id
stringlengths 8
11
| title
stringlengths 14
124
| content
stringlengths 0
34k
| contents
stringlengths 20
34k
| nordid
int64 0
1.32k
| rare-disease
stringlengths 4
103
|
|---|---|---|---|---|---|
nord_428_4 | Related disorders of Essential Iris Atrophy | Related disorders of Essential Iris Atrophy. | 428 | Essential Iris Atrophy |
|
nord_428_5 | Diagnosis of Essential Iris Atrophy | Symptoms of the following disorders can be similar to those of essential iris atrophy. Comparisons may be useful for a differential diagnosis:Chandler's syndrome (CS) is a rare eye disorder in which the endothelium, the single layer of cells lining the inner surface of the cornea, proliferates causing corneal edema, distortion of the iris, and unusually high pressure in the eye (glaucoma). CS is one of three syndromes affecting the eyes (progressive iris atrophy and Cogan-Reese syndrome are the other two) that make up the iridocorneal endothelial syndrome (ICE syndrome). The spectrum is an acquired, unilateral disorder, which typically occurs in early to middle adulthood and predominantly affects women. Chandler's syndrome is the most commonly encountered clinical variant of this spectrum. (For more information on this disorder, choose “Chandler’s” as your search term in the Rare Disease Database.)Cogan-Reese syndrome is an extremely rare disorder characterized by loss of iris tissue and the development of small wart-like growths on the iris. Increased pressure within the eye (glaucoma) and corneal swelling (edema) are also evident. This disorder differs from Cogan corneal dystrophy which is inherited as an autosomal dominant disorder. The displacement and/or distortion of the pupil characteristic of essential iris atrophy does not occur in Cogan corneal dystrophy. (For more information on this disorder, choose “Cogan Reese” as your search term in the Rare Disease Database.)Axenfeld’s anomaly is characterized by attachment of portions of the iris to the cornea (peripheral anterior synechiae). Axenfeld’s anomaly is considered to be an inherited, developmental defect, while the iridocorneal syndromes (Cogan-Reese syndrome, Chandler’s syndrome, and essential iris atrophy) are thought to be acquired disorders. There is some confusion in the medical literature as to whether Axenfeld’s and Rieger’s anomalies are separate disorders or whether they occur together in what is called the Axenfeld-Rieger (A-R) syndrome. Of note, A-R syndrome is a bilateral condition, whereas ICE syndrome is usually unilateral.Rieger’s anomaly is characterized by attachment of portions of the iris to the cornea, a distorted pupil, clouding of the edges of the cornea (peripheral corneal opacification), displacement of iris tissue (hypoplasia), and/or secondary glaucoma. When Rieger’s anomaly occurs in association with dental abnormalities (i.e., a decrease in the number of teeth, small teeth, or anodontia) and facial malformations (i.e., displacement of the jaw, flattening of the midface, a receding upper lip and prominent lower lip) it is referred to as Rieger’s syndrome. Rieger anomaly is considered to be an inherited, developmental defect. | Diagnosis of Essential Iris Atrophy. Symptoms of the following disorders can be similar to those of essential iris atrophy. Comparisons may be useful for a differential diagnosis:Chandler's syndrome (CS) is a rare eye disorder in which the endothelium, the single layer of cells lining the inner surface of the cornea, proliferates causing corneal edema, distortion of the iris, and unusually high pressure in the eye (glaucoma). CS is one of three syndromes affecting the eyes (progressive iris atrophy and Cogan-Reese syndrome are the other two) that make up the iridocorneal endothelial syndrome (ICE syndrome). The spectrum is an acquired, unilateral disorder, which typically occurs in early to middle adulthood and predominantly affects women. Chandler's syndrome is the most commonly encountered clinical variant of this spectrum. (For more information on this disorder, choose “Chandler’s” as your search term in the Rare Disease Database.)Cogan-Reese syndrome is an extremely rare disorder characterized by loss of iris tissue and the development of small wart-like growths on the iris. Increased pressure within the eye (glaucoma) and corneal swelling (edema) are also evident. This disorder differs from Cogan corneal dystrophy which is inherited as an autosomal dominant disorder. The displacement and/or distortion of the pupil characteristic of essential iris atrophy does not occur in Cogan corneal dystrophy. (For more information on this disorder, choose “Cogan Reese” as your search term in the Rare Disease Database.)Axenfeld’s anomaly is characterized by attachment of portions of the iris to the cornea (peripheral anterior synechiae). Axenfeld’s anomaly is considered to be an inherited, developmental defect, while the iridocorneal syndromes (Cogan-Reese syndrome, Chandler’s syndrome, and essential iris atrophy) are thought to be acquired disorders. There is some confusion in the medical literature as to whether Axenfeld’s and Rieger’s anomalies are separate disorders or whether they occur together in what is called the Axenfeld-Rieger (A-R) syndrome. Of note, A-R syndrome is a bilateral condition, whereas ICE syndrome is usually unilateral.Rieger’s anomaly is characterized by attachment of portions of the iris to the cornea, a distorted pupil, clouding of the edges of the cornea (peripheral corneal opacification), displacement of iris tissue (hypoplasia), and/or secondary glaucoma. When Rieger’s anomaly occurs in association with dental abnormalities (i.e., a decrease in the number of teeth, small teeth, or anodontia) and facial malformations (i.e., displacement of the jaw, flattening of the midface, a receding upper lip and prominent lower lip) it is referred to as Rieger’s syndrome. Rieger anomaly is considered to be an inherited, developmental defect. | 428 | Essential Iris Atrophy |
nord_428_6 | Therapies of Essential Iris Atrophy | Secondary Glaucoma and Treatment:In general, glaucoma is one of the leading causes of blindness in the world. Glaucoma is characterized by increased pressure within the eye. If left untreated, the increased pressure affects the optic nerve, resulting in eventual blindness.. The etiology of glaucoma in unclear and remains an active area of research. The American Academy of Ophthalmology recommends a complete eye exam by the age of 40 or earlier for those at increased risk. Important elements of the examination include visual acuity test, tonometry to measure intraocular pressure, gonioscopy to assess if the drainage angle is open or closed, slit lamp examination to assess the anterior segment of the eye, use of special lenses to examine the optic nerve and posterior segment of the eye, and visual field test to assess the loss of peripheral or central vision.Glaucoma may occur as a secondary disorder to essential iris atrophy. The mechanism of glaucoma in ICE syndrome (all three variants) is believed to be related to a cellular membrane secreted by the abnormal endothelial cells. This membrane covers the trabecular meshwork of the drainage angle, thereby obstructing aqueous outflow facility and elevating intraocular pressure. In the early stages, the angle may appear open clinically although it is covered by this transparent membrane. Over time, contraction of this membrane leads to peripheral anterior synechiae and secondary angle closure glaucoma.Treatment of essential iris atrophy usually involves the use of drops in the eyes to control the glaucoma and swelling (edema). Mild cases or corneal edema are often managed with soft contact lenses and hypertonic saline solutions. In advanced cases penetrating or endothelial keratoplasty may be required, although the failure rate is high with need for repeat corneal grafts. In some individuals, the corneal edema may be improved with reduction in intraocular pressure. Medical therapy for glaucoma is usually initiated with aqueous suppressants, including beta blockers, alpha-2 agonists and carbonic anhydrase inhibitors. Prostaglandin analogues may be helpful in some cases. Surgical intervention for glaucoma is eventually required in a high percentage of patients with ICE syndrome. The most commonly performed procedure is trabeculectomy, with variable success rates. Glaucoma drainage devices have shown favorable outcomes in a small number of patients, but further studies are warranted to validate these results in a large series. Laser surgery is rarely effective. | Therapies of Essential Iris Atrophy. Secondary Glaucoma and Treatment:In general, glaucoma is one of the leading causes of blindness in the world. Glaucoma is characterized by increased pressure within the eye. If left untreated, the increased pressure affects the optic nerve, resulting in eventual blindness.. The etiology of glaucoma in unclear and remains an active area of research. The American Academy of Ophthalmology recommends a complete eye exam by the age of 40 or earlier for those at increased risk. Important elements of the examination include visual acuity test, tonometry to measure intraocular pressure, gonioscopy to assess if the drainage angle is open or closed, slit lamp examination to assess the anterior segment of the eye, use of special lenses to examine the optic nerve and posterior segment of the eye, and visual field test to assess the loss of peripheral or central vision.Glaucoma may occur as a secondary disorder to essential iris atrophy. The mechanism of glaucoma in ICE syndrome (all three variants) is believed to be related to a cellular membrane secreted by the abnormal endothelial cells. This membrane covers the trabecular meshwork of the drainage angle, thereby obstructing aqueous outflow facility and elevating intraocular pressure. In the early stages, the angle may appear open clinically although it is covered by this transparent membrane. Over time, contraction of this membrane leads to peripheral anterior synechiae and secondary angle closure glaucoma.Treatment of essential iris atrophy usually involves the use of drops in the eyes to control the glaucoma and swelling (edema). Mild cases or corneal edema are often managed with soft contact lenses and hypertonic saline solutions. In advanced cases penetrating or endothelial keratoplasty may be required, although the failure rate is high with need for repeat corneal grafts. In some individuals, the corneal edema may be improved with reduction in intraocular pressure. Medical therapy for glaucoma is usually initiated with aqueous suppressants, including beta blockers, alpha-2 agonists and carbonic anhydrase inhibitors. Prostaglandin analogues may be helpful in some cases. Surgical intervention for glaucoma is eventually required in a high percentage of patients with ICE syndrome. The most commonly performed procedure is trabeculectomy, with variable success rates. Glaucoma drainage devices have shown favorable outcomes in a small number of patients, but further studies are warranted to validate these results in a large series. Laser surgery is rarely effective. | 428 | Essential Iris Atrophy |
nord_429_0 | Overview of Essential Thrombocythemia | SummaryEssential thrombocythemia, also known as ET, is a rare disease. The most important first fact about ET: on average, people with ET have a normal life expectancy.
Patients with ET have increased numbers of platelets. Platelets are the smallest of the three types of blood cells and are needed for successful blood clotting after an injury. The two other types of blood cells are red blood cells, which carry oxygen to all tissues in the body, and white blood cells, which help to fight infections. Red blood cell numbers (often measured as a percentage of whole blood, called a hematocrit) are generally normal in ET, while white blood cell numbers are normal or slightly elevated in ET. Importantly, most people with an elevated platelet count do not have ET. Common alternative causes of an elevated platelet count are iron deficiency, infection or generalized inflammation; less common causes are blood disorders such as ET or other related blood diseases (also see below).IntroductionIn the 1950’s, a pioneering hematologist, William Dameshek, placed ET within a family of blood diseases called myeloproliferative disorders. These were unified by their propensity to lead to abnormal increases in various blood cells, perhaps, in Dr. Dameshek’s words, “due to a hitherto undiscovered stimulus”. At the time, it was unclear if these “proliferations” represented a natural response to some external cause, or were the result of an internal defect.Over time, it became obvious that the myeloproliferative disorders are caused by genetic accidents (an internal defect) in very early blood cells (stem cells), which are then passed along to all of the progeny of that cell, even as they mature into platelets, red cells, or white blood cells (see below). In acknowledgement of this new understanding, myeloproliferative disorders have been renamed myeloproliferative neoplasms (MPN). For this reason, ET is best thought of as a chronic type of leukemia – albeit one with an overall excellent prognosis and often requiring minimal or no treatment. | Overview of Essential Thrombocythemia. SummaryEssential thrombocythemia, also known as ET, is a rare disease. The most important first fact about ET: on average, people with ET have a normal life expectancy.
Patients with ET have increased numbers of platelets. Platelets are the smallest of the three types of blood cells and are needed for successful blood clotting after an injury. The two other types of blood cells are red blood cells, which carry oxygen to all tissues in the body, and white blood cells, which help to fight infections. Red blood cell numbers (often measured as a percentage of whole blood, called a hematocrit) are generally normal in ET, while white blood cell numbers are normal or slightly elevated in ET. Importantly, most people with an elevated platelet count do not have ET. Common alternative causes of an elevated platelet count are iron deficiency, infection or generalized inflammation; less common causes are blood disorders such as ET or other related blood diseases (also see below).IntroductionIn the 1950’s, a pioneering hematologist, William Dameshek, placed ET within a family of blood diseases called myeloproliferative disorders. These were unified by their propensity to lead to abnormal increases in various blood cells, perhaps, in Dr. Dameshek’s words, “due to a hitherto undiscovered stimulus”. At the time, it was unclear if these “proliferations” represented a natural response to some external cause, or were the result of an internal defect.Over time, it became obvious that the myeloproliferative disorders are caused by genetic accidents (an internal defect) in very early blood cells (stem cells), which are then passed along to all of the progeny of that cell, even as they mature into platelets, red cells, or white blood cells (see below). In acknowledgement of this new understanding, myeloproliferative disorders have been renamed myeloproliferative neoplasms (MPN). For this reason, ET is best thought of as a chronic type of leukemia – albeit one with an overall excellent prognosis and often requiring minimal or no treatment. | 429 | Essential Thrombocythemia |
nord_429_1 | Symptoms of Essential Thrombocythemia | The greatest health risk in patients with ET is an increased risk of developing blood clots. Blood clots can be in the deep vessels of the legs or lungs; ET patients are also more likely to experience strokes and heart attacks. ET patients can develop clots elsewhere, including within the abdomen, an otherwise rare site for clots to form. The risk of clotting increases with age, and disease-associated risks may be quite different for children than for adults, with children generally being at low risk for clots and other problems related to ET. In addition, (and somewhat counter-intuitively) a subset of ET patients may also be more likely to bleed; this appears to be restricted to a small minority of patients with a very high (over 1.5 million) platelet count. Other symptoms in ET include headaches, fatigue, temporary changes in vision, dizziness, ringing in the ears, vertigo and tingling in the hands.Very rarely, patients with ET can experience an evolution from ET to a more advanced blood disease. ET can evolve into a related disease called myelofibrosis, or into acute leukemia. This evolution is sufficiently rare (within what is already a rare disease), that the estimates of the risk are imprecise but are thought to be on the order of 1-2% of patients with ET over a lifetime. | Symptoms of Essential Thrombocythemia. The greatest health risk in patients with ET is an increased risk of developing blood clots. Blood clots can be in the deep vessels of the legs or lungs; ET patients are also more likely to experience strokes and heart attacks. ET patients can develop clots elsewhere, including within the abdomen, an otherwise rare site for clots to form. The risk of clotting increases with age, and disease-associated risks may be quite different for children than for adults, with children generally being at low risk for clots and other problems related to ET. In addition, (and somewhat counter-intuitively) a subset of ET patients may also be more likely to bleed; this appears to be restricted to a small minority of patients with a very high (over 1.5 million) platelet count. Other symptoms in ET include headaches, fatigue, temporary changes in vision, dizziness, ringing in the ears, vertigo and tingling in the hands.Very rarely, patients with ET can experience an evolution from ET to a more advanced blood disease. ET can evolve into a related disease called myelofibrosis, or into acute leukemia. This evolution is sufficiently rare (within what is already a rare disease), that the estimates of the risk are imprecise but are thought to be on the order of 1-2% of patients with ET over a lifetime. | 429 | Essential Thrombocythemia |
nord_429_2 | Causes of Essential Thrombocythemia | Over the ensuing decades, Dr. Dameshek’s predictions about a stimulus triggering the proliferation of blood cells were confirmed. The first came in the 1960s, when the genetic basis for another MPN family member known as chronic myelogenous leukemia (CML) was identified as the Philadelphia chromosome, named after the city in which it was discovered. The Philadelphia chromosome is an abnormal chromosome caused by the fusion of two chromosomes in the leukemia cells. This genetic change causes a specific protein, called a kinase, to be overactive. Because kinases are very powerful drivers of cell growth, this genetic change leads to an elevation in blood counts and enlargement of the liver and spleen. Once the genetic basis of CML was identified, drugs that might interfere with kinase activity (kinase inhibitors) were tested and proved to be extraordinarily successful in treating CML. Collectively these studies radically reversed the natural history of the CML by converting what was previously a fatal disease to one with an excellent prognosis. The majority of patients with CML are diagnosed because they have a high white blood cell count, but on occasion patients with CML will only have a high platelet count, therefore every patient with suspected ET is also evaluated for CML, with a test for the Philadelphia chromosome.It took decades longer for the specific genetic basis for ET to be identified. In 2005, four separate groups of investigators discovered a variation (mutation) in the JAK2 gene in 50-60% of patients with ET. This variation, like that in CML, leads to overactivity in a type of enzyme called a kinase, specifically Janus kinase 2 (JAK2). 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, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body.The liver normally produces a hormone called thrombopoietin. This hormone binds to hematopoietic stem cells, which are immature cells found in the bone marrow that eventually become red cells, white cells, and platelets. When this binding occurs. The JAK2 enzyme makes the hematopoietic cells divide into precursor cells that become platelets (megakaryocytes) and platelets. The platelets are misshapen and can be abnormally large. These extra, abnormally-shaped platelets increase the risk of blood clots. For the more than 40% of ET patients without the JAK2 mutation, the genetic basis for those patients was unknown until 2013. Two groups of investigators reported that ET patients commonly have a variation in a gene called calreticulin (CALR). CALR mutations were found in approximately 70% of the patients with ET who did not have a JAK2 mutation. Although the function of CALR within a cell is less well understood than that of JAK2, it appears that CALR revs up the same cellular machinery that is abnormally active in ET with a JAK2 mutation. This makes sense, since CALR-mutated patients with ET are virtually indistinguishable from those ET patients who have the JAK2 mutation. Calreticulin is a receptor, a protein found on the surface of hematopoietic cells to which thrombopoietin binds. Much more rarely other variations are found in ET, but mutations either in JAK2 or in CALR are by far the most common, accounting for over 75% of patients with ET. | Causes of Essential Thrombocythemia. Over the ensuing decades, Dr. Dameshek’s predictions about a stimulus triggering the proliferation of blood cells were confirmed. The first came in the 1960s, when the genetic basis for another MPN family member known as chronic myelogenous leukemia (CML) was identified as the Philadelphia chromosome, named after the city in which it was discovered. The Philadelphia chromosome is an abnormal chromosome caused by the fusion of two chromosomes in the leukemia cells. This genetic change causes a specific protein, called a kinase, to be overactive. Because kinases are very powerful drivers of cell growth, this genetic change leads to an elevation in blood counts and enlargement of the liver and spleen. Once the genetic basis of CML was identified, drugs that might interfere with kinase activity (kinase inhibitors) were tested and proved to be extraordinarily successful in treating CML. Collectively these studies radically reversed the natural history of the CML by converting what was previously a fatal disease to one with an excellent prognosis. The majority of patients with CML are diagnosed because they have a high white blood cell count, but on occasion patients with CML will only have a high platelet count, therefore every patient with suspected ET is also evaluated for CML, with a test for the Philadelphia chromosome.It took decades longer for the specific genetic basis for ET to be identified. In 2005, four separate groups of investigators discovered a variation (mutation) in the JAK2 gene in 50-60% of patients with ET. This variation, like that in CML, leads to overactivity in a type of enzyme called a kinase, specifically Janus kinase 2 (JAK2). 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, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body.The liver normally produces a hormone called thrombopoietin. This hormone binds to hematopoietic stem cells, which are immature cells found in the bone marrow that eventually become red cells, white cells, and platelets. When this binding occurs. The JAK2 enzyme makes the hematopoietic cells divide into precursor cells that become platelets (megakaryocytes) and platelets. The platelets are misshapen and can be abnormally large. These extra, abnormally-shaped platelets increase the risk of blood clots. For the more than 40% of ET patients without the JAK2 mutation, the genetic basis for those patients was unknown until 2013. Two groups of investigators reported that ET patients commonly have a variation in a gene called calreticulin (CALR). CALR mutations were found in approximately 70% of the patients with ET who did not have a JAK2 mutation. Although the function of CALR within a cell is less well understood than that of JAK2, it appears that CALR revs up the same cellular machinery that is abnormally active in ET with a JAK2 mutation. This makes sense, since CALR-mutated patients with ET are virtually indistinguishable from those ET patients who have the JAK2 mutation. Calreticulin is a receptor, a protein found on the surface of hematopoietic cells to which thrombopoietin binds. Much more rarely other variations are found in ET, but mutations either in JAK2 or in CALR are by far the most common, accounting for over 75% of patients with ET. | 429 | Essential Thrombocythemia |
nord_429_3 | Affects of Essential Thrombocythemia | Fewer than 1 in 100,000 people are diagnosed with ET in any year (the most recent estimates range from 0.38 to 1.7 per 100,000). Women are more likely to be diagnosed with ET than men, although the reason for this is unknown. The average age of onset is mid-fifties, but the range is wide, and includes women in their childbearing years, which makes up an important subset of ET patients with special therapeutic considerations (discussed below). In children ET is exceedingly rare and typically is an inherited genetic disorder. In adults, the genetic mutations typically identified in ET (described below) are not inherited, and instead are acquired genetic accidents (known as an acquired mutation) that happen during an individual’s lifetime. Genetic accidents happen to all of us as we age, although they do not always result in a disease. | Affects of Essential Thrombocythemia. Fewer than 1 in 100,000 people are diagnosed with ET in any year (the most recent estimates range from 0.38 to 1.7 per 100,000). Women are more likely to be diagnosed with ET than men, although the reason for this is unknown. The average age of onset is mid-fifties, but the range is wide, and includes women in their childbearing years, which makes up an important subset of ET patients with special therapeutic considerations (discussed below). In children ET is exceedingly rare and typically is an inherited genetic disorder. In adults, the genetic mutations typically identified in ET (described below) are not inherited, and instead are acquired genetic accidents (known as an acquired mutation) that happen during an individual’s lifetime. Genetic accidents happen to all of us as we age, although they do not always result in a disease. | 429 | Essential Thrombocythemia |
nord_429_4 | Related disorders of Essential Thrombocythemia | Symptoms of the related myeloproliferative disorders can be similar to those of essential thrombocythemia, although as a general rule the burden of symptoms is milder in ET patients. Comparisons may be useful for a differential diagnosis.Polycythemia vera is a rare, chronic disorder involving the overproduction of blood cells in the bone marrow (myeloproliferation). The overproduction of red blood cells is most dramatic, but the production of white blood cells and platelets are also elevated in most cases. Since red blood cells are overproduced in the marrow, this leads to abnormally high numbers of circulating red blood cells (red blood mass) within the circulatory system. Consequently, the blood thickens and increases in volume, a condition called hyperviscosity. Thickened blood may not flow through smaller blood vessels properly. A variety of symptoms can occur in individuals with polycythemia vera including nonspecific symptoms such as headaches, fatigue, weakness, dizziness or itchy skin; an enlarged spleen (splenomegaly); a variety of gastrointestinal issues; and the risk of blood clot formation, which may prevent blood flow to vital organs. More than 90 percent of individuals with polycythemia vera have a mutation of the JAK2 gene. (For more information on this disorder, choose “polycythemia vera” as your search term in the Rare Disease Database.)Primary myelofibrosis is a rare bone marrow disorder that is characterized by abnormalities in blood cell production (hematopoiesis) and scarring (formation of fibrous tissue) within the bone marrow. Bone marrow is the soft, spongy tissue that fills the center of most bones. Bone marrow contains specialized cells called hematopoietic stem cells that grow and eventually develop into one of the three main types of blood cells: red blood cells, white blood cells or platelets. In primary myelofibrosis, a change in the DNA of a single hematopoietic stem cell causes the abnormal cell to continually reproduce itself. Eventually, these abnormal cells crowd out normal, healthy cells in the marrow and, along with scarring within the marrow, disrupt the production of red and white blood cells and platelets. The symptoms associated with primary myelofibrosis vary, and are related to the abnormalities affecting blood cell production. Affected individuals may not have symptoms at the time of diagnosis (asymptomatic) and may remain symptom-free for many years. Eventually, affected individuals may develop fatigue, fever, frequent infections, pale skin, night sweats and unexplained weight loss. An enlarged spleen is a common finding. An enlarged liver may also occur. (For more information on this disorder, choose “primary myelofibrosis” as your search term in the Rare Disease Database.)Chronic myelogenous leukemia (CML), discussed above, is a rare myeloproliferative disorder characterized by the excessive development of white blood cells in the spongy tissue found inside large bones of the body (bone marrow), spleen, liver and blood. As the disease progresses, the leukemic cells invade other areas of the body including the intestinal tract, kidneys, lungs, gonads and lymph nodes. There are two phases to chronic myelogenous leukemia. The first phase, or chronic phase, is characterized by a slow, progressive overproduction of white blood cells. An advanced phase is called the acute phase or blast crisis. At this point, the leukemia is very aggressive and does not typically respond well to therapy. (For more information on this disorder, choose “chronic myelogenous leukemia” as your search term in the Rare Disease Database.) | Related disorders of Essential Thrombocythemia. Symptoms of the related myeloproliferative disorders can be similar to those of essential thrombocythemia, although as a general rule the burden of symptoms is milder in ET patients. Comparisons may be useful for a differential diagnosis.Polycythemia vera is a rare, chronic disorder involving the overproduction of blood cells in the bone marrow (myeloproliferation). The overproduction of red blood cells is most dramatic, but the production of white blood cells and platelets are also elevated in most cases. Since red blood cells are overproduced in the marrow, this leads to abnormally high numbers of circulating red blood cells (red blood mass) within the circulatory system. Consequently, the blood thickens and increases in volume, a condition called hyperviscosity. Thickened blood may not flow through smaller blood vessels properly. A variety of symptoms can occur in individuals with polycythemia vera including nonspecific symptoms such as headaches, fatigue, weakness, dizziness or itchy skin; an enlarged spleen (splenomegaly); a variety of gastrointestinal issues; and the risk of blood clot formation, which may prevent blood flow to vital organs. More than 90 percent of individuals with polycythemia vera have a mutation of the JAK2 gene. (For more information on this disorder, choose “polycythemia vera” as your search term in the Rare Disease Database.)Primary myelofibrosis is a rare bone marrow disorder that is characterized by abnormalities in blood cell production (hematopoiesis) and scarring (formation of fibrous tissue) within the bone marrow. Bone marrow is the soft, spongy tissue that fills the center of most bones. Bone marrow contains specialized cells called hematopoietic stem cells that grow and eventually develop into one of the three main types of blood cells: red blood cells, white blood cells or platelets. In primary myelofibrosis, a change in the DNA of a single hematopoietic stem cell causes the abnormal cell to continually reproduce itself. Eventually, these abnormal cells crowd out normal, healthy cells in the marrow and, along with scarring within the marrow, disrupt the production of red and white blood cells and platelets. The symptoms associated with primary myelofibrosis vary, and are related to the abnormalities affecting blood cell production. Affected individuals may not have symptoms at the time of diagnosis (asymptomatic) and may remain symptom-free for many years. Eventually, affected individuals may develop fatigue, fever, frequent infections, pale skin, night sweats and unexplained weight loss. An enlarged spleen is a common finding. An enlarged liver may also occur. (For more information on this disorder, choose “primary myelofibrosis” as your search term in the Rare Disease Database.)Chronic myelogenous leukemia (CML), discussed above, is a rare myeloproliferative disorder characterized by the excessive development of white blood cells in the spongy tissue found inside large bones of the body (bone marrow), spleen, liver and blood. As the disease progresses, the leukemic cells invade other areas of the body including the intestinal tract, kidneys, lungs, gonads and lymph nodes. There are two phases to chronic myelogenous leukemia. The first phase, or chronic phase, is characterized by a slow, progressive overproduction of white blood cells. An advanced phase is called the acute phase or blast crisis. At this point, the leukemia is very aggressive and does not typically respond well to therapy. (For more information on this disorder, choose “chronic myelogenous leukemia” as your search term in the Rare Disease Database.) | 429 | Essential Thrombocythemia |
nord_429_5 | Diagnosis of Essential Thrombocythemia | Many, if not most ET patients have no symptoms related to their disease when they are diagnosed, and instead have an abnormally high platelet count identified on routine blood tests. Other ET patients are identified when they have symptoms or a complication – often a blood clot – related to ET. Additional tests may be performed to confirm the elevated platelet count, and to elucidate its possible causes. These may include blood tests that evaluate for iron deficiency and/or inflammatory diseases, and genetic tests for mutations that are seen in ET or related diseases. If no other obvious cause for an elevated platelet count is identified, and/or ET or a related blood disorder is suspected, a hematologist will typically recommend a bone marrow biopsy.A bone marrow biopsy is a safe office procedure where a small piece of bone and a small amount of liquid bone marrow are obtained from the hip bone. Because all blood cells are born in and go through early life in the bone marrow, a bone marrow biopsy is used to directly visualize the bone marrow cells and their architecture within the bone. Many blood disorders are diagnosed by looking at the early blood cells within the bone marrow. Additional genetic and molecular testing on the liquid bone marrow (bone marrow aspirate) also provides valuable information. Together, these findings are used to establish a diagnosis of ET or a related disorder. | Diagnosis of Essential Thrombocythemia. Many, if not most ET patients have no symptoms related to their disease when they are diagnosed, and instead have an abnormally high platelet count identified on routine blood tests. Other ET patients are identified when they have symptoms or a complication – often a blood clot – related to ET. Additional tests may be performed to confirm the elevated platelet count, and to elucidate its possible causes. These may include blood tests that evaluate for iron deficiency and/or inflammatory diseases, and genetic tests for mutations that are seen in ET or related diseases. If no other obvious cause for an elevated platelet count is identified, and/or ET or a related blood disorder is suspected, a hematologist will typically recommend a bone marrow biopsy.A bone marrow biopsy is a safe office procedure where a small piece of bone and a small amount of liquid bone marrow are obtained from the hip bone. Because all blood cells are born in and go through early life in the bone marrow, a bone marrow biopsy is used to directly visualize the bone marrow cells and their architecture within the bone. Many blood disorders are diagnosed by looking at the early blood cells within the bone marrow. Additional genetic and molecular testing on the liquid bone marrow (bone marrow aspirate) also provides valuable information. Together, these findings are used to establish a diagnosis of ET or a related disorder. | 429 | Essential Thrombocythemia |
nord_429_6 | Therapies of Essential Thrombocythemia | Treatment
Treatment is geared towards two goals: making patients with ET-related symptoms feel better, and reducing the risk of clotting events.Risk of clotting events is what guides hematologists in their treatment recommendations. Hematologists are doctors that specialize in the diagnosis and treatment of blood disorders. The risk of clots in ET patients increases over time, with patients over the age of 60 having a relatively high risk. In addition, patients who have had a clotting event in the past are at high risk for subsequent events. Other meaningful but less significant risk factors for clots are tobacco use, high blood pressure, diabetes, and the presence of the JAK2 mutation that was discussed above.For most patients with ET, a low dose aspirin (usually 81-100 mg daily) is recommended to reduce the risk of clots. Aspirin may not be recommended for some patients who are thought to be at a very low risk for blood clots, or who may be at a higher risk for bleeding (a side-effect of aspirin), or in those with an allergy or other sensitivity to aspirin. Likewise, aspirin may not be recommended for patients on other medications such as blood thinners that increase the risk of bleeding.For patients considered at high risk for clotting, such as those with a prior clot, or a combination of other risks, a medication known as hydroxyurea or hydroxycarbamide is often recommended. This medication is recommended because it has been proven to meaningfully reduce the risk of ET-related complications such as clots. Patients at high risk for events have a risk of experiencing a significant clotting event that can exceed 3.5% per year. Hydroxyurea is an oral chemotherapy, and the most common effect of hydroxyurea is the lowering of blood counts. Less common side effects include mouth sores, and leg ulcers. Hypersensitivity reactions, such as fevers, rash or other allergic-type symptoms are uncommon. Long term use of hydroxyurea can also increase the risk of non-melanoma skin cancers, thus patients on hydroxyurea should be particularly mindful about sun exposure. There also remains an unresolved debate among hematologists as to whether hydroxyurea may marginally increase the risk of evolution of ET to acute leukemia. Although available data on the safety of hydroxyurea in ET and other MPN are reassuring and no studies have demonstrated an increased risk for leukemia, there have not been definitive studies to resolve this issue. Generally, if a hematologist recommends hydroxyurea it is because she or he feels that the benefits of this therapy outweigh its risks.Other medications used to treat ET include an oral medication called anagrelide, the chemotherapy medication busulfan, and an injectable medication called interferon; some patients with ET (such as those who have had a clot in liver veins) take blood-thinning medications such as warfarin. For those ET patients not considered at high risk for clots, but who are experiencing symptoms related to ET, the same treatments options discussed above are available.Several special considerations should be given in women with ET who are pregnant or attempting to become pregnant. Because of the risks to the developing fetus, many medications used to treat ET should be avoided, including hydroxyurea, anagrelide and warfarin. Pregnancy in general increases a woman’s risk of clots, and women with ET are particularly vulnerable. An injectable blood thinner that is safe in pregnancy – such as heparin or low molecular weight heparin – may be recommended to ET patients during and/or for a short period after pregnancy. If additional ET therapy is needed, interferon can also be safely used during pregnancy.Smoking puts patients with ET at a particularly high risk for clots, so it is always recommended that an ET patient stop smoking, as difficult as that may be. There are no known additional diets or special lifestyle recommendations for patients with ET.Summary
People with ET can live a long life with an excellent quality of life.Establishing a diagnosis of ET requires evaluating the bone marrow and a thorough evaluation for other disorders.Patients with ET should periodically see a hematologist who is experienced in treating patients with this disorder.Low dose aspirin is commonly recommended to treat symptoms and to reduce the risk of clots in patients with ET.Patients with uncontrolled symptoms related to ET or patients at high risk for clots may need additional medical therapy | Therapies of Essential Thrombocythemia. Treatment
Treatment is geared towards two goals: making patients with ET-related symptoms feel better, and reducing the risk of clotting events.Risk of clotting events is what guides hematologists in their treatment recommendations. Hematologists are doctors that specialize in the diagnosis and treatment of blood disorders. The risk of clots in ET patients increases over time, with patients over the age of 60 having a relatively high risk. In addition, patients who have had a clotting event in the past are at high risk for subsequent events. Other meaningful but less significant risk factors for clots are tobacco use, high blood pressure, diabetes, and the presence of the JAK2 mutation that was discussed above.For most patients with ET, a low dose aspirin (usually 81-100 mg daily) is recommended to reduce the risk of clots. Aspirin may not be recommended for some patients who are thought to be at a very low risk for blood clots, or who may be at a higher risk for bleeding (a side-effect of aspirin), or in those with an allergy or other sensitivity to aspirin. Likewise, aspirin may not be recommended for patients on other medications such as blood thinners that increase the risk of bleeding.For patients considered at high risk for clotting, such as those with a prior clot, or a combination of other risks, a medication known as hydroxyurea or hydroxycarbamide is often recommended. This medication is recommended because it has been proven to meaningfully reduce the risk of ET-related complications such as clots. Patients at high risk for events have a risk of experiencing a significant clotting event that can exceed 3.5% per year. Hydroxyurea is an oral chemotherapy, and the most common effect of hydroxyurea is the lowering of blood counts. Less common side effects include mouth sores, and leg ulcers. Hypersensitivity reactions, such as fevers, rash or other allergic-type symptoms are uncommon. Long term use of hydroxyurea can also increase the risk of non-melanoma skin cancers, thus patients on hydroxyurea should be particularly mindful about sun exposure. There also remains an unresolved debate among hematologists as to whether hydroxyurea may marginally increase the risk of evolution of ET to acute leukemia. Although available data on the safety of hydroxyurea in ET and other MPN are reassuring and no studies have demonstrated an increased risk for leukemia, there have not been definitive studies to resolve this issue. Generally, if a hematologist recommends hydroxyurea it is because she or he feels that the benefits of this therapy outweigh its risks.Other medications used to treat ET include an oral medication called anagrelide, the chemotherapy medication busulfan, and an injectable medication called interferon; some patients with ET (such as those who have had a clot in liver veins) take blood-thinning medications such as warfarin. For those ET patients not considered at high risk for clots, but who are experiencing symptoms related to ET, the same treatments options discussed above are available.Several special considerations should be given in women with ET who are pregnant or attempting to become pregnant. Because of the risks to the developing fetus, many medications used to treat ET should be avoided, including hydroxyurea, anagrelide and warfarin. Pregnancy in general increases a woman’s risk of clots, and women with ET are particularly vulnerable. An injectable blood thinner that is safe in pregnancy – such as heparin or low molecular weight heparin – may be recommended to ET patients during and/or for a short period after pregnancy. If additional ET therapy is needed, interferon can also be safely used during pregnancy.Smoking puts patients with ET at a particularly high risk for clots, so it is always recommended that an ET patient stop smoking, as difficult as that may be. There are no known additional diets or special lifestyle recommendations for patients with ET.Summary
People with ET can live a long life with an excellent quality of life.Establishing a diagnosis of ET requires evaluating the bone marrow and a thorough evaluation for other disorders.Patients with ET should periodically see a hematologist who is experienced in treating patients with this disorder.Low dose aspirin is commonly recommended to treat symptoms and to reduce the risk of clots in patients with ET.Patients with uncontrolled symptoms related to ET or patients at high risk for clots may need additional medical therapy | 429 | Essential Thrombocythemia |
nord_430_0 | Overview of Evans Syndrome | Evans syndrome is a rare disorder in which the body’s immune system produces antibodies that mistakenly destroy red blood cells, platelets and sometimes certain white blood cell known as neutrophils. This leads to abnormally low levels of these blood cells in the body (cytopenia). The premature destruction of red blood cells (hemolysis) is known as autoimmune hemolytic anemia or AIHA. Thrombocytopenia refers to low levels of platelets (idiopathic thrombocytopenia purpura or ITP in this instance). Neutropenia refers to low levels of certain white blood cells known as neutrophils. Evans syndrome is defined as the association of AIHA along with ITP; neutropenia occurs less often. In some cases, autoimmune destruction of these blood cells occurs at the same time (simultaneously); in most cases, one condition develops first before another condition develops later on (sequentially). The symptoms and severity of Evans syndrome can vary greatly from one person to another. Evans syndrome can potentially cause severe, life-threatening complications. Evans syndrome may occur by itself as a primary (idiopathic) disorder or in association with other autoimmune disorders or lymphoproliferative disorders as a secondary disorder. (Lymphoproliferative disorders are characterized by the overproduction of white blood cells.) The distinction between primary and secondary Evans syndrome is important as it can influence treatment.Evans syndrome was first described in the medical literature in 1951 by Dr. Robert Evans and associates. For years, the disorder was considered a coincidental occurrence of AIHA with thrombocytopenia and/or neutropenia. However, researchers now believe that the disorder represents a distinct condition characterized by a chronic, profound (more than in ITP or AIHA alone) state of immune system malfunction (dysregulation). | Overview of Evans Syndrome. Evans syndrome is a rare disorder in which the body’s immune system produces antibodies that mistakenly destroy red blood cells, platelets and sometimes certain white blood cell known as neutrophils. This leads to abnormally low levels of these blood cells in the body (cytopenia). The premature destruction of red blood cells (hemolysis) is known as autoimmune hemolytic anemia or AIHA. Thrombocytopenia refers to low levels of platelets (idiopathic thrombocytopenia purpura or ITP in this instance). Neutropenia refers to low levels of certain white blood cells known as neutrophils. Evans syndrome is defined as the association of AIHA along with ITP; neutropenia occurs less often. In some cases, autoimmune destruction of these blood cells occurs at the same time (simultaneously); in most cases, one condition develops first before another condition develops later on (sequentially). The symptoms and severity of Evans syndrome can vary greatly from one person to another. Evans syndrome can potentially cause severe, life-threatening complications. Evans syndrome may occur by itself as a primary (idiopathic) disorder or in association with other autoimmune disorders or lymphoproliferative disorders as a secondary disorder. (Lymphoproliferative disorders are characterized by the overproduction of white blood cells.) The distinction between primary and secondary Evans syndrome is important as it can influence treatment.Evans syndrome was first described in the medical literature in 1951 by Dr. Robert Evans and associates. For years, the disorder was considered a coincidental occurrence of AIHA with thrombocytopenia and/or neutropenia. However, researchers now believe that the disorder represents a distinct condition characterized by a chronic, profound (more than in ITP or AIHA alone) state of immune system malfunction (dysregulation). | 430 | Evans Syndrome |
nord_430_1 | Symptoms of Evans Syndrome | The symptoms and severity of Evans syndrome can vary greatly from one person to another as can the onset, course and duration of the disorder. Most individuals exhibit a chronic course with periods of worsening symptoms (exacerbation) and remissions usually induced transiently by treatment. Most symptoms are caused by low levels of specific blood cells in the body. These blood cells perform specific functions. Red blood cells deliver oxygen to the body and remove carbon dioxide, platelets assist in clotting to stop blood loss, and white blood cells help to fight infection.Some individuals with Evans syndrome may first present with accelerated destruction of red blood cells faster than the body can replace them. Low levels of circulating red blood cells, known as anemia, can cause a variety of symptoms including fatigue, pale skin color (pallor), lightheadedness, shortness of breath, dark colored urine, and a rapid heartbeat. Some individuals may develop yellowing of the skin and especially the whites of the eyes (jaundice).Other individuals may first present with low levels of platelets, known as thrombocytopenia. Thrombocytopenia may cause tiny reddish or purple spots on the skin (petechiae), larger purplish discoloration on the skin caused by bleeding from ruptured blood vessels into subcutaneous tissue (ecchymosis), and purpura, a rash consisting of purple spots cause by internal bleeding from small blood vessels. Affected individuals may be more susceptible to bruising following minimal injury and spontaneous bleeding from the mucous membranes.Low levels of white blood cells, known as neutropenia, occurs less frequently in individuals with Evans syndrome than anemia or thrombocytopenia. Individuals with neutropenia may be susceptible to recurrent infections. General symptoms may include fever, a general feeling of poor health (malaise) and sores (ulcers) on the mucous membranes of the mouth.Additional symptoms that may occur in individuals with Evans syndrome include enlargement of the lymph nodes, spleen and liver. These findings may come and go or, in some cases, may only occur during acute episodes.All too often, patients with Evans syndrome may not respond to treatment (refractory Evans syndrome) and can eventually progress to cause life-threatening complications including sepsis, severe bleeding (hemorrhaging) episodes, and significant cardiovascular problems including heart failure. | Symptoms of Evans Syndrome. The symptoms and severity of Evans syndrome can vary greatly from one person to another as can the onset, course and duration of the disorder. Most individuals exhibit a chronic course with periods of worsening symptoms (exacerbation) and remissions usually induced transiently by treatment. Most symptoms are caused by low levels of specific blood cells in the body. These blood cells perform specific functions. Red blood cells deliver oxygen to the body and remove carbon dioxide, platelets assist in clotting to stop blood loss, and white blood cells help to fight infection.Some individuals with Evans syndrome may first present with accelerated destruction of red blood cells faster than the body can replace them. Low levels of circulating red blood cells, known as anemia, can cause a variety of symptoms including fatigue, pale skin color (pallor), lightheadedness, shortness of breath, dark colored urine, and a rapid heartbeat. Some individuals may develop yellowing of the skin and especially the whites of the eyes (jaundice).Other individuals may first present with low levels of platelets, known as thrombocytopenia. Thrombocytopenia may cause tiny reddish or purple spots on the skin (petechiae), larger purplish discoloration on the skin caused by bleeding from ruptured blood vessels into subcutaneous tissue (ecchymosis), and purpura, a rash consisting of purple spots cause by internal bleeding from small blood vessels. Affected individuals may be more susceptible to bruising following minimal injury and spontaneous bleeding from the mucous membranes.Low levels of white blood cells, known as neutropenia, occurs less frequently in individuals with Evans syndrome than anemia or thrombocytopenia. Individuals with neutropenia may be susceptible to recurrent infections. General symptoms may include fever, a general feeling of poor health (malaise) and sores (ulcers) on the mucous membranes of the mouth.Additional symptoms that may occur in individuals with Evans syndrome include enlargement of the lymph nodes, spleen and liver. These findings may come and go or, in some cases, may only occur during acute episodes.All too often, patients with Evans syndrome may not respond to treatment (refractory Evans syndrome) and can eventually progress to cause life-threatening complications including sepsis, severe bleeding (hemorrhaging) episodes, and significant cardiovascular problems including heart failure. | 430 | Evans Syndrome |
nord_430_2 | Causes of Evans Syndrome | The exact, underlying cause of Evans syndrome is unknown. Evans syndrome is an autoimmune disorder. It occurs when the immune system produces antibodies that mistakenly attack healthy tissue, specifically red blood cells, platelets and sometimes certain white blood cells.The immune system normally responds to foreign substances by producing specialized proteins called antibodies. Antibodies work by destroying foreign substances directly or 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 an underlying disorder) may induce the immune system to produce autoantibodies in Evans syndrome.Evans syndrome may occur in combination with another disorder as a secondary condition. Secondary Evans syndrome can be associated with other disorders including autoimmune lymphoproliferative syndrome (ALPS), lupus, antiphospholipid syndrome, Sjogren’s syndrome, common variable immunodeficiency, IgA deficiency, certain lymphomas, and chronic lymphocytic leukemia. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | Causes of Evans Syndrome. The exact, underlying cause of Evans syndrome is unknown. Evans syndrome is an autoimmune disorder. It occurs when the immune system produces antibodies that mistakenly attack healthy tissue, specifically red blood cells, platelets and sometimes certain white blood cells.The immune system normally responds to foreign substances by producing specialized proteins called antibodies. Antibodies work by destroying foreign substances directly or 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 an underlying disorder) may induce the immune system to produce autoantibodies in Evans syndrome.Evans syndrome may occur in combination with another disorder as a secondary condition. Secondary Evans syndrome can be associated with other disorders including autoimmune lymphoproliferative syndrome (ALPS), lupus, antiphospholipid syndrome, Sjogren’s syndrome, common variable immunodeficiency, IgA deficiency, certain lymphomas, and chronic lymphocytic leukemia. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | 430 | Evans Syndrome |
nord_430_3 | Affects of Evans Syndrome | The incidence and prevalence of Evans syndrome is unknown. The disorder can affect children or adults. | Affects of Evans Syndrome. The incidence and prevalence of Evans syndrome is unknown. The disorder can affect children or adults. | 430 | Evans Syndrome |
nord_430_4 | Related disorders of Evans Syndrome | Symptoms of the following disorders can be similar to those of Evans syndrome. Comparisons may be useful for a differential diagnosis.Several different disorders may be characterized by the presence of both hemolytic anemia and thrombocytopenia. These disorders include paroxysmal nocturnal hemoglobinuria (PNH), acquired thrombotic thrombocytopenic purpura, hemolytic-uremic syndrome, and Kasabach-Merritt syndrome. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Autoimmune lymphoproliferative syndrome (ALPS) is a rare genetic disorder that overlaps with Evans syndrome. The characteristic finding in ALPS is the presence of abnormally high numbers of white blood cells called lymphocytes that may accumulate in the lymph nodes, liver and spleen causing enlargement of these organs. ALPS may result in symptoms similar to Evans syndrome, particularly anemia, thrombocytopenia and neutropenia. Most individuals with ALPS have a mutation in the tumor necrosis factor receptor gene superfamily member (TNFRSF6) also called CD95 or Fas. The exact relationship between these disorders, if any, is not fully understood. It is thought that approximately half of children diagnosed with Evans syndrome may have underlying ALPS as the cause because of a failure of auto-reactive cells to undergo normal programmed cell death (apoptosis). The intersection of ALPS and Evans syndrome is less clear in adults. | Related disorders of Evans Syndrome. Symptoms of the following disorders can be similar to those of Evans syndrome. Comparisons may be useful for a differential diagnosis.Several different disorders may be characterized by the presence of both hemolytic anemia and thrombocytopenia. These disorders include paroxysmal nocturnal hemoglobinuria (PNH), acquired thrombotic thrombocytopenic purpura, hemolytic-uremic syndrome, and Kasabach-Merritt syndrome. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Autoimmune lymphoproliferative syndrome (ALPS) is a rare genetic disorder that overlaps with Evans syndrome. The characteristic finding in ALPS is the presence of abnormally high numbers of white blood cells called lymphocytes that may accumulate in the lymph nodes, liver and spleen causing enlargement of these organs. ALPS may result in symptoms similar to Evans syndrome, particularly anemia, thrombocytopenia and neutropenia. Most individuals with ALPS have a mutation in the tumor necrosis factor receptor gene superfamily member (TNFRSF6) also called CD95 or Fas. The exact relationship between these disorders, if any, is not fully understood. It is thought that approximately half of children diagnosed with Evans syndrome may have underlying ALPS as the cause because of a failure of auto-reactive cells to undergo normal programmed cell death (apoptosis). The intersection of ALPS and Evans syndrome is less clear in adults. | 430 | Evans Syndrome |
nord_430_5 | Diagnosis of Evans Syndrome | A diagnosis of Evans syndrome is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation, and a variety of specialized tests. No specific test is conclusive for Evans syndrome and a diagnosis is made after excluding other possible diagnoses. Specifically, a diagnosis of Evans syndrome may be made when autoimmune hemolytic anemia (with a positive direct coombs test) and thrombocytopenia (ITP) occur in the same patient even if not at the same time.Clinical Testing and WorkupLaboratory studies include a complete blood count (CBC), which can reveal low levels of red blood cells, platelets and white blood cells. Another blood test known as a direct antiglobulin test or DAT is used to determine whether the amount of certain antibodies is higher than normal. A variety of different tests may be administered to rule out other conditions. Such tests can include a bone marrow biopsy, additional antibody assays, and computed tomography (CT) scans of the chest, abdomen and pelvis.Some physicians recommend that children with Evans syndrome be screened for ALPS because of the high prevalence of these two disorders occurring together. Screening involves testing for the presence of double negative ??T-cells (DNTs) by flow cytometry, the presence of which is indicative of ALPS. | Diagnosis of Evans Syndrome. A diagnosis of Evans syndrome is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation, and a variety of specialized tests. No specific test is conclusive for Evans syndrome and a diagnosis is made after excluding other possible diagnoses. Specifically, a diagnosis of Evans syndrome may be made when autoimmune hemolytic anemia (with a positive direct coombs test) and thrombocytopenia (ITP) occur in the same patient even if not at the same time.Clinical Testing and WorkupLaboratory studies include a complete blood count (CBC), which can reveal low levels of red blood cells, platelets and white blood cells. Another blood test known as a direct antiglobulin test or DAT is used to determine whether the amount of certain antibodies is higher than normal. A variety of different tests may be administered to rule out other conditions. Such tests can include a bone marrow biopsy, additional antibody assays, and computed tomography (CT) scans of the chest, abdomen and pelvis.Some physicians recommend that children with Evans syndrome be screened for ALPS because of the high prevalence of these two disorders occurring together. Screening involves testing for the presence of double negative ??T-cells (DNTs) by flow cytometry, the presence of which is indicative of ALPS. | 430 | Evans Syndrome |
nord_430_6 | Therapies of Evans Syndrome | TreatmentThere is no cure for Evans syndrome and treatment is often challenging. Treatment is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, hematologists, pediatric hematologists, immunologists, rheumatologists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment.Most affected individuals require treatment, although, in rare cases, spontaneously remission has been reported. A variety of different therapies have been used to treat individuals with Evans syndrome and their effectiveness among affected individuals has been highly variable. Some individuals have long remissions of the disorder; others experience chronic problems with no remission.Consequently, specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease severity; blood cell count levels; the presence or absence of certain symptoms; an individual’s age and general health; and/or other elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.First-line therapy for Evans syndrome often consists of corticosteroids such as prednisolone. Corticosteroids help to suppress the immune system and decrease the production of autoantibodies. Initial results are often effective.Intravenous immunoglobulin (IVIg) therapy has also been used to treat individuals with Evans syndrome. IVIg therapy modifies the activity of the immune system. IVIg is a solution containing antibodies donated from healthy individuals and delivered directly into a vein.Surgical removal of the spleen (splenectomy) has been used to treat some individuals with Evans syndrome. Most reports are inconclusive and anecdotal and the effectiveness of the procedure is difficult to determine because of the simultaneous (concomitant) use of other therapies such as drugs. Splenectomy is generally reserved for individuals who do not respond to other therapeutic options (refractory Evans syndrome). In children, splenectomy rarely produces long term remission of symptoms. In adults, the effectiveness varies and symptoms usually return at some point. Therefore, it is usually delayed as long as possible and every effort is made not to perform it.During an acute episode, blood and/or platelet transfusions may be necessary to address symptoms. However, the use of blood or platelet transfusions should be avoided as much as possible.New therapies are being explored for Evans syndrome. Rituximab appears to be a highly effective treatment for patients with Evans syndrome. Rituximab is classified as a monoclonal antibody or biologic therapy – medications that act like antibodies, but are artificially created in a lab. Initial studies have shown that the drug is generally safe and effective. Advantages of rituximab are that it avoids serious immunosuppression and side effects associated with other immunosuppressive agents. The disadvantage is that in cases of Evans syndrome in which underlying ALPS is the cause it appears likely that hypogammaglobulinemia will develop and may persist in rituximab-treated patients. Hypogammaglobulinemia is a condition in which the body’s immune system does not produce sufficient antibodies, potentially leaving affected individuals susceptible to bacterial infections and to a lesser extent certain viral infections.Additional medications have been studied in small case series of individuals with Evans syndrome. The next agent that appears to be relatively effective in this disorder is mycophenolate mofetil. These drugs may be used alone or in combination (multi-agent therapy) as second-line therapies for individuals with Evans syndrome who do not respond to corticosteroids or IVIg therapy. More research is necessary to determine the long-term safety and effectiveness of these potential therapies for individuals with Evans syndrome. | Therapies of Evans Syndrome. TreatmentThere is no cure for Evans syndrome and treatment is often challenging. Treatment is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, hematologists, pediatric hematologists, immunologists, rheumatologists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment.Most affected individuals require treatment, although, in rare cases, spontaneously remission has been reported. A variety of different therapies have been used to treat individuals with Evans syndrome and their effectiveness among affected individuals has been highly variable. Some individuals have long remissions of the disorder; others experience chronic problems with no remission.Consequently, specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease severity; blood cell count levels; the presence or absence of certain symptoms; an individual’s age and general health; and/or other elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.First-line therapy for Evans syndrome often consists of corticosteroids such as prednisolone. Corticosteroids help to suppress the immune system and decrease the production of autoantibodies. Initial results are often effective.Intravenous immunoglobulin (IVIg) therapy has also been used to treat individuals with Evans syndrome. IVIg therapy modifies the activity of the immune system. IVIg is a solution containing antibodies donated from healthy individuals and delivered directly into a vein.Surgical removal of the spleen (splenectomy) has been used to treat some individuals with Evans syndrome. Most reports are inconclusive and anecdotal and the effectiveness of the procedure is difficult to determine because of the simultaneous (concomitant) use of other therapies such as drugs. Splenectomy is generally reserved for individuals who do not respond to other therapeutic options (refractory Evans syndrome). In children, splenectomy rarely produces long term remission of symptoms. In adults, the effectiveness varies and symptoms usually return at some point. Therefore, it is usually delayed as long as possible and every effort is made not to perform it.During an acute episode, blood and/or platelet transfusions may be necessary to address symptoms. However, the use of blood or platelet transfusions should be avoided as much as possible.New therapies are being explored for Evans syndrome. Rituximab appears to be a highly effective treatment for patients with Evans syndrome. Rituximab is classified as a monoclonal antibody or biologic therapy – medications that act like antibodies, but are artificially created in a lab. Initial studies have shown that the drug is generally safe and effective. Advantages of rituximab are that it avoids serious immunosuppression and side effects associated with other immunosuppressive agents. The disadvantage is that in cases of Evans syndrome in which underlying ALPS is the cause it appears likely that hypogammaglobulinemia will develop and may persist in rituximab-treated patients. Hypogammaglobulinemia is a condition in which the body’s immune system does not produce sufficient antibodies, potentially leaving affected individuals susceptible to bacterial infections and to a lesser extent certain viral infections.Additional medications have been studied in small case series of individuals with Evans syndrome. The next agent that appears to be relatively effective in this disorder is mycophenolate mofetil. These drugs may be used alone or in combination (multi-agent therapy) as second-line therapies for individuals with Evans syndrome who do not respond to corticosteroids or IVIg therapy. More research is necessary to determine the long-term safety and effectiveness of these potential therapies for individuals with Evans syndrome. | 430 | Evans Syndrome |
nord_431_0 | Overview of Ewing Sarcoma | Ewing sarcoma is a rare bone tumor that occurs most often in adolescents. It can also arise outside of the bone in soft tissue (extraosseous Ewing sarcoma). Ewing sarcoma is related to another type of tumor known as primitive neuroectodermal tumor (PNET). Researchers have learned that these tumors are associated with the same chromosomal abnormality (balanced reciprocal translocation) and share many physiological characteristics. Consequently, these tumors are sometimes collectively classified as the Ewing family of tumors (EFT). This general term encompasses Ewing sarcoma of bone, extraosseous Ewing sarcoma, primitive neuroectodermal tumor, and Askin’s tumor (a tumor of the chest wall). Ewing sarcoma of bone accounts for approximately 70 percent of the tumors in this family. Generally, the term Ewing sarcoma is preferred because, despite the different names, it is one tumor, molecularly. Ewing sarcoma of bone most often affects the long bone of the legs (femur) and flat bones such as those found in the pelvis and chest well. Ewing sarcoma is an aggressive cancer that may spread (metastasize) to the lungs, other bones, and bone marrow potentially causing life-threatening complications. The exact cause of these tumors is unknown.Ewing sarcoma was first described in the medical literature in 1921 by Dr. James Ewing. Ewing sarcoma is the second most common primary bone tumor in children and accounts for approximately 2% of all childhood cancer diagnoses.NORD’s report on Ewing sarcoma is a detailed summary of the main aspects of this rare disorder. The National Cancer Institute offers comprehensive, in-depth information on this disorder, which is available at,For patients: http://www.cancer.gov/cancertopics/pdq/treatment/ewings/PatientFor healthcare professionals: http://www.cancer.gov/cancertopics/pdq/treatment/ewings/HealthProfessional | Overview of Ewing Sarcoma. Ewing sarcoma is a rare bone tumor that occurs most often in adolescents. It can also arise outside of the bone in soft tissue (extraosseous Ewing sarcoma). Ewing sarcoma is related to another type of tumor known as primitive neuroectodermal tumor (PNET). Researchers have learned that these tumors are associated with the same chromosomal abnormality (balanced reciprocal translocation) and share many physiological characteristics. Consequently, these tumors are sometimes collectively classified as the Ewing family of tumors (EFT). This general term encompasses Ewing sarcoma of bone, extraosseous Ewing sarcoma, primitive neuroectodermal tumor, and Askin’s tumor (a tumor of the chest wall). Ewing sarcoma of bone accounts for approximately 70 percent of the tumors in this family. Generally, the term Ewing sarcoma is preferred because, despite the different names, it is one tumor, molecularly. Ewing sarcoma of bone most often affects the long bone of the legs (femur) and flat bones such as those found in the pelvis and chest well. Ewing sarcoma is an aggressive cancer that may spread (metastasize) to the lungs, other bones, and bone marrow potentially causing life-threatening complications. The exact cause of these tumors is unknown.Ewing sarcoma was first described in the medical literature in 1921 by Dr. James Ewing. Ewing sarcoma is the second most common primary bone tumor in children and accounts for approximately 2% of all childhood cancer diagnoses.NORD’s report on Ewing sarcoma is a detailed summary of the main aspects of this rare disorder. The National Cancer Institute offers comprehensive, in-depth information on this disorder, which is available at,For patients: http://www.cancer.gov/cancertopics/pdq/treatment/ewings/PatientFor healthcare professionals: http://www.cancer.gov/cancertopics/pdq/treatment/ewings/HealthProfessional | 431 | Ewing Sarcoma |
nord_431_1 | Symptoms of Ewing Sarcoma | Individuals with a tumor in the Ewing family of tumors may exhibit pain, tenderness, and swelling near the affected part of the body. Pain often comes and goes (intermittent) initially, eventually progressing to be more consistent. Weakness and numbness in the affected area can also occur. In some cases, affected individuals may also experience fever, lack of energy, weight loss, low levels of circulating red blood cells (anemia), and increased levels of circulating white blood cells (leukocytosis). A palpable mass is often present. Ewing sarcoma most often affects the middle portion (diaphyseal region) of the long bones of the arms and legs, especially the long bone of the leg (femur). These tumors also commonly affect flat bones such as those found in the pelvis, chest wall, and spinal column (vertebrae). Ewing sarcoma may occur in any bone of the body such as the bones of the foot, the hand, the lower jaw (mandible), the skull, and/or additional locations. Soft tissue tumors develop most often in the trunk and chest. However, the most common site of presentation is the pelvis accounting for about 25% of cases. Ewing sarcoma may weaken bones sometimes resulting in fractures. These tumors are often aggressive and may spread (metastasize) to additional areas of the body, especially to other bones and the lungs. In rare cases, the bone marrow may become involved. Symptoms associated with these tumors are secondary to their location. For example, a tumor of the leg may result in a limp, a tumor in the lungs may result in breathing problems and an accumulation of fluid in the tissue layers that line the lungs and chest cavity (pleural effusion), or a tumor in the spinal column may cause weakness or paralysis of affected muscles (paraplegia). | Symptoms of Ewing Sarcoma. Individuals with a tumor in the Ewing family of tumors may exhibit pain, tenderness, and swelling near the affected part of the body. Pain often comes and goes (intermittent) initially, eventually progressing to be more consistent. Weakness and numbness in the affected area can also occur. In some cases, affected individuals may also experience fever, lack of energy, weight loss, low levels of circulating red blood cells (anemia), and increased levels of circulating white blood cells (leukocytosis). A palpable mass is often present. Ewing sarcoma most often affects the middle portion (diaphyseal region) of the long bones of the arms and legs, especially the long bone of the leg (femur). These tumors also commonly affect flat bones such as those found in the pelvis, chest wall, and spinal column (vertebrae). Ewing sarcoma may occur in any bone of the body such as the bones of the foot, the hand, the lower jaw (mandible), the skull, and/or additional locations. Soft tissue tumors develop most often in the trunk and chest. However, the most common site of presentation is the pelvis accounting for about 25% of cases. Ewing sarcoma may weaken bones sometimes resulting in fractures. These tumors are often aggressive and may spread (metastasize) to additional areas of the body, especially to other bones and the lungs. In rare cases, the bone marrow may become involved. Symptoms associated with these tumors are secondary to their location. For example, a tumor of the leg may result in a limp, a tumor in the lungs may result in breathing problems and an accumulation of fluid in the tissue layers that line the lungs and chest cavity (pleural effusion), or a tumor in the spinal column may cause weakness or paralysis of affected muscles (paraplegia). | 431 | Ewing Sarcoma |
nord_431_2 | Causes of Ewing Sarcoma | The exact cause of Ewing sarcoma is unknown and the underlying cell type has not been identified. Most cases are thought to occur randomly, for no specific reason (sporadically). Chromosomal (cytogenetic) studies have found that Ewing sarcoma cells are often characterized by an abnormal change in their genetic makeup known as a reciprocal translocation. A reciprocal translocation means pieces of two separate chromosomes break off and “trade places”. Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Pairs of human chromosomes are numbered from 1 through 22, and an additional 23rd pair of sex chromosomes which include one X and one Y chromosome in males and two X chromosomes in females. 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. In Ewing sarcoma, the chromosomal areas involved are the long arms (q) of chromosome 11 and 22 (11q24-22q12). These pieces break off and trade places. In most cases, this results in the abnormal fusion of two genes, usually the EWS and FLI genes. Genes normally produce (encode) proteins that have several functions within the body. The abnormal fusion of the EWS and FLI genes results in a “fusion” gene that produces an abnormal protein product. Researchers believe that this abnormal protein may contribute to or influence the development of Ewing sarcoma, although, currently, the exact functions or impact of this protein is not fully understood. The reason that the chromosomal translocation between chromosomes 11 and 22 occurs is also unknown. According to some estimates, however, more than 85 percent of tumors in the Ewing family of tumors have this translocation. Less often, the EWS gene may fuse with another gene other than the FLI gene; these are often genes from the same family as FLI1, most often involving the gene ERG. In extremely rare cases, Ewing sarcoma may develop as a second malignancy, which means that the disorder develops as a late-onset complication of earlier treatment for another form of cancer. | Causes of Ewing Sarcoma. The exact cause of Ewing sarcoma is unknown and the underlying cell type has not been identified. Most cases are thought to occur randomly, for no specific reason (sporadically). Chromosomal (cytogenetic) studies have found that Ewing sarcoma cells are often characterized by an abnormal change in their genetic makeup known as a reciprocal translocation. A reciprocal translocation means pieces of two separate chromosomes break off and “trade places”. Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Pairs of human chromosomes are numbered from 1 through 22, and an additional 23rd pair of sex chromosomes which include one X and one Y chromosome in males and two X chromosomes in females. 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. In Ewing sarcoma, the chromosomal areas involved are the long arms (q) of chromosome 11 and 22 (11q24-22q12). These pieces break off and trade places. In most cases, this results in the abnormal fusion of two genes, usually the EWS and FLI genes. Genes normally produce (encode) proteins that have several functions within the body. The abnormal fusion of the EWS and FLI genes results in a “fusion” gene that produces an abnormal protein product. Researchers believe that this abnormal protein may contribute to or influence the development of Ewing sarcoma, although, currently, the exact functions or impact of this protein is not fully understood. The reason that the chromosomal translocation between chromosomes 11 and 22 occurs is also unknown. According to some estimates, however, more than 85 percent of tumors in the Ewing family of tumors have this translocation. Less often, the EWS gene may fuse with another gene other than the FLI gene; these are often genes from the same family as FLI1, most often involving the gene ERG. In extremely rare cases, Ewing sarcoma may develop as a second malignancy, which means that the disorder develops as a late-onset complication of earlier treatment for another form of cancer. | 431 | Ewing Sarcoma |
nord_431_3 | Affects of Ewing Sarcoma | Ewing sarcoma affects males more often than females. It may affect individuals of any age, but most often occurs in individuals between 10 and 20 years of age. The annual incidence of Ewing sarcoma is 2.93 children per 1,000,000. Approximately 200-250 children and adolescents in the United States are diagnosed with a tumor in the Ewing family of tumors each year. Two-thirds will be long-term survivors (more than five years). The tumor occurs with greater frequency in Caucasians. It is extremely rare in African Americans and Asians. Studies have shown that there are distinct differences between extraosseous (extraskeletal) Ewing sarcoma (EOE) and Ewing sarcoma of bone. EOE is more likely to occur in individuals above the age of 35 or below the age of 5, with a higher mean age than Ewing sarcoma of bone. | Affects of Ewing Sarcoma. Ewing sarcoma affects males more often than females. It may affect individuals of any age, but most often occurs in individuals between 10 and 20 years of age. The annual incidence of Ewing sarcoma is 2.93 children per 1,000,000. Approximately 200-250 children and adolescents in the United States are diagnosed with a tumor in the Ewing family of tumors each year. Two-thirds will be long-term survivors (more than five years). The tumor occurs with greater frequency in Caucasians. It is extremely rare in African Americans and Asians. Studies have shown that there are distinct differences between extraosseous (extraskeletal) Ewing sarcoma (EOE) and Ewing sarcoma of bone. EOE is more likely to occur in individuals above the age of 35 or below the age of 5, with a higher mean age than Ewing sarcoma of bone. | 431 | Ewing Sarcoma |
nord_431_4 | Related disorders of Ewing Sarcoma | Symptoms of the following disorders can be similar to those of Ewing sarcoma. Comparisons may be useful for a differential diagnosis: Osteosarcoma is a tumor affecting the bones. It is the most common form of bone cancer. Approximately 60 percent of cases occur in children and adolescents during the second decade of life. Osteosarcomas affect males twice as often as females. The bones most commonly affected are the long bones of the arms and legs. Symptoms may vary depending upon the location and extent of the disease. Pain, swelling, tenderness and eventually the formation of a lump may occur in the affected area. General symptoms may include fever, weight loss, anemia, and lack of energy. Osteosarcomas may weaken the surrounding bone resulting in fractures. Osteosarcomas may spread (metastasize) to other areas of the body. The exact cause of osteosarcoma is unknown. Additional tumors must also be differentiated from Ewing sarcoma including chondrosarcomas, osteochondromas, medulloblastomas, neuroblastoma, rhabdomyosarcoma, and lymphoma of bone. (For more information on these tumors, choose the specific tumor name as your search term in the Rare Disease Database.) Osteomyelitis is a bone infection, usually caused by bacteria. Osteomyelitis can be either acute or chronic. The disorder usually occurs as a result of an infection in one part of the body that is transported through the bloodstream to a bone in a distant location. Among children and teens, the long bones of the legs and arms are most frequently affected. In adults, osteomyelitis most often affects the vertebrae of the spine and/or the hips. Initially there may be several days of fever and a generalized feeling of ill health (malaise). This may be followed by an increase in fever, deep localized bone pain, chills, sweating, swelling and painful or limited movement of the nearby joints. The skin near the affected bone may be red (erythema) and there may be pus, destruction of the surrounding tissue (necrosis) and bone deterioration or deformity. (For more information on this disorder, choose “osteomyelitis” as your search term in the Rare Disease Database.) Eosinophilic granuloma is a subdivision of a rare spectrum of disorders known as Langherhans cell histiocytosis (LCH). LCH is characterized by overproduction (proliferation) and accumulation of a specific type of white blood cell (histiocyte) in the various tissues and organs of the body. These may include certain distinctive granule-containing cells (Langerhans cells) involved in certain immune responses, as well as other white blood cells (e.g., monocytes, eosinophils). Most individuals with LCH develop single or multiple bone lesions (eosinophilic granulomas) caused by the abnormal accumulation of Langerhans cells and eosinophils. In some cases, these lesions may be not by accompanied by any symptoms (asymptomatic). However, in most cases, the lesions are associated with bone pain and swelling of adjacent tissue. In many cases, loss of the calcium of bone (osteolysis) may also occur. The skull, spine, and long bones of the arms and legs are most often affected. Secondary complications may also occur including spontaneous fractures of the long bones or vertebral collapse and compression of the spinal cord. (For more information on this disorder, choose “Langerhans cell histiocytosis” as your search term in the Rare Disease Database.) | Related disorders of Ewing Sarcoma. Symptoms of the following disorders can be similar to those of Ewing sarcoma. Comparisons may be useful for a differential diagnosis: Osteosarcoma is a tumor affecting the bones. It is the most common form of bone cancer. Approximately 60 percent of cases occur in children and adolescents during the second decade of life. Osteosarcomas affect males twice as often as females. The bones most commonly affected are the long bones of the arms and legs. Symptoms may vary depending upon the location and extent of the disease. Pain, swelling, tenderness and eventually the formation of a lump may occur in the affected area. General symptoms may include fever, weight loss, anemia, and lack of energy. Osteosarcomas may weaken the surrounding bone resulting in fractures. Osteosarcomas may spread (metastasize) to other areas of the body. The exact cause of osteosarcoma is unknown. Additional tumors must also be differentiated from Ewing sarcoma including chondrosarcomas, osteochondromas, medulloblastomas, neuroblastoma, rhabdomyosarcoma, and lymphoma of bone. (For more information on these tumors, choose the specific tumor name as your search term in the Rare Disease Database.) Osteomyelitis is a bone infection, usually caused by bacteria. Osteomyelitis can be either acute or chronic. The disorder usually occurs as a result of an infection in one part of the body that is transported through the bloodstream to a bone in a distant location. Among children and teens, the long bones of the legs and arms are most frequently affected. In adults, osteomyelitis most often affects the vertebrae of the spine and/or the hips. Initially there may be several days of fever and a generalized feeling of ill health (malaise). This may be followed by an increase in fever, deep localized bone pain, chills, sweating, swelling and painful or limited movement of the nearby joints. The skin near the affected bone may be red (erythema) and there may be pus, destruction of the surrounding tissue (necrosis) and bone deterioration or deformity. (For more information on this disorder, choose “osteomyelitis” as your search term in the Rare Disease Database.) Eosinophilic granuloma is a subdivision of a rare spectrum of disorders known as Langherhans cell histiocytosis (LCH). LCH is characterized by overproduction (proliferation) and accumulation of a specific type of white blood cell (histiocyte) in the various tissues and organs of the body. These may include certain distinctive granule-containing cells (Langerhans cells) involved in certain immune responses, as well as other white blood cells (e.g., monocytes, eosinophils). Most individuals with LCH develop single or multiple bone lesions (eosinophilic granulomas) caused by the abnormal accumulation of Langerhans cells and eosinophils. In some cases, these lesions may be not by accompanied by any symptoms (asymptomatic). However, in most cases, the lesions are associated with bone pain and swelling of adjacent tissue. In many cases, loss of the calcium of bone (osteolysis) may also occur. The skull, spine, and long bones of the arms and legs are most often affected. Secondary complications may also occur including spontaneous fractures of the long bones or vertebral collapse and compression of the spinal cord. (For more information on this disorder, choose “Langerhans cell histiocytosis” as your search term in the Rare Disease Database.) | 431 | Ewing Sarcoma |
nord_431_5 | Diagnosis of Ewing Sarcoma | The diagnosis of a tumor in the Ewing family of tumors is based upon a thorough clinical evaluation, the identification of characteristic symptoms and physical findings, a detailed patient history, and a variety of specialized tests. Such testing includes microscopic evaluation of tumor cells and affected tissue (histopathology) and molecular analysis looking for the EWS-FLI1 translocation.Clinical Testing and Work-upX-rays may be taken initially, especially if there is a palpable mass. X-rays are used to obtain images of the tumor or affected area. More specialized imaging techniques may be used to help evaluate the size, placement, and extension of the tumor (e.g. into the soft tissue or bone marrow), to determine whether the tumor has spread (metastasized) to other areas of the body (for example, the lungs and other bones), and to serve as an aid for future surgical procedures. Such imaging techniques may include computerized tomography (CT) scanning, magnetic resonance imaging (MRI), and bone scans. A biopsy of the bone marrow may reveal whether the tumor has spread to the bone marrow.The diagnosis of Ewing sarcoma may be made through the surgical removal (biopsy) and microscopic evaluation of a portion of affected tissue. A specialized surface protein known as CD99 is found on most tumors in the Ewing family of tumors. Detecting the presence of this protein may aid in making a diagnosis of Ewing sarcoma.Another test used to diagnose Ewing sarcoma is polymerase chain reaction (PCR). PCR is a laboratory technique that has been described as "photocopying". It enables researchers to enlarge and repeatedly copy sequences of DNA. As a result, they are able to closely analyze DNA and more easily identify genes and genetic changes such as the reciprocal translocation that characterizes Ewing sarcoma. This test is available on a research basis. | Diagnosis of Ewing Sarcoma. The diagnosis of a tumor in the Ewing family of tumors is based upon a thorough clinical evaluation, the identification of characteristic symptoms and physical findings, a detailed patient history, and a variety of specialized tests. Such testing includes microscopic evaluation of tumor cells and affected tissue (histopathology) and molecular analysis looking for the EWS-FLI1 translocation.Clinical Testing and Work-upX-rays may be taken initially, especially if there is a palpable mass. X-rays are used to obtain images of the tumor or affected area. More specialized imaging techniques may be used to help evaluate the size, placement, and extension of the tumor (e.g. into the soft tissue or bone marrow), to determine whether the tumor has spread (metastasized) to other areas of the body (for example, the lungs and other bones), and to serve as an aid for future surgical procedures. Such imaging techniques may include computerized tomography (CT) scanning, magnetic resonance imaging (MRI), and bone scans. A biopsy of the bone marrow may reveal whether the tumor has spread to the bone marrow.The diagnosis of Ewing sarcoma may be made through the surgical removal (biopsy) and microscopic evaluation of a portion of affected tissue. A specialized surface protein known as CD99 is found on most tumors in the Ewing family of tumors. Detecting the presence of this protein may aid in making a diagnosis of Ewing sarcoma.Another test used to diagnose Ewing sarcoma is polymerase chain reaction (PCR). PCR is a laboratory technique that has been described as "photocopying". It enables researchers to enlarge and repeatedly copy sequences of DNA. As a result, they are able to closely analyze DNA and more easily identify genes and genetic changes such as the reciprocal translocation that characterizes Ewing sarcoma. This test is available on a research basis. | 431 | Ewing Sarcoma |
nord_431_6 | Therapies of Ewing Sarcoma | TreatmentThe therapeutic management of individuals with Ewing sarcoma may require the coordinated efforts of a team of medical professionals, such as physicians who specialize in the diagnosis and treatment of cancer in children (pediatric oncologists), adult oncologists, specialists in the use of radiation to treat cancer (radiation oncologists), surgeons, (orthopedic surgeons), oncology nurses, and other specialists (depending upon the primary tumor site).Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as primary tumor location, extent of the primary tumor (stage), and degree of malignancy (grade); whether the tumor has spread to lymph nodes or distant sites; individual's age and general health; and/or other elements. Decisions concerning the use of particular interventions should be made by physicians and other members of the health care team in careful consultation with the patient, based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks; patient preference; and other appropriate factors.Individuals with Ewing sarcoma and their families are encouraged to seek counseling after a diagnosis and before treatment 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.Individuals with a tumor in the Ewing family of tumors are treated with multiple anticancer drugs (chemotherapy) in combination with surgical procedures and/or radiation. Surgical removal of the malignancy and affected tissue or radiation is used to treat the primary tumor site. Chemotherapy kills cancer cells in the primary site as well as hidden cancer cells that may have spread into other areas of the body. Generally, systemic chemotherapy is administered first, followed by surgery or radiation. Surgery or radiation therapy without adjuvant chemotherapy has been far less effective than combination therapy. Radiation is often used to treat tumors that are inoperable and sometimes for metastatic disease.Physicians use multiple chemotherapeutic drugs because different drugs have different modes of action in destroying tumor cells and/or preventing them from multiplying. Chemotherapy drugs often used to treat individuals with Ewing sarcoma include doxorubicin, vincristine, cyclophosphamide, dactinomycin, ifosfamide, and etoposide. | Therapies of Ewing Sarcoma. TreatmentThe therapeutic management of individuals with Ewing sarcoma may require the coordinated efforts of a team of medical professionals, such as physicians who specialize in the diagnosis and treatment of cancer in children (pediatric oncologists), adult oncologists, specialists in the use of radiation to treat cancer (radiation oncologists), surgeons, (orthopedic surgeons), oncology nurses, and other specialists (depending upon the primary tumor site).Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as primary tumor location, extent of the primary tumor (stage), and degree of malignancy (grade); whether the tumor has spread to lymph nodes or distant sites; individual's age and general health; and/or other elements. Decisions concerning the use of particular interventions should be made by physicians and other members of the health care team in careful consultation with the patient, based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks; patient preference; and other appropriate factors.Individuals with Ewing sarcoma and their families are encouraged to seek counseling after a diagnosis and before treatment 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.Individuals with a tumor in the Ewing family of tumors are treated with multiple anticancer drugs (chemotherapy) in combination with surgical procedures and/or radiation. Surgical removal of the malignancy and affected tissue or radiation is used to treat the primary tumor site. Chemotherapy kills cancer cells in the primary site as well as hidden cancer cells that may have spread into other areas of the body. Generally, systemic chemotherapy is administered first, followed by surgery or radiation. Surgery or radiation therapy without adjuvant chemotherapy has been far less effective than combination therapy. Radiation is often used to treat tumors that are inoperable and sometimes for metastatic disease.Physicians use multiple chemotherapeutic drugs because different drugs have different modes of action in destroying tumor cells and/or preventing them from multiplying. Chemotherapy drugs often used to treat individuals with Ewing sarcoma include doxorubicin, vincristine, cyclophosphamide, dactinomycin, ifosfamide, and etoposide. | 431 | Ewing Sarcoma |
nord_432_0 | Overview of Extrinsic Allergic Alveolitis | SummaryExtrinsic allergic alveolitis (EAA) is a lung disorder resulting from repeated inhalation of environmental agents including, but not limited to: (1) fungal and microbial agents, (2) agricultural dust or proteins, (3) bioaerosols and (4) various reactive chemicals. These agents, frequently found in certain occupational settings, cause a reaction from the immune system (allergic reaction) that causes inflammation in the lungs. It is important to note that EAA does not occur on the first day of exposure, since repeated and prolonged exposure is necessary for the immune system to become ‘sensitized’ to the foreign matter (antigens) and cause an allergic reaction. Even with repeated exposure, 10-40% of people show no symptoms. The allergic reactions and inflammation associated with EAA occurs in the alveoli, the air sacs inside the lungs that are responsible for breathing and gas exchange. This distinguishes EAA from allergic asthma, as EAA occurs in the alveoli, while asthma occurs in the airways or bronchi of the lungs. EAA is a complex respiratory syndrome with varying intensity and clinical presentation. EAA can occur for a short duration (acute form) with respiratory symptoms and fever lasting from hours to several weeks after a subsequent exposure. The chronic form arises from long-term exposure to the irritant and may last from weeks to years. Chronic EAA can ultimately lead to permanent lung scarring (pulmonary fibrosis) and inadequate oxygen intake (respiratory insufficiency).IntroductionExtrinsic means that the cause originates outside the body. Allergic means that it involves an exaggerated immune system response. Alveolitis is inflammation of the alveoli, the small air sacs of the lungs responsible for breathing (exchange of carbon dioxide and oxygen).Also known as hypersensitivity pneumonitis (HP), EAA was first described in farmers more than a century ago, but it was not until the early 1960s that its causes and immune mechanisms were identified by Dr. Jack Pepys. | Overview of Extrinsic Allergic Alveolitis. SummaryExtrinsic allergic alveolitis (EAA) is a lung disorder resulting from repeated inhalation of environmental agents including, but not limited to: (1) fungal and microbial agents, (2) agricultural dust or proteins, (3) bioaerosols and (4) various reactive chemicals. These agents, frequently found in certain occupational settings, cause a reaction from the immune system (allergic reaction) that causes inflammation in the lungs. It is important to note that EAA does not occur on the first day of exposure, since repeated and prolonged exposure is necessary for the immune system to become ‘sensitized’ to the foreign matter (antigens) and cause an allergic reaction. Even with repeated exposure, 10-40% of people show no symptoms. The allergic reactions and inflammation associated with EAA occurs in the alveoli, the air sacs inside the lungs that are responsible for breathing and gas exchange. This distinguishes EAA from allergic asthma, as EAA occurs in the alveoli, while asthma occurs in the airways or bronchi of the lungs. EAA is a complex respiratory syndrome with varying intensity and clinical presentation. EAA can occur for a short duration (acute form) with respiratory symptoms and fever lasting from hours to several weeks after a subsequent exposure. The chronic form arises from long-term exposure to the irritant and may last from weeks to years. Chronic EAA can ultimately lead to permanent lung scarring (pulmonary fibrosis) and inadequate oxygen intake (respiratory insufficiency).IntroductionExtrinsic means that the cause originates outside the body. Allergic means that it involves an exaggerated immune system response. Alveolitis is inflammation of the alveoli, the small air sacs of the lungs responsible for breathing (exchange of carbon dioxide and oxygen).Also known as hypersensitivity pneumonitis (HP), EAA was first described in farmers more than a century ago, but it was not until the early 1960s that its causes and immune mechanisms were identified by Dr. Jack Pepys. | 432 | Extrinsic Allergic Alveolitis |
nord_432_1 | Symptoms of Extrinsic Allergic Alveolitis | EAA can be categorized as acute, subacute or chronic, depending on the intensity and frequency of exposure to the causative allergens. In general, symptoms of all forms of EAA include shortness of breath (dyspnea) and cough. Less common symptoms include chest tightness and constitutional symptoms like fever, chills, weight loss and a general feeling of discomfort (malaise). Most cases of this condition are characterized by mild, short (acute) episodes that may be ‘flu-like’ and occur several hours after subsequent exposures to the antigen. Chronic cases develop with repeated episodes or prolonged exposure to the irritant and may result in more serious symptoms like fever, crackling sounds during breathing (rales), difficulty breathing, bluish appearance of the skin (cyanosis) and possibly coughing blood. Chronic cases can lead to serious damage to the lungs involving permanent lung scarring and decreased lung capacity. Lung biopsies may show abnormal formation of white blood cells (granulomas) in the air sacs, which are generally not compact (poorly formed or loose). Since many of its characteristics and symptoms overlap with other lung diseases, EAA is easily misdiagnosed. | Symptoms of Extrinsic Allergic Alveolitis. EAA can be categorized as acute, subacute or chronic, depending on the intensity and frequency of exposure to the causative allergens. In general, symptoms of all forms of EAA include shortness of breath (dyspnea) and cough. Less common symptoms include chest tightness and constitutional symptoms like fever, chills, weight loss and a general feeling of discomfort (malaise). Most cases of this condition are characterized by mild, short (acute) episodes that may be ‘flu-like’ and occur several hours after subsequent exposures to the antigen. Chronic cases develop with repeated episodes or prolonged exposure to the irritant and may result in more serious symptoms like fever, crackling sounds during breathing (rales), difficulty breathing, bluish appearance of the skin (cyanosis) and possibly coughing blood. Chronic cases can lead to serious damage to the lungs involving permanent lung scarring and decreased lung capacity. Lung biopsies may show abnormal formation of white blood cells (granulomas) in the air sacs, which are generally not compact (poorly formed or loose). Since many of its characteristics and symptoms overlap with other lung diseases, EAA is easily misdiagnosed. | 432 | Extrinsic Allergic Alveolitis |
nord_432_2 | Causes of Extrinsic Allergic Alveolitis | EAA is caused by an allergic response to an environmental irritant (allergen) that triggers an allergic reaction. These irritants could have a range of possible sources, including but not limited to, agricultural (animal and vegetable) dusts, funguses, molds and reactive chemicals. The particulates must also be very small (under 5 microns in diameter) to reach the alveoli where oxygen exchange occurs (a micron is one-millionth of a meter in size). As stated earlier, repeated exposure is required to develop an immune or allergic response to the irritant. This sort of repeated inhalation of microscopic particles is generally associated with certain occupational settings or geographic regions. A wide variety of substances encountered in occupational settings may be linked to this disorder, including irritants associated with birds (avian dust), cheese manufacturing (mold), sugar manufacturing (moldy sugar cane dust), bath tub refinishing (paint catalyst), farming (moldy hay dust), mushroom farming (mushroom compost), working in a laboratory (rat or gerbil urine residue), tobacco (snuff), heating and cooling systems (moldy water), malt working/beer brewing (moldy barley), maple bark disease (moldy maple bark dust), sequoiosis (moldy redwood bark dust), suberosis (moldy cork dust), plastic working (plastic residue), epoxy resin (heated epoxy residue), enzyme detergent (dust) or wheat weevil disease (wheat mold or dust). | Causes of Extrinsic Allergic Alveolitis. EAA is caused by an allergic response to an environmental irritant (allergen) that triggers an allergic reaction. These irritants could have a range of possible sources, including but not limited to, agricultural (animal and vegetable) dusts, funguses, molds and reactive chemicals. The particulates must also be very small (under 5 microns in diameter) to reach the alveoli where oxygen exchange occurs (a micron is one-millionth of a meter in size). As stated earlier, repeated exposure is required to develop an immune or allergic response to the irritant. This sort of repeated inhalation of microscopic particles is generally associated with certain occupational settings or geographic regions. A wide variety of substances encountered in occupational settings may be linked to this disorder, including irritants associated with birds (avian dust), cheese manufacturing (mold), sugar manufacturing (moldy sugar cane dust), bath tub refinishing (paint catalyst), farming (moldy hay dust), mushroom farming (mushroom compost), working in a laboratory (rat or gerbil urine residue), tobacco (snuff), heating and cooling systems (moldy water), malt working/beer brewing (moldy barley), maple bark disease (moldy maple bark dust), sequoiosis (moldy redwood bark dust), suberosis (moldy cork dust), plastic working (plastic residue), epoxy resin (heated epoxy residue), enzyme detergent (dust) or wheat weevil disease (wheat mold or dust). | 432 | Extrinsic Allergic Alveolitis |
nord_432_3 | Affects of Extrinsic Allergic Alveolitis | EAA is predominantly an occupational disease and is more likely to affect those who have repeated exposure to certain air particulates. Some occupations put workers at higher risk for this condition, such as those in which animal or vegetable dusts are inhaled. For this reason, some subtypes of EAA are named after specific occupations: farmer’s lung, mushroom picker's disease, and bird breeder's or bird fancier's lung, which has a worse prognosis than farmer’s lung, and humidifier lung which is caused by the inhalation of fungus growing in humidifiers, air conditioners and heating systems.Prevalence depends on climate, pollution levels, geographic conditions, occupational, and industry factors. EAA also occurs more commonly among older individuals, with the average patient’s diagnosis occurring around 50-60 years of age, though it can also be diagnosed in younger adults and children.Because this condition develops only in certain exposed individuals, a genetic predisposition was hypothesized and tested. Studies investigating genetic susceptibility of EAA have been limited, but human leukocyte antigen (HLA class II) genes, which play a major role in the immune response, have been identified as critical factors contributing to EAA. Additionally, depending on individual genetics, variable amounts of signaling molecules used by the immune system (cytokines) during inflammation may be responsible for EAA’s varying severity. | Affects of Extrinsic Allergic Alveolitis. EAA is predominantly an occupational disease and is more likely to affect those who have repeated exposure to certain air particulates. Some occupations put workers at higher risk for this condition, such as those in which animal or vegetable dusts are inhaled. For this reason, some subtypes of EAA are named after specific occupations: farmer’s lung, mushroom picker's disease, and bird breeder's or bird fancier's lung, which has a worse prognosis than farmer’s lung, and humidifier lung which is caused by the inhalation of fungus growing in humidifiers, air conditioners and heating systems.Prevalence depends on climate, pollution levels, geographic conditions, occupational, and industry factors. EAA also occurs more commonly among older individuals, with the average patient’s diagnosis occurring around 50-60 years of age, though it can also be diagnosed in younger adults and children.Because this condition develops only in certain exposed individuals, a genetic predisposition was hypothesized and tested. Studies investigating genetic susceptibility of EAA have been limited, but human leukocyte antigen (HLA class II) genes, which play a major role in the immune response, have been identified as critical factors contributing to EAA. Additionally, depending on individual genetics, variable amounts of signaling molecules used by the immune system (cytokines) during inflammation may be responsible for EAA’s varying severity. | 432 | Extrinsic Allergic Alveolitis |
nord_432_4 | Related disorders of Extrinsic Allergic Alveolitis | Symptoms of the following disorders can be similar to EAA. Comparisons may be useful for a differential diagnosis:Allergic asthma is a condition in which the airways narrow when you breathe in allergen such as pollen and dander, making breathing difficult. The pathology of both allergic asthma and EAA is induced by repeated exposure to airborne irritants by sensitized individuals. In allergic asthma, the inflammation affects the conducting airways of the lungs. The inflammation of EAA affects the alveoli, which are the air sacs deep inside the lungs. As a result, the excessive mucus production that may accompany asthma is typically not observed with EAA. Rather, with EAA, repeated exposures can lead to labored breathing (dyspnea), cough, and respiratory insufficiency caused by impaired gas exchange and reduced lung volume.Desquamative interstitial pneumonia (DIP) is a chronic lung disease where white blood cells (macrophages) accumulate in the alveoli (pneumonia). About 90% of DIP occurs in current or former tobacco smokers. DIP is characterized by breathing difficulty and is accompanied by a harsh cough that does not seem to clear the obstruction.Airway-centered interstitial fibrosis, also known as chronic bronchiolitis with fibrosis, is a serious lung disease. It is associated with chronic airway-centered injuries like tissue death, scarring (fibrosis) and inflammation in the small airways (bronchiolitis) of the lungs.Idiopathic pulmonary fibrosis (IPF), also called fibrosing alveolitis, is an inflammatory lung disorder that can be difficult to differentiate from EAA (chronic form). This is because the microscopic zones of lung injury (fibroblast foci) typical of IPF are also common in EAA. IPF is characterized by abnormal formation of fibrous scar tissue between air sacs in the lungs. Coughing and rapid, shallow breathing may develop even with moderate exercise. The skin may become bluish (cyanotic) due to a lack of oxygen circulating in the blood. Complications such as infections, emphysema or heart problems may develop. Differentiating between EAA and IPF typically requires consultation with multiple specialists due to the overlap of clinical features and induction by external agents. The term idiopathic in IPF means that the cause is unknown.Granulomatous pneumonitis (GP) is a broad group of infectious and non-infectious conditions characterized by the formation of abnormal clusters of white blood cells (granulomas) in the lungs. In this disease, the inhalation of various antigens such as bacteria or microbial fragments trigger an overactive immune response in the lungs, leading to associated GP symptoms. Often misdiagnosed as tuberculosis, GP symptoms include lung complications such as dry cough and shortness of breath.Sarcoidosis is a disorder that involves the formation of abnormal clusters of white blood cells (granulomas) in different body systems. In certain cases, granulomas may develop in the lungs causing symptoms like coughing and breathing difficulty.Other conditions characterized by the inhalation of irritating agents include the following: ● Hot tub lung is lung disease caused by recurrent exposure to Mycobacterium avium complex (MAC, a type of bacteria) from hot tub use. It shares some clinical features with EAA, such as cough and difficulty breathing with variable fever. The granulomas that arise from hot tub lung in the bronchioles tend to be well-formed and compact, unlike the loose and poorly formed granulomas that occur with EAA.● Inhalation fever, including metal fume fever and polymer fume fever, can be caused by the inhalation of fumes from heated metals or plastics (polymers). Symptoms of this condition include fevers, chills, malaise, headaches and muscle pain (myalgias). Pulmonary findings are not usually prominent. A mild cough and difficulty breathing may occur.● Organic dust toxic syndrome arises from inhaling toxins released by fungi (mycotoxins) or bacteria (endotoxins). This condition is often associated with exposure to grains, moldy hay and textile materials contaminated with the fungus, Fusarium fungus. This condition is believed to be triggered by the toxins themselves, thus is distinguished from EAA, which is triggered by the immune system following allergen exposure.● Fire-eater’s lung is a condition seen in people who demonstrate fire-eating. The gas they breathe in from fire-eating can cause choking, coughing and respiratory distress. | Related disorders of Extrinsic Allergic Alveolitis. Symptoms of the following disorders can be similar to EAA. Comparisons may be useful for a differential diagnosis:Allergic asthma is a condition in which the airways narrow when you breathe in allergen such as pollen and dander, making breathing difficult. The pathology of both allergic asthma and EAA is induced by repeated exposure to airborne irritants by sensitized individuals. In allergic asthma, the inflammation affects the conducting airways of the lungs. The inflammation of EAA affects the alveoli, which are the air sacs deep inside the lungs. As a result, the excessive mucus production that may accompany asthma is typically not observed with EAA. Rather, with EAA, repeated exposures can lead to labored breathing (dyspnea), cough, and respiratory insufficiency caused by impaired gas exchange and reduced lung volume.Desquamative interstitial pneumonia (DIP) is a chronic lung disease where white blood cells (macrophages) accumulate in the alveoli (pneumonia). About 90% of DIP occurs in current or former tobacco smokers. DIP is characterized by breathing difficulty and is accompanied by a harsh cough that does not seem to clear the obstruction.Airway-centered interstitial fibrosis, also known as chronic bronchiolitis with fibrosis, is a serious lung disease. It is associated with chronic airway-centered injuries like tissue death, scarring (fibrosis) and inflammation in the small airways (bronchiolitis) of the lungs.Idiopathic pulmonary fibrosis (IPF), also called fibrosing alveolitis, is an inflammatory lung disorder that can be difficult to differentiate from EAA (chronic form). This is because the microscopic zones of lung injury (fibroblast foci) typical of IPF are also common in EAA. IPF is characterized by abnormal formation of fibrous scar tissue between air sacs in the lungs. Coughing and rapid, shallow breathing may develop even with moderate exercise. The skin may become bluish (cyanotic) due to a lack of oxygen circulating in the blood. Complications such as infections, emphysema or heart problems may develop. Differentiating between EAA and IPF typically requires consultation with multiple specialists due to the overlap of clinical features and induction by external agents. The term idiopathic in IPF means that the cause is unknown.Granulomatous pneumonitis (GP) is a broad group of infectious and non-infectious conditions characterized by the formation of abnormal clusters of white blood cells (granulomas) in the lungs. In this disease, the inhalation of various antigens such as bacteria or microbial fragments trigger an overactive immune response in the lungs, leading to associated GP symptoms. Often misdiagnosed as tuberculosis, GP symptoms include lung complications such as dry cough and shortness of breath.Sarcoidosis is a disorder that involves the formation of abnormal clusters of white blood cells (granulomas) in different body systems. In certain cases, granulomas may develop in the lungs causing symptoms like coughing and breathing difficulty.Other conditions characterized by the inhalation of irritating agents include the following: ● Hot tub lung is lung disease caused by recurrent exposure to Mycobacterium avium complex (MAC, a type of bacteria) from hot tub use. It shares some clinical features with EAA, such as cough and difficulty breathing with variable fever. The granulomas that arise from hot tub lung in the bronchioles tend to be well-formed and compact, unlike the loose and poorly formed granulomas that occur with EAA.● Inhalation fever, including metal fume fever and polymer fume fever, can be caused by the inhalation of fumes from heated metals or plastics (polymers). Symptoms of this condition include fevers, chills, malaise, headaches and muscle pain (myalgias). Pulmonary findings are not usually prominent. A mild cough and difficulty breathing may occur.● Organic dust toxic syndrome arises from inhaling toxins released by fungi (mycotoxins) or bacteria (endotoxins). This condition is often associated with exposure to grains, moldy hay and textile materials contaminated with the fungus, Fusarium fungus. This condition is believed to be triggered by the toxins themselves, thus is distinguished from EAA, which is triggered by the immune system following allergen exposure.● Fire-eater’s lung is a condition seen in people who demonstrate fire-eating. The gas they breathe in from fire-eating can cause choking, coughing and respiratory distress. | 432 | Extrinsic Allergic Alveolitis |
nord_432_5 | Diagnosis of Extrinsic Allergic Alveolitis | Due to the varied presentation of symptoms and low prevalence, EAA is easily misdiagnosed. Prompt diagnosis, however, is important because avoiding the causative allergens may provide relief, especially in the early stages. Diagnosis may be reached through a physical or historical information but often requires a combination of findings. The first step in a patient’s evaluation is to gather a detailed history of potential exposures. EAA can be categorized as either acute, subacute or chronic. Patients with acute EAA may experience symptoms such as fever, cough, difficulty breathing, chills, malaise, chest tightness and muscle pain (myalgias) within 4 to 12 hours after exposure. Patients with subacute and chronic EAA report a gradual onset of difficulty breathing, fatigue and weight loss. These signs and symptoms may be identified during a physical examination. Typical lung sounds associated with EAA include bubbling or crackling sound from the base of the lungs (bibasilar crackles) and mid-inspiratory squeaks. Wheezing is rarely present with EAA. Airway obstruction or restriction may be revealed in pulmonary function testing, often alongside exercise-induced gas exchange abnormalities.A chest X-ray of someone with EAA could be either normal or abnormal, depending on the severity of the condition. X-rays also may differ between different types of EAA. For example, the upper lung zone frequently appears to be affected in patients with bird fanciers’ lung, whereas the lower lung zone is more frequently affected in individuals with summer-type hypersensitivity pneumonitis (SHP), which is the most prevalent type of EAA in Japan, caused by seasonal mold contamination. X-rays may also reveal air trapping, scarring, or air-filled sacs of lung tissue (lung cysts).Antibody testing of the patient’s blood serum may enable identification of the causative allergen (since antibodies are produced to the specific allergen). Most patients have high serum concentrations of circulating antibodies specific for the causative antigen. Unfortunately, there are over 300 known antigens to cause EAA, so pinpointing the cause can be challenging.For further analysis, it may be recommended to obtain a sample of the lung fluids (bronchoalveolar lavage (BAL) fluid) for analysis of white blood cells in the lungs or a biopsy of the lung (transbronchial lung biopsy or a surgical lung biopsy). Patients with more advanced EAA (fibrotic EAA – lung tissue has been replaced with scar tissue) are generally older (above 65 years old), tend to have lower lung capacity (maximal expiratory volume) and decreased oxygen uptake by the lungs (decrease rate of gas exchange in the alveoli). In advanced cases of lung fibrosis, heart failure and abnormally rounded fingertips (digital clubbing) may occur. | Diagnosis of Extrinsic Allergic Alveolitis. Due to the varied presentation of symptoms and low prevalence, EAA is easily misdiagnosed. Prompt diagnosis, however, is important because avoiding the causative allergens may provide relief, especially in the early stages. Diagnosis may be reached through a physical or historical information but often requires a combination of findings. The first step in a patient’s evaluation is to gather a detailed history of potential exposures. EAA can be categorized as either acute, subacute or chronic. Patients with acute EAA may experience symptoms such as fever, cough, difficulty breathing, chills, malaise, chest tightness and muscle pain (myalgias) within 4 to 12 hours after exposure. Patients with subacute and chronic EAA report a gradual onset of difficulty breathing, fatigue and weight loss. These signs and symptoms may be identified during a physical examination. Typical lung sounds associated with EAA include bubbling or crackling sound from the base of the lungs (bibasilar crackles) and mid-inspiratory squeaks. Wheezing is rarely present with EAA. Airway obstruction or restriction may be revealed in pulmonary function testing, often alongside exercise-induced gas exchange abnormalities.A chest X-ray of someone with EAA could be either normal or abnormal, depending on the severity of the condition. X-rays also may differ between different types of EAA. For example, the upper lung zone frequently appears to be affected in patients with bird fanciers’ lung, whereas the lower lung zone is more frequently affected in individuals with summer-type hypersensitivity pneumonitis (SHP), which is the most prevalent type of EAA in Japan, caused by seasonal mold contamination. X-rays may also reveal air trapping, scarring, or air-filled sacs of lung tissue (lung cysts).Antibody testing of the patient’s blood serum may enable identification of the causative allergen (since antibodies are produced to the specific allergen). Most patients have high serum concentrations of circulating antibodies specific for the causative antigen. Unfortunately, there are over 300 known antigens to cause EAA, so pinpointing the cause can be challenging.For further analysis, it may be recommended to obtain a sample of the lung fluids (bronchoalveolar lavage (BAL) fluid) for analysis of white blood cells in the lungs or a biopsy of the lung (transbronchial lung biopsy or a surgical lung biopsy). Patients with more advanced EAA (fibrotic EAA – lung tissue has been replaced with scar tissue) are generally older (above 65 years old), tend to have lower lung capacity (maximal expiratory volume) and decreased oxygen uptake by the lungs (decrease rate of gas exchange in the alveoli). In advanced cases of lung fibrosis, heart failure and abnormally rounded fingertips (digital clubbing) may occur. | 432 | Extrinsic Allergic Alveolitis |
nord_432_6 | Therapies of Extrinsic Allergic Alveolitis | All symptoms can usually be resolved in acute cases if they are diagnosed and treated early before permanent changes in the lungs can develop. If permanent lung changes such lung scarring are present at the time of diagnosis, it is possible that the patient may not respond well to treatment.Treatment of EAA initially depends on identifying the allergen. Once the causative antigen is identified, preventative measures can be taken to avoid or reduce exposure. For example, in an occupational setting, mild cases may be alleviated by improved ventilation or use of air filtering masks, while severe or prolonged cases may warrant a career change. If symptoms persist after avoiding exposure, an anti-inflammatory drug such as corticosteroid may be helpful. In acute cases, avoidance measures, in combination with corticosteroids, can often reduce the severity of symptoms. Studies have shown that corticosteroid use is significantly more helpful in acute cases of EAA patients in which no fibrosis has occurred. Drugs that suppress the immune system may also be used to reduce the allergic response in EAA patients. It is important to note that while these drugs may alleviate symptoms and improve breathing capacity in EAA patients, they do suppress the immune system. As a result, patients may be more susceptible to infections. In patients with advanced EAA, some supportive therapies may be prescribed, such as oxygen therapy to increase oxygen uptake by the lungs or drugs that open the airways (bronchodilator). In addition, opioids to control shortness of breath or chronic cough may be prescribed as supportive care for advanced EAA. | Therapies of Extrinsic Allergic Alveolitis. All symptoms can usually be resolved in acute cases if they are diagnosed and treated early before permanent changes in the lungs can develop. If permanent lung changes such lung scarring are present at the time of diagnosis, it is possible that the patient may not respond well to treatment.Treatment of EAA initially depends on identifying the allergen. Once the causative antigen is identified, preventative measures can be taken to avoid or reduce exposure. For example, in an occupational setting, mild cases may be alleviated by improved ventilation or use of air filtering masks, while severe or prolonged cases may warrant a career change. If symptoms persist after avoiding exposure, an anti-inflammatory drug such as corticosteroid may be helpful. In acute cases, avoidance measures, in combination with corticosteroids, can often reduce the severity of symptoms. Studies have shown that corticosteroid use is significantly more helpful in acute cases of EAA patients in which no fibrosis has occurred. Drugs that suppress the immune system may also be used to reduce the allergic response in EAA patients. It is important to note that while these drugs may alleviate symptoms and improve breathing capacity in EAA patients, they do suppress the immune system. As a result, patients may be more susceptible to infections. In patients with advanced EAA, some supportive therapies may be prescribed, such as oxygen therapy to increase oxygen uptake by the lungs or drugs that open the airways (bronchodilator). In addition, opioids to control shortness of breath or chronic cough may be prescribed as supportive care for advanced EAA. | 432 | Extrinsic Allergic Alveolitis |
nord_433_0 | Overview of Fabry Disease | Fabry disease is a rare inherited disorder of glycosphingolipid (fat) metabolism resulting from the absent or markedly deficient activity of the lysosomal enzyme, α-galactosidase A (α-Gal A). This disorder belongs to a group of diseases known as lysosomal storage disorders. This enzymatic deficiency is caused by alterations (mutations) in the α-galactosidase A (GLA) gene that instructs cells to make the α-galactosidase A (α-Gal A) enzyme. Lysosomes function as the primary digestive tract of cells. Enzymes within lysosomes break down or digest particular compounds and intracellular structures. α-Gal A functions to break down complex sugar-lipid molecules called glycolipids, specifically, globotriaosylceramide (GL-3 or Gb3), its deacylated form Lyso-GL-3/Gb3 and related glycolipids, by removing the terminal galactose sugar from the end of these glycolipid molecules. The enzyme deficiency causes a continuous build-up of GL-3/Gb3 and related glycolipids in the body’s cells, resulting in the cell abnormalities and organ dysfunction that particularly affect small blood vessels, the heart and kidneys (Desnick 2001, Germain 2010).The GLA gene is located on the X-chromosome and therefore, Fabry disease is inherited as an X-linked disorder. Males with the type 1 classic and type 2 later-onset phenotypes (see below) are typically significantly more severely affected than their affected female relatives (Arends 2017). Females typically have a more variable course and may be asymptomatic or as severely affected as their male relatives (see Genetics section below).There are two major disease phenotypes: type 1 “classic” and type 2 “later-onset” subtypes. Both lead to renal failure, and/or cardiac disease, and early death (Desnick 2001, Desnick and Banikazemi 2006, Arends 2017, Doheny 2018). Type 1 males have little or no functional α-Gal A enzymatic activity (<3% of normal mean activity), and marked accumulation of GL-3/Gb3 and related glycolipids in capillaries and small blood vessels which cause the major symptoms in childhood or adolescence. These include acroparesthesias (excruciating pain in the hands and feet which occur with exercise, fevers, stress, etc.); angiokeratomas (clusters of red to blue rash-like discolorations on the skin); anhidrosis or hypohidrosis (absent or markedly decreased sweating); gastrointestinal symptoms including abdominal pain and cramping, and frequent bowel movements; and a characteristic corneal dystrophy (star-burst pattern of the cornea seen by an slit-lamp ophthalmologic examination) that does not affect vision (Sher 1979, Desnick 2001). With increasing age, the systemic GL-3/Gb3 deposition, especially in the heart leads to arrhythmias, left ventricular hypertrophy (LVH) and then hypertrophic cardiomyopathy (HCM), and in the kidneys to progressive proteinuria, renal insufficiency, and renal failure, and/or to cerebrovascular disease including transient ischemic attacks (TIAs) and strokes. Prior to renal replacement therapy (i.e., dialysis and transplantation) and enzyme replacement therapy (ERT), the average age of death of affected males with the type 1 classic phenotype was ~40 years (Columbi 1967). The incidence of males with the type 1 classic phenotype is about 1 in 40,000 (Desnick 2001), but varies with geographic region and race, ranging from about ~1 in 18,000 to 1 in 95,000 based on newborn screening studies (e.g., Spada 2006, Hwu 2009, Burlina 2018, and Wasserstein 2019).In contrast, males with the type 2 “later-onset” phenotype (previously called cardiac or renal variants) have residual α-Gal A activity, lack GL-3/Gb3 accumulation in capillaries and small blood vessels, and do not show the early manifestations of type 1 males (i.e., the acroparesthesias, hypohidrosis, angiokeratomas, corneal dystrophy, etc). They experience an essentially normal childhood and adolescence, and typically present with renal and/or cardiac disease in the third to seventh decades of life. Most type 2 later-onset patients have been identified by enzyme screening of patients in cardiac, hemodialysis, renal transplant, and stroke clinics (Doheny 2018), and recently by newborn screening (e.g. Spada 2006, Hwu 2009, Burlina 2018, Wasserstein 2019). Based on these screening studies the incidence of type 2 later-onset disease in males varies by demography, ethnicity, and race, but is at least 5-10 times more frequent than that of the type 1 males from the same region, ethnic group, or race.Clinical manifestations in heterozygous females from families with the type 1 classic phenotype are variable due to random X-chromosomal inactivation (Dobrovolny 2005, Echevarria 2015) and range from asymptomatic to as severe as type 1 classic males (Desnick and Banikazemi 2006, Arends 2017). Type 2 heterozygotes may be asymptomatic or develop renal or cardiac manifestations later in life. Approximately 90% of type 1 heterozygotes have the characteristic corneal dystrophy, while the type 2 heterozygous females typically lack the characteristic corneal findings or other early type 1 manifestation (Desnick 2001, Desnick and Banikazemi 2006, Doheny 2018). The frequency and severity of manifestations in type 2 heterozygous females has only been systematically investigated recently, and they are typically less frequent and less severe than those seen in their type 2 male relatives (Arends 2017). | Overview of Fabry Disease. Fabry disease is a rare inherited disorder of glycosphingolipid (fat) metabolism resulting from the absent or markedly deficient activity of the lysosomal enzyme, α-galactosidase A (α-Gal A). This disorder belongs to a group of diseases known as lysosomal storage disorders. This enzymatic deficiency is caused by alterations (mutations) in the α-galactosidase A (GLA) gene that instructs cells to make the α-galactosidase A (α-Gal A) enzyme. Lysosomes function as the primary digestive tract of cells. Enzymes within lysosomes break down or digest particular compounds and intracellular structures. α-Gal A functions to break down complex sugar-lipid molecules called glycolipids, specifically, globotriaosylceramide (GL-3 or Gb3), its deacylated form Lyso-GL-3/Gb3 and related glycolipids, by removing the terminal galactose sugar from the end of these glycolipid molecules. The enzyme deficiency causes a continuous build-up of GL-3/Gb3 and related glycolipids in the body’s cells, resulting in the cell abnormalities and organ dysfunction that particularly affect small blood vessels, the heart and kidneys (Desnick 2001, Germain 2010).The GLA gene is located on the X-chromosome and therefore, Fabry disease is inherited as an X-linked disorder. Males with the type 1 classic and type 2 later-onset phenotypes (see below) are typically significantly more severely affected than their affected female relatives (Arends 2017). Females typically have a more variable course and may be asymptomatic or as severely affected as their male relatives (see Genetics section below).There are two major disease phenotypes: type 1 “classic” and type 2 “later-onset” subtypes. Both lead to renal failure, and/or cardiac disease, and early death (Desnick 2001, Desnick and Banikazemi 2006, Arends 2017, Doheny 2018). Type 1 males have little or no functional α-Gal A enzymatic activity (<3% of normal mean activity), and marked accumulation of GL-3/Gb3 and related glycolipids in capillaries and small blood vessels which cause the major symptoms in childhood or adolescence. These include acroparesthesias (excruciating pain in the hands and feet which occur with exercise, fevers, stress, etc.); angiokeratomas (clusters of red to blue rash-like discolorations on the skin); anhidrosis or hypohidrosis (absent or markedly decreased sweating); gastrointestinal symptoms including abdominal pain and cramping, and frequent bowel movements; and a characteristic corneal dystrophy (star-burst pattern of the cornea seen by an slit-lamp ophthalmologic examination) that does not affect vision (Sher 1979, Desnick 2001). With increasing age, the systemic GL-3/Gb3 deposition, especially in the heart leads to arrhythmias, left ventricular hypertrophy (LVH) and then hypertrophic cardiomyopathy (HCM), and in the kidneys to progressive proteinuria, renal insufficiency, and renal failure, and/or to cerebrovascular disease including transient ischemic attacks (TIAs) and strokes. Prior to renal replacement therapy (i.e., dialysis and transplantation) and enzyme replacement therapy (ERT), the average age of death of affected males with the type 1 classic phenotype was ~40 years (Columbi 1967). The incidence of males with the type 1 classic phenotype is about 1 in 40,000 (Desnick 2001), but varies with geographic region and race, ranging from about ~1 in 18,000 to 1 in 95,000 based on newborn screening studies (e.g., Spada 2006, Hwu 2009, Burlina 2018, and Wasserstein 2019).In contrast, males with the type 2 “later-onset” phenotype (previously called cardiac or renal variants) have residual α-Gal A activity, lack GL-3/Gb3 accumulation in capillaries and small blood vessels, and do not show the early manifestations of type 1 males (i.e., the acroparesthesias, hypohidrosis, angiokeratomas, corneal dystrophy, etc). They experience an essentially normal childhood and adolescence, and typically present with renal and/or cardiac disease in the third to seventh decades of life. Most type 2 later-onset patients have been identified by enzyme screening of patients in cardiac, hemodialysis, renal transplant, and stroke clinics (Doheny 2018), and recently by newborn screening (e.g. Spada 2006, Hwu 2009, Burlina 2018, Wasserstein 2019). Based on these screening studies the incidence of type 2 later-onset disease in males varies by demography, ethnicity, and race, but is at least 5-10 times more frequent than that of the type 1 males from the same region, ethnic group, or race.Clinical manifestations in heterozygous females from families with the type 1 classic phenotype are variable due to random X-chromosomal inactivation (Dobrovolny 2005, Echevarria 2015) and range from asymptomatic to as severe as type 1 classic males (Desnick and Banikazemi 2006, Arends 2017). Type 2 heterozygotes may be asymptomatic or develop renal or cardiac manifestations later in life. Approximately 90% of type 1 heterozygotes have the characteristic corneal dystrophy, while the type 2 heterozygous females typically lack the characteristic corneal findings or other early type 1 manifestation (Desnick 2001, Desnick and Banikazemi 2006, Doheny 2018). The frequency and severity of manifestations in type 2 heterozygous females has only been systematically investigated recently, and they are typically less frequent and less severe than those seen in their type 2 male relatives (Arends 2017). | 433 | Fabry Disease |
nord_433_1 | Symptoms of Fabry Disease | Type 1 Classic Phenotype The signs and symptoms of males with the type 1 classic phenotype typically begin in childhood or adolescence (Desnick 2001, Desnick and Brady 2004). Symptoms increase with age primarily due to the progressive glycolipid accumulation in the micro-vascular system, kidney podocytes, and cardiomyocytes leading to kidney insufficiency and failure, heart disease, and/or strokes. Early and progressive clinical symptoms include:Common Manifestations in Type 1 and 2 MalesWith advancing age in type 1 males, typically in the third to fourth decades, and in type 2 males in the third to sixth decades, the progressive GL-3/Gb3 glycolipid deposition leads to renal and/or heart manifestations as described below (Desnick 2001, Arends 2017). Many of the type 2 later-onset males who lack the early manifestations seen in the type 1 males, are detected in renal, heart, or stroke clinics (Nakao 1995, 2003; Doheny 2018). Patients with the type 2 later-onset subtype typically do not have the skin lesions (angiokeratoma), sweat normally, do not experience the Fabry pain or crises, and do not have heat intolerance or corneal involvement. These individuals develop heart or kidney disease later in adult life.Signs of progressive organ involvement include:Renal dysfunction. Progressive decrease in renal function is due to the progressive accumulation of GL-3/Gb3 in the kidneys, particularly in the endothelial cells, smooth muscle cells and podocytes (Najafian 2013; Tondel 2008, 2013). There is histological evidence of this accumulation and ensuing cellular and vascular injury to renal tissue beginning in childhood and adolescence (Tondel 2008, 2013; Najafian 2013) in type 1 classic males and females. In type 1 classic males, the decline in typically begins with podocyte involvement and microalbuminuria leading to frank proteinuria, increasing loss of function (decreasing glomerular filtration rate or GFR), all leading to kidney failure and the need for dialysis or transplantation typically by 35 to 45 years of age. In type 2 males, kidney involvement typically occurs in the fourth decade or later, but some patients do not develop renal failure (Meehan 2004). Kidney involvement in type 1 female heterozygotes is more variable. Only about 10-15% of type 1 females develop kidney failure. It is not clear what percentage of type 2 females develop renal failure, if any (Arends 2017).Cardiac disease. GL-3/Gb3 deposition can be found in all cardiac tissues, including valves, cardiomyocytes, nerves, and coronary arteries (Desnick 1976). Heart disease includes heart enlargement, typically left ventricular hypertrophy (LVH) leading to hypertrophic cardiomyopathy (HCM), rhythm abnormalities (arrhythmias), and heart failure (Frustaci 2017). LVH occurs in about 20% of males and females with an average age of diagnosis in the early 20s to 40s among type 1 males and late 30s to 40s among type 1 female heterozygotes. Early heart involvement in type 1 males typically includes arrhythmias and mitral insufficiency in their 20s followed by LVH leading to HCM. Type 2 later-onset males develop similar heart manifestations as type 1 males, but at older ages and may be first diagnosed in cardiac clinics among patients with LVH or HCM (Doheny 2018). Heterozygous females with the type 1 phenotype often have sinus bradycardia as an early finding and may more severely affected heterozygotes can develop LVH progressing to HCM.Cerebrovascular complications. As a result of the progressive GL-3/Gb3 deposition in the heart leading to atrial fibrillation and in the small blood vessels in the brain, about 7% of males and 4% of females with Fabry disease, particularly those with the type 1 phenotype, experience ischemic or hemorrhagic strokes, occurring typically in the fourth decade of life or later (Fellgiebel 2006, Wilcox 2008).Respiratory abnormalities: Accumulation of glycosphingolipids and consequent fibrosis can cause interstitial lung disease. Pathological changes and tissue remodeling may involve both alveoli and the bronchial tree leading to restrictive lung disease, obstructive airway disease, or a mixture of obstructive and restrictive disease. (Svensson 2015). Respiratory symptoms may occur independent of cardiovascular disease in these patients.Other pathology: Hearing loss, tinnitus, dizziness and vertigo potentially due to GL-3/Gb3 deposition in vestibular structures and/or auditory neuropathy are commonly reported in adult patients and while these are not life threatening, contribute to disease burden and negatively affect quality of life. Depression has been reported and a portion of these cases, especially Type I Classic males, were classified as having severe depression. (Cole 2007) | Symptoms of Fabry Disease. Type 1 Classic Phenotype The signs and symptoms of males with the type 1 classic phenotype typically begin in childhood or adolescence (Desnick 2001, Desnick and Brady 2004). Symptoms increase with age primarily due to the progressive glycolipid accumulation in the micro-vascular system, kidney podocytes, and cardiomyocytes leading to kidney insufficiency and failure, heart disease, and/or strokes. Early and progressive clinical symptoms include:Common Manifestations in Type 1 and 2 MalesWith advancing age in type 1 males, typically in the third to fourth decades, and in type 2 males in the third to sixth decades, the progressive GL-3/Gb3 glycolipid deposition leads to renal and/or heart manifestations as described below (Desnick 2001, Arends 2017). Many of the type 2 later-onset males who lack the early manifestations seen in the type 1 males, are detected in renal, heart, or stroke clinics (Nakao 1995, 2003; Doheny 2018). Patients with the type 2 later-onset subtype typically do not have the skin lesions (angiokeratoma), sweat normally, do not experience the Fabry pain or crises, and do not have heat intolerance or corneal involvement. These individuals develop heart or kidney disease later in adult life.Signs of progressive organ involvement include:Renal dysfunction. Progressive decrease in renal function is due to the progressive accumulation of GL-3/Gb3 in the kidneys, particularly in the endothelial cells, smooth muscle cells and podocytes (Najafian 2013; Tondel 2008, 2013). There is histological evidence of this accumulation and ensuing cellular and vascular injury to renal tissue beginning in childhood and adolescence (Tondel 2008, 2013; Najafian 2013) in type 1 classic males and females. In type 1 classic males, the decline in typically begins with podocyte involvement and microalbuminuria leading to frank proteinuria, increasing loss of function (decreasing glomerular filtration rate or GFR), all leading to kidney failure and the need for dialysis or transplantation typically by 35 to 45 years of age. In type 2 males, kidney involvement typically occurs in the fourth decade or later, but some patients do not develop renal failure (Meehan 2004). Kidney involvement in type 1 female heterozygotes is more variable. Only about 10-15% of type 1 females develop kidney failure. It is not clear what percentage of type 2 females develop renal failure, if any (Arends 2017).Cardiac disease. GL-3/Gb3 deposition can be found in all cardiac tissues, including valves, cardiomyocytes, nerves, and coronary arteries (Desnick 1976). Heart disease includes heart enlargement, typically left ventricular hypertrophy (LVH) leading to hypertrophic cardiomyopathy (HCM), rhythm abnormalities (arrhythmias), and heart failure (Frustaci 2017). LVH occurs in about 20% of males and females with an average age of diagnosis in the early 20s to 40s among type 1 males and late 30s to 40s among type 1 female heterozygotes. Early heart involvement in type 1 males typically includes arrhythmias and mitral insufficiency in their 20s followed by LVH leading to HCM. Type 2 later-onset males develop similar heart manifestations as type 1 males, but at older ages and may be first diagnosed in cardiac clinics among patients with LVH or HCM (Doheny 2018). Heterozygous females with the type 1 phenotype often have sinus bradycardia as an early finding and may more severely affected heterozygotes can develop LVH progressing to HCM.Cerebrovascular complications. As a result of the progressive GL-3/Gb3 deposition in the heart leading to atrial fibrillation and in the small blood vessels in the brain, about 7% of males and 4% of females with Fabry disease, particularly those with the type 1 phenotype, experience ischemic or hemorrhagic strokes, occurring typically in the fourth decade of life or later (Fellgiebel 2006, Wilcox 2008).Respiratory abnormalities: Accumulation of glycosphingolipids and consequent fibrosis can cause interstitial lung disease. Pathological changes and tissue remodeling may involve both alveoli and the bronchial tree leading to restrictive lung disease, obstructive airway disease, or a mixture of obstructive and restrictive disease. (Svensson 2015). Respiratory symptoms may occur independent of cardiovascular disease in these patients.Other pathology: Hearing loss, tinnitus, dizziness and vertigo potentially due to GL-3/Gb3 deposition in vestibular structures and/or auditory neuropathy are commonly reported in adult patients and while these are not life threatening, contribute to disease burden and negatively affect quality of life. Depression has been reported and a portion of these cases, especially Type I Classic males, were classified as having severe depression. (Cole 2007) | 433 | Fabry Disease |
nord_433_2 | Causes of Fabry Disease | Genetics
Fabry disease is caused by alterations (mutations) in the alpha-galactosidase A (GLA) gene located on the X-chromosome. Chromosomes are found in the nucleus of all cells. They carry the genetic characteristics of each individual in thousands of specific segments, called “genes” that span the length of the chromosomes. Each of these genes has a specific function in the body. Human chromosomes are organized in pairs, numbered from 1 through 22, with the 23rd pair of X- and Y-chromosomes for males and two X-chromosomes for females. Individuals inherit one chromosome in each pair from each parent. Therefore, in X-linked disorders including Fabry disease, disease traits on the X-chromosome can be masked or reduced in females by the normal gene on the other X-chromosome. More specifically, because only one functioning X-chromosome is required in males and females, one of the X-chromosomes in each cell of a female is essentially “turned off”, usually in a random pattern (random X-chromosome inactivation). This means that in X-linked disorders, some cells will have the X-chromosome with the mutated “Fabry” gene activated, while others will have the X-chromosome with the functioning, normal gene activated. Therefore, in Fabry disease the symptoms and severity of organ involvement are dependent on the percentage of cells in the tissue/organ where the X-chromosome with the GLA gene mutation is active, but with no or markedly decreased function, which partially explains why the disease severity in females is more variable than in their affected male relatives. Since males have only one X-chromosome, if a male has the X-chromosome with the GLA gene mutation, he will be affected with the disorder. Therefore, type 1 classic and type 2 later-onset males with Fabry disease are more uniformly affected, whereas symptoms in females, due to random X-inactivation, may range from asymptomatic or as severely affected as their affected male relatives (Dobrovolny 2005, Echevarria 2016)Males with X-linked Fabry disease transmit the GLA gene mutation to all their daughters, who are heterozygotes, but never to their sons. Female heterozygotes have a 50 percent risk of transmitting the disease to each of their children, both daughters and sons, with each pregnancy.The GLA gene normally instructs the body’s cells to make the α-Gal A enzyme, which breaks down the accumulating glycolipids (GL-3/Gb3) in the cell’s lysosomes. Fabry disease is caused by mutations in the GLA gene. There are over 965 reported mutations in the GLA gene that are responsible for Fabry disease (Stenson 2017; Human Gene Mutation Database; http://www.hgmd.org), causing the type 1 or 2 phenotypes. Two databases provide phenotype assignments for all reported mutations: dbFGP.org and Fabry-Database.org (Saito 2011). Thus, the severity and range of symptoms may vary among individuals depending on the GLA mutation in their family. Some mutations markedly alter the enzyme such that it has little to no activity. These mutations cause the type 1 classic subtype (e.g., Eng 1997, Shabber 2006), while other mutations result in a small amount of residual enzyme activity and the type 2 later-onset subtype (e.g., von Scheidt 1991, Eng 1997, Nakao 2003, Spada 2006). The signs and symptoms of Fabry disease develop due to absent or markedly deficient α-Gal A enzymatic activity. Patients with the type 1 classic phenotype, who have no or very low activity levels (less than 3% of normal), accumulate the GL-3/Gb-3 glycolipid substance (and related glycolipids) in most tissues of the body, especially small blood vessels, and certain cells in the heart and kidneys. Patients with the type 2 later-onset phenotype have residual enzyme activity (3-15% of mean normal activity, Desnick 2001), also accumulate GL-3/Gb3, but to a lesser extent and at a slower rate. They tend to have a somewhat less severe form of the disease, but males with the type 2 subtype ultimately develop severe cardiac disease and/or renal failure. There are also mutations in the GLA gene that are benign and do not cause Fabry disease (e.g., Froissart 2003, Doheny 2018) | Causes of Fabry Disease. Genetics
Fabry disease is caused by alterations (mutations) in the alpha-galactosidase A (GLA) gene located on the X-chromosome. Chromosomes are found in the nucleus of all cells. They carry the genetic characteristics of each individual in thousands of specific segments, called “genes” that span the length of the chromosomes. Each of these genes has a specific function in the body. Human chromosomes are organized in pairs, numbered from 1 through 22, with the 23rd pair of X- and Y-chromosomes for males and two X-chromosomes for females. Individuals inherit one chromosome in each pair from each parent. Therefore, in X-linked disorders including Fabry disease, disease traits on the X-chromosome can be masked or reduced in females by the normal gene on the other X-chromosome. More specifically, because only one functioning X-chromosome is required in males and females, one of the X-chromosomes in each cell of a female is essentially “turned off”, usually in a random pattern (random X-chromosome inactivation). This means that in X-linked disorders, some cells will have the X-chromosome with the mutated “Fabry” gene activated, while others will have the X-chromosome with the functioning, normal gene activated. Therefore, in Fabry disease the symptoms and severity of organ involvement are dependent on the percentage of cells in the tissue/organ where the X-chromosome with the GLA gene mutation is active, but with no or markedly decreased function, which partially explains why the disease severity in females is more variable than in their affected male relatives. Since males have only one X-chromosome, if a male has the X-chromosome with the GLA gene mutation, he will be affected with the disorder. Therefore, type 1 classic and type 2 later-onset males with Fabry disease are more uniformly affected, whereas symptoms in females, due to random X-inactivation, may range from asymptomatic or as severely affected as their affected male relatives (Dobrovolny 2005, Echevarria 2016)Males with X-linked Fabry disease transmit the GLA gene mutation to all their daughters, who are heterozygotes, but never to their sons. Female heterozygotes have a 50 percent risk of transmitting the disease to each of their children, both daughters and sons, with each pregnancy.The GLA gene normally instructs the body’s cells to make the α-Gal A enzyme, which breaks down the accumulating glycolipids (GL-3/Gb3) in the cell’s lysosomes. Fabry disease is caused by mutations in the GLA gene. There are over 965 reported mutations in the GLA gene that are responsible for Fabry disease (Stenson 2017; Human Gene Mutation Database; http://www.hgmd.org), causing the type 1 or 2 phenotypes. Two databases provide phenotype assignments for all reported mutations: dbFGP.org and Fabry-Database.org (Saito 2011). Thus, the severity and range of symptoms may vary among individuals depending on the GLA mutation in their family. Some mutations markedly alter the enzyme such that it has little to no activity. These mutations cause the type 1 classic subtype (e.g., Eng 1997, Shabber 2006), while other mutations result in a small amount of residual enzyme activity and the type 2 later-onset subtype (e.g., von Scheidt 1991, Eng 1997, Nakao 2003, Spada 2006). The signs and symptoms of Fabry disease develop due to absent or markedly deficient α-Gal A enzymatic activity. Patients with the type 1 classic phenotype, who have no or very low activity levels (less than 3% of normal), accumulate the GL-3/Gb-3 glycolipid substance (and related glycolipids) in most tissues of the body, especially small blood vessels, and certain cells in the heart and kidneys. Patients with the type 2 later-onset phenotype have residual enzyme activity (3-15% of mean normal activity, Desnick 2001), also accumulate GL-3/Gb3, but to a lesser extent and at a slower rate. They tend to have a somewhat less severe form of the disease, but males with the type 2 subtype ultimately develop severe cardiac disease and/or renal failure. There are also mutations in the GLA gene that are benign and do not cause Fabry disease (e.g., Froissart 2003, Doheny 2018) | 433 | Fabry Disease |
nord_433_3 | Affects of Fabry Disease | Fabry disease is a rare pan-ethnic disorder, meaning that it occurs in all racial and ethnic populations affecting males and females. It is estimated that type 1 classic Fabry disease affects approximately one in 40,000 males. The type 2 later-onset phenotype is more frequent, than the type 1 phenotype by 3-10 fold, and in some populations may occur as frequently as about 1 in 1,500 to 4,000 males (Spada 2006, Hwu 2009, Chien 2012). Data emerging from the newborn screening studies suggests that the incidence of Fabry disease varies in different geographic regions (Spada 2006, Hwu 2009, Burlina 2018, Wasserstein 2019). Already, newborn screening for Fabry disease has been initiated in several states in the USA. | Affects of Fabry Disease. Fabry disease is a rare pan-ethnic disorder, meaning that it occurs in all racial and ethnic populations affecting males and females. It is estimated that type 1 classic Fabry disease affects approximately one in 40,000 males. The type 2 later-onset phenotype is more frequent, than the type 1 phenotype by 3-10 fold, and in some populations may occur as frequently as about 1 in 1,500 to 4,000 males (Spada 2006, Hwu 2009, Chien 2012). Data emerging from the newborn screening studies suggests that the incidence of Fabry disease varies in different geographic regions (Spada 2006, Hwu 2009, Burlina 2018, Wasserstein 2019). Already, newborn screening for Fabry disease has been initiated in several states in the USA. | 433 | Fabry Disease |
nord_433_4 | Related disorders of Fabry Disease | Symptoms of the following disorders can be similar to those of Fabry disease. Comparisons may be useful for a differential diagnosis:Schindler disease is a rare inherited metabolic disorder characterized by a deficiency of the lysosomal enzyme alpha-N-acetylgalactosaminidase (alpha-NAGA), which leads to an abnormal accumulation of certain complex compounds (glycosphingolipids and oligosaccharides) in many tissues of the body (Schindler 1989). Schindler disease is inherited as an autosomal recessive disorder. There are three types of Schindler disease. The classic form of the disorder, known as Schindler disease, type I, has an infantile onset. Affected individuals appear to develop normally until approximately one year of age, when they begin to lose previously acquired skills that require the coordination of physical and mental activities (developmental regression). Additional neurological and neuromuscular symptoms may become apparent, including diminished muscle tone (hypotonia) and weakness; involuntary, rapid eye movements (nystagmus); visual impairment; and episodes of uncontrolled electrical activity in the brain (seizures). With continuing disease progression, affected children typically develop restricted movements of certain muscles due to progressively increased muscle rigidity, severe intellectual disability, hearing and visual impairment, and a lack of response to stimuli in the environment. Type II Schindler disease also known as Kanzaki disease, is the adult-onset form with symptoms presenting in the second or third decade of life (Kanzaki 1993). The disorder is characterized by angiokeratoma, a skin lesion and distribution similar to that seen in type 1 classic Fabry disease. Presentation may also include lymphedema, intellectual impairment, and distinct facial features including mildly coarse features, thick lips, a depressed nasal bridge and an enlarged tip of the nose. Type III Schindler disease is an intermediate form the disorder. Symptoms can range from more serious intellectual impairment, neurological dysfunction and seizures to milder neurological and psychiatric issues such as speech and language delays and mild autism-like symptoms. (For more information on this disorder, choose “Schindler” as your search term in the Rare Disease Database.)Gaucher disease is one of the most common of the lipid storage diseases and is characterized by the abnormal accumulation of certain fatty substances in various organs of the body (Balwani 2010). Symptoms develop due to a deficiency in the enzyme glucocerebrosidase and may include enlargement of the liver (hepatomegaly) and spleen (splenomegaly), a general feeling of ill health (malaise), visual difficulties, abdominal swelling, severe bone pain and bone disease. Gaucher disease is inherited as an autosomal recessive trait. (For more information on this disorder, choose “Gaucher” as your search term in the Rare Disease Database.)Fucosidosis is an extremely rare inherited lysosomal storage disease characterized by a deficiency of the enzyme alpha-L-fucosidase. There are at least two types of fucosidosis (i.e., type 1 and type 2), determined mainly by the severity of the enzyme deficiency and resulting symptoms. The symptoms of fucosidosis type 1, the most severe form of the disease, may become apparent as early as six months of age. Symptoms may include a skin lesion similar to Fabry disease (angiokeratoma), progressive deterioration of the brain and spinal cord (central nervous system), intellectual disability, loss of previously acquired intellectual skills, and growth retardation leading to short stature. Other physical findings and features become apparent over time, including multiple deformities of the bones (dysostosis multiplex), coarse facial features, enlargement of the heart (cardiomegaly), enlargement of the liver and spleen (hepatosplenomegaly), and/or episodes of uncontrolled electrical activity in the brain (seizures). Additional symptoms may include increased or decreased perspiration and/or malfunction of the gallbladder and/or salivary glands. Fucosidosis is inherited as an autosomal recessive trait. (For more information on this disorder, choose “fucosidosis” as your search term in the Rare Disease Database.)Erythromelalgia is a rare condition that primarily affects the feet and, less commonly, the hands. It is characterized by intense burning pain of affected extremities, severe redness, and increased skin temperature that may be episodic or almost continuous in nature. (For more information on this disorder, choose “Erythromelalgia” as your search term in the Rare Disease Database.) | Related disorders of Fabry Disease. Symptoms of the following disorders can be similar to those of Fabry disease. Comparisons may be useful for a differential diagnosis:Schindler disease is a rare inherited metabolic disorder characterized by a deficiency of the lysosomal enzyme alpha-N-acetylgalactosaminidase (alpha-NAGA), which leads to an abnormal accumulation of certain complex compounds (glycosphingolipids and oligosaccharides) in many tissues of the body (Schindler 1989). Schindler disease is inherited as an autosomal recessive disorder. There are three types of Schindler disease. The classic form of the disorder, known as Schindler disease, type I, has an infantile onset. Affected individuals appear to develop normally until approximately one year of age, when they begin to lose previously acquired skills that require the coordination of physical and mental activities (developmental regression). Additional neurological and neuromuscular symptoms may become apparent, including diminished muscle tone (hypotonia) and weakness; involuntary, rapid eye movements (nystagmus); visual impairment; and episodes of uncontrolled electrical activity in the brain (seizures). With continuing disease progression, affected children typically develop restricted movements of certain muscles due to progressively increased muscle rigidity, severe intellectual disability, hearing and visual impairment, and a lack of response to stimuli in the environment. Type II Schindler disease also known as Kanzaki disease, is the adult-onset form with symptoms presenting in the second or third decade of life (Kanzaki 1993). The disorder is characterized by angiokeratoma, a skin lesion and distribution similar to that seen in type 1 classic Fabry disease. Presentation may also include lymphedema, intellectual impairment, and distinct facial features including mildly coarse features, thick lips, a depressed nasal bridge and an enlarged tip of the nose. Type III Schindler disease is an intermediate form the disorder. Symptoms can range from more serious intellectual impairment, neurological dysfunction and seizures to milder neurological and psychiatric issues such as speech and language delays and mild autism-like symptoms. (For more information on this disorder, choose “Schindler” as your search term in the Rare Disease Database.)Gaucher disease is one of the most common of the lipid storage diseases and is characterized by the abnormal accumulation of certain fatty substances in various organs of the body (Balwani 2010). Symptoms develop due to a deficiency in the enzyme glucocerebrosidase and may include enlargement of the liver (hepatomegaly) and spleen (splenomegaly), a general feeling of ill health (malaise), visual difficulties, abdominal swelling, severe bone pain and bone disease. Gaucher disease is inherited as an autosomal recessive trait. (For more information on this disorder, choose “Gaucher” as your search term in the Rare Disease Database.)Fucosidosis is an extremely rare inherited lysosomal storage disease characterized by a deficiency of the enzyme alpha-L-fucosidase. There are at least two types of fucosidosis (i.e., type 1 and type 2), determined mainly by the severity of the enzyme deficiency and resulting symptoms. The symptoms of fucosidosis type 1, the most severe form of the disease, may become apparent as early as six months of age. Symptoms may include a skin lesion similar to Fabry disease (angiokeratoma), progressive deterioration of the brain and spinal cord (central nervous system), intellectual disability, loss of previously acquired intellectual skills, and growth retardation leading to short stature. Other physical findings and features become apparent over time, including multiple deformities of the bones (dysostosis multiplex), coarse facial features, enlargement of the heart (cardiomegaly), enlargement of the liver and spleen (hepatosplenomegaly), and/or episodes of uncontrolled electrical activity in the brain (seizures). Additional symptoms may include increased or decreased perspiration and/or malfunction of the gallbladder and/or salivary glands. Fucosidosis is inherited as an autosomal recessive trait. (For more information on this disorder, choose “fucosidosis” as your search term in the Rare Disease Database.)Erythromelalgia is a rare condition that primarily affects the feet and, less commonly, the hands. It is characterized by intense burning pain of affected extremities, severe redness, and increased skin temperature that may be episodic or almost continuous in nature. (For more information on this disorder, choose “Erythromelalgia” as your search term in the Rare Disease Database.) | 433 | Fabry Disease |
nord_433_5 | Diagnosis of Fabry Disease | The clinical diagnosis of the type 1 classic phenotype can be made clinically by physicians who recognize the characteristic findings of episodic pain in the extremities, absent or decreased sweating (anhidrosis or hypohidrosis), typical skin lesions (angiokeratoma), gastrointestinal abnormalities, and the corneal dystrophy in childhood or adolescence (Desnick 2003). The disease progresses to renal insufficiency, and/or heart and cerebrovascular disease in adulthood. In type 2 males, the diagnosis is often missed, and may be made in adulthood when the cardiac and/or kidney disease becomes manifest. Many males with the type 2 later-onset phenotype have been diagnosed by screening patients in hemodialysis, cardiac, and stroke clinics (Doheny 2018). The diagnosis of both type 1 and 2 males is confirmed by demonstrating the enzyme deficiency and by identifying the specific GLA gene mutation.Female heterozygotes can have α-GAL A enzymatic activity from markedly decreased to values in the normal range. Therefore, heterozygous females are only accurately diagnosed by demonstrating the specific α-galactosidase A (GLA) gene mutation. Early prenatal diagnosis at about 10 weeks of pregnancy can be made by α-Gal A enzyme and GLA mutation analyses of villi obtained by chronic villus sampling, or by amniocentesis at about 15 weeks of gestation by determining the α-Gal A enzyme activity and demonstrating the family-specific GLA mutation (Desnick 2007). Preimplantation genetic diagnosis is available when the familial mutation in the GLA gene is known. Newborn screening studies have identified affected males by demonstrating the reduced α-Gal A activity in dried blood spots followed by GLA gene sequencing (e.g., Spada 2006, Burlina 2018, Wasserstein 2019). | Diagnosis of Fabry Disease. The clinical diagnosis of the type 1 classic phenotype can be made clinically by physicians who recognize the characteristic findings of episodic pain in the extremities, absent or decreased sweating (anhidrosis or hypohidrosis), typical skin lesions (angiokeratoma), gastrointestinal abnormalities, and the corneal dystrophy in childhood or adolescence (Desnick 2003). The disease progresses to renal insufficiency, and/or heart and cerebrovascular disease in adulthood. In type 2 males, the diagnosis is often missed, and may be made in adulthood when the cardiac and/or kidney disease becomes manifest. Many males with the type 2 later-onset phenotype have been diagnosed by screening patients in hemodialysis, cardiac, and stroke clinics (Doheny 2018). The diagnosis of both type 1 and 2 males is confirmed by demonstrating the enzyme deficiency and by identifying the specific GLA gene mutation.Female heterozygotes can have α-GAL A enzymatic activity from markedly decreased to values in the normal range. Therefore, heterozygous females are only accurately diagnosed by demonstrating the specific α-galactosidase A (GLA) gene mutation. Early prenatal diagnosis at about 10 weeks of pregnancy can be made by α-Gal A enzyme and GLA mutation analyses of villi obtained by chronic villus sampling, or by amniocentesis at about 15 weeks of gestation by determining the α-Gal A enzyme activity and demonstrating the family-specific GLA mutation (Desnick 2007). Preimplantation genetic diagnosis is available when the familial mutation in the GLA gene is known. Newborn screening studies have identified affected males by demonstrating the reduced α-Gal A activity in dried blood spots followed by GLA gene sequencing (e.g., Spada 2006, Burlina 2018, Wasserstein 2019). | 433 | Fabry Disease |
nord_433_6 | Therapies of Fabry Disease | Treatment
Fabry disease causes multi-organ dysfunction and patients need a comprehensive, multi-disciplinary treatment plan that is individually tailored and includes specific therapies that target abnormal substrate accumulation and adjuvant therapies that address end-organ damage (Ortiz 2018). Enzyme replacement therapy (ERT) is the cornerstone for treatment of Fabry disease and synthetic enzyme, produced by recombinant DNA technology, is infused intravenously. Two forms of the recombinant enzyme are available, agalsidase alpha (Replagal®, Shire pharmaceuticals) and agalsidase beta (Fabrazyme®, Sanofi Genzyme). Fabrazyme is the only ERT approved by the Food and Drug Administration (FDA) in 2003. Both Replagal and Fabrazyme are available in Europe and other regions of the world. ERT replaces the missing enzyme and reduces the accumulated glycolipids in cells throughout the body. Double-blind, placebo-controlled Phase 3 and 4 clinical trials have demonstrated the safety and effectiveness of Fabrazyme (Eng 2001A, 2001B; Banikazemi 2007, Fellgiebel 2014, Germain 2015).ERT has been shown to slow or prevent the decline of renal function especially if initiated early before advanced kidney damage, improve neuropathic pain and heat intolerance (Eng 2001, Germain 2015). Globotriaosylceramide accumulation is cleared from various cell types in the kidney following ERT (Tondel 2013, Skrunnes 2017). Early initiation of ERT is important especially in type 1 classically affected males. ERT initiation is currently recommended for type 1 Classic males with clnical manifestations at any age, or if asymptomatic, by age 15 (Hopkin 2016, Ortiz 2018). Recombinant enzyme “biosimilars” are available in certain countries including Korea and Japan. Several other recombinant enzyme preparations are in clinical development.An oral therapy, Galafold (migalastat, Amicus Therapeutics) was approved in the EU (2017) and in the US (2018) to treat adults with Fabry disease. The drug is a pharmacologic chaperone that can bind to, stabilize, and enhance the residual enzymatic activity of certain missense mutations (Desnick and Schuchman 2002, Benjamin 2017). Clinical studies have demonstrated the effectiveness of this approach (Germain 2016). Future studies will determine the clinical and biochemical effectiveness of specific missense mutations with residual activity. Adjunct therapies include low daily doses of diphenylhydantoin, carbamazepine, or neurontin, to help to manage the acroparesthesia (Burlina 2011). Other later complications (e.g., kidney failure or heart problems) should be treated symptomatically after consultation with a physician who is experienced in the care of patients with Fabry disease. Hemodialysis and kidney (renal) transplantation may be necessary in cases that have progressed to kidney failure (Thadhani 2002, Ersözlü 2018). Genetic counseling is recommended for affected individuals and their families. | Therapies of Fabry Disease. Treatment
Fabry disease causes multi-organ dysfunction and patients need a comprehensive, multi-disciplinary treatment plan that is individually tailored and includes specific therapies that target abnormal substrate accumulation and adjuvant therapies that address end-organ damage (Ortiz 2018). Enzyme replacement therapy (ERT) is the cornerstone for treatment of Fabry disease and synthetic enzyme, produced by recombinant DNA technology, is infused intravenously. Two forms of the recombinant enzyme are available, agalsidase alpha (Replagal®, Shire pharmaceuticals) and agalsidase beta (Fabrazyme®, Sanofi Genzyme). Fabrazyme is the only ERT approved by the Food and Drug Administration (FDA) in 2003. Both Replagal and Fabrazyme are available in Europe and other regions of the world. ERT replaces the missing enzyme and reduces the accumulated glycolipids in cells throughout the body. Double-blind, placebo-controlled Phase 3 and 4 clinical trials have demonstrated the safety and effectiveness of Fabrazyme (Eng 2001A, 2001B; Banikazemi 2007, Fellgiebel 2014, Germain 2015).ERT has been shown to slow or prevent the decline of renal function especially if initiated early before advanced kidney damage, improve neuropathic pain and heat intolerance (Eng 2001, Germain 2015). Globotriaosylceramide accumulation is cleared from various cell types in the kidney following ERT (Tondel 2013, Skrunnes 2017). Early initiation of ERT is important especially in type 1 classically affected males. ERT initiation is currently recommended for type 1 Classic males with clnical manifestations at any age, or if asymptomatic, by age 15 (Hopkin 2016, Ortiz 2018). Recombinant enzyme “biosimilars” are available in certain countries including Korea and Japan. Several other recombinant enzyme preparations are in clinical development.An oral therapy, Galafold (migalastat, Amicus Therapeutics) was approved in the EU (2017) and in the US (2018) to treat adults with Fabry disease. The drug is a pharmacologic chaperone that can bind to, stabilize, and enhance the residual enzymatic activity of certain missense mutations (Desnick and Schuchman 2002, Benjamin 2017). Clinical studies have demonstrated the effectiveness of this approach (Germain 2016). Future studies will determine the clinical and biochemical effectiveness of specific missense mutations with residual activity. Adjunct therapies include low daily doses of diphenylhydantoin, carbamazepine, or neurontin, to help to manage the acroparesthesia (Burlina 2011). Other later complications (e.g., kidney failure or heart problems) should be treated symptomatically after consultation with a physician who is experienced in the care of patients with Fabry disease. Hemodialysis and kidney (renal) transplantation may be necessary in cases that have progressed to kidney failure (Thadhani 2002, Ersözlü 2018). Genetic counseling is recommended for affected individuals and their families. | 433 | Fabry Disease |
nord_434_0 | Overview of Facioscapulohumeral Muscular Dystrophy | Facioscapulohumeral muscular dystrophy (FSHD) is a disorder characterized by muscle weakness and wasting (atrophy). The disorder gets its name from muscles that are affected in the face (facio), around the shoulder blades (scapulo), and in the upper arms (humeral). Hamstring and trunk muscles are affected -early on but are less well recognized. Other arm and leg muscles are frequently eventually affected in the course of the disease. Symptoms usually appear before age 20, but can begin in infancy or later in adulthood. Severity of the condition varies widely and some people with the disease allele remain asymptomatic. FSHD is most typically characterized by relatively slow disease progression. Specific symptoms and findings may also vary in range and severity, including among affected members of the same family. Life expectancy is not shortened. FSHD is usually inherited as an autosomal dominant genetic condition. | Overview of Facioscapulohumeral Muscular Dystrophy. Facioscapulohumeral muscular dystrophy (FSHD) is a disorder characterized by muscle weakness and wasting (atrophy). The disorder gets its name from muscles that are affected in the face (facio), around the shoulder blades (scapulo), and in the upper arms (humeral). Hamstring and trunk muscles are affected -early on but are less well recognized. Other arm and leg muscles are frequently eventually affected in the course of the disease. Symptoms usually appear before age 20, but can begin in infancy or later in adulthood. Severity of the condition varies widely and some people with the disease allele remain asymptomatic. FSHD is most typically characterized by relatively slow disease progression. Specific symptoms and findings may also vary in range and severity, including among affected members of the same family. Life expectancy is not shortened. FSHD is usually inherited as an autosomal dominant genetic condition. | 434 | Facioscapulohumeral Muscular Dystrophy |
nord_434_1 | Symptoms of Facioscapulohumeral Muscular Dystrophy | FSHD may initially involve weakness of muscles of the face, shoulder girdle and arms. Facial weakness may result in limited movements of the lips, causing difficulties whistling, using a straw, or puckering the lips. Affected individuals may also develop a distinctive “mask-like” facial appearance. Upper facial weakness may also lead to an inability to completely close the eyes during sleep.FSHD is also typically associated with weakening and atrophy of muscles of the neck and shoulder blades and muscles at the front and back of the upper arms (biceps and triceps brachii muscles). With disease progression, there is a decrease in the ability to lift the arms due to weakness of muscles stabilizing the shoulder blades; and “scapular winging,” one of the most common initial finding, characterized by abnormal prominence of the borders of the shoulder blades. This finding tends to become more obvious when affected individuals attempt to raise their arms to the side (laterally). In addition, when viewed from the front, the collarbones (clavicles) may appear to sag. Some affected individuals may also develop wrist drop or downward flexion of the wrist due to weakness of certain muscles of the fingers and hands.FSHD may also be characterized by weakness and atrophy of other muscles, including abdominal wall, hip, and thigh muscles. Involvement of the muscle that rotates and moves the thigh outward (gluteus medius) may cause affected individuals to sway or lurch toward the affected side while walking (Trendelenburg gait). There may also be weakness of muscles of the lower legs and feet. Such involvement may lead to a condition known as footdrop, which is characterized by an impaired ability to flex or bend the foot upward. In some affected individuals, involvement of certain muscles may result in unusually pronounced inward curvature of the lower region of the spine (lordosis) or abnormal front-to-back and sideways spinal curvature (kyphoscoliosis).For unknown reasons, in most individuals with FSHD, the degree of muscle weakness may differ from one side of the body to the other (asymmetrical).Those with the disorder may have relatively slow or moderate progression of muscle weakness or, in some cases, apparently non-progressive involvement of certain muscles. However, evidence suggests that the disease course is most frequently characterized by slow progression with short periods of rapid muscle deterioration. Associated muscle weakness may result in minimal disability or, in other people, lead to difficulties speaking; abnormalities in the manner of walking (gait disturbances); and/or an impaired ability to perform certain activities of daily living. In approximately 20% of those affected, disease progression may lead to severe muscle weakness that necessitates the use of a wheelchair or other mobility equipment. Families have been described in which disease manifestations ranged from minor facial weakness in a parent to severe infantile onset in an affected child.In some individuals with FSHD, particularly those with early onset, the disorder may also be associated with hearing impairment and/or abnormalities of blood vessels within the nerve-rich, innermost membrane of the eye (retinal vasculopathy) that may, in rare cases, lead to visual impairment.Two types of FSHD have been described, FSHD1 (95% of those affected) and FSHD2 (5% of those affected). FSHD1 and FSHD2 have the same signs and symptoms but different genetic causes. | Symptoms of Facioscapulohumeral Muscular Dystrophy. FSHD may initially involve weakness of muscles of the face, shoulder girdle and arms. Facial weakness may result in limited movements of the lips, causing difficulties whistling, using a straw, or puckering the lips. Affected individuals may also develop a distinctive “mask-like” facial appearance. Upper facial weakness may also lead to an inability to completely close the eyes during sleep.FSHD is also typically associated with weakening and atrophy of muscles of the neck and shoulder blades and muscles at the front and back of the upper arms (biceps and triceps brachii muscles). With disease progression, there is a decrease in the ability to lift the arms due to weakness of muscles stabilizing the shoulder blades; and “scapular winging,” one of the most common initial finding, characterized by abnormal prominence of the borders of the shoulder blades. This finding tends to become more obvious when affected individuals attempt to raise their arms to the side (laterally). In addition, when viewed from the front, the collarbones (clavicles) may appear to sag. Some affected individuals may also develop wrist drop or downward flexion of the wrist due to weakness of certain muscles of the fingers and hands.FSHD may also be characterized by weakness and atrophy of other muscles, including abdominal wall, hip, and thigh muscles. Involvement of the muscle that rotates and moves the thigh outward (gluteus medius) may cause affected individuals to sway or lurch toward the affected side while walking (Trendelenburg gait). There may also be weakness of muscles of the lower legs and feet. Such involvement may lead to a condition known as footdrop, which is characterized by an impaired ability to flex or bend the foot upward. In some affected individuals, involvement of certain muscles may result in unusually pronounced inward curvature of the lower region of the spine (lordosis) or abnormal front-to-back and sideways spinal curvature (kyphoscoliosis).For unknown reasons, in most individuals with FSHD, the degree of muscle weakness may differ from one side of the body to the other (asymmetrical).Those with the disorder may have relatively slow or moderate progression of muscle weakness or, in some cases, apparently non-progressive involvement of certain muscles. However, evidence suggests that the disease course is most frequently characterized by slow progression with short periods of rapid muscle deterioration. Associated muscle weakness may result in minimal disability or, in other people, lead to difficulties speaking; abnormalities in the manner of walking (gait disturbances); and/or an impaired ability to perform certain activities of daily living. In approximately 20% of those affected, disease progression may lead to severe muscle weakness that necessitates the use of a wheelchair or other mobility equipment. Families have been described in which disease manifestations ranged from minor facial weakness in a parent to severe infantile onset in an affected child.In some individuals with FSHD, particularly those with early onset, the disorder may also be associated with hearing impairment and/or abnormalities of blood vessels within the nerve-rich, innermost membrane of the eye (retinal vasculopathy) that may, in rare cases, lead to visual impairment.Two types of FSHD have been described, FSHD1 (95% of those affected) and FSHD2 (5% of those affected). FSHD1 and FSHD2 have the same signs and symptoms but different genetic causes. | 434 | Facioscapulohumeral Muscular Dystrophy |
nord_434_2 | Causes of Facioscapulohumeral Muscular Dystrophy | FSHD1 is caused by abnormal expression of the DUX4 gene, which is located in the D4Z4 region of chromosome 4. Normally, the DNA in the D4Z4 region is hypermethylated (has many methyl groups: 1 carbon atom and 3 hydrogen atoms) and includes 11-100 repeated segments of DNA. In individuals with FSHD1, this region of chromosome 4 is shortened and contains 1-10 repeats and fewer methyl groups. The lack of methyl groups allows the DUX4 gene to be “turned on” and produce DUX4 protein in cells and tissues where it is usually not produced, resulting in progressive muscle weakness and atrophy. Generally, a smaller number of repeats is associated with more severe disease.FSHD1 is an autosomal dominant genetic condition. 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.In approximately 30 percent of individuals with FSHD1, there is no apparent family history of the disorder and in these people FSHD is thought to be caused by new mutations.FSHD2 is also an autosomal dominant genetic condition. People with FSHD2 have a mutation in the SMCHD1 gene that results in demethylation of the D4Z4 region, allowing misexpression of the DUX4 gene and resulting in progressive muscle weakness and atrophy. | Causes of Facioscapulohumeral Muscular Dystrophy. FSHD1 is caused by abnormal expression of the DUX4 gene, which is located in the D4Z4 region of chromosome 4. Normally, the DNA in the D4Z4 region is hypermethylated (has many methyl groups: 1 carbon atom and 3 hydrogen atoms) and includes 11-100 repeated segments of DNA. In individuals with FSHD1, this region of chromosome 4 is shortened and contains 1-10 repeats and fewer methyl groups. The lack of methyl groups allows the DUX4 gene to be “turned on” and produce DUX4 protein in cells and tissues where it is usually not produced, resulting in progressive muscle weakness and atrophy. Generally, a smaller number of repeats is associated with more severe disease.FSHD1 is an autosomal dominant genetic condition. 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.In approximately 30 percent of individuals with FSHD1, there is no apparent family history of the disorder and in these people FSHD is thought to be caused by new mutations.FSHD2 is also an autosomal dominant genetic condition. People with FSHD2 have a mutation in the SMCHD1 gene that results in demethylation of the D4Z4 region, allowing misexpression of the DUX4 gene and resulting in progressive muscle weakness and atrophy. | 434 | Facioscapulohumeral Muscular Dystrophy |
nord_434_3 | Affects of Facioscapulohumeral Muscular Dystrophy | FSHD appears to affect males and females in relatively equal numbers. The estimated prevalence is between four and ten per 100,000 people. | Affects of Facioscapulohumeral Muscular Dystrophy. FSHD appears to affect males and females in relatively equal numbers. The estimated prevalence is between four and ten per 100,000 people. | 434 | Facioscapulohumeral Muscular Dystrophy |
nord_434_4 | Related disorders of Facioscapulohumeral Muscular Dystrophy | There are a number of genetic neuromuscular diseases that may be characterized by muscle weakness of varying severity, muscle atrophy, and associated symptoms that may be similar to those that may occur with FSHD. These include some limb girdle muscular dystrophies such as due to calpainopathy and inclusion body myositis. These conditions typically have characteristic features that may differentiate them from FSHD. (For more information on such disorders, choose the exact disease name in question as your search term in the Rare Disease Database.) | Related disorders of Facioscapulohumeral Muscular Dystrophy. There are a number of genetic neuromuscular diseases that may be characterized by muscle weakness of varying severity, muscle atrophy, and associated symptoms that may be similar to those that may occur with FSHD. These include some limb girdle muscular dystrophies such as due to calpainopathy and inclusion body myositis. These conditions typically have characteristic features that may differentiate them from FSHD. (For more information on such disorders, choose the exact disease name in question as your search term in the Rare Disease Database.) | 434 | Facioscapulohumeral Muscular Dystrophy |
nord_434_5 | Diagnosis of Facioscapulohumeral Muscular Dystrophy | FSHD may be diagnosed based upon a thorough clinical examination, identification of characteristic physical findings, a complete individual and family history, and genetic testing. In some affected individuals, laboratory studies may reveal elevated levels of a particular enzyme in the fluid portion of the blood (serum creatine kinase). Tests may also be conducted to record electrical activity in voluntary (skeletal) muscles at rest and during muscle contraction (electromyography [EMG]). Surgical removal (biopsy) and microscopic examination of small samples of muscle tissue is generally not informative in FSHD.Family members of those diagnosed with FSHD may also benefit from clinical examination to help detect any symptoms and signs that may be associated with FSHD as well as genetic testing to assist with diagnosis and family planning.Molecular genetic testing to determine the number of repeats in the D4Z4 region of chromosome 4 is available to confirm the diagnosis of FSHD1. Most affected individuals have fewer than 10 repeats. Molecular genetic testing for mutations in the SMCHD1 gene associated with FSHD2 is available and may be indicated if the D4Z4 region is not contracted (shortened). | Diagnosis of Facioscapulohumeral Muscular Dystrophy. FSHD may be diagnosed based upon a thorough clinical examination, identification of characteristic physical findings, a complete individual and family history, and genetic testing. In some affected individuals, laboratory studies may reveal elevated levels of a particular enzyme in the fluid portion of the blood (serum creatine kinase). Tests may also be conducted to record electrical activity in voluntary (skeletal) muscles at rest and during muscle contraction (electromyography [EMG]). Surgical removal (biopsy) and microscopic examination of small samples of muscle tissue is generally not informative in FSHD.Family members of those diagnosed with FSHD may also benefit from clinical examination to help detect any symptoms and signs that may be associated with FSHD as well as genetic testing to assist with diagnosis and family planning.Molecular genetic testing to determine the number of repeats in the D4Z4 region of chromosome 4 is available to confirm the diagnosis of FSHD1. Most affected individuals have fewer than 10 repeats. Molecular genetic testing for mutations in the SMCHD1 gene associated with FSHD2 is available and may be indicated if the D4Z4 region is not contracted (shortened). | 434 | Facioscapulohumeral Muscular Dystrophy |
nord_434_6 | Therapies of Facioscapulohumeral Muscular Dystrophy | TreatmentThe treatment of FSHD 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 physicians who specialize in the treatment of neurological disorders (neurologists); physicians who diagnose and treat disorders of the skeleton, joints, muscles, and related tissues (orthopedists); physicians who specialize in physical medicine and rehabilitation (physiatrists); specialists who assess and treat hearing problems (audiologists); physicians who specialize in respiration (pulmonologists) and/or other health care professionals.Disease management may include orthopedic measures and physical therapy to help maintain muscle flexibility, counter atrophy and manage pain. Several studies indicate that those with FSHD benefit from exercise. Various physical and adaptive aids may be helpful in performing certain activities. Ankle-foot orthotics can help with walking. In some cases, severe muscle weakness may necessitate the use of wheelchairs, motorized carts, and other mobility and physical aids.In addition, speech therapy, use of appropriate assistive devices, and/or other supportive techniques may help to improve speech and communication problems associated with hearing impairment and/or facial weakness.In some people, recommended treatment may include surgery to mechanically attach the shoulder blades to the chest wall in order to help stabilize the scapulae and improve mobility of the upper arms.Pulmonary function testing is recommended for all with FSHD. Depending in these results, a sleep study may be recommended to determine breathing capacity while supine and asleep. Noninvasive ventilator support, usually beginning at night, is provided for those whose pulmonary function testing and sleep study are suggestive of respiratory compromise.Testing for retinal eye problems may be indicated for those with severe disease. Hearing testing may be indicated for children and some adults.
Genetic counseling is recommended for affected individuals and their families. Other treatment for this disorder is symptomatic and supportive. | Therapies of Facioscapulohumeral Muscular Dystrophy. TreatmentThe treatment of FSHD 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 physicians who specialize in the treatment of neurological disorders (neurologists); physicians who diagnose and treat disorders of the skeleton, joints, muscles, and related tissues (orthopedists); physicians who specialize in physical medicine and rehabilitation (physiatrists); specialists who assess and treat hearing problems (audiologists); physicians who specialize in respiration (pulmonologists) and/or other health care professionals.Disease management may include orthopedic measures and physical therapy to help maintain muscle flexibility, counter atrophy and manage pain. Several studies indicate that those with FSHD benefit from exercise. Various physical and adaptive aids may be helpful in performing certain activities. Ankle-foot orthotics can help with walking. In some cases, severe muscle weakness may necessitate the use of wheelchairs, motorized carts, and other mobility and physical aids.In addition, speech therapy, use of appropriate assistive devices, and/or other supportive techniques may help to improve speech and communication problems associated with hearing impairment and/or facial weakness.In some people, recommended treatment may include surgery to mechanically attach the shoulder blades to the chest wall in order to help stabilize the scapulae and improve mobility of the upper arms.Pulmonary function testing is recommended for all with FSHD. Depending in these results, a sleep study may be recommended to determine breathing capacity while supine and asleep. Noninvasive ventilator support, usually beginning at night, is provided for those whose pulmonary function testing and sleep study are suggestive of respiratory compromise.Testing for retinal eye problems may be indicated for those with severe disease. Hearing testing may be indicated for children and some adults.
Genetic counseling is recommended for affected individuals and their families. Other treatment for this disorder is symptomatic and supportive. | 434 | Facioscapulohumeral Muscular Dystrophy |
nord_435_0 | Overview of Factor VII Deficiency | SummaryFactor VII deficiency is a rare genetic bleeding disorder characterized by a deficiency or reduced activity of clotting factor VII. Clotting factors are specialized proteins that are essential for the blood to clot normally. Individuals with factor VII deficiency can experience prolonged, uncontrolled bleeding episodes. The severity of factor VII deficiency can vary greatly from one person to another. Some individuals may have no symptoms (asymptomatic); others may develop mild, moderate or potentially severe, life-threatening complications as early as in infancy. Factor VII deficiency is caused by mutations of the F7 gene and is inherited as an autosomal recessive disorder.IntroductionFactor VII deficiency was first described in the medical literature by Dr. Alexander, et al. in 1951 and was referred to as prothrombin conversion accelerator deficiency. The disorder has also been known as Alexander's disease. In extremely rare instances, factor VII deficiency can be acquired during life; this report deals with the genetic form, which is present at birth (although symptoms may develop later). | Overview of Factor VII Deficiency. SummaryFactor VII deficiency is a rare genetic bleeding disorder characterized by a deficiency or reduced activity of clotting factor VII. Clotting factors are specialized proteins that are essential for the blood to clot normally. Individuals with factor VII deficiency can experience prolonged, uncontrolled bleeding episodes. The severity of factor VII deficiency can vary greatly from one person to another. Some individuals may have no symptoms (asymptomatic); others may develop mild, moderate or potentially severe, life-threatening complications as early as in infancy. Factor VII deficiency is caused by mutations of the F7 gene and is inherited as an autosomal recessive disorder.IntroductionFactor VII deficiency was first described in the medical literature by Dr. Alexander, et al. in 1951 and was referred to as prothrombin conversion accelerator deficiency. The disorder has also been known as Alexander's disease. In extremely rare instances, factor VII deficiency can be acquired during life; this report deals with the genetic form, which is present at birth (although symptoms may develop later). | 435 | Factor VII Deficiency |
nord_435_1 | Symptoms of Factor VII Deficiency | The symptoms and severity of factor VII deficiency are highly variable; no consistent correlation between the amount of factor VII in the blood and overall severity is seen. Some individuals may not develop any symptoms (asymptomatic), including individuals with relatively low levels of factor VII. Other individuals may have mild cases that are only apparent after trauma or surgery. Mild symptoms can include chronic nosebleeds, easy bruising, and bleeding from the gums. People who menstruate may develop heavy and prolonged periods (menorrhagia).More serious bleeding complications occur in some individuals and may mimic bleeding patterns seen in hemophilia. Bleeding into the joints (hemarthrosis) can result in progressive joint damage and degeneration, eventually limiting the range of motion of an affected joint. Soft tissue bleeding can result in bruising that seems spontaneous or out of proportion to an injury. Affected individuals can develop masses of congealed blood called hematomas that can cause symptoms due to compression of nearby structures or organs. Bleeding in the stomach, intestines and urogenital tract can also occur resulting in blood in the urine (hematuria) or black, tarry, bloody stools (melena or hematochezia).Bleeding in severe factor VII deficiency can result in life-threatening complications. These include major gastrointestinal bleeds as well as head bleeds (intracranial hemorrhage), often during the first few weeks or months of life. Although quite rare, head bleeds have been reported in adults as well.Individuals with factor VII deficiency may experience bleeding after surgery or minor procedures or following trauma or injury. They may also bleed excessively following childbirth (postpartum bleeding). Some newborns have experienced abnormal bleeding from the umbilical cord stump at birth.A seemingly paradoxical increased incidence of clotting (thrombosis) has been noted in factor VII deficiency in recent years. These thromboses can be arterial or venous and they can occur spontaneously or in conjunction with treatment. | Symptoms of Factor VII Deficiency. The symptoms and severity of factor VII deficiency are highly variable; no consistent correlation between the amount of factor VII in the blood and overall severity is seen. Some individuals may not develop any symptoms (asymptomatic), including individuals with relatively low levels of factor VII. Other individuals may have mild cases that are only apparent after trauma or surgery. Mild symptoms can include chronic nosebleeds, easy bruising, and bleeding from the gums. People who menstruate may develop heavy and prolonged periods (menorrhagia).More serious bleeding complications occur in some individuals and may mimic bleeding patterns seen in hemophilia. Bleeding into the joints (hemarthrosis) can result in progressive joint damage and degeneration, eventually limiting the range of motion of an affected joint. Soft tissue bleeding can result in bruising that seems spontaneous or out of proportion to an injury. Affected individuals can develop masses of congealed blood called hematomas that can cause symptoms due to compression of nearby structures or organs. Bleeding in the stomach, intestines and urogenital tract can also occur resulting in blood in the urine (hematuria) or black, tarry, bloody stools (melena or hematochezia).Bleeding in severe factor VII deficiency can result in life-threatening complications. These include major gastrointestinal bleeds as well as head bleeds (intracranial hemorrhage), often during the first few weeks or months of life. Although quite rare, head bleeds have been reported in adults as well.Individuals with factor VII deficiency may experience bleeding after surgery or minor procedures or following trauma or injury. They may also bleed excessively following childbirth (postpartum bleeding). Some newborns have experienced abnormal bleeding from the umbilical cord stump at birth.A seemingly paradoxical increased incidence of clotting (thrombosis) has been noted in factor VII deficiency in recent years. These thromboses can be arterial or venous and they can occur spontaneously or in conjunction with treatment. | 435 | Factor VII Deficiency |
nord_435_2 | Causes of Factor VII Deficiency | Factor VII deficiency is caused by mutations of the F7 gene. These mutations are inherited in an autosomal recessive manner. Genetic diseases are determined by the combination of genes for a particular trait that are received from the father and the mother.Recessive genetic disorders occur when an individual inherits the same abnormal gene 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 on the defective gene and, therefore, have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent 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 percent. The risk is the same for males and females.The F7 gene creates (encodes) factor VII, which is a clotting factor. Clotting factors are specialized proteins that play an essential role in enabling the blood to clot. Clotting is the process by which blood clumps together to plug the site of a wound to stop bleeding. Clotting requires a series of reactions to ultimately form a clot to plug a wound. This is referred to as the clotting (coagulation) cascade. The clotting cascade involves different substances in addition to clotting factors. Factor VII, which is produced (synthesized) in the liver, eventually interacts with other clotting factors and certain cells or substances, e.g. platelets or fibrinogen, to help to form a clot. Mutations of the F7 gene result in deficient levels of functional factor VII, which in affected individuals, prevents the blood from clotting properly. Consequently, affected individuals have difficulty stopping the flow of blood from a wound; but they do not bleed faster or more profusely than healthy individuals.Individuals with factor VII deficiency often have varying levels of residual factor VII deficiency. In many disorders, the amount of residual protein activity correlates with the severity of the disease (e.g. little to no residual protein activity results in severe disease). However, in factor VII deficiency the severity of the disorder does not always correlate with the residual activity of factor VII, suggesting that additional genetic and environmental factors play a role in the severity of the disorder. | Causes of Factor VII Deficiency. Factor VII deficiency is caused by mutations of the F7 gene. These mutations are inherited in an autosomal recessive manner. Genetic diseases are determined by the combination of genes for a particular trait that are received from the father and the mother.Recessive genetic disorders occur when an individual inherits the same abnormal gene 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 on the defective gene and, therefore, have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent 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 percent. The risk is the same for males and females.The F7 gene creates (encodes) factor VII, which is a clotting factor. Clotting factors are specialized proteins that play an essential role in enabling the blood to clot. Clotting is the process by which blood clumps together to plug the site of a wound to stop bleeding. Clotting requires a series of reactions to ultimately form a clot to plug a wound. This is referred to as the clotting (coagulation) cascade. The clotting cascade involves different substances in addition to clotting factors. Factor VII, which is produced (synthesized) in the liver, eventually interacts with other clotting factors and certain cells or substances, e.g. platelets or fibrinogen, to help to form a clot. Mutations of the F7 gene result in deficient levels of functional factor VII, which in affected individuals, prevents the blood from clotting properly. Consequently, affected individuals have difficulty stopping the flow of blood from a wound; but they do not bleed faster or more profusely than healthy individuals.Individuals with factor VII deficiency often have varying levels of residual factor VII deficiency. In many disorders, the amount of residual protein activity correlates with the severity of the disease (e.g. little to no residual protein activity results in severe disease). However, in factor VII deficiency the severity of the disorder does not always correlate with the residual activity of factor VII, suggesting that additional genetic and environmental factors play a role in the severity of the disorder. | 435 | Factor VII Deficiency |
nord_435_3 | Affects of Factor VII Deficiency | Factor VII deficiency affects males and females in equal numbers. The disorder is estimated to affect 1 in 300,000 to 500,000 individuals in the general population. However, many cases of factor VII deficiency go undiagnosed or misdiagnosed, making it difficult to determine the true frequency in the general population. The incidence of factor VII deficiency tends to be higher in countries where marriage to close relatives (consanguineous marriage) is more common. According to the medical literature, more than 200 cases of true factor VII deficiency have been reported. Because of the variable severity of factor VII deficiency, the age of presentation can vary widely from birth until adulthood. | Affects of Factor VII Deficiency. Factor VII deficiency affects males and females in equal numbers. The disorder is estimated to affect 1 in 300,000 to 500,000 individuals in the general population. However, many cases of factor VII deficiency go undiagnosed or misdiagnosed, making it difficult to determine the true frequency in the general population. The incidence of factor VII deficiency tends to be higher in countries where marriage to close relatives (consanguineous marriage) is more common. According to the medical literature, more than 200 cases of true factor VII deficiency have been reported. Because of the variable severity of factor VII deficiency, the age of presentation can vary widely from birth until adulthood. | 435 | Factor VII Deficiency |
nord_435_4 | Related disorders of Factor VII Deficiency | Symptoms of the following disorders can be similar to those of factor VII deficiency. Comparisons may be useful for a differential diagnosis.Acquired factor VII deficiency is a general term for individuals who develop factor VII deficiency that is not inherited, but acquired at some point during life. Acquired factor VII deficiency can result from severe liver disease, sepsis or vitamin K deficiency. Certain drugs such as warfarin (Coumadin®) can result in acquired factor VII deficiency. Acquired factor VII deficiency is more common than the inherited form.Combined deficiency of vitamin K-dependent clotting factors (VKCFD) is a rare inherited disorder in which individuals have abnormalities affecting several clotting factors, specifically factors II, VII, IX, and X. These four factors are known as the vitamin K-dependent factors because vitamin K is required for the chemical reactions to produce (synthesize) these factors. Individuals with VKCFD cannot form blood clots properly. The severity of the disorder can vary greatly from one person to another. Many individuals may only develop mild symptoms, although cases associated with severe complications can develop. Symptoms can include easy bruising, frequent nosebleeds, gastrointestinal bleeding, and bleeding into the soft tissue and muscle. Bleeding in the joints can also occur. VKCFD is inherited as an autosomal recessive disorder. | Related disorders of Factor VII Deficiency. Symptoms of the following disorders can be similar to those of factor VII deficiency. Comparisons may be useful for a differential diagnosis.Acquired factor VII deficiency is a general term for individuals who develop factor VII deficiency that is not inherited, but acquired at some point during life. Acquired factor VII deficiency can result from severe liver disease, sepsis or vitamin K deficiency. Certain drugs such as warfarin (Coumadin®) can result in acquired factor VII deficiency. Acquired factor VII deficiency is more common than the inherited form.Combined deficiency of vitamin K-dependent clotting factors (VKCFD) is a rare inherited disorder in which individuals have abnormalities affecting several clotting factors, specifically factors II, VII, IX, and X. These four factors are known as the vitamin K-dependent factors because vitamin K is required for the chemical reactions to produce (synthesize) these factors. Individuals with VKCFD cannot form blood clots properly. The severity of the disorder can vary greatly from one person to another. Many individuals may only develop mild symptoms, although cases associated with severe complications can develop. Symptoms can include easy bruising, frequent nosebleeds, gastrointestinal bleeding, and bleeding into the soft tissue and muscle. Bleeding in the joints can also occur. VKCFD is inherited as an autosomal recessive disorder. | 435 | Factor VII Deficiency |
nord_435_5 | Diagnosis of Factor VII Deficiency | A diagnosis of factor VII deficiency is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized blood tests.Clinical Testing and Work-Up
Specialized tests will include screening coagulation tests that measure how long it takes the blood to clot, specifically two tests known as activated partial thromboplastin time (aPTT) and prothrombin time (PT). Individuals with factor VII deficiency have a normal aPTT and a prolonged PT.Further tests known as assays are required to confirm a diagnosis. An assay is a test that can measure the activity of certain substances in the blood. In affected individuals a factor VII assay will demonstrate reduced activity of factor VII. | Diagnosis of Factor VII Deficiency. A diagnosis of factor VII deficiency is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized blood tests.Clinical Testing and Work-Up
Specialized tests will include screening coagulation tests that measure how long it takes the blood to clot, specifically two tests known as activated partial thromboplastin time (aPTT) and prothrombin time (PT). Individuals with factor VII deficiency have a normal aPTT and a prolonged PT.Further tests known as assays are required to confirm a diagnosis. An assay is a test that can measure the activity of certain substances in the blood. In affected individuals a factor VII assay will demonstrate reduced activity of factor VII. | 435 | Factor VII Deficiency |
nord_435_6 | Therapies of Factor VII Deficiency | Treatment
The specific therapeutic procedures and interventions for individuals with factor VII deficiency depend primarily on the severity of the individual’s disease. Factors that will influence therapy decisions include specific symptoms present; the natural course of the disorder including underlying cause (congenital versus acquired); an individual’s age and overall health (e.g., concomitant disease), risks of certain medications or procedures, personal preference; and other factors. Decisions concerning the use of particular therapeutic interventions should be made by physicians and other members of the healthcare team, in careful consultation with the patient and/or parents, and based upon the specifics of the individual’s case. Such a discussion will review the potential benefits and risks including possible side effects and long-term effects; consider patient preferences; and include other appropriate factors in order to come to a consensus.Specific treatment options for acute bleeds in individuals with factor VII deficiency include recombinant factor VII, prothrombin complex concentrates, and fresh frozen plasma. Antifibrinolytics such as aminocaproic acid can help alleviate the bleeding symptoms.Coagulation factor VIIa (NovoSeven RT) has been approved by the U.S. Food and Drug Administration (FDA) to treat bleeding episodes in individuals with congenital factor VII deficiency. NovoSeven is a genetically engineered (recombinant) version of factor VII. Because it does not contain human blood or plasma, there is no risk of transmitting blood-borne viruses or other pathogens. NovoSeven has been well-tolerated and associated with few side effects. Individuals with factor VII deficiency have also been treated with prothrombin complex concentrates (PCCs), which are blood products that contain a concentrated form of four different clotting factors: II, VII, IX and X. However, the amount of each specific factor contained in these products can vary from one preparation to another, making it difficult to determine the most appropriate dosage. PCCs undergo a purification process to eliminate viruses and other pathogens. PCCs are associated with an increased risk of developing blood clots, especially following repeated administration.Theoretically, factor VII deficiency can be treated with fresh frozen plasma. However, in clinical practice the very large volume required to stop bleeding renders this impractical, primarily due to the short half-life of factor VII. Half-life refers to the time it takes for half of the infused factor to breakdown and to disappear from the bloodstream.Some individuals with factor VII deficiency may undergo preventative (prophylactic) therapy in an attempt to prevent or minimize future bleeding complications. Prophylactic therapy has been used for individuals with a history of bleeding into the joints or the brain. The decision to undergo prophylactic therapy in factor VII deficiency is made after careful consultation with a patient’s medical team. The specific prophylactic regimen in factor VII deficiency is case dependent.Additional treatment options for individuals with factor VII deficiency are symptomatic and supportive. For example, excessive menstrual bleeding may be treated by birth control pills or drugs known as antifibrinolytics.Genetic counseling is recommended for affected individuals and their families.Individuals with factor VII deficiency will benefit from a referral to a federally-funded hemophilia treatment center. These specialized centers can provide comprehensive care for individuals with hemophilia and rare bleeding disorders, such as factor VII deficiency. The treatment center’s medical team, headed by a hematologist with expert knowledge in bleeding disorders, will develop specific treatment plans and organize the monitoring and long term follow up of affected individuals, thus ensuring 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 therapist, social worker and genetic counselor) experienced in treating individuals with rare bleeding disorders. | Therapies of Factor VII Deficiency. Treatment
The specific therapeutic procedures and interventions for individuals with factor VII deficiency depend primarily on the severity of the individual’s disease. Factors that will influence therapy decisions include specific symptoms present; the natural course of the disorder including underlying cause (congenital versus acquired); an individual’s age and overall health (e.g., concomitant disease), risks of certain medications or procedures, personal preference; and other factors. Decisions concerning the use of particular therapeutic interventions should be made by physicians and other members of the healthcare team, in careful consultation with the patient and/or parents, and based upon the specifics of the individual’s case. Such a discussion will review the potential benefits and risks including possible side effects and long-term effects; consider patient preferences; and include other appropriate factors in order to come to a consensus.Specific treatment options for acute bleeds in individuals with factor VII deficiency include recombinant factor VII, prothrombin complex concentrates, and fresh frozen plasma. Antifibrinolytics such as aminocaproic acid can help alleviate the bleeding symptoms.Coagulation factor VIIa (NovoSeven RT) has been approved by the U.S. Food and Drug Administration (FDA) to treat bleeding episodes in individuals with congenital factor VII deficiency. NovoSeven is a genetically engineered (recombinant) version of factor VII. Because it does not contain human blood or plasma, there is no risk of transmitting blood-borne viruses or other pathogens. NovoSeven has been well-tolerated and associated with few side effects. Individuals with factor VII deficiency have also been treated with prothrombin complex concentrates (PCCs), which are blood products that contain a concentrated form of four different clotting factors: II, VII, IX and X. However, the amount of each specific factor contained in these products can vary from one preparation to another, making it difficult to determine the most appropriate dosage. PCCs undergo a purification process to eliminate viruses and other pathogens. PCCs are associated with an increased risk of developing blood clots, especially following repeated administration.Theoretically, factor VII deficiency can be treated with fresh frozen plasma. However, in clinical practice the very large volume required to stop bleeding renders this impractical, primarily due to the short half-life of factor VII. Half-life refers to the time it takes for half of the infused factor to breakdown and to disappear from the bloodstream.Some individuals with factor VII deficiency may undergo preventative (prophylactic) therapy in an attempt to prevent or minimize future bleeding complications. Prophylactic therapy has been used for individuals with a history of bleeding into the joints or the brain. The decision to undergo prophylactic therapy in factor VII deficiency is made after careful consultation with a patient’s medical team. The specific prophylactic regimen in factor VII deficiency is case dependent.Additional treatment options for individuals with factor VII deficiency are symptomatic and supportive. For example, excessive menstrual bleeding may be treated by birth control pills or drugs known as antifibrinolytics.Genetic counseling is recommended for affected individuals and their families.Individuals with factor VII deficiency will benefit from a referral to a federally-funded hemophilia treatment center. These specialized centers can provide comprehensive care for individuals with hemophilia and rare bleeding disorders, such as factor VII deficiency. The treatment center’s medical team, headed by a hematologist with expert knowledge in bleeding disorders, will develop specific treatment plans and organize the monitoring and long term follow up of affected individuals, thus ensuring 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 therapist, social worker and genetic counselor) experienced in treating individuals with rare bleeding disorders. | 435 | Factor VII Deficiency |
nord_436_0 | Overview of Factor X Deficiency | Factor X deficiency is a rare genetic blood disorder that causes the normal clotting process (coagulation) to take longer than normal. This causes people to bleed for a longer amount of time spontaneously or after trauma/surgery. Factor X is a clotting protein (also called a clotting factor). Clotting factors are specialized proteins that are essential for proper clotting, the process by which blood clumps together to plug the site of a wound to stop bleeding. Clotting requires a series of reactions to ultimately form a clot to plug a wound. This is referred to as the clotting (coagulation) cascade. The clotting cascade involves different substances in addition to clotting factors. Factor X, which is produced (synthesized) in the liver, eventually interacts with other clotting factors and certain cells or substances, e.g., platelets or fibrinogen, to help to form a clot. Factor X deficiency is caused by a change (variant or mutation) in the F10 gene. The U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approved a drug called Coagadex for adults and children over 12. This medication restores functional factor X levels. | Overview of Factor X Deficiency. Factor X deficiency is a rare genetic blood disorder that causes the normal clotting process (coagulation) to take longer than normal. This causes people to bleed for a longer amount of time spontaneously or after trauma/surgery. Factor X is a clotting protein (also called a clotting factor). Clotting factors are specialized proteins that are essential for proper clotting, the process by which blood clumps together to plug the site of a wound to stop bleeding. Clotting requires a series of reactions to ultimately form a clot to plug a wound. This is referred to as the clotting (coagulation) cascade. The clotting cascade involves different substances in addition to clotting factors. Factor X, which is produced (synthesized) in the liver, eventually interacts with other clotting factors and certain cells or substances, e.g., platelets or fibrinogen, to help to form a clot. Factor X deficiency is caused by a change (variant or mutation) in the F10 gene. The U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approved a drug called Coagadex for adults and children over 12. This medication restores functional factor X levels. | 436 | Factor X Deficiency |
nord_436_1 | Symptoms of Factor X Deficiency | The signs and symptoms of factor X deficiency are highly variable; this means that how the disorder affects one person can be very different from how it affects another person. Symptoms can develop at any age. Generally, the more severe the disorder, the earlier the symptoms begin.Sometimes, factor X deficiency is broken down based on the residual amount of factor X activity. In many disorders, the amount of residual protein activity correlates with the severity of the disease (e.g., little to no residual protein activity results in severe disease). This is not true for all bleeding disorders but is true for factor X deficiency – generally the less protein activity the more severe the bleeding complications.
Individuals with about 40% or more protein activity have mild disorder and often do not have symptoms (asymptomatic). Individuals with 10%-40% activity have moderate disease and general symptoms associated with bleeding disorders. Individuals with 10% or less factor X activity have severe disease, particularly those with less than 1% of factor X. In some instances, the amount of secreted factor X is normal or near normal, but cannot function normally; in other cases, FX is not secreted at all.Symptoms of moderate forms can include bruising easily, nosebleeds and bleeding from the mouth and the gums. There may be blood in the urine (hematuria). Some individuals may not have any symptoms except for when they experience trauma or surgery. Without treatment, these symptoms can occur throughout life.With the most severe forms, symptoms can begin at or shortly after birth and, in addition to the symptoms common to moderate forms, patients with the severe deficiency may present bleeding into the joints. This is called hemarthrosis and can result in progressive joint damage and degeneration, eventually limiting the range of motion of an affected joint. Bleeding into the muscles (intramuscular bleeds) can also occur, which can cause pain and stiffness in the affected muscles. Some affected individuals will develop masses of congealed blood called hematomas that can cause symptoms due to compression of nearby structures or organs. Bleeding in the stomach and intestines (gastrointestinal tract) is frequent in severe factor X deficiency. The urogenital tract can also be affected resulting in blood in the urine (hematuria) or black, tarry bloody stools (melena).There is a high risk of intracranial hemorrhaging, a life-threatening complication in which there is bleeding inside the skull. This risk can be present from birth. Sometimes, umbilical stump bleeding can result at birth. The umbilical stump is the small piece of the umbilical cord that remains in the bellybutton after birth. The stump usually dries up and falls off about 7 to 21 days.People with factor X deficiency may experience heavy menstrual bleeding (menorrhagia). Pregnant people are at a greater risk of complications with their pregnancies including miscarriage or heavy bleeding during birth. Some people can experience heavy bleeding in the time after delivery (postpartum hemorrhaging). | Symptoms of Factor X Deficiency. The signs and symptoms of factor X deficiency are highly variable; this means that how the disorder affects one person can be very different from how it affects another person. Symptoms can develop at any age. Generally, the more severe the disorder, the earlier the symptoms begin.Sometimes, factor X deficiency is broken down based on the residual amount of factor X activity. In many disorders, the amount of residual protein activity correlates with the severity of the disease (e.g., little to no residual protein activity results in severe disease). This is not true for all bleeding disorders but is true for factor X deficiency – generally the less protein activity the more severe the bleeding complications.
Individuals with about 40% or more protein activity have mild disorder and often do not have symptoms (asymptomatic). Individuals with 10%-40% activity have moderate disease and general symptoms associated with bleeding disorders. Individuals with 10% or less factor X activity have severe disease, particularly those with less than 1% of factor X. In some instances, the amount of secreted factor X is normal or near normal, but cannot function normally; in other cases, FX is not secreted at all.Symptoms of moderate forms can include bruising easily, nosebleeds and bleeding from the mouth and the gums. There may be blood in the urine (hematuria). Some individuals may not have any symptoms except for when they experience trauma or surgery. Without treatment, these symptoms can occur throughout life.With the most severe forms, symptoms can begin at or shortly after birth and, in addition to the symptoms common to moderate forms, patients with the severe deficiency may present bleeding into the joints. This is called hemarthrosis and can result in progressive joint damage and degeneration, eventually limiting the range of motion of an affected joint. Bleeding into the muscles (intramuscular bleeds) can also occur, which can cause pain and stiffness in the affected muscles. Some affected individuals will develop masses of congealed blood called hematomas that can cause symptoms due to compression of nearby structures or organs. Bleeding in the stomach and intestines (gastrointestinal tract) is frequent in severe factor X deficiency. The urogenital tract can also be affected resulting in blood in the urine (hematuria) or black, tarry bloody stools (melena).There is a high risk of intracranial hemorrhaging, a life-threatening complication in which there is bleeding inside the skull. This risk can be present from birth. Sometimes, umbilical stump bleeding can result at birth. The umbilical stump is the small piece of the umbilical cord that remains in the bellybutton after birth. The stump usually dries up and falls off about 7 to 21 days.People with factor X deficiency may experience heavy menstrual bleeding (menorrhagia). Pregnant people are at a greater risk of complications with their pregnancies including miscarriage or heavy bleeding during birth. Some people can experience heavy bleeding in the time after delivery (postpartum hemorrhaging). | 436 | Factor X Deficiency |
nord_436_2 | Causes of Factor X Deficiency | The F10 gene creates (encodes) factor X. 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, absent or overproduced. Variants in the F10 gene result in deficient levels of functional factor X, which in affected individuals, prevents the blood from clotting properly. Depending upon the functions of the protein, this can affect many organ systems of the body. Consequently, affected individuals have difficulty stopping the flow of blood from a wound; but they do not bleed faster or more profusely than healthy individuals.Factor X deficiency is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a mutated gene from each parent. If an individual receives one normal gene and one mutated gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the mutated gene and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. | Causes of Factor X Deficiency. The F10 gene creates (encodes) factor X. 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, absent or overproduced. Variants in the F10 gene result in deficient levels of functional factor X, which in affected individuals, prevents the blood from clotting properly. Depending upon the functions of the protein, this can affect many organ systems of the body. Consequently, affected individuals have difficulty stopping the flow of blood from a wound; but they do not bleed faster or more profusely than healthy individuals.Factor X deficiency is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a mutated gene from each parent. If an individual receives one normal gene and one mutated gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the mutated gene and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. | 436 | Factor X Deficiency |
nord_436_3 | Affects of Factor X Deficiency | Factor X deficiency affects males and females and can occur in individuals of any ethnic or racial group. The disorder is estimated to affect about 1 in every 500,000-1,000,000 people in the general population. Rare disorders like factor X deficiency often go unrecognized or misdiagnosed, making it difficult to determine the true frequency in the general population. | Affects of Factor X Deficiency. Factor X deficiency affects males and females and can occur in individuals of any ethnic or racial group. The disorder is estimated to affect about 1 in every 500,000-1,000,000 people in the general population. Rare disorders like factor X deficiency often go unrecognized or misdiagnosed, making it difficult to determine the true frequency in the general population. | 436 | Factor X Deficiency |
nord_436_4 | Related disorders of Factor X Deficiency | Symptoms of the following disorders can be similar to those of factor X deficiency. Comparisons may be useful for a differential diagnosis.Factor X deficiency belongs to a group of rare forms of bleeding disorders; a group that includes deficiencies of fibrinogen, prothrombin and factors V, VII, XI, and XIII. There are also combined deficiencies of more than one factor. The rare forms of bleeding disorders account for 3-5% of all bleeding disorders collectively. These disorders are inherited in an autosomal recessive pattern. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Hemophilia is a general term for a group of rare bleeding disorders. Most forms of hemophilia are rare inherited blood clotting (coagulation) disorders caused by inactive or deficient blood coagulation proteins. There are two major forms of inherited hemophilia: hemophilia A and hemophilia B. Hemophilia A and B are inherited as X-linked recessive genetic disorders since males inherit only one copy of the X chromosome, if that chromosome carries the mutated gene, then they will have the disease. Females have a second, usually normal gene on their other X chromosome, so they maybe carrier of the disease without experiencing its symptoms. Hemophilia A is the most common form of hemophilia and is characterized by a deficiency of factor VIII, one of several specialized proteins required for the blood to clot. 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.)Acquired factor X deficiency is a rare bleeding disorder characterized by low levels of factor X. The signs and symptoms are similar to those seen in the inherited form. The acquired form is more common and can be caused by certain liver disorders, systemic amyloidosis, the use of certain drugs and deficiency of vitamin K. Acquired factor X deficiency is treated by managing the underlying cause. | Related disorders of Factor X Deficiency. Symptoms of the following disorders can be similar to those of factor X deficiency. Comparisons may be useful for a differential diagnosis.Factor X deficiency belongs to a group of rare forms of bleeding disorders; a group that includes deficiencies of fibrinogen, prothrombin and factors V, VII, XI, and XIII. There are also combined deficiencies of more than one factor. The rare forms of bleeding disorders account for 3-5% of all bleeding disorders collectively. These disorders are inherited in an autosomal recessive pattern. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Hemophilia is a general term for a group of rare bleeding disorders. Most forms of hemophilia are rare inherited blood clotting (coagulation) disorders caused by inactive or deficient blood coagulation proteins. There are two major forms of inherited hemophilia: hemophilia A and hemophilia B. Hemophilia A and B are inherited as X-linked recessive genetic disorders since males inherit only one copy of the X chromosome, if that chromosome carries the mutated gene, then they will have the disease. Females have a second, usually normal gene on their other X chromosome, so they maybe carrier of the disease without experiencing its symptoms. Hemophilia A is the most common form of hemophilia and is characterized by a deficiency of factor VIII, one of several specialized proteins required for the blood to clot. 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.)Acquired factor X deficiency is a rare bleeding disorder characterized by low levels of factor X. The signs and symptoms are similar to those seen in the inherited form. The acquired form is more common and can be caused by certain liver disorders, systemic amyloidosis, the use of certain drugs and deficiency of vitamin K. Acquired factor X deficiency is treated by managing the underlying cause. | 436 | Factor X Deficiency |
nord_436_5 | Diagnosis of Factor X Deficiency | A diagnosis of factor X deficiency is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests.Clinical Testing and WorkupSpecialized tests will include screening coagulation tests that measure how long it takes the blood to clot, specifically two tests known as activated partial thromboplastin time (aPTT) and prothrombin time (PT). Individuals with factor X deficiency have both prolonged aPTT and PT.Further tests known as assays are required to confirm a diagnosis and differentiate factor X deficiency from deficiencies in other clotting factors. An assay is a test that can measure the activity of certain substances in the blood. In affected individuals a factor X assay will demonstrate reduced activity of factor X.Molecular genetic testing can confirm a diagnosis of factor X deficiency but is usually not necessary. Molecular genetic testing can detect a variation in the F10 gene but is available only as a diagnostic service at specialized laboratories. | Diagnosis of Factor X Deficiency. A diagnosis of factor X deficiency is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests.Clinical Testing and WorkupSpecialized tests will include screening coagulation tests that measure how long it takes the blood to clot, specifically two tests known as activated partial thromboplastin time (aPTT) and prothrombin time (PT). Individuals with factor X deficiency have both prolonged aPTT and PT.Further tests known as assays are required to confirm a diagnosis and differentiate factor X deficiency from deficiencies in other clotting factors. An assay is a test that can measure the activity of certain substances in the blood. In affected individuals a factor X assay will demonstrate reduced activity of factor X.Molecular genetic testing can confirm a diagnosis of factor X deficiency but is usually not necessary. Molecular genetic testing can detect a variation in the F10 gene but is available only as a diagnostic service at specialized laboratories. | 436 | Factor X Deficiency |
nord_436_6 | Therapies of Factor X Deficiency | Treatment of factor X deficiency may require the coordinated efforts of a team of specialists. Pediatricians, general internists, physicians who specialize in diagnosing and treating blood disorders (hematologists), dental specialists and other healthcare professionals may need to plan treatment systematically and comprehensively. Psychosocial support for the entire family is essential as well. Genetic counseling is recommended for affected individuals and their families.The treatment of factor X deficiency has greatly improved in the last several years, progressing from broad treatments like fresh frozen plasma to prothrombin complexes (PCCs) and then to a dedicated factor X concentrate approved by the FDA.Coagadex (human coagulation factor X) is a high-purity, high-potency plasma-derived factor X concentrate approved by FDA and EMA for the treatment of hereditary factor X deficiency in adults and children over the age of 12. It is approved for on-demand treatment and control of bleeding episodes, and for individuals, including those with mild disease, who are about to undergo surgical procedure (perioperative management). This therapy restores functional levels of factor X to affected individuals.Individuals with factor X deficiency have also been treated with prothrombin complex concentrates (PCCs), which are blood products that contain a concentrated form of four different clotting factors: II, VII, IX and X. However, the amount of each specific factor contained in these products can vary from one preparation to another, making it difficult to determine the most appropriate dosage. Monitoring of the therapy with PCCs is therefore mandatory because they are associated with an increased risk of developing blood clots, especially following repeated administration because most people are only deficient in one of these clotting factors. PCCs undergo a purification process to eliminate viruses and other pathogens.Some affected individuals may be treated with fresh frozen plasma, which is a blood derivative that comes from blood donors. Fresh frozen plasma contains all the blood clotting factors. Fresh frozen plasma can be virally inactivated, but sometimes is not virally inactivated so there can be risk of infection, however, this risk is extremely low because donors are carefully selected, and the products are screened to ensure they do not contain viruses. There is also a risk of allergic reaction.In people with mild forms of the disorder, drugs known as antifibrinolytics can be used. These drugs prevent the breakdown of clots in the blood. People who experience heavy menstrual bleeding can be treated with hormonal contraceptives such as birth control pills or with antifibrinolytics. Some individuals may be treated with fibrin glue (sealants). Fibrin glue is applied directly to the site of bleeding. Fibrin is a protein that is essential to the formation of a blood clot. Fibrin glue acts to hold platelets together to strengthen a clot. Fibrin glue is often used for surgery or dental procedures in affected individuals. Fibrin glue is manufactured from various clotting factors obtained from donated plasma. | Therapies of Factor X Deficiency. Treatment of factor X deficiency may require the coordinated efforts of a team of specialists. Pediatricians, general internists, physicians who specialize in diagnosing and treating blood disorders (hematologists), dental specialists and other healthcare professionals may need to plan treatment systematically and comprehensively. Psychosocial support for the entire family is essential as well. Genetic counseling is recommended for affected individuals and their families.The treatment of factor X deficiency has greatly improved in the last several years, progressing from broad treatments like fresh frozen plasma to prothrombin complexes (PCCs) and then to a dedicated factor X concentrate approved by the FDA.Coagadex (human coagulation factor X) is a high-purity, high-potency plasma-derived factor X concentrate approved by FDA and EMA for the treatment of hereditary factor X deficiency in adults and children over the age of 12. It is approved for on-demand treatment and control of bleeding episodes, and for individuals, including those with mild disease, who are about to undergo surgical procedure (perioperative management). This therapy restores functional levels of factor X to affected individuals.Individuals with factor X deficiency have also been treated with prothrombin complex concentrates (PCCs), which are blood products that contain a concentrated form of four different clotting factors: II, VII, IX and X. However, the amount of each specific factor contained in these products can vary from one preparation to another, making it difficult to determine the most appropriate dosage. Monitoring of the therapy with PCCs is therefore mandatory because they are associated with an increased risk of developing blood clots, especially following repeated administration because most people are only deficient in one of these clotting factors. PCCs undergo a purification process to eliminate viruses and other pathogens.Some affected individuals may be treated with fresh frozen plasma, which is a blood derivative that comes from blood donors. Fresh frozen plasma contains all the blood clotting factors. Fresh frozen plasma can be virally inactivated, but sometimes is not virally inactivated so there can be risk of infection, however, this risk is extremely low because donors are carefully selected, and the products are screened to ensure they do not contain viruses. There is also a risk of allergic reaction.In people with mild forms of the disorder, drugs known as antifibrinolytics can be used. These drugs prevent the breakdown of clots in the blood. People who experience heavy menstrual bleeding can be treated with hormonal contraceptives such as birth control pills or with antifibrinolytics. Some individuals may be treated with fibrin glue (sealants). Fibrin glue is applied directly to the site of bleeding. Fibrin is a protein that is essential to the formation of a blood clot. Fibrin glue acts to hold platelets together to strengthen a clot. Fibrin glue is often used for surgery or dental procedures in affected individuals. Fibrin glue is manufactured from various clotting factors obtained from donated plasma. | 436 | Factor X Deficiency |
nord_437_0 | Overview of Factor XI Deficiency | SummaryFactor XI deficiency is a rare genetic bleeding disorder caused by reduced levels and insufficient activity of a blood protein called factor XI. Factor XI is a clotting factor. Clotting factors are specialized proteins that are essential for proper clotting, the process by which blood solidifies like glue to plug the site of a wound to stop bleeding. Individuals with factor XI deficiency do not bleed faster or more profusely than healthy individuals, but, because their blood clots poorly, they may have difficulty stopping the flow of blood from a deep or surgical wound. This may be referred to as prolonged bleeding or a prolonged bleeding episode. The severity of symptoms in factor XI deficiency can vary from one person to another and is not clearly related to the blood factor XI level. In most patients, prolonged bleeding episodes only occur after surgery, dental procedures or trauma. Bleeding tendencies in factor XI deficiency are unpredictable and inconsistent, making the disorder difficult to manage in some cases. Factor XI deficiency is caused by disruptions or changes (mutations) to the F11 gene and can occur in males and females.IntroductionFactor XI deficiency was first described in the medical literature in 1953. It used to be also referred to as hemophilia C in order to distinguish it from the better known hemophilia types A and B. In rare cases, factor XI deficiency can be acquired during life (acquired factor XI deficiency). This report deals with the genetic form. Although the genetic form is present at birth, as it is a mild bleeding disorder symptoms do not usually occur until later in life. | Overview of Factor XI Deficiency. SummaryFactor XI deficiency is a rare genetic bleeding disorder caused by reduced levels and insufficient activity of a blood protein called factor XI. Factor XI is a clotting factor. Clotting factors are specialized proteins that are essential for proper clotting, the process by which blood solidifies like glue to plug the site of a wound to stop bleeding. Individuals with factor XI deficiency do not bleed faster or more profusely than healthy individuals, but, because their blood clots poorly, they may have difficulty stopping the flow of blood from a deep or surgical wound. This may be referred to as prolonged bleeding or a prolonged bleeding episode. The severity of symptoms in factor XI deficiency can vary from one person to another and is not clearly related to the blood factor XI level. In most patients, prolonged bleeding episodes only occur after surgery, dental procedures or trauma. Bleeding tendencies in factor XI deficiency are unpredictable and inconsistent, making the disorder difficult to manage in some cases. Factor XI deficiency is caused by disruptions or changes (mutations) to the F11 gene and can occur in males and females.IntroductionFactor XI deficiency was first described in the medical literature in 1953. It used to be also referred to as hemophilia C in order to distinguish it from the better known hemophilia types A and B. In rare cases, factor XI deficiency can be acquired during life (acquired factor XI deficiency). This report deals with the genetic form. Although the genetic form is present at birth, as it is a mild bleeding disorder symptoms do not usually occur until later in life. | 437 | Factor XI Deficiency |
nord_437_1 | Symptoms of Factor XI Deficiency | In most cases, the bleeding tendency in individuals with factor XI deficiency, even with very low factor levels, is mild. Affected individuals may experience bleeding episodes following trauma or surgery including dental procedures, tonsillectomies or surgery involving the urinary or genital tracts. Bleeding may also occur after circumcision. Bleeding may begin at the time of injury and persist if untreated, or bleeding may develop several hours after the injury. Untreated individuals may develop large, solid swellings of congealed blood (hematomas) following a surgical procedure.Affected individuals may be prone to bruising or nosebleeds. Women may experience prolonged, heavy bleeding during their menstrual periods (menorrhagia). Some affected women experience prolonged bleeding after childbirth.Bleeding into the joints or spontaneous bleeding (both common with hemophilia types A and B) does not occur in individuals with factor XI deficiency (unless there is underlying joint disease). Blood in the urine (hematuria) is rare. Bleeding in the gut (gastrointestinal hemorrhaging) has been reported usually in relation to an underlying disease rather than the factor deficiency itself. | Symptoms of Factor XI Deficiency. In most cases, the bleeding tendency in individuals with factor XI deficiency, even with very low factor levels, is mild. Affected individuals may experience bleeding episodes following trauma or surgery including dental procedures, tonsillectomies or surgery involving the urinary or genital tracts. Bleeding may also occur after circumcision. Bleeding may begin at the time of injury and persist if untreated, or bleeding may develop several hours after the injury. Untreated individuals may develop large, solid swellings of congealed blood (hematomas) following a surgical procedure.Affected individuals may be prone to bruising or nosebleeds. Women may experience prolonged, heavy bleeding during their menstrual periods (menorrhagia). Some affected women experience prolonged bleeding after childbirth.Bleeding into the joints or spontaneous bleeding (both common with hemophilia types A and B) does not occur in individuals with factor XI deficiency (unless there is underlying joint disease). Blood in the urine (hematuria) is rare. Bleeding in the gut (gastrointestinal hemorrhaging) has been reported usually in relation to an underlying disease rather than the factor deficiency itself. | 437 | Factor XI Deficiency |
nord_437_2 | Causes of Factor XI Deficiency | Factor XI deficiency is caused by mutations in the F11 gene. The F11 gene encodes factor XI. Factor XI is one of the essential blood proteins and plays a role in aiding the blood to clot. Mutations of the F11 gene result in deficient levels of functional factor XI. The symptoms of factor XI deficiency occur, in part, due to this deficiency. Individuals with factor XI deficiency often have varying levels of residual factor XI. In many disorders, the amount of residual protein activity correlates with the severity of the disease (e.g. little to no residual protein activity results in severe disease). However, in factor XI deficiency the severity of the disorder does not always correlate with the residual activity of factor XI. For example, individuals with a severe deficiency of factor XI may have mild or no symptoms of the disorder and individuals with a partial deficiency of factor XI may have more significant symptoms. This suggests that additional genetic and environmental factors play a role in the severity of the disorder. This variability even exists among members of the same family.Factor XI deficiency is usually inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females. Sometimes, factor XI deficiency is inherited in an autosomal dominant pattern. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.Factor XI deficiency sometimes occurs in patients with Noonan syndrome, which is a disorder characterized by a wide spectrum of symptoms and physical features that vary greatly in range and severity. In many affected individuals, associated abnormalities include a distinctive facial appearance; a broad or webbed neck; a low posterior hairline; a typical chest deformity and short stature. Noonan syndrome is inherited as an autosomal dominant trait. (For more information on this disorder, choose “Noonan” as your search term in the Rare Disease Database.) | Causes of Factor XI Deficiency. Factor XI deficiency is caused by mutations in the F11 gene. The F11 gene encodes factor XI. Factor XI is one of the essential blood proteins and plays a role in aiding the blood to clot. Mutations of the F11 gene result in deficient levels of functional factor XI. The symptoms of factor XI deficiency occur, in part, due to this deficiency. Individuals with factor XI deficiency often have varying levels of residual factor XI. In many disorders, the amount of residual protein activity correlates with the severity of the disease (e.g. little to no residual protein activity results in severe disease). However, in factor XI deficiency the severity of the disorder does not always correlate with the residual activity of factor XI. For example, individuals with a severe deficiency of factor XI may have mild or no symptoms of the disorder and individuals with a partial deficiency of factor XI may have more significant symptoms. This suggests that additional genetic and environmental factors play a role in the severity of the disorder. This variability even exists among members of the same family.Factor XI deficiency is usually inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females. Sometimes, factor XI deficiency is inherited in an autosomal dominant pattern. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.Factor XI deficiency sometimes occurs in patients with Noonan syndrome, which is a disorder characterized by a wide spectrum of symptoms and physical features that vary greatly in range and severity. In many affected individuals, associated abnormalities include a distinctive facial appearance; a broad or webbed neck; a low posterior hairline; a typical chest deformity and short stature. Noonan syndrome is inherited as an autosomal dominant trait. (For more information on this disorder, choose “Noonan” as your search term in the Rare Disease Database.) | 437 | Factor XI Deficiency |
nord_437_3 | Affects of Factor XI Deficiency | Factor XI deficiency affects males and females in equal numbers. The disorder can affect individuals of any age and any ethnic group. It is the second most common bleeding disorder to affect women (after von Willebrand disease). The incidence of factor XI deficiency is higher in individuals of Ashkenazi Jewish descent where it is estimated to affect 8% of the population. The severe form of the disorder is estimated to affect approximately 1 in 1,000,000 people in the general population. | Affects of Factor XI Deficiency. Factor XI deficiency affects males and females in equal numbers. The disorder can affect individuals of any age and any ethnic group. It is the second most common bleeding disorder to affect women (after von Willebrand disease). The incidence of factor XI deficiency is higher in individuals of Ashkenazi Jewish descent where it is estimated to affect 8% of the population. The severe form of the disorder is estimated to affect approximately 1 in 1,000,000 people in the general population. | 437 | Factor XI Deficiency |
nord_437_4 | Related disorders of Factor XI Deficiency | Symptoms of the following disorders can be similar to those of factor XI deficiency. Comparisons may be useful for a differential diagnosis.Acquired factor XI deficiency is a general term for individuals who develop factor XI deficiency that is not inherited, but acquired at some point during life. Acquired factor XI deficiency can result when the body produces autoantibodies (inhibitors) that attack factor XI. Acquired factor XI deficiency can be associated with an underlying condition such as lupus or other immunological disorders.Hemophilia (Hemo = bleed; philia = tendency) is a general term for a group of rare bleeding disorders. Most forms of hemophilia are rare inherited blood clotting (coagulation) disorders caused by inactive or deficient blood coagulation proteins. There are three major forms of inherited hemophilia: hemophilia A (also known as classical hemophilia, factor VIII deficiency or antihemophilic globulin [AHG] deficiency); 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. Therefore, hemophilia A and B are fully expressed in males only. Hemophilia A is the most common form of hemophilia and is characterized by a deficiency of factor VIII, one of several specialized proteins required for the blood to clot. Hemophilia may be classified as mild, moderate, or severe, but this classification does not apply to hemophilia C/factor XI deficiency.Von Willebrand disease (VWD) is a genetic bleeding disorder resulting in prolonged bleeding and varies widely in its effects. Individuals with VWD have a defect in or deficiency of a clotting protein known as von Willebrand factor (VWF). Deficient or defective VWF results in improper functioning of platelets, which are specialized red blood cells that mass together to form clots to stop bleeding. In individuals with VWD, platelets do not stick to holes in blood vessels and bleeding is prolonged. Defective VWF can also cause reduced levels of another clotting protein in the blood (factor VIII). Most people have relatively mild symptoms and are not diagnosed until they are adults. A small percentage of individuals 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. Most cases are inherited as autosomal dominant disorders; some cases are inherited as autosomal recessive disorders. (For more information on this disorder, choose “Von Willebrand” as your search term in the Rare Disease Database.)Fibrinogen disorders are a group of rare bleeding disorders characterized by deficiency or absence of a certain protein in the blood that is essential in the blood clotting (coagulation) process. This protein is known as fibrinogen or coagulation factor I. Three forms have been identified: congenital afibrinogenemia, hypofibrinogenemia and dysfibrinogenemia. Individuals with congenital afibrinogenemia may be susceptible to severe bleeding (hemorrhaging) episodes and prolonged bleeding from minor cuts. Individuals with hypofibrinogenemia or dysfibrinogenemia may not have symptoms (asymptomatic) or may develop mild bleeding episodes. (For more information on this disorder, choose “fibrinogenemia” as your search term in the Rare Disease Database.) | Related disorders of Factor XI Deficiency. Symptoms of the following disorders can be similar to those of factor XI deficiency. Comparisons may be useful for a differential diagnosis.Acquired factor XI deficiency is a general term for individuals who develop factor XI deficiency that is not inherited, but acquired at some point during life. Acquired factor XI deficiency can result when the body produces autoantibodies (inhibitors) that attack factor XI. Acquired factor XI deficiency can be associated with an underlying condition such as lupus or other immunological disorders.Hemophilia (Hemo = bleed; philia = tendency) is a general term for a group of rare bleeding disorders. Most forms of hemophilia are rare inherited blood clotting (coagulation) disorders caused by inactive or deficient blood coagulation proteins. There are three major forms of inherited hemophilia: hemophilia A (also known as classical hemophilia, factor VIII deficiency or antihemophilic globulin [AHG] deficiency); 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. Therefore, hemophilia A and B are fully expressed in males only. Hemophilia A is the most common form of hemophilia and is characterized by a deficiency of factor VIII, one of several specialized proteins required for the blood to clot. Hemophilia may be classified as mild, moderate, or severe, but this classification does not apply to hemophilia C/factor XI deficiency.Von Willebrand disease (VWD) is a genetic bleeding disorder resulting in prolonged bleeding and varies widely in its effects. Individuals with VWD have a defect in or deficiency of a clotting protein known as von Willebrand factor (VWF). Deficient or defective VWF results in improper functioning of platelets, which are specialized red blood cells that mass together to form clots to stop bleeding. In individuals with VWD, platelets do not stick to holes in blood vessels and bleeding is prolonged. Defective VWF can also cause reduced levels of another clotting protein in the blood (factor VIII). Most people have relatively mild symptoms and are not diagnosed until they are adults. A small percentage of individuals 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. Most cases are inherited as autosomal dominant disorders; some cases are inherited as autosomal recessive disorders. (For more information on this disorder, choose “Von Willebrand” as your search term in the Rare Disease Database.)Fibrinogen disorders are a group of rare bleeding disorders characterized by deficiency or absence of a certain protein in the blood that is essential in the blood clotting (coagulation) process. This protein is known as fibrinogen or coagulation factor I. Three forms have been identified: congenital afibrinogenemia, hypofibrinogenemia and dysfibrinogenemia. Individuals with congenital afibrinogenemia may be susceptible to severe bleeding (hemorrhaging) episodes and prolonged bleeding from minor cuts. Individuals with hypofibrinogenemia or dysfibrinogenemia may not have symptoms (asymptomatic) or may develop mild bleeding episodes. (For more information on this disorder, choose “fibrinogenemia” as your search term in the Rare Disease Database.) | 437 | Factor XI Deficiency |
nord_437_5 | Diagnosis of Factor XI Deficiency | A diagnosis of factor XI deficiency is based upon identification of characteristic symptoms, a detailed patient and family history, and a thorough clinical evaluation. Several different tests may be necessary to confirm a diagnosis.Clinical Testing and Workup
Laboratories studies can include a complete blood count (CBC), coagulation tests and factor assay. Screening coagulation tests that measure how long it takes the blood to clot include activated partial thromboplastin time (aPTT) and prothrombin time (PT). In individuals with deficiency of factor XI, the aPTT test will be prolonged (it will take the sample longer to clot than normal). The sensitivity of this test varies with the reagents used; it can be normal. PT tests are normal in individuals with factor XI deficiency (but may be abnormal in individuals with other bleeding disorders).Further tests known as assays are required to confirm a diagnosis. An assay is a test that can measure the activity of certain substances in the blood. In affected individuals a factor XI assay will demonstrate reduced activity of factor XI. As this test does not predict for bleeding risk additional tests of whole blood clotting have been developed which may be more useful (thrombin generation tests) as they reflect the whole clotting process whereas the aPTT and factor XI levels only reflect the start of clotting. However, this test is not widely available. Other factors have been shown to be relevant. | Diagnosis of Factor XI Deficiency. A diagnosis of factor XI deficiency is based upon identification of characteristic symptoms, a detailed patient and family history, and a thorough clinical evaluation. Several different tests may be necessary to confirm a diagnosis.Clinical Testing and Workup
Laboratories studies can include a complete blood count (CBC), coagulation tests and factor assay. Screening coagulation tests that measure how long it takes the blood to clot include activated partial thromboplastin time (aPTT) and prothrombin time (PT). In individuals with deficiency of factor XI, the aPTT test will be prolonged (it will take the sample longer to clot than normal). The sensitivity of this test varies with the reagents used; it can be normal. PT tests are normal in individuals with factor XI deficiency (but may be abnormal in individuals with other bleeding disorders).Further tests known as assays are required to confirm a diagnosis. An assay is a test that can measure the activity of certain substances in the blood. In affected individuals a factor XI assay will demonstrate reduced activity of factor XI. As this test does not predict for bleeding risk additional tests of whole blood clotting have been developed which may be more useful (thrombin generation tests) as they reflect the whole clotting process whereas the aPTT and factor XI levels only reflect the start of clotting. However, this test is not widely available. Other factors have been shown to be relevant. | 437 | Factor XI Deficiency |
nord_437_6 | Therapies of Factor XI Deficiency | Treatment
The treatment of factor XI deficiency is not always straightforward, the bleeding tendency is unpredictable and does not correlate with residual enzyme activity as detected by aPTT-based measurements, and the various treatment options have side effects.Individuals with factor XI deficiency will benefit from referral to federally-funded hemophilia treatment centers. These specialized centers can provide comprehensive care for individuals with hemophilia 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 therapist, social worker and genetic counselor) experienced in the treatment of individuals with hemophilia. Genetic counseling is recommended for affected individuals and their families.Several different treatments are available for factor XI deficiency including fresh frozen plasma (preferably pathogen-inactivated), factor XI concentrates and antifibrinolytics. Individuals with factor XI deficiency do not require therapy for daily activities. Usually, affected individuals only require preventive (prophylactic) therapy before undergoing some types of surgery or similar procedures. In the United States, fresh frozen plasma is the most widely used treatment and is effective in treating individuals with factor XI deficiency. Fresh frozen plasma is a blood derivative that is obtained from donors and is rich in coagulation factors including factor XI. Fresh frozen plasma carries a risk of infection as well as of an allergic reaction. The risk of infection is extremely low because donors are carefully selected and the products are screened to ensure they do not contain viruses. A large volume of fresh frozen plasma is often necessary because factor XI is not concentrated in fresh frozen plasma.Fresh frozen plasma is used in the United States because factor XI concentrates are unavailable. Factor XI concentrates are blood products that contain a concentrated form of factor XI. Although not available in the United States, these products are available in certain European countries. Such products are created from the plasma of thousands of different blood donors. These products are fully treated to kill any viruses or similar pathogens that can potentially be present in the blood (viral inactivation). They have much shorter infusion times than fresh frozen plasma and are not associated with unnecessary elevation of other coagulation factor levels. Factor XI concentrates may be associated with thrombotic events (e.g. blood clots) in some individuals (1, 2). However, most of those affected had pre-existing risk factors for thrombotic events. Many affected individuals are best treated with drugs known as antifibrinolytics, which slow the breakdown of clotting factors in the blood. Antifibrinolytics include aminocaproic acid and tranexamic acid. These drugs are especially beneficial in treating bleeding from the mucous membranes such as bleeding in the mouth and menstrual periods. Antifibrinolytics are often sufficient for dental procedures.Excessive menstrual bleeding in women may be treated by hormonal contraceptives such as birth control pills or antifibrinolytics.Inhibitors
In some cases, inhibitors have developed in individuals with factor XI deficiency. Inhibitors are autoantibodies. Antibodies are specialized proteins produced by the body’s immune system that destroy foreign substances directly or coats 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. In factor XI deficiency they are also called inhibitors because they can mistakenly attack replacement factor XI, inhibiting the effectiveness of the treatment. When inhibitors develop in individuals with factor XI deficiency, additional therapy is required (see investigational therapies below). | Therapies of Factor XI Deficiency. Treatment
The treatment of factor XI deficiency is not always straightforward, the bleeding tendency is unpredictable and does not correlate with residual enzyme activity as detected by aPTT-based measurements, and the various treatment options have side effects.Individuals with factor XI deficiency will benefit from referral to federally-funded hemophilia treatment centers. These specialized centers can provide comprehensive care for individuals with hemophilia 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 therapist, social worker and genetic counselor) experienced in the treatment of individuals with hemophilia. Genetic counseling is recommended for affected individuals and their families.Several different treatments are available for factor XI deficiency including fresh frozen plasma (preferably pathogen-inactivated), factor XI concentrates and antifibrinolytics. Individuals with factor XI deficiency do not require therapy for daily activities. Usually, affected individuals only require preventive (prophylactic) therapy before undergoing some types of surgery or similar procedures. In the United States, fresh frozen plasma is the most widely used treatment and is effective in treating individuals with factor XI deficiency. Fresh frozen plasma is a blood derivative that is obtained from donors and is rich in coagulation factors including factor XI. Fresh frozen plasma carries a risk of infection as well as of an allergic reaction. The risk of infection is extremely low because donors are carefully selected and the products are screened to ensure they do not contain viruses. A large volume of fresh frozen plasma is often necessary because factor XI is not concentrated in fresh frozen plasma.Fresh frozen plasma is used in the United States because factor XI concentrates are unavailable. Factor XI concentrates are blood products that contain a concentrated form of factor XI. Although not available in the United States, these products are available in certain European countries. Such products are created from the plasma of thousands of different blood donors. These products are fully treated to kill any viruses or similar pathogens that can potentially be present in the blood (viral inactivation). They have much shorter infusion times than fresh frozen plasma and are not associated with unnecessary elevation of other coagulation factor levels. Factor XI concentrates may be associated with thrombotic events (e.g. blood clots) in some individuals (1, 2). However, most of those affected had pre-existing risk factors for thrombotic events. Many affected individuals are best treated with drugs known as antifibrinolytics, which slow the breakdown of clotting factors in the blood. Antifibrinolytics include aminocaproic acid and tranexamic acid. These drugs are especially beneficial in treating bleeding from the mucous membranes such as bleeding in the mouth and menstrual periods. Antifibrinolytics are often sufficient for dental procedures.Excessive menstrual bleeding in women may be treated by hormonal contraceptives such as birth control pills or antifibrinolytics.Inhibitors
In some cases, inhibitors have developed in individuals with factor XI deficiency. Inhibitors are autoantibodies. Antibodies are specialized proteins produced by the body’s immune system that destroy foreign substances directly or coats 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. In factor XI deficiency they are also called inhibitors because they can mistakenly attack replacement factor XI, inhibiting the effectiveness of the treatment. When inhibitors develop in individuals with factor XI deficiency, additional therapy is required (see investigational therapies below). | 437 | Factor XI Deficiency |
nord_438_0 | Overview of Factor XII Deficiency | Factor XII deficiency is a rare genetic blood disorder that causes prolonged clotting (coagulation) of blood in a test tube without the presence of prolonged clinical bleeding tendencies. It is caused by a deficiency of the factor XII (Hageman factor), a plasma protein (glycoprotein). Specifically, factor XII is a clotting factor. Clotting factors are specialized proteins that are essential for proper clotting, the process by which blood clumps together to plug the site of a wound to stop bleeding. Although it is thought that factor XII is needed for proper blood clotting, when it is deficient, other blood clotting factors appear to compensate for its absence. Therefore, the disorder is thought to be benign and usually presents no symptoms (asymptomatic); it is usually only accidentally discovered through pre-operative blood tests that are required by hospitals.Factor XII deficiency was first described in the medical literature in 1955 by doctors Oscar Ratnoff and Jane Colopy in a patient named John Hageman. The disorder is sometimes known as Hageman factor deficiency or Hageman trait. | Overview of Factor XII Deficiency. Factor XII deficiency is a rare genetic blood disorder that causes prolonged clotting (coagulation) of blood in a test tube without the presence of prolonged clinical bleeding tendencies. It is caused by a deficiency of the factor XII (Hageman factor), a plasma protein (glycoprotein). Specifically, factor XII is a clotting factor. Clotting factors are specialized proteins that are essential for proper clotting, the process by which blood clumps together to plug the site of a wound to stop bleeding. Although it is thought that factor XII is needed for proper blood clotting, when it is deficient, other blood clotting factors appear to compensate for its absence. Therefore, the disorder is thought to be benign and usually presents no symptoms (asymptomatic); it is usually only accidentally discovered through pre-operative blood tests that are required by hospitals.Factor XII deficiency was first described in the medical literature in 1955 by doctors Oscar Ratnoff and Jane Colopy in a patient named John Hageman. The disorder is sometimes known as Hageman factor deficiency or Hageman trait. | 438 | Factor XII Deficiency |
nord_438_1 | Symptoms of Factor XII Deficiency | Factor XII deficiency is rarely associated with any symptoms (asymptomatic). However, when blood from a patient is subjected to a partial thromboplastin time test (PTT), a test measuring clotting time, it takes an abnormally long time for the blood to clot. Serum prothrombin (PT) time, another test of blood clotting, is also abnormally long. The blood level of factor XII tends to vary greatly. According to some older medical reports, factor XII deficiency may predispose affected individuals to developing blood clots (thrombi) at an early age. For example, individuals may have a greater risk than the general population in developing deep vein thrombosis or acquired thrombotic disorders. However, such an association remains unproven. Researchers are now studying drugs to block (inhibit) factor XII as a potential therapy for individuals who are prone to developing blood clots. More research is necessary to determine the exact role that factor XII plays in the development or prevention of blood clots and its overall functions in the body. There are also reports in the medical literature that suggest an association between factor XII deficiency and repeated unexplained miscarriages in some affected women. However, such an association remains controversial and unproven. | Symptoms of Factor XII Deficiency. Factor XII deficiency is rarely associated with any symptoms (asymptomatic). However, when blood from a patient is subjected to a partial thromboplastin time test (PTT), a test measuring clotting time, it takes an abnormally long time for the blood to clot. Serum prothrombin (PT) time, another test of blood clotting, is also abnormally long. The blood level of factor XII tends to vary greatly. According to some older medical reports, factor XII deficiency may predispose affected individuals to developing blood clots (thrombi) at an early age. For example, individuals may have a greater risk than the general population in developing deep vein thrombosis or acquired thrombotic disorders. However, such an association remains unproven. Researchers are now studying drugs to block (inhibit) factor XII as a potential therapy for individuals who are prone to developing blood clots. More research is necessary to determine the exact role that factor XII plays in the development or prevention of blood clots and its overall functions in the body. There are also reports in the medical literature that suggest an association between factor XII deficiency and repeated unexplained miscarriages in some affected women. However, such an association remains controversial and unproven. | 438 | Factor XII Deficiency |
nord_438_2 | Causes of Factor XII Deficiency | Factor XII deficiency is inherited as an autosomal recessive disorder. Genetic diseases are determined by two genes, one received from the father and one from 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. Investigators have determined that factor XII deficiency occurs due to mutations of the F12 gene located on the long arm of chromosome 5 (5q33-qter). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Pairs of human chromosomes are numbered from 1 through 22, and an additional 23rd pair of sex chromosomes which include one X and one Y chromosome in males and two X chromosomes in females. 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 5q33” refers to band 33 on the long arm of chromosome 5. The numbered bands specify the location of the thousands of genes that are present on each chromosome.The F12 gene creates (encodes) factor XII, which is a clotting factor. Mutations of the F12 gene lead to low levels of functional factor XII in the blood (potentially less than 1%). The exact role that factor XII plays in the clotting process and any additional effects it has on the body are not fully understood. In addition to the clotting process, factor XII is believed to play a role tissue repair and the formation of blood vessels (angiogenesis). | Causes of Factor XII Deficiency. Factor XII deficiency is inherited as an autosomal recessive disorder. Genetic diseases are determined by two genes, one received from the father and one from 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. Investigators have determined that factor XII deficiency occurs due to mutations of the F12 gene located on the long arm of chromosome 5 (5q33-qter). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Pairs of human chromosomes are numbered from 1 through 22, and an additional 23rd pair of sex chromosomes which include one X and one Y chromosome in males and two X chromosomes in females. 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 5q33” refers to band 33 on the long arm of chromosome 5. The numbered bands specify the location of the thousands of genes that are present on each chromosome.The F12 gene creates (encodes) factor XII, which is a clotting factor. Mutations of the F12 gene lead to low levels of functional factor XII in the blood (potentially less than 1%). The exact role that factor XII plays in the clotting process and any additional effects it has on the body are not fully understood. In addition to the clotting process, factor XII is believed to play a role tissue repair and the formation of blood vessels (angiogenesis). | 438 | Factor XII Deficiency |
nord_438_3 | Affects of Factor XII Deficiency | Factor XII deficiency affects persons of Asian descent more often than individuals of other ethnicities. Males and females are affected in equal numbers. Since no symptoms are usually associated with factor XII deficiency, many individuals remain undiagnosed. The exact incidence of the disorder in the general population is unknown, but estimated to be approximately 1 in 1 million individuals. | Affects of Factor XII Deficiency. Factor XII deficiency affects persons of Asian descent more often than individuals of other ethnicities. Males and females are affected in equal numbers. Since no symptoms are usually associated with factor XII deficiency, many individuals remain undiagnosed. The exact incidence of the disorder in the general population is unknown, but estimated to be approximately 1 in 1 million individuals. | 438 | Factor XII Deficiency |
nord_438_4 | Related disorders of Factor XII Deficiency | Symptoms of the following disorders can be similar to those of factor XII deficiency. Comparisons may be useful for a differential diagnosis: Hemophilia is a general term for a group of rare bleeding disorders. Most forms of hemophilia rare 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); 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. Therefore, while hemophilia A and B are fully expressed in males only, hemophilia C affects males and females in equal numbers. Hemophilia A is the most common form of hemophilia and is characterized by a deficiency of factor VIII, one of several specialized proteins required for the blood to clot. 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. Factor XIII deficiency is classified as a rare form of bleeding disorders; a group that includes deficiencies of fibrinogen, prothrombin and factors V, VII, X, and XIII. There are also combined deficiencies of more than one factor. The rare forms of bleeding disorders account for 3-5% of all bleeding disorders collectively. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Factor XIII deficiency is a rare, genetic bleeding disorder characterized by deficiency or reduced activity of clotting factor XIII. Clotting factors are specialized proteins that are essential for the blood to clot properly. Specifically, individuals with factor XIII form blood clots like normal, but these clots are unstable and often break down, resulting in prolonged, uncontrolled bleeding episodes. Factor XIII also affects other processes in the body and is known to play a role in proper wound healing and pregnancy. The severity of factor XIII deficiency can vary greatly from one person to another. Some individuals may have no symptoms (asymptomatic) or only mild symptoms; other individuals may have severe, life-threatening complications. With early diagnosis and prompt treatment, the more serious complications of factor XIII deficiency can be avoided. Factor XIII deficiency is caused by mutations to one of two different genes. Factor XIII deficiency is inherited as an autosomal recessive disorder. (For more information on these disorders, choose factor XIII deficiency as your search term in the Rare Disease Database.) | Related disorders of Factor XII Deficiency. Symptoms of the following disorders can be similar to those of factor XII deficiency. Comparisons may be useful for a differential diagnosis: Hemophilia is a general term for a group of rare bleeding disorders. Most forms of hemophilia rare 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); 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. Therefore, while hemophilia A and B are fully expressed in males only, hemophilia C affects males and females in equal numbers. Hemophilia A is the most common form of hemophilia and is characterized by a deficiency of factor VIII, one of several specialized proteins required for the blood to clot. 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. Factor XIII deficiency is classified as a rare form of bleeding disorders; a group that includes deficiencies of fibrinogen, prothrombin and factors V, VII, X, and XIII. There are also combined deficiencies of more than one factor. The rare forms of bleeding disorders account for 3-5% of all bleeding disorders collectively. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Factor XIII deficiency is a rare, genetic bleeding disorder characterized by deficiency or reduced activity of clotting factor XIII. Clotting factors are specialized proteins that are essential for the blood to clot properly. Specifically, individuals with factor XIII form blood clots like normal, but these clots are unstable and often break down, resulting in prolonged, uncontrolled bleeding episodes. Factor XIII also affects other processes in the body and is known to play a role in proper wound healing and pregnancy. The severity of factor XIII deficiency can vary greatly from one person to another. Some individuals may have no symptoms (asymptomatic) or only mild symptoms; other individuals may have severe, life-threatening complications. With early diagnosis and prompt treatment, the more serious complications of factor XIII deficiency can be avoided. Factor XIII deficiency is caused by mutations to one of two different genes. Factor XIII deficiency is inherited as an autosomal recessive disorder. (For more information on these disorders, choose factor XIII deficiency as your search term in the Rare Disease Database.) | 438 | Factor XII Deficiency |
nord_438_5 | Diagnosis of Factor XII Deficiency | Factor XII deficiency is often diagnosed accidentally during a routine blood clotting (coagulation) tests as in one done before surgery. In affected individuals, it will take longer for their blood to clot during these tests. Further tests can reveal low levels of factor XII in the blood.Clinical Testing and Work-upA diagnosis of factor XII deficiency may be suspected in individuals without clinical signs or a previous history of a bleeding disorder in whom specialized tests called screening coagulation tests known as activated partial thromboplastin time (aPTT) or prothrombin time PT) are abnormal. These tests measure how long it takes the blood to clot.Individuals with abnormal results on these tests but no bleeding symptoms may then be screened for a condition known as antiphospholipid syndrome. A test will be run to detect a specific inhibitor called lupus anticoagulant, which is present in individuals with acquired antiphospholipid syndrome and can cause similar abnormal results on the aPTT or PT tests.A diagnosis of factor XII deficiency can be confirmed by a test called an assay. An assay is a test that measures the activity of coagulation factors. It can demonstrate a deficiency of factor XII. | Diagnosis of Factor XII Deficiency. Factor XII deficiency is often diagnosed accidentally during a routine blood clotting (coagulation) tests as in one done before surgery. In affected individuals, it will take longer for their blood to clot during these tests. Further tests can reveal low levels of factor XII in the blood.Clinical Testing and Work-upA diagnosis of factor XII deficiency may be suspected in individuals without clinical signs or a previous history of a bleeding disorder in whom specialized tests called screening coagulation tests known as activated partial thromboplastin time (aPTT) or prothrombin time PT) are abnormal. These tests measure how long it takes the blood to clot.Individuals with abnormal results on these tests but no bleeding symptoms may then be screened for a condition known as antiphospholipid syndrome. A test will be run to detect a specific inhibitor called lupus anticoagulant, which is present in individuals with acquired antiphospholipid syndrome and can cause similar abnormal results on the aPTT or PT tests.A diagnosis of factor XII deficiency can be confirmed by a test called an assay. An assay is a test that measures the activity of coagulation factors. It can demonstrate a deficiency of factor XII. | 438 | Factor XII Deficiency |
nord_438_6 | Therapies of Factor XII Deficiency | TreatmentTreatment for this disorder is usually not necessary since bleeding abnormalities only mild or nonexistent. | Therapies of Factor XII Deficiency. TreatmentTreatment for this disorder is usually not necessary since bleeding abnormalities only mild or nonexistent. | 438 | Factor XII Deficiency |
nord_439_0 | Overview of Factor XIII Deficiency | SummaryFactor XIII deficiency is a rare, genetic bleeding disorder characterized by deficiency of clotting factor XIII. Clotting factors are specialized proteins that are essential for the blood to clot properly. Specifically, individuals with factor XIII deficiency form blood clots like normal, but these clots are unstable and often break down, resulting in prolonged, uncontrolled bleeding episodes. Factor XIII also affects other processes in the body and is known to play a role in proper wound healing and pregnancy. The severity of factor XIII deficiency bleeds can vary greatly from one person to another. Some individuals may have only mild symptoms; other individuals may have severe, life-threatening bleeds. With early diagnosis and prompt treatment, the more serious bleeds of factor XIII deficiency can be avoided. FXIII consists of two subunits: subunit A and subunit B. Most of the Factor XIII deficiency states are caused by mutations in subunit A; very few have a mutation in subunit B. Factor XIII deficiency is inherited as an autosomal recessive disorder.IntroductionThis report deals with the genetic form of factor XIII deficiency, which is present at birth (congenital); the disorder can also be acquired during life. Although the genetic form is present at birth, symptoms may not become apparent until later during life. Congenital factor XIII deficiency was first described in the medical literature by Duckert, et al., in 1960. | Overview of Factor XIII Deficiency. SummaryFactor XIII deficiency is a rare, genetic bleeding disorder characterized by deficiency of clotting factor XIII. Clotting factors are specialized proteins that are essential for the blood to clot properly. Specifically, individuals with factor XIII deficiency form blood clots like normal, but these clots are unstable and often break down, resulting in prolonged, uncontrolled bleeding episodes. Factor XIII also affects other processes in the body and is known to play a role in proper wound healing and pregnancy. The severity of factor XIII deficiency bleeds can vary greatly from one person to another. Some individuals may have only mild symptoms; other individuals may have severe, life-threatening bleeds. With early diagnosis and prompt treatment, the more serious bleeds of factor XIII deficiency can be avoided. FXIII consists of two subunits: subunit A and subunit B. Most of the Factor XIII deficiency states are caused by mutations in subunit A; very few have a mutation in subunit B. Factor XIII deficiency is inherited as an autosomal recessive disorder.IntroductionThis report deals with the genetic form of factor XIII deficiency, which is present at birth (congenital); the disorder can also be acquired during life. Although the genetic form is present at birth, symptoms may not become apparent until later during life. Congenital factor XIII deficiency was first described in the medical literature by Duckert, et al., in 1960. | 439 | Factor XIII Deficiency |
nord_439_1 | Symptoms of Factor XIII Deficiency | The symptoms and severity of factor XIII deficiency can vary from one person to another. However, in most of the patients (80%) bleeding symptoms appear after birth with bleeding from the umbilical stump being most common. Some individuals may only have a mild expression of the disorder that will not become apparent until after a bleeding complication occurs following trauma or surgery. In more serious cases, bleeding can occur spontaneously or following activities that normally would not produce problems such as strenuous exercise. It is important to note the variability of factor XIII deficiency and to understand that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.The symptoms of factor XIII deficiency may become apparent at any age, but most patients are diagnosed during infancy. Symptoms commonly associated with factor XIII deficiency include chronic nosebleeds (epistaxis), bleeding from the gums, discoloration of the skin due to bleeding underneath the skin (ecchymoses), and solid swellings of congealed blood (hematomas). Affected individuals may bruise easily, extensively, and without cause (spontaneously). Bruising due to minor trauma may be delayed. Women with factor XIII deficiency may experience prolonged, heavy bleeding during the periods (menorrhagia). Bleeding into the soft tissues and around the joints (periarticular bleeding) can also occur. Bleeding into the joints (hemoarthrosis) is rare.Thirty percent of the affected individuals may also experience spontaneous bleeding into the brain (intracranial hemorrhages), about 25% experience poor or delayed wound healing and others may have enhanced bleeding after trauma or surgery. The risk of intracranial hemorrhaging is greater in factor XIII deficiency than in other related bleeding disorders. Bleeding after trauma or surgery is initially normal, but abnormal, heavy bleeding often develops within 12-36 hours. In homozygous women, factor XIII deficiency has also been associated with recurrent miscarriages (spontaneous abortion). | Symptoms of Factor XIII Deficiency. The symptoms and severity of factor XIII deficiency can vary from one person to another. However, in most of the patients (80%) bleeding symptoms appear after birth with bleeding from the umbilical stump being most common. Some individuals may only have a mild expression of the disorder that will not become apparent until after a bleeding complication occurs following trauma or surgery. In more serious cases, bleeding can occur spontaneously or following activities that normally would not produce problems such as strenuous exercise. It is important to note the variability of factor XIII deficiency and to understand that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.The symptoms of factor XIII deficiency may become apparent at any age, but most patients are diagnosed during infancy. Symptoms commonly associated with factor XIII deficiency include chronic nosebleeds (epistaxis), bleeding from the gums, discoloration of the skin due to bleeding underneath the skin (ecchymoses), and solid swellings of congealed blood (hematomas). Affected individuals may bruise easily, extensively, and without cause (spontaneously). Bruising due to minor trauma may be delayed. Women with factor XIII deficiency may experience prolonged, heavy bleeding during the periods (menorrhagia). Bleeding into the soft tissues and around the joints (periarticular bleeding) can also occur. Bleeding into the joints (hemoarthrosis) is rare.Thirty percent of the affected individuals may also experience spontaneous bleeding into the brain (intracranial hemorrhages), about 25% experience poor or delayed wound healing and others may have enhanced bleeding after trauma or surgery. The risk of intracranial hemorrhaging is greater in factor XIII deficiency than in other related bleeding disorders. Bleeding after trauma or surgery is initially normal, but abnormal, heavy bleeding often develops within 12-36 hours. In homozygous women, factor XIII deficiency has also been associated with recurrent miscarriages (spontaneous abortion). | 439 | Factor XIII Deficiency |
nord_439_2 | Causes of Factor XIII Deficiency | Mutations causing factor XIII deficiency are inherited as autosomal recessive traits. 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 inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. 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. Investigators have determined that the F13A1 gene is located on the short arm (p) of chromosome 6 (6p24.2-p23). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes (23 pairs). 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 6p24.2-p23” refers to bands 24.2-23 on the short arm of chromosome 6. The numbered bands specify the location of the thousands of genes that are present on each chromosome.Cases of factor XIII deficiency due to mutations of the F13A1 gene are sometimes referred to as factor XIIIA deficiency or factor XIII deficiency type 2.The F13B gene is located on the long arm (q) of chromosome 1 (1q31-q32.1). Factor XIII deficiency due to mutations of the F13B gene occurs very rarely and is generally less severe than when the disorder is caused by mutations of the F13A1 gene. Less than 5% of the report cases of factor XIII deficiency are due to mutations of the F13B gene. These cases are sometimes referred to as factor XIIIB deficiency or factor XIII deficiency type 1.Factor XIII consists of two catalytic a subunits and two noncatalytic b subunits. The a subunits are regulated (encoded) by the F13A1 gene and produced (synthesized) in various cells including bone marrow cells that eventually become platelets (megakaryocytes) and certain white blood cells (monocytes and macrophages). The b subunits are encoded by the F13B gene and are synthesized in liver cells (hepatocytes).Factor XIII plays a vital role in stabilizing blood clots. Clotting is the process by which blood specific (coagulation) proteins clump together to plug the site of a wound to stop bleeding. Clotting requires a series of reactions to ultimately form a clot to plug a wound. This is referred to as the clotting (coagulation) cascade. The clotting cascade involves different substances in addition to clotting factors. Factor XIII is the last step of the clotting cascade, and it functions to stabilize the clot. Mutations of the F13A1 or the F13b gene result in deficient levels of functional factor XIII, which causes blood clots to be weak and unstable resulting in fast breakdown.For years, it was believed that factor XIII only played a role in helping to stabilize the formation of blood clots. However, researchers have learned that factor XIII has multiple roles in the body and is involved in proper wound healing, carrying a pregnancy to full term, and in the development of new blood vessels (angiogenesis). More research is necessary to determine the exact functions that factor XIII plays in the body and the full spectrum of symptoms potentially associated with the disorder. | Causes of Factor XIII Deficiency. Mutations causing factor XIII deficiency are inherited as autosomal recessive traits. 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 inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. 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. Investigators have determined that the F13A1 gene is located on the short arm (p) of chromosome 6 (6p24.2-p23). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes (23 pairs). 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 6p24.2-p23” refers to bands 24.2-23 on the short arm of chromosome 6. The numbered bands specify the location of the thousands of genes that are present on each chromosome.Cases of factor XIII deficiency due to mutations of the F13A1 gene are sometimes referred to as factor XIIIA deficiency or factor XIII deficiency type 2.The F13B gene is located on the long arm (q) of chromosome 1 (1q31-q32.1). Factor XIII deficiency due to mutations of the F13B gene occurs very rarely and is generally less severe than when the disorder is caused by mutations of the F13A1 gene. Less than 5% of the report cases of factor XIII deficiency are due to mutations of the F13B gene. These cases are sometimes referred to as factor XIIIB deficiency or factor XIII deficiency type 1.Factor XIII consists of two catalytic a subunits and two noncatalytic b subunits. The a subunits are regulated (encoded) by the F13A1 gene and produced (synthesized) in various cells including bone marrow cells that eventually become platelets (megakaryocytes) and certain white blood cells (monocytes and macrophages). The b subunits are encoded by the F13B gene and are synthesized in liver cells (hepatocytes).Factor XIII plays a vital role in stabilizing blood clots. Clotting is the process by which blood specific (coagulation) proteins clump together to plug the site of a wound to stop bleeding. Clotting requires a series of reactions to ultimately form a clot to plug a wound. This is referred to as the clotting (coagulation) cascade. The clotting cascade involves different substances in addition to clotting factors. Factor XIII is the last step of the clotting cascade, and it functions to stabilize the clot. Mutations of the F13A1 or the F13b gene result in deficient levels of functional factor XIII, which causes blood clots to be weak and unstable resulting in fast breakdown.For years, it was believed that factor XIII only played a role in helping to stabilize the formation of blood clots. However, researchers have learned that factor XIII has multiple roles in the body and is involved in proper wound healing, carrying a pregnancy to full term, and in the development of new blood vessels (angiogenesis). More research is necessary to determine the exact functions that factor XIII plays in the body and the full spectrum of symptoms potentially associated with the disorder. | 439 | Factor XIII Deficiency |
nord_439_3 | Affects of Factor XIII Deficiency | Factor XIII deficiency affects males and females in equal numbers. Symptoms can become apparent at any age. Individuals of any race or ethnicity can be affected. The incidence of factor XIII deficiency has been estimated to be between 1 in 2,000,000-5,000,000 people in the general population. However, factor XIII deficiency can go undiagnosed or misdiagnosed, making it difficult to determine the disorder’s true frequency. Most researchers believe that the disorder is under-diagnosed. The incidence of factor XIII deficiency tends to be higher in countries where marriage to close relatives (consanguineous marriage) is more common. | Affects of Factor XIII Deficiency. Factor XIII deficiency affects males and females in equal numbers. Symptoms can become apparent at any age. Individuals of any race or ethnicity can be affected. The incidence of factor XIII deficiency has been estimated to be between 1 in 2,000,000-5,000,000 people in the general population. However, factor XIII deficiency can go undiagnosed or misdiagnosed, making it difficult to determine the disorder’s true frequency. Most researchers believe that the disorder is under-diagnosed. The incidence of factor XIII deficiency tends to be higher in countries where marriage to close relatives (consanguineous marriage) is more common. | 439 | Factor XIII Deficiency |
nord_439_4 | Related disorders of Factor XIII Deficiency | Symptoms of the following disorders can be similar to those of factor XIII deficiency. Comparisons may be useful for a differential diagnosis.Acquired factor XIII deficiency is a general term for individuals who develop factor XIII deficiency that is not inherited, but acquired at some point during life. Acquired factor XIII deficiency can result when the body produces autoantibodies (inhibitors) that attack factor XIII. Acquired factor XIII deficiency can be associated with an underlying condition such as severe liver disease, chronic kidney (renal) failure, inflammatory bowel disease, Henoch-Schonlein purpura, autoimmune disorders such as lupus or scleroderma, or certain cancers such as myeloid forms of leukemia. Acquired factor XIII deficiency has also been linked to the use of certain medications including isoniazid, penicillin, and phenytoin. The exact reason these autoantibodies develop is not always known. Acquired factor XIII deficiency occurs much less often than the genetic form and usually affects middle-aged or elderly individuals.Hemophilia (Hemo = bleed; philia = tendency) is a general term for a group of rare bleeding disorders. Most forms of hemophilia are rare inherited blood clotting (coagulation) disorders caused by inactive or deficient blood coagulation proteins. There are three major forms of inherited hemophilia: hemophilia A (also known as classical hemophilia, factor VIII deficiency or antihemophilic globulin [AHG] deficiency); 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. Therefore, while hemophilia A and B are fully expressed in males only, hemophilia C affects males and females in equal numbers. Hemophilia A is the most common form of hemophilia and is characterized by a deficiency of factor VIII, one of several specialized proteins required for the blood to clot. 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. Factor XIII deficiency belongs to a group of rare forms of bleeding disorders; a group that includes deficiencies of fibrinogen, prothrombin and factors V, VII, and X. There are also combined deficiencies of more than one factor. The rare forms of bleeding disorders account for 3-5% of all bleeding disorders collectively. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | Related disorders of Factor XIII Deficiency. Symptoms of the following disorders can be similar to those of factor XIII deficiency. Comparisons may be useful for a differential diagnosis.Acquired factor XIII deficiency is a general term for individuals who develop factor XIII deficiency that is not inherited, but acquired at some point during life. Acquired factor XIII deficiency can result when the body produces autoantibodies (inhibitors) that attack factor XIII. Acquired factor XIII deficiency can be associated with an underlying condition such as severe liver disease, chronic kidney (renal) failure, inflammatory bowel disease, Henoch-Schonlein purpura, autoimmune disorders such as lupus or scleroderma, or certain cancers such as myeloid forms of leukemia. Acquired factor XIII deficiency has also been linked to the use of certain medications including isoniazid, penicillin, and phenytoin. The exact reason these autoantibodies develop is not always known. Acquired factor XIII deficiency occurs much less often than the genetic form and usually affects middle-aged or elderly individuals.Hemophilia (Hemo = bleed; philia = tendency) is a general term for a group of rare bleeding disorders. Most forms of hemophilia are rare inherited blood clotting (coagulation) disorders caused by inactive or deficient blood coagulation proteins. There are three major forms of inherited hemophilia: hemophilia A (also known as classical hemophilia, factor VIII deficiency or antihemophilic globulin [AHG] deficiency); 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. Therefore, while hemophilia A and B are fully expressed in males only, hemophilia C affects males and females in equal numbers. Hemophilia A is the most common form of hemophilia and is characterized by a deficiency of factor VIII, one of several specialized proteins required for the blood to clot. 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. Factor XIII deficiency belongs to a group of rare forms of bleeding disorders; a group that includes deficiencies of fibrinogen, prothrombin and factors V, VII, and X. There are also combined deficiencies of more than one factor. The rare forms of bleeding disorders account for 3-5% of all bleeding disorders collectively. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | 439 | Factor XIII Deficiency |
nord_439_5 | Diagnosis of Factor XIII Deficiency | A diagnosis of factor XIII deficiency is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Standard tests used to diagnose bleeding disorders such as activated partial thromboplastin time (aPTT) and prothrombin time (PT) are normal and therefore ineffective. A diagnosis of factor XIII may be suspected in infants that experience heavy or abnormal bleeding at birth.Clinical Testing and WorkupA clot solubility test may be used to aid in a diagnosis factor XIII deficiency. However, this test is only effective when an affected individual has very low levels of factor XIII. During these tests, a clot is exposed to a solution of 1% monochloracetic acid or 5 m urea. In individuals with less than 1% factor XIII, the clots will breakdown. Most untreated individuals with factor XIII deficiency will have close to 0% factor XIII activity in the blood.To confirm a diagnosis, the quantity (amount) of factor XIII is tested in a blood sample through quantitative analysis of factor XIII (assay). A quantitative assay is a test that can measure the amount or activity of certain substances in the blood. In affected individuals this will demonstrate reduced amount and activity of factor XIII. | Diagnosis of Factor XIII Deficiency. A diagnosis of factor XIII deficiency is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Standard tests used to diagnose bleeding disorders such as activated partial thromboplastin time (aPTT) and prothrombin time (PT) are normal and therefore ineffective. A diagnosis of factor XIII may be suspected in infants that experience heavy or abnormal bleeding at birth.Clinical Testing and WorkupA clot solubility test may be used to aid in a diagnosis factor XIII deficiency. However, this test is only effective when an affected individual has very low levels of factor XIII. During these tests, a clot is exposed to a solution of 1% monochloracetic acid or 5 m urea. In individuals with less than 1% factor XIII, the clots will breakdown. Most untreated individuals with factor XIII deficiency will have close to 0% factor XIII activity in the blood.To confirm a diagnosis, the quantity (amount) of factor XIII is tested in a blood sample through quantitative analysis of factor XIII (assay). A quantitative assay is a test that can measure the amount or activity of certain substances in the blood. In affected individuals this will demonstrate reduced amount and activity of factor XIII. | 439 | Factor XIII Deficiency |
nord_439_6 | Therapies of Factor XIII Deficiency | TreatmentFactor XIII deficiency can be treated by factor XIII concentrates. Factor XIII levels only need to be elevated slightly to prevent or stop the bleeding symptoms associated with the disorder.Factor XIII concentrate, which is a blood product that contains a concentrated form of factor XIII, is used to treat individuals with factor XIII deficiency. Such products are created from the plasma of thousands of different blood donors. These products undergo a viral inactivation process that kills any viruses or similar pathogens that can potentially be present in the blood.In the past, individuals with factor XIII deficiency were treated with fresh frozen plasma or cryoprecipitates. Fresh frozen plasma may be used if factor XIII concentrates are unavailable. Cryoprecipitates are no longer recommended because of the risk (albeit small) of infection from a virus or similar pathogen. There is also a risk of an allergic reaction with fresh frozen plasma or cryoprecipitates.It is recommended that individuals with factor XIII deficiency undergo preventive (prophylactic) therapy with FXIII concentrate every 3-4 weeks in an attempt to prevent or minimize the symptoms of the disorder. Prophylactic therapy has been used to prevent mostly bleeding into the brain. The decision to undergo prophylactic therapy in factor XIII deficiency is made after careful consultation with a patient’s medical team.In 2011, the U.S. Food and Drug and Administration (FDA) approved Corifact (FXIII Concentrate) for the routine prophylactic treatment of congenital factor XIII deficiency. Corifact is administered intravenously. In some cases, Corifact has been associated with adverse side effects such as blood clots (thromboses), and the benefits versus the risks of such therapy must be assessed on an individual basis. For more information, contact:CSL Behring
Website: http://www.corifact.com/In extremely rare cases, inhibitors have developed in individuals with factor XIII deficiency. Inhibitors are autoantibodies. Antibodies are specialized proteins produced by the body’s immune system that destroy foreign substances directly or coats 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. In factor XIII deficiency they are also called inhibitors because they mistakenly attack replacement factor XIII, inhibiting the effectiveness of the treatment. When inhibitors develop in individuals with factor XIII deficiency, additional therapy is required, specifically drugs that reduce the activity of the immune system (immunosuppressive agents).In 2014, Tretten, a recombinant factor XIII replacement product, was approved for the prevention of bleeding in adults and children who have the rare clotting disorder congenital factor XIII A-subunit deficiency. Tretten is distributed by Novo Nordisk, Inc. USA. For more information, contact:Novo Nordisk, Inc.
Website: http://www.tretten-us.com/Additional treatment for individuals with factor XIII deficiency is symptomatic and supportive. For example, excessive menstrual bleeding in women may be treated by hormonal contraceptives such as birth control pills or drugs known as antifibrinolytics, which prevent the breakdown of clots in the blood. Genetic counseling may be of benefit for affected individuals and their families. | Therapies of Factor XIII Deficiency. TreatmentFactor XIII deficiency can be treated by factor XIII concentrates. Factor XIII levels only need to be elevated slightly to prevent or stop the bleeding symptoms associated with the disorder.Factor XIII concentrate, which is a blood product that contains a concentrated form of factor XIII, is used to treat individuals with factor XIII deficiency. Such products are created from the plasma of thousands of different blood donors. These products undergo a viral inactivation process that kills any viruses or similar pathogens that can potentially be present in the blood.In the past, individuals with factor XIII deficiency were treated with fresh frozen plasma or cryoprecipitates. Fresh frozen plasma may be used if factor XIII concentrates are unavailable. Cryoprecipitates are no longer recommended because of the risk (albeit small) of infection from a virus or similar pathogen. There is also a risk of an allergic reaction with fresh frozen plasma or cryoprecipitates.It is recommended that individuals with factor XIII deficiency undergo preventive (prophylactic) therapy with FXIII concentrate every 3-4 weeks in an attempt to prevent or minimize the symptoms of the disorder. Prophylactic therapy has been used to prevent mostly bleeding into the brain. The decision to undergo prophylactic therapy in factor XIII deficiency is made after careful consultation with a patient’s medical team.In 2011, the U.S. Food and Drug and Administration (FDA) approved Corifact (FXIII Concentrate) for the routine prophylactic treatment of congenital factor XIII deficiency. Corifact is administered intravenously. In some cases, Corifact has been associated with adverse side effects such as blood clots (thromboses), and the benefits versus the risks of such therapy must be assessed on an individual basis. For more information, contact:CSL Behring
Website: http://www.corifact.com/In extremely rare cases, inhibitors have developed in individuals with factor XIII deficiency. Inhibitors are autoantibodies. Antibodies are specialized proteins produced by the body’s immune system that destroy foreign substances directly or coats 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. In factor XIII deficiency they are also called inhibitors because they mistakenly attack replacement factor XIII, inhibiting the effectiveness of the treatment. When inhibitors develop in individuals with factor XIII deficiency, additional therapy is required, specifically drugs that reduce the activity of the immune system (immunosuppressive agents).In 2014, Tretten, a recombinant factor XIII replacement product, was approved for the prevention of bleeding in adults and children who have the rare clotting disorder congenital factor XIII A-subunit deficiency. Tretten is distributed by Novo Nordisk, Inc. USA. For more information, contact:Novo Nordisk, Inc.
Website: http://www.tretten-us.com/Additional treatment for individuals with factor XIII deficiency is symptomatic and supportive. For example, excessive menstrual bleeding in women may be treated by hormonal contraceptives such as birth control pills or drugs known as antifibrinolytics, which prevent the breakdown of clots in the blood. Genetic counseling may be of benefit for affected individuals and their families. | 439 | Factor XIII Deficiency |
nord_440_0 | Overview of Familial Adenomatous Polyposis | Familial adenomatous polyposis (FAP) is a rare inherited cancer predisposition syndrome characterized by hundreds to thousands of precancerous colorectal polyps (adenomatous polyps). If left untreated, affected individuals inevitably develop cancer of the colon and/or rectum at a relatively young age. FAP is inherited in an autosomal dominant manner and caused by abnormalities (mutations) in the APC gene. Mutations in the APC gene cause a group of polyposis conditions that have overlapping features: familial adenomatous polyposis, Gardner syndrome, Turcot syndrome and attenuated FAP. | Overview of Familial Adenomatous Polyposis. Familial adenomatous polyposis (FAP) is a rare inherited cancer predisposition syndrome characterized by hundreds to thousands of precancerous colorectal polyps (adenomatous polyps). If left untreated, affected individuals inevitably develop cancer of the colon and/or rectum at a relatively young age. FAP is inherited in an autosomal dominant manner and caused by abnormalities (mutations) in the APC gene. Mutations in the APC gene cause a group of polyposis conditions that have overlapping features: familial adenomatous polyposis, Gardner syndrome, Turcot syndrome and attenuated FAP. | 440 | Familial Adenomatous Polyposis |
nord_440_1 | Symptoms of Familial Adenomatous Polyposis | Classic FAP is characterized by hundreds to thousands of colorectal adenomatous polyps, with polyps appearing on average at age 16 years. Without colectomy, affected individuals usually develop colorectal cancer by the third or fourth decade of life. FAP is also associated with an increased risk for cancer of the small intestine including the duodenum, and cancer of the thyroid, pancreas, liver (hepatoblatoma), central nervous system (CNS), and bile ducts, although these typically occur in less than 10% of affected individuals. Individuals with CNS tumors and colorectal polyposis have historically been defined as Turcot syndrome. Two-thirds of cases of Turcot syndrome develop from mutations in the APC gene. The remaining cases develop from mutations in the genes that cause hereditary non-polyposis colorectal cancer (HNPCC) also known as Lynch syndrome. Mutations in the APC gene are more commonly associated with medulloblastoma; mutations in the genes that cause HNPCC are more commonly associated with glioblastoma. Extracolonic manifestations are variably present in FAP, including polyps of the stomach, duodenum and small bowel; and osteomas (bony growths), dental abnormalities, congenital hypertrophy of the retinal pigment epithelium (CHRPE), and soft tissue tumors including epidermoid cysts, fibromas and desmoid tumors. About 5% of individuals with FAP experience morbidity and/or mortality from desmoid tumors. The term Gardner syndrome is often used when colonic polyposis is accompanied by clinically obvious osteomas and soft tissue tumors. Attenuated FAP is a variant of familial adenomatous polyposis. The disorder is characterized by an increased risk for colorectal cancer (although lower risk than classical FAP) but with fewer polyps (average of 30) and later age of onset of polyps and cancer than is typically seen in classic FAP. Extra-colonic manifestations are also associated with attenuated FAP. | Symptoms of Familial Adenomatous Polyposis. Classic FAP is characterized by hundreds to thousands of colorectal adenomatous polyps, with polyps appearing on average at age 16 years. Without colectomy, affected individuals usually develop colorectal cancer by the third or fourth decade of life. FAP is also associated with an increased risk for cancer of the small intestine including the duodenum, and cancer of the thyroid, pancreas, liver (hepatoblatoma), central nervous system (CNS), and bile ducts, although these typically occur in less than 10% of affected individuals. Individuals with CNS tumors and colorectal polyposis have historically been defined as Turcot syndrome. Two-thirds of cases of Turcot syndrome develop from mutations in the APC gene. The remaining cases develop from mutations in the genes that cause hereditary non-polyposis colorectal cancer (HNPCC) also known as Lynch syndrome. Mutations in the APC gene are more commonly associated with medulloblastoma; mutations in the genes that cause HNPCC are more commonly associated with glioblastoma. Extracolonic manifestations are variably present in FAP, including polyps of the stomach, duodenum and small bowel; and osteomas (bony growths), dental abnormalities, congenital hypertrophy of the retinal pigment epithelium (CHRPE), and soft tissue tumors including epidermoid cysts, fibromas and desmoid tumors. About 5% of individuals with FAP experience morbidity and/or mortality from desmoid tumors. The term Gardner syndrome is often used when colonic polyposis is accompanied by clinically obvious osteomas and soft tissue tumors. Attenuated FAP is a variant of familial adenomatous polyposis. The disorder is characterized by an increased risk for colorectal cancer (although lower risk than classical FAP) but with fewer polyps (average of 30) and later age of onset of polyps and cancer than is typically seen in classic FAP. Extra-colonic manifestations are also associated with attenuated FAP. | 440 | Familial Adenomatous Polyposis |
nord_440_2 | Causes of Familial Adenomatous Polyposis | Familial adenomatous polyposis is caused by germline (present in the first cell of the embryo) mutations in the APC gene and is inherited in an autosomal dominant manner, meaning that on average 50% of children of an affected parent will have the disease passed on to them. Dominant genetic disorders occur when only a single copy or allele of a specific gene is mutated, thereby causing 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 Familial Adenomatous Polyposis. Familial adenomatous polyposis is caused by germline (present in the first cell of the embryo) mutations in the APC gene and is inherited in an autosomal dominant manner, meaning that on average 50% of children of an affected parent will have the disease passed on to them. Dominant genetic disorders occur when only a single copy or allele of a specific gene is mutated, thereby causing 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. | 440 | Familial Adenomatous Polyposis |
nord_440_3 | Affects of Familial Adenomatous Polyposis | Familial adenomatous polyposis affects males and females in equal numbers. It occurs in approximately one in 5,000 to 10,000 individuals in the United States and accounts for about 0.5% of all cases of colorectal cancer. One estimate suggests that familial adenomatous polyposis affects 50,000 American families. According to national registries, familial adenomatous polyposis occurs in 2.29-3.2 per 100,000 individuals. | Affects of Familial Adenomatous Polyposis. Familial adenomatous polyposis affects males and females in equal numbers. It occurs in approximately one in 5,000 to 10,000 individuals in the United States and accounts for about 0.5% of all cases of colorectal cancer. One estimate suggests that familial adenomatous polyposis affects 50,000 American families. According to national registries, familial adenomatous polyposis occurs in 2.29-3.2 per 100,000 individuals. | 440 | Familial Adenomatous Polyposis |
nord_440_4 | Related disorders of Familial Adenomatous Polyposis | Features of the following disorders can be similar to those of the APC gene-associated polyposis conditions. Comparisons may be useful for a differential diagnosis: MYH gene-associated polyposis (MAP) is an autosomal recessive cancer predisposition syndrome with a colonic phenotype similar to attenuated FAP. Mutations in the MYH gene are associated with this condition. Hereditary non-polyposis colon cancer (HNPCC) or Lynch syndrome is an autosomal dominant cancer predisposition syndrome that causes a very high risk for colorectal and endometrial cancer in addition to an increased risk for cancers of the ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. Individuals with Lynch syndrome most often exhibit only one or several precancerous polys of the colon. Thus, Lynch syndrome is sometimes difficult to distinguish from attenuated FAP, as some individuals with attenuated FAP may have a low number of polyps. Peutz-Jeghers syndrome is an autosomal dominant genetic condition characterized by multiple benign hamartomatous polyps (Peutz-Jeghers polyps) in the gastrointestinal system. Hamartomatous polyps have a much lower risk of becoming cancerous compared to adenomatous polyps. These polyps occur most often in the small intestine but also occur in the stomach and large intestine. Affected individuals also have dark skin discoloration, like freckles or spots around the lips and on the face but much darker,These pigmented spots often presents in childhood and can be also be seen around the eyes, and nostrils, and on the mucous membranes of the mouth and in the perianal area. Affected individuals have an increased risk for intestinal and other cancers. This condition can be distinguished from FAP by clinical features and histology (microscopic examination) of the polyps. (For more information on this disorder, choose “Peutz-Jeghers” as your search term in the Rare Disease Database) Juvenile polyposis syndrome (JPS) is an autosomal dominant genetic condition characterized by a predisposition to gastrointestinal polyps. The term “juvenile” refers to the type of polyp as opposed to the age of onset. Polyps are usually diagnosed by 20 years of age and are usually benign, although malignant transformation can occur. JPS is associated with mutations in the SMAD4 and BMPR1A genes. Cronkhite-Canada disease is a very rare acquired (not inherited) disease and is characterized by intestinal polyps, loss of taste and hair, and nail growth problems. It is difficult to treat because of malabsorption that accompanies the polyps. Cronkhite-Canada disease occurs primarily in older people (the average age is 59). There have been fewer than 400 cases reported in the past 50 years, primarily in Japan but also in the U.S. and other countries (For more information on this disorder, choose “Cronkhite-Canada” as your search term in the Rare Disease Database.) | Related disorders of Familial Adenomatous Polyposis. Features of the following disorders can be similar to those of the APC gene-associated polyposis conditions. Comparisons may be useful for a differential diagnosis: MYH gene-associated polyposis (MAP) is an autosomal recessive cancer predisposition syndrome with a colonic phenotype similar to attenuated FAP. Mutations in the MYH gene are associated with this condition. Hereditary non-polyposis colon cancer (HNPCC) or Lynch syndrome is an autosomal dominant cancer predisposition syndrome that causes a very high risk for colorectal and endometrial cancer in addition to an increased risk for cancers of the ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. Individuals with Lynch syndrome most often exhibit only one or several precancerous polys of the colon. Thus, Lynch syndrome is sometimes difficult to distinguish from attenuated FAP, as some individuals with attenuated FAP may have a low number of polyps. Peutz-Jeghers syndrome is an autosomal dominant genetic condition characterized by multiple benign hamartomatous polyps (Peutz-Jeghers polyps) in the gastrointestinal system. Hamartomatous polyps have a much lower risk of becoming cancerous compared to adenomatous polyps. These polyps occur most often in the small intestine but also occur in the stomach and large intestine. Affected individuals also have dark skin discoloration, like freckles or spots around the lips and on the face but much darker,These pigmented spots often presents in childhood and can be also be seen around the eyes, and nostrils, and on the mucous membranes of the mouth and in the perianal area. Affected individuals have an increased risk for intestinal and other cancers. This condition can be distinguished from FAP by clinical features and histology (microscopic examination) of the polyps. (For more information on this disorder, choose “Peutz-Jeghers” as your search term in the Rare Disease Database) Juvenile polyposis syndrome (JPS) is an autosomal dominant genetic condition characterized by a predisposition to gastrointestinal polyps. The term “juvenile” refers to the type of polyp as opposed to the age of onset. Polyps are usually diagnosed by 20 years of age and are usually benign, although malignant transformation can occur. JPS is associated with mutations in the SMAD4 and BMPR1A genes. Cronkhite-Canada disease is a very rare acquired (not inherited) disease and is characterized by intestinal polyps, loss of taste and hair, and nail growth problems. It is difficult to treat because of malabsorption that accompanies the polyps. Cronkhite-Canada disease occurs primarily in older people (the average age is 59). There have been fewer than 400 cases reported in the past 50 years, primarily in Japan but also in the U.S. and other countries (For more information on this disorder, choose “Cronkhite-Canada” as your search term in the Rare Disease Database.) | 440 | Familial Adenomatous Polyposis |
nord_440_5 | Diagnosis of Familial Adenomatous Polyposis | Classical FAP is diagnosed clinically when an individual has 100 or more adenomatous colorectal polyps (typically occurring by the third decade of life) or fewer than 100 polyps and a relative with FAP. Genetic testing for mutations in the APC gene is available to confirm the diagnosis of FAP and the associated conditions. Younger individuals may have fewer polyps. A diagnosis is made in younger people by the presence of the typical polyps and in immediate relative with FAP or by genetic testing. | Diagnosis of Familial Adenomatous Polyposis. Classical FAP is diagnosed clinically when an individual has 100 or more adenomatous colorectal polyps (typically occurring by the third decade of life) or fewer than 100 polyps and a relative with FAP. Genetic testing for mutations in the APC gene is available to confirm the diagnosis of FAP and the associated conditions. Younger individuals may have fewer polyps. A diagnosis is made in younger people by the presence of the typical polyps and in immediate relative with FAP or by genetic testing. | 440 | Familial Adenomatous Polyposis |
nord_440_6 | Therapies of Familial Adenomatous Polyposis | TreatmentPartial or complete removal of the colon (colectomy) is usually recommended for individuals with classical FAP at an appropriate age, usually between the late teens and late 30s. Sulindac is a nonsteroidal antiinflammatory drug (NSAID) usually used for arthritis, but is sometimes prescribed for individuals with FAP who have had a colectomy to treat polyps in the remaining rectum. Polyps will almost always regress, but it is uncertain if the cancer risk is changed, so surveillance must be continued.Removal of duodenal polyps is sometimes recommended if they cause symptoms, are large or contain large numbers of abnormal cells (dysplasia). This is to prevent them from becoming cancerous.Desmoid tumors are benign, but may cause problems by compressing organs and/or blood vessels in the abdomen. These are treated variously with surgery, NSAIDs, anti-estrogen medications, chemotherapy and/or radiation depending on the details in each case. They are sometimes just followed when they do not grow.Genetic counseling is recommended for individuals with familial adenomatous polyposis and their at-risk family members. This is very helpful to properly obtain and interpret genetic testing. Affected individuals should be screened clinically and endoscopically on a regular basis in order to identify cancerous and pre-cancerous tumors at an early stage. Colon cancer is virtually always prevented by screening and properly timed colectomy. This is similar for duodenal cancer. Other cancers are usually detected early, rather than prevented. | Therapies of Familial Adenomatous Polyposis. TreatmentPartial or complete removal of the colon (colectomy) is usually recommended for individuals with classical FAP at an appropriate age, usually between the late teens and late 30s. Sulindac is a nonsteroidal antiinflammatory drug (NSAID) usually used for arthritis, but is sometimes prescribed for individuals with FAP who have had a colectomy to treat polyps in the remaining rectum. Polyps will almost always regress, but it is uncertain if the cancer risk is changed, so surveillance must be continued.Removal of duodenal polyps is sometimes recommended if they cause symptoms, are large or contain large numbers of abnormal cells (dysplasia). This is to prevent them from becoming cancerous.Desmoid tumors are benign, but may cause problems by compressing organs and/or blood vessels in the abdomen. These are treated variously with surgery, NSAIDs, anti-estrogen medications, chemotherapy and/or radiation depending on the details in each case. They are sometimes just followed when they do not grow.Genetic counseling is recommended for individuals with familial adenomatous polyposis and their at-risk family members. This is very helpful to properly obtain and interpret genetic testing. Affected individuals should be screened clinically and endoscopically on a regular basis in order to identify cancerous and pre-cancerous tumors at an early stage. Colon cancer is virtually always prevented by screening and properly timed colectomy. This is similar for duodenal cancer. Other cancers are usually detected early, rather than prevented. | 440 | Familial Adenomatous Polyposis |
nord_441_0 | Overview of Familial Cold Autoinflammatory Syndrome | Familial cold autoinflammatory syndrome (FCAS), also known as familial cold urticaria, is a rare, inherited inflammatory disorder characterized by intermittent episodes of rash, fever, joint pain and other signs/symptoms of systemic inflammation triggered by exposure to cold. Onset of FCAS occurs during infancy and early childhood and persists throughout the patient's life.FCAS is one of the cryopyrin associated periodic syndromes (CAPS) caused by mutations in the CIAS1/NLRP3 gene. These syndromes are characterized by fever, rash, and joint pain. As in other CAPS, amyloidosis can rarely develop later in life in FCAS patients. Amyloidosis is due to an abnormal accumulation of the protein amyloid in a patient's tissues and organs such as the kidneys where it results in damage and often kidney failure if untreated.FCAS shares symptoms, and should not be confused, with acquired cold urticaria, a more common condition mediated by different mechanisms that usually develops later in life and is rarely inherited. | Overview of Familial Cold Autoinflammatory Syndrome. Familial cold autoinflammatory syndrome (FCAS), also known as familial cold urticaria, is a rare, inherited inflammatory disorder characterized by intermittent episodes of rash, fever, joint pain and other signs/symptoms of systemic inflammation triggered by exposure to cold. Onset of FCAS occurs during infancy and early childhood and persists throughout the patient's life.FCAS is one of the cryopyrin associated periodic syndromes (CAPS) caused by mutations in the CIAS1/NLRP3 gene. These syndromes are characterized by fever, rash, and joint pain. As in other CAPS, amyloidosis can rarely develop later in life in FCAS patients. Amyloidosis is due to an abnormal accumulation of the protein amyloid in a patient's tissues and organs such as the kidneys where it results in damage and often kidney failure if untreated.FCAS shares symptoms, and should not be confused, with acquired cold urticaria, a more common condition mediated by different mechanisms that usually develops later in life and is rarely inherited. | 441 | Familial Cold Autoinflammatory Syndrome |
nord_441_1 | Symptoms of Familial Cold Autoinflammatory Syndrome | Patients with FCAS experience mild to debilitating symptoms such as rash, fatigue, recurrent fever and chills, recurrent joint pain, and recurrent conjunctivitis (inflammation of the outer most layer of the eye causing redness, discomfort and discharge from the eye).Other symptoms include profuse sweating, drowsiness, headache, extreme thirst, red eyes, blurred vision, eye pain, watering eyes and nauseaSymptoms occur within hours after exposure to cold. In most cases, a rash will occur within the first 1-2 hours, followed by a fever and joint pain. Episodes usually last for less than 24 hours. | Symptoms of Familial Cold Autoinflammatory Syndrome. Patients with FCAS experience mild to debilitating symptoms such as rash, fatigue, recurrent fever and chills, recurrent joint pain, and recurrent conjunctivitis (inflammation of the outer most layer of the eye causing redness, discomfort and discharge from the eye).Other symptoms include profuse sweating, drowsiness, headache, extreme thirst, red eyes, blurred vision, eye pain, watering eyes and nauseaSymptoms occur within hours after exposure to cold. In most cases, a rash will occur within the first 1-2 hours, followed by a fever and joint pain. Episodes usually last for less than 24 hours. | 441 | Familial Cold Autoinflammatory Syndrome |
nord_441_2 | Causes of Familial Cold Autoinflammatory Syndrome | FCAS is usually inherited in an autosomal dominant condition and is caused by a heterozygous mutation in a gene identified as CIAS1/NLRP3 that codes for the protein cryopyrin (NALP3). Mutations in this gene are hypothesized to cause increased activity of a protein complex containing cryopyrin. This protein complex is known as the inflammasome and regulates inflammation in the body. Increased inflammasome activity results in increased release of a protein known as interleukin (IL) 1ß, which leads to symptoms of inflammation such as fever and joint pain.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 Familial Cold Autoinflammatory Syndrome. FCAS is usually inherited in an autosomal dominant condition and is caused by a heterozygous mutation in a gene identified as CIAS1/NLRP3 that codes for the protein cryopyrin (NALP3). Mutations in this gene are hypothesized to cause increased activity of a protein complex containing cryopyrin. This protein complex is known as the inflammasome and regulates inflammation in the body. Increased inflammasome activity results in increased release of a protein known as interleukin (IL) 1ß, which leads to symptoms of inflammation such as fever and joint pain.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. | 441 | Familial Cold Autoinflammatory Syndrome |
nord_441_3 | Affects of Familial Cold Autoinflammatory Syndrome | Since FCAS is a newly discovered condition, the actual incidence and prevalence of the disease is difficult to determine at this time. | Affects of Familial Cold Autoinflammatory Syndrome. Since FCAS is a newly discovered condition, the actual incidence and prevalence of the disease is difficult to determine at this time. | 441 | Familial Cold Autoinflammatory Syndrome |
nord_441_4 | Related disorders of Familial Cold Autoinflammatory Syndrome | Symptoms of the following disorders can be similar to those of FCAS and there is significant phenotypic overlap. Comparisons may be useful for a differential diagnosis.Neonatal-onset multisystem inflammatory disease (NOMID), also known as chronic infantile neurologic cutaneous articular (CINCA) syndrome, is a rare, congenital, systemic, inflammatory condition characterized by fever, abnormal joint findings, rash, and central nervous system (CNS) disease with onset during infancy. NOMID is the most severe form of the cryopyrin associated periodic syndromes (CAPS) and is often caused by mutations in the CIAS1/NLRP3 gene.Muckle-Wells syndrome (MWS) is one of the cryopyrin associated periodic syndromes (CAPS). Individuals with MWS often have episodic fever, chills, and painful joints. Sometimes these symptoms are exacerbated by cold similar to the related condition FCAS, but can also be triggered by other stimuli. In most cases, MWS patients develop progressive hearing loss. In some MWS cases amyloidosis develops later in life, a disease in which an abnormal accumulation of the protein amyloid occurs in a patient's tissues and organs. Accumulation of amyloid in the kidneys results in damage and often kidney failure if untreated. | Related disorders of Familial Cold Autoinflammatory Syndrome. Symptoms of the following disorders can be similar to those of FCAS and there is significant phenotypic overlap. Comparisons may be useful for a differential diagnosis.Neonatal-onset multisystem inflammatory disease (NOMID), also known as chronic infantile neurologic cutaneous articular (CINCA) syndrome, is a rare, congenital, systemic, inflammatory condition characterized by fever, abnormal joint findings, rash, and central nervous system (CNS) disease with onset during infancy. NOMID is the most severe form of the cryopyrin associated periodic syndromes (CAPS) and is often caused by mutations in the CIAS1/NLRP3 gene.Muckle-Wells syndrome (MWS) is one of the cryopyrin associated periodic syndromes (CAPS). Individuals with MWS often have episodic fever, chills, and painful joints. Sometimes these symptoms are exacerbated by cold similar to the related condition FCAS, but can also be triggered by other stimuli. In most cases, MWS patients develop progressive hearing loss. In some MWS cases amyloidosis develops later in life, a disease in which an abnormal accumulation of the protein amyloid occurs in a patient's tissues and organs. Accumulation of amyloid in the kidneys results in damage and often kidney failure if untreated. | 441 | Familial Cold Autoinflammatory Syndrome |
nord_441_5 | Diagnosis of Familial Cold Autoinflammatory Syndrome | Diagnosis of FCAS is determined through an evaluation of a patient's symptoms. Confirmation of the diagnosis is achieved through DNA gene analysis and the identification of a CIAS1/NLRP3 mutation(4), although not all FCAS patients possess a mutation in this gene.Some of the common criteria that distinguish FCAS from other hereditary periodic fevers and acquired cold urticaria include: | Diagnosis of Familial Cold Autoinflammatory Syndrome. Diagnosis of FCAS is determined through an evaluation of a patient's symptoms. Confirmation of the diagnosis is achieved through DNA gene analysis and the identification of a CIAS1/NLRP3 mutation(4), although not all FCAS patients possess a mutation in this gene.Some of the common criteria that distinguish FCAS from other hereditary periodic fevers and acquired cold urticaria include: | 441 | Familial Cold Autoinflammatory Syndrome |
nord_441_6 | Therapies of Familial Cold Autoinflammatory Syndrome | TreatmentNon-steroidal anti-inflammatory drugs are often used to alleviate joint pain. High doses of corticosteroids have shown to be somewhat effective, but may cause short- and long-term side effects.Arcalyst (Rilonacept) by Regeneron Pharmaceuticals, an interleukin-1 blocker, was approved by the FDA in 2008 for the treatment of CAPS, including FCAS and MWS, in adults and children 12 and older.Ilaris (Canakinumab) by Novartis Pharmaceuticals, a monoclonal antibody to interleukin-1 beta,. was approved by the FDA in 2009 as a treatment for children and adults with CAPS, including FCAS and MWS.Kineret (Anakinra) by Biovitrum pharmaceuticals, an IL-1 receptor antagonist, has been used extensively in FCAS patients with excellent clinical results. However, it is not currently approved by the FDA for the treatment of FCAS or any of the CAPS diseases. | Therapies of Familial Cold Autoinflammatory Syndrome. TreatmentNon-steroidal anti-inflammatory drugs are often used to alleviate joint pain. High doses of corticosteroids have shown to be somewhat effective, but may cause short- and long-term side effects.Arcalyst (Rilonacept) by Regeneron Pharmaceuticals, an interleukin-1 blocker, was approved by the FDA in 2008 for the treatment of CAPS, including FCAS and MWS, in adults and children 12 and older.Ilaris (Canakinumab) by Novartis Pharmaceuticals, a monoclonal antibody to interleukin-1 beta,. was approved by the FDA in 2009 as a treatment for children and adults with CAPS, including FCAS and MWS.Kineret (Anakinra) by Biovitrum pharmaceuticals, an IL-1 receptor antagonist, has been used extensively in FCAS patients with excellent clinical results. However, it is not currently approved by the FDA for the treatment of FCAS or any of the CAPS diseases. | 441 | Familial Cold Autoinflammatory Syndrome |
nord_442_0 | Overview of Familial Encephalopathy with Neuroserpin Inclusion Bodies | Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a rare genetic degenerative disorder affecting the brain and spinal cord, or central nervous system (neurodegenerative disorder). Affected individuals display poor attention and concentration, declining work or academic performance, and language difficulties. Eventually, they experience a decline in their intellectual abilities (dementia). Memory, however, is relatively well-preserved early in the course of the disease compared to the severe memory deficits that are typical of Alzheimer's disease. Some affected individuals develop additional symptoms such as uncontrolled, irregular muscle contractions and seizures. Changes in mood, such as apathy, depression, or anger frequently occur. Eventually, affected individuals require comprehensive medical care. | Overview of Familial Encephalopathy with Neuroserpin Inclusion Bodies. Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a rare genetic degenerative disorder affecting the brain and spinal cord, or central nervous system (neurodegenerative disorder). Affected individuals display poor attention and concentration, declining work or academic performance, and language difficulties. Eventually, they experience a decline in their intellectual abilities (dementia). Memory, however, is relatively well-preserved early in the course of the disease compared to the severe memory deficits that are typical of Alzheimer's disease. Some affected individuals develop additional symptoms such as uncontrolled, irregular muscle contractions and seizures. Changes in mood, such as apathy, depression, or anger frequently occur. Eventually, affected individuals require comprehensive medical care. | 442 | Familial Encephalopathy with Neuroserpin Inclusion Bodies |
nord_442_1 | Symptoms of Familial Encephalopathy with Neuroserpin Inclusion Bodies | The age of onset, rate of progression, and severity of FENIB varies depending on the specific mutation in the neuroserpin gene. All individuals with a given mutation tend to become symptomatic at approximately the same age and to have similar clinical manifestations. The symptoms of FENIB may become apparent as early as the first decade or as late as the fifth or sixth decade of life. Our knowledge of FENIB is limited by the fact that only a few families with FENIB have been described.When FENIB begins in the fifth or sixth decade, affected individuals typically experience declining cognitive function that affects their ability to work, often resulting in job loss. In addition to deficits in attention, concentration, and language usage, they may develop an impaired ability to judge the spatial relationship between objects (poor visuospatial skills). A striking finding is perseveration, a condition marked by uncontrolled, repetitive behaviors such as continually repeating a word, phrase or gesture. Daily living skills are gradually lost and they become increasingly dependent on family or other care givers. Eventually, most will require comprehensive care in a skilled nursing facility. Other symptoms may include tremor, motor restlessness, dystonia (sustained muscle contractions associated with abnormal, uncontrolled movements and postures) and occasionally seizures. The rate of decline is relatively slow, and with adequate supportive care, patients may survive for many years or even decades.When FENIB begins earlier in life, from the first to third decade, there are additional neurological symptoms and the disease may progress quite rapidly. Seizures may be the first manifestation, including a syndrome called progressive myoclonic epilepsy (PME). The seizures may be difficult to control with medication, and episodes of status epilepticus, or persistent, repetitive seizures may occur, sometimes resulting in death. In general, an earlier age of onset is associated with more severe symptoms, and the patient may survive for only a few years. | Symptoms of Familial Encephalopathy with Neuroserpin Inclusion Bodies. The age of onset, rate of progression, and severity of FENIB varies depending on the specific mutation in the neuroserpin gene. All individuals with a given mutation tend to become symptomatic at approximately the same age and to have similar clinical manifestations. The symptoms of FENIB may become apparent as early as the first decade or as late as the fifth or sixth decade of life. Our knowledge of FENIB is limited by the fact that only a few families with FENIB have been described.When FENIB begins in the fifth or sixth decade, affected individuals typically experience declining cognitive function that affects their ability to work, often resulting in job loss. In addition to deficits in attention, concentration, and language usage, they may develop an impaired ability to judge the spatial relationship between objects (poor visuospatial skills). A striking finding is perseveration, a condition marked by uncontrolled, repetitive behaviors such as continually repeating a word, phrase or gesture. Daily living skills are gradually lost and they become increasingly dependent on family or other care givers. Eventually, most will require comprehensive care in a skilled nursing facility. Other symptoms may include tremor, motor restlessness, dystonia (sustained muscle contractions associated with abnormal, uncontrolled movements and postures) and occasionally seizures. The rate of decline is relatively slow, and with adequate supportive care, patients may survive for many years or even decades.When FENIB begins earlier in life, from the first to third decade, there are additional neurological symptoms and the disease may progress quite rapidly. Seizures may be the first manifestation, including a syndrome called progressive myoclonic epilepsy (PME). The seizures may be difficult to control with medication, and episodes of status epilepticus, or persistent, repetitive seizures may occur, sometimes resulting in death. In general, an earlier age of onset is associated with more severe symptoms, and the patient may survive for only a few years. | 442 | Familial Encephalopathy with Neuroserpin Inclusion Bodies |
nord_442_2 | Causes of Familial Encephalopathy with Neuroserpin Inclusion Bodies | FENIB is caused by changes (mutations) of the serine protease inhibitor 1 (SERPINI1) gene. The SERPINI1 gene contains instructions for creating (encoding) a protein known as neuroserpin. Neuroserpin is normally found in nerve cells and, although its exact function is not fully understood, it is believed to play a vital role in the development, repair, and maintenance of the central nervous system. In FENIB, mutant neuroserpin proteins link together (a process called polymerization) to form long chains that entangle and aggregate. Microscopically, these aggregates are observed as distinct inclusions called Collins bodies within the nerve cells. Collins bodies are believed to disrupt the normal functioning of affected nerve cells, eventually causing the symptoms of FENIB. As the disorder progresses, more Collins bodies are formed and a greater portion of the central nervous system is affected. The relationship between the accumulation and deposition of neuroserpin in the form of Collins bodies in individuals with FENIB and the subsequent development of characteristic symptoms is not fully understood. More research is necessary to determine exactly how Collins bodies may damage or injure nerve cells.FENIB is inherited in an autosomal dominant pattern. 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 percent for each pregnancy. The risk is the same for males and females. Most, if not all individuals who carry the mutant SERPINI1 gene will eventually become symptomatic (high penetrance). | Causes of Familial Encephalopathy with Neuroserpin Inclusion Bodies. FENIB is caused by changes (mutations) of the serine protease inhibitor 1 (SERPINI1) gene. The SERPINI1 gene contains instructions for creating (encoding) a protein known as neuroserpin. Neuroserpin is normally found in nerve cells and, although its exact function is not fully understood, it is believed to play a vital role in the development, repair, and maintenance of the central nervous system. In FENIB, mutant neuroserpin proteins link together (a process called polymerization) to form long chains that entangle and aggregate. Microscopically, these aggregates are observed as distinct inclusions called Collins bodies within the nerve cells. Collins bodies are believed to disrupt the normal functioning of affected nerve cells, eventually causing the symptoms of FENIB. As the disorder progresses, more Collins bodies are formed and a greater portion of the central nervous system is affected. The relationship between the accumulation and deposition of neuroserpin in the form of Collins bodies in individuals with FENIB and the subsequent development of characteristic symptoms is not fully understood. More research is necessary to determine exactly how Collins bodies may damage or injure nerve cells.FENIB is inherited in an autosomal dominant pattern. 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 percent for each pregnancy. The risk is the same for males and females. Most, if not all individuals who carry the mutant SERPINI1 gene will eventually become symptomatic (high penetrance). | 442 | Familial Encephalopathy with Neuroserpin Inclusion Bodies |
nord_442_3 | Affects of Familial Encephalopathy with Neuroserpin Inclusion Bodies | FENIB affects males and females in equal numbers. Only a few families with this disorder have been reported in the medical literature. FENIB was originally described in the medical literature in 1999. The incidence of FENIB in the general population is unknown. The age of onset of FENIB can be as early as the first decade or as late as the fifth or sixth. | Affects of Familial Encephalopathy with Neuroserpin Inclusion Bodies. FENIB affects males and females in equal numbers. Only a few families with this disorder have been reported in the medical literature. FENIB was originally described in the medical literature in 1999. The incidence of FENIB in the general population is unknown. The age of onset of FENIB can be as early as the first decade or as late as the fifth or sixth. | 442 | Familial Encephalopathy with Neuroserpin Inclusion Bodies |
nord_442_4 | Related disorders of Familial Encephalopathy with Neuroserpin Inclusion Bodies | Symptoms of the following disorders can be similar to those of FENIB. Comparisons may be useful for a differential diagnosis.Alzheimer disease is a progressive disorder of the brain affecting memory, thought and language. An abnormal protein fragment called beta amyloid accumulates in the brain and appears to entrap the processes of nerve cells that pass through it. These areas of degeneration are called “plaques.” Degenerative changes known as “neurofibrillary tangles” also occur in nerve cells of the brain’s cortex. Communication between nerve cells is disrupted and points of contact, or synapses between cells are gradually lost. The neurotransmitters that carry messages between cells are decreased, including one called acetylcholine. In less than five percent of affected individuals, Alzheimer disease is inherited in a dominant genetic pattern. Some, but not all researchers believe that the build up of beta amyloid in the brain is the fundamental cause of the disorder. Huntington disease is a genetic, progressive, neurodegenerative disorder characterized by the gradual development of involuntary muscle movements affecting the hands, feet, face, and trunk and progressive deterioration of cognitive processes and memory (dementia). Neurologic movement abnormalities may include uncontrolled, irregular, rapid, jerky movements (chorea) and athetosis, a condition characterized by relatively slow, writhing involuntary movements. Dementia is typically associated with progressive disorientation and confusion, personality disintegration, impairment of memory, restlessness, agitation, and other symptoms and findings. In individuals with the disorder, disease duration may range from approximately 10 years up to 25 years or more. Life-threatening complications may result from pneumonia or other infections, injuries related to falls, or other associated developments. Huntington’s disease is inherited in an autosomal dominant pattern. The disease results from mutations in the huntingtin gene. (For more information, choose “Huntington” as your search term in the Rare Disease Database.)Dementia may be associated with many other disorders that have symptoms similar to those of FENIB including a group of disorders characterized by dementia due to degeneration of the frontal and temporal lobes of the brain (frontotemporal degeneration). (For more information on these disorders, choose “FTD” as your search term in the Rare Disease Database.) | Related disorders of Familial Encephalopathy with Neuroserpin Inclusion Bodies. Symptoms of the following disorders can be similar to those of FENIB. Comparisons may be useful for a differential diagnosis.Alzheimer disease is a progressive disorder of the brain affecting memory, thought and language. An abnormal protein fragment called beta amyloid accumulates in the brain and appears to entrap the processes of nerve cells that pass through it. These areas of degeneration are called “plaques.” Degenerative changes known as “neurofibrillary tangles” also occur in nerve cells of the brain’s cortex. Communication between nerve cells is disrupted and points of contact, or synapses between cells are gradually lost. The neurotransmitters that carry messages between cells are decreased, including one called acetylcholine. In less than five percent of affected individuals, Alzheimer disease is inherited in a dominant genetic pattern. Some, but not all researchers believe that the build up of beta amyloid in the brain is the fundamental cause of the disorder. Huntington disease is a genetic, progressive, neurodegenerative disorder characterized by the gradual development of involuntary muscle movements affecting the hands, feet, face, and trunk and progressive deterioration of cognitive processes and memory (dementia). Neurologic movement abnormalities may include uncontrolled, irregular, rapid, jerky movements (chorea) and athetosis, a condition characterized by relatively slow, writhing involuntary movements. Dementia is typically associated with progressive disorientation and confusion, personality disintegration, impairment of memory, restlessness, agitation, and other symptoms and findings. In individuals with the disorder, disease duration may range from approximately 10 years up to 25 years or more. Life-threatening complications may result from pneumonia or other infections, injuries related to falls, or other associated developments. Huntington’s disease is inherited in an autosomal dominant pattern. The disease results from mutations in the huntingtin gene. (For more information, choose “Huntington” as your search term in the Rare Disease Database.)Dementia may be associated with many other disorders that have symptoms similar to those of FENIB including a group of disorders characterized by dementia due to degeneration of the frontal and temporal lobes of the brain (frontotemporal degeneration). (For more information on these disorders, choose “FTD” as your search term in the Rare Disease Database.) | 442 | Familial Encephalopathy with Neuroserpin Inclusion Bodies |
nord_442_5 | Diagnosis of Familial Encephalopathy with Neuroserpin Inclusion Bodies | A diagnosis of FENIB may be suspected based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic symptoms and a variety of specialized tests that can rule out other conditions. Such tests may include brain imaging studies such as magnetic resonance imaging (MRI), computed tomography (CT) scans, a test that measures the electrical activity of the brain (electroencephalogram [EEG]), and neuropsychological assessment. The diagnosis of FENIB is usually confirmed by a physician who specializes in the treatment of neurological disorders. The principal confirmatory test is genetic analysis to identify the causative mutation in the SERPINI1 gene or more rarely the identification of Collins bodies in a brain tissue biopsy specimen. | Diagnosis of Familial Encephalopathy with Neuroserpin Inclusion Bodies. A diagnosis of FENIB may be suspected based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic symptoms and a variety of specialized tests that can rule out other conditions. Such tests may include brain imaging studies such as magnetic resonance imaging (MRI), computed tomography (CT) scans, a test that measures the electrical activity of the brain (electroencephalogram [EEG]), and neuropsychological assessment. The diagnosis of FENIB is usually confirmed by a physician who specializes in the treatment of neurological disorders. The principal confirmatory test is genetic analysis to identify the causative mutation in the SERPINI1 gene or more rarely the identification of Collins bodies in a brain tissue biopsy specimen. | 442 | Familial Encephalopathy with Neuroserpin Inclusion Bodies |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.