional symptoms have been reported in individuals with mixed cryoglobulinemia including lung disease, widespread (diffuse) vasculitis, and certain endocrine disorders such as disorders of affecting the thyroid including autoimmune thyroiditis, hypothyroidism and thyroid cancer. Diffuse vasculitis is a severe, potentially life-threatening complication. When the gastrointestinal tract is involved, sudden, severe abdominal pain (acute abdomen) may be the initial symptom.Diabetes mellitus type 2 occurs with greater frequency in individuals with hepatitis C infection with and without mixed cryoglobulinemia than it does in the general population. Whether individuals with mixed cryoglobulinemia have a higher risk of developing diabetes is not known. Some individuals with mixed cryoglobulinemia may develop cancer as a late complication of the disorder, specifically a type of B-cell lymphoma or a form of liver cancer known as hepatocellular carcinoma.
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Mixed Cryoglobulinemia
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