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nord_14_2 | Causes of Acquired Aplastic Anemia | Most cases of acquired aplastic anemia occur unrelated to any identifiable causes, or for unknown reasons (idiopathic). Researchers believe that most are due to the immune system mistakenly targeting the bone marrow (autoimmunity). Autoimmune disorders are caused when the body’s natural defenses against “foreign” or invading organisms begin to attack healthy tissue for unknown reasons. Tests to confirm this in any individual case are not readily available, but there is much evidence to support this pathogenic mechanism.The bone marrow contains hematopoietic stem cells. These stem cells can divide, differentiate and become red or white blood cells or platelets. In aplastic anemia, a precipitating event is hypothesized to trigger immune-mediated destruction of hematopoietic stem cells. It is believed that certain immune system cells (T-lymphocytes) target and destroy the most primitive cells capable of developing into blood cells, hematopoietic stem cells. Individuals with aplastic anemia do not have enough stem cells to produce mature blood cells. The bone marrow appears to be replaced by fat. Affected individuals eventually develop a deficiency of red and white blood cells and platelets (pancytopenia).In the past, acquired aplastic anemia has been linked to a variety of environmental factors, especially benzene; benzene likely is directly harmful to bone marrow cells. The relationship of bone marrow failure to other chemicals, such as pesticides or insecticides, is less well established. Use of certain medical drugs, also is rarely associated with aplastic anemia, as is nonviral hepatitis. Both may trigger the immune system response that mistakenly destroys hematopoietic stem cells. However, most cases of acquired aplastic anemia have no identifiable environmental trigger. | Causes of Acquired Aplastic Anemia. Most cases of acquired aplastic anemia occur unrelated to any identifiable causes, or for unknown reasons (idiopathic). Researchers believe that most are due to the immune system mistakenly targeting the bone marrow (autoimmunity). Autoimmune disorders are caused when the body’s natural defenses against “foreign” or invading organisms begin to attack healthy tissue for unknown reasons. Tests to confirm this in any individual case are not readily available, but there is much evidence to support this pathogenic mechanism.The bone marrow contains hematopoietic stem cells. These stem cells can divide, differentiate and become red or white blood cells or platelets. In aplastic anemia, a precipitating event is hypothesized to trigger immune-mediated destruction of hematopoietic stem cells. It is believed that certain immune system cells (T-lymphocytes) target and destroy the most primitive cells capable of developing into blood cells, hematopoietic stem cells. Individuals with aplastic anemia do not have enough stem cells to produce mature blood cells. The bone marrow appears to be replaced by fat. Affected individuals eventually develop a deficiency of red and white blood cells and platelets (pancytopenia).In the past, acquired aplastic anemia has been linked to a variety of environmental factors, especially benzene; benzene likely is directly harmful to bone marrow cells. The relationship of bone marrow failure to other chemicals, such as pesticides or insecticides, is less well established. Use of certain medical drugs, also is rarely associated with aplastic anemia, as is nonviral hepatitis. Both may trigger the immune system response that mistakenly destroys hematopoietic stem cells. However, most cases of acquired aplastic anemia have no identifiable environmental trigger. | 14 | Acquired Aplastic Anemia |
nord_14_3 | Affects of Acquired Aplastic Anemia | Acquired aplastic anemia affects males and females in about equal numbers. Most cases affect older children, teenagers or young adults. The incidence of aplastic anemia in Europe and Israel is two new cases among 1 million people per year. The incidence rate is two or three times greater in Asia. The exact incidence rates exist for the United States is unknown although some sources say that approximately 500-1,000 new cases of aplastic anemia are diagnosed each year. | Affects of Acquired Aplastic Anemia. Acquired aplastic anemia affects males and females in about equal numbers. Most cases affect older children, teenagers or young adults. The incidence of aplastic anemia in Europe and Israel is two new cases among 1 million people per year. The incidence rate is two or three times greater in Asia. The exact incidence rates exist for the United States is unknown although some sources say that approximately 500-1,000 new cases of aplastic anemia are diagnosed each year. | 14 | Acquired Aplastic Anemia |
nord_14_4 | Related disorders of Acquired Aplastic Anemia | Symptoms of the following disorders can be similar to those of acquired aplastic anemia. Comparisons may be useful for a differential diagnosis:Myelodysplastic syndromes (myelodysplasias, MDS) are a rare group of blood disorders that occur as a result of improper development of blood cells within the bone marrow. The three main types of blood cells (i.e., red blood cells, white blood cells and platelets) are affected. Red blood cells deliver oxygen to the body, white blood cells help fight infections, and platelets assist in clotting to stop blood loss. These improperly developed blood cells fail to develop normally and enter the bloodstream. As a result, individuals with MDS have abnormally low blood cell levels (low blood counts). It is sometimes difficult to distinguish acquired aplastic anemia from MDS. In MDS, patients often suffer due to failure of the bone marrow to produce blood cell, and some MDS can develop into an acute leukemia. In MDS, there are often typical abnormalities of chromosomes of marrow cells and/or harmful mutations in specific genes present in hematopoietic stem. (For more information on this disorder, choose “myelodysplastic syndromes” as your search term in the Rare Disease Database.)Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired stem cell disorder. The classic finding is the premature destruction of red blood cells (hemolysis), resulting in repeated episodes of hemoglobin in the urine (hemoglobinuria). Hemoglobin is the red, iron-rich pigment of blood. Individuals with hemoglobinuria may exhibit dark-colored or bloody urine. This finding is most prominent in the morning, after the urine has concentrated overnight during sleep. In addition to hemolysis, individuals with PNH are also susceptible to developing repeated, potentially life-threatening blood clots (thromboses). Affected individuals also have some degree of underlying bone marrow dysfunction. Severe bone marrow dysfunction potentially results in low levels of red and white blood cells and platelets (pancytopenia). The specific symptoms of PNH vary great and affected individuals usually do not exhibit all of the symptoms potentially associated with the disorder.Two factors are necessary for the development of PNH: an acquired somatic (not passed on to children) mutation of the PIG-A gene, which affects hematopoietic stem cells creating defective “PNH” blood cells, and a predisposition to the multiplication and expansion of these defective stem cells. PNH arises in the setting of autoimmune bone marrow failure,. Researchers believe that defective PNH stem cells survive the misguided attack by the immune system and multiply, while the healthy stem cells are destroyed, resulting in the development of PNH. (For more information on this disorder, choose “paroxysmal nocturnal hemoglobinuria” as your search term in the Rare Disease Database.)Aplastic anemia may also occur as part of an inherited disorder such as Fanconi anemia, the telomere diseases, Schwachman-Diamond syndrome, ataxia-pancytopenia syndrome, and others.Fanconi anemia is a rare genetic disorder that may be apparent at birth or during childhood. In some cases, Fanconi’s anemia may not be diagnosed until adulthood. Many different genes have been identified as mutated in Fanconi anemia, and they generally cells ability to repair chromosome damage, and predisposes to damage to stem cells and eventually to leukemic transformation. The disorder is characterized by deficiency of all bone marrow elements including red blood cells, white blood cells, and platelets (pancytopenia). Fanconi anemia may also be associated with heart (cardiac), kidney (renal), and/or skeletal abnormalities, as well as patchy, brown discolorations (pigmentation changes) of the skin. There are several different subtypes (complementation groups) of Fanconi’s anemia, each of which is thought to result from abnormal changes (mutations) to different genes. Each subtype appears to share the same characteristic symptoms and findings (phenotype). Fanconi’s anemia has autosomal recessive inheritance. (For more information on this disorder, choose “Fanconi Anemia” as your search term in the Rare Disease Database.)The telomere diseases or telomeropathies can also lead to aplastic anemia. In these inherited conditions, there are inherited mutations in genes that maintain the ends of the chromosomes, called telomeres. Chromosome ends erode normally with healthy aging of cells and organisms, but attrition is accelerated in the telomere diseases. As with Fanconi anemia, patients may not show signs of disease until adulthood. In addition to bone marrow failure, telomeropathies can also lead to pulmonary fibrosis and liver cirrhosis. Family members may have different and/or multiple organs affected, and manifestations can range from mild to severe. | Related disorders of Acquired Aplastic Anemia. Symptoms of the following disorders can be similar to those of acquired aplastic anemia. Comparisons may be useful for a differential diagnosis:Myelodysplastic syndromes (myelodysplasias, MDS) are a rare group of blood disorders that occur as a result of improper development of blood cells within the bone marrow. The three main types of blood cells (i.e., red blood cells, white blood cells and platelets) are affected. Red blood cells deliver oxygen to the body, white blood cells help fight infections, and platelets assist in clotting to stop blood loss. These improperly developed blood cells fail to develop normally and enter the bloodstream. As a result, individuals with MDS have abnormally low blood cell levels (low blood counts). It is sometimes difficult to distinguish acquired aplastic anemia from MDS. In MDS, patients often suffer due to failure of the bone marrow to produce blood cell, and some MDS can develop into an acute leukemia. In MDS, there are often typical abnormalities of chromosomes of marrow cells and/or harmful mutations in specific genes present in hematopoietic stem. (For more information on this disorder, choose “myelodysplastic syndromes” as your search term in the Rare Disease Database.)Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired stem cell disorder. The classic finding is the premature destruction of red blood cells (hemolysis), resulting in repeated episodes of hemoglobin in the urine (hemoglobinuria). Hemoglobin is the red, iron-rich pigment of blood. Individuals with hemoglobinuria may exhibit dark-colored or bloody urine. This finding is most prominent in the morning, after the urine has concentrated overnight during sleep. In addition to hemolysis, individuals with PNH are also susceptible to developing repeated, potentially life-threatening blood clots (thromboses). Affected individuals also have some degree of underlying bone marrow dysfunction. Severe bone marrow dysfunction potentially results in low levels of red and white blood cells and platelets (pancytopenia). The specific symptoms of PNH vary great and affected individuals usually do not exhibit all of the symptoms potentially associated with the disorder.Two factors are necessary for the development of PNH: an acquired somatic (not passed on to children) mutation of the PIG-A gene, which affects hematopoietic stem cells creating defective “PNH” blood cells, and a predisposition to the multiplication and expansion of these defective stem cells. PNH arises in the setting of autoimmune bone marrow failure,. Researchers believe that defective PNH stem cells survive the misguided attack by the immune system and multiply, while the healthy stem cells are destroyed, resulting in the development of PNH. (For more information on this disorder, choose “paroxysmal nocturnal hemoglobinuria” as your search term in the Rare Disease Database.)Aplastic anemia may also occur as part of an inherited disorder such as Fanconi anemia, the telomere diseases, Schwachman-Diamond syndrome, ataxia-pancytopenia syndrome, and others.Fanconi anemia is a rare genetic disorder that may be apparent at birth or during childhood. In some cases, Fanconi’s anemia may not be diagnosed until adulthood. Many different genes have been identified as mutated in Fanconi anemia, and they generally cells ability to repair chromosome damage, and predisposes to damage to stem cells and eventually to leukemic transformation. The disorder is characterized by deficiency of all bone marrow elements including red blood cells, white blood cells, and platelets (pancytopenia). Fanconi anemia may also be associated with heart (cardiac), kidney (renal), and/or skeletal abnormalities, as well as patchy, brown discolorations (pigmentation changes) of the skin. There are several different subtypes (complementation groups) of Fanconi’s anemia, each of which is thought to result from abnormal changes (mutations) to different genes. Each subtype appears to share the same characteristic symptoms and findings (phenotype). Fanconi’s anemia has autosomal recessive inheritance. (For more information on this disorder, choose “Fanconi Anemia” as your search term in the Rare Disease Database.)The telomere diseases or telomeropathies can also lead to aplastic anemia. In these inherited conditions, there are inherited mutations in genes that maintain the ends of the chromosomes, called telomeres. Chromosome ends erode normally with healthy aging of cells and organisms, but attrition is accelerated in the telomere diseases. As with Fanconi anemia, patients may not show signs of disease until adulthood. In addition to bone marrow failure, telomeropathies can also lead to pulmonary fibrosis and liver cirrhosis. Family members may have different and/or multiple organs affected, and manifestations can range from mild to severe. | 14 | Acquired Aplastic Anemia |
nord_14_5 | Diagnosis of Acquired Aplastic Anemia | A diagnosis of acquired aplastic anemia may be suspected when an otherwise healthy individual has low levels of all three blood cell types (pancytopenia). A diagnosis may be confirmed by a thorough clinical evaluation, a detailed patient history, and a variety of specialized tests, including a bone marrow biopsy. During this procedure, a small specimen of bone marrow tissue is surgically removed, usually from the hip or pelvis, and studied under a microscope. In acquired aplastic anemia this sample will show a dramatic reduction or complete lack of cells. Additional tests may be necessary to rule out other disorders such as leukemia and to determine if there is an inherited or genetic cause. | Diagnosis of Acquired Aplastic Anemia. A diagnosis of acquired aplastic anemia may be suspected when an otherwise healthy individual has low levels of all three blood cell types (pancytopenia). A diagnosis may be confirmed by a thorough clinical evaluation, a detailed patient history, and a variety of specialized tests, including a bone marrow biopsy. During this procedure, a small specimen of bone marrow tissue is surgically removed, usually from the hip or pelvis, and studied under a microscope. In acquired aplastic anemia this sample will show a dramatic reduction or complete lack of cells. Additional tests may be necessary to rule out other disorders such as leukemia and to determine if there is an inherited or genetic cause. | 14 | Acquired Aplastic Anemia |
nord_14_6 | Therapies of Acquired Aplastic Anemia | TreatmentTreatment of acquired aplastic anemia varies, depending upon the individual’s age, general health, and the severity of aplastic anemia. Treatment aims to correct the bone marrow failure, as well as to treat the patient’s immediate signs and symptoms. The two main forms of specific treatment are bone marrow transplantation and immunosuppressive therapies.Initial treatment of acquired aplastic anemia may be directed toward improving the symptoms that may result from low blood counts. Such treatment consists of giving red blood cell transfusions to correct anemia, platelet transfusions to treat or prevent serious bleeding, and antibiotics to treat or prevent infections.Bone marrow transplantation, specifically an allogeneic transplant, is the treatment of choice in children and younger adults. With allogeneic bone marrow transplant, an affected individual’s abnormal bone marrow cells are eradicated or destroyed by chemotherapy and replaced with healthy marrow obtained from a donor. The donor marrow is transplanted by injecting the cells of the donor intravenously into the patient’s body, where it travels to the patient’s bone marrow and eventually begins producing new blood cells. The best match for a bone marrow transplant is an identical twin, sibling or close relative who shares most of the same genetic makeup as the patient. However, in many cases, a search for an unrelated, matched donor is necessary, or more recently a partly matched family member is the donor.Graft rejection and graft-versus-host disease are potential complications with any transplant procedures, including bone marrow transplant. Complications of graft-versus-host disease from a bone marrow transplant may range from mild to life threatening. Drugs may be used to prevent or treat graft rejection or graft-versus-host disease. (For more information on this disorder, choose “graft versus host disease” as your search term in the Rare Disease Database.)Individuals who are not candidates for a bone marrow transplant, either because of advanced age or lack of a suitable donor, are usually treated with immunosuppressive treatment. In this case, drugs are used to suppress the activity of the immune system. Since many cases of acquired aplastic anemia are believed to result from an individual’s immune system mistakenly attacking bone marrow, suppressing the activity of the immune system often allows the bone marrow to recover and eventually to begin producing new blood cells. The two most commonly used immunosuppressive agents, given alone or in combination, are antithymocyte globulin (ATG) and cyclosporine. Horse ATG is more effective than rabbit ATG in the treatment of aplastic anemia.Immunosuppressive therapy can restore an affected individual’s blood count to normal or near normal levels for prolonged periods. However, the improvement may not be permanent and the treatment must be repeated if relapses of aplastic anemia occur. In addition, individuals who successfully respond to immunosuppressive therapy are still at risk of eventually developing PNH, myelodysplasia, or leukemia.Approximately one-third of individuals treated with immunosuppressive drugs do not respond to therapy (refractory aplastic anemia). In these cases, treatment with hematopoietic stem cell transplantation may be considered. Immunosuppression can be repeated in refractory aplastic anemia and also for patients who have relapsed.Hematopoietic growth factors such as erythropoietin and neupogen are not effective in aplastic anemia, but surprisingly eltrombopag, a stimulator of platelet production, was effective in improving blood counts in refractory aplastic anemia. In 2014, Promacta was approved to treat patients with severe aplastic anemia who have had an insufficient response to immunosuppressive therapy and are not candidates for a hematopoietic stem cell transplant. When eltrombopag was combined with standard immunosuppression as first-line therapy, response and complete response rates were higher than with immunosuppression alone. | Therapies of Acquired Aplastic Anemia. TreatmentTreatment of acquired aplastic anemia varies, depending upon the individual’s age, general health, and the severity of aplastic anemia. Treatment aims to correct the bone marrow failure, as well as to treat the patient’s immediate signs and symptoms. The two main forms of specific treatment are bone marrow transplantation and immunosuppressive therapies.Initial treatment of acquired aplastic anemia may be directed toward improving the symptoms that may result from low blood counts. Such treatment consists of giving red blood cell transfusions to correct anemia, platelet transfusions to treat or prevent serious bleeding, and antibiotics to treat or prevent infections.Bone marrow transplantation, specifically an allogeneic transplant, is the treatment of choice in children and younger adults. With allogeneic bone marrow transplant, an affected individual’s abnormal bone marrow cells are eradicated or destroyed by chemotherapy and replaced with healthy marrow obtained from a donor. The donor marrow is transplanted by injecting the cells of the donor intravenously into the patient’s body, where it travels to the patient’s bone marrow and eventually begins producing new blood cells. The best match for a bone marrow transplant is an identical twin, sibling or close relative who shares most of the same genetic makeup as the patient. However, in many cases, a search for an unrelated, matched donor is necessary, or more recently a partly matched family member is the donor.Graft rejection and graft-versus-host disease are potential complications with any transplant procedures, including bone marrow transplant. Complications of graft-versus-host disease from a bone marrow transplant may range from mild to life threatening. Drugs may be used to prevent or treat graft rejection or graft-versus-host disease. (For more information on this disorder, choose “graft versus host disease” as your search term in the Rare Disease Database.)Individuals who are not candidates for a bone marrow transplant, either because of advanced age or lack of a suitable donor, are usually treated with immunosuppressive treatment. In this case, drugs are used to suppress the activity of the immune system. Since many cases of acquired aplastic anemia are believed to result from an individual’s immune system mistakenly attacking bone marrow, suppressing the activity of the immune system often allows the bone marrow to recover and eventually to begin producing new blood cells. The two most commonly used immunosuppressive agents, given alone or in combination, are antithymocyte globulin (ATG) and cyclosporine. Horse ATG is more effective than rabbit ATG in the treatment of aplastic anemia.Immunosuppressive therapy can restore an affected individual’s blood count to normal or near normal levels for prolonged periods. However, the improvement may not be permanent and the treatment must be repeated if relapses of aplastic anemia occur. In addition, individuals who successfully respond to immunosuppressive therapy are still at risk of eventually developing PNH, myelodysplasia, or leukemia.Approximately one-third of individuals treated with immunosuppressive drugs do not respond to therapy (refractory aplastic anemia). In these cases, treatment with hematopoietic stem cell transplantation may be considered. Immunosuppression can be repeated in refractory aplastic anemia and also for patients who have relapsed.Hematopoietic growth factors such as erythropoietin and neupogen are not effective in aplastic anemia, but surprisingly eltrombopag, a stimulator of platelet production, was effective in improving blood counts in refractory aplastic anemia. In 2014, Promacta was approved to treat patients with severe aplastic anemia who have had an insufficient response to immunosuppressive therapy and are not candidates for a hematopoietic stem cell transplant. When eltrombopag was combined with standard immunosuppression as first-line therapy, response and complete response rates were higher than with immunosuppression alone. | 14 | Acquired Aplastic Anemia |
nord_15_0 | Overview of Acquired Hemophilia | SummaryAcquired hemophilia (AH) is a rare autoimmune disorder characterized by bleeding that occurs in patients with no personal or family history of diseases related to clotting/coagulation. Autoimmune disorders occur when the body's immune system mistakenly attacks healthy cells or tissue. In AH, the body produces antibodies (known as inhibitors) that attack clotting factors, most often factor VIII. Clotting factors are specialized proteins required for the blood to clot normally. Consequently, affected individuals develop complications associated with abnormal, uncontrolled bleeding into the muscles, skin and soft tissue that can occur spontaneously, during surgery or following trauma. Specific symptoms can include nosebleeds (epistaxis), bruising throughout the body, solid swellings of congealed blood (hematomas), blood in the urine (hematuria) and gastrointestinal or urogenital bleeding. AH can potentially cause life-threatening bleeding complications in severe cases. In approximately 50% of patients, there is an identifiable underlying clinical condition; in the other 50%, no cause is known (idiopathic).IntroductionAH is different from congenital hemophilia, a group of rare genetic disorders caused by mutations in the genes encoding certain clotting factors. The main form of hemophilia is hemophilia A (classic hemophilia), which is an X-linked disorder that mostly affects males but can also affect females. It is caused by deficiency or inactivation of factor VIII, the same clotting factor that is affected in most individuals with AH. Although both disorders involve deficiency of the same clotting factor, the bleeding pattern is quite different. The reason the bleeding patterns differ between these disorders is not fully understood. | Overview of Acquired Hemophilia. SummaryAcquired hemophilia (AH) is a rare autoimmune disorder characterized by bleeding that occurs in patients with no personal or family history of diseases related to clotting/coagulation. Autoimmune disorders occur when the body's immune system mistakenly attacks healthy cells or tissue. In AH, the body produces antibodies (known as inhibitors) that attack clotting factors, most often factor VIII. Clotting factors are specialized proteins required for the blood to clot normally. Consequently, affected individuals develop complications associated with abnormal, uncontrolled bleeding into the muscles, skin and soft tissue that can occur spontaneously, during surgery or following trauma. Specific symptoms can include nosebleeds (epistaxis), bruising throughout the body, solid swellings of congealed blood (hematomas), blood in the urine (hematuria) and gastrointestinal or urogenital bleeding. AH can potentially cause life-threatening bleeding complications in severe cases. In approximately 50% of patients, there is an identifiable underlying clinical condition; in the other 50%, no cause is known (idiopathic).IntroductionAH is different from congenital hemophilia, a group of rare genetic disorders caused by mutations in the genes encoding certain clotting factors. The main form of hemophilia is hemophilia A (classic hemophilia), which is an X-linked disorder that mostly affects males but can also affect females. It is caused by deficiency or inactivation of factor VIII, the same clotting factor that is affected in most individuals with AH. Although both disorders involve deficiency of the same clotting factor, the bleeding pattern is quite different. The reason the bleeding patterns differ between these disorders is not fully understood. | 15 | Acquired Hemophilia |
nord_15_1 | Symptoms of Acquired Hemophilia | The symptoms of AH develop because the blood cannot clot properly. Clotting is the process by which blood clumps together to plug the site of a wound. Clotting factors, such as factor VIII, are specialized proteins that are essential for the blood to clot properly.Although about 1/3 of patients do not require therapy to control bleeds, bleeding severity varies and more than 1/3 of patients suffer multiple bleeding episodes. Subcutaneous bleeding (ecchymoses) is the most common manifestation of AH followed by muscle bleeding (hematoma), gastrointestinal (melena), genitourinary (hematuria) and retroperitoneal. Intracranial hemorrhage is rare, but can be fatal. In contrast to congenital hemophilia A, joint bleeding (hemarthrosis) is infrequent.Bleeding often occurs without cause (spontaneously).Bleeding episodes are often severe and can become life-threatening. In some patients, delayed diagnosis and the presence of additional medical issues are often contributing factors to the overall severity of AH. Bleeding into the soft tissues can progress rapidly, potentially causing compartment syndrome, a potentially serious, painful condition characterized by increased pressure on muscles, nerves and blood vessels most often within the arms and legs, with damage due to compression of these structures.Affected Individuals are also at risk of excessive bleeding during surgery or following trauma, even trivial. Genital heavy bleeding in pregnant women may occur especially after childbirth (postpartum period). | Symptoms of Acquired Hemophilia. The symptoms of AH develop because the blood cannot clot properly. Clotting is the process by which blood clumps together to plug the site of a wound. Clotting factors, such as factor VIII, are specialized proteins that are essential for the blood to clot properly.Although about 1/3 of patients do not require therapy to control bleeds, bleeding severity varies and more than 1/3 of patients suffer multiple bleeding episodes. Subcutaneous bleeding (ecchymoses) is the most common manifestation of AH followed by muscle bleeding (hematoma), gastrointestinal (melena), genitourinary (hematuria) and retroperitoneal. Intracranial hemorrhage is rare, but can be fatal. In contrast to congenital hemophilia A, joint bleeding (hemarthrosis) is infrequent.Bleeding often occurs without cause (spontaneously).Bleeding episodes are often severe and can become life-threatening. In some patients, delayed diagnosis and the presence of additional medical issues are often contributing factors to the overall severity of AH. Bleeding into the soft tissues can progress rapidly, potentially causing compartment syndrome, a potentially serious, painful condition characterized by increased pressure on muscles, nerves and blood vessels most often within the arms and legs, with damage due to compression of these structures.Affected Individuals are also at risk of excessive bleeding during surgery or following trauma, even trivial. Genital heavy bleeding in pregnant women may occur especially after childbirth (postpartum period). | 15 | Acquired Hemophilia |
nord_15_2 | Causes of Acquired Hemophilia | AH is an autoimmune disorder. It occurs when the immune system produces antibodies that mistakenly attack healthy tissue, specifically specialized proteins known as clotting factors, most often clotting factor VIII.The immune system normally responds to a foreign substance by producing specialized proteins called antibodies. Antibodies work by destroying foreign substances directly or by coating them with a substance that marks them for destruction by white blood cells. When antibodies target healthy tissue they may be referred to as autoantibodies. Researchers believe that a triggering event (such as an infection or underlying disorder) may induce the immune system to produce autoantibodies. Autoantibodies in AH are termed inhibitors because they inhibit the function of the affected clotting factor.AH is predominantly a disease of the elderly. In approximately 50% of the patients, no underlying disorder or triggering event can be identified (idiopathic form). The remaining 50% have coexisting disorders or conditions including autoimmune disorders such as lupus, rheumatoid arthritis, multiple sclerosis, Sjogren syndrome, and temporal arteritis; inflammatory bowel disease or ulcerative colitis; infections; diabetes; hepatitis; respiratory or dermatological diseases; blood (hematological) cancer or certain solid tumors. AH has also been associated with drugs such as penicillin or interferon and an association with pregnancy has also been reported, mainly in the post-partum period. | Causes of Acquired Hemophilia. AH is an autoimmune disorder. It occurs when the immune system produces antibodies that mistakenly attack healthy tissue, specifically specialized proteins known as clotting factors, most often clotting factor VIII.The immune system normally responds to a foreign substance by producing specialized proteins called antibodies. Antibodies work by destroying foreign substances directly or by coating them with a substance that marks them for destruction by white blood cells. When antibodies target healthy tissue they may be referred to as autoantibodies. Researchers believe that a triggering event (such as an infection or underlying disorder) may induce the immune system to produce autoantibodies. Autoantibodies in AH are termed inhibitors because they inhibit the function of the affected clotting factor.AH is predominantly a disease of the elderly. In approximately 50% of the patients, no underlying disorder or triggering event can be identified (idiopathic form). The remaining 50% have coexisting disorders or conditions including autoimmune disorders such as lupus, rheumatoid arthritis, multiple sclerosis, Sjogren syndrome, and temporal arteritis; inflammatory bowel disease or ulcerative colitis; infections; diabetes; hepatitis; respiratory or dermatological diseases; blood (hematological) cancer or certain solid tumors. AH has also been associated with drugs such as penicillin or interferon and an association with pregnancy has also been reported, mainly in the post-partum period. | 15 | Acquired Hemophilia |
nord_15_3 | Affects of Acquired Hemophilia | AH develops in individuals with no previous history of bleeding disorder with approximately equal numbers of males and females affected. In the United States, the disorder is estimated to affect approximately .2-1 individuals per 1,000,000/year in the general population. In the United Kingdom, the disorder is estimated to affect 1.4 per 1,000,000/year. However, affected individuals may go undiagnosed or misdiagnosed, making it difficult to determine the true frequency of the disorder in the general population.Individuals of any age can be affected, although AH is extremely rare in children. The incidence increases with age and mostly affects elderly individuals (between 60-80 years of age). A small increase in incidence occurs in pregnant woman between the ages of 20-40. AH affects individuals of all ethnic groups and has been reported worldwide. The majority of cases involve deficiency of factor VIII (acquired hemophilia A). A handful of cases have been described that involve deficiency of factor IX (acquired hemophilia B). Although extremely rare, acquired hemophilia involving other clotting factors has also been reported. | Affects of Acquired Hemophilia. AH develops in individuals with no previous history of bleeding disorder with approximately equal numbers of males and females affected. In the United States, the disorder is estimated to affect approximately .2-1 individuals per 1,000,000/year in the general population. In the United Kingdom, the disorder is estimated to affect 1.4 per 1,000,000/year. However, affected individuals may go undiagnosed or misdiagnosed, making it difficult to determine the true frequency of the disorder in the general population.Individuals of any age can be affected, although AH is extremely rare in children. The incidence increases with age and mostly affects elderly individuals (between 60-80 years of age). A small increase in incidence occurs in pregnant woman between the ages of 20-40. AH affects individuals of all ethnic groups and has been reported worldwide. The majority of cases involve deficiency of factor VIII (acquired hemophilia A). A handful of cases have been described that involve deficiency of factor IX (acquired hemophilia B). Although extremely rare, acquired hemophilia involving other clotting factors has also been reported. | 15 | Acquired Hemophilia |
nord_15_4 | Related disorders of Acquired Hemophilia | Symptoms of the following disorders can be similar to those of AH. Comparisons may be useful for a differential diagnosis. Hemophilia is a general term for a group of rare bleeding disorders. Most forms of hemophilia are inherited blood clotting (coagulation) disorder caused by inactive or deficient blood proteins. There are three major forms of inherited hemophilia: hemophilia A (also known as classical hemophilia, factor VIII deficiency or antihemophilic globulin [AHG] deficiency), the most common form; hemophilia B (Christmas disease or factor IX deficiency); and hemophilia C (factor XI deficiency). Hemophilia A and B are inherited as X-linked recessive genetic disorders, while hemophilia C is inherited as an autosomal recessive genetic disorder. Hemophilia A and B are mostly expressed in males, but females can also be affected. Hemophilia C affects males and females in equal numbers. Hemophilia may be classified as mild, moderate, or severe; the level of severity is determined by the percentage of active clotting factor in the blood (normal percentage ranges from 50 to 150 percent). People who have severe hemophilia have less than one percent of active clotting factor in their blood. (For more information on these disorders, choose “hemophilia” as your search term in the Rare Disease Database.)Von Willebrand disease (VWD) is an inherited bleeding disorder resulting in prolonged bleeding and varies widely in its effects. Individuals with VWD have a defect in or deficiency of von Willebrand factor. They may also have low levels of an additional factor known as factor VIII. Deficient or defective von Willebrand factor results in improper functioning of platelets, specialized blood cell fragments that are involved in the early events of hemostasis, the formation of the plug at the site of vessel wall lesion to stop bleeding. In individuals with VWD, platelets do not stick to holes in blood vessels and bleeding is prolonged. Most people have relatively mild disease and are not diagnosed until they are adults. A small percentage of individuals begin to have problems during infancy or early childhood, such as prolonged bleeding and an abnormally slow clotting time. Symptoms can include gastrointestinal bleeding, nosebleeds, bleeding from the gums, and easy bruising. Affected individuals may bleed easily after injury, childbirth, and/or surgery. There are three main forms of the disorder. Two types are inherited as autosomal dominant disorders; the third type is inherited as an autosomal recessive disorder. (For more information on this disorder, choose “von Willebrand” as your search term in the Rare Disease Database.) | Related disorders of Acquired Hemophilia. Symptoms of the following disorders can be similar to those of AH. Comparisons may be useful for a differential diagnosis. Hemophilia is a general term for a group of rare bleeding disorders. Most forms of hemophilia are inherited blood clotting (coagulation) disorder caused by inactive or deficient blood proteins. There are three major forms of inherited hemophilia: hemophilia A (also known as classical hemophilia, factor VIII deficiency or antihemophilic globulin [AHG] deficiency), the most common form; hemophilia B (Christmas disease or factor IX deficiency); and hemophilia C (factor XI deficiency). Hemophilia A and B are inherited as X-linked recessive genetic disorders, while hemophilia C is inherited as an autosomal recessive genetic disorder. Hemophilia A and B are mostly expressed in males, but females can also be affected. Hemophilia C affects males and females in equal numbers. Hemophilia may be classified as mild, moderate, or severe; the level of severity is determined by the percentage of active clotting factor in the blood (normal percentage ranges from 50 to 150 percent). People who have severe hemophilia have less than one percent of active clotting factor in their blood. (For more information on these disorders, choose “hemophilia” as your search term in the Rare Disease Database.)Von Willebrand disease (VWD) is an inherited bleeding disorder resulting in prolonged bleeding and varies widely in its effects. Individuals with VWD have a defect in or deficiency of von Willebrand factor. They may also have low levels of an additional factor known as factor VIII. Deficient or defective von Willebrand factor results in improper functioning of platelets, specialized blood cell fragments that are involved in the early events of hemostasis, the formation of the plug at the site of vessel wall lesion to stop bleeding. In individuals with VWD, platelets do not stick to holes in blood vessels and bleeding is prolonged. Most people have relatively mild disease and are not diagnosed until they are adults. A small percentage of individuals begin to have problems during infancy or early childhood, such as prolonged bleeding and an abnormally slow clotting time. Symptoms can include gastrointestinal bleeding, nosebleeds, bleeding from the gums, and easy bruising. Affected individuals may bleed easily after injury, childbirth, and/or surgery. There are three main forms of the disorder. Two types are inherited as autosomal dominant disorders; the third type is inherited as an autosomal recessive disorder. (For more information on this disorder, choose “von Willebrand” as your search term in the Rare Disease Database.) | 15 | Acquired Hemophilia |
nord_15_5 | Diagnosis of Acquired Hemophilia | AH should be suspected by the clinical picture and confirmed by an abnormal coagulation test. A diagnosis should be considered in patients with a recent onset of abnormal bleeding and an isolated prolongation of the activated partial thromboplastin time (aPTT), especially the elderly and peri- and post-partum women.Clinical Testing and Work-UpRoutine first line coagulation tests include activated partial thromboplastin time (aPTT) and prothrombin time (PT). The two tests measure coagulation time of plasma, triggered by two different tissue factors (in aPTT partial thromboplastin). aPTT is sensitive mainly to FVIII, FIX, FXI and XII, whereas PT is sensitive to coagulation proteins synthesized by the liver (FII, FVII, FIX, the so called “prothrombin complex” with synthesis depending on vitamin K).Individuals with AH have an isolated prolonged aPTT, with normal PT. Tests to rule out other causes of isolated prolonged aPTT such as non-specific inhibitors (e.g., lupus anticoagulant) or heparin therapy are also performed.aPTT mixing tests, carried out by mixing patient’s plasma with normal plasma, can further confirm the diagnosis. A mixing study differentiates genetic factor deficiencies from factor inhibitors. A sample of blood is taken and mixed with blood from a control subject. In individuals with a factor deficiency the normal plasma restores the test value to normal; in individuals with a factor inhibitor it does not.Once a factor inhibitor is established, an assay will be done to measure the activity of coagulation factors (in the majority of cases FVIII) and the titer of the inhibitor. In individuals with AHA, this will demonstrate factor VIII deficiency and can ascertain the severity (titer count) as well. | Diagnosis of Acquired Hemophilia. AH should be suspected by the clinical picture and confirmed by an abnormal coagulation test. A diagnosis should be considered in patients with a recent onset of abnormal bleeding and an isolated prolongation of the activated partial thromboplastin time (aPTT), especially the elderly and peri- and post-partum women.Clinical Testing and Work-UpRoutine first line coagulation tests include activated partial thromboplastin time (aPTT) and prothrombin time (PT). The two tests measure coagulation time of plasma, triggered by two different tissue factors (in aPTT partial thromboplastin). aPTT is sensitive mainly to FVIII, FIX, FXI and XII, whereas PT is sensitive to coagulation proteins synthesized by the liver (FII, FVII, FIX, the so called “prothrombin complex” with synthesis depending on vitamin K).Individuals with AH have an isolated prolonged aPTT, with normal PT. Tests to rule out other causes of isolated prolonged aPTT such as non-specific inhibitors (e.g., lupus anticoagulant) or heparin therapy are also performed.aPTT mixing tests, carried out by mixing patient’s plasma with normal plasma, can further confirm the diagnosis. A mixing study differentiates genetic factor deficiencies from factor inhibitors. A sample of blood is taken and mixed with blood from a control subject. In individuals with a factor deficiency the normal plasma restores the test value to normal; in individuals with a factor inhibitor it does not.Once a factor inhibitor is established, an assay will be done to measure the activity of coagulation factors (in the majority of cases FVIII) and the titer of the inhibitor. In individuals with AHA, this will demonstrate factor VIII deficiency and can ascertain the severity (titer count) as well. | 15 | Acquired Hemophilia |
nord_15_6 | Therapies of Acquired Hemophilia | Treatment
Because AH is a rare disorder, most therapies used to treat affected individuals are based upon anecdotal reports or small cases series. There are few studies directly comparing the efficacy of specific treatments. Consequently, treatment is highly individualized.The specific therapeutic procedures and interventions will vary, depending upon numerous factors including the specific symptoms present; the natural course of the disorder including underlying cause (if known); age and overall health (e.g., concomitant disease), tolerance of certain medications or procedures, and personal preference; and other factors. Decisions concerning the use of particular therapeutic interventions should be made by physicians and other members of the healthcare team in careful consultation with the patient and/or parents based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks including possible side effects and long-term effects; patient preference; and other appropriate factors.Spontaneous remission has been reported; in general, it may occur in postpartum cases (within a few months of delivery) and, in the cases secondary to an allergic drug reaction, usually within a few months of stopping the offending medication. Spontaneous remission can also occur in other affected individuals such as those who have low titer inhibitors. The exact percentage of patients that undergo spontaneous resolution is unknown.The management of AH focuses on the following goals: controlling and preventing bleeding (if present or significant), eradication of the inhibitor, and treatment of the underlying disease (if applicable).Controlling Bleeding EpisodesBleeding may be very severe and may have a sudden onset. Therefore, prompt hemostatic control is mandatory in order to reduce morbidity and mortality. The International Recommendations state that anti-hemorrhagic treatment should be started in patients with severe bleeding in which a diagnosis of AH is confirmed, irrespective of inhibitor titer and factor VIII activity. Two approaches are available: the use of bypassing agents (concentrates of factors that bypass the acquired deficiency) or strategies to increase FVIII levels. The choice between these two options is based on the site and the severity of bleeding and the characteristics of each individual patient. Since hemostatic agents do not have a predictable effect, treatment of bleeding should be supervised by an expert in this field and proper laboratory tests. Imaging techniques and a skillful clinical evaluation are necessary to confirm hemostatic control and bleeding resolution. Fibrin glue or antifibrinolytic agents may be useful in the control of local bleeding.Bypassing agents are the recommended first-line therapy due to their rapid action and high level of effectiveness. The dosage is largely based on experience with the management of patients with FVIII inhibitors in congenital hemophilia and is generally based on the clinical assessment.The bypassing agents presently available are recombinant activated factor VII (rFVIIa, NovoSeven® RT, or Sevenfact) or activated prothrombin complex concentrate (aPCC or FEIBA®). None of these therapies are effective in all individuals.NovoSeven® RT is a genetically engineered (recombinant) version of factor VII. Because it is artificially created in a lab, it does not contain human blood or plasma and consequently, there is no risk of blood-borne viruses or other such pathogens. NovoSeven has been well-tolerated and associated with few side effects. Risk of thrombotic adverse effects (thrombosis) is below 1% for individuals with AH. NovoSeven has been approved by the Food and Drug Administration (FDA) for use as a bypassing agent for the treatment of individuals with acquired hemophilia. In 2020, the FDA approved Sevenfact (recombinant human coagulation factor VIIa expressed in the mammary gland of genetically engineered rabbits and secreted into the rabbits’ milk) for treatment and control of bleeding in adults and adolescents age 12 and older with hemophilia A or B with inhibitors. It is presumed that Sevenfact could also be used in the treatment of acquired hemophilia A, but studies have not yet been published to corroborate this assumption.Activated prothrombin complex concentrate (aPCC) is a plasma-derived, anti-inhibitor complex that contains various activated clotting factors. These factors allow the drug to bypass certain steps in the formation of blood clots (including the steps that require factor VIII). aPCC is treated to inactivate any potential viruses or similar pathogens and adverse thrombotic events are rare. The only form of aPCC currently available in the United States is FEIBA® (Factor eight inhibitor bypassing activity).Therapeutic modalities that allow an increase of FVIII, such as infusion of FVIII concentrate or DDAVP, that induces release of FVIII by the endothelial cells, are usually considered inadequate unless the inhibitor titer is very low (i.e. < 5 Bethesda units [BU]) and bypassing agents are not available. In 2014 The US FDA approved Obizur [Antihemophilic Factor (Recombinant), Porcine Sequence] for the treatment of bleeding episodes in adults with acquired hemophilia A (acquired Factor VIII [FVIII] deficiency).
Inhibitor EradicationAlthough in some cases inhibitor can disappear spontaneously, as long as the inhibitor is present, bleeding-related morbidity and mortality is significant. Therefore, therapy to eradicate the inhibitor (immunosuppression therapy) in adults is recommended to start immediately after the diagnosis of AH unless clearly contraindicated. Recommendations are largely derived from observation made in registries that have collected real life data.In general, corticosteroids alone or in combination with cyclophosphamide are the first line therapy. No clear difference in long-term survival was observed between these two modalities. However, individuals respond differently to immunosuppressive drugs, and what is effective in one individual may be ineffective in another. A variety of additional immunosuppressive agents have been used to treat acquired hemophilia including cyclosporine A, azathioprine, vincristine, mycophenolate mofetil, and 2-chlorodeoxyadenosine.Criteria for the response to treatment have not been established; nevertheless, high inhibitor titer and low FVIII level seem to be the best predictor of the response to therapy.Relapse of AH can occur in individuals who achieve remission once immunosuppressive therapy is stopped or if the dose is reduced. Unfortunately, because of the associated side effects, long-term immunosuppressive therapy is not recommended.Individuals with AH are encouraged to avoid activities that have a significant risk of trauma until after inhibitor eradication.Patients with AH will benefit from referral to a federally-funded hemophilia treatment center. These specialized centers can provide comprehensive care for individuals with hemophilia and related disorders including the development of specific treatment plans, monitoring and follow-up of affected individuals, and state-of-the-art medical care. Treatment at a hemophilia treatment center ensures that individuals and their family members will be cared for by a professional healthcare team (physicians, nurses, physical therapists, social workers and genetic counselors) experienced at treating individuals with hemophilia. | Therapies of Acquired Hemophilia. Treatment
Because AH is a rare disorder, most therapies used to treat affected individuals are based upon anecdotal reports or small cases series. There are few studies directly comparing the efficacy of specific treatments. Consequently, treatment is highly individualized.The specific therapeutic procedures and interventions will vary, depending upon numerous factors including the specific symptoms present; the natural course of the disorder including underlying cause (if known); age and overall health (e.g., concomitant disease), tolerance of certain medications or procedures, and personal preference; and other factors. Decisions concerning the use of particular therapeutic interventions should be made by physicians and other members of the healthcare team in careful consultation with the patient and/or parents based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks including possible side effects and long-term effects; patient preference; and other appropriate factors.Spontaneous remission has been reported; in general, it may occur in postpartum cases (within a few months of delivery) and, in the cases secondary to an allergic drug reaction, usually within a few months of stopping the offending medication. Spontaneous remission can also occur in other affected individuals such as those who have low titer inhibitors. The exact percentage of patients that undergo spontaneous resolution is unknown.The management of AH focuses on the following goals: controlling and preventing bleeding (if present or significant), eradication of the inhibitor, and treatment of the underlying disease (if applicable).Controlling Bleeding EpisodesBleeding may be very severe and may have a sudden onset. Therefore, prompt hemostatic control is mandatory in order to reduce morbidity and mortality. The International Recommendations state that anti-hemorrhagic treatment should be started in patients with severe bleeding in which a diagnosis of AH is confirmed, irrespective of inhibitor titer and factor VIII activity. Two approaches are available: the use of bypassing agents (concentrates of factors that bypass the acquired deficiency) or strategies to increase FVIII levels. The choice between these two options is based on the site and the severity of bleeding and the characteristics of each individual patient. Since hemostatic agents do not have a predictable effect, treatment of bleeding should be supervised by an expert in this field and proper laboratory tests. Imaging techniques and a skillful clinical evaluation are necessary to confirm hemostatic control and bleeding resolution. Fibrin glue or antifibrinolytic agents may be useful in the control of local bleeding.Bypassing agents are the recommended first-line therapy due to their rapid action and high level of effectiveness. The dosage is largely based on experience with the management of patients with FVIII inhibitors in congenital hemophilia and is generally based on the clinical assessment.The bypassing agents presently available are recombinant activated factor VII (rFVIIa, NovoSeven® RT, or Sevenfact) or activated prothrombin complex concentrate (aPCC or FEIBA®). None of these therapies are effective in all individuals.NovoSeven® RT is a genetically engineered (recombinant) version of factor VII. Because it is artificially created in a lab, it does not contain human blood or plasma and consequently, there is no risk of blood-borne viruses or other such pathogens. NovoSeven has been well-tolerated and associated with few side effects. Risk of thrombotic adverse effects (thrombosis) is below 1% for individuals with AH. NovoSeven has been approved by the Food and Drug Administration (FDA) for use as a bypassing agent for the treatment of individuals with acquired hemophilia. In 2020, the FDA approved Sevenfact (recombinant human coagulation factor VIIa expressed in the mammary gland of genetically engineered rabbits and secreted into the rabbits’ milk) for treatment and control of bleeding in adults and adolescents age 12 and older with hemophilia A or B with inhibitors. It is presumed that Sevenfact could also be used in the treatment of acquired hemophilia A, but studies have not yet been published to corroborate this assumption.Activated prothrombin complex concentrate (aPCC) is a plasma-derived, anti-inhibitor complex that contains various activated clotting factors. These factors allow the drug to bypass certain steps in the formation of blood clots (including the steps that require factor VIII). aPCC is treated to inactivate any potential viruses or similar pathogens and adverse thrombotic events are rare. The only form of aPCC currently available in the United States is FEIBA® (Factor eight inhibitor bypassing activity).Therapeutic modalities that allow an increase of FVIII, such as infusion of FVIII concentrate or DDAVP, that induces release of FVIII by the endothelial cells, are usually considered inadequate unless the inhibitor titer is very low (i.e. < 5 Bethesda units [BU]) and bypassing agents are not available. In 2014 The US FDA approved Obizur [Antihemophilic Factor (Recombinant), Porcine Sequence] for the treatment of bleeding episodes in adults with acquired hemophilia A (acquired Factor VIII [FVIII] deficiency).
Inhibitor EradicationAlthough in some cases inhibitor can disappear spontaneously, as long as the inhibitor is present, bleeding-related morbidity and mortality is significant. Therefore, therapy to eradicate the inhibitor (immunosuppression therapy) in adults is recommended to start immediately after the diagnosis of AH unless clearly contraindicated. Recommendations are largely derived from observation made in registries that have collected real life data.In general, corticosteroids alone or in combination with cyclophosphamide are the first line therapy. No clear difference in long-term survival was observed between these two modalities. However, individuals respond differently to immunosuppressive drugs, and what is effective in one individual may be ineffective in another. A variety of additional immunosuppressive agents have been used to treat acquired hemophilia including cyclosporine A, azathioprine, vincristine, mycophenolate mofetil, and 2-chlorodeoxyadenosine.Criteria for the response to treatment have not been established; nevertheless, high inhibitor titer and low FVIII level seem to be the best predictor of the response to therapy.Relapse of AH can occur in individuals who achieve remission once immunosuppressive therapy is stopped or if the dose is reduced. Unfortunately, because of the associated side effects, long-term immunosuppressive therapy is not recommended.Individuals with AH are encouraged to avoid activities that have a significant risk of trauma until after inhibitor eradication.Patients with AH will benefit from referral to a federally-funded hemophilia treatment center. These specialized centers can provide comprehensive care for individuals with hemophilia and related disorders including the development of specific treatment plans, monitoring and follow-up of affected individuals, and state-of-the-art medical care. Treatment at a hemophilia treatment center ensures that individuals and their family members will be cared for by a professional healthcare team (physicians, nurses, physical therapists, social workers and genetic counselors) experienced at treating individuals with hemophilia. | 15 | Acquired Hemophilia |
nord_16_0 | Overview of Acquired Lipodystrophy | SummaryAcquired lipodystrophy is a general term for types of lipodystrophy that are not inherited, but rather acquired at some point during life. Acquired lipodystrophies do not have a direct genetic cause, but rather many different factors may be involved. Acquired lipodystrophies can be caused by medications, autoimmunity or for unknown reasons (idiopathic). Subtypes of acquired lipodystrophy include acquired generalized lipodystrophy (Lawrence syndrome), acquired partial lipodystrophy (Barraquer-Simons syndrome), localized lipodystrophy, and high active antiretroviral induced lipodystrophy, which may develop in HIV-infected individuals undergoing a specific form of treatment. Onset of acquired forms of lipodystrophy can occur during childhood, adolescence or adulthood. Affected individuals develop characteristic loss of body fat (adipose tissue) affecting specific areas of the body, especially the arms, legs, face, neck, and chest or thoracic regions. In some cases, metabolic complications associated with insulin resistance can develop. Such complications include an inability to break down glucose (glucose intolerance), elevated levels of triglycerides (a type of fat) in the blood (hypertriglyceridemia), and diabetes. Additional symptoms such as fat accumulation in the liver (fatty liver or hepatic steatosis) may also occur.IntroductionLipodystrophy is a general term for a group of disorders that are characterized by complete (generalized) or partial loss of adipose tissue. Some forms of lipodystrophy are acquired; others are genetic. The degree of severity and the specific areas of the body affected can vary among the lipodystrophies. Some physicians refer to the loss of adipose tissue that characterizes these disorders as lipoatrophy rather than lipodystrophy. | Overview of Acquired Lipodystrophy. SummaryAcquired lipodystrophy is a general term for types of lipodystrophy that are not inherited, but rather acquired at some point during life. Acquired lipodystrophies do not have a direct genetic cause, but rather many different factors may be involved. Acquired lipodystrophies can be caused by medications, autoimmunity or for unknown reasons (idiopathic). Subtypes of acquired lipodystrophy include acquired generalized lipodystrophy (Lawrence syndrome), acquired partial lipodystrophy (Barraquer-Simons syndrome), localized lipodystrophy, and high active antiretroviral induced lipodystrophy, which may develop in HIV-infected individuals undergoing a specific form of treatment. Onset of acquired forms of lipodystrophy can occur during childhood, adolescence or adulthood. Affected individuals develop characteristic loss of body fat (adipose tissue) affecting specific areas of the body, especially the arms, legs, face, neck, and chest or thoracic regions. In some cases, metabolic complications associated with insulin resistance can develop. Such complications include an inability to break down glucose (glucose intolerance), elevated levels of triglycerides (a type of fat) in the blood (hypertriglyceridemia), and diabetes. Additional symptoms such as fat accumulation in the liver (fatty liver or hepatic steatosis) may also occur.IntroductionLipodystrophy is a general term for a group of disorders that are characterized by complete (generalized) or partial loss of adipose tissue. Some forms of lipodystrophy are acquired; others are genetic. The degree of severity and the specific areas of the body affected can vary among the lipodystrophies. Some physicians refer to the loss of adipose tissue that characterizes these disorders as lipoatrophy rather than lipodystrophy. | 16 | Acquired Lipodystrophy |
nord_16_1 | Symptoms of Acquired Lipodystrophy | Acquired lipodystrophy encompasses several subtypes. The specific symptoms present, severity, and prognosis can vary greatly depending upon the specific type of acquired lipodystrophy and the presence and extent of associated symptoms. The specific symptoms and severity can also vary among individuals with the same subtype. It is important to note that affected individuals will not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms, and overall prognosis.ACQUIRED GENERALIZED LIPODYSTROPHY (AGL; LAWRENCE SYNDROME)
Individuals with this form of lipodystrophy experience the loss of subcutaneous fat from the face, neck, and arms and legs. The overall extent and pattern of fat loss in AGL is highly variable and can differ significantly from one person to another. In some cases, fat may also be lost from the palms of the hands and the soles of the feet. Intra-abdominal fat may be lost in some people, but preserved in others. The loss of bone marrow fat rarely occurs. Fat loss associated with AGL may occur rapidly over a few weeks or slowly over several months or even years. Fat loss can be severe. Eventually, generalized and near complete loss of fat may occur resulting in prominent veins that bulge out from underneath the skin and an overall muscular appearance.AGL usually develops during childhood or adolescence, but can occur at any age. During childhood, affected individuals are described as being voracious eaters and may experience accelerated growth. Affected individuals may also experience fatigue.Individuals with AGL often develop severe insulin resistance, which can result in a variety of metabolic complications. Affected individuals may develop acanthosis nigricans, a skin condition characterized by abnormally increased coloration (hyperpigmentation) and “velvety” thickening (hyperkeratosis) of the skin, particularly of skin fold regions, such as of the neck and groin and under the arms (axillae). Other complications of insulin resistance may occur including glucose intolerance, hypertriglyceridemia, and diabetes. These symptoms are often very difficult to control and diabetes is often severe. Diabetes often occurs after the development of lipodystrophy, but in some cases may occur almost simultaneously.Some individuals develop abnormal enlargement of the liver (hepatomegaly) due to the infiltration and accumulation of fat within the liver. This can be known as hepatic steatosis or fatty liver. Fatty accumulation of the liver in individuals with AGL is often severe and can cause damage and scarring (cirrhosis) to the liver and, eventually, liver dysfunction. In some patients, liver enlargement may be due to autoimmune hepatitis. However, the diagnosis of autoimmune hepatitis should be made after review by expert pathologists.Some individuals may experience extreme hypertriglyceridemia and chylomicronemia, a condition characterized by the accumulation of fatty droplets called chylomicrons in the plasma. In some cases, this can result in episodes of acute inflammation of the pancreas (pancreatitis). Pancreatitis can be associated with abdominal pain, chills, jaundice, weakness, sweating, vomiting, and weight loss.After puberty, some women with AGL may develop polycystic ovary syndrome (PCOS). PCOS is characterized by an imbalance of sex hormones. Affected women have too much androgen, a male hormone, in the body. PCOS can result in irregular menstrual periods or a lack of menstruation, oily skin that is prone to acne, cysts on the ovaries, and mild hirsutism (a male pattern of hair growth). Hair may develop on the upper lip and chin.AGL can be subdivided into three separate subtypes, known as panniculitis-associated AGL, autoimmune-associated AGL, and AGL of unknown cause (idiopathic).Individuals with panniculitis-associated AGL generally have a less severe form of the disorder. Panniculitis is inflammation of subcutaneous fat. Individuals with panniculitis-associated AGL may have less severe fat loss and metabolic complications. Fat loss in panniculitis-associated AGL may be localized to a specific part of the body. Lipodystrophy in panniculitis-associated AGL is preceded by the development of painful subcutaneous nodules or lesions consisting of small spots or bumps (maculopapular lesions).Individuals with autoimmune-associated AGL have past or present evidence of an autoimmune disorder in addition to lipodystrophy. In these cases, AGL is believed to be caused by underlying autoimmune abnormalities. Autoimmune disorders that have been associated with AGL include juvenile dermatomyositis, Sjogren's syndrome, and rheumatoid arthritis.In the third type of AGL, panniculitis and autoimmune disorders do not occur and the underlying cause is unknown (idiopathic).ACQUIRED PARTIAL LIPODYSTROPHY (APL; BARRAQUER-SIMONS SYNDROME)
This form of acquired lipodystrophy usually has onset during childhood. Fat distribution is normal at birth and during early childhood. However, at some point later during childhood or adolescence, affected individuals lose subcutaneous fat from the face. Most individuals have noticeable fat loss by the age of 13. Eventually, fat loss extends to the arms, neck, chest and sometimes the upper abdomen. The legs, hips and gluteal regions are usually spared. After puberty in some women, these areas may experience disproportionately excess fat accumulation in the hips and legs. Fat loss is often gradual and may occur over a few months to several years.Approximately, one fourth of individuals with APL eventually develop a kidney disorder known as membranoproliferative glomerulonephritis, which is characterized by inflammation and degeneration of the tiny clusters of blood vessels (capillaries) in the special structures called renal glomeruli that filter the blood as it passes through the kidneys. Glomerulonephritis results in an impaired ability to remove waste and fluid products from the body, which then build up in the blood stream. Kidney problems can develop including blood in the urine, dark urine, decreased urine output, and swelling of various parts of the body. Potentially, kidney disease can progress so that the kidneys fail to function adequately (renal failure or insufficiency). Membranoproliferative glomerulonephritis specifically refers to when the condition is caused by an abnormal immune system response.As they age, some affected individuals may develop abnormally accumulation of yellow or white extracellular material (drusen) in the retina, a membrane in the back of the eyes. Some older affected individuals may develop macular degeneration. Macular degeneration is a general term for a group of eye disorders characterized by the deterioration of the oval-shaped yellow spot (macula) near the center of the retina. The macula is essential for proper vision when looking straight ahead (central vision) and with seeing fine details.APL is often associated with autoimmune disorders including lupus, dermatomyositis, Celiac disease, pernicious anemia, and vasculitis. Abnormal enlargement of liver (hepatomegaly) has been reported in some cases.Most forms of lipodystrophy are associated with metabolic complications due to insulin resistance. However, in most cases of APL, insulin resistance and such associated symptoms do not occur. In rare cases, in which insulin resistance does develop, associated symptoms can include glucose intolerance, hypertriglyceridemia, hirsutism, and diabetes.HIGH ACTIVE ANTIRETROVIRAL THERAPY (HAART) INDUCED LIPODYSTROPHY (LD-HIV)
This form of lipodystrophy occurs in individuals with human immunodeficiency virus (HIV) after receiving antiretroviral therapy known as HIV-1 protease inhibitor-containing HAART. The development of lipodystrophy is related to the intensity and duration of treatment. In many individuals, protease inhibitors and nucleoside reverse transcriptase inhibitors are implicated in the development of lipodystrophy. In most cases, LD-HIV develops in individuals who have received this therapy for 2 years or more.In most cases, affected individuals gradually lose subcutaneous fat from the arms, legs and face. Some individuals may develop excess fat in the face, neck, upper back and waist. This can cause a double chin, a hump on the upper back, and expand the circumference of the waist. Fat loss gets progressively worse with ongoing HAART therapy and does not reverse when the therapy is discontinued. Many individuals may also develop hypertriglyceridemia. Diabetes may also occur, but is rare. Individuals may be at an increased risk of developing coronary heart disease.LOCALIZED LIPODYSTROPHY
This form of lipodystrophy is characterized by subcutaneous fat loss in a small area of the body only. Localized lipodystrophy may result at the site of a drug injection (such as insulin). Affected individuals have a loss of subcutaneous fat in the affected area that presents as a dimple or crater with overlying skin usually unaffected. In some individuals, large adjacent (contiguous) areas of the body may be involved. | Symptoms of Acquired Lipodystrophy. Acquired lipodystrophy encompasses several subtypes. The specific symptoms present, severity, and prognosis can vary greatly depending upon the specific type of acquired lipodystrophy and the presence and extent of associated symptoms. The specific symptoms and severity can also vary among individuals with the same subtype. It is important to note that affected individuals will not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms, and overall prognosis.ACQUIRED GENERALIZED LIPODYSTROPHY (AGL; LAWRENCE SYNDROME)
Individuals with this form of lipodystrophy experience the loss of subcutaneous fat from the face, neck, and arms and legs. The overall extent and pattern of fat loss in AGL is highly variable and can differ significantly from one person to another. In some cases, fat may also be lost from the palms of the hands and the soles of the feet. Intra-abdominal fat may be lost in some people, but preserved in others. The loss of bone marrow fat rarely occurs. Fat loss associated with AGL may occur rapidly over a few weeks or slowly over several months or even years. Fat loss can be severe. Eventually, generalized and near complete loss of fat may occur resulting in prominent veins that bulge out from underneath the skin and an overall muscular appearance.AGL usually develops during childhood or adolescence, but can occur at any age. During childhood, affected individuals are described as being voracious eaters and may experience accelerated growth. Affected individuals may also experience fatigue.Individuals with AGL often develop severe insulin resistance, which can result in a variety of metabolic complications. Affected individuals may develop acanthosis nigricans, a skin condition characterized by abnormally increased coloration (hyperpigmentation) and “velvety” thickening (hyperkeratosis) of the skin, particularly of skin fold regions, such as of the neck and groin and under the arms (axillae). Other complications of insulin resistance may occur including glucose intolerance, hypertriglyceridemia, and diabetes. These symptoms are often very difficult to control and diabetes is often severe. Diabetes often occurs after the development of lipodystrophy, but in some cases may occur almost simultaneously.Some individuals develop abnormal enlargement of the liver (hepatomegaly) due to the infiltration and accumulation of fat within the liver. This can be known as hepatic steatosis or fatty liver. Fatty accumulation of the liver in individuals with AGL is often severe and can cause damage and scarring (cirrhosis) to the liver and, eventually, liver dysfunction. In some patients, liver enlargement may be due to autoimmune hepatitis. However, the diagnosis of autoimmune hepatitis should be made after review by expert pathologists.Some individuals may experience extreme hypertriglyceridemia and chylomicronemia, a condition characterized by the accumulation of fatty droplets called chylomicrons in the plasma. In some cases, this can result in episodes of acute inflammation of the pancreas (pancreatitis). Pancreatitis can be associated with abdominal pain, chills, jaundice, weakness, sweating, vomiting, and weight loss.After puberty, some women with AGL may develop polycystic ovary syndrome (PCOS). PCOS is characterized by an imbalance of sex hormones. Affected women have too much androgen, a male hormone, in the body. PCOS can result in irregular menstrual periods or a lack of menstruation, oily skin that is prone to acne, cysts on the ovaries, and mild hirsutism (a male pattern of hair growth). Hair may develop on the upper lip and chin.AGL can be subdivided into three separate subtypes, known as panniculitis-associated AGL, autoimmune-associated AGL, and AGL of unknown cause (idiopathic).Individuals with panniculitis-associated AGL generally have a less severe form of the disorder. Panniculitis is inflammation of subcutaneous fat. Individuals with panniculitis-associated AGL may have less severe fat loss and metabolic complications. Fat loss in panniculitis-associated AGL may be localized to a specific part of the body. Lipodystrophy in panniculitis-associated AGL is preceded by the development of painful subcutaneous nodules or lesions consisting of small spots or bumps (maculopapular lesions).Individuals with autoimmune-associated AGL have past or present evidence of an autoimmune disorder in addition to lipodystrophy. In these cases, AGL is believed to be caused by underlying autoimmune abnormalities. Autoimmune disorders that have been associated with AGL include juvenile dermatomyositis, Sjogren's syndrome, and rheumatoid arthritis.In the third type of AGL, panniculitis and autoimmune disorders do not occur and the underlying cause is unknown (idiopathic).ACQUIRED PARTIAL LIPODYSTROPHY (APL; BARRAQUER-SIMONS SYNDROME)
This form of acquired lipodystrophy usually has onset during childhood. Fat distribution is normal at birth and during early childhood. However, at some point later during childhood or adolescence, affected individuals lose subcutaneous fat from the face. Most individuals have noticeable fat loss by the age of 13. Eventually, fat loss extends to the arms, neck, chest and sometimes the upper abdomen. The legs, hips and gluteal regions are usually spared. After puberty in some women, these areas may experience disproportionately excess fat accumulation in the hips and legs. Fat loss is often gradual and may occur over a few months to several years.Approximately, one fourth of individuals with APL eventually develop a kidney disorder known as membranoproliferative glomerulonephritis, which is characterized by inflammation and degeneration of the tiny clusters of blood vessels (capillaries) in the special structures called renal glomeruli that filter the blood as it passes through the kidneys. Glomerulonephritis results in an impaired ability to remove waste and fluid products from the body, which then build up in the blood stream. Kidney problems can develop including blood in the urine, dark urine, decreased urine output, and swelling of various parts of the body. Potentially, kidney disease can progress so that the kidneys fail to function adequately (renal failure or insufficiency). Membranoproliferative glomerulonephritis specifically refers to when the condition is caused by an abnormal immune system response.As they age, some affected individuals may develop abnormally accumulation of yellow or white extracellular material (drusen) in the retina, a membrane in the back of the eyes. Some older affected individuals may develop macular degeneration. Macular degeneration is a general term for a group of eye disorders characterized by the deterioration of the oval-shaped yellow spot (macula) near the center of the retina. The macula is essential for proper vision when looking straight ahead (central vision) and with seeing fine details.APL is often associated with autoimmune disorders including lupus, dermatomyositis, Celiac disease, pernicious anemia, and vasculitis. Abnormal enlargement of liver (hepatomegaly) has been reported in some cases.Most forms of lipodystrophy are associated with metabolic complications due to insulin resistance. However, in most cases of APL, insulin resistance and such associated symptoms do not occur. In rare cases, in which insulin resistance does develop, associated symptoms can include glucose intolerance, hypertriglyceridemia, hirsutism, and diabetes.HIGH ACTIVE ANTIRETROVIRAL THERAPY (HAART) INDUCED LIPODYSTROPHY (LD-HIV)
This form of lipodystrophy occurs in individuals with human immunodeficiency virus (HIV) after receiving antiretroviral therapy known as HIV-1 protease inhibitor-containing HAART. The development of lipodystrophy is related to the intensity and duration of treatment. In many individuals, protease inhibitors and nucleoside reverse transcriptase inhibitors are implicated in the development of lipodystrophy. In most cases, LD-HIV develops in individuals who have received this therapy for 2 years or more.In most cases, affected individuals gradually lose subcutaneous fat from the arms, legs and face. Some individuals may develop excess fat in the face, neck, upper back and waist. This can cause a double chin, a hump on the upper back, and expand the circumference of the waist. Fat loss gets progressively worse with ongoing HAART therapy and does not reverse when the therapy is discontinued. Many individuals may also develop hypertriglyceridemia. Diabetes may also occur, but is rare. Individuals may be at an increased risk of developing coronary heart disease.LOCALIZED LIPODYSTROPHY
This form of lipodystrophy is characterized by subcutaneous fat loss in a small area of the body only. Localized lipodystrophy may result at the site of a drug injection (such as insulin). Affected individuals have a loss of subcutaneous fat in the affected area that presents as a dimple or crater with overlying skin usually unaffected. In some individuals, large adjacent (contiguous) areas of the body may be involved. | 16 | Acquired Lipodystrophy |
nord_16_2 | Causes of Acquired Lipodystrophy | Acquired lipodystrophies can be caused by medications, autoimmune reactions or other unknown mechanisms. Acquired lipodystrophies do not have a direct genetic basis. Some researchers have speculated that individuals may have a genetic predisposition to developing certain forms of acquired lipodystrophy, however, this remains unproven and controversial. Most likely, several different underlying mechanisms are involved in the development of acquired lipodystrophies.AGL may occur following an infection or autoimmune disease. Infections that have preceded the onset of AGL include varicella, measles, pertussis, diphtheria, pneumonia, osteomyelitis, infectious mononucleosis, and parotitis. Autoimmune disorders that have been linked to AGL include autoimmune thyroiditis, autoimmune hepatitis, juvenile dermatomyositis, rheumatoid arthritis, Sjogren's syndrome, Sicca syndrome, and autoimmune hemolytic anemia. Some affected individuals have low levels in their blood of complement 4, a protein factor that normally plays a role in the body's immune system response. However, specific autoantibodies which may cause destruction of fat cells have not been identified. In many cases, the cause of AGL is unknown. (For more information on these conditions, choose the specific disorder name as your search term in the Rare Disease Database.)APL is believed to be caused because the immune system mistakenly brings about the destruction of fat cells (autoimmune-mediated destruction of adipocytes). More than 80% of affected individuals have low levels in their blood of complement 3, a protein factor that normally plays a role in the body's immune system response. Affected individuals also have a circulating autoantibody called complement 3-nephritic factor. An autoantibody is an immune protein that mistakenly targets and damages healthy tissue.Both AGL and APL may be associated with complement proteins, which are specialized proteins found in the blood that help fight off infection and disease. These proteins are also believed to be involved in the metabolic functions associated with body fat (adipose tissue). In affected individuals, these proteins may render fat cells susceptible to improper destruction by the immune system.The exact reason why therapy with protease inhibitors and reverse transcriptase inhibitors (nucleoside analogues) in individuals with HIV causes lipodystrophy is not fully understood.Localized lipodystrophy may be caused by the injection of various drugs, such as insulin, into the subcutaneous tissue. Panniculitis, pressure on a specific area of the body, and other mechanisms may also cause localized lipodystrophy.The underlying issue in individuals with acquired lipodystrophy is the complete or partial loss of adipose tissue. The primary role of adipose tissue is to store fat for energy. Adipose tissue also secretes a variety of molecules that are involved with or influence various hormonal functions. For example, patients with AGL may have reduced levels of leptin, a hormone or cytokine produced by adipose cells which plays a role in controlling appetite by working centrally in the brain and hypothalamus. Adipose tissue is made up of fat cells (adipocytes). Each adipocyte has a lipid droplet that accounts for approximately 90% of its cell volume. An adipocyte stores fats (triglycerides) within its lipid droplet. Damage to adipose tissue in acquired lipodystrophy prevents proper fat storage. Consequently, fat is lost from adipose tissue and, in some cases, is improperly stored in other tissue of the body such as the liver and skeletal muscle causing symptoms such as liver disease and insulin resistance. | Causes of Acquired Lipodystrophy. Acquired lipodystrophies can be caused by medications, autoimmune reactions or other unknown mechanisms. Acquired lipodystrophies do not have a direct genetic basis. Some researchers have speculated that individuals may have a genetic predisposition to developing certain forms of acquired lipodystrophy, however, this remains unproven and controversial. Most likely, several different underlying mechanisms are involved in the development of acquired lipodystrophies.AGL may occur following an infection or autoimmune disease. Infections that have preceded the onset of AGL include varicella, measles, pertussis, diphtheria, pneumonia, osteomyelitis, infectious mononucleosis, and parotitis. Autoimmune disorders that have been linked to AGL include autoimmune thyroiditis, autoimmune hepatitis, juvenile dermatomyositis, rheumatoid arthritis, Sjogren's syndrome, Sicca syndrome, and autoimmune hemolytic anemia. Some affected individuals have low levels in their blood of complement 4, a protein factor that normally plays a role in the body's immune system response. However, specific autoantibodies which may cause destruction of fat cells have not been identified. In many cases, the cause of AGL is unknown. (For more information on these conditions, choose the specific disorder name as your search term in the Rare Disease Database.)APL is believed to be caused because the immune system mistakenly brings about the destruction of fat cells (autoimmune-mediated destruction of adipocytes). More than 80% of affected individuals have low levels in their blood of complement 3, a protein factor that normally plays a role in the body's immune system response. Affected individuals also have a circulating autoantibody called complement 3-nephritic factor. An autoantibody is an immune protein that mistakenly targets and damages healthy tissue.Both AGL and APL may be associated with complement proteins, which are specialized proteins found in the blood that help fight off infection and disease. These proteins are also believed to be involved in the metabolic functions associated with body fat (adipose tissue). In affected individuals, these proteins may render fat cells susceptible to improper destruction by the immune system.The exact reason why therapy with protease inhibitors and reverse transcriptase inhibitors (nucleoside analogues) in individuals with HIV causes lipodystrophy is not fully understood.Localized lipodystrophy may be caused by the injection of various drugs, such as insulin, into the subcutaneous tissue. Panniculitis, pressure on a specific area of the body, and other mechanisms may also cause localized lipodystrophy.The underlying issue in individuals with acquired lipodystrophy is the complete or partial loss of adipose tissue. The primary role of adipose tissue is to store fat for energy. Adipose tissue also secretes a variety of molecules that are involved with or influence various hormonal functions. For example, patients with AGL may have reduced levels of leptin, a hormone or cytokine produced by adipose cells which plays a role in controlling appetite by working centrally in the brain and hypothalamus. Adipose tissue is made up of fat cells (adipocytes). Each adipocyte has a lipid droplet that accounts for approximately 90% of its cell volume. An adipocyte stores fats (triglycerides) within its lipid droplet. Damage to adipose tissue in acquired lipodystrophy prevents proper fat storage. Consequently, fat is lost from adipose tissue and, in some cases, is improperly stored in other tissue of the body such as the liver and skeletal muscle causing symptoms such as liver disease and insulin resistance. | 16 | Acquired Lipodystrophy |
nord_16_3 | Affects of Acquired Lipodystrophy | AGL and APL generally affect women more than men, although this may be due in part to ascertainment bias because women tend to be more severely affected and more easily recognized. APL has been reported in approximately 250 individuals with a male to female ratio of 1:4. It has been reported in individuals of various different ethnicities. AGL has been reported in approximately 100 individuals with a male to female ratio of 1:3. Most cases have been reported in Caucasians. LD-HIV is estimated to affect approximately 100,000 individuals in the United States. Consistent with the increase prevalence of HIV in males, LD-HIV is also more prevalent in males. | Affects of Acquired Lipodystrophy. AGL and APL generally affect women more than men, although this may be due in part to ascertainment bias because women tend to be more severely affected and more easily recognized. APL has been reported in approximately 250 individuals with a male to female ratio of 1:4. It has been reported in individuals of various different ethnicities. AGL has been reported in approximately 100 individuals with a male to female ratio of 1:3. Most cases have been reported in Caucasians. LD-HIV is estimated to affect approximately 100,000 individuals in the United States. Consistent with the increase prevalence of HIV in males, LD-HIV is also more prevalent in males. | 16 | Acquired Lipodystrophy |
nord_16_4 | Related disorders of Acquired Lipodystrophy | Symptoms of the following disorders can be similar to those of acquired lipodystrophy. Comparisons may be useful for a differential diagnosis.Familial partial lipodystrophy (FPL) is a rare genetic disorder characterized by selective, progressive loss of body fat (adipose tissue) in various areas of the body. Individuals with FPL often have reduced subcutaneous fat in the arms and legs and the chest and trunk of the body. Conversely, affected individuals may also have excess subcutaneous fat deposits in other areas of the body, especially the neck, face and intra-abdominal regions. In most cases, adipose tissue loss begins during puberty. FPL can be associated with a variety of metabolic abnormalities. The extent of adipose tissue loss usually determines the severity of the associated metabolic complications. These complications can include glucose intolerance, hypertriglyceridemia and diabetes. Additional findings can occur in some cases. Five different subtypes of FPL have been identified. Each subtype is caused by mutations in a different gene. Three forms of FPL are inherited as autosomal dominant traits. One form is inherited as an autosomal recessive trait. The mode of inheritance of one form is not fully understood. (For more information on this disorder, choose “familial partial lipodystrophy” as your search term in the Rare Disease Database.)Parry-Romberg syndrome is a rare, acquired disorder characterized by slowly progressive shrinkage (atrophy) of the skin and soft tissues of half of the face (hemifacial atrophy). In rare cases, both sides of the face are affected. In some cases, atrophy may also affect the limbs usually on the same side of the body as the facial atrophy. The severity and specific symptoms of Parry-Romberg syndrome are highly variable from one person to another. Additional symptoms can potentially develop in some people including neurological abnormalities or abnormalities affecting the eyes or teeth. Parry-Romberg syndrome usually becomes apparent during the first decade of life or early during the second decade. The majority of individuals with Parry-Romberg syndrome experience symptoms before the age of 20 years. The exact cause of Parry-Romberg syndrome is unknown; cases appear to occur randomly for unknown reasons (sporadically).Cushing syndrome is a rare endocrine disorder that results from excessive production of the hormone cortisol by the adrenal glands. Affected individuals may gain excessive amounts of weight (central obesity) and/or may have a round, moon-shaped face. They may also have abnormally pigmented, thin, fragile skin; abnormally high blood pressure (hypertension) and blood sugar (hyperglycemia); and/or weakened bones that may fracture easily. In addition, some individuals with Cushing syndrome may demonstrate depression or other emotional changes. (For more information on this disorder, choose “Cushing” as your search term in the Rare Disease Database.)A variety of syndromic disorders may be associated with lipodystrophy and/or have symptoms similar to CGL including Rabson-Mendenhall syndrome, SHORT syndrome, mandibuloacral dysplasia, Wiedemann-Rautenstrauch syndrome (neonatal progeroid syndrome), Hutchinson-Guilford progeria syndrome, Werner syndrome, and leprechaunism. Individuals with lipodystrophy should also be differentiated from individuals with anorexia nervosa, cachexia, diencephalic syndrome (due to brain tumors), multiple symmetric lipomatosis (mostly due to excess alcohol intake), and other disorders that affect growth and development. NORD has individual reports on most of these disorders. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | Related disorders of Acquired Lipodystrophy. Symptoms of the following disorders can be similar to those of acquired lipodystrophy. Comparisons may be useful for a differential diagnosis.Familial partial lipodystrophy (FPL) is a rare genetic disorder characterized by selective, progressive loss of body fat (adipose tissue) in various areas of the body. Individuals with FPL often have reduced subcutaneous fat in the arms and legs and the chest and trunk of the body. Conversely, affected individuals may also have excess subcutaneous fat deposits in other areas of the body, especially the neck, face and intra-abdominal regions. In most cases, adipose tissue loss begins during puberty. FPL can be associated with a variety of metabolic abnormalities. The extent of adipose tissue loss usually determines the severity of the associated metabolic complications. These complications can include glucose intolerance, hypertriglyceridemia and diabetes. Additional findings can occur in some cases. Five different subtypes of FPL have been identified. Each subtype is caused by mutations in a different gene. Three forms of FPL are inherited as autosomal dominant traits. One form is inherited as an autosomal recessive trait. The mode of inheritance of one form is not fully understood. (For more information on this disorder, choose “familial partial lipodystrophy” as your search term in the Rare Disease Database.)Parry-Romberg syndrome is a rare, acquired disorder characterized by slowly progressive shrinkage (atrophy) of the skin and soft tissues of half of the face (hemifacial atrophy). In rare cases, both sides of the face are affected. In some cases, atrophy may also affect the limbs usually on the same side of the body as the facial atrophy. The severity and specific symptoms of Parry-Romberg syndrome are highly variable from one person to another. Additional symptoms can potentially develop in some people including neurological abnormalities or abnormalities affecting the eyes or teeth. Parry-Romberg syndrome usually becomes apparent during the first decade of life or early during the second decade. The majority of individuals with Parry-Romberg syndrome experience symptoms before the age of 20 years. The exact cause of Parry-Romberg syndrome is unknown; cases appear to occur randomly for unknown reasons (sporadically).Cushing syndrome is a rare endocrine disorder that results from excessive production of the hormone cortisol by the adrenal glands. Affected individuals may gain excessive amounts of weight (central obesity) and/or may have a round, moon-shaped face. They may also have abnormally pigmented, thin, fragile skin; abnormally high blood pressure (hypertension) and blood sugar (hyperglycemia); and/or weakened bones that may fracture easily. In addition, some individuals with Cushing syndrome may demonstrate depression or other emotional changes. (For more information on this disorder, choose “Cushing” as your search term in the Rare Disease Database.)A variety of syndromic disorders may be associated with lipodystrophy and/or have symptoms similar to CGL including Rabson-Mendenhall syndrome, SHORT syndrome, mandibuloacral dysplasia, Wiedemann-Rautenstrauch syndrome (neonatal progeroid syndrome), Hutchinson-Guilford progeria syndrome, Werner syndrome, and leprechaunism. Individuals with lipodystrophy should also be differentiated from individuals with anorexia nervosa, cachexia, diencephalic syndrome (due to brain tumors), multiple symmetric lipomatosis (mostly due to excess alcohol intake), and other disorders that affect growth and development. NORD has individual reports on most of these disorders. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | 16 | Acquired Lipodystrophy |
nord_16_5 | Diagnosis of Acquired Lipodystrophy | A diagnosis of acquired lipodystrophies is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. AGL may be suspected in individuals who have a generalized lack of subcutaneous fat and overall muscular appearance during childhood.The presence of panniculitis preceding the development of lipodystrophy is supportive of a diagnosis of AGL. The presence of an autoimmune disease preceding the development of lipodystrophy is supportive of AGL or APL. With APL, a progressive loss of fat from the upper body that spares the lower body in children under the age of 16 is suggestive of a diagnosis.Clinical Testing and Workup
Although the diagnosis of lipodystrophy is primarily clinical, a variety of tests can be used to aid in the diagnosis and/or rule out other conditions. A blood chemical profile may be conducted to assess the levels of glucose, lipids, liver enzymes, and uric acid. Individuals with APL may have decreased serum C3 levels, normal C1 and C4 levels, and high levels of the autoantibody C3NeF, while some patients with AGL may have low serum C4 levels.The characteristic pattern of fat loss in acquired lipodystrophies can be noted on whole body magnetic resonance imaging (MRI).A renal biopsy, the surgical removal and microscopic examination of kidney tissue, may be performed to assess kidney involvement in individuals with APL. | Diagnosis of Acquired Lipodystrophy. A diagnosis of acquired lipodystrophies is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. AGL may be suspected in individuals who have a generalized lack of subcutaneous fat and overall muscular appearance during childhood.The presence of panniculitis preceding the development of lipodystrophy is supportive of a diagnosis of AGL. The presence of an autoimmune disease preceding the development of lipodystrophy is supportive of AGL or APL. With APL, a progressive loss of fat from the upper body that spares the lower body in children under the age of 16 is suggestive of a diagnosis.Clinical Testing and Workup
Although the diagnosis of lipodystrophy is primarily clinical, a variety of tests can be used to aid in the diagnosis and/or rule out other conditions. A blood chemical profile may be conducted to assess the levels of glucose, lipids, liver enzymes, and uric acid. Individuals with APL may have decreased serum C3 levels, normal C1 and C4 levels, and high levels of the autoantibody C3NeF, while some patients with AGL may have low serum C4 levels.The characteristic pattern of fat loss in acquired lipodystrophies can be noted on whole body magnetic resonance imaging (MRI).A renal biopsy, the surgical removal and microscopic examination of kidney tissue, may be performed to assess kidney involvement in individuals with APL. | 16 | Acquired Lipodystrophy |
nord_16_6 | Therapies of Acquired Lipodystrophy | Treatment
The treatment of acquired lipodystrophies is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, plastic surgeons, cardiologists, endocrinologists, nutritionists, and other healthcare professionals may need to systematically and comprehensively plan an affect child's treatment.Individuals with acquired lipodystrophies and their families are encouraged to seek counseling after a diagnosis because the diagnosis can cause anxiety, stress, and extreme psychological distress. Psychological support and counseling both professionally and through support groups is recommended for affected individuals and their families. Genetic counseling may be of benefit for affected individuals and their families as well.Despite the lack of clinical trial evaluation, individuals with acquired lipodystrophy are encouraged to follow a high carbohydrate, low-fat diet. Such a diet can improve chylomicronemia associated with acute pancreatitis. Chylomicronemia is a condition characterized by the accumulation of fatty droplets called chylomicrons in the plasma. However, such diets may also raise very low density lipoprotein triglyceride concentration.Regular exercise and maintaining a healthy weight are also encouraged as a way to decrease the chances of developing diabetes. In individuals with acquired lipodystrophy, exercise and reducing energy intake can is also necessary to avoid excess fat deposition and accumulation in non-lipodystrophic areas such as the face or neck.Individuals with extreme hypertriglyceridemia may be treated with fibric acid derivatives, statins, or n-3 polyunsaturated fatty acids supplementation from fish oils.The characteristic loss of adipose tissue in individuals with acquired lipodystrophy cannot be reversed. Consequently, cosmetic surgery may be beneficial in improving appearance and management metabolic complications. Procedures such as liposuction can be performed to remove excess, unwanted fat in areas where fat accumulates (e.g. chin).In some cases, liver disease associated with acquired lipodystrophy can ultimately require a liver transplantation.Additional therapies to treat individuals with acquired lipodystrophy are symptomatic and supportive and follow regular, standard guidelines. Diabetes is treated with standard therapies. After the onset of diabetes, hyperglycemic drugs such as metformin, sulfonylureas, thiazolidinediones and other agents may be recommended to treat hyperglycemia, although their long-term safety and efficacy is unknown. Insulin can also be used to treat individuals with acquired lipodystrophy and diabetes, although extremely high doses are often required. High blood pressure (anti-hypertensives) may also be recommended. Although drug therapy is commonly used, there have been no clinical trials to establish the optimal use of drug therapy to treat the metabolic complications in individuals with FPL.In February 2014, metreleptin (an analogue of leptin) was been approved in the United States for patients with generalized lipodystrophies, including AGL and congenial generalized lipodystrophy. An analog drug has the same or similar physical structure to another drug or chemical, but differs chemically. Severe lipodystrophy is sometimes associated with leptin deficiency. Initial studies have shown that leptin-replacement therapy (metreleptin) has improved the symptoms of AGL including hyperglycemia and hypertriglyceridemia and reduced liver size in affected individuals. However drug related risks, cost and benefits should be carefully weighed prior to considering the treatment. Metreleptin therapy has been associated with two important side effects (black box warnings): development of neutralizing anti-leptin antibodies, and lymphomas in patients with AGL. While the precise health effects of neutralizing anti-leptin antibodies remain unclear, there is a possibility that these may reduce the efficacy of metreleptin in such individuals and may induce unwanted weight gain. The precise causal relationship of development of lymphomas to metreleptin therapy is not clear as lymphomas have been reported in some AGL patients who never took metreleptin therapy. Metreleptin, however, is not approved for treating metabolic complications in patients with partial or localized lipodystrophies, such as APL or LD-HIV. | Therapies of Acquired Lipodystrophy. Treatment
The treatment of acquired lipodystrophies is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, plastic surgeons, cardiologists, endocrinologists, nutritionists, and other healthcare professionals may need to systematically and comprehensively plan an affect child's treatment.Individuals with acquired lipodystrophies and their families are encouraged to seek counseling after a diagnosis because the diagnosis can cause anxiety, stress, and extreme psychological distress. Psychological support and counseling both professionally and through support groups is recommended for affected individuals and their families. Genetic counseling may be of benefit for affected individuals and their families as well.Despite the lack of clinical trial evaluation, individuals with acquired lipodystrophy are encouraged to follow a high carbohydrate, low-fat diet. Such a diet can improve chylomicronemia associated with acute pancreatitis. Chylomicronemia is a condition characterized by the accumulation of fatty droplets called chylomicrons in the plasma. However, such diets may also raise very low density lipoprotein triglyceride concentration.Regular exercise and maintaining a healthy weight are also encouraged as a way to decrease the chances of developing diabetes. In individuals with acquired lipodystrophy, exercise and reducing energy intake can is also necessary to avoid excess fat deposition and accumulation in non-lipodystrophic areas such as the face or neck.Individuals with extreme hypertriglyceridemia may be treated with fibric acid derivatives, statins, or n-3 polyunsaturated fatty acids supplementation from fish oils.The characteristic loss of adipose tissue in individuals with acquired lipodystrophy cannot be reversed. Consequently, cosmetic surgery may be beneficial in improving appearance and management metabolic complications. Procedures such as liposuction can be performed to remove excess, unwanted fat in areas where fat accumulates (e.g. chin).In some cases, liver disease associated with acquired lipodystrophy can ultimately require a liver transplantation.Additional therapies to treat individuals with acquired lipodystrophy are symptomatic and supportive and follow regular, standard guidelines. Diabetes is treated with standard therapies. After the onset of diabetes, hyperglycemic drugs such as metformin, sulfonylureas, thiazolidinediones and other agents may be recommended to treat hyperglycemia, although their long-term safety and efficacy is unknown. Insulin can also be used to treat individuals with acquired lipodystrophy and diabetes, although extremely high doses are often required. High blood pressure (anti-hypertensives) may also be recommended. Although drug therapy is commonly used, there have been no clinical trials to establish the optimal use of drug therapy to treat the metabolic complications in individuals with FPL.In February 2014, metreleptin (an analogue of leptin) was been approved in the United States for patients with generalized lipodystrophies, including AGL and congenial generalized lipodystrophy. An analog drug has the same or similar physical structure to another drug or chemical, but differs chemically. Severe lipodystrophy is sometimes associated with leptin deficiency. Initial studies have shown that leptin-replacement therapy (metreleptin) has improved the symptoms of AGL including hyperglycemia and hypertriglyceridemia and reduced liver size in affected individuals. However drug related risks, cost and benefits should be carefully weighed prior to considering the treatment. Metreleptin therapy has been associated with two important side effects (black box warnings): development of neutralizing anti-leptin antibodies, and lymphomas in patients with AGL. While the precise health effects of neutralizing anti-leptin antibodies remain unclear, there is a possibility that these may reduce the efficacy of metreleptin in such individuals and may induce unwanted weight gain. The precise causal relationship of development of lymphomas to metreleptin therapy is not clear as lymphomas have been reported in some AGL patients who never took metreleptin therapy. Metreleptin, however, is not approved for treating metabolic complications in patients with partial or localized lipodystrophies, such as APL or LD-HIV. | 16 | Acquired Lipodystrophy |
nord_17_0 | Overview of Acquired Neuromyotonia | Acquired neuromyotonia is an inflammatory disorder characterized by abnormal nerve impulses from the peripheral nerves that result in continuous muscle fiber activity. Affected individuals often experience progressive muscle stiffness and cramping especially in the hands and feet, increased sweating (hyperhidrosis), and delayed muscle relaxation. Symptoms may persist even during sleep or under general anesthesia. | Overview of Acquired Neuromyotonia. Acquired neuromyotonia is an inflammatory disorder characterized by abnormal nerve impulses from the peripheral nerves that result in continuous muscle fiber activity. Affected individuals often experience progressive muscle stiffness and cramping especially in the hands and feet, increased sweating (hyperhidrosis), and delayed muscle relaxation. Symptoms may persist even during sleep or under general anesthesia. | 17 | Acquired Neuromyotonia |
nord_17_1 | Symptoms of Acquired Neuromyotonia | Acquired neuromyotonia is characterized by involuntary continuous muscle fiber activity (fasciculations, doublet and triplet discharges on electromyography) that cause stiffness and delayed relaxation in the affected muscles. Muscle twitching with a rippling appearance (myokymia) may occur along with these symptoms. Affected individuals may, at times, be unable to coordinate voluntary muscle movement and find difficulty in walking (ataxia). Other symptoms may include staggering and reeling (titubation), stiffness, and lack of balance in response to being startled. There may be diminished spontaneous gross motor activity.The disorder is characterized by progressive stiffness, cramping, and weakness. Muscle activity is constant, and patients describe the feeling of continuous writhing or rippling of muscles under the skin. These movements continue during sleep. Diminished reflexes are also frequently a sign of this disorder. In some instances, muscle relaxation following voluntary muscle movement is delayed (grip myotonia) in the affected muscles. For example, affected individuals may not be able to open their fists or eyes immediately after closing them tightly for a few seconds.Affected individuals frequently have excessive sweating (hyperhidrosis), rapid heartbeats (tachycardia) and weight loss. Symptoms of pain are common.In slightly fewer than 20% of patients, a set of symptoms, including arrhythmias, excessive salivation, memory loss, confusion, hallucinations, constipation, personality change and sleep disorders, are found. In such cases the disorder may be referred to as Morvan syndrome.Approximately 20% of affected individuals have a tumor of the thymus gland (thymoma). The thymus glands are the source of a number of specialized cells associated with autoimmune functions. The disorder is also associated with peripheral neuropathies and autoimmune diseases including myasthenia gravis in some individuals. It has also been reported following infections and radiation therapy. | Symptoms of Acquired Neuromyotonia. Acquired neuromyotonia is characterized by involuntary continuous muscle fiber activity (fasciculations, doublet and triplet discharges on electromyography) that cause stiffness and delayed relaxation in the affected muscles. Muscle twitching with a rippling appearance (myokymia) may occur along with these symptoms. Affected individuals may, at times, be unable to coordinate voluntary muscle movement and find difficulty in walking (ataxia). Other symptoms may include staggering and reeling (titubation), stiffness, and lack of balance in response to being startled. There may be diminished spontaneous gross motor activity.The disorder is characterized by progressive stiffness, cramping, and weakness. Muscle activity is constant, and patients describe the feeling of continuous writhing or rippling of muscles under the skin. These movements continue during sleep. Diminished reflexes are also frequently a sign of this disorder. In some instances, muscle relaxation following voluntary muscle movement is delayed (grip myotonia) in the affected muscles. For example, affected individuals may not be able to open their fists or eyes immediately after closing them tightly for a few seconds.Affected individuals frequently have excessive sweating (hyperhidrosis), rapid heartbeats (tachycardia) and weight loss. Symptoms of pain are common.In slightly fewer than 20% of patients, a set of symptoms, including arrhythmias, excessive salivation, memory loss, confusion, hallucinations, constipation, personality change and sleep disorders, are found. In such cases the disorder may be referred to as Morvan syndrome.Approximately 20% of affected individuals have a tumor of the thymus gland (thymoma). The thymus glands are the source of a number of specialized cells associated with autoimmune functions. The disorder is also associated with peripheral neuropathies and autoimmune diseases including myasthenia gravis in some individuals. It has also been reported following infections and radiation therapy. | 17 | Acquired Neuromyotonia |
nord_17_2 | Causes of Acquired Neuromyotonia | Acquired neuromyotonia is an autoimmune disease in which the immune system malfunctions so that it damages parts of one’s own body. Approximately 40% of affected individuals have antibodies to voltage-gated potassium channels (VGKC’s) that affect the points at which the signals from the nerve fiber meet the muscle cell (neuromuscular junction). | Causes of Acquired Neuromyotonia. Acquired neuromyotonia is an autoimmune disease in which the immune system malfunctions so that it damages parts of one’s own body. Approximately 40% of affected individuals have antibodies to voltage-gated potassium channels (VGKC’s) that affect the points at which the signals from the nerve fiber meet the muscle cell (neuromuscular junction). | 17 | Acquired Neuromyotonia |
nord_17_3 | Affects of Acquired Neuromyotonia | Aquired neuromyotonia is a rare disorder affecting males and females but is slightly more common among men. Disease onset is usually between the ages of 15 and 60 years but has also been reported in childhood. | Affects of Acquired Neuromyotonia. Aquired neuromyotonia is a rare disorder affecting males and females but is slightly more common among men. Disease onset is usually between the ages of 15 and 60 years but has also been reported in childhood. | 17 | Acquired Neuromyotonia |
nord_17_4 | Related disorders of Acquired Neuromyotonia | Symptoms of the following disorders can be similar to those of acquired neuromyotonia. Comparisons may be useful for a differential diagnosis:Amyotrophic lateral sclerosis (ALS) is one of a group of disorders known as motor neuron diseases. It is characterized by the progressive degeneration and eventual death of nerve cells (motor neurons) in the brain, brainstem and spinal cord that facilitate communication between the nervous system and voluntary muscles of the body. Ordinarily, motor neurons in the brain (upper motor neurons) sent messages to motor neurons in the spinal cord (lower motor neurons) and then to various muscles. ALS affects both the upper and lower motor neurons, so that the transmission of messages is interrupted, and muscles gradually weaken and waste away. As a result, the ability to initiate and control voluntary movement is lost. Ultimately, ALS leads to respiratory failure because affected individuals lose the ability to control muscles in the chest and diaphragm. ALS is often called Lou Gehrig’s disease. (For more information on these disorders, choose “ALS” as your search terms in the Rare Disease Database.)Neurodegeneration with brain iron accumulation (NBIA) type 1 (Hallervorden-Spatz syndrome) is a rare, inherited, neurological movement disorder characterized by the progressive degeneration of the nervous system (neurodegenerative disorder). Individuals with NBIA1 have iron accumulation in the brain along with a progressive movement disorder. Individuals can plateau for long periods of time and then undergo intervals of rapid deterioration. Symptoms may vary greatly from person to person. Common features include an abnormality in muscle tone (dystonia), muscular rigidity, and sudden involuntary muscle spasms (spasticity). These features can result in clumsiness, walking problems, difficulty controlling movement, and speech problems. Another common feature is degeneration of the retina, resulting in progressive night blindness and loss of peripheral (side) vision. Approximately 50% of individuals with a clinical diagnosis of NBIA1 have gene mutations in PANK2, which helps to metabolize vitamin B5. (For more information on these disorders, choose “NBIA” as your search terms in the Rare Disease Database.)Hereditary spastic paraplegia (HSP) is a group of inherited neurological disorders characterized by progressive weakness (paraplegia), increased muscle tone and spasticity of leg muscles. The age of onset and severity of symptoms may be extremely variable from person to person, including among individuals within the same family. Symptoms usually develop during early to mid-adulthood. Initial findings typically include stiffness and relatively mild weakness of leg muscles, balance difficulties, unexplained tripping and falls, and an unusually “clumsy” manner of walking. As the disorder progresses, walking may become increasingly difficult, however, complete loss of the ability to walk is relatively rare. (For more information on this disorder, choose “paraplegia” as your search term in the Rare Disease Database.)Stiff-person syndrome (SPS) is a rare acquired neurological disorder characterized by progressive muscle stiffness (rigidity) and repeated episodes of painful muscle spasms. Muscular rigidity often fluctuates and usually occurs along with the muscle spasms. Spasms may occur randomly or be triggered by a variety of different events including a sudden noise or light physical contact. In most affected individuals, other neurological signs or symptoms do not occur. The severity and progression of SPS varies from one person to another. If left untreated, SPS can potentially progress to cause difficulty walking and significantly impact a person’s ability to perform routine, daily tasks. Although the exact cause of SPS is unknown, it is believed to be an autoimmune disorder and sometimes occurs along with other autoimmune disorders. (For more information on this disorder, choose “SPS” as your search term in the Rare Disease Database.)Episodic ataxia type 1(EA1) is an autosomal dominant genetic disorder characterized by muscle cramps and stiffness; muscle twitching with a rippling appearance; spastic contraction of skeletal muscles of the head, arms and legs; and loss of motor coordination and balance. EA1 is caused by mutations in the KCNA1 gene. | Related disorders of Acquired Neuromyotonia. Symptoms of the following disorders can be similar to those of acquired neuromyotonia. Comparisons may be useful for a differential diagnosis:Amyotrophic lateral sclerosis (ALS) is one of a group of disorders known as motor neuron diseases. It is characterized by the progressive degeneration and eventual death of nerve cells (motor neurons) in the brain, brainstem and spinal cord that facilitate communication between the nervous system and voluntary muscles of the body. Ordinarily, motor neurons in the brain (upper motor neurons) sent messages to motor neurons in the spinal cord (lower motor neurons) and then to various muscles. ALS affects both the upper and lower motor neurons, so that the transmission of messages is interrupted, and muscles gradually weaken and waste away. As a result, the ability to initiate and control voluntary movement is lost. Ultimately, ALS leads to respiratory failure because affected individuals lose the ability to control muscles in the chest and diaphragm. ALS is often called Lou Gehrig’s disease. (For more information on these disorders, choose “ALS” as your search terms in the Rare Disease Database.)Neurodegeneration with brain iron accumulation (NBIA) type 1 (Hallervorden-Spatz syndrome) is a rare, inherited, neurological movement disorder characterized by the progressive degeneration of the nervous system (neurodegenerative disorder). Individuals with NBIA1 have iron accumulation in the brain along with a progressive movement disorder. Individuals can plateau for long periods of time and then undergo intervals of rapid deterioration. Symptoms may vary greatly from person to person. Common features include an abnormality in muscle tone (dystonia), muscular rigidity, and sudden involuntary muscle spasms (spasticity). These features can result in clumsiness, walking problems, difficulty controlling movement, and speech problems. Another common feature is degeneration of the retina, resulting in progressive night blindness and loss of peripheral (side) vision. Approximately 50% of individuals with a clinical diagnosis of NBIA1 have gene mutations in PANK2, which helps to metabolize vitamin B5. (For more information on these disorders, choose “NBIA” as your search terms in the Rare Disease Database.)Hereditary spastic paraplegia (HSP) is a group of inherited neurological disorders characterized by progressive weakness (paraplegia), increased muscle tone and spasticity of leg muscles. The age of onset and severity of symptoms may be extremely variable from person to person, including among individuals within the same family. Symptoms usually develop during early to mid-adulthood. Initial findings typically include stiffness and relatively mild weakness of leg muscles, balance difficulties, unexplained tripping and falls, and an unusually “clumsy” manner of walking. As the disorder progresses, walking may become increasingly difficult, however, complete loss of the ability to walk is relatively rare. (For more information on this disorder, choose “paraplegia” as your search term in the Rare Disease Database.)Stiff-person syndrome (SPS) is a rare acquired neurological disorder characterized by progressive muscle stiffness (rigidity) and repeated episodes of painful muscle spasms. Muscular rigidity often fluctuates and usually occurs along with the muscle spasms. Spasms may occur randomly or be triggered by a variety of different events including a sudden noise or light physical contact. In most affected individuals, other neurological signs or symptoms do not occur. The severity and progression of SPS varies from one person to another. If left untreated, SPS can potentially progress to cause difficulty walking and significantly impact a person’s ability to perform routine, daily tasks. Although the exact cause of SPS is unknown, it is believed to be an autoimmune disorder and sometimes occurs along with other autoimmune disorders. (For more information on this disorder, choose “SPS” as your search term in the Rare Disease Database.)Episodic ataxia type 1(EA1) is an autosomal dominant genetic disorder characterized by muscle cramps and stiffness; muscle twitching with a rippling appearance; spastic contraction of skeletal muscles of the head, arms and legs; and loss of motor coordination and balance. EA1 is caused by mutations in the KCNA1 gene. | 17 | Acquired Neuromyotonia |
nord_17_5 | Diagnosis of Acquired Neuromyotonia | The diagnosis of acquired neuromyotonia is based on the presence of continuous muscle contractions (myokymia), especially in the face and hands, rhythmic tics or twitches (fasciculations), and muscle cramps. The diagnosis is confirmed by studies of the electrical signs of muscle activity (electromyography). Serum investigations include auto-immune serology and specifically testing for the presence of anti-VGKC. | Diagnosis of Acquired Neuromyotonia. The diagnosis of acquired neuromyotonia is based on the presence of continuous muscle contractions (myokymia), especially in the face and hands, rhythmic tics or twitches (fasciculations), and muscle cramps. The diagnosis is confirmed by studies of the electrical signs of muscle activity (electromyography). Serum investigations include auto-immune serology and specifically testing for the presence of anti-VGKC. | 17 | Acquired Neuromyotonia |
nord_17_6 | Therapies of Acquired Neuromyotonia | TreatmentAcquired neuromyotonia may be treated with anticonvulsant drugs such as phenytoin or carbamazepine, which may stop the abnormal impulses and prevent the symptoms from reoccurring. Plasma exchange (plasmapheresis) and intravenous immune globulin have been effective in a few cases but no long-term, controlled, clinical studies have been carried out.Testing for acetylcholine receptor antibodies should be done if thymoma is suspected. The thymus gland should be surgically removed if thymoma is present. | Therapies of Acquired Neuromyotonia. TreatmentAcquired neuromyotonia may be treated with anticonvulsant drugs such as phenytoin or carbamazepine, which may stop the abnormal impulses and prevent the symptoms from reoccurring. Plasma exchange (plasmapheresis) and intravenous immune globulin have been effective in a few cases but no long-term, controlled, clinical studies have been carried out.Testing for acetylcholine receptor antibodies should be done if thymoma is suspected. The thymus gland should be surgically removed if thymoma is present. | 17 | Acquired Neuromyotonia |
nord_18_0 | Overview of Acrocallosal Syndrome, Schinzel Type | Acrocallosal syndrome, Schinzel type is a rare genetic disorder that is apparent at birth (congenital). Associated symptoms and findings may be variable, including among affected members of the same family (kindred). However, the disorder is typically characterized by underdevelopment (hypoplasia) or absence (agenesis) of the thick band of nerve fibers joining the two hemispheres of the brain (corpus callosum) and moderate to severe mental retardation. In addition, many affected individuals have malformations of the skull and facial (craniofacial) region and/or distinctive abnormalities of the fingers and toes (digits). Characteristic craniofacial abnormalities may include an unusually large head (macrocephaly) with a prominent forehead, widely spaced eyes (ocular hypertelorism), downslanting eyelid folds (palpebral fissures), a small nose with a broad nasal bridge; and malformed (dysplastic) ears. Most affected individuals also have distinctive digital malformations, such as the presence of extra (supernumerary) fingers and toes (polydactyly) and webbing or fusion (syndactyly) of certain digits. Additional physical abnormalities may also be present, including growth retardation, resulting in short stature. Although autosomal recessive inheritance has been suggested, acrocallosal syndrome often appears to occur randomly for unknown reasons (sporadically). | Overview of Acrocallosal Syndrome, Schinzel Type. Acrocallosal syndrome, Schinzel type is a rare genetic disorder that is apparent at birth (congenital). Associated symptoms and findings may be variable, including among affected members of the same family (kindred). However, the disorder is typically characterized by underdevelopment (hypoplasia) or absence (agenesis) of the thick band of nerve fibers joining the two hemispheres of the brain (corpus callosum) and moderate to severe mental retardation. In addition, many affected individuals have malformations of the skull and facial (craniofacial) region and/or distinctive abnormalities of the fingers and toes (digits). Characteristic craniofacial abnormalities may include an unusually large head (macrocephaly) with a prominent forehead, widely spaced eyes (ocular hypertelorism), downslanting eyelid folds (palpebral fissures), a small nose with a broad nasal bridge; and malformed (dysplastic) ears. Most affected individuals also have distinctive digital malformations, such as the presence of extra (supernumerary) fingers and toes (polydactyly) and webbing or fusion (syndactyly) of certain digits. Additional physical abnormalities may also be present, including growth retardation, resulting in short stature. Although autosomal recessive inheritance has been suggested, acrocallosal syndrome often appears to occur randomly for unknown reasons (sporadically). | 18 | Acrocallosal Syndrome, Schinzel Type |
nord_18_1 | Symptoms of Acrocallosal Syndrome, Schinzel Type | In individuals with acrocallosal syndrome, Schinzel type, the range and severity of associated findings may be extremely variable. However, in all reported cases to date, the disorder has been characterized by underdevelopment (hypoplasia) or absence (agenesis) of the thick band of nerve fibers joining the two hemispheres of the brain (corpus callosum) as well as moderate to severe mental retardation. In some cases, brain malformations may be associated with additional complications, such as sudden episodes of uncontrolled electrical activity in the brain (seizures) or hydrocephalus, a condition in which impaired flow or absorption of the fluid that circulates through cavities (ventricles) of the brain and the spinal canal (cerebrospinal fluid [CSF]) potentially leads to increasing fluid pressure in the brain. Individuals with acrocallosal syndrome may also have abnormally diminished muscle tone (hypotonia) and experience severe psychomotor retardation–or marked delays in the development of certain physical, mental, or behavioral skills that are typically acquired at particular stages (i.e, “developmental milestones”). Over 50 percent of affected individuals also have abnormal growth delays, often resulting in short stature.Acrocallosal syndrome, Schinzel type is also often associated with distinctive malformations of the skull and facial (craniofacial) region. Such abnormalities often include an unusually large head (macrocephaly) with a high, broad, bulging forehead; a prominent back region of the head (occiput); and underdeveloped midfacial regions (midface hypoplasia). In addition, the “soft spot” at the front of the skull (anterior fontanelle) may be abnormally large in some affected infants or children. (The “soft spots” or fontanelles [anterior and posterior fontanelles] are the membrane-covered gaps between bones of the skull at birth.) Individuals with acrocallosal syndrome may also have a small, short nose; a broad nasal bridge; upwardly turned nostrils (anteverted nares); and malformed (dysplastic) ears that may be abnormally rotated toward the back of the head (posteriorly rotated). In some instances, additional craniofacial abnormalities may also be present, such as protruding lips, an abnormal groove in the upper lip (cleft lip), and/or incomplete closure of the roof of the mouth (cleft palate).Individuals with acrocallosal syndrome may also have abnormalities affecting the eyes. These may include widely spaced eyes (ocular hypertelorism); downwardly slanting eyelid folds (palpebral fissures); vertical skin folds (epicanthal folds) that may cover the eyes' inner corners; and drooping of the upper eyelids (ptosis). In some instances, additional eye (ocular) defects may be present, such as internal deviation of one eye toward the other (convergent strabismus or esotropia); abnormalities of the colored (pigmented) layers of the retinas or the nerve-rich, innermost membranes of the eyes (i.e., decreased retinal pigmentation); and/or degeneration of the nerves that transmit impulses from the retinas to the brain (optic atrophy). In such cases, the degree of visual impairment depends upon the severity and/or combination of eye abnormalities present.Acrocallosal syndrome, Schinzel type is also typically characterized by distinctive malformations of the fingers and toes (digits). For example, in many affected individuals, there may be duplication or the presence of extra (supernumerary) great toes (halluces) and, in some cases, partial duplication of the thumbs (preaxial polydactyly) with abnormal division of the bones at the ends of the thumbs (bifid terminal phalanges). There may also be duplication of certain digits toward the “pinky” side of the hands and the “small toe” side of the feet (i.e., postaxial polydactyly). Additional digital abnormalities often include webbing or fusion (syndactyly) of certain fingers or toes, particularly of the first to the third toes, and underdevelopment or fusion of affected nails.In some cases, additional physical abnormalities may also be associated with the disorder. Some affected infants may have structural heart malformations at birth (congenital heart defects). These typically include an abnormal opening in the fibrous partition (septum) that separates the upper or lower chambers of the heart (atrial or ventricular septal defects) or abnormalities of the heart valve (i.e., pulmonary valve) that enables blood to flow from the lower right chamber (ventricle) of the heart to the lungs while preventing the backflow of blood into the right ventricle. In addition, in some affected individuals, there may be protrusion of part of the intestines into muscles of the groin (inguinal hernia) or through a weakness in the abdominal wall around the navel (umbilical hernia). Others may have an epigastric hernia or protrusion of an internal organ through the membrane in the middle region of the abdomen above the navel. Some affected males may also have genital abnormalities, such as undescended testes (cryptorchidism), abnormal placement of the urinary opening (hypospadias), and/or an unusually small penis (micropenis).In some infants with acrocallosal syndrome, the period shortly after birth (neonatal period) may be complicated by seizure episodes, feeding difficulties, and an increased risk of respiratory infections. In some cases, respiratory infections as well as breathing difficulties (dyspnea), lack of sufficient oxygen supply to bodily tissues (hypoxia), and other associated abnormalities (i.e., respiratory distress) may lead to potentially life-threatening complications.As mentioned previously, reports in the medical literature suggest that the symptoms and findings associated with acrocallosal syndrome, Schinzel type may vary greatly in range and severity from case to case. For example, some investigators have reported “incomplete” forms of the disorder in which duplication of the great toes (preaxial polydactyly) or certain characteristic craniofacial features were not present. In other reported cases, the siblings of some individuals with the disorder have been affected by anencephaly, a congenital abnormality characterized by absence of the top of the skull (skullcap or calvaria) and major portions of the brain (e.g., cerebral hemispheres). Some researchers suggest that anencephaly may represent a severe manifestation of the spectrum of brain malformations potentially associated with acrocallosal syndrome. | Symptoms of Acrocallosal Syndrome, Schinzel Type. In individuals with acrocallosal syndrome, Schinzel type, the range and severity of associated findings may be extremely variable. However, in all reported cases to date, the disorder has been characterized by underdevelopment (hypoplasia) or absence (agenesis) of the thick band of nerve fibers joining the two hemispheres of the brain (corpus callosum) as well as moderate to severe mental retardation. In some cases, brain malformations may be associated with additional complications, such as sudden episodes of uncontrolled electrical activity in the brain (seizures) or hydrocephalus, a condition in which impaired flow or absorption of the fluid that circulates through cavities (ventricles) of the brain and the spinal canal (cerebrospinal fluid [CSF]) potentially leads to increasing fluid pressure in the brain. Individuals with acrocallosal syndrome may also have abnormally diminished muscle tone (hypotonia) and experience severe psychomotor retardation–or marked delays in the development of certain physical, mental, or behavioral skills that are typically acquired at particular stages (i.e, “developmental milestones”). Over 50 percent of affected individuals also have abnormal growth delays, often resulting in short stature.Acrocallosal syndrome, Schinzel type is also often associated with distinctive malformations of the skull and facial (craniofacial) region. Such abnormalities often include an unusually large head (macrocephaly) with a high, broad, bulging forehead; a prominent back region of the head (occiput); and underdeveloped midfacial regions (midface hypoplasia). In addition, the “soft spot” at the front of the skull (anterior fontanelle) may be abnormally large in some affected infants or children. (The “soft spots” or fontanelles [anterior and posterior fontanelles] are the membrane-covered gaps between bones of the skull at birth.) Individuals with acrocallosal syndrome may also have a small, short nose; a broad nasal bridge; upwardly turned nostrils (anteverted nares); and malformed (dysplastic) ears that may be abnormally rotated toward the back of the head (posteriorly rotated). In some instances, additional craniofacial abnormalities may also be present, such as protruding lips, an abnormal groove in the upper lip (cleft lip), and/or incomplete closure of the roof of the mouth (cleft palate).Individuals with acrocallosal syndrome may also have abnormalities affecting the eyes. These may include widely spaced eyes (ocular hypertelorism); downwardly slanting eyelid folds (palpebral fissures); vertical skin folds (epicanthal folds) that may cover the eyes' inner corners; and drooping of the upper eyelids (ptosis). In some instances, additional eye (ocular) defects may be present, such as internal deviation of one eye toward the other (convergent strabismus or esotropia); abnormalities of the colored (pigmented) layers of the retinas or the nerve-rich, innermost membranes of the eyes (i.e., decreased retinal pigmentation); and/or degeneration of the nerves that transmit impulses from the retinas to the brain (optic atrophy). In such cases, the degree of visual impairment depends upon the severity and/or combination of eye abnormalities present.Acrocallosal syndrome, Schinzel type is also typically characterized by distinctive malformations of the fingers and toes (digits). For example, in many affected individuals, there may be duplication or the presence of extra (supernumerary) great toes (halluces) and, in some cases, partial duplication of the thumbs (preaxial polydactyly) with abnormal division of the bones at the ends of the thumbs (bifid terminal phalanges). There may also be duplication of certain digits toward the “pinky” side of the hands and the “small toe” side of the feet (i.e., postaxial polydactyly). Additional digital abnormalities often include webbing or fusion (syndactyly) of certain fingers or toes, particularly of the first to the third toes, and underdevelopment or fusion of affected nails.In some cases, additional physical abnormalities may also be associated with the disorder. Some affected infants may have structural heart malformations at birth (congenital heart defects). These typically include an abnormal opening in the fibrous partition (septum) that separates the upper or lower chambers of the heart (atrial or ventricular septal defects) or abnormalities of the heart valve (i.e., pulmonary valve) that enables blood to flow from the lower right chamber (ventricle) of the heart to the lungs while preventing the backflow of blood into the right ventricle. In addition, in some affected individuals, there may be protrusion of part of the intestines into muscles of the groin (inguinal hernia) or through a weakness in the abdominal wall around the navel (umbilical hernia). Others may have an epigastric hernia or protrusion of an internal organ through the membrane in the middle region of the abdomen above the navel. Some affected males may also have genital abnormalities, such as undescended testes (cryptorchidism), abnormal placement of the urinary opening (hypospadias), and/or an unusually small penis (micropenis).In some infants with acrocallosal syndrome, the period shortly after birth (neonatal period) may be complicated by seizure episodes, feeding difficulties, and an increased risk of respiratory infections. In some cases, respiratory infections as well as breathing difficulties (dyspnea), lack of sufficient oxygen supply to bodily tissues (hypoxia), and other associated abnormalities (i.e., respiratory distress) may lead to potentially life-threatening complications.As mentioned previously, reports in the medical literature suggest that the symptoms and findings associated with acrocallosal syndrome, Schinzel type may vary greatly in range and severity from case to case. For example, some investigators have reported “incomplete” forms of the disorder in which duplication of the great toes (preaxial polydactyly) or certain characteristic craniofacial features were not present. In other reported cases, the siblings of some individuals with the disorder have been affected by anencephaly, a congenital abnormality characterized by absence of the top of the skull (skullcap or calvaria) and major portions of the brain (e.g., cerebral hemispheres). Some researchers suggest that anencephaly may represent a severe manifestation of the spectrum of brain malformations potentially associated with acrocallosal syndrome. | 18 | Acrocallosal Syndrome, Schinzel Type |
nord_18_2 | Causes of Acrocallosal Syndrome, Schinzel Type | According to many investigators, acrocallosal syndrome, Schinzel type may be inherited as an 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 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.Parents of some individuals with acrocallosal syndrome, Schinzel type have been closely related by blood (consanguineous). In recessive disorders, if both parents carry the same gene for the same disease trait, there is an increased risk that their children may inherit the two genes necessary for development of the disease.Numerous cases have also been reported in which there was no apparent family history of the disease. In such instances, researchers indicate that the disorder may result from new genetic changes (mutations) that appear to occur randomly for unknown reasons (sporadically). Since many reported cases have appeared to occur sporadically, some researchers question whether the disorder is inherited as an autosomal recessive trait, instead indicating that there may be an autosomal dominant mode of inheritance.In dominant disorders, a single copy of the disease gene (received from either the mother or father) will be expressed “dominating” the other normal gene and resulting in the appearance of the disease. The risk of transmitting the disorder from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child. The risk is the same for each pregnancy.Some investigators have suggested that acrocallosal syndrome may be a variant of Greig cephalopolysyndactyly syndrome, resulting from different changes (mutations) of the same disease gene. Greig cephalopolysyndactyly syndrome, an autosomal dominant disorder, is known to result from mutations disrupting the normal functioning of a gene known as GLI3, which is located on the short arm (p) of chromosome 7 (7p13)*. However, during genetic analysis of individuals with acrocallosal syndrome in one family, evidence appeared to exclude the chromosomal location involved in Greig cephalopolysyndactyly syndrome. *Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q.” Chromosomes are further subdivided into bands that are numbered. For example, 7p13 refers to band 13 on the short arm of chromosome 7.According to other researchers, trisomy 12p was confirmed in an individual with apparent acrocallosal syndrome. Trisomy 12p is a chromosomal disorder in which a portion of the short arm of chromosome 12 appears three times rather than twice in cells of the body. (For further information, please see the “Related Disorders” section below.) Due to the “overlapping” of certain symptoms associated with acrocallosal syndrome and trisomy 12p, some researchers have suggested that acrocallosal syndrome may result from mutations of a gene located on chromosome 12p. Further research is needed to determine the disease gene (or genes) that may play a role in causing acrocallosal syndrome, Schinzel type. | Causes of Acrocallosal Syndrome, Schinzel Type. According to many investigators, acrocallosal syndrome, Schinzel type may be inherited as an 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 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.Parents of some individuals with acrocallosal syndrome, Schinzel type have been closely related by blood (consanguineous). In recessive disorders, if both parents carry the same gene for the same disease trait, there is an increased risk that their children may inherit the two genes necessary for development of the disease.Numerous cases have also been reported in which there was no apparent family history of the disease. In such instances, researchers indicate that the disorder may result from new genetic changes (mutations) that appear to occur randomly for unknown reasons (sporadically). Since many reported cases have appeared to occur sporadically, some researchers question whether the disorder is inherited as an autosomal recessive trait, instead indicating that there may be an autosomal dominant mode of inheritance.In dominant disorders, a single copy of the disease gene (received from either the mother or father) will be expressed “dominating” the other normal gene and resulting in the appearance of the disease. The risk of transmitting the disorder from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child. The risk is the same for each pregnancy.Some investigators have suggested that acrocallosal syndrome may be a variant of Greig cephalopolysyndactyly syndrome, resulting from different changes (mutations) of the same disease gene. Greig cephalopolysyndactyly syndrome, an autosomal dominant disorder, is known to result from mutations disrupting the normal functioning of a gene known as GLI3, which is located on the short arm (p) of chromosome 7 (7p13)*. However, during genetic analysis of individuals with acrocallosal syndrome in one family, evidence appeared to exclude the chromosomal location involved in Greig cephalopolysyndactyly syndrome. *Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q.” Chromosomes are further subdivided into bands that are numbered. For example, 7p13 refers to band 13 on the short arm of chromosome 7.According to other researchers, trisomy 12p was confirmed in an individual with apparent acrocallosal syndrome. Trisomy 12p is a chromosomal disorder in which a portion of the short arm of chromosome 12 appears three times rather than twice in cells of the body. (For further information, please see the “Related Disorders” section below.) Due to the “overlapping” of certain symptoms associated with acrocallosal syndrome and trisomy 12p, some researchers have suggested that acrocallosal syndrome may result from mutations of a gene located on chromosome 12p. Further research is needed to determine the disease gene (or genes) that may play a role in causing acrocallosal syndrome, Schinzel type. | 18 | Acrocallosal Syndrome, Schinzel Type |
nord_18_3 | Affects of Acrocallosal Syndrome, Schinzel Type | Acrocallosal syndrome, Schinzel type appears to affect males and females in relatively equal numbers. The disorder was originally reported in 1979 (A. Schinzel). Over 25 cases have been recorded in the medical literature. | Affects of Acrocallosal Syndrome, Schinzel Type. Acrocallosal syndrome, Schinzel type appears to affect males and females in relatively equal numbers. The disorder was originally reported in 1979 (A. Schinzel). Over 25 cases have been recorded in the medical literature. | 18 | Acrocallosal Syndrome, Schinzel Type |
nord_18_4 | Related disorders of Acrocallosal Syndrome, Schinzel Type | Symptoms of the following disorders may be similar to those of acrocallosal syndrome, Schinzel type. Comparisons may be useful for a differential diagnosis:Greig cephalopolysyndactyly syndrome is a rare genetic disorder characterized by distinctive abnormalities of the skull and facial (craniofacial) region, the hands, and the feet. Craniofacial abnormalities may include an abnormally large head (macrocephaly) with a high, prominent forehead; widely spaced eyes (ocular hypertelorism); and a broad nasal root. In many cases, there is also duplication of the great toes (preaxial polydactyly) as well as webbing or fusion (syndactyly) of certain toes, primarily the first to the third toes. Abnormalities of the hands may include unusually broad thumbs; duplication of certain fingers toward the “pinky” side of the hands (postaxial polydactyly); and webbing or fusion of certain fingers, particularly the third and fourth fingers. Rarely, malformation or absence of the corpus callosum; as well as mental retardation, have been reported in association with Greig cephalopolysyndactyly syndrome. In most cases, the disorder appears to be inherited as an autosomal dominant trait. (For more information on this disorder, choose “Greig cephalopolysyndactyly” as your search term in the Rare Disease Database.)Oral-facial-digital syndrome refers to a group of rare genetic disorders characterized by malformations of the facial area, the mouth region (oral defects), and the fingers and toes (digits). Researchers indicate that various forms of the disorder, particularly type II or Mohr syndrom; have certain features similar to those potentially associated with acrocallosal syndrome, Schinzel type. In those with Mohr syndrome craniofacial malformations may include widely spaced eyes (ocular hypertelorism), an abnormal groove in the upper lip (cleft lip), a small lower jaw (micrognathia), and low-set ears that may be rotated toward the back of the head (posteriorly rotated). Oral malformations may include an abnormal length-wise groove in the tongue (cleft tongue), a highly arched roof of the mouth (palate), or incomplete closure of the palate (cleft palate). Affected individuals may also have certain digital malformations, such as duplication of the great toes and/or pinkies (fifth fingers) and webbing or fusion (syndactyly) of certain digits. In some instances, additional abnormalities may include short stature, mental retardation, diminished muscle tone (hypotonia) with poor coordination, and/or other features. Mohr syndrome is inherited as an autosomal recessive trait. (For more information on this disorder, choose “oral facial digital” as your search term in the Rare Disease Database.)Chromosome 12, Trisomy 12p is a rare chromosomal disorder in which part or most of the short arm (p) of chromosome 12 appears three times rather than twice in cells of the body. Associated symptoms and findings may be variable, depending upon the specific location of the duplicated (trisomic) portion of chromosome 12p. Affected individuals may have mental retardation, diminished muscle tone (hypotonia), and distinctive craniofacial malformations. These may include an abnormally large head (macrocephaly) with a high forehead, underdeveloped midfacial regions, a small nose with upturned nostrils (anteverted nares), puffy cheeks, and/or a broad lower lip. In addition, cases have been reported in which trisomy 12p was associated with the presence of extra fingers or toes (polydactyly); absence of the thick band of nerve fibers that normally joins the two hemispheres of the brain (agenesis of corpus callosum); and sudden episodes of uncontrolled electrical activity in the brain (seizures). Due to the similarity of associated symptoms with those seen in acrocallosal syndrome, some researchers have suggested that the gene responsible for that disorder may be located on the short arm of chromosome 12. (For further information, please see the “Causes” section of this report above.)Additional congenital disorders may be characterized by agenesis or hypoplasia of the corpus callosum, mental retardation, craniofacial malformations, digital abnormalities, and/or other symptoms and findings similar to those potentially associated with acrocallosal syndrome, Schinzel type. (For more information on these disorders, choose the exact disease name in question as your search term in the Rare Disease Database.) | Related disorders of Acrocallosal Syndrome, Schinzel Type. Symptoms of the following disorders may be similar to those of acrocallosal syndrome, Schinzel type. Comparisons may be useful for a differential diagnosis:Greig cephalopolysyndactyly syndrome is a rare genetic disorder characterized by distinctive abnormalities of the skull and facial (craniofacial) region, the hands, and the feet. Craniofacial abnormalities may include an abnormally large head (macrocephaly) with a high, prominent forehead; widely spaced eyes (ocular hypertelorism); and a broad nasal root. In many cases, there is also duplication of the great toes (preaxial polydactyly) as well as webbing or fusion (syndactyly) of certain toes, primarily the first to the third toes. Abnormalities of the hands may include unusually broad thumbs; duplication of certain fingers toward the “pinky” side of the hands (postaxial polydactyly); and webbing or fusion of certain fingers, particularly the third and fourth fingers. Rarely, malformation or absence of the corpus callosum; as well as mental retardation, have been reported in association with Greig cephalopolysyndactyly syndrome. In most cases, the disorder appears to be inherited as an autosomal dominant trait. (For more information on this disorder, choose “Greig cephalopolysyndactyly” as your search term in the Rare Disease Database.)Oral-facial-digital syndrome refers to a group of rare genetic disorders characterized by malformations of the facial area, the mouth region (oral defects), and the fingers and toes (digits). Researchers indicate that various forms of the disorder, particularly type II or Mohr syndrom; have certain features similar to those potentially associated with acrocallosal syndrome, Schinzel type. In those with Mohr syndrome craniofacial malformations may include widely spaced eyes (ocular hypertelorism), an abnormal groove in the upper lip (cleft lip), a small lower jaw (micrognathia), and low-set ears that may be rotated toward the back of the head (posteriorly rotated). Oral malformations may include an abnormal length-wise groove in the tongue (cleft tongue), a highly arched roof of the mouth (palate), or incomplete closure of the palate (cleft palate). Affected individuals may also have certain digital malformations, such as duplication of the great toes and/or pinkies (fifth fingers) and webbing or fusion (syndactyly) of certain digits. In some instances, additional abnormalities may include short stature, mental retardation, diminished muscle tone (hypotonia) with poor coordination, and/or other features. Mohr syndrome is inherited as an autosomal recessive trait. (For more information on this disorder, choose “oral facial digital” as your search term in the Rare Disease Database.)Chromosome 12, Trisomy 12p is a rare chromosomal disorder in which part or most of the short arm (p) of chromosome 12 appears three times rather than twice in cells of the body. Associated symptoms and findings may be variable, depending upon the specific location of the duplicated (trisomic) portion of chromosome 12p. Affected individuals may have mental retardation, diminished muscle tone (hypotonia), and distinctive craniofacial malformations. These may include an abnormally large head (macrocephaly) with a high forehead, underdeveloped midfacial regions, a small nose with upturned nostrils (anteverted nares), puffy cheeks, and/or a broad lower lip. In addition, cases have been reported in which trisomy 12p was associated with the presence of extra fingers or toes (polydactyly); absence of the thick band of nerve fibers that normally joins the two hemispheres of the brain (agenesis of corpus callosum); and sudden episodes of uncontrolled electrical activity in the brain (seizures). Due to the similarity of associated symptoms with those seen in acrocallosal syndrome, some researchers have suggested that the gene responsible for that disorder may be located on the short arm of chromosome 12. (For further information, please see the “Causes” section of this report above.)Additional congenital disorders may be characterized by agenesis or hypoplasia of the corpus callosum, mental retardation, craniofacial malformations, digital abnormalities, and/or other symptoms and findings similar to those potentially associated with acrocallosal syndrome, Schinzel type. (For more information on these disorders, choose the exact disease name in question as your search term in the Rare Disease Database.) | 18 | Acrocallosal Syndrome, Schinzel Type |
nord_18_5 | Diagnosis of Acrocallosal Syndrome, Schinzel Type | In some instances, such as in families with members previously diagnosed with the disorder, acrocallosal syndrome, Schinzel type may be suspected before birth (prenatally) based upon certain specialized tests, such as ultrasound or fetoscopy. Fetal ultrasonography is a noninvasive diagnostic procedure in which reflected sound waves create an image of the developing fetus. During fetoscopy, a flexible, ultrasound-guided, viewing instrument is introduced into the uterus through the abdominal wall to directly observe the fetus.The diagnosis is usually made or confirmed at birth based upon a thorough clinical examination, identification of characteristic physical findings, and various specialized tests. Such testing may include x-ray studies; advanced imaging techniques, such as computed tomography (CT) scanning or magnetic resonance imaging (MRI); or other studies to help detect or characterize certain malformations that may be associated with the disorder (e.g., agenesis or hypoplasia of the corpus callosum, certain craniofacial abnormalities, polydactyly and syndactyly, etc.). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of internal structures. MRI uses a magnetic field and radio waves to create detailed cross-sectional images of certain organs and tissues.A thorough cardiac evaluation may also be recommended to detect any heart abnormalities that may be associated with the disorder. Such evaluation may include a thorough clinical examination, during which heart and lung sounds are evaluated through use of a stethoscope, and specialized tests that enable physicians to assess the structure and function of the heart (e.g., x-ray studies, electrocardiography, echocardiography, cardiac catheterization). | Diagnosis of Acrocallosal Syndrome, Schinzel Type. In some instances, such as in families with members previously diagnosed with the disorder, acrocallosal syndrome, Schinzel type may be suspected before birth (prenatally) based upon certain specialized tests, such as ultrasound or fetoscopy. Fetal ultrasonography is a noninvasive diagnostic procedure in which reflected sound waves create an image of the developing fetus. During fetoscopy, a flexible, ultrasound-guided, viewing instrument is introduced into the uterus through the abdominal wall to directly observe the fetus.The diagnosis is usually made or confirmed at birth based upon a thorough clinical examination, identification of characteristic physical findings, and various specialized tests. Such testing may include x-ray studies; advanced imaging techniques, such as computed tomography (CT) scanning or magnetic resonance imaging (MRI); or other studies to help detect or characterize certain malformations that may be associated with the disorder (e.g., agenesis or hypoplasia of the corpus callosum, certain craniofacial abnormalities, polydactyly and syndactyly, etc.). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of internal structures. MRI uses a magnetic field and radio waves to create detailed cross-sectional images of certain organs and tissues.A thorough cardiac evaluation may also be recommended to detect any heart abnormalities that may be associated with the disorder. Such evaluation may include a thorough clinical examination, during which heart and lung sounds are evaluated through use of a stethoscope, and specialized tests that enable physicians to assess the structure and function of the heart (e.g., x-ray studies, electrocardiography, echocardiography, cardiac catheterization). | 18 | Acrocallosal Syndrome, Schinzel Type |
nord_18_6 | Therapies of Acrocallosal Syndrome, Schinzel Type | TreatmentThe treatment of acrocallosal syndrome, Schinzel type is directed toward the specific symptoms that are apparent in each individual. Such treatment may require the coordinated efforts of a team of medical professionals, such as pediatricians; surgeons; physicians who diagnose and treat neurological disorders (neurologists); physicians who specialize in heart disease (cardiologists); physicians who diagnose and treat disorders of the skeleton, joints, muscles, and related tissues (orthopedists); eye specialists; and/or other health care professionals.Specific therapies for individuals with acrocallosal syndrome, Schinzel type are symptomatic and supportive. For those with hydrocephalus, early surgery may be advised to insert a tube (shunt) to drain excess cerebrospinal fluid (CSF) away from the brain and into another part of the body where the CSF can be absorbed.In some instances, surgery may also be recommended to help correct certain craniofacial malformations, polydactyly and syndactyly, and/or other physical abnormalities potentially associated with the disorder. In addition, for those with congenital heart defects, treatment with certain medications, surgical intervention, and/or other measures may be necessary. The surgical procedures performed will depend upon the severity and location of the anatomical abnormalities, their associated symptoms, and other factors.Physicians may regularly monitor affected infants and children to help ensure prompt detection and early aggressive treatment of respiratory infections. In addition, in some instances, certain preventive measures may be recommended for those who may be prone to repeated respiratory infections. For affected infants who develop respiratory distress, treatment may include various supportive measures, including appropriate oxygen therapy.Disease management may also include supportive therapies to help ensure proper caloric intake and nutrition in those with feeding difficulties. In some cases, treatment with certain anticonvulsant medications may also be recommended to help prevent, reduce, or control seizures.Early intervention may be important to ensure that children with the disorder reach their potential. Special services that may be beneficial include special education, physical therapy, and/or other medical, social, or vocational services.Genetic counseling will be of benefit for affected individuals and their families. Other treatment for this disorder is symptomatic and supportive. | Therapies of Acrocallosal Syndrome, Schinzel Type. TreatmentThe treatment of acrocallosal syndrome, Schinzel type is directed toward the specific symptoms that are apparent in each individual. Such treatment may require the coordinated efforts of a team of medical professionals, such as pediatricians; surgeons; physicians who diagnose and treat neurological disorders (neurologists); physicians who specialize in heart disease (cardiologists); physicians who diagnose and treat disorders of the skeleton, joints, muscles, and related tissues (orthopedists); eye specialists; and/or other health care professionals.Specific therapies for individuals with acrocallosal syndrome, Schinzel type are symptomatic and supportive. For those with hydrocephalus, early surgery may be advised to insert a tube (shunt) to drain excess cerebrospinal fluid (CSF) away from the brain and into another part of the body where the CSF can be absorbed.In some instances, surgery may also be recommended to help correct certain craniofacial malformations, polydactyly and syndactyly, and/or other physical abnormalities potentially associated with the disorder. In addition, for those with congenital heart defects, treatment with certain medications, surgical intervention, and/or other measures may be necessary. The surgical procedures performed will depend upon the severity and location of the anatomical abnormalities, their associated symptoms, and other factors.Physicians may regularly monitor affected infants and children to help ensure prompt detection and early aggressive treatment of respiratory infections. In addition, in some instances, certain preventive measures may be recommended for those who may be prone to repeated respiratory infections. For affected infants who develop respiratory distress, treatment may include various supportive measures, including appropriate oxygen therapy.Disease management may also include supportive therapies to help ensure proper caloric intake and nutrition in those with feeding difficulties. In some cases, treatment with certain anticonvulsant medications may also be recommended to help prevent, reduce, or control seizures.Early intervention may be important to ensure that children with the disorder reach their potential. Special services that may be beneficial include special education, physical therapy, and/or other medical, social, or vocational services.Genetic counseling will be of benefit for affected individuals and their families. Other treatment for this disorder is symptomatic and supportive. | 18 | Acrocallosal Syndrome, Schinzel Type |
nord_19_0 | Overview of Acrodermatitis Enteropathica | Acrodermatitis enteropathica (AE) is a disorder of zinc metabolism that occurs in one of three forms: an inborn (congenital) form and two acquired forms. The inborn form of AE is a rare genetic disorder characterized by intestinal abnormalities that lead to the inability to absorb zinc from the intestine. The lack of zinc presents, characteristically, as: (1) skin inflammation with pimples (pustular dermatitis) occurring around the mouth and/or anus, (2) diarrhea, and (3) abnormal nails (nail dystrophy). In the acute phase, irritability and emotional disturbances are evident due to wasting (atrophy) of the brain cortex. It is important to recognize and treat this disorder.The acquired form of this disorder generates similar symptoms. One transient form can result from failure of the mother to secrete zinc into her breast milk. Other acquired forms of AE sometimes result after surgery to bypass some of the upper intestine or from special intravenous nutritional programs that are prepared without the appropriate amount of zinc.Supplemental zinc usually eliminates the symptoms. | Overview of Acrodermatitis Enteropathica. Acrodermatitis enteropathica (AE) is a disorder of zinc metabolism that occurs in one of three forms: an inborn (congenital) form and two acquired forms. The inborn form of AE is a rare genetic disorder characterized by intestinal abnormalities that lead to the inability to absorb zinc from the intestine. The lack of zinc presents, characteristically, as: (1) skin inflammation with pimples (pustular dermatitis) occurring around the mouth and/or anus, (2) diarrhea, and (3) abnormal nails (nail dystrophy). In the acute phase, irritability and emotional disturbances are evident due to wasting (atrophy) of the brain cortex. It is important to recognize and treat this disorder.The acquired form of this disorder generates similar symptoms. One transient form can result from failure of the mother to secrete zinc into her breast milk. Other acquired forms of AE sometimes result after surgery to bypass some of the upper intestine or from special intravenous nutritional programs that are prepared without the appropriate amount of zinc.Supplemental zinc usually eliminates the symptoms. | 19 | Acrodermatitis Enteropathica |
nord_19_1 | Symptoms of Acrodermatitis Enteropathica | Acrodermatitis enteropathica is characterized by chronic diarrhea which may be mild or severe, and the presence of fatty substances in the feces (steatorrhea). In the congenital form symptoms start gradually, frequently at the time of weaning of an infant. The skin around body openings such as the mouth, anus, and eyes, and the skin on elbows, knees, hands, and feet become inflamed. Skin lesions are usually blistered (vesicobullous) and after drying out become psoriasis-like. The skin around the nails may also be inflamed and the nail may be abnormal due to malnourished tissue. Hair loss on the scalp, eyelids, and eyebrows may be total (alopecia). Inflammation of the membrane that lines the eyelid (conjunctivitis), usually also occurs.The blood zinc level in people with the congenital form of this disorder is abnormally low, although rarely normal blood zinc levels have also been observed.A separate type of transient zinc deficiency in infants can result from a different congenital abnormality – but one which is not in the infant but rather in the mother. Notably in some lactating women, a zinc-binding factor produced by the pancreas and present in human milk may be lacking. Breast-fed infants of these women may also develop lowered blood levels of zinc with other symptoms of this disorder, because the milk is deficient in the proper amount of the zinc- binding factor. Once an alternative source of oral zinc is introduced into the infant’s diet (e.g. formula milk) the zinc deficiency rectifies and the infant is cured.With treatment, all patients with acrodermatitis enteropathica can lead normal lives.Frequently, long remissions may occur, usually starting during puberty. However, in rare cases, women may have a recurrence of the disorder during pregnancy and increased zinc supplementation may be necessary. | Symptoms of Acrodermatitis Enteropathica. Acrodermatitis enteropathica is characterized by chronic diarrhea which may be mild or severe, and the presence of fatty substances in the feces (steatorrhea). In the congenital form symptoms start gradually, frequently at the time of weaning of an infant. The skin around body openings such as the mouth, anus, and eyes, and the skin on elbows, knees, hands, and feet become inflamed. Skin lesions are usually blistered (vesicobullous) and after drying out become psoriasis-like. The skin around the nails may also be inflamed and the nail may be abnormal due to malnourished tissue. Hair loss on the scalp, eyelids, and eyebrows may be total (alopecia). Inflammation of the membrane that lines the eyelid (conjunctivitis), usually also occurs.The blood zinc level in people with the congenital form of this disorder is abnormally low, although rarely normal blood zinc levels have also been observed.A separate type of transient zinc deficiency in infants can result from a different congenital abnormality – but one which is not in the infant but rather in the mother. Notably in some lactating women, a zinc-binding factor produced by the pancreas and present in human milk may be lacking. Breast-fed infants of these women may also develop lowered blood levels of zinc with other symptoms of this disorder, because the milk is deficient in the proper amount of the zinc- binding factor. Once an alternative source of oral zinc is introduced into the infant’s diet (e.g. formula milk) the zinc deficiency rectifies and the infant is cured.With treatment, all patients with acrodermatitis enteropathica can lead normal lives.Frequently, long remissions may occur, usually starting during puberty. However, in rare cases, women may have a recurrence of the disorder during pregnancy and increased zinc supplementation may be necessary. | 19 | Acrodermatitis Enteropathica |
nord_19_2 | Causes of Acrodermatitis Enteropathica | The congenital form of acrodermatitis enteropathica is transmitted as an autosomal recessive genetic disorder. It appears to be the result of mutations in the SLC39A4 gene.Genetic diseases are determined by a 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.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.Some women fail to generate adequate zinc levels in their breast milk – and that can also have a genetic cause. A single mutation in the SLC30A2 mutation can reduce breast milk zinc. This tendency does not require two gene abnormalities, one is sufficient and people who have this condition have a 50% chance of passing it on to their offspring. | Causes of Acrodermatitis Enteropathica. The congenital form of acrodermatitis enteropathica is transmitted as an autosomal recessive genetic disorder. It appears to be the result of mutations in the SLC39A4 gene.Genetic diseases are determined by a 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.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.Some women fail to generate adequate zinc levels in their breast milk – and that can also have a genetic cause. A single mutation in the SLC30A2 mutation can reduce breast milk zinc. This tendency does not require two gene abnormalities, one is sufficient and people who have this condition have a 50% chance of passing it on to their offspring. | 19 | Acrodermatitis Enteropathica |
nord_19_3 | Affects of Acrodermatitis Enteropathica | The congenital form of arodermatitis enteropathica is a rare disorder beginning during infancy. The incidence is about 1 in 500,000 births and the condition affects males and females in equal numbers. Healthy breast-fed infants of female patients with the disorder can also become affected. The acquired form of AE is rare because in recent years zinc supplements have been added to the parenteral nutrition regimen, although acquired forms are more common in some regions such as Southeast Asia and sub-Saharan Africa where gastro-intestinal malabsorption syndrome are more frequent. | Affects of Acrodermatitis Enteropathica. The congenital form of arodermatitis enteropathica is a rare disorder beginning during infancy. The incidence is about 1 in 500,000 births and the condition affects males and females in equal numbers. Healthy breast-fed infants of female patients with the disorder can also become affected. The acquired form of AE is rare because in recent years zinc supplements have been added to the parenteral nutrition regimen, although acquired forms are more common in some regions such as Southeast Asia and sub-Saharan Africa where gastro-intestinal malabsorption syndrome are more frequent. | 19 | Acrodermatitis Enteropathica |
nord_19_4 | Related disorders of Acrodermatitis Enteropathica | Symptoms of the following disorder can be similar to those of acrodermatitis enteropathica. Comparisons may be useful for a differential diagnosis:Celiac sprue (gluten enteropathy) is a chronic, hereditary, intestinal malabsorption disorder caused by intolerance to dietary gluten. The illness is characterized by a flat mucous lining of the jejunum (part of the small intestine). Symptoms include weight loss, chronic diarrhea, abdominal cramping and bloating, intestinal gas, and muscle wasting. Clinical and/or histologic improvement of symptoms, follow withdrawal of dietary gluten. (For more information on this disorder, choose “Celiac Sprue” as your search term in the Rare Disease Database.) | Related disorders of Acrodermatitis Enteropathica. Symptoms of the following disorder can be similar to those of acrodermatitis enteropathica. Comparisons may be useful for a differential diagnosis:Celiac sprue (gluten enteropathy) is a chronic, hereditary, intestinal malabsorption disorder caused by intolerance to dietary gluten. The illness is characterized by a flat mucous lining of the jejunum (part of the small intestine). Symptoms include weight loss, chronic diarrhea, abdominal cramping and bloating, intestinal gas, and muscle wasting. Clinical and/or histologic improvement of symptoms, follow withdrawal of dietary gluten. (For more information on this disorder, choose “Celiac Sprue” as your search term in the Rare Disease Database.) | 19 | Acrodermatitis Enteropathica |
nord_19_5 | Diagnosis of Acrodermatitis Enteropathica | Diagnosis of Acrodermatitis Enteropathica. | 19 | Acrodermatitis Enteropathica |
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nord_19_6 | Therapies of Acrodermatitis Enteropathica | Acrodermatitis enteropathica is treated with zinc supplements in the form of zinc sulfate. These supplements should be given as soon as diagnosis of the disorder is made and they have to be continued for life. The drug Diodoquin (iodoquinol) is another treatment that usually clears up symptoms within a week. If the disorder is caused by intravenous feeding, adding zinc supplements to the nutritional regimen can prevent and/or clear up manifestations of AE.Genetic counseling is recommended for families of patients with the congenital form of acrodermatitis enteropathica. | Therapies of Acrodermatitis Enteropathica. Acrodermatitis enteropathica is treated with zinc supplements in the form of zinc sulfate. These supplements should be given as soon as diagnosis of the disorder is made and they have to be continued for life. The drug Diodoquin (iodoquinol) is another treatment that usually clears up symptoms within a week. If the disorder is caused by intravenous feeding, adding zinc supplements to the nutritional regimen can prevent and/or clear up manifestations of AE.Genetic counseling is recommended for families of patients with the congenital form of acrodermatitis enteropathica. | 19 | Acrodermatitis Enteropathica |
nord_20_0 | Overview of Acrodysostosis | Acrodysostosis is a rare genetic disorder characterized by skeletal malformations, growth delays, short stature, and distinctive facial features caused, in part, by underdeveloped (hypoplastic) of certain facial bones, particularly those in the middle portion of the face. A characteristic symptom is abnormally small hands and feet with short, stubby fingers and toes that may affect all or some of the fingers and toes. Some affected children have varying degrees of intellectual disability; in other children intelligence is unaffected. Some children experience resistance to certain hormones, which means that the tissues of the body do not respond to the hormone in question despite normal or high activity levels of the hormone. Acrodysostosis may be caused by mutations in the PRKAR1A gene (type 1) or the PDE4D gene (type 2). These mutations usually occur sporadically without a positive family history; mutations in PDE4D can be inherited in an autosomal dominant manner. It is likely that additional forms of acrodysostosis exist; caused by as-yet-unidentified gene mutations. | Overview of Acrodysostosis. Acrodysostosis is a rare genetic disorder characterized by skeletal malformations, growth delays, short stature, and distinctive facial features caused, in part, by underdeveloped (hypoplastic) of certain facial bones, particularly those in the middle portion of the face. A characteristic symptom is abnormally small hands and feet with short, stubby fingers and toes that may affect all or some of the fingers and toes. Some affected children have varying degrees of intellectual disability; in other children intelligence is unaffected. Some children experience resistance to certain hormones, which means that the tissues of the body do not respond to the hormone in question despite normal or high activity levels of the hormone. Acrodysostosis may be caused by mutations in the PRKAR1A gene (type 1) or the PDE4D gene (type 2). These mutations usually occur sporadically without a positive family history; mutations in PDE4D can be inherited in an autosomal dominant manner. It is likely that additional forms of acrodysostosis exist; caused by as-yet-unidentified gene mutations. | 20 | Acrodysostosis |
nord_20_1 | Symptoms of Acrodysostosis | Although researchers have been able to establish a clear syndrome with characteristic or “core” symptoms, much about the disorder is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of other genes influencing the disorder prevent physicians from developing a complete picture of associated symptoms and prognosis. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below. Parents should talk to their children’s physicians and medical team about their specific case, associated symptoms and overall prognosis.Skeletal malformations that characterize acrodysostosis include abnormal short, malformed (dysplastic) bones in the hands and feet. These dysplastic bones cause the hands and feet to be abnormally small with short, stubby fingers and toes (severe brachydactyly). In some individuals, the shortness may affect only one or two fingers and/or toes. The big toes are often not affected, or can be abnormally large. Abnormalities of the hands and feet are detected early in childhood (congenital). Abnormal shortening of the long bones is also common and can result in short stature. Additional skeletal malformations include spinal malformations such as abnormal curvature of the spine (e.g. scoliosis or kyphosis), and a risk of spinal stenosis, a condition marked by narrowing (stenosis) of the spaces within the spinal canal, spinal nerve root canals, or bones of the spinal column. Affected individuals may experience numbness or pain in the lower back and/or legs. The chondrodysplasia develops and becomes more noticeable over time.Individuals with acrodysostosis often have distinctive facial features including underdevelopment of the upper jaw (maxillary hypoplasia) and underdevelopment of the nasal bone (nasal hypoplasia) so that the nose is abnormally small and the bridge of the nose may be flattened or depressed. In some cases, the tip of the nose is rounded (bulbous) and the nostrils point upward giving the appearance of an upturned nose (anteverted nares). The lower jaw bone (mandible) may appear abnormally prominent. Additional features can include widely-spaced eyes (hypertelorism), an extra fold of skin on either side of the nose that may cover the inner corners of the eyes (epicanthal folds), failure of the upper and lower teeth to meet properly (malocclusion), and low-set ears. Some affected individuals may exhibit mild to moderate intellectual disability and experience delays in acquiring skills that require both mental and motor coordination (psychomotor delays), learning disabilities, and delays in learning to walk and talk. Growth before birth (antenatal growth) is usually severely affected and babies are born small for gestational age. Mild to moderate growth delays after birth may also occur and affected individuals are often below average height for their age (short stature). A great part of the height deficit is due to the lack of the pubertal growth spurt.Some individuals develop resistance to multiple hormones such as parathyroid hormone and thyroid-stimulating hormone. Resistance means that although the hormones are present in normal -or even high- levels, the tissues of the body do not fully respond to their presence or effects. In most patients with hormone resistance, the rise of the circulating level of the hormone is sufficient to induce the expected effect of the hormone (for example, the rise in parathyroid hormone will allow the body to maintain a normal serum calcium level). Under certain conditions, individuals may develop symptoms similar to those seen in individuals with deficiency of these hormones. Additional physical findings have been reported in individuals with acrodysostosis including repeated middle ear infections (otitis media), hearing loss, obesity, skin lesions that are flesh-colored, brown or black (pigmented nevi), blue eyes, and red or blond hair. Affected individuals may eventually develop arthritic changes in the hands which can lead to problems moving the hands with skill and coordination (manual dexterity). In some affected males the opening of the urethra is on the underside of the penis rather than the tip (hypospadias) and/or testes may fail to descend into the scrotum (cryptorchidism). Certain metabolic and cardiovascular manifestations have also been reported in acrodysostosis including high blood pressure (hypertension). Some reports suggest that affected individuals are at an increased risk for narrowing of the blood vessels (vascular stenosis). Individuals with acrodysostosis type 1 appear to be more likely to develop hormone resistance. Individuals with acrodysostosis type 2 are more likely to have intellectual disability and characteristic facial features. Some recent cases described in the medical literature suggest that hormone resistance is more common in individuals with acrodysostosis type 2 than previously believed. | Symptoms of Acrodysostosis. Although researchers have been able to establish a clear syndrome with characteristic or “core” symptoms, much about the disorder is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of other genes influencing the disorder prevent physicians from developing a complete picture of associated symptoms and prognosis. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below. Parents should talk to their children’s physicians and medical team about their specific case, associated symptoms and overall prognosis.Skeletal malformations that characterize acrodysostosis include abnormal short, malformed (dysplastic) bones in the hands and feet. These dysplastic bones cause the hands and feet to be abnormally small with short, stubby fingers and toes (severe brachydactyly). In some individuals, the shortness may affect only one or two fingers and/or toes. The big toes are often not affected, or can be abnormally large. Abnormalities of the hands and feet are detected early in childhood (congenital). Abnormal shortening of the long bones is also common and can result in short stature. Additional skeletal malformations include spinal malformations such as abnormal curvature of the spine (e.g. scoliosis or kyphosis), and a risk of spinal stenosis, a condition marked by narrowing (stenosis) of the spaces within the spinal canal, spinal nerve root canals, or bones of the spinal column. Affected individuals may experience numbness or pain in the lower back and/or legs. The chondrodysplasia develops and becomes more noticeable over time.Individuals with acrodysostosis often have distinctive facial features including underdevelopment of the upper jaw (maxillary hypoplasia) and underdevelopment of the nasal bone (nasal hypoplasia) so that the nose is abnormally small and the bridge of the nose may be flattened or depressed. In some cases, the tip of the nose is rounded (bulbous) and the nostrils point upward giving the appearance of an upturned nose (anteverted nares). The lower jaw bone (mandible) may appear abnormally prominent. Additional features can include widely-spaced eyes (hypertelorism), an extra fold of skin on either side of the nose that may cover the inner corners of the eyes (epicanthal folds), failure of the upper and lower teeth to meet properly (malocclusion), and low-set ears. Some affected individuals may exhibit mild to moderate intellectual disability and experience delays in acquiring skills that require both mental and motor coordination (psychomotor delays), learning disabilities, and delays in learning to walk and talk. Growth before birth (antenatal growth) is usually severely affected and babies are born small for gestational age. Mild to moderate growth delays after birth may also occur and affected individuals are often below average height for their age (short stature). A great part of the height deficit is due to the lack of the pubertal growth spurt.Some individuals develop resistance to multiple hormones such as parathyroid hormone and thyroid-stimulating hormone. Resistance means that although the hormones are present in normal -or even high- levels, the tissues of the body do not fully respond to their presence or effects. In most patients with hormone resistance, the rise of the circulating level of the hormone is sufficient to induce the expected effect of the hormone (for example, the rise in parathyroid hormone will allow the body to maintain a normal serum calcium level). Under certain conditions, individuals may develop symptoms similar to those seen in individuals with deficiency of these hormones. Additional physical findings have been reported in individuals with acrodysostosis including repeated middle ear infections (otitis media), hearing loss, obesity, skin lesions that are flesh-colored, brown or black (pigmented nevi), blue eyes, and red or blond hair. Affected individuals may eventually develop arthritic changes in the hands which can lead to problems moving the hands with skill and coordination (manual dexterity). In some affected males the opening of the urethra is on the underside of the penis rather than the tip (hypospadias) and/or testes may fail to descend into the scrotum (cryptorchidism). Certain metabolic and cardiovascular manifestations have also been reported in acrodysostosis including high blood pressure (hypertension). Some reports suggest that affected individuals are at an increased risk for narrowing of the blood vessels (vascular stenosis). Individuals with acrodysostosis type 1 appear to be more likely to develop hormone resistance. Individuals with acrodysostosis type 2 are more likely to have intellectual disability and characteristic facial features. Some recent cases described in the medical literature suggest that hormone resistance is more common in individuals with acrodysostosis type 2 than previously believed. | 20 | Acrodysostosis |
nord_20_2 | Causes of Acrodysostosis | Acrodysostosis is caused by a mutation in either the PRKAR1A gene or the PDE4D 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, including the brain.In many cases, these gene mutations are believed to occur as a new (sporadic or de novo) mutations, which means that a gene mutation has occurred at the time of the formation of the egg or sperm for that child only, and no other family member will be affected. The disorder is usually not inherited from or “carried” by a healthy parent. However, dominant inheritance (where a trait is transmitted from either an affected mother or father to their child) has been documented in acrodysostosis type 2.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 gender of the resulting child.Investigators have determined that the PRKAR1A gene is located on the long arm (q) of chromosome 17 (17q24.2) and that the PDE4D gene is located on the long arm of chromosome 5 (5q11.2-q12.1). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”.The PRKAR1A and PDE4D genes both create (encode) proteins that play a key role in the cAMP signaling pathway. A signaling pathway is the series of chemical processes by which certain cell activities are controlled and managed. The cAMP signaling pathway is essential for the proper formation of bone (skeletogenesis) and for the action of many hormones including the parathyroid hormone and the thyroid stimulating hormone. Mutations in these genes modify the function of the specific protein product, which ultimately leads to the symptoms of acrodysostosis. | Causes of Acrodysostosis. Acrodysostosis is caused by a mutation in either the PRKAR1A gene or the PDE4D 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, including the brain.In many cases, these gene mutations are believed to occur as a new (sporadic or de novo) mutations, which means that a gene mutation has occurred at the time of the formation of the egg or sperm for that child only, and no other family member will be affected. The disorder is usually not inherited from or “carried” by a healthy parent. However, dominant inheritance (where a trait is transmitted from either an affected mother or father to their child) has been documented in acrodysostosis type 2.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 gender of the resulting child.Investigators have determined that the PRKAR1A gene is located on the long arm (q) of chromosome 17 (17q24.2) and that the PDE4D gene is located on the long arm of chromosome 5 (5q11.2-q12.1). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”.The PRKAR1A and PDE4D genes both create (encode) proteins that play a key role in the cAMP signaling pathway. A signaling pathway is the series of chemical processes by which certain cell activities are controlled and managed. The cAMP signaling pathway is essential for the proper formation of bone (skeletogenesis) and for the action of many hormones including the parathyroid hormone and the thyroid stimulating hormone. Mutations in these genes modify the function of the specific protein product, which ultimately leads to the symptoms of acrodysostosis. | 20 | Acrodysostosis |
nord_20_3 | Affects of Acrodysostosis | Acrodysostosis affects males and females in equal numbers. The disorder is present at birth (congenital) but may not be apparent until years after birth. The exact incidence and prevalence of the disorder is unknown. Because many cases can go misdiagnosed or undiagnosed, determining the true frequency of acrodysostosis in the general population is difficult. | Affects of Acrodysostosis. Acrodysostosis affects males and females in equal numbers. The disorder is present at birth (congenital) but may not be apparent until years after birth. The exact incidence and prevalence of the disorder is unknown. Because many cases can go misdiagnosed or undiagnosed, determining the true frequency of acrodysostosis in the general population is difficult. | 20 | Acrodysostosis |
nord_20_4 | Related disorders of Acrodysostosis | Symptoms of the following disorders can be similar to those of acrodysostosis. Comparisons may be useful for a differential diagnosis.Albright hereditary osteodystrophy (AHO) is a rare disorder characterized by short stature, an unusually round face, abnormally short fingers (brachydactyly), and/or the development of bony growths (osseous plaques) on the surface of the skin but not in the deep connective tissue. These growths may spread to the lower level of the skin as well (subcutaneous ossification). Other symptoms may include mild intellectual disability and obesity. AHO may be isolated or associated with hormone resistance, such as parathyroid hormone resistance which manifests as abnormally low levels of calcium in the blood (hypocalcemia). Therefore, symptoms of pseudohypoparathyroidism include weakness, muscle cramps, excessive nervousness, headaches, and/or abnormal sensations such as tingling, burning, and numbness of the hands. The association of AHO and hormone resistance is termed pseudohypoparathyroidism type 1A. AHO (sometimes called pseudopseudohypoparathyroidism or PPHP) and PHP1A are caused by loss of function mutations of the same gene (GNAS). GNAS encodes the alpha stimulatory subunit of the G-proteins that are needed to properly respond to parathyroid hormone and other hormones. Each condition can be inherited in an autosomal dominant manner. However, isolated AHO (PPHP) is inherited from fathers whereas PHP1A is inherited from mothers. (For more information on this disorder, choose “Albright” as your search term in the Rare Disease Database.)5q12.1-haploinsufficiency syndrome is an extremely rare disorder that has only been described in several individuals. These individuals have structural chromosome abnormalities (e.g. deletions) that involve the PDE4D gene, resulting in half the normal production of the protein product of that gene (haploinsufficiency). The symptoms of these individuals were extremely similar to those seen in individuals with acrodysostosis type 2 including underdevelopment of certain facial bones, brachydactyly, and intellectual disability. 2q37 microdeletion syndrome is a rare disorder characterized by a broad range of signs and symptoms. Affected individuals often develop varying degrees of intellectual disability, abnormal short bones in the fingers and hands (brachymetaphalangy), short stature, obesity, and distinctive facial features. Additional symptoms include diminished muscle tone (hypotonia), joint abnormalities, abnormal sideways curvature of the spine (scoliosis), and autism spectrum disorder. Some affected individuals may have congenital heart disease, seizures, central nervous system abnormalities, hernias, gastrointestinal abnormalities, and kidney (renal) malformations. Parathyroid hormone resistance was described in few cases. 2q37 microdeletion syndrome is caused by a small loss of genetic material on the long arm (q) of chromosome 2. The specific gene(s) involved in this disorder are not known. | Related disorders of Acrodysostosis. Symptoms of the following disorders can be similar to those of acrodysostosis. Comparisons may be useful for a differential diagnosis.Albright hereditary osteodystrophy (AHO) is a rare disorder characterized by short stature, an unusually round face, abnormally short fingers (brachydactyly), and/or the development of bony growths (osseous plaques) on the surface of the skin but not in the deep connective tissue. These growths may spread to the lower level of the skin as well (subcutaneous ossification). Other symptoms may include mild intellectual disability and obesity. AHO may be isolated or associated with hormone resistance, such as parathyroid hormone resistance which manifests as abnormally low levels of calcium in the blood (hypocalcemia). Therefore, symptoms of pseudohypoparathyroidism include weakness, muscle cramps, excessive nervousness, headaches, and/or abnormal sensations such as tingling, burning, and numbness of the hands. The association of AHO and hormone resistance is termed pseudohypoparathyroidism type 1A. AHO (sometimes called pseudopseudohypoparathyroidism or PPHP) and PHP1A are caused by loss of function mutations of the same gene (GNAS). GNAS encodes the alpha stimulatory subunit of the G-proteins that are needed to properly respond to parathyroid hormone and other hormones. Each condition can be inherited in an autosomal dominant manner. However, isolated AHO (PPHP) is inherited from fathers whereas PHP1A is inherited from mothers. (For more information on this disorder, choose “Albright” as your search term in the Rare Disease Database.)5q12.1-haploinsufficiency syndrome is an extremely rare disorder that has only been described in several individuals. These individuals have structural chromosome abnormalities (e.g. deletions) that involve the PDE4D gene, resulting in half the normal production of the protein product of that gene (haploinsufficiency). The symptoms of these individuals were extremely similar to those seen in individuals with acrodysostosis type 2 including underdevelopment of certain facial bones, brachydactyly, and intellectual disability. 2q37 microdeletion syndrome is a rare disorder characterized by a broad range of signs and symptoms. Affected individuals often develop varying degrees of intellectual disability, abnormal short bones in the fingers and hands (brachymetaphalangy), short stature, obesity, and distinctive facial features. Additional symptoms include diminished muscle tone (hypotonia), joint abnormalities, abnormal sideways curvature of the spine (scoliosis), and autism spectrum disorder. Some affected individuals may have congenital heart disease, seizures, central nervous system abnormalities, hernias, gastrointestinal abnormalities, and kidney (renal) malformations. Parathyroid hormone resistance was described in few cases. 2q37 microdeletion syndrome is caused by a small loss of genetic material on the long arm (q) of chromosome 2. The specific gene(s) involved in this disorder are not known. | 20 | Acrodysostosis |
nord_20_5 | Diagnosis of Acrodysostosis | A diagnosis of acrodysostosis is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests including X-rays.Clinical Testing and WorkupPrenatal fetal ultrasonography, an exam in which reflected sound waves create an image of the developing fetus, may potentially reveal intrauterine growth retardation and short long bones that are compatible with the diagnosis of acrodysostosis. However, no specific antenatal signs have been isolated.Some symptoms of acrodysostosis may be obvious at birth such as characteristic facial features and growth retardation. Traditional x-ray studies may reveal abnormally short bones in the hands and feet and premature fusion of the end portions (epiphyses) of certain bones of the hands, feet, and elbows. The appearance of spots on the epiphyses (stippling) may also be detected by traditional x-ray.In some cases, molecular genetic testing can confirm a diagnosis of acrodysostosis. Molecular genetic testing can detect mutations in one of the two specific genes known to cause the disorder, but is available only as a diagnostic service at specialized laboratories. | Diagnosis of Acrodysostosis. A diagnosis of acrodysostosis is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests including X-rays.Clinical Testing and WorkupPrenatal fetal ultrasonography, an exam in which reflected sound waves create an image of the developing fetus, may potentially reveal intrauterine growth retardation and short long bones that are compatible with the diagnosis of acrodysostosis. However, no specific antenatal signs have been isolated.Some symptoms of acrodysostosis may be obvious at birth such as characteristic facial features and growth retardation. Traditional x-ray studies may reveal abnormally short bones in the hands and feet and premature fusion of the end portions (epiphyses) of certain bones of the hands, feet, and elbows. The appearance of spots on the epiphyses (stippling) may also be detected by traditional x-ray.In some cases, molecular genetic testing can confirm a diagnosis of acrodysostosis. Molecular genetic testing can detect mutations in one of the two specific genes known to cause the disorder, but is available only as a diagnostic service at specialized laboratories. | 20 | Acrodysostosis |
nord_20_6 | Therapies of Acrodysostosis | TreatmentThe treatment of acrodysostosis is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, specialists who diagnose and treat skeletal abnormalities (orthopedists), specialists who diagnose and treat hormonal imbalance (pediatric endocrinologists), orthopedic surgeons, specialists who diagnose, prevent, and/or treat abnormalities of the teeth (orthodontists), neurologists, ophthalmologists, physical therapists, and other health care professionals may need to systematically and comprehensively plan an affected child’s long-term treatment.There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with acrodysostosis.Specific therapies for the treatment of acrodysostosis are symptomatic and supportive. Surgery may be performed to correct specific abnormalities such as underdeveloped (hypoplastic) and/or abnormally prominent jaws (prognathism). In some cases, dental braces may be required to correct misaligned teeth (malocclusion). In addition, in some cases, physical therapy may also be required. Thyroid hormone supplementation and vitamin D supplements may contribute to improve growth and prevent obesity.Early intervention is important to ensure that children with acrodysostosis reach their full potential. Special services that may be beneficial to affected children may include special remedial education, social support, and/or other medical, social, and/or vocational services. | Therapies of Acrodysostosis. TreatmentThe treatment of acrodysostosis is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, specialists who diagnose and treat skeletal abnormalities (orthopedists), specialists who diagnose and treat hormonal imbalance (pediatric endocrinologists), orthopedic surgeons, specialists who diagnose, prevent, and/or treat abnormalities of the teeth (orthodontists), neurologists, ophthalmologists, physical therapists, and other health care professionals may need to systematically and comprehensively plan an affected child’s long-term treatment.There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with acrodysostosis.Specific therapies for the treatment of acrodysostosis are symptomatic and supportive. Surgery may be performed to correct specific abnormalities such as underdeveloped (hypoplastic) and/or abnormally prominent jaws (prognathism). In some cases, dental braces may be required to correct misaligned teeth (malocclusion). In addition, in some cases, physical therapy may also be required. Thyroid hormone supplementation and vitamin D supplements may contribute to improve growth and prevent obesity.Early intervention is important to ensure that children with acrodysostosis reach their full potential. Special services that may be beneficial to affected children may include special remedial education, social support, and/or other medical, social, and/or vocational services. | 20 | Acrodysostosis |
nord_21_0 | Overview of Acromegaly | Acromegaly is a rare, slowly progressive, acquired disorder that affects adults. It occurs when the pituitary gland produces too much growth hormone (GH). The pituitary gland is a small gland located near the base of the skull that stores several hormones and releases them into the bloodstream as needed by the body. These hormones regulate many different bodily functions. In most patients, acromegaly is caused by the growth of a benign tumor (adenoma), arising from the pituitary gland. Symptoms of acromegaly include abnormal enlargement in bones of the hands, arms, feet, legs and head. Enlargement of the bones in the jaws and in the front of the skull are typically the most apparent bony changes. Acromegaly may also cause thickening of the soft tissues of the body, including the heart, lips and tongue. If untreated, acromegaly can potentially cause serious illness and life-threatening complications. When excessive secretion of growth hormone occurs before puberty, the disorder is known as gigantism, not acromegaly. | Overview of Acromegaly. Acromegaly is a rare, slowly progressive, acquired disorder that affects adults. It occurs when the pituitary gland produces too much growth hormone (GH). The pituitary gland is a small gland located near the base of the skull that stores several hormones and releases them into the bloodstream as needed by the body. These hormones regulate many different bodily functions. In most patients, acromegaly is caused by the growth of a benign tumor (adenoma), arising from the pituitary gland. Symptoms of acromegaly include abnormal enlargement in bones of the hands, arms, feet, legs and head. Enlargement of the bones in the jaws and in the front of the skull are typically the most apparent bony changes. Acromegaly may also cause thickening of the soft tissues of the body, including the heart, lips and tongue. If untreated, acromegaly can potentially cause serious illness and life-threatening complications. When excessive secretion of growth hormone occurs before puberty, the disorder is known as gigantism, not acromegaly. | 21 | Acromegaly |
nord_21_1 | Symptoms of Acromegaly | The symptoms of acromegaly generally occur slowly and become more noticeable as affected individuals age. The specific symptoms that develop may vary greatly from one person to another. Acromegaly can potentially cause a wide variety of symptoms and physical findings.Facial features gradually become coarse because of the overgrowth of soft tissues and cartilage. Facial bones gradually become prominent, the lower jaw protrudes (prognathism) and an underbite may cause a wide separation and misalignment between the teeth (malocclusion). Affected individuals may also have an abnormally large tongue and unusually thick, full lips. People with acromegaly eventually develop a deep and husky voice due to thickening of the vocal cords and enlargement of the sinuses.Acromegaly also results in a gradual enlargement of the hands and feet. Affected individuals may notice that rings feel tighter or no longer fit at all, and that their shoe size and width has increased. Overgrowth (hypertrophy) of bone and enlargement of cartilage in the joints may result in inflammation and gradual degeneration of involved joints (osteoarthritis). Joint and muscle pain (arthralgia and myalgia) often develops, especially affecting the large joints such as the knees, shoulders, hands, wrists and hips.In some people with acromegaly, the spine may abnormally curve from side to side and from front to back (kyphoscoliosis). Overgrowth of tissue may trap nerves, causing numbness and weakness of the hands (carpal tunnel syndrome). Abnormal darkening and thickening of patches of skin in certain areas of the body (acanthosis nigricans), an excessive amount of body hair (hirsutism) and small abnormal outgrowths of extra skin (skin tags) may also be present.In some patients, acromegaly may cause abnormal enlargement of certain organs including the heart. Symptoms may include difficulty breathing upon exertion (dyspnea) and/or irregular heartbeats (arrhythmias). Heart involvement in acromegaly can ultimately lead to congestive heart failure, in which the heart cannot properly circulate blood to the lungs and the rest of the body, resulting in fluid buildup in the heart, lung and various body tissues.Additional symptoms of acromegaly may include abnormal enlargement of the liver (hepatomegaly), spleen (splenomegaly), intestines and/or kidneys. The thyroid (goiter) and/or the adrenal glands may also become abnormally enlarged.Approximately 25 percent of people with acromegaly have elevated blood pressure (hypertension). Abnormal enlargement of the pituitary gland, located at the base of the skull, may cause headaches, visual abnormalities and/or hormonal deficiencies. In approximately 50 percent of people with acromegaly, excessive levels of growth hormone (GH) secreted by the pituitary gland may influence the production of insulin, a hormone produced by the pancreas that regulates blood sugar (glucose) levels by promoting the movement of glucose into cells in the body. Abnormalities in insulin action may result in elevated levels of blood sugar (glucose) and some individuals with acromegaly may develop insulin resistance or type 2 diabetes mellitus. Some people with acromegaly may have an increased metabolic rate, excessive sweating (hyperhidrosis) and/or increased production of oil (sebum) by the sebaceous glands in the skin, resulting in abnormally oily skin.Individuals with acromegaly may develop breathing (respiratory) abnormalities including sleep apnea, a common sleep disorder characterized by temporary, recurrent interruptions of breathing during sleep. Symptoms of the disorder include wakefulness during the night, excessive sleepiness during the day, loud snoring and/or obesity. In obstructive apnea, the most common form of sleep apnea, labored breathing is interrupted by airway collapse or blockage from enlarged soft tissue. Partial awakening may then occur and the person may gasp for air. Sleep is resumed as breathing begins again. Untreated sleep apnea may be associated with high blood pressure, irregular heartbeats, swelling in the arms and/or legs, hallucinations, anxiety and/or irritability.Females with acromegaly may experience an abnormal flow of milk from the breasts (galactorrhea), and infrequent or delayed menstrual flow (oligomenorrhea). Males with acromegaly may experience impotence and a decrease in sexual drive (decreased libido). Individuals with acromegaly have an increased risk of developing polyps in the colon. Individuals with acromegaly may have a slightly greater risk of developing colon cancer than the general population.Symptoms that may develop late during the course of acromegaly include muscle weakness and impaired function of peripheral nerves (i.e., nerves that lie outside the brain and spinal cord). Vision of some affected individuals may become impaired and possibly progress to blindness. If untreated, 25 percent of people with acromegaly experience symptoms associated with uncontrolled diabetes including an increase in the amount of sugar in their urine (glycosuria), abnormally excessive thirst (polydipsia) and/or an abnormally increased appetite (polyphagia). | Symptoms of Acromegaly. The symptoms of acromegaly generally occur slowly and become more noticeable as affected individuals age. The specific symptoms that develop may vary greatly from one person to another. Acromegaly can potentially cause a wide variety of symptoms and physical findings.Facial features gradually become coarse because of the overgrowth of soft tissues and cartilage. Facial bones gradually become prominent, the lower jaw protrudes (prognathism) and an underbite may cause a wide separation and misalignment between the teeth (malocclusion). Affected individuals may also have an abnormally large tongue and unusually thick, full lips. People with acromegaly eventually develop a deep and husky voice due to thickening of the vocal cords and enlargement of the sinuses.Acromegaly also results in a gradual enlargement of the hands and feet. Affected individuals may notice that rings feel tighter or no longer fit at all, and that their shoe size and width has increased. Overgrowth (hypertrophy) of bone and enlargement of cartilage in the joints may result in inflammation and gradual degeneration of involved joints (osteoarthritis). Joint and muscle pain (arthralgia and myalgia) often develops, especially affecting the large joints such as the knees, shoulders, hands, wrists and hips.In some people with acromegaly, the spine may abnormally curve from side to side and from front to back (kyphoscoliosis). Overgrowth of tissue may trap nerves, causing numbness and weakness of the hands (carpal tunnel syndrome). Abnormal darkening and thickening of patches of skin in certain areas of the body (acanthosis nigricans), an excessive amount of body hair (hirsutism) and small abnormal outgrowths of extra skin (skin tags) may also be present.In some patients, acromegaly may cause abnormal enlargement of certain organs including the heart. Symptoms may include difficulty breathing upon exertion (dyspnea) and/or irregular heartbeats (arrhythmias). Heart involvement in acromegaly can ultimately lead to congestive heart failure, in which the heart cannot properly circulate blood to the lungs and the rest of the body, resulting in fluid buildup in the heart, lung and various body tissues.Additional symptoms of acromegaly may include abnormal enlargement of the liver (hepatomegaly), spleen (splenomegaly), intestines and/or kidneys. The thyroid (goiter) and/or the adrenal glands may also become abnormally enlarged.Approximately 25 percent of people with acromegaly have elevated blood pressure (hypertension). Abnormal enlargement of the pituitary gland, located at the base of the skull, may cause headaches, visual abnormalities and/or hormonal deficiencies. In approximately 50 percent of people with acromegaly, excessive levels of growth hormone (GH) secreted by the pituitary gland may influence the production of insulin, a hormone produced by the pancreas that regulates blood sugar (glucose) levels by promoting the movement of glucose into cells in the body. Abnormalities in insulin action may result in elevated levels of blood sugar (glucose) and some individuals with acromegaly may develop insulin resistance or type 2 diabetes mellitus. Some people with acromegaly may have an increased metabolic rate, excessive sweating (hyperhidrosis) and/or increased production of oil (sebum) by the sebaceous glands in the skin, resulting in abnormally oily skin.Individuals with acromegaly may develop breathing (respiratory) abnormalities including sleep apnea, a common sleep disorder characterized by temporary, recurrent interruptions of breathing during sleep. Symptoms of the disorder include wakefulness during the night, excessive sleepiness during the day, loud snoring and/or obesity. In obstructive apnea, the most common form of sleep apnea, labored breathing is interrupted by airway collapse or blockage from enlarged soft tissue. Partial awakening may then occur and the person may gasp for air. Sleep is resumed as breathing begins again. Untreated sleep apnea may be associated with high blood pressure, irregular heartbeats, swelling in the arms and/or legs, hallucinations, anxiety and/or irritability.Females with acromegaly may experience an abnormal flow of milk from the breasts (galactorrhea), and infrequent or delayed menstrual flow (oligomenorrhea). Males with acromegaly may experience impotence and a decrease in sexual drive (decreased libido). Individuals with acromegaly have an increased risk of developing polyps in the colon. Individuals with acromegaly may have a slightly greater risk of developing colon cancer than the general population.Symptoms that may develop late during the course of acromegaly include muscle weakness and impaired function of peripheral nerves (i.e., nerves that lie outside the brain and spinal cord). Vision of some affected individuals may become impaired and possibly progress to blindness. If untreated, 25 percent of people with acromegaly experience symptoms associated with uncontrolled diabetes including an increase in the amount of sugar in their urine (glycosuria), abnormally excessive thirst (polydipsia) and/or an abnormally increased appetite (polyphagia). | 21 | Acromegaly |
nord_21_2 | Causes of Acromegaly | Acromegaly is a rare disorder that is caused by excess levels of growth hormone (GH) in the body. In most patients, excess levels of GH are causes by a benign (noncancerous) tumor in the pituitary gland (pituitary adenoma). Most adenomas form from excessive growth of a pituitary cell called a somatotrope cell (the pituitary cell that normally secretes GH). In the overwhelming majority of patients, the disease is sporadic and not due to an inherited genetic mutation.GH is a hormone that is involved in many different physiological processes in the body including helping to regulate the physical growth of the body. One of the functions of GH is to stimulate the production of another hormone, known as insulin-like growth factor-1 (IGF-1). Consequently, individuals with acromegaly also have elevated levels of IGF-1.Rarely acromegaly may be caused by the ineffective control of growth hormone-secreting cells by the hypothalamus (a gland in the brain that regulates hormone secretions). Growth hormone excess may sometimes be due to over-stimulation by production of too much growth hormone releasing hormone (GHRH) secreted by the hypothalamus or other tissues.Rarely, non-pituitary tumors in the pancreas, lungs or adrenal glands may cause acromegaly. These tumors may directly produce excess growth hormone or they may produce growth hormone-releasing hormone (GHRH), which stimulates the pituitary gland to release GH.In some patients, acromegaly may occur as part of certain genetic syndromes including multiple endocrine neoplasia type 1, familial isolated pituitary adenoma, Carney complex and McCune-Albright syndrome. X-linked acrogigantism causes gigantism and is due to microduplications of segments of the X chromosome. (For more information, choose the specific disorder name as your search term in the Rare Disease Database.) | Causes of Acromegaly. Acromegaly is a rare disorder that is caused by excess levels of growth hormone (GH) in the body. In most patients, excess levels of GH are causes by a benign (noncancerous) tumor in the pituitary gland (pituitary adenoma). Most adenomas form from excessive growth of a pituitary cell called a somatotrope cell (the pituitary cell that normally secretes GH). In the overwhelming majority of patients, the disease is sporadic and not due to an inherited genetic mutation.GH is a hormone that is involved in many different physiological processes in the body including helping to regulate the physical growth of the body. One of the functions of GH is to stimulate the production of another hormone, known as insulin-like growth factor-1 (IGF-1). Consequently, individuals with acromegaly also have elevated levels of IGF-1.Rarely acromegaly may be caused by the ineffective control of growth hormone-secreting cells by the hypothalamus (a gland in the brain that regulates hormone secretions). Growth hormone excess may sometimes be due to over-stimulation by production of too much growth hormone releasing hormone (GHRH) secreted by the hypothalamus or other tissues.Rarely, non-pituitary tumors in the pancreas, lungs or adrenal glands may cause acromegaly. These tumors may directly produce excess growth hormone or they may produce growth hormone-releasing hormone (GHRH), which stimulates the pituitary gland to release GH.In some patients, acromegaly may occur as part of certain genetic syndromes including multiple endocrine neoplasia type 1, familial isolated pituitary adenoma, Carney complex and McCune-Albright syndrome. X-linked acrogigantism causes gigantism and is due to microduplications of segments of the X chromosome. (For more information, choose the specific disorder name as your search term in the Rare Disease Database.) | 21 | Acromegaly |
nord_21_3 | Affects of Acromegaly | Acromegaly is a rare disorder that affects males and females in equal numbers. This disorder occurs in approximately 50 to 70 people per million. Researchers estimate that three to eleven people out of every million develop the disorder each year. However, because the symptoms of acromegaly may develop slowly, the disorder may often remain unrecognized and may therefore be underdiagnosed, making it difficult to determine the true frequency of acromegaly in the general population.Acromegaly can occur at any age after puberty, but most often occurs during the fourth and fifth decades. When excessive secretion of growth hormone occurs before puberty, the disorder is known as gigantism, not acromegaly. | Affects of Acromegaly. Acromegaly is a rare disorder that affects males and females in equal numbers. This disorder occurs in approximately 50 to 70 people per million. Researchers estimate that three to eleven people out of every million develop the disorder each year. However, because the symptoms of acromegaly may develop slowly, the disorder may often remain unrecognized and may therefore be underdiagnosed, making it difficult to determine the true frequency of acromegaly in the general population.Acromegaly can occur at any age after puberty, but most often occurs during the fourth and fifth decades. When excessive secretion of growth hormone occurs before puberty, the disorder is known as gigantism, not acromegaly. | 21 | Acromegaly |
nord_21_4 | Related disorders of Acromegaly | Symptoms of the following disorders can be similar to those of acromegaly. Comparisons may be useful for a differential diagnosis:Gigantism is an abnormal condition characterized by excessive height and size. This disorder typically occurs before puberty as a result of the over secretion of growth hormone by the pituitary gland. Gigantism is associated with enlarged soft tissues and late closure of the epiphyses (heads of the long bones), which results in excessive growth during childhood. Height may reach 7 or 8 feet. Low levels of gonadotropin (gonad stimulating) hormones may be secreted by the pituitary gland later in the course of this disorder and result in low levels of hormone secretions by the ovaries or testes. Sexual development may be normal or it may be affected by the low levels of circulating sex hormones. Some children with gigantism may experience tingling and/or burning sensations in the arms and/or legs (peripheral neuropathy).Marfan syndrome is a genetic disorder that affects connective tissue, which is the material between cells of the body that gives the tissues form and strength. Connective tissue is found all over the body and multiple organ systems may be affected in individuals with Marfan syndrome. The heart and blood vessels (cardiovascular), skeletal, and eye (ocular) systems are most often affected. Major symptoms include overgrowth of the long bones of the arms and legs, abnormal side-to-side curvature of the spine (scoliosis), indentation or protrusion of the chest wall (pectus), dislocation of the lenses of the eyes (ectopia lentis), nearsightedness (myopia), widening (aneurysm) and degeneration of the main artery that carries blood away from the heart (aorta), floppiness of the mitral valve (mitral valve prolapse) and backward flow of blood through the aortic and mitral valves (aortic and mitral regurgitation). The specific symptoms and the severity of Marfan syndrome vary greatly from person to person. Marfan syndrome is inherited in an autosomal dominant pattern. Changes (mutations) in the fibrillin-1 (FBN1) gene cause Marfan syndrome and related disorders. (For more information on this disorder, choose “Marfan” as your search term in the Rare Disease Database.)Pachydermoperiostosis is a rare disorder characterized by clubbing of the fingers, thickening of the skin of the face (pachyderma), and excessive sweating (hyperhidrosis). It typically appears during childhood or adolescence, often around the time of puberty, and progresses slowly for about ten years. Specific symptoms include enlargement of the fingers and toes (clubbing), a condition in which there is a fibrous covering on the ends of the long bones (periostosis), coarse facial features, increased bulk of the skin on the scalp forming folds, depressions or furrows of the scalp (cutis verticis gyrata) and/or excessive sweating of the hands and feet. Pachydermoperiostosis is thought to be inherited in an autosomal dominant or recessive pattern. (For more information on this disorder, choose “pachydermoperiostosis” as your search term in the Rare Disease Database.) | Related disorders of Acromegaly. Symptoms of the following disorders can be similar to those of acromegaly. Comparisons may be useful for a differential diagnosis:Gigantism is an abnormal condition characterized by excessive height and size. This disorder typically occurs before puberty as a result of the over secretion of growth hormone by the pituitary gland. Gigantism is associated with enlarged soft tissues and late closure of the epiphyses (heads of the long bones), which results in excessive growth during childhood. Height may reach 7 or 8 feet. Low levels of gonadotropin (gonad stimulating) hormones may be secreted by the pituitary gland later in the course of this disorder and result in low levels of hormone secretions by the ovaries or testes. Sexual development may be normal or it may be affected by the low levels of circulating sex hormones. Some children with gigantism may experience tingling and/or burning sensations in the arms and/or legs (peripheral neuropathy).Marfan syndrome is a genetic disorder that affects connective tissue, which is the material between cells of the body that gives the tissues form and strength. Connective tissue is found all over the body and multiple organ systems may be affected in individuals with Marfan syndrome. The heart and blood vessels (cardiovascular), skeletal, and eye (ocular) systems are most often affected. Major symptoms include overgrowth of the long bones of the arms and legs, abnormal side-to-side curvature of the spine (scoliosis), indentation or protrusion of the chest wall (pectus), dislocation of the lenses of the eyes (ectopia lentis), nearsightedness (myopia), widening (aneurysm) and degeneration of the main artery that carries blood away from the heart (aorta), floppiness of the mitral valve (mitral valve prolapse) and backward flow of blood through the aortic and mitral valves (aortic and mitral regurgitation). The specific symptoms and the severity of Marfan syndrome vary greatly from person to person. Marfan syndrome is inherited in an autosomal dominant pattern. Changes (mutations) in the fibrillin-1 (FBN1) gene cause Marfan syndrome and related disorders. (For more information on this disorder, choose “Marfan” as your search term in the Rare Disease Database.)Pachydermoperiostosis is a rare disorder characterized by clubbing of the fingers, thickening of the skin of the face (pachyderma), and excessive sweating (hyperhidrosis). It typically appears during childhood or adolescence, often around the time of puberty, and progresses slowly for about ten years. Specific symptoms include enlargement of the fingers and toes (clubbing), a condition in which there is a fibrous covering on the ends of the long bones (periostosis), coarse facial features, increased bulk of the skin on the scalp forming folds, depressions or furrows of the scalp (cutis verticis gyrata) and/or excessive sweating of the hands and feet. Pachydermoperiostosis is thought to be inherited in an autosomal dominant or recessive pattern. (For more information on this disorder, choose “pachydermoperiostosis” as your search term in the Rare Disease Database.) | 21 | Acromegaly |
nord_21_5 | Diagnosis of Acromegaly | A diagnosis of acromegaly is sometimes difficult to make because the development of symptoms occurs slowly over several years. A diagnosis is made based upon a detailed patient history, a thorough clinical evaluation, identification of characteristic findings and specialized tests such as blood tests, a glucose tolerance test, magnetic resonance imaging (MRI) or computerized tomography (CT).Physicians may test the blood for elevated levels of growth hormone or IGF-1 (insulin growth factor) associated with acromegaly. Measurement of IGF-I is the most accurate available screening blood test. Measurement of growth hormone is often done in conjunction with a glucose tolerance test. During a glucose tolerance test, individuals ingest a specific amount of sugar that should lower GH levels in the blood. In individuals with overproduction of growth hormone, this reduction does not occur.Physicians may also order an MRI, preferably, or CT scan of the brain to reveal the presence and size of a pituitary tumor. During MRI, a magnetic field and radio waves are used to create cross-sectional images of organs and structures in the body. During CT scanning, a computer and X-rays are used to create a film showing cross-sectional images of an organ’s tissue structure.Additional tests may be performed to assess the extent of acromegaly in an individual including echocardiography to evaluate whether the heart is involved, tests to determine whether sleep apnea is present and a colonoscopy to assess the health of the colon and establish a baseline for further testing. Patients with acromegaly may be at increased risk for bone fractures, and testing with X-rays or assessment of bone mineral density with a DXA (dual X-ray absorptiometry) scan may be ordered. | Diagnosis of Acromegaly. A diagnosis of acromegaly is sometimes difficult to make because the development of symptoms occurs slowly over several years. A diagnosis is made based upon a detailed patient history, a thorough clinical evaluation, identification of characteristic findings and specialized tests such as blood tests, a glucose tolerance test, magnetic resonance imaging (MRI) or computerized tomography (CT).Physicians may test the blood for elevated levels of growth hormone or IGF-1 (insulin growth factor) associated with acromegaly. Measurement of IGF-I is the most accurate available screening blood test. Measurement of growth hormone is often done in conjunction with a glucose tolerance test. During a glucose tolerance test, individuals ingest a specific amount of sugar that should lower GH levels in the blood. In individuals with overproduction of growth hormone, this reduction does not occur.Physicians may also order an MRI, preferably, or CT scan of the brain to reveal the presence and size of a pituitary tumor. During MRI, a magnetic field and radio waves are used to create cross-sectional images of organs and structures in the body. During CT scanning, a computer and X-rays are used to create a film showing cross-sectional images of an organ’s tissue structure.Additional tests may be performed to assess the extent of acromegaly in an individual including echocardiography to evaluate whether the heart is involved, tests to determine whether sleep apnea is present and a colonoscopy to assess the health of the colon and establish a baseline for further testing. Patients with acromegaly may be at increased risk for bone fractures, and testing with X-rays or assessment of bone mineral density with a DXA (dual X-ray absorptiometry) scan may be ordered. | 21 | Acromegaly |
nord_21_6 | Therapies of Acromegaly | TreatmentThe treatment of acromegaly is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. The goals of treatment of acromegaly are to return growth hormone levels to normal, decrease the size of a pituitary adenoma (if present) thereby relieving pressure on the surrounding tissue, maintain normal pituitary function and reverse or improve associated symptoms.Acromegaly is usually treated by surgery, medications and/or radiation therapy. No single therapeutic option is effective for everyone. An individual’s specific treatment plan will based on several factors including the size and location of the pituitary tumor; the presence or absence of certain symptoms; an individual’s age and general health; and/or other issues. Decisions concerning the use of particular therapies should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.Acromegaly is usually treated by transsphenoidal surgery; a procedure in which all or part of a pituitary tumor is removed. Surgery often results in a rapid therapeutic response, immediately relieving pressure on surrounding brain structures and lowering growth hormone levels. When surgery is successful, soft tissue swelling may decrease in just a few days. Surgery is more effective in individuals with small tumors (microadenomas) than in those with large tumors (macroadenomas). Surgery may not successfully improve all symptoms (e.g., headaches may persist) and, in some patients, removal of the entire tumor may not be possible, resulting in growth hormone levels that remain too high.Individuals treated by surgery should be periodically monitored by a physician because of the possible recurrence of the disorder. In some patients, surgery will improve the hormone levels, but not return them to normal, which necessitates further treatment, often with medications.Certain medications may be used to treat individuals with acromegaly. Medical therapy may be recommended in individuals in whom surgery in contraindicated, in whom surgery did not work or failed to return hormone levels to normal or to shrink large tumors before surgery.Three different classes of medications are often used to treat individuals with acromegaly. These are somatostatin analogues including octreotide, lanreotide and pasireotide; growth hormone receptor antagonists such as pegvisomant; and dopamine antagonists.The U.S. Food and Drug Administration (FDA) approved the drug octreotide acetate (Sandostatin® LAR) for its use in the treatment of acromegaly. Octreotide is an artificially produced (synthetic) compound similar to somatostatin (somatostatin analog), a natural hormone produced by the hypothalamus that serves to inhibit the secretion of growth hormone. (The hypothalamus is an area of the brain that plays a role in coordinating hormone function.) Treatment with octreotide has demonstrated decreases in serum levels of GH and IGF-I and tumor shrinkage in some patients receiving the drug. Safety and efficacy studies have been extensively published with decades of experience in treating patients with acromegaly.The FDA has approved Somatuline® Depot (lanreotide) Injection for the treatment of acromegaly. The FDA approved Somatuline® Depot (lanreotide) Injection for the long-term treatment of individuals with acromegaly who have had inadequate response to or cannot be treated with surgery and/or radiation therapy. This treatment lowers the levels of GH and IGF-I.The FDA has approved an oral formulation of octreotide, (Mycapssa®) for its use in the treatment of acromegaly. The drug is administered twice daily and is indicated for the treatment of patients who have responded to and tolerated treatment with octreotide or lanreotide. This drug has been shown in clinical trials to maintain control of GH and IGF-I levels in patients with acromegaly previously treated with somatostatin analog therapy.The FDA has approved the drug pasireotide (Signifor LAR®) for injectable suspension in the treatment of acromegaly. Pasireotide is indicated for patients who have had an inadequate response to surgery or for whom surgery is not an option. Similar to octreotide and lanreotide, pasireotide acts on the somatostatin receptors, with interactions with somatostatin receptor subtypes 1, 2, 3, and 5. Recent publications have demonstrated the safety and efficacy of pasireotide in comparison to octreotide LAR in a randomized, double-blind clinical trial, open label extension studies and crossover studies comparing pasireotide to octreotide or lanreotide.The FDA has approved the orphan drug Somavert® (pegvisomant for injection) for the treatment of acromegaly in individuals who have had an inadequate response to surgery and/or radiation therapy and/or other medical therapies or for whom these therapies are not appropriate. Somavert, which blocks the effects of excess growth hormone in acromegaly, is administered by subcutaneous injection.The third class of medications sometimes used to treat individuals with acromegaly is dopamine agonists. However, these drugs, which include bromocriptine and cabergoline, are generally effective for fewer individuals than other medications. Physicians may prescribe these medications in conjunction with other medications used to treat acromegaly.Surgery and drug therapy may be supplemented by radiation treatment (proton beam, heavy particle, and supravoltage irradiation.) Radiation therapy is most often used in individuals in whom surgery has failed to sufficiently reduce tumor size or growth hormone levels. Conventional fractionated radiation therapy usually requires daily treatments over a four to six week period and may reduce growth hormones levels by 50 percent, but successful results may not occur until two to five years later. Because results are delayed, radiation therapy is rarely used to treat acromegaly without combining it with surgery or drug therapy.After initial therapies, individuals with acromegaly need to be routinely monitored by a physician to ensure that the pituitary is functioning normally and that the existing symptoms continue to improve. Titration of medications may be necessary to optimally control hormone levels.In addition to conventional radiation therapy described above, some individuals may be treated by other forms radiotherapy. These forms of radiotherapy offer more precise targeting of high-beam radiation delivered at varying angles. This option limits the damage to surrounding tissue and can be delivered in a single session. A person is not eligible for this form of radiotherapy if the pituitary tumor is not at least 5mm away from the spot where the optic nerves from eyes cross at the base of the brain (optic chiasm). More research is necessary to determine the long-term safety and effective of this form of therapy for individuals with acromegaly. | Therapies of Acromegaly. TreatmentThe treatment of acromegaly is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. The goals of treatment of acromegaly are to return growth hormone levels to normal, decrease the size of a pituitary adenoma (if present) thereby relieving pressure on the surrounding tissue, maintain normal pituitary function and reverse or improve associated symptoms.Acromegaly is usually treated by surgery, medications and/or radiation therapy. No single therapeutic option is effective for everyone. An individual’s specific treatment plan will based on several factors including the size and location of the pituitary tumor; the presence or absence of certain symptoms; an individual’s age and general health; and/or other issues. Decisions concerning the use of particular therapies should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.Acromegaly is usually treated by transsphenoidal surgery; a procedure in which all or part of a pituitary tumor is removed. Surgery often results in a rapid therapeutic response, immediately relieving pressure on surrounding brain structures and lowering growth hormone levels. When surgery is successful, soft tissue swelling may decrease in just a few days. Surgery is more effective in individuals with small tumors (microadenomas) than in those with large tumors (macroadenomas). Surgery may not successfully improve all symptoms (e.g., headaches may persist) and, in some patients, removal of the entire tumor may not be possible, resulting in growth hormone levels that remain too high.Individuals treated by surgery should be periodically monitored by a physician because of the possible recurrence of the disorder. In some patients, surgery will improve the hormone levels, but not return them to normal, which necessitates further treatment, often with medications.Certain medications may be used to treat individuals with acromegaly. Medical therapy may be recommended in individuals in whom surgery in contraindicated, in whom surgery did not work or failed to return hormone levels to normal or to shrink large tumors before surgery.Three different classes of medications are often used to treat individuals with acromegaly. These are somatostatin analogues including octreotide, lanreotide and pasireotide; growth hormone receptor antagonists such as pegvisomant; and dopamine antagonists.The U.S. Food and Drug Administration (FDA) approved the drug octreotide acetate (Sandostatin® LAR) for its use in the treatment of acromegaly. Octreotide is an artificially produced (synthetic) compound similar to somatostatin (somatostatin analog), a natural hormone produced by the hypothalamus that serves to inhibit the secretion of growth hormone. (The hypothalamus is an area of the brain that plays a role in coordinating hormone function.) Treatment with octreotide has demonstrated decreases in serum levels of GH and IGF-I and tumor shrinkage in some patients receiving the drug. Safety and efficacy studies have been extensively published with decades of experience in treating patients with acromegaly.The FDA has approved Somatuline® Depot (lanreotide) Injection for the treatment of acromegaly. The FDA approved Somatuline® Depot (lanreotide) Injection for the long-term treatment of individuals with acromegaly who have had inadequate response to or cannot be treated with surgery and/or radiation therapy. This treatment lowers the levels of GH and IGF-I.The FDA has approved an oral formulation of octreotide, (Mycapssa®) for its use in the treatment of acromegaly. The drug is administered twice daily and is indicated for the treatment of patients who have responded to and tolerated treatment with octreotide or lanreotide. This drug has been shown in clinical trials to maintain control of GH and IGF-I levels in patients with acromegaly previously treated with somatostatin analog therapy.The FDA has approved the drug pasireotide (Signifor LAR®) for injectable suspension in the treatment of acromegaly. Pasireotide is indicated for patients who have had an inadequate response to surgery or for whom surgery is not an option. Similar to octreotide and lanreotide, pasireotide acts on the somatostatin receptors, with interactions with somatostatin receptor subtypes 1, 2, 3, and 5. Recent publications have demonstrated the safety and efficacy of pasireotide in comparison to octreotide LAR in a randomized, double-blind clinical trial, open label extension studies and crossover studies comparing pasireotide to octreotide or lanreotide.The FDA has approved the orphan drug Somavert® (pegvisomant for injection) for the treatment of acromegaly in individuals who have had an inadequate response to surgery and/or radiation therapy and/or other medical therapies or for whom these therapies are not appropriate. Somavert, which blocks the effects of excess growth hormone in acromegaly, is administered by subcutaneous injection.The third class of medications sometimes used to treat individuals with acromegaly is dopamine agonists. However, these drugs, which include bromocriptine and cabergoline, are generally effective for fewer individuals than other medications. Physicians may prescribe these medications in conjunction with other medications used to treat acromegaly.Surgery and drug therapy may be supplemented by radiation treatment (proton beam, heavy particle, and supravoltage irradiation.) Radiation therapy is most often used in individuals in whom surgery has failed to sufficiently reduce tumor size or growth hormone levels. Conventional fractionated radiation therapy usually requires daily treatments over a four to six week period and may reduce growth hormones levels by 50 percent, but successful results may not occur until two to five years later. Because results are delayed, radiation therapy is rarely used to treat acromegaly without combining it with surgery or drug therapy.After initial therapies, individuals with acromegaly need to be routinely monitored by a physician to ensure that the pituitary is functioning normally and that the existing symptoms continue to improve. Titration of medications may be necessary to optimally control hormone levels.In addition to conventional radiation therapy described above, some individuals may be treated by other forms radiotherapy. These forms of radiotherapy offer more precise targeting of high-beam radiation delivered at varying angles. This option limits the damage to surrounding tissue and can be delivered in a single session. A person is not eligible for this form of radiotherapy if the pituitary tumor is not at least 5mm away from the spot where the optic nerves from eyes cross at the base of the brain (optic chiasm). More research is necessary to determine the long-term safety and effective of this form of therapy for individuals with acromegaly. | 21 | Acromegaly |
nord_22_0 | Overview of Acromesomelic Dysplasia | Acromesomelic dysplasia is an extremely rare, inherited, progressive skeletal disorder that results in a particular form of short stature known as short-limb dwarfism. The disorder is characterized by acromelia and mesomelia. Mesomelia describes the shortening of the bones of the forearms and lower legs relative to the upper parts of those limbs. Acromelia is the shortening of the bones of the hands and feet. Thus, the short stature of affected individuals is the result of unusually short forearms and abnormal shortening of bones of the lower legs. The very short hands, fingers, feet, and toes are characteristic. These findings are apparent during the first years of life. | Overview of Acromesomelic Dysplasia. Acromesomelic dysplasia is an extremely rare, inherited, progressive skeletal disorder that results in a particular form of short stature known as short-limb dwarfism. The disorder is characterized by acromelia and mesomelia. Mesomelia describes the shortening of the bones of the forearms and lower legs relative to the upper parts of those limbs. Acromelia is the shortening of the bones of the hands and feet. Thus, the short stature of affected individuals is the result of unusually short forearms and abnormal shortening of bones of the lower legs. The very short hands, fingers, feet, and toes are characteristic. These findings are apparent during the first years of life. | 22 | Acromesomelic Dysplasia |
nord_22_1 | Symptoms of Acromesomelic Dysplasia | Acromesomelic dysplasia (AMD) is characterized by inhibition of growth of certain long bones (i.e. bones of the forearms and lower legs). As a result, affected individuals exhibit unusually short forearms and lower legs and short stature (short-limbed dwarfism). These findings typically become apparent during the first years of life. Abnormal cartilage and bone development also affect other bones, particularly those of the hands and feet (i.e. metacarpals, phalanges, metatarsals).Infants with acromesomelic dysplasia often have a normal birth weight. In most cases, in addition to having unusually short, broad hands and feet, affected infants often have characteristic facial abnormalities that are apparent at birth. Such features may include a relatively enlarged head (macrocephaly), unusually prominent forehead (frontal bossing), and pronounced back portion of the head (occipital prominence); a slightly flattened midface; and/or an abnormally small, pug nose.During the first years of life, as the forearms, lower legs, hands, and feet do not grow proportionally with the rest of the body, short stature (short-limbed dwarfism) begins to become apparent. Due to abnormal development and premature fusion (ossification) of the growth portions and the shafts of the long bones of the arm, the bones on the outer aspect and the thumb side of the forearm (ulna and radius, respectively) may be markedly shortened (hypoplastic) and abnormally curved. In addition, the end portion of the radius (that normally meets with the bone of the upper arm [humerus] to form part of the elbow joint) may be completely or partially dislocated (subluxation). This is known as Madelung deformity. As a result, affected individuals may be unable to fully extend their arms, rotate the arms so the palms face down (pronation), or rotate their arms so the palms face upward (supination). Some affected individuals may also experience progressive degeneration, stiffness, tenderness, and pain of the elbows (osteoarthritis).The hands and feet appear unusually short and broad at birth. Because the abnormalities of cartilage and bone development in the hands and feet are also progressive, the bones within the fingers and toes (phalanges), as well as in the body of the hands (metacarpals) and feet (metatarsals), become increasingly shorter and broader during the first years of life. During the second year of life, the growing ends of these bones (epiphyses) may begin to appear abnormally shaped like a cone or a square and may fuse prematurely. Thus, the fingers and toes appear short and stubby (brachydactyly); the hands and feet may seem unusually short, broad, and square; and the feet may appear abnormally flat. In many individuals, the great toes may appear relatively large in comparison to the other toes. In addition, the fingernails and toenails may also appear abnormally short and broad, though they are otherwise normal. In early childhood, extra, loose (redundant) skin may develop over the fingers.During early childhood, individuals with AMD may also begin to demonstrate abnormalities of bones of the spinal column (vertebrae) and to experience progressive, abnormal curvature of the spine. Affected children may demonstrate unusual front-to-back curvature of the central portion of the spine (low thoracic kyphosis) and/or abnormally exaggerated inward curvature of the lower spine (lumbar hyperlordosis).In rare cases, additional abnormalities may be present. For example, some individuals with AMD experience delayed puberty and, in a few reported cases, affected children have demonstrated corneal clouding. | Symptoms of Acromesomelic Dysplasia. Acromesomelic dysplasia (AMD) is characterized by inhibition of growth of certain long bones (i.e. bones of the forearms and lower legs). As a result, affected individuals exhibit unusually short forearms and lower legs and short stature (short-limbed dwarfism). These findings typically become apparent during the first years of life. Abnormal cartilage and bone development also affect other bones, particularly those of the hands and feet (i.e. metacarpals, phalanges, metatarsals).Infants with acromesomelic dysplasia often have a normal birth weight. In most cases, in addition to having unusually short, broad hands and feet, affected infants often have characteristic facial abnormalities that are apparent at birth. Such features may include a relatively enlarged head (macrocephaly), unusually prominent forehead (frontal bossing), and pronounced back portion of the head (occipital prominence); a slightly flattened midface; and/or an abnormally small, pug nose.During the first years of life, as the forearms, lower legs, hands, and feet do not grow proportionally with the rest of the body, short stature (short-limbed dwarfism) begins to become apparent. Due to abnormal development and premature fusion (ossification) of the growth portions and the shafts of the long bones of the arm, the bones on the outer aspect and the thumb side of the forearm (ulna and radius, respectively) may be markedly shortened (hypoplastic) and abnormally curved. In addition, the end portion of the radius (that normally meets with the bone of the upper arm [humerus] to form part of the elbow joint) may be completely or partially dislocated (subluxation). This is known as Madelung deformity. As a result, affected individuals may be unable to fully extend their arms, rotate the arms so the palms face down (pronation), or rotate their arms so the palms face upward (supination). Some affected individuals may also experience progressive degeneration, stiffness, tenderness, and pain of the elbows (osteoarthritis).The hands and feet appear unusually short and broad at birth. Because the abnormalities of cartilage and bone development in the hands and feet are also progressive, the bones within the fingers and toes (phalanges), as well as in the body of the hands (metacarpals) and feet (metatarsals), become increasingly shorter and broader during the first years of life. During the second year of life, the growing ends of these bones (epiphyses) may begin to appear abnormally shaped like a cone or a square and may fuse prematurely. Thus, the fingers and toes appear short and stubby (brachydactyly); the hands and feet may seem unusually short, broad, and square; and the feet may appear abnormally flat. In many individuals, the great toes may appear relatively large in comparison to the other toes. In addition, the fingernails and toenails may also appear abnormally short and broad, though they are otherwise normal. In early childhood, extra, loose (redundant) skin may develop over the fingers.During early childhood, individuals with AMD may also begin to demonstrate abnormalities of bones of the spinal column (vertebrae) and to experience progressive, abnormal curvature of the spine. Affected children may demonstrate unusual front-to-back curvature of the central portion of the spine (low thoracic kyphosis) and/or abnormally exaggerated inward curvature of the lower spine (lumbar hyperlordosis).In rare cases, additional abnormalities may be present. For example, some individuals with AMD experience delayed puberty and, in a few reported cases, affected children have demonstrated corneal clouding. | 22 | Acromesomelic Dysplasia |
nord_22_2 | Causes of Acromesomelic Dysplasia | There are thought to be five types of acromesomelic dysplasia. Each is extremely rare, and each is inherited as an autosomal recessive genetic trait, except for AMD Osebold-Remondini type, which appears to be autosomal dominant. The Maroteaux type has been traced to chromosome 9 at gene map locus 9p13-12. Grebe dysplasia (including AMD Hunter-Thompson type) and Du Pan syndrome all have each been mapped to chromosome 20 at gene map locus 20q11.2. Acromesomelic dysplasia with genital anomalies maps to 4q23-24. Osebold-Remondini type has not been genetically mapped yet.Genetic studies indicate that the change (mutation) at chromosome 9p13-12 (AMD Maroteaux type) is in a gene that codes for a protein the affects bone development, natriuretic peptide receptor B (NPR-B). This is a receptor (a protein that binds another protein) for a hormone called C-type natriuretic peptide, a hormone that is very important for bone growth. The gene located at chromosome 20q11.2 (Grebe dysplasia) codes for a protein known as growth and development factor-5 (GDF5, previously named cartilage-derived morphogenetic protein-1, CDMP1). The gene located at chromosome 4q23-24 (AMD with genital anomalies) codes for a protein known as bone morphogenetic protein receptor, type 1B (BMPR1B). This is a receptor for GDF5.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 9p13-12” refers to a region on the short arm of chromosome 9 between bands 13 and 12. 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.Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females. | Causes of Acromesomelic Dysplasia. There are thought to be five types of acromesomelic dysplasia. Each is extremely rare, and each is inherited as an autosomal recessive genetic trait, except for AMD Osebold-Remondini type, which appears to be autosomal dominant. The Maroteaux type has been traced to chromosome 9 at gene map locus 9p13-12. Grebe dysplasia (including AMD Hunter-Thompson type) and Du Pan syndrome all have each been mapped to chromosome 20 at gene map locus 20q11.2. Acromesomelic dysplasia with genital anomalies maps to 4q23-24. Osebold-Remondini type has not been genetically mapped yet.Genetic studies indicate that the change (mutation) at chromosome 9p13-12 (AMD Maroteaux type) is in a gene that codes for a protein the affects bone development, natriuretic peptide receptor B (NPR-B). This is a receptor (a protein that binds another protein) for a hormone called C-type natriuretic peptide, a hormone that is very important for bone growth. The gene located at chromosome 20q11.2 (Grebe dysplasia) codes for a protein known as growth and development factor-5 (GDF5, previously named cartilage-derived morphogenetic protein-1, CDMP1). The gene located at chromosome 4q23-24 (AMD with genital anomalies) codes for a protein known as bone morphogenetic protein receptor, type 1B (BMPR1B). This is a receptor for GDF5.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 9p13-12” refers to a region on the short arm of chromosome 9 between bands 13 and 12. 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.Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females. | 22 | Acromesomelic Dysplasia |
nord_22_3 | Affects of Acromesomelic Dysplasia | As of 2005, there were about 10 affected individuals of Hunter-Thompson type ADM and about 40 to 50 patients of Maroteaux type AMD reported in the medical literature. The number of cases of Grebe type ADM is not known, but that type is believed to be almost entirely limited to persons living in Brazil. | Affects of Acromesomelic Dysplasia. As of 2005, there were about 10 affected individuals of Hunter-Thompson type ADM and about 40 to 50 patients of Maroteaux type AMD reported in the medical literature. The number of cases of Grebe type ADM is not known, but that type is believed to be almost entirely limited to persons living in Brazil. | 22 | Acromesomelic Dysplasia |
nord_22_4 | Related disorders of Acromesomelic Dysplasia | Achondroplasia is the most common disorder of short-limbed dwarfism. Affected individuals have arms and legs that are very short, while the torso is more nearly normal in size. During fetal development and childhood, cartilage normally develops into bone, except in a few places, such as the nose and ears. In individuals with achondroplasia, something goes wrong during this process, especially in the long bones (such as those of the upper arms and thighs). The rate at which cartilage cells in the growth plates of the long bones turn into bone is slow, leading to short bones and reduced height. This syndrome is caused by specific mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. Achondroplasia differs from AMD in that the upper bones of the arms and legs (the humerus and femur) are the most affected in achondroplasia, while it is the lower bones (radius and ulna in the arm, tibia and fibula in the leg) and the hands and the feet that are the most affected in AMD. (For more information on this disorder, choose “ Achondroplasia ” as your search term in the Rare Disease Database.)Acrodysostosis is an extremely rare disorder characterized by abnormally short, malformed bones of the hands and feet (peripheral dysostosis), abnormally short fingers and toes (brachydactyly), malformation and shortening of the forearm bones (radius and ulna), and progressive growth retardation, resulting in short-limbed dwarfism. As children with the disorder grow older, they may experience progressively impaired and limited movements of the hands, feet, and/or elbows as well as pain and swelling in various joints (arthritis) of the body. Affected individuals also exhibit characteristic malformations of the head and facial (craniofacial) area including an abnormally flat, underdeveloped (hypoplastic) “pug” nose, an underdeveloped upper jaw bone (maxillary hypoplasia), widely spaced eyes (ocular hypertelorism), and/or extra folds of skin that may partially cover the eyes’ inner corners (epicanthal folds). Intellectual disability may also be present. In most cases, acrodysostosis is thought to occur randomly, for unknown reasons (sporadic). (For more information on this disorder, choose “Acrodysostosis” as your search term in the Rare Disease Database.)Acromicric dysplasia is another extremely rare inherited disorder characterized by abnormally short hands and feet, growth retardation and delayed bone maturation leading to short-limbed dwarfism, and mild facial abnormalities. Craniofacial malformations may include an abnormally narrow opening between the upper and lower eyelids (palpebral fissures) and a short nose with upturned (anteverted) nostrils. In most cases, acromicric dysplasia appears to occur randomly, for unknown reasons (sporadically). However, autosomal dominant inheritance has not been ruled out. (For more information on this disorder, choose “Acromicric Dysplasia” as your search term in the Rare Disease Database.)There are several syndromes of isolated shortening of the bones in the hands and feet, known as brachydactyly. Two of these syndromes, brachydactyly types A2 and C are also caused by mutations in the GDF5 gene.Short stature may be the normal expression of genetic potential, in which case the growth rate is normal, or it may be the result of a condition causing growth failure with a lower-than-normal growth rate. Growth failure is the term that describes a growth rate below the appropriate growth velocity for age.A child is considered short if he or she has a height that is below the fifth percentile; alternatively, some define short stature as height less than 2 standard deviations below the mean, which is near the third percentile. Thus, 3-5% of all children are considered short. Many of these children actually have normal growth velocity. These short children include those with familial short stature or constitutional delay in growth and maturation. In order to maintain the same height percentile on the growth chart, growth velocity must be at least at the 25th percentile. When considering all children with short stature, only a few actually have a specific treatable diagnosis, such as growth hormone deficiency or hypothyroidism. Most of these are children with a slow growth velocity. | Related disorders of Acromesomelic Dysplasia. Achondroplasia is the most common disorder of short-limbed dwarfism. Affected individuals have arms and legs that are very short, while the torso is more nearly normal in size. During fetal development and childhood, cartilage normally develops into bone, except in a few places, such as the nose and ears. In individuals with achondroplasia, something goes wrong during this process, especially in the long bones (such as those of the upper arms and thighs). The rate at which cartilage cells in the growth plates of the long bones turn into bone is slow, leading to short bones and reduced height. This syndrome is caused by specific mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. Achondroplasia differs from AMD in that the upper bones of the arms and legs (the humerus and femur) are the most affected in achondroplasia, while it is the lower bones (radius and ulna in the arm, tibia and fibula in the leg) and the hands and the feet that are the most affected in AMD. (For more information on this disorder, choose “ Achondroplasia ” as your search term in the Rare Disease Database.)Acrodysostosis is an extremely rare disorder characterized by abnormally short, malformed bones of the hands and feet (peripheral dysostosis), abnormally short fingers and toes (brachydactyly), malformation and shortening of the forearm bones (radius and ulna), and progressive growth retardation, resulting in short-limbed dwarfism. As children with the disorder grow older, they may experience progressively impaired and limited movements of the hands, feet, and/or elbows as well as pain and swelling in various joints (arthritis) of the body. Affected individuals also exhibit characteristic malformations of the head and facial (craniofacial) area including an abnormally flat, underdeveloped (hypoplastic) “pug” nose, an underdeveloped upper jaw bone (maxillary hypoplasia), widely spaced eyes (ocular hypertelorism), and/or extra folds of skin that may partially cover the eyes’ inner corners (epicanthal folds). Intellectual disability may also be present. In most cases, acrodysostosis is thought to occur randomly, for unknown reasons (sporadic). (For more information on this disorder, choose “Acrodysostosis” as your search term in the Rare Disease Database.)Acromicric dysplasia is another extremely rare inherited disorder characterized by abnormally short hands and feet, growth retardation and delayed bone maturation leading to short-limbed dwarfism, and mild facial abnormalities. Craniofacial malformations may include an abnormally narrow opening between the upper and lower eyelids (palpebral fissures) and a short nose with upturned (anteverted) nostrils. In most cases, acromicric dysplasia appears to occur randomly, for unknown reasons (sporadically). However, autosomal dominant inheritance has not been ruled out. (For more information on this disorder, choose “Acromicric Dysplasia” as your search term in the Rare Disease Database.)There are several syndromes of isolated shortening of the bones in the hands and feet, known as brachydactyly. Two of these syndromes, brachydactyly types A2 and C are also caused by mutations in the GDF5 gene.Short stature may be the normal expression of genetic potential, in which case the growth rate is normal, or it may be the result of a condition causing growth failure with a lower-than-normal growth rate. Growth failure is the term that describes a growth rate below the appropriate growth velocity for age.A child is considered short if he or she has a height that is below the fifth percentile; alternatively, some define short stature as height less than 2 standard deviations below the mean, which is near the third percentile. Thus, 3-5% of all children are considered short. Many of these children actually have normal growth velocity. These short children include those with familial short stature or constitutional delay in growth and maturation. In order to maintain the same height percentile on the growth chart, growth velocity must be at least at the 25th percentile. When considering all children with short stature, only a few actually have a specific treatable diagnosis, such as growth hormone deficiency or hypothyroidism. Most of these are children with a slow growth velocity. | 22 | Acromesomelic Dysplasia |
nord_22_5 | Diagnosis of Acromesomelic Dysplasia | In most patients, acromesomelic dysplasia is diagnosed within the first few years of life based upon a thorough clinical evaluation, detailed patient history, identification of characteristic findings, and advanced imaging techniques. Although the hands and feet may appear unusually short and broad at birth, the progressive abnormalities associated with the disorder (e.g. abnormal shortening of bones in the forearms and lower legs and short stature, further shortening and broadening of bones of the hands and feet, progressive vertebral abnormalities, limited elbow and arm extension, etc.) typically do not become apparent until late infancy or early childhood.Specialized x-ray studies may confirm the abnormal development and premature fusion of the regions where the shafts (diaphyses) of certain long bones (i.e. bones of the arms and legs) meet their growing ends (epiphyses). In addition, they may reveal abnormal fusion of the growing ends of bones within the fingers, toes, hands, and feet (i.e. phalanges, metacarpals, metatarsals). Such studies may also confirm the presence and/or extent of resulting bone abnormalities (e.g. short, bowed ulna and radius, dislocated or subluxated radial head, short, malformed phalanges, etc.) as well as other skeletal abnormalities that may be associated with acromesomelic dysplasia (e.g. vertebral abnormalities and resulting low thoracic kyphosis and/or lumbar hyperlordosis; hypoplastic ilia; etc.). | Diagnosis of Acromesomelic Dysplasia. In most patients, acromesomelic dysplasia is diagnosed within the first few years of life based upon a thorough clinical evaluation, detailed patient history, identification of characteristic findings, and advanced imaging techniques. Although the hands and feet may appear unusually short and broad at birth, the progressive abnormalities associated with the disorder (e.g. abnormal shortening of bones in the forearms and lower legs and short stature, further shortening and broadening of bones of the hands and feet, progressive vertebral abnormalities, limited elbow and arm extension, etc.) typically do not become apparent until late infancy or early childhood.Specialized x-ray studies may confirm the abnormal development and premature fusion of the regions where the shafts (diaphyses) of certain long bones (i.e. bones of the arms and legs) meet their growing ends (epiphyses). In addition, they may reveal abnormal fusion of the growing ends of bones within the fingers, toes, hands, and feet (i.e. phalanges, metacarpals, metatarsals). Such studies may also confirm the presence and/or extent of resulting bone abnormalities (e.g. short, bowed ulna and radius, dislocated or subluxated radial head, short, malformed phalanges, etc.) as well as other skeletal abnormalities that may be associated with acromesomelic dysplasia (e.g. vertebral abnormalities and resulting low thoracic kyphosis and/or lumbar hyperlordosis; hypoplastic ilia; etc.). | 22 | Acromesomelic Dysplasia |
nord_22_6 | Therapies of Acromesomelic Dysplasia | TreatmentThe treatment of acromesomelic dysplasia is directed toward the specific symptoms and physical characteristics that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, specialists who assess and treat skeletal abnormalities (orthopedists), physical therapists, and/or other health care professionals may need to systematically and comprehensively plan an affected child's treatment.Specific therapies for the treatment of acromesomelic dysplasia are symptomatic and supportive. Abnormal curvature of the spine (i.e. low thoracic kyphosis and/or lumbar hyperlordosis) may be treated with a combination of exercises and physical therapy, other supportive techniques, braces, casts, and/or, in severe cases, corrective surgery. Physical therapy, other supportive techniques, and/or orthopedic surgery may help correct certain specific findings associated with acromesomelic dysplasia.Early intervention is important to ensure that children with acromesomelic dysplasia reach their potential. Special services that may be beneficial to affected children may include social support and other medical, social, and/or vocational services.Genetic counseling is recommended for affected individuals and their families. Other treatment for this disorder is symptomatic and supportive. | Therapies of Acromesomelic Dysplasia. TreatmentThe treatment of acromesomelic dysplasia is directed toward the specific symptoms and physical characteristics that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, specialists who assess and treat skeletal abnormalities (orthopedists), physical therapists, and/or other health care professionals may need to systematically and comprehensively plan an affected child's treatment.Specific therapies for the treatment of acromesomelic dysplasia are symptomatic and supportive. Abnormal curvature of the spine (i.e. low thoracic kyphosis and/or lumbar hyperlordosis) may be treated with a combination of exercises and physical therapy, other supportive techniques, braces, casts, and/or, in severe cases, corrective surgery. Physical therapy, other supportive techniques, and/or orthopedic surgery may help correct certain specific findings associated with acromesomelic dysplasia.Early intervention is important to ensure that children with acromesomelic dysplasia reach their potential. Special services that may be beneficial to affected children may include social support and other medical, social, and/or vocational services.Genetic counseling is recommended for affected individuals and their families. Other treatment for this disorder is symptomatic and supportive. | 22 | Acromesomelic Dysplasia |
nord_23_0 | Overview of Acromicric Dysplasia | Acromicric Dysplasia is an extremely rare inherited disorder characterized by abnormally short hands and feet, growth retardation and delayed bone maturation leading to short stature, and mild facial abnormalities. Most cases have occurred randomly for no apparent reason (sporadically). However, autosomal dominant inheritance has not been ruled out. | Overview of Acromicric Dysplasia. Acromicric Dysplasia is an extremely rare inherited disorder characterized by abnormally short hands and feet, growth retardation and delayed bone maturation leading to short stature, and mild facial abnormalities. Most cases have occurred randomly for no apparent reason (sporadically). However, autosomal dominant inheritance has not been ruled out. | 23 | Acromicric Dysplasia |
nord_23_1 | Symptoms of Acromicric Dysplasia | Acromicric Dysplasia is an extremely rare inherited disorder that usually becomes apparent during late infancy. It is characterized by abnormally short hands and feet, growth delays leading to short stature, and mild facial abnormalities. Infants with Acromicric Dysplasia exhibit severe shortening of hands and feet. Certain bones in the hands and fingers (i.e., metacarpals and phalanges) as well as the feet and toes (i.e., metatarsals and phalanges) are abnormally short and stubby (brachydactyly). In addition, certain bones in the middle of the hand (metacarpals) may taper downward forming a point (with the exception of the thumb), while bones in the toes (phalanges) may be abnormally “cone shaped” (epiphyseal coning). The long bones (i.e., those of the arms and legs) may also be abnormally short and, in some cases, individuals may exhibit malformation of the end portion (head) of the thigh bone (femur). By early childhood, growth retardation and delayed bone maturation eventually result in short stature (dwarfism). Most affected individuals described in the medical literature attained an average adult height of about four feet (120 centimeters). Infants with Acromicric Dysplasia may also exhibit mild abnormalities of the face including an abnormally narrow opening between the upper and lower eyelids (palpebral fissures) and an abnormally short nose with upturned nostrils (anteverted). As affected individuals age, facial abnormalities become less obvious. Some adults with Acromicric Dysplasia have developed carpal tunnel syndrome. | Symptoms of Acromicric Dysplasia. Acromicric Dysplasia is an extremely rare inherited disorder that usually becomes apparent during late infancy. It is characterized by abnormally short hands and feet, growth delays leading to short stature, and mild facial abnormalities. Infants with Acromicric Dysplasia exhibit severe shortening of hands and feet. Certain bones in the hands and fingers (i.e., metacarpals and phalanges) as well as the feet and toes (i.e., metatarsals and phalanges) are abnormally short and stubby (brachydactyly). In addition, certain bones in the middle of the hand (metacarpals) may taper downward forming a point (with the exception of the thumb), while bones in the toes (phalanges) may be abnormally “cone shaped” (epiphyseal coning). The long bones (i.e., those of the arms and legs) may also be abnormally short and, in some cases, individuals may exhibit malformation of the end portion (head) of the thigh bone (femur). By early childhood, growth retardation and delayed bone maturation eventually result in short stature (dwarfism). Most affected individuals described in the medical literature attained an average adult height of about four feet (120 centimeters). Infants with Acromicric Dysplasia may also exhibit mild abnormalities of the face including an abnormally narrow opening between the upper and lower eyelids (palpebral fissures) and an abnormally short nose with upturned nostrils (anteverted). As affected individuals age, facial abnormalities become less obvious. Some adults with Acromicric Dysplasia have developed carpal tunnel syndrome. | 23 | Acromicric Dysplasia |
nord_23_2 | Causes of Acromicric Dysplasia | Acromicric Dysplasia is an extremely rare disorder that, in most cases, appears to occur randomly for no apparent reason (sporadically). However, autosomal dominant inheritance has not been ruled out. | Causes of Acromicric Dysplasia. Acromicric Dysplasia is an extremely rare disorder that, in most cases, appears to occur randomly for no apparent reason (sporadically). However, autosomal dominant inheritance has not been ruled out. | 23 | Acromicric Dysplasia |
nord_23_3 | Affects of Acromicric Dysplasia | Acromicric Dysplasia is an extremely rare disorder that, in theory, affects males and females in equal numbers. Only a very small number of cases have been reported in the medical literature. | Affects of Acromicric Dysplasia. Acromicric Dysplasia is an extremely rare disorder that, in theory, affects males and females in equal numbers. Only a very small number of cases have been reported in the medical literature. | 23 | Acromicric Dysplasia |
nord_23_4 | Related disorders of Acromicric Dysplasia | Symptoms of the following disorders can be similar to those of Acromicric Dysplasia. Comparisons may be useful for a differential diagnosis: Acrodysostosis is an extremely rare disorder characterized by abnormally short, malformed bones in the hands and feet (peripheral dysostosis), underdevelopment of the nose (nasal hypoplasia), and mental retardation. Other findings may include progressive growth delays, short stature, and/or additional abnormalities of the head and facial (craniofacial) area. Affected infants may exhibit early (premature) maturation of bones in the hands and feet, malformation and shortening of the forearm bones (radius and ulna) near the wrist, and/or abnormally short fingers and toes (brachydactyly). Characteristic facial features may include a flattened, underdeveloped (hypoplastic) “pug” nose, an underdeveloped upper jaw bone (maxilliary hypoplasia), widely spaced eyes (ocular hypertelorism), and/or an extra fold of skin on either side of the nose that may cover the eyes' inner corners (epicanthal folds). In most cases, Acrodysostosis is thought to occur randomly, for no apparent reason (sporadic). (For more information on this disorder, choose “Acrodysostosis” as your search term in the Rare Disease Database.) Leri Pleonosteosis is an extremely rare inherited disorder characterized by unusual, flattened facial features, abnormalities of the hands and feet, skeletal malformations, short stature, and/or limitation of joint movements. Characteristic abnormalities may include abnormally short broad fingers (brachydactyly); as a result, the hands may have a “spade-shaped” appearance. In addition, the toes may also be abnormally short and the great toes may be bent outward from the body (valgus position). Skeletal malformations may include knees that are bent backward (genu recurvitum) and abnormal enlargement of the cartilaginous structures that surround the upper portion of the spinal cord (posterior neural arches of the cervical vertebrae). In addition, affected individuals may develop thickened tissue on the palms (palmar) and forearms. Symptoms may vary from case to case. Leri Pleonosteosis is inherited as an autosomal dominant genetic trait. (For more information on this disorder, choose “Leri Pleonosteosis” as your search term in the Rare Disease Database.) Acromesomelic Dwarfism, also known as Acromesomelic Dysplasia, is a rare genetic disorder characterized by short stature and abnormally short hands and feet (brachydactyly). Certain bones of the hands (metacarpals), feet (metatarsals), and/or arms (radius) may be abnormally short and/or malformed. Characteristic facial features may include a short “pug” nose and/or an abnormally prominent of the forehead (frontal bossing). In some cases, affected individuals may exhibit front-to-back curvature of the spine (kyphosis). Acromesomelic Dwarfism is thought to be inherited as an autosomal recessive genetic trait. | Related disorders of Acromicric Dysplasia. Symptoms of the following disorders can be similar to those of Acromicric Dysplasia. Comparisons may be useful for a differential diagnosis: Acrodysostosis is an extremely rare disorder characterized by abnormally short, malformed bones in the hands and feet (peripheral dysostosis), underdevelopment of the nose (nasal hypoplasia), and mental retardation. Other findings may include progressive growth delays, short stature, and/or additional abnormalities of the head and facial (craniofacial) area. Affected infants may exhibit early (premature) maturation of bones in the hands and feet, malformation and shortening of the forearm bones (radius and ulna) near the wrist, and/or abnormally short fingers and toes (brachydactyly). Characteristic facial features may include a flattened, underdeveloped (hypoplastic) “pug” nose, an underdeveloped upper jaw bone (maxilliary hypoplasia), widely spaced eyes (ocular hypertelorism), and/or an extra fold of skin on either side of the nose that may cover the eyes' inner corners (epicanthal folds). In most cases, Acrodysostosis is thought to occur randomly, for no apparent reason (sporadic). (For more information on this disorder, choose “Acrodysostosis” as your search term in the Rare Disease Database.) Leri Pleonosteosis is an extremely rare inherited disorder characterized by unusual, flattened facial features, abnormalities of the hands and feet, skeletal malformations, short stature, and/or limitation of joint movements. Characteristic abnormalities may include abnormally short broad fingers (brachydactyly); as a result, the hands may have a “spade-shaped” appearance. In addition, the toes may also be abnormally short and the great toes may be bent outward from the body (valgus position). Skeletal malformations may include knees that are bent backward (genu recurvitum) and abnormal enlargement of the cartilaginous structures that surround the upper portion of the spinal cord (posterior neural arches of the cervical vertebrae). In addition, affected individuals may develop thickened tissue on the palms (palmar) and forearms. Symptoms may vary from case to case. Leri Pleonosteosis is inherited as an autosomal dominant genetic trait. (For more information on this disorder, choose “Leri Pleonosteosis” as your search term in the Rare Disease Database.) Acromesomelic Dwarfism, also known as Acromesomelic Dysplasia, is a rare genetic disorder characterized by short stature and abnormally short hands and feet (brachydactyly). Certain bones of the hands (metacarpals), feet (metatarsals), and/or arms (radius) may be abnormally short and/or malformed. Characteristic facial features may include a short “pug” nose and/or an abnormally prominent of the forehead (frontal bossing). In some cases, affected individuals may exhibit front-to-back curvature of the spine (kyphosis). Acromesomelic Dwarfism is thought to be inherited as an autosomal recessive genetic trait. | 23 | Acromicric Dysplasia |
nord_23_5 | Diagnosis of Acromicric Dysplasia | Acromicric Dysplasia may be diagnosed based upon a thorough clinical evaluation, characteristic physical findings (e.g., abnormally short hands), a detailed patient history, and a variety of specialized tests such as advanced imaging techniques. X-rays may reveal characteristic abnormalities of the bones in the hands and feet (e.g., abnormally short broad phalanges, metacarpals, and metatarsals; epiphyseal coning of the phalanges in the toes; pointing of the last four metacarpals; and the presence of an abnormal notch on the radial side of the 2nd metacarpal and ulnar side of the 5th metacarpal). The removal and study of cartilage cells (biopsy) under a microscope may reveal distinctive abnormalities affecting the growth cartilage. These abnormalities may include disorganization of the "growing" portion of certain bones, especially abnormal organization of cells that form cartilage (chondrocytes) and of a protein substance (collagen) that forms fibers within the ligaments, tendons, and connective tissue. In addition, an abnormally high number of such cells may demonstrate degeneration. | Diagnosis of Acromicric Dysplasia. Acromicric Dysplasia may be diagnosed based upon a thorough clinical evaluation, characteristic physical findings (e.g., abnormally short hands), a detailed patient history, and a variety of specialized tests such as advanced imaging techniques. X-rays may reveal characteristic abnormalities of the bones in the hands and feet (e.g., abnormally short broad phalanges, metacarpals, and metatarsals; epiphyseal coning of the phalanges in the toes; pointing of the last four metacarpals; and the presence of an abnormal notch on the radial side of the 2nd metacarpal and ulnar side of the 5th metacarpal). The removal and study of cartilage cells (biopsy) under a microscope may reveal distinctive abnormalities affecting the growth cartilage. These abnormalities may include disorganization of the "growing" portion of certain bones, especially abnormal organization of cells that form cartilage (chondrocytes) and of a protein substance (collagen) that forms fibers within the ligaments, tendons, and connective tissue. In addition, an abnormally high number of such cells may demonstrate degeneration. | 23 | Acromicric Dysplasia |
nord_23_6 | Therapies of Acromicric Dysplasia | TreatmentThe treatment of Acromicric Dysplasia is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, specialists who diagnose and treat skeletal abnormalities (orthopedists), physical therapists, and/or other health care professionals may need to systematically and comprehensively plan an affected child's treatment.Genetic counseling will be of benefit for affected individuals and their families. Other treatment for this disorder is symptomatic and supportive. | Therapies of Acromicric Dysplasia. TreatmentThe treatment of Acromicric Dysplasia is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, specialists who diagnose and treat skeletal abnormalities (orthopedists), physical therapists, and/or other health care professionals may need to systematically and comprehensively plan an affected child's treatment.Genetic counseling will be of benefit for affected individuals and their families. Other treatment for this disorder is symptomatic and supportive. | 23 | Acromicric Dysplasia |
nord_24_0 | Overview of ACTH Deficiency | ACTH deficiency arises as a result of decreased or absent production of adrenocorticotropic hormone (ACTH) by the pituitary gland. A decline in the concentration of ACTH in the blood leads to a reduction in the secretion of adrenal hormones, resulting in adrenal insufficiency (hypoadrenalism). Adrenal insufficiency leads to weight loss, lack of appetite (anorexia), weakness, nausea, vomiting, and low blood pressure (hypotension). Because these symptoms are so general, the diagnosis is sometimes delayed or missed entirely. For that reason, some clinicians believe the disorder to be more common than previously thought. | Overview of ACTH Deficiency. ACTH deficiency arises as a result of decreased or absent production of adrenocorticotropic hormone (ACTH) by the pituitary gland. A decline in the concentration of ACTH in the blood leads to a reduction in the secretion of adrenal hormones, resulting in adrenal insufficiency (hypoadrenalism). Adrenal insufficiency leads to weight loss, lack of appetite (anorexia), weakness, nausea, vomiting, and low blood pressure (hypotension). Because these symptoms are so general, the diagnosis is sometimes delayed or missed entirely. For that reason, some clinicians believe the disorder to be more common than previously thought. | 24 | ACTH Deficiency |
nord_24_1 | Symptoms of ACTH Deficiency | ACTH deficiency can either be congenital or acquired, and its manifestations are clinically indistinguishable from those of glucocorticoid deficiency. Symptoms include weight loss, lack of appetite (anorexia), muscle weakness, nausea and vomiting, and low blood pressure (hypotension). Low blood levels of sugar and dilutional hyponatremia (low blood sodium levels) may occur; however, blood potassium levels are typically normal as affected patients are deficient in glucocorticoids and not mineralocorticoids due to their intact renin-angiotensin-aldosterone system. The pituitary hormone ACTH may be undetectable in blood tests, and the level of the adrenal hormone cortisol is abnormally low. Concentrations of 17-hydroxycorticosteroids and 17-ketosteroids, produced from the adrenal cortex, are also abnormally low in the urine. Some adrenal hormones that are decreased are precursors of male sex hormones and are also known as “pre-androgens”.Although males with this disorder usually have a normal hair pattern, females may have very little pubic and underarm (axillary) hair. In contrast to Addison’s disease, skin pigmentation usually remains normal. Emotional symptoms may range from depression to psychosis. | Symptoms of ACTH Deficiency. ACTH deficiency can either be congenital or acquired, and its manifestations are clinically indistinguishable from those of glucocorticoid deficiency. Symptoms include weight loss, lack of appetite (anorexia), muscle weakness, nausea and vomiting, and low blood pressure (hypotension). Low blood levels of sugar and dilutional hyponatremia (low blood sodium levels) may occur; however, blood potassium levels are typically normal as affected patients are deficient in glucocorticoids and not mineralocorticoids due to their intact renin-angiotensin-aldosterone system. The pituitary hormone ACTH may be undetectable in blood tests, and the level of the adrenal hormone cortisol is abnormally low. Concentrations of 17-hydroxycorticosteroids and 17-ketosteroids, produced from the adrenal cortex, are also abnormally low in the urine. Some adrenal hormones that are decreased are precursors of male sex hormones and are also known as “pre-androgens”.Although males with this disorder usually have a normal hair pattern, females may have very little pubic and underarm (axillary) hair. In contrast to Addison’s disease, skin pigmentation usually remains normal. Emotional symptoms may range from depression to psychosis. | 24 | ACTH Deficiency |
nord_24_2 | Causes of ACTH Deficiency | The exact cause(s) of ACTH deficiency remain unknown. A defect in the brain’s hypothalamus or in the pituitary gland may cause the deficiency. Also, there is a congenital (present at birth) form of ACTH deficiency that has been tracked to mutations of the T-box 19 (TBX19) gene (also referred to as TPIT) on the long arm of chromosome one (1q23-q24) and the corticotropin releasing hormone (CRH) gene on the long arm of chromosome eight (8q13). The inheritance pattern is thought to be autosomal recessive.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 1q23-q24 refers to a region on the long arm of chromosome 1 between bands 23 and 24. Similarly chromosome 8q13 refers to the band numbered 13 on the long arm of chromosome 8. 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.Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms.The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child. | Causes of ACTH Deficiency. The exact cause(s) of ACTH deficiency remain unknown. A defect in the brain’s hypothalamus or in the pituitary gland may cause the deficiency. Also, there is a congenital (present at birth) form of ACTH deficiency that has been tracked to mutations of the T-box 19 (TBX19) gene (also referred to as TPIT) on the long arm of chromosome one (1q23-q24) and the corticotropin releasing hormone (CRH) gene on the long arm of chromosome eight (8q13). The inheritance pattern is thought to be autosomal recessive.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 1q23-q24 refers to a region on the long arm of chromosome 1 between bands 23 and 24. Similarly chromosome 8q13 refers to the band numbered 13 on the long arm of chromosome 8. 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.Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms.The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.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. | 24 | ACTH Deficiency |
nord_24_3 | Affects of ACTH Deficiency | Symptoms of ACTH deficiency most often occur in adults, but the disorder may also be diagnosed in infancy. The disorder affects males and females in equal numbers. | Affects of ACTH Deficiency. Symptoms of ACTH deficiency most often occur in adults, but the disorder may also be diagnosed in infancy. The disorder affects males and females in equal numbers. | 24 | ACTH Deficiency |
nord_24_4 | Related disorders of ACTH Deficiency | Symptoms of the following disorders may be similar to those of ACTH Deficiency. Comparisons may be useful for a differential diagnosis:Congenital adrenal hyperplasia (CAH) is a group of disorders resulting from defective synthesis of the corticosteroid hormones of the adrenal gland. The adrenal gland becomes enlarged. In certain forms of CAH, the adrenal gland produces excessive amounts of “male” sex hormones (“pre-androgens”) in both males and females. The external genitals of some females with this disorder become masculinized to various degrees. Lack of glucocorticoids, especially cortisol, causes various metabolic problems. Lack of mineralocorticoids, primarily aldosterone, causes salt and water imbalances which may be life threatening. (For more information on this disorder, choose “Congenital Adrenal Hyperplasia” as your search term in the Rare Disease Database.)Addison’s disease (primary adrenal insufficiency) usually develops later in life. It is characterized by chronic diminished adrenocortical function. The resulting deficiencies of glucocorticoids and mineralocorticoids cause weakness, low resistance to physiological stress, metabolic abnormalities, and circulatory insufficiency. Many Addison’s patients have sufficient levels of these corticosteroids to permit adequate functioning under normal circumstances. Even mild physiologic stress, however, can precipitate an Addisonian crisis consisting of circulatory collapse and, if untreated, death. With replacement of the essential adrenal hormones, Addison’s patients can lead a normal life. (For more information on this disorder, choose “Addison” as your search term in the Rare Disease Database.)Secondary adrenal insufficiency results from insufficient production or release of the pituitary hormone ACTH. It may be caused by prolonged corticosteroid therapy. ACTH production doesn’t return to normal for several months after completion of the therapy. Central nervous system tumors affecting the pituitary gland, granulomatous disease, and death (necrosis) of the pituitary gland after a pregnancy (Sheehan’s syndrome) also may cause secondary adrenal insufficiency. | Related disorders of ACTH Deficiency. Symptoms of the following disorders may be similar to those of ACTH Deficiency. Comparisons may be useful for a differential diagnosis:Congenital adrenal hyperplasia (CAH) is a group of disorders resulting from defective synthesis of the corticosteroid hormones of the adrenal gland. The adrenal gland becomes enlarged. In certain forms of CAH, the adrenal gland produces excessive amounts of “male” sex hormones (“pre-androgens”) in both males and females. The external genitals of some females with this disorder become masculinized to various degrees. Lack of glucocorticoids, especially cortisol, causes various metabolic problems. Lack of mineralocorticoids, primarily aldosterone, causes salt and water imbalances which may be life threatening. (For more information on this disorder, choose “Congenital Adrenal Hyperplasia” as your search term in the Rare Disease Database.)Addison’s disease (primary adrenal insufficiency) usually develops later in life. It is characterized by chronic diminished adrenocortical function. The resulting deficiencies of glucocorticoids and mineralocorticoids cause weakness, low resistance to physiological stress, metabolic abnormalities, and circulatory insufficiency. Many Addison’s patients have sufficient levels of these corticosteroids to permit adequate functioning under normal circumstances. Even mild physiologic stress, however, can precipitate an Addisonian crisis consisting of circulatory collapse and, if untreated, death. With replacement of the essential adrenal hormones, Addison’s patients can lead a normal life. (For more information on this disorder, choose “Addison” as your search term in the Rare Disease Database.)Secondary adrenal insufficiency results from insufficient production or release of the pituitary hormone ACTH. It may be caused by prolonged corticosteroid therapy. ACTH production doesn’t return to normal for several months after completion of the therapy. Central nervous system tumors affecting the pituitary gland, granulomatous disease, and death (necrosis) of the pituitary gland after a pregnancy (Sheehan’s syndrome) also may cause secondary adrenal insufficiency. | 24 | ACTH Deficiency |
nord_24_5 | Diagnosis of ACTH Deficiency | When ACTH deficiency is suspected, blood samples are taken for analysis, especially of the level of cortisol in the blood. Cortisol is the name of one of the hormones produced by the outer portion (cortex) of the adrenal glands. If the concentration of cortisol is low, it typically indicates a low concentration of ACTH. On occasion, an ACTH stimulation test may be administered. | Diagnosis of ACTH Deficiency. When ACTH deficiency is suspected, blood samples are taken for analysis, especially of the level of cortisol in the blood. Cortisol is the name of one of the hormones produced by the outer portion (cortex) of the adrenal glands. If the concentration of cortisol is low, it typically indicates a low concentration of ACTH. On occasion, an ACTH stimulation test may be administered. | 24 | ACTH Deficiency |
nord_24_6 | Therapies of ACTH Deficiency | TreatmentHormone replacement therapy with cortisol is the treatment of choice for this disorder. With such therapy, patients can lead a normal life. | Therapies of ACTH Deficiency. TreatmentHormone replacement therapy with cortisol is the treatment of choice for this disorder. With such therapy, patients can lead a normal life. | 24 | ACTH Deficiency |
nord_25_0 | Overview of Activated Phosphoinositide 3-Kinase Delta Syndrome (APDS) | Summary
Activated phosphoinositide 3-kinase delta syndrome (APDS) is a rare, inherited condition that affects the way the immune system works. The most common symptoms of APDS are frequent upper respiratory tract infections, sinus infections, ear infections, bronchitis and pneumonia (lung infection). Most people with APDS get their first infection in early childhood, but symptoms can begin at any age. Other symptoms include gastrointestinal irritation, lymph node swelling, enlarged liver and spleen and an increased risk for lymphoma. Over time, frequent ear and respiratory tract infections can lead to permanent hearing loss and scarring of the lungs (bronchiectasis).There are two types of APDS: APDS1 is due to changes in the PIK3CD gene and APDS2 is due to changes in the PIK3R1 gene. Both have similar symptoms and are inherited in an autosomal dominant pattern in families. Treatment for APDS is focused on managing symptoms, preventing infections and lowering inflammation. It includes antibiotics to treat infections, anti-inflammatory drugs, immunoglobulin replacement and hematopoietic stem-cell transplant (HSCT).Introduction
APDS was first described in 2013 and is one of the primary immunodeficiencies. People with a primary immunodeficiency are born with an immune system that doesn’t work correctly and get frequent infections that can be hard to treat. There are hundreds of primary immunodeficiencies, many with similar signs and symptoms. Specialized testing is often necessary to tell the primary immunodeficiencies apart and make a specific diagnosis. | Overview of Activated Phosphoinositide 3-Kinase Delta Syndrome (APDS). Summary
Activated phosphoinositide 3-kinase delta syndrome (APDS) is a rare, inherited condition that affects the way the immune system works. The most common symptoms of APDS are frequent upper respiratory tract infections, sinus infections, ear infections, bronchitis and pneumonia (lung infection). Most people with APDS get their first infection in early childhood, but symptoms can begin at any age. Other symptoms include gastrointestinal irritation, lymph node swelling, enlarged liver and spleen and an increased risk for lymphoma. Over time, frequent ear and respiratory tract infections can lead to permanent hearing loss and scarring of the lungs (bronchiectasis).There are two types of APDS: APDS1 is due to changes in the PIK3CD gene and APDS2 is due to changes in the PIK3R1 gene. Both have similar symptoms and are inherited in an autosomal dominant pattern in families. Treatment for APDS is focused on managing symptoms, preventing infections and lowering inflammation. It includes antibiotics to treat infections, anti-inflammatory drugs, immunoglobulin replacement and hematopoietic stem-cell transplant (HSCT).Introduction
APDS was first described in 2013 and is one of the primary immunodeficiencies. People with a primary immunodeficiency are born with an immune system that doesn’t work correctly and get frequent infections that can be hard to treat. There are hundreds of primary immunodeficiencies, many with similar signs and symptoms. Specialized testing is often necessary to tell the primary immunodeficiencies apart and make a specific diagnosis. | 25 | Activated Phosphoinositide 3-Kinase Delta Syndrome (APDS) |
nord_25_1 | Symptoms of Activated Phosphoinositide 3-Kinase Delta Syndrome (APDS) | APDS affects each person differently. Some people have very mild symptoms, while others are much more severely impacted. Most people with APDS begin to have symptoms in childhood. However, symptoms can begin at any age, and some people do not develop symptoms until adulthood. There are some reports of people who have been diagnosed with APDS who do not have any symptoms.The first signs of APDS are usually infections beginning in early childhood. The most common of these are ear infections, sinus infections and pneumonia. Over time, frequent respiratory tract infections can lead to scarring of the lungs (bronchiectasis). This is more common in APDS1 than APDS2. Viral infections are also common, especially infections with Epstein-Barr virus and herpes simplex viruses. These infections may be difficult to treat and may never completely go away.People with APDS may develop enlarged lymph nodes, as well as an enlarged liver (hepatomegaly) or spleen (splenomegaly). Inflammation of the intestine can also occur, leading to severe diarrhea which sometimes results in hospitalization. Skin infections are also common.Some people develop autoimmunity, causing the body’s immune system to attack its own healthy cells. Autoimmune disease can have an impact on many different organs and body systems. In APDS, the most common sign of autoimmune disease is a low level of red blood cells causing anemia, or fewer platelets leading to bleeding problems and easy bruising.Growth delay, short stature and neurodevelopmental delay have also been seen in people with APDS. Shorter than average stature is more common in APDS2. People with APDS also have an increased risk of developing lymphoma and other blood cancers. | Symptoms of Activated Phosphoinositide 3-Kinase Delta Syndrome (APDS). APDS affects each person differently. Some people have very mild symptoms, while others are much more severely impacted. Most people with APDS begin to have symptoms in childhood. However, symptoms can begin at any age, and some people do not develop symptoms until adulthood. There are some reports of people who have been diagnosed with APDS who do not have any symptoms.The first signs of APDS are usually infections beginning in early childhood. The most common of these are ear infections, sinus infections and pneumonia. Over time, frequent respiratory tract infections can lead to scarring of the lungs (bronchiectasis). This is more common in APDS1 than APDS2. Viral infections are also common, especially infections with Epstein-Barr virus and herpes simplex viruses. These infections may be difficult to treat and may never completely go away.People with APDS may develop enlarged lymph nodes, as well as an enlarged liver (hepatomegaly) or spleen (splenomegaly). Inflammation of the intestine can also occur, leading to severe diarrhea which sometimes results in hospitalization. Skin infections are also common.Some people develop autoimmunity, causing the body’s immune system to attack its own healthy cells. Autoimmune disease can have an impact on many different organs and body systems. In APDS, the most common sign of autoimmune disease is a low level of red blood cells causing anemia, or fewer platelets leading to bleeding problems and easy bruising.Growth delay, short stature and neurodevelopmental delay have also been seen in people with APDS. Shorter than average stature is more common in APDS2. People with APDS also have an increased risk of developing lymphoma and other blood cancers. | 25 | Activated Phosphoinositide 3-Kinase Delta Syndrome (APDS) |
nord_25_2 | Causes of Activated Phosphoinositide 3-Kinase Delta Syndrome (APDS) | APDS is caused by pathogenic variants in either the PIK3CD gene (APDS1) or the PIK3R1 gene (APDS2). Both genes are important for the growth, survival and function of certain types of immune cells called T cells and B cells. These are specialized white blood cells that help fight infection. Pathogenic variants in these two genes affect how B cells and T cells grow and work. People with APDS often have B cells and T cells that are not functioning normally, leading to infections, inflammation of the intestine and autoimmune disease.APDS1 and APDS2 are inherited in a dominant pattern in families. Dominant genetic disorders occur when only a single copy of a mutated gene is necessary to cause a particular disease. The mutated gene can be inherited from either parent or can be the result of a changed gene in the affected individual. The risk of passing the mutated gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females. | Causes of Activated Phosphoinositide 3-Kinase Delta Syndrome (APDS). APDS is caused by pathogenic variants in either the PIK3CD gene (APDS1) or the PIK3R1 gene (APDS2). Both genes are important for the growth, survival and function of certain types of immune cells called T cells and B cells. These are specialized white blood cells that help fight infection. Pathogenic variants in these two genes affect how B cells and T cells grow and work. People with APDS often have B cells and T cells that are not functioning normally, leading to infections, inflammation of the intestine and autoimmune disease.APDS1 and APDS2 are inherited in a dominant pattern in families. Dominant genetic disorders occur when only a single copy of a mutated gene is necessary to cause a particular disease. The mutated gene can be inherited from either parent or can be the result of a changed gene in the affected individual. The risk of passing the mutated gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females. | 25 | Activated Phosphoinositide 3-Kinase Delta Syndrome (APDS) |
nord_25_3 | Affects of Activated Phosphoinositide 3-Kinase Delta Syndrome (APDS) | APDS has been diagnosed in people from around the world and does not seem to be more common in any one ethnic group. It affects males and females equally. The exact number of people with this condition is unknown. | Affects of Activated Phosphoinositide 3-Kinase Delta Syndrome (APDS). APDS has been diagnosed in people from around the world and does not seem to be more common in any one ethnic group. It affects males and females equally. The exact number of people with this condition is unknown. | 25 | Activated Phosphoinositide 3-Kinase Delta Syndrome (APDS) |
nord_25_4 | Related disorders of Activated Phosphoinositide 3-Kinase Delta Syndrome (APDS) | Hyper-IgM Syndrome (HIGM)Hyper-IgM syndrome (HIGM) is a rare primary immunodeficiency disorder that is usually inherited as an X-linked recessive condition. People with this disorder have low levels of IgG, IgA and IgE antibodies. Levels of IgM antibodies may be high or in the normal range. Symptoms and physical findings usually become apparent in the first or second year of life. HIGM is characterized by recurrent bacterial infections of the middle ear, sinuses, lungs, the membrane that lines the eyelid and the white part of the eyes, the skin and/or other areas. Affected children may have an impaired absorption of nutrients, chronic diarrhea and failure to gain weight (failure to thrive) and enlargement of the tonsils and/or enlargement of the liver and spleen (hepatosplenomegaly). In addition, affected individuals are prone to the development of autoimmune disorders of the blood such as neutropenia, in which there is a decreased level of certain white blood cells. Because about 70 percent of reported cases of HIGM are X-linked, most affected individuals are male. However, autosomal recessive and autosomal dominant forms of the disorder have also been described. (For more information on this disorder, choose “Hyper IgM” as your search term in the Rare Disease Database.)Common Variable Immune Deficiency (CVID)Common variable immune deficiency (CVID) is one of the most common symptomatic primary immunodeficiencies and has a wide variability of symptoms and range of severity. While considered a genetic condition, the syndrome consists of a group of diseases, and most of the causes are still unknown. CVID is characterized by low levels of specific proteins (immunoglobulins) in the fluid portion of the blood. This results in a loss of antibodies and a decreased ability to fight invading microorganisms, toxins, or other foreign substances. These immunoglobulins are produced by specialized white blood cells (B cells) as they mature into plasma cells. Autosomal dominant, autosomal recessive and X-linked forms of CVID have been reported. (For more information on this disorder, choose “Common Variable Immune Deficiency” as your search term in the Rare Disease Database.) | Related disorders of Activated Phosphoinositide 3-Kinase Delta Syndrome (APDS). Hyper-IgM Syndrome (HIGM)Hyper-IgM syndrome (HIGM) is a rare primary immunodeficiency disorder that is usually inherited as an X-linked recessive condition. People with this disorder have low levels of IgG, IgA and IgE antibodies. Levels of IgM antibodies may be high or in the normal range. Symptoms and physical findings usually become apparent in the first or second year of life. HIGM is characterized by recurrent bacterial infections of the middle ear, sinuses, lungs, the membrane that lines the eyelid and the white part of the eyes, the skin and/or other areas. Affected children may have an impaired absorption of nutrients, chronic diarrhea and failure to gain weight (failure to thrive) and enlargement of the tonsils and/or enlargement of the liver and spleen (hepatosplenomegaly). In addition, affected individuals are prone to the development of autoimmune disorders of the blood such as neutropenia, in which there is a decreased level of certain white blood cells. Because about 70 percent of reported cases of HIGM are X-linked, most affected individuals are male. However, autosomal recessive and autosomal dominant forms of the disorder have also been described. (For more information on this disorder, choose “Hyper IgM” as your search term in the Rare Disease Database.)Common Variable Immune Deficiency (CVID)Common variable immune deficiency (CVID) is one of the most common symptomatic primary immunodeficiencies and has a wide variability of symptoms and range of severity. While considered a genetic condition, the syndrome consists of a group of diseases, and most of the causes are still unknown. CVID is characterized by low levels of specific proteins (immunoglobulins) in the fluid portion of the blood. This results in a loss of antibodies and a decreased ability to fight invading microorganisms, toxins, or other foreign substances. These immunoglobulins are produced by specialized white blood cells (B cells) as they mature into plasma cells. Autosomal dominant, autosomal recessive and X-linked forms of CVID have been reported. (For more information on this disorder, choose “Common Variable Immune Deficiency” as your search term in the Rare Disease Database.) | 25 | Activated Phosphoinositide 3-Kinase Delta Syndrome (APDS) |
nord_25_5 | Diagnosis of Activated Phosphoinositide 3-Kinase Delta Syndrome (APDS) | APDS is diagnosed based on the symptoms, clinical examination, a detailed family history and laboratory testing to look for abnormalities in the levels and function of immune cells. Because APDS can look like other immunodeficiencies, genetic testing is necessary to make a specific diagnosis. Genetic testing for immunodeficiencies often involves using a gene panel. Gene panels test for pathogenic variants in a group of genes that are related to disorders that have similar symptoms. Genetic testing is usually done with a blood or saliva sample. It is helpful to speak to a genetics professional before having genetic testing to learn more about the risk, benefits and limitations. | Diagnosis of Activated Phosphoinositide 3-Kinase Delta Syndrome (APDS). APDS is diagnosed based on the symptoms, clinical examination, a detailed family history and laboratory testing to look for abnormalities in the levels and function of immune cells. Because APDS can look like other immunodeficiencies, genetic testing is necessary to make a specific diagnosis. Genetic testing for immunodeficiencies often involves using a gene panel. Gene panels test for pathogenic variants in a group of genes that are related to disorders that have similar symptoms. Genetic testing is usually done with a blood or saliva sample. It is helpful to speak to a genetics professional before having genetic testing to learn more about the risk, benefits and limitations. | 25 | Activated Phosphoinositide 3-Kinase Delta Syndrome (APDS) |
nord_25_6 | Therapies of Activated Phosphoinositide 3-Kinase Delta Syndrome (APDS) | Treatment for APDS is focused on managing the symptoms. APDS is treated using a combination of long-term immunoglobulin replacement therapy to help support the immune system and immunosuppressive medications to help with symptoms due to autoimmunity and inflammation. In addition, people with APDS often require daily antibiotics to help prevent infections before they happen.Children with APDS may require ear tubes (tympanostomy tubes) due to frequent ear infections. Some may have their tonsils removed because of swelling and sinus infections. People with more severe APDS may eventually require respiratory support including extra oxygen and chest physiotherapy. In addition, physical, occupational and/or speech therapy may help with some of the long-term complications.Hematopoietic stem cell transplant (HSCT) has been used to treat some people with APDS who do not respond to standard therapy. Hematopoietic stem cells develop in the bone marrow and have the potential to become any type of blood cell. In APDS, HSCT involves replacing the bone marrow with new stem cells that can become healthy, functioning immune cells. HSCT is used as a treatment for several primary immunodeficiencies as well as for certain types of blood cancers.In 2023, leniolisib (Joenja) was approved by the U.S. Food and Drug Administration (FDA) to treat APDS in adults and children 12 years of age and older.People with APDS may need to see a variety of specialists. These might include an immunologist, infectious disease doctor, pulmonologist, ear, nose, and throat specialist and gastroenterologist.Genetic counseling is recommended for families with an affected child. | Therapies of Activated Phosphoinositide 3-Kinase Delta Syndrome (APDS). Treatment for APDS is focused on managing the symptoms. APDS is treated using a combination of long-term immunoglobulin replacement therapy to help support the immune system and immunosuppressive medications to help with symptoms due to autoimmunity and inflammation. In addition, people with APDS often require daily antibiotics to help prevent infections before they happen.Children with APDS may require ear tubes (tympanostomy tubes) due to frequent ear infections. Some may have their tonsils removed because of swelling and sinus infections. People with more severe APDS may eventually require respiratory support including extra oxygen and chest physiotherapy. In addition, physical, occupational and/or speech therapy may help with some of the long-term complications.Hematopoietic stem cell transplant (HSCT) has been used to treat some people with APDS who do not respond to standard therapy. Hematopoietic stem cells develop in the bone marrow and have the potential to become any type of blood cell. In APDS, HSCT involves replacing the bone marrow with new stem cells that can become healthy, functioning immune cells. HSCT is used as a treatment for several primary immunodeficiencies as well as for certain types of blood cancers.In 2023, leniolisib (Joenja) was approved by the U.S. Food and Drug Administration (FDA) to treat APDS in adults and children 12 years of age and older.People with APDS may need to see a variety of specialists. These might include an immunologist, infectious disease doctor, pulmonologist, ear, nose, and throat specialist and gastroenterologist.Genetic counseling is recommended for families with an affected child. | 25 | Activated Phosphoinositide 3-Kinase Delta Syndrome (APDS) |
nord_26_0 | Overview of Acute Cholecystitis | The gallbladder is a small pear shaped organ that stores and concentrates bile used for digestion of fats. Bile is a compound composed mainly of cholesterol, bile salts and bilirubin, produced by the liver and stored in the gallbladder during fasting states. When food is consumed, it is partially digested by the stomach and enters the small intestine, where bile is released by the gallbladder to aid in the breakdown of fats. Gallstones develop when the components of bile, such as cholesterol and bilirubin, remain in the gallbladder and solidify into “pebble-like” material. Gallstones may lodge in the bile ducts and block the release of bile causing a backup. Up to 80% of all gallstones do not cause symptoms but obstruction within the bile ducts can cause gallbladder swelling (distension) and severe pain and tenderness of right side of abdomen and/or back (biliary colic). If the obstruction persists, it results in inflammation, infection, and even lack of blood flow (ischemia), a common condition known as acute cholecystitis, or acute calculous cholecystitis (ACC). Repeated mild episodes of acute cholecystitis may result in chronic cholecystitis, causing thickening and shrinking of the gallbladder wall resulting in an inability to store bile. Another form of cholecystitis, acute acalulous cholecystitis (AAC) is an inflammatory disease of the gallbladder without evidence of gallstones or obstruction of the cystic ducts. Approximately 2-15% of cases of cholecystitis are acalculous and usually occur in very sick hospitalized patients. The exact causal mechanism is not clear. Acalculous cholecystitis is associated with a higher mortality rate (~45%) due in part to serious underlying medical conditions and delayed diagnosis. | Overview of Acute Cholecystitis. The gallbladder is a small pear shaped organ that stores and concentrates bile used for digestion of fats. Bile is a compound composed mainly of cholesterol, bile salts and bilirubin, produced by the liver and stored in the gallbladder during fasting states. When food is consumed, it is partially digested by the stomach and enters the small intestine, where bile is released by the gallbladder to aid in the breakdown of fats. Gallstones develop when the components of bile, such as cholesterol and bilirubin, remain in the gallbladder and solidify into “pebble-like” material. Gallstones may lodge in the bile ducts and block the release of bile causing a backup. Up to 80% of all gallstones do not cause symptoms but obstruction within the bile ducts can cause gallbladder swelling (distension) and severe pain and tenderness of right side of abdomen and/or back (biliary colic). If the obstruction persists, it results in inflammation, infection, and even lack of blood flow (ischemia), a common condition known as acute cholecystitis, or acute calculous cholecystitis (ACC). Repeated mild episodes of acute cholecystitis may result in chronic cholecystitis, causing thickening and shrinking of the gallbladder wall resulting in an inability to store bile. Another form of cholecystitis, acute acalulous cholecystitis (AAC) is an inflammatory disease of the gallbladder without evidence of gallstones or obstruction of the cystic ducts. Approximately 2-15% of cases of cholecystitis are acalculous and usually occur in very sick hospitalized patients. The exact causal mechanism is not clear. Acalculous cholecystitis is associated with a higher mortality rate (~45%) due in part to serious underlying medical conditions and delayed diagnosis. | 26 | Acute Cholecystitis |
nord_26_1 | Symptoms of Acute Cholecystitis | Acute Calculous Cholecystitis The specific symptoms associated with cholecystitis vary among patients. Upper abdominal pain, often localized to the right upper quadrant, is the most common symptom. In acute calculous cholecystitis, the pain is often sudden and intense but it can be described as cramping, dull, or steady. Pain can become excruciating. Upper abdominal pain usually lasts longer than six hours, often beginning a few hours after a meal or at night. It can worsen with deep breaths and may radiate into the back and right shoulder blade (scapula). The right upper quadrant will likely be tender and 25% of patients have a perceptible mass there after 24 hours of symptoms.In addition to pain, many affected individuals experience nausea, vomiting and shortness of breath when inhaling (due to pain). Additional symptoms of cholecystitis include stiffening of the muscles on the right side of the abdomen, bloating of the abdomen, chills, and fever. Blood testing may show an increase in white blood cell count and C-reactive protein (elevation indicates inflammation). If serum amylase levels are elevated, the patient may also have gallstone pancreatitis or gangrenous cholecystitis. Although bilirubin may be elevated, development of frank jaundice in the absence of other complications is rare. If jaundice does occur, persistent yellowing of the skin, mucous membranes, and whites of the eyes will be present. In rare cases, symptoms such as dark urine and clay colored stools are indicative of common bile duct obstruction.Older individuals with cholecystitis may not develop pain or fever. Their only symptoms may be tenderness of the upper right portion of the abdomen, altered mental status, or decreased food intake.Affected individuals may develop a bacterial infection preceding or during a gallbladder attack. In most patients, a gallbladder attack will last one to four days and then subside. In rare severely affected patients, the gallbladder wall may rupture (perforate) or pus may build up within the gallbladder (empyema). In these patients, surgery may be necessary. Acute Acalculous Cholecystitis (AAC)AAC is generally distinguishable from calculous cholecystitis because it usually occurs in association with other serious conditions requiring hospital admission. As in calculous cholecystitis patients, AAC often presents with pain in the upper right quadrant of the abdomen that radiates into the back. It is also characterized by fever, nausea, and vomiting. Increased white blood cell count (leukocytosis), decreased intestinal muscle contraction (paralytic ileus), gallbladder abscess and/or gangrene are all signs of AAC. A palpable mass or Murphy’s sign are sometimes present. Nonspecific symptoms include diarrhea, upset stomach, fatigue, altered mental status, and jaundice. Hemorrhagic AAC has been reported in patients with end-stage renal disease (ESRD). | Symptoms of Acute Cholecystitis. Acute Calculous Cholecystitis The specific symptoms associated with cholecystitis vary among patients. Upper abdominal pain, often localized to the right upper quadrant, is the most common symptom. In acute calculous cholecystitis, the pain is often sudden and intense but it can be described as cramping, dull, or steady. Pain can become excruciating. Upper abdominal pain usually lasts longer than six hours, often beginning a few hours after a meal or at night. It can worsen with deep breaths and may radiate into the back and right shoulder blade (scapula). The right upper quadrant will likely be tender and 25% of patients have a perceptible mass there after 24 hours of symptoms.In addition to pain, many affected individuals experience nausea, vomiting and shortness of breath when inhaling (due to pain). Additional symptoms of cholecystitis include stiffening of the muscles on the right side of the abdomen, bloating of the abdomen, chills, and fever. Blood testing may show an increase in white blood cell count and C-reactive protein (elevation indicates inflammation). If serum amylase levels are elevated, the patient may also have gallstone pancreatitis or gangrenous cholecystitis. Although bilirubin may be elevated, development of frank jaundice in the absence of other complications is rare. If jaundice does occur, persistent yellowing of the skin, mucous membranes, and whites of the eyes will be present. In rare cases, symptoms such as dark urine and clay colored stools are indicative of common bile duct obstruction.Older individuals with cholecystitis may not develop pain or fever. Their only symptoms may be tenderness of the upper right portion of the abdomen, altered mental status, or decreased food intake.Affected individuals may develop a bacterial infection preceding or during a gallbladder attack. In most patients, a gallbladder attack will last one to four days and then subside. In rare severely affected patients, the gallbladder wall may rupture (perforate) or pus may build up within the gallbladder (empyema). In these patients, surgery may be necessary. Acute Acalculous Cholecystitis (AAC)AAC is generally distinguishable from calculous cholecystitis because it usually occurs in association with other serious conditions requiring hospital admission. As in calculous cholecystitis patients, AAC often presents with pain in the upper right quadrant of the abdomen that radiates into the back. It is also characterized by fever, nausea, and vomiting. Increased white blood cell count (leukocytosis), decreased intestinal muscle contraction (paralytic ileus), gallbladder abscess and/or gangrene are all signs of AAC. A palpable mass or Murphy’s sign are sometimes present. Nonspecific symptoms include diarrhea, upset stomach, fatigue, altered mental status, and jaundice. Hemorrhagic AAC has been reported in patients with end-stage renal disease (ESRD). | 26 | Acute Cholecystitis |
nord_26_2 | Causes of Acute Cholecystitis | Acute Calculous CholecystitisThe medical term for the presence of a gallstone is cholelithiasis. Approximately 90 percent of cases of cholecystitis are associated with the presence of a gallstone obstructing the cystic duct (calculous cholecystitis), often resulting in buildup of cholesterol- saturated bile in the gallbladder. The cystic duct is a short tube that carries bile from the gallbladder to the common bile duct. Severity of the cholecystitis depends on the length of time the cystic duct is blocked. If brief, it may result in short term pain. If longer than a couple of hours, the cholelithiasis results in inflammation. The gallbladder becomes enlarged, tense, and reddened with thickened walls that may exude pericholecystic fluid. This is often accompanied by secondary infections that can cause necrosis, gangrene, or gas buildup in the wall of the gallbladder which may result in perforation if left untreated. Perforation can cause inflammation of the abdominal inner lining (peritonitis) or the upper right quadrant of the liver. Acute Acalculous Cholecystitis (AAC)AAC is not associated with the presence of gallstones, but an underlying medical condition or clinical trauma such as major burns, end-stage renal disease, post-hemorrhagic shock resuscitation, surgery, polytrauma or leukemia that can produce systemic inflammation. In addition, viral, bacterial, and parasitic infectious diseases have been associated with AAC. The exact cause of AAC is unknown but thought to be induced by reduced blood flow to the gallbladder (ischemia), infectious disease or lack of gallbladder stimulation (not eating) causing biliary stasis (bile immobility) Although gallstones do not obstruct the bile duct in this form of cholecystitis, there may be other physical barriers present. These barriers may be infectious or noninfectious. For example, bile duct blockages may be caused by cysts full of parasitic Echinococcus eggs, ascariasis (intestinal infection from roundworm), hemophilia, generic cysts, and narrowing of bile duct (ampullary stenosis). Additionally, infections can kill gallbladder tissue (gangrene), causing AAC. Other medical conditions such as diabetes mellitus, inflammation of blood vessels (vasculitis), opioid use, sickle cell anemia, dehydration, positive pressure ventilation, and blockage of oxygenated blood from getting to gallbladder (cystic artery obstruction). The following is a list of diseases associated with acute acalculous cholecystitis:Bacterial:
○ Most commonly gram-negative intestinal (enteric) bacteria like Escherichia Coli
○ Candidiasis (fungal)
○ Leptospirosis
○ Coxiella Burnett
○ Salmonella (rarely)
○ Lactococcus garvieae (rarely)
○ Typhoid fever and non- Typhoid Salmonella Typhoid (impacting the biliary tract)
○ Cholera (diarrheal)
○ Campylobacter enteritis (diarrheal)
○ TuberculosisParasitic:
○ Cryptosporidium parasite
○ Plasmodium falciparum (Malaria)End-stage renal disease (ESRD)Viral:
○ Hepatitis A
○ Hepatitis B
○ Cytomegalovirus
○ Chickenpox (varicella zoster virus)
○ HIV- AIDS
○ Dengue fever
○ Epstein-Barr virus
■ In the presence of viral infections, portal lymphadenitis with extrinsic cystic duct obstruction | Causes of Acute Cholecystitis. Acute Calculous CholecystitisThe medical term for the presence of a gallstone is cholelithiasis. Approximately 90 percent of cases of cholecystitis are associated with the presence of a gallstone obstructing the cystic duct (calculous cholecystitis), often resulting in buildup of cholesterol- saturated bile in the gallbladder. The cystic duct is a short tube that carries bile from the gallbladder to the common bile duct. Severity of the cholecystitis depends on the length of time the cystic duct is blocked. If brief, it may result in short term pain. If longer than a couple of hours, the cholelithiasis results in inflammation. The gallbladder becomes enlarged, tense, and reddened with thickened walls that may exude pericholecystic fluid. This is often accompanied by secondary infections that can cause necrosis, gangrene, or gas buildup in the wall of the gallbladder which may result in perforation if left untreated. Perforation can cause inflammation of the abdominal inner lining (peritonitis) or the upper right quadrant of the liver. Acute Acalculous Cholecystitis (AAC)AAC is not associated with the presence of gallstones, but an underlying medical condition or clinical trauma such as major burns, end-stage renal disease, post-hemorrhagic shock resuscitation, surgery, polytrauma or leukemia that can produce systemic inflammation. In addition, viral, bacterial, and parasitic infectious diseases have been associated with AAC. The exact cause of AAC is unknown but thought to be induced by reduced blood flow to the gallbladder (ischemia), infectious disease or lack of gallbladder stimulation (not eating) causing biliary stasis (bile immobility) Although gallstones do not obstruct the bile duct in this form of cholecystitis, there may be other physical barriers present. These barriers may be infectious or noninfectious. For example, bile duct blockages may be caused by cysts full of parasitic Echinococcus eggs, ascariasis (intestinal infection from roundworm), hemophilia, generic cysts, and narrowing of bile duct (ampullary stenosis). Additionally, infections can kill gallbladder tissue (gangrene), causing AAC. Other medical conditions such as diabetes mellitus, inflammation of blood vessels (vasculitis), opioid use, sickle cell anemia, dehydration, positive pressure ventilation, and blockage of oxygenated blood from getting to gallbladder (cystic artery obstruction). The following is a list of diseases associated with acute acalculous cholecystitis:Bacterial:
○ Most commonly gram-negative intestinal (enteric) bacteria like Escherichia Coli
○ Candidiasis (fungal)
○ Leptospirosis
○ Coxiella Burnett
○ Salmonella (rarely)
○ Lactococcus garvieae (rarely)
○ Typhoid fever and non- Typhoid Salmonella Typhoid (impacting the biliary tract)
○ Cholera (diarrheal)
○ Campylobacter enteritis (diarrheal)
○ TuberculosisParasitic:
○ Cryptosporidium parasite
○ Plasmodium falciparum (Malaria)End-stage renal disease (ESRD)Viral:
○ Hepatitis A
○ Hepatitis B
○ Cytomegalovirus
○ Chickenpox (varicella zoster virus)
○ HIV- AIDS
○ Dengue fever
○ Epstein-Barr virus
■ In the presence of viral infections, portal lymphadenitis with extrinsic cystic duct obstruction | 26 | Acute Cholecystitis |
nord_26_3 | Affects of Acute Cholecystitis | Although the incidence of acute cholecystitis is unknown, about 120,000 Americans are treated for acute cholecystitis annually. At age 65, 25% of women and 12% of men will have gallstone disease. Approximately 10% of all patients with symptomatic gallstones will develop cholecystitis. If the gallbladder is not removed after acute cholecystitis, there is a 29% chance of a second gallstone related event within a year. Although 60% of acute cholecystitis patients are women, the proportion of people with gallstones who develop cholecystitis is higher in men. Men also tend to have more severe symptoms. Diabetes and older age increase the risk of developing cholecystitis. Acalculous cholecystitis has an incidence rate of 0.12% in the entire population. 80% of cases of acalculous cholecystitis are in male patients of age 50 and older. | Affects of Acute Cholecystitis. Although the incidence of acute cholecystitis is unknown, about 120,000 Americans are treated for acute cholecystitis annually. At age 65, 25% of women and 12% of men will have gallstone disease. Approximately 10% of all patients with symptomatic gallstones will develop cholecystitis. If the gallbladder is not removed after acute cholecystitis, there is a 29% chance of a second gallstone related event within a year. Although 60% of acute cholecystitis patients are women, the proportion of people with gallstones who develop cholecystitis is higher in men. Men also tend to have more severe symptoms. Diabetes and older age increase the risk of developing cholecystitis. Acalculous cholecystitis has an incidence rate of 0.12% in the entire population. 80% of cases of acalculous cholecystitis are in male patients of age 50 and older. | 26 | Acute Cholecystitis |
nord_26_4 | Related disorders of Acute Cholecystitis | Symptoms of the following disorders can be similar to those of cholecystitis. Comparisons may be useful for a differential diagnosis.Acute emphysematous cholecystitis (clostridial cholecystitis) occurs when gas forming bacteria like Clostridium and E. Coli cause acute infection and cell death (necrosis) in the gallbladder wall. Since this often results in early gangrene and perforation of the gallbladder, the disease has a high mortality rate and is considered a surgical emergency requiring cholecystectomy or if the patient is not a surgical candidate then percutaneous cholecystectomy. This form of acute cholecystitis is identified by the presence of air bubbles in the lumen or gallbladder wall seen in ultrasound or CT scans. It often progresses gradually without outward symptoms at first and then progresses very rapidly. AAC and acute emphysematous cholecystitis are closely associated; AAC is present in 50% of emphysematous cases. However, the emphysematous form is far more likely to result in gallbladder perforation. Physicians can tell if such perforation has occurred if pneumoperitoneum is seen on CT scans. Male diabetics are most susceptible to this disease. Gallbladder cancer is the uncontrolled growth of abnormal cells in the gallbladder. It is difficult to detect as patients may have no early symptoms thus diagnosis occurs at an advanced stage. Symptoms of gallbladder cancer mimic many other illnesses that include abdominal pain, bloating, itching, and fever. As in cholecystitis, blood tests from patients with this cancer may have abnormal levels of bilirubin, albumin, alkaline phosphatase, aspartate aminotransferase, alanine transaminase, and gamma-glutamyl transferase. These compounds are all indicators of liver and bile duct function. Imaging techniques like ultrasound and CT scanning may help distinguish tumors from gallstones. A variety of other conditions and diseases can cause symptoms similar to those seen in cholecystitis. These conditions include appendicitis, biliary colic, cholangitis, gastric ulcers, pancreatitis, acute gastritis, peptic ulcer disease, nephrolithiasis, pyelonephritis, irritable bowel syndrome and gastroenteritis.Although some cases show a relationship between AAC and Kawasaki disease, the pathophysiology is unknown. It is occasionally the initial sign of systemic lupus erythematosus (SLE). (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | Related disorders of Acute Cholecystitis. Symptoms of the following disorders can be similar to those of cholecystitis. Comparisons may be useful for a differential diagnosis.Acute emphysematous cholecystitis (clostridial cholecystitis) occurs when gas forming bacteria like Clostridium and E. Coli cause acute infection and cell death (necrosis) in the gallbladder wall. Since this often results in early gangrene and perforation of the gallbladder, the disease has a high mortality rate and is considered a surgical emergency requiring cholecystectomy or if the patient is not a surgical candidate then percutaneous cholecystectomy. This form of acute cholecystitis is identified by the presence of air bubbles in the lumen or gallbladder wall seen in ultrasound or CT scans. It often progresses gradually without outward symptoms at first and then progresses very rapidly. AAC and acute emphysematous cholecystitis are closely associated; AAC is present in 50% of emphysematous cases. However, the emphysematous form is far more likely to result in gallbladder perforation. Physicians can tell if such perforation has occurred if pneumoperitoneum is seen on CT scans. Male diabetics are most susceptible to this disease. Gallbladder cancer is the uncontrolled growth of abnormal cells in the gallbladder. It is difficult to detect as patients may have no early symptoms thus diagnosis occurs at an advanced stage. Symptoms of gallbladder cancer mimic many other illnesses that include abdominal pain, bloating, itching, and fever. As in cholecystitis, blood tests from patients with this cancer may have abnormal levels of bilirubin, albumin, alkaline phosphatase, aspartate aminotransferase, alanine transaminase, and gamma-glutamyl transferase. These compounds are all indicators of liver and bile duct function. Imaging techniques like ultrasound and CT scanning may help distinguish tumors from gallstones. A variety of other conditions and diseases can cause symptoms similar to those seen in cholecystitis. These conditions include appendicitis, biliary colic, cholangitis, gastric ulcers, pancreatitis, acute gastritis, peptic ulcer disease, nephrolithiasis, pyelonephritis, irritable bowel syndrome and gastroenteritis.Although some cases show a relationship between AAC and Kawasaki disease, the pathophysiology is unknown. It is occasionally the initial sign of systemic lupus erythematosus (SLE). (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | 26 | Acute Cholecystitis |
nord_26_5 | Diagnosis of Acute Cholecystitis | Acute cholecystitis has no single clinical or laboratory finding with the level of diagnostic accuracy needed for diagnosis. Instead, the recommended diagnostic technique combines clinical observations with an abdominal ultrasound. The Tokyo Guidelines require one local sign or symptom, one systemic sign, and a confirmatory image test to form a diagnosis. However, these requirements may lead to under-diagnosis in patients presenting fewer symptoms. The Murphy’s sign test is a commonly used diagnostic tool. The physician applies pressure just below the ribs on the right side and asks the patient to inhale. Inhalation will bring the gallbladder into contact with the physician’s fingers, causing pain and an arrest in inspiration if the gallbladder is inflamed. Blood tests showing elevated levels of white blood cells (leukocytosis), elevated C-reactive protein, may be signs of infection and inflammation.Imaging techniques are used to directly observe gallstones, gallbladder wall thickness, or cystic duct obstruction. The gallbladder wall is pathologically thickened if it is >3mm or wider. The two main imaging techniques used for cholecystitis are abdominal ultrasound and hepatobiliary scintigraphy (HIDA scan). Abdominal ultrasound is often the first test due to its widespread availability, lack of invasiveness, lack of ionizing radiation, and high accuracy in detecting gallbladder stones. Ultrasound can show the presence of stones, wall thickening and pericholecystic fluid.A hepatobiliary iminodiacetic acid (HIDA) scan tracks the production and flow of bile from the liver to the small intestine and shows blockage. This test involves the intravenous injection of HIDA, a radioactively labelled compound, secreted into bile. A specialized camera can detect the radioactivity, allowing it to trace the movement of this bile. If the gallbladder does not fill within an hour, the cystic duct is likely obstructed. Although it is the most sensitive and specific diagnostic tool, it is limited in its use because of limited availability, long testing time, and ionizing radiation exposure. It can also be inaccurate if bilirubin is elevated which is indicative of decreased ability of the liver to secrete compounds such as HIDA into bile. Cholangiography and computed tomography (CT) may also be used to identify cholecystitis, although their diagnostic accuracy is unknown. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. During cholangiography, a contrast dye is injected into the bloodstream, which enables x-rays to create an image of the bile ducts. Additional imaging techniques include MRI.Diagnosis is often delayed in elderly patients, as the only symptoms may be an alteration of mental state or decreased food intake.
The 2007 Tokyo Guidelines grade the severity of the disease to help guide its treatment. Cases are graded as mild, moderate, and severe as follows:Mild (grade 1):
• Having none of the features of moderate or severe cholecystitisModerate (grade 2):
● Elevated white cell count
● Palpable, tender mass in upper right quadrant
● Duration longer than 72 hours
● Local inflammation (could be biliary peritonitis, pericholecystic abscess, hepatic abscess, gangrenous cholecystitis, or emphysematous cholecystitis)Severe (Grade 3):
● Cardiovascular dysfunction
● Neurological dysfunction
● Respiratory dysfunction
● Renal dysfunction
● Hepatic dysfunction
● Hematologic dysfunctionAcute Acalculous Cholecystitis (AAC)Diagnosis of AAC is often much more difficult than that of typical cholecystitis because it is much less common and patients often have severe concomitant medical problems that are the reason for hospital admission. The disease is generally suspected in any critically or chronically ill patient presenting with abdominal pain, fever and unexplained leukocytosis and sepsis. Blood tests may show increases in white blood cells (leukocytosis), transaminases, alkaline phosphatase, bilirubin, and amylase. As in calculous cholecystitis, ultrasound is the primary diagnostic imaging technique for AAC. Ultrasound may show gallbladder wall thickening greater than 5 mm, pericholecystic fluid, biliary sludge, gallbladder distention, gallbladder striation, mucosal peeling, air bubbles (emphysematous cholecystitis), and gallbladder perforation. Presence of at least two of the following is generally used to diagnose AAC: positive ultrasound Murphy’s sign, gallbladder wall thickening, gallbladder distension and pericholecystic fluid, in the absence of gallstones. CT and MRI are used when ultrasounds are inconclusive. An MRI can show gallbladder wall thickening, increased bile density, air bubbles, fluid buildup, and bleeding inside the gallbladder.Hepatobiliary scintigraphy is the best diagnostic tool for AAC because it can detect those without the disease 100% of the time. This test shows improper gallbladder filling in both AAC and calculous cholecystitis. | Diagnosis of Acute Cholecystitis. Acute cholecystitis has no single clinical or laboratory finding with the level of diagnostic accuracy needed for diagnosis. Instead, the recommended diagnostic technique combines clinical observations with an abdominal ultrasound. The Tokyo Guidelines require one local sign or symptom, one systemic sign, and a confirmatory image test to form a diagnosis. However, these requirements may lead to under-diagnosis in patients presenting fewer symptoms. The Murphy’s sign test is a commonly used diagnostic tool. The physician applies pressure just below the ribs on the right side and asks the patient to inhale. Inhalation will bring the gallbladder into contact with the physician’s fingers, causing pain and an arrest in inspiration if the gallbladder is inflamed. Blood tests showing elevated levels of white blood cells (leukocytosis), elevated C-reactive protein, may be signs of infection and inflammation.Imaging techniques are used to directly observe gallstones, gallbladder wall thickness, or cystic duct obstruction. The gallbladder wall is pathologically thickened if it is >3mm or wider. The two main imaging techniques used for cholecystitis are abdominal ultrasound and hepatobiliary scintigraphy (HIDA scan). Abdominal ultrasound is often the first test due to its widespread availability, lack of invasiveness, lack of ionizing radiation, and high accuracy in detecting gallbladder stones. Ultrasound can show the presence of stones, wall thickening and pericholecystic fluid.A hepatobiliary iminodiacetic acid (HIDA) scan tracks the production and flow of bile from the liver to the small intestine and shows blockage. This test involves the intravenous injection of HIDA, a radioactively labelled compound, secreted into bile. A specialized camera can detect the radioactivity, allowing it to trace the movement of this bile. If the gallbladder does not fill within an hour, the cystic duct is likely obstructed. Although it is the most sensitive and specific diagnostic tool, it is limited in its use because of limited availability, long testing time, and ionizing radiation exposure. It can also be inaccurate if bilirubin is elevated which is indicative of decreased ability of the liver to secrete compounds such as HIDA into bile. Cholangiography and computed tomography (CT) may also be used to identify cholecystitis, although their diagnostic accuracy is unknown. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. During cholangiography, a contrast dye is injected into the bloodstream, which enables x-rays to create an image of the bile ducts. Additional imaging techniques include MRI.Diagnosis is often delayed in elderly patients, as the only symptoms may be an alteration of mental state or decreased food intake.
The 2007 Tokyo Guidelines grade the severity of the disease to help guide its treatment. Cases are graded as mild, moderate, and severe as follows:Mild (grade 1):
• Having none of the features of moderate or severe cholecystitisModerate (grade 2):
● Elevated white cell count
● Palpable, tender mass in upper right quadrant
● Duration longer than 72 hours
● Local inflammation (could be biliary peritonitis, pericholecystic abscess, hepatic abscess, gangrenous cholecystitis, or emphysematous cholecystitis)Severe (Grade 3):
● Cardiovascular dysfunction
● Neurological dysfunction
● Respiratory dysfunction
● Renal dysfunction
● Hepatic dysfunction
● Hematologic dysfunctionAcute Acalculous Cholecystitis (AAC)Diagnosis of AAC is often much more difficult than that of typical cholecystitis because it is much less common and patients often have severe concomitant medical problems that are the reason for hospital admission. The disease is generally suspected in any critically or chronically ill patient presenting with abdominal pain, fever and unexplained leukocytosis and sepsis. Blood tests may show increases in white blood cells (leukocytosis), transaminases, alkaline phosphatase, bilirubin, and amylase. As in calculous cholecystitis, ultrasound is the primary diagnostic imaging technique for AAC. Ultrasound may show gallbladder wall thickening greater than 5 mm, pericholecystic fluid, biliary sludge, gallbladder distention, gallbladder striation, mucosal peeling, air bubbles (emphysematous cholecystitis), and gallbladder perforation. Presence of at least two of the following is generally used to diagnose AAC: positive ultrasound Murphy’s sign, gallbladder wall thickening, gallbladder distension and pericholecystic fluid, in the absence of gallstones. CT and MRI are used when ultrasounds are inconclusive. An MRI can show gallbladder wall thickening, increased bile density, air bubbles, fluid buildup, and bleeding inside the gallbladder.Hepatobiliary scintigraphy is the best diagnostic tool for AAC because it can detect those without the disease 100% of the time. This test shows improper gallbladder filling in both AAC and calculous cholecystitis. | 26 | Acute Cholecystitis |
nord_26_6 | Therapies of Acute Cholecystitis | Treatment
When first admitted for ACC, patients receive nothing by mouth as they may need immediate surgery. The primary treatment for the disease is usually cholecystectomy, the surgical removal of the entire gallbladder. Surgical removal of just the gallstones has a high rate of pathological recurrence within 5 years.For patients with mild cholecystitis, immediate laparoscopic cholecystectomy is recommended. During this procedure, a small, thin tube called a laparoscope is passed through a small incision in the abdominal wall, allowing a surgeon to remove the diseased gallbladder. It can be performed openly (operative cholecystostomy/ laparotomy) or laparoscopically. Patients with moderate cholecystitis may have immediate surgical removal of the gall bladder. Others will be put on bowel rest and receive intravenous hydration with fluids/electrolytes and pain medications followed by surgery once patient improves.Many patients with moderate to severe disease may not undergo cholecystectomy if complicated by infection and systemic dysfunctions that make them high risk for surgery. Instead, high surgical risk patients such as the elderly or those with immunodeficiency or diabetes may have a percutaneous, transhepatic cholecystostomy drainage tube permanently placed in their gall bladder with the guidance of ultrasonography. Severely affected patients are treated with resuscitation and IV antibiotics in the intensive care unit and surgery is performed once patient improves. The 2013 Tokyo Guidelines suggest immediate use of antibiotics in all patients with cholecysititis. Treatment for AAC is dependent on the type of underlying disease or trauma that is involved. Emergency cholecystectomy is necessary in many patients. The closed version of this surgery is usually preferred because AAC has such a high rate of tissue death (gangrene) and perforation. Conservative treatment by broad spectrum antibiotics is best when caused by Salmonella Enteritidis infection or Dengue. Gram-negative and anaerobic microorganism targeting antibiotics should be used in all patients. Treatment for any underlying conditions is also necessary. | Therapies of Acute Cholecystitis. Treatment
When first admitted for ACC, patients receive nothing by mouth as they may need immediate surgery. The primary treatment for the disease is usually cholecystectomy, the surgical removal of the entire gallbladder. Surgical removal of just the gallstones has a high rate of pathological recurrence within 5 years.For patients with mild cholecystitis, immediate laparoscopic cholecystectomy is recommended. During this procedure, a small, thin tube called a laparoscope is passed through a small incision in the abdominal wall, allowing a surgeon to remove the diseased gallbladder. It can be performed openly (operative cholecystostomy/ laparotomy) or laparoscopically. Patients with moderate cholecystitis may have immediate surgical removal of the gall bladder. Others will be put on bowel rest and receive intravenous hydration with fluids/electrolytes and pain medications followed by surgery once patient improves.Many patients with moderate to severe disease may not undergo cholecystectomy if complicated by infection and systemic dysfunctions that make them high risk for surgery. Instead, high surgical risk patients such as the elderly or those with immunodeficiency or diabetes may have a percutaneous, transhepatic cholecystostomy drainage tube permanently placed in their gall bladder with the guidance of ultrasonography. Severely affected patients are treated with resuscitation and IV antibiotics in the intensive care unit and surgery is performed once patient improves. The 2013 Tokyo Guidelines suggest immediate use of antibiotics in all patients with cholecysititis. Treatment for AAC is dependent on the type of underlying disease or trauma that is involved. Emergency cholecystectomy is necessary in many patients. The closed version of this surgery is usually preferred because AAC has such a high rate of tissue death (gangrene) and perforation. Conservative treatment by broad spectrum antibiotics is best when caused by Salmonella Enteritidis infection or Dengue. Gram-negative and anaerobic microorganism targeting antibiotics should be used in all patients. Treatment for any underlying conditions is also necessary. | 26 | Acute Cholecystitis |
nord_27_0 | Overview of Acute Disseminated Encephalomyelitis | SummaryAcute disseminated encephalomyelitis (ADEM) is a neurological, immune-mediated disorder in which widespread inflammation of the central nervous system (brain and spinal cord) damages tissue known as white matter. White matter is composed of nerve fibers that are covered by a collection of fats and proteins known as myelin. Myelin, also called the myelin sheath, protects the nerve fibers, acts as an insulator and increases the speed of transmission of nerve signals. Damage to the myelin sheath (demyelination) affects the ability of the nerves to transmit information and can potentially cause a wide range of neurological symptoms. The most common neurological symptoms of ADEM include arm/leg weakness, seizures, numbness or tingling, changes in mental status and vision loss; however, the specific symptoms and severity can vary between individuals. Onset can be at any age, but children are more likely to be affected than adults. Long-term outcomes for patients are generally favorable. The exact cause of ADEM is unknown, but it is thought to be associated with an autoimmune response that is triggered by an infection or, in rare instances, certain vaccinations. | Overview of Acute Disseminated Encephalomyelitis. SummaryAcute disseminated encephalomyelitis (ADEM) is a neurological, immune-mediated disorder in which widespread inflammation of the central nervous system (brain and spinal cord) damages tissue known as white matter. White matter is composed of nerve fibers that are covered by a collection of fats and proteins known as myelin. Myelin, also called the myelin sheath, protects the nerve fibers, acts as an insulator and increases the speed of transmission of nerve signals. Damage to the myelin sheath (demyelination) affects the ability of the nerves to transmit information and can potentially cause a wide range of neurological symptoms. The most common neurological symptoms of ADEM include arm/leg weakness, seizures, numbness or tingling, changes in mental status and vision loss; however, the specific symptoms and severity can vary between individuals. Onset can be at any age, but children are more likely to be affected than adults. Long-term outcomes for patients are generally favorable. The exact cause of ADEM is unknown, but it is thought to be associated with an autoimmune response that is triggered by an infection or, in rare instances, certain vaccinations. | 27 | Acute Disseminated Encephalomyelitis |
nord_27_1 | Symptoms of Acute Disseminated Encephalomyelitis | Symptoms of ADEM can present within days to weeks following an infection. In a subset of patients, there is no identifiable infectious “trigger” for ADEM. Most commonly, ADEM occurs only once in a particular individual, meaning the disease is most often considered a monophasic disorder; however, a small percentage of patients may exhibit future attacks of ADEM (termed multiphasic ADEM).The extent and progression of ADEM symptoms vary between affected individuals and may depend on the location of the brain lesions and the age of onset. Some individuals may have a mild, limited form of the disorder, while others may develop more severe symptoms. In the most severe cases, life-threatening complications such as respiratory failure is possible.Initial symptoms usually develop rapidly and are common to many different illnesses, such as the flu. These symptoms are considered nonspecific and include headache, fever, irritability, fatigue, lethargy and a general feeling of ill health (malaise). Nausea and vomiting may be present and lead to unintended weight loss. Confusion, stupor and delirium may also occur, and severely affected patients may fall into a coma.Additional neurological symptoms include the inability to coordinate voluntary movements (ataxia), weakness of the arms and/or legs, slurred speech, cranial nerve dysfunction, numbness of the body and seizures. Seizures are more common in children than adults, typically occurring in children under five years of age. Inflammation of the optic nerve(s) (optic neuritis) may develop along with ADEM and result in vision loss.Adults with ADEM may exhibit peripheral nerve damage (neuropathy). Individuals with neuropathy can experience weakness, pain, numbness or a burning or tingling sensation in the extremities and they typically have a worse prognosis. In some people, additional symptoms may develop including involuntary movements, amnesia, personality changes and depression. This appears to be a rare occurrence in children. Rarely, ataxia has been reported in patients who had ADEM following a Sars-Cov-2 infection. It is important to diagnose and treat ADEM associated with Sars-Cov-2 early to prevent poor outcomes.Acute hemorrhagic leukoencephalitis (AHL) is thought to be a severe, hyperacute form of ADEM. This variant is associated with rapid onset of fever, headaches, vomiting, neck stiffness and seizures. It may involve the neurological signs and symptoms associated with ADEM. AHL is often associated with rapid deterioration and life-threatening complications such as swelling of the brain (brain edema). Despite the severe, rapid course of AHL, some individuals have had a favorable neurological outcome when treated quickly and aggressively. | Symptoms of Acute Disseminated Encephalomyelitis. Symptoms of ADEM can present within days to weeks following an infection. In a subset of patients, there is no identifiable infectious “trigger” for ADEM. Most commonly, ADEM occurs only once in a particular individual, meaning the disease is most often considered a monophasic disorder; however, a small percentage of patients may exhibit future attacks of ADEM (termed multiphasic ADEM).The extent and progression of ADEM symptoms vary between affected individuals and may depend on the location of the brain lesions and the age of onset. Some individuals may have a mild, limited form of the disorder, while others may develop more severe symptoms. In the most severe cases, life-threatening complications such as respiratory failure is possible.Initial symptoms usually develop rapidly and are common to many different illnesses, such as the flu. These symptoms are considered nonspecific and include headache, fever, irritability, fatigue, lethargy and a general feeling of ill health (malaise). Nausea and vomiting may be present and lead to unintended weight loss. Confusion, stupor and delirium may also occur, and severely affected patients may fall into a coma.Additional neurological symptoms include the inability to coordinate voluntary movements (ataxia), weakness of the arms and/or legs, slurred speech, cranial nerve dysfunction, numbness of the body and seizures. Seizures are more common in children than adults, typically occurring in children under five years of age. Inflammation of the optic nerve(s) (optic neuritis) may develop along with ADEM and result in vision loss.Adults with ADEM may exhibit peripheral nerve damage (neuropathy). Individuals with neuropathy can experience weakness, pain, numbness or a burning or tingling sensation in the extremities and they typically have a worse prognosis. In some people, additional symptoms may develop including involuntary movements, amnesia, personality changes and depression. This appears to be a rare occurrence in children. Rarely, ataxia has been reported in patients who had ADEM following a Sars-Cov-2 infection. It is important to diagnose and treat ADEM associated with Sars-Cov-2 early to prevent poor outcomes.Acute hemorrhagic leukoencephalitis (AHL) is thought to be a severe, hyperacute form of ADEM. This variant is associated with rapid onset of fever, headaches, vomiting, neck stiffness and seizures. It may involve the neurological signs and symptoms associated with ADEM. AHL is often associated with rapid deterioration and life-threatening complications such as swelling of the brain (brain edema). Despite the severe, rapid course of AHL, some individuals have had a favorable neurological outcome when treated quickly and aggressively. | 27 | Acute Disseminated Encephalomyelitis |
nord_27_2 | Causes of Acute Disseminated Encephalomyelitis | The exact cause of ADEM is not known but it may be associated with an atypical immune response following an infectious trigger. An initial illness or infection is observed in 70-80% of patients with ADEM. For instance, ADEM can develop following an upper respiratory tract viral infection. Other ADEM inducing infections include influenza, measles, mumps, rubella, varicella-zoster, Epstein Barr virus, cytomegalovirus and herpes simplex virus.Less commonly, ADEM may develop following a vaccination, but this has become very rare and noted in <5% of all ADEM cases. These case reports do not necessarily indicate that ADEM is caused by vaccination.
Recent studies indicate that ADEM is also linked to the presence of antibodies against myelin oligodendrocyte glycoprotein (MOG). MOG is a protein that is found in the CNS and is a component of the myelin sheath. Antibodies to the MOG protein, more commonly noted in children, have been linked to a variety of inflammatory demyelinating conditions including ADEM.
| Causes of Acute Disseminated Encephalomyelitis. The exact cause of ADEM is not known but it may be associated with an atypical immune response following an infectious trigger. An initial illness or infection is observed in 70-80% of patients with ADEM. For instance, ADEM can develop following an upper respiratory tract viral infection. Other ADEM inducing infections include influenza, measles, mumps, rubella, varicella-zoster, Epstein Barr virus, cytomegalovirus and herpes simplex virus.Less commonly, ADEM may develop following a vaccination, but this has become very rare and noted in <5% of all ADEM cases. These case reports do not necessarily indicate that ADEM is caused by vaccination.
Recent studies indicate that ADEM is also linked to the presence of antibodies against myelin oligodendrocyte glycoprotein (MOG). MOG is a protein that is found in the CNS and is a component of the myelin sheath. Antibodies to the MOG protein, more commonly noted in children, have been linked to a variety of inflammatory demyelinating conditions including ADEM.
| 27 | Acute Disseminated Encephalomyelitis |
nord_27_3 | Affects of Acute Disseminated Encephalomyelitis | ADEM can develop at any age but is much more frequent in younger children. Outcomes and severity of ADEM are typically worse in adults than in children. Males and females are affected, but males may be affected more often. In children, the mean age of onset is between 5-8 years old, but ADEM has been diagnosed in children as young as 7 months.The incidence of ADEM in the general population is unknown, but the incidence of childhood ADEM is estimated to be 0.07 – 0.09 per 100,000. In the U.S., ADEM seems to peak in the winter and spring months and evidence also suggests that incidence increases with increasing distance from the equator.ADEM is not an inherited disorder, but genetic factors may play a role in the risk to develop ADEM. | Affects of Acute Disseminated Encephalomyelitis. ADEM can develop at any age but is much more frequent in younger children. Outcomes and severity of ADEM are typically worse in adults than in children. Males and females are affected, but males may be affected more often. In children, the mean age of onset is between 5-8 years old, but ADEM has been diagnosed in children as young as 7 months.The incidence of ADEM in the general population is unknown, but the incidence of childhood ADEM is estimated to be 0.07 – 0.09 per 100,000. In the U.S., ADEM seems to peak in the winter and spring months and evidence also suggests that incidence increases with increasing distance from the equator.ADEM is not an inherited disorder, but genetic factors may play a role in the risk to develop ADEM. | 27 | Acute Disseminated Encephalomyelitis |
nord_27_4 | Related disorders of Acute Disseminated Encephalomyelitis | Symptoms of the following disorders can be similar to those of ADEM. Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system involving the brain, spinal cord and optic nerves. As a result of an unknown mechanism in MS, the myelin sheath that surrounds the nerve is destroyed. The inflammatory attacks that damage the myelin sheath occur randomly and vary in intensity and location. The randomness of the location of the lesions affects the nerve’s ability to transmit information and causes a wide range of neurological symptoms which vary from person to person. Although MS is similar in presentation to ADEM, ADEM typically involves symptoms of encephalopathy such as lethargy and coma. Additionally, MS may relapse multiple times in the same individual which is a less commonly noted with ADEM. (For more information on this disorder, choose “multiple sclerosis” as your search term in the Rare Disease Database.)Neuromyelitis optica spectrum disorder (NMOSD), also known as Devic disease, is a chronic disorder of the brain and spinal cord characterized by inflammation of the optic nerve (optic neuritis) and inflammation of the spinal cord (myelitis). NMOSD can cause vision loss, eye pain, weakness, numbness and sometimes paralysis of the arms and legs. Recovery from NMOSD is often not as good as recovery noted in patients with ADEM. (For more information on this disorder, choose “NMOSD” as your search term in the Rare Disease Database.)Transverse myelitis is a neurological disorder caused by inflammation within the spinal cord (myelitis). This inflammation results in changed function below this level of the spine while function remains normal above. Symptoms are related to movement and sensory functions, and this disorder occurs in adults and children. Transverse myelitis involves a rapid onset of symptoms that occur over the course of several hours, days, or weeks. Symptoms include lower back pain, weakness in the legs and arms, sensory disturbance, spasms leading to gradual paralysis and bowel or bladder dysfunction. In most people, this disorder occurs on a single occasion, although a small number of individuals may experience recurrence. The initial occurrence may be followed, over a period of several weeks or months, by a period of recovery, although this does not happen in all patients. Similar to ADEM, transverse myelitis may occur following viral or bacterial infections. (For more information on this disorder, choose “transverse myelitis” as your search term in the Rare Disease Database.)Other disorders can present with signs and symptoms that are similar to those found in ADEM, which may include:
• Inflammatory, demyelinating disorders of the central or peripheral nervous system such as Behcet’s disease, infectious encephalitis, Guillain-Barre syndrome and neurosarcoidosis
• Vascular disorders affecting the central nervous system such as promthrombotic conditions, antiphospholipid antibody syndrome, sickle cell disease, and CADASIL
• Certain malignancies such as central nervous system lymphoma or glioblastoma multiforme
• Inherited leukodystrophies
• A variety of toxic, nutritional and metabolic disorders including vitamin B12 deficiency, folate deficiency, mercury poisoning, Marchiafava- Bignami disease, organic acidurias and lactic acidosis
• Psychotic disorders with acute onsetFor more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database. | Related disorders of Acute Disseminated Encephalomyelitis. Symptoms of the following disorders can be similar to those of ADEM. Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system involving the brain, spinal cord and optic nerves. As a result of an unknown mechanism in MS, the myelin sheath that surrounds the nerve is destroyed. The inflammatory attacks that damage the myelin sheath occur randomly and vary in intensity and location. The randomness of the location of the lesions affects the nerve’s ability to transmit information and causes a wide range of neurological symptoms which vary from person to person. Although MS is similar in presentation to ADEM, ADEM typically involves symptoms of encephalopathy such as lethargy and coma. Additionally, MS may relapse multiple times in the same individual which is a less commonly noted with ADEM. (For more information on this disorder, choose “multiple sclerosis” as your search term in the Rare Disease Database.)Neuromyelitis optica spectrum disorder (NMOSD), also known as Devic disease, is a chronic disorder of the brain and spinal cord characterized by inflammation of the optic nerve (optic neuritis) and inflammation of the spinal cord (myelitis). NMOSD can cause vision loss, eye pain, weakness, numbness and sometimes paralysis of the arms and legs. Recovery from NMOSD is often not as good as recovery noted in patients with ADEM. (For more information on this disorder, choose “NMOSD” as your search term in the Rare Disease Database.)Transverse myelitis is a neurological disorder caused by inflammation within the spinal cord (myelitis). This inflammation results in changed function below this level of the spine while function remains normal above. Symptoms are related to movement and sensory functions, and this disorder occurs in adults and children. Transverse myelitis involves a rapid onset of symptoms that occur over the course of several hours, days, or weeks. Symptoms include lower back pain, weakness in the legs and arms, sensory disturbance, spasms leading to gradual paralysis and bowel or bladder dysfunction. In most people, this disorder occurs on a single occasion, although a small number of individuals may experience recurrence. The initial occurrence may be followed, over a period of several weeks or months, by a period of recovery, although this does not happen in all patients. Similar to ADEM, transverse myelitis may occur following viral or bacterial infections. (For more information on this disorder, choose “transverse myelitis” as your search term in the Rare Disease Database.)Other disorders can present with signs and symptoms that are similar to those found in ADEM, which may include:
• Inflammatory, demyelinating disorders of the central or peripheral nervous system such as Behcet’s disease, infectious encephalitis, Guillain-Barre syndrome and neurosarcoidosis
• Vascular disorders affecting the central nervous system such as promthrombotic conditions, antiphospholipid antibody syndrome, sickle cell disease, and CADASIL
• Certain malignancies such as central nervous system lymphoma or glioblastoma multiforme
• Inherited leukodystrophies
• A variety of toxic, nutritional and metabolic disorders including vitamin B12 deficiency, folate deficiency, mercury poisoning, Marchiafava- Bignami disease, organic acidurias and lactic acidosis
• Psychotic disorders with acute onsetFor more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database. | 27 | Acute Disseminated Encephalomyelitis |
nord_27_5 | Diagnosis of Acute Disseminated Encephalomyelitis | A diagnosis of ADEM is made based on the identification of characteristic symptoms, a detailed patient history, thorough clinical evaluation and a variety of specialized tests including imaging techniques such as magnetic resonance imaging (MRI). An MRI uses a magnetic field and radio waves to produce cross-sectional images of organs and bodily tissues and can demonstrate characteristic brain lesions in individuals with ADEM. Additional tests such as spinal fluid testing may be needed to exclude other conditions. New diagnostic serum testing for the myelin oligodendrocyte glycoprotein antibody (MOG-Ab), a protein that makes up the myelin sheath in the CNS, is being increasingly utilized. This test is a cell-based assay that specifically tests for the presence of antibodies against the MOG protein which has been associated with a variety of CNS demyelinating disorders such as ADEM. | Diagnosis of Acute Disseminated Encephalomyelitis. A diagnosis of ADEM is made based on the identification of characteristic symptoms, a detailed patient history, thorough clinical evaluation and a variety of specialized tests including imaging techniques such as magnetic resonance imaging (MRI). An MRI uses a magnetic field and radio waves to produce cross-sectional images of organs and bodily tissues and can demonstrate characteristic brain lesions in individuals with ADEM. Additional tests such as spinal fluid testing may be needed to exclude other conditions. New diagnostic serum testing for the myelin oligodendrocyte glycoprotein antibody (MOG-Ab), a protein that makes up the myelin sheath in the CNS, is being increasingly utilized. This test is a cell-based assay that specifically tests for the presence of antibodies against the MOG protein which has been associated with a variety of CNS demyelinating disorders such as ADEM. | 27 | Acute Disseminated Encephalomyelitis |
nord_27_6 | Therapies of Acute Disseminated Encephalomyelitis | TreatmentNo standard therapy for ADEM has been established. Most therapies that have been used to treat ADEM have some effect of modifying the activity of the host immune system. Such therapies include corticosteroids, immunoglobulin (IVIg) therapy or plasmapheresis. High doses of corticosteroids are the primary treatment for ADEM and are generally effective. Methylprednisolone and dexamethasone are the most prescribed corticosteroids. These medications typically reduce the severity of symptoms and hasten recovery in affected individuals but may cause significant side effects such as alterations in mood and behavior, irritated stomach lining and elevated blood pressure or blood sugar. Intravenous immunoglobulin (IVIg) may be used to treat patients with ADEM who do not respond to or have an intolerance to corticosteroid therapy. IVIg is a concentrated solution of antibodies that have been extracted from the blood of healthy donors. IVIg is effective against autoimmune disorders because the extracted antibodies neutralize the effects of autoantibodies (antibodies that target healthy tissues).Plasmapheresis has been used to treat patients with ADEM who do not respond to other forms of therapy. Plasmapheresis filters toxins and metabolic substances from the blood. The procedure works by separating blood cells from plasma. The patient’s plasma is then replaced with human plasma and the patient’s blood (blood cells and plasma) is transfused back into the body. The treatment typically requires hospitalization and is performed every other day for 10-14 days. Other possible second-line treatments include intravenous immunosuppressive medications such as rituximab or cyclophosphamide.Rehabilitation therapy may be helpful for affected individuals that experience longer-term effects such as cognitive and speech impairments, epilepsy and visual and/or motor problems. | Therapies of Acute Disseminated Encephalomyelitis. TreatmentNo standard therapy for ADEM has been established. Most therapies that have been used to treat ADEM have some effect of modifying the activity of the host immune system. Such therapies include corticosteroids, immunoglobulin (IVIg) therapy or plasmapheresis. High doses of corticosteroids are the primary treatment for ADEM and are generally effective. Methylprednisolone and dexamethasone are the most prescribed corticosteroids. These medications typically reduce the severity of symptoms and hasten recovery in affected individuals but may cause significant side effects such as alterations in mood and behavior, irritated stomach lining and elevated blood pressure or blood sugar. Intravenous immunoglobulin (IVIg) may be used to treat patients with ADEM who do not respond to or have an intolerance to corticosteroid therapy. IVIg is a concentrated solution of antibodies that have been extracted from the blood of healthy donors. IVIg is effective against autoimmune disorders because the extracted antibodies neutralize the effects of autoantibodies (antibodies that target healthy tissues).Plasmapheresis has been used to treat patients with ADEM who do not respond to other forms of therapy. Plasmapheresis filters toxins and metabolic substances from the blood. The procedure works by separating blood cells from plasma. The patient’s plasma is then replaced with human plasma and the patient’s blood (blood cells and plasma) is transfused back into the body. The treatment typically requires hospitalization and is performed every other day for 10-14 days. Other possible second-line treatments include intravenous immunosuppressive medications such as rituximab or cyclophosphamide.Rehabilitation therapy may be helpful for affected individuals that experience longer-term effects such as cognitive and speech impairments, epilepsy and visual and/or motor problems. | 27 | Acute Disseminated Encephalomyelitis |
nord_28_0 | Overview of Acute Eosinophilic Pneumonia | SummaryAcute eosinophilic pneumonia (AEP) is a rare disorder characterized by the rapid accumulation of eosinophils in the lungs (pulmonary eosinophilia). Eosinophils are a type of white blood cell and are part of the immune system. They are usually produced in response to allergens, inflammation or infection (especially parasitic ones) and are particularly active in the respiratory tract. Common symptoms associated with AEP include progressive shortness of breath (dyspnea) of rapid onset and possibly acute respiratory failure, cough, fatigue, night sweats, fever, and unintended weight loss. The exact cause of the disorder is unknown (idiopathic) in many patients, however, recent change in tobacco smoking habits and drug intake can trigger the disease. Outcome is favorable with corticosteroids, without relapse.Introduction AEP was first described as a distinct entity in the medical literature in 1989. AEP is classified as a form of eosinophilic lung disease, a large group of interstitial lung diseases. AEP is different from chronic eosinophilic pneumonia (CEP), which is marked by slower progression, lack of progression to acute respiratory failure, frequent relapses and is often associated with asthma. For more information on CEP, choose “chronic eosinophilic pneumonia” as your search term in the NORD Rare Disease Database. | Overview of Acute Eosinophilic Pneumonia. SummaryAcute eosinophilic pneumonia (AEP) is a rare disorder characterized by the rapid accumulation of eosinophils in the lungs (pulmonary eosinophilia). Eosinophils are a type of white blood cell and are part of the immune system. They are usually produced in response to allergens, inflammation or infection (especially parasitic ones) and are particularly active in the respiratory tract. Common symptoms associated with AEP include progressive shortness of breath (dyspnea) of rapid onset and possibly acute respiratory failure, cough, fatigue, night sweats, fever, and unintended weight loss. The exact cause of the disorder is unknown (idiopathic) in many patients, however, recent change in tobacco smoking habits and drug intake can trigger the disease. Outcome is favorable with corticosteroids, without relapse.Introduction AEP was first described as a distinct entity in the medical literature in 1989. AEP is classified as a form of eosinophilic lung disease, a large group of interstitial lung diseases. AEP is different from chronic eosinophilic pneumonia (CEP), which is marked by slower progression, lack of progression to acute respiratory failure, frequent relapses and is often associated with asthma. For more information on CEP, choose “chronic eosinophilic pneumonia” as your search term in the NORD Rare Disease Database. | 28 | Acute Eosinophilic Pneumonia |
nord_28_1 | Symptoms of Acute Eosinophilic Pneumonia | AEP is characterized by a sudden, rapid onset of symptoms usually within 1-7 days. However, in some cases, symptoms may develop less rapidly over the course of up to one month. AEP often develops in young, otherwise healthy individuals. Associated symptoms are nonspecific and can include fever, cough, difficulty breathing (dyspnea) and chest pain. Less common symptoms include fatigue, muscle pain (myalgia), joint aches, and abdominal discomfort or pain.AEP can rapidly progress to acute respiratory failure. Acute respiratory failure occurs when the level of oxygen in the blood decreases severely (hypoxemia), potentially resulting in life-threatening breathing complications. This can occur within a few days or even within hours in individuals with AEP. Approximately two-thirds of individuals may require mechanical ventilation.AEP is an extremely rare disorder and may be confused with infectious pneumonia, especially in the absence of differential cell count on bronchoalveolar lavage. As AEP becomes better known and more affected individuals are identified, researchers should be able to obtain a better clinical understanding of the disorder. For example, some researchers believe that milder cases of AEP exist, but may go undiagnosed as they can improve spontaneously. These mild cases may cause less severe symptoms and complications. | Symptoms of Acute Eosinophilic Pneumonia. AEP is characterized by a sudden, rapid onset of symptoms usually within 1-7 days. However, in some cases, symptoms may develop less rapidly over the course of up to one month. AEP often develops in young, otherwise healthy individuals. Associated symptoms are nonspecific and can include fever, cough, difficulty breathing (dyspnea) and chest pain. Less common symptoms include fatigue, muscle pain (myalgia), joint aches, and abdominal discomfort or pain.AEP can rapidly progress to acute respiratory failure. Acute respiratory failure occurs when the level of oxygen in the blood decreases severely (hypoxemia), potentially resulting in life-threatening breathing complications. This can occur within a few days or even within hours in individuals with AEP. Approximately two-thirds of individuals may require mechanical ventilation.AEP is an extremely rare disorder and may be confused with infectious pneumonia, especially in the absence of differential cell count on bronchoalveolar lavage. As AEP becomes better known and more affected individuals are identified, researchers should be able to obtain a better clinical understanding of the disorder. For example, some researchers believe that milder cases of AEP exist, but may go undiagnosed as they can improve spontaneously. These mild cases may cause less severe symptoms and complications. | 28 | Acute Eosinophilic Pneumonia |
nord_28_2 | Causes of Acute Eosinophilic Pneumonia | The cause of IAEP is unknown (idiopathic). Researchers believe that AEP develops due to an unidentified, nonspecific triggering agent that causes the body to produce eosinophils and recruit them to the lungs. The exact reason for the overproduction and accumulation of eosinophils is unknown.Several environmental factors including occupational factors have been shown to trigger AEP including exposure to dust and smoke. It is unlikely that a single environmental factor causes AEP. Most likely, multiple factors are necessary for the development of the disorder, with association of a triggering condition in a predisposed individual. The triggering factor in AEP can be different from one individual to another.In many cases, cigarette smoking is believed to play a key role in the development of the disorder, specifically in individuals who had just begun smoking within the last three months before the onset of the disorder, have resumed smoking after temporary cessation, or have recently increased the number of cigarettes smoked daily. Several reports in the medical literature have demonstrated an association between cigarette smoking and “idiopathic” AEP in a subset of affected individuals. The exact role that smoking plays in the development of AEP in such cases is not fully understood.Occupational factors that have been showed to trigger AEP are numerous and varied; they have in common a usually important exposure to inhaled dusts. These cases suggest that breathing in some type of contaminate or inhaled agent that induces damage to the lungs can trigger AEP.Additional reports in the medical literature have linked some cases of AEP to the use of a number of drugs. Drug-induced cases have been linked to minocycline, daptomycin, and velafaxine, an antidepressant, and others (www.pneumotox.com). New causes continue to be described.Some researchers believe that cytokines (specialized proteins secreted from certain immune system cells that either stimulate or inhibit the function of other immune system cells) may play a role in the development of eosinophilic disorders. Interleukin-5 (IL-5) is a cytokine that is known to be a regulator of the development and function of eosinophils. IL-5 also suppresses the normal disintegration (apoptosis) of eosinophils resulting in their accumulation within the lungs and bloodstream. More research is necessary to determine the exact role and mechanism of agents that trigger AEP in the appropriate context. | Causes of Acute Eosinophilic Pneumonia. The cause of IAEP is unknown (idiopathic). Researchers believe that AEP develops due to an unidentified, nonspecific triggering agent that causes the body to produce eosinophils and recruit them to the lungs. The exact reason for the overproduction and accumulation of eosinophils is unknown.Several environmental factors including occupational factors have been shown to trigger AEP including exposure to dust and smoke. It is unlikely that a single environmental factor causes AEP. Most likely, multiple factors are necessary for the development of the disorder, with association of a triggering condition in a predisposed individual. The triggering factor in AEP can be different from one individual to another.In many cases, cigarette smoking is believed to play a key role in the development of the disorder, specifically in individuals who had just begun smoking within the last three months before the onset of the disorder, have resumed smoking after temporary cessation, or have recently increased the number of cigarettes smoked daily. Several reports in the medical literature have demonstrated an association between cigarette smoking and “idiopathic” AEP in a subset of affected individuals. The exact role that smoking plays in the development of AEP in such cases is not fully understood.Occupational factors that have been showed to trigger AEP are numerous and varied; they have in common a usually important exposure to inhaled dusts. These cases suggest that breathing in some type of contaminate or inhaled agent that induces damage to the lungs can trigger AEP.Additional reports in the medical literature have linked some cases of AEP to the use of a number of drugs. Drug-induced cases have been linked to minocycline, daptomycin, and velafaxine, an antidepressant, and others (www.pneumotox.com). New causes continue to be described.Some researchers believe that cytokines (specialized proteins secreted from certain immune system cells that either stimulate or inhibit the function of other immune system cells) may play a role in the development of eosinophilic disorders. Interleukin-5 (IL-5) is a cytokine that is known to be a regulator of the development and function of eosinophils. IL-5 also suppresses the normal disintegration (apoptosis) of eosinophils resulting in their accumulation within the lungs and bloodstream. More research is necessary to determine the exact role and mechanism of agents that trigger AEP in the appropriate context. | 28 | Acute Eosinophilic Pneumonia |
nord_28_3 | Affects of Acute Eosinophilic Pneumonia | AEP affects males approximately twice as often as females. Fewer than 200 cases have been reported in the medical literature and the exact prevalence is unknown. AEP can affect individuals of any age, but occurs most often in individuals between 20-40 years of age. | Affects of Acute Eosinophilic Pneumonia. AEP affects males approximately twice as often as females. Fewer than 200 cases have been reported in the medical literature and the exact prevalence is unknown. AEP can affect individuals of any age, but occurs most often in individuals between 20-40 years of age. | 28 | Acute Eosinophilic Pneumonia |
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