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nord_157_1 | Symptoms of Beta Thalassemia | The symptoms and severity of beta thalassemia varies greatly from one person to another. Individuals with beta thalassemia minor do not develop symptoms of the disorder but may have a mild anemia. Many individuals with beta thalassemia minor go through life never knowing they carry an altered gene for the disorder.A beta thalassemia major diagnosis is usually made during the first two years of life and individuals require regular blood transfusions and lifelong medical care to survive. When the disorder develops later during life, a diagnosis of beta thalassemia intermedia is given; individuals may only require blood transfusions on rare, specific instances.BETA THALASSEMIA MAJOR
Beta thalassemia major, also known as Cooley’s anemia, is the most severe form of beta thalassemia. Affected infants exhibit symptoms within the first two years of life, often between 3 and 6 months after birth. The full or classic “description” of beta thalassemia major tends to primarily occur in developing countries. Most individuals will not develop the severe symptoms discussed below. Although beta thalassemia major is a chronic, lifelong illness, if individuals follow the current recommended treatments, most individuals can live happy, fulfilling lives.Severe anemia develops and is associated with fatigue, weakness, shortness of breath, dizziness, headaches, and yellowing of the skin, mucous membranes and whites of the eyes (jaundice). Affected infants often fail to grow and gain weight as expected based upon age and gender (failure to thrive). Some infants become progressively pale (pallor). Feeding problems, diarrhea, irritability or fussiness, recurrent fevers, abnormal enlargement of the liver (hepatomegaly), and the abnormal enlargement of the spleen (splenomegaly) may also occur.Splenomegaly may cause abdominal enlargement or swelling. Splenomegaly may be associated with an overactive spleen (hypersplenism), a condition that can develops because too many blood cells build up and are destroyed within the spleen. Hypersplenism can contribute to anemia in individuals with beta thalassemia and cause low levels of white blood cells, increasing the risk of infection, and low levels of platelets, which can lead to prolonged bleeding.If untreated, additional complications can develop. Beta thalassemia major can cause the bone marrow, the spongy material within certain bones, to expand. Bone marrow is where most of the blood cells are produced in the body. The bone marrow expands because it is trying to compensate for chronic anemia. This abnormal expansion causes bones to become thinner, wider and brittle. Affected bones may grow abnormally (bone deformities), particularly the long bones of the arms and legs and certain bones of the face. When facial bones are affected it can result in distinctive facial features including an abnormally prominent forehead (frontal bossing), full cheek bones (prominent malar eminence), a depressed bridge of the nose, and overgrowth (hypertrophy) of the upper jaw (maxillae), exposing the upper teeth. The affected bones have an increased fracture risk, particularly the long bones of the arms and legs. Some individuals may develop ‘knock knees’ (genu valgum), a condition in which the legs bend inward so that when a person is standing the knees will touch even if the ankles and feet are not.Even when treated, complications may develop, specifically the buildup of iron in the body (iron overload). Iron overload results from the blood transfusions required to treat individuals with beta thalassemia major. In addition, affected individuals experience greater iron absorption from the gastrointestinal tract, which contributes to iron overload (although this primarily occurs in untreated individuals). Iron overload can cause tissue damage and impaired function of affected organs such as the heart, liver and endocrine glands. Iron overload can damage the heart causing abnormal heart rhythms, inflammation of the membrane (pericardium) that lines the heart (pericarditis), enlargement of the heart and disease of the heart muscle (dilated cardiomyopathy). Heart involvement can progress to life-threatening complications such as heart failure. Liver involvement can cause scarring and inflammation of the liver (cirrhosis) and high pressure of the main liver vein (portal hypertension). Endocrine gland involvement can cause insufficiency of certain glands such as the thyroid (hypothyroidism) and, in rare cases, diabetes mellitus. Iron overload can also be associated with growth retardation and the failure or delay of sexual maturation.Additional symptoms that may occur include masses that form because of blood cell production outside of the bone marrow (extramedullary hematopoiesis). These masses primarily form in the spleen, liver, lymph nodes, chest, and spine and can potentially cause compression of nearby structures and a variety of symptoms. Affected individuals may develop leg ulcers, an increased risk of developing blood clots within a vein (venous thrombosis) and decreased bone mineralization resulting in brittle bones that are prone to fracture (osteoporosis).BETA THALASSEMIA INTERMEDIA
Individuals diagnosed with beta thalassemia intermedia have a widely varied expression of the disorder. Moderately severe anemia is common and affected individuals may require periodic blood transfusions. Each individual case is unique. Common symptoms include pallor, jaundice, leg ulcers, gallstones (cholelithiasis), and abnormal enlargement of the liver and spleen. Moderate to severe skeletal malformations (as described in beta thalassemia major) may also occur.DOMINANT BETA THALASSEMIA
Dominant beta thalassemia is an extremely rare form in which individuals who have one mutated HBB gene develop certain symptoms associated with beta thalassemia. Affected individuals may develop mild to moderate anemia, jaundice, and an abnormally enlarged spleen (splenomegaly). | Symptoms of Beta Thalassemia. The symptoms and severity of beta thalassemia varies greatly from one person to another. Individuals with beta thalassemia minor do not develop symptoms of the disorder but may have a mild anemia. Many individuals with beta thalassemia minor go through life never knowing they carry an altered gene for the disorder.A beta thalassemia major diagnosis is usually made during the first two years of life and individuals require regular blood transfusions and lifelong medical care to survive. When the disorder develops later during life, a diagnosis of beta thalassemia intermedia is given; individuals may only require blood transfusions on rare, specific instances.BETA THALASSEMIA MAJOR
Beta thalassemia major, also known as Cooley’s anemia, is the most severe form of beta thalassemia. Affected infants exhibit symptoms within the first two years of life, often between 3 and 6 months after birth. The full or classic “description” of beta thalassemia major tends to primarily occur in developing countries. Most individuals will not develop the severe symptoms discussed below. Although beta thalassemia major is a chronic, lifelong illness, if individuals follow the current recommended treatments, most individuals can live happy, fulfilling lives.Severe anemia develops and is associated with fatigue, weakness, shortness of breath, dizziness, headaches, and yellowing of the skin, mucous membranes and whites of the eyes (jaundice). Affected infants often fail to grow and gain weight as expected based upon age and gender (failure to thrive). Some infants become progressively pale (pallor). Feeding problems, diarrhea, irritability or fussiness, recurrent fevers, abnormal enlargement of the liver (hepatomegaly), and the abnormal enlargement of the spleen (splenomegaly) may also occur.Splenomegaly may cause abdominal enlargement or swelling. Splenomegaly may be associated with an overactive spleen (hypersplenism), a condition that can develops because too many blood cells build up and are destroyed within the spleen. Hypersplenism can contribute to anemia in individuals with beta thalassemia and cause low levels of white blood cells, increasing the risk of infection, and low levels of platelets, which can lead to prolonged bleeding.If untreated, additional complications can develop. Beta thalassemia major can cause the bone marrow, the spongy material within certain bones, to expand. Bone marrow is where most of the blood cells are produced in the body. The bone marrow expands because it is trying to compensate for chronic anemia. This abnormal expansion causes bones to become thinner, wider and brittle. Affected bones may grow abnormally (bone deformities), particularly the long bones of the arms and legs and certain bones of the face. When facial bones are affected it can result in distinctive facial features including an abnormally prominent forehead (frontal bossing), full cheek bones (prominent malar eminence), a depressed bridge of the nose, and overgrowth (hypertrophy) of the upper jaw (maxillae), exposing the upper teeth. The affected bones have an increased fracture risk, particularly the long bones of the arms and legs. Some individuals may develop ‘knock knees’ (genu valgum), a condition in which the legs bend inward so that when a person is standing the knees will touch even if the ankles and feet are not.Even when treated, complications may develop, specifically the buildup of iron in the body (iron overload). Iron overload results from the blood transfusions required to treat individuals with beta thalassemia major. In addition, affected individuals experience greater iron absorption from the gastrointestinal tract, which contributes to iron overload (although this primarily occurs in untreated individuals). Iron overload can cause tissue damage and impaired function of affected organs such as the heart, liver and endocrine glands. Iron overload can damage the heart causing abnormal heart rhythms, inflammation of the membrane (pericardium) that lines the heart (pericarditis), enlargement of the heart and disease of the heart muscle (dilated cardiomyopathy). Heart involvement can progress to life-threatening complications such as heart failure. Liver involvement can cause scarring and inflammation of the liver (cirrhosis) and high pressure of the main liver vein (portal hypertension). Endocrine gland involvement can cause insufficiency of certain glands such as the thyroid (hypothyroidism) and, in rare cases, diabetes mellitus. Iron overload can also be associated with growth retardation and the failure or delay of sexual maturation.Additional symptoms that may occur include masses that form because of blood cell production outside of the bone marrow (extramedullary hematopoiesis). These masses primarily form in the spleen, liver, lymph nodes, chest, and spine and can potentially cause compression of nearby structures and a variety of symptoms. Affected individuals may develop leg ulcers, an increased risk of developing blood clots within a vein (venous thrombosis) and decreased bone mineralization resulting in brittle bones that are prone to fracture (osteoporosis).BETA THALASSEMIA INTERMEDIA
Individuals diagnosed with beta thalassemia intermedia have a widely varied expression of the disorder. Moderately severe anemia is common and affected individuals may require periodic blood transfusions. Each individual case is unique. Common symptoms include pallor, jaundice, leg ulcers, gallstones (cholelithiasis), and abnormal enlargement of the liver and spleen. Moderate to severe skeletal malformations (as described in beta thalassemia major) may also occur.DOMINANT BETA THALASSEMIA
Dominant beta thalassemia is an extremely rare form in which individuals who have one mutated HBB gene develop certain symptoms associated with beta thalassemia. Affected individuals may develop mild to moderate anemia, jaundice, and an abnormally enlarged spleen (splenomegaly). | 157 | Beta Thalassemia |
nord_157_2 | Causes of Beta Thalassemia | Most beta thalassemia cases are caused by a mutation in the HBB gene. In extremely rare cases, a loss of genetic material (deletion) that includes the HBB gene causes the disorder. Genes provide instructions for creating proteins that play a critical role in many body functions. When a gene mutation occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body. Individuals with beta thalassemia minor have a mutation in one HBB gene and are carriers for the disorder. Individuals with beta thalassemia intermedia or major have mutations in both HBB genes. Normal hemoglobin is made up of specialized proteins called globins, specifically two alpha chains and two beta chain proteins attached to a central heme ring. The HBB gene creates (encodes) beta globin protein chains. A mutation in one HBB gene results in either reduced or no production of beta chains from that gene. Regardless, the second (unaffected) copy of the HBB gene functions normally and produces enough beta chain protein to avoid symptoms, although red blood cells are still abnormally small and mild anemia can still develop. A mutation in two HBB genes results in either significantly reduced levels of beta chains (beta thalassemia intermedia) or an almost complete lack of beta chains (beta thalassemia major). The reduction or lack of beta globin protein chains leads to an imbalance with the normally-produced alpha globin protein chains and, ultimately, the defective formation of red blood cells, a lack of functional hemoglobin, and the failure to deliver sufficient amounts of oxygen to the body.In individuals with dominant beta thalassemia, the mutated HBB gene creates (synthesizes) an extremely unstable type of hemoglobin. Affected individuals have ineffective red blood cell formation (erythropoiesis).Researchers believe that additional factors influence the severity of beta thalassemia major and intermedia including modifier genes. Modifier genes, unlike the gene that causes beta thalassemia, affect the clinical severity of the disorder. More research is necessary to discover the various modifier genes associated with beta thalassemia and their role in the development of the disorder.Beta thalassemia is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits an abnormal gene from each parent. If an individual receives one normal gene and one abnormal gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the abnormal gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. | Causes of Beta Thalassemia. Most beta thalassemia cases are caused by a mutation in the HBB gene. In extremely rare cases, a loss of genetic material (deletion) that includes the HBB gene causes the disorder. Genes provide instructions for creating proteins that play a critical role in many body functions. When a gene mutation occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body. Individuals with beta thalassemia minor have a mutation in one HBB gene and are carriers for the disorder. Individuals with beta thalassemia intermedia or major have mutations in both HBB genes. Normal hemoglobin is made up of specialized proteins called globins, specifically two alpha chains and two beta chain proteins attached to a central heme ring. The HBB gene creates (encodes) beta globin protein chains. A mutation in one HBB gene results in either reduced or no production of beta chains from that gene. Regardless, the second (unaffected) copy of the HBB gene functions normally and produces enough beta chain protein to avoid symptoms, although red blood cells are still abnormally small and mild anemia can still develop. A mutation in two HBB genes results in either significantly reduced levels of beta chains (beta thalassemia intermedia) or an almost complete lack of beta chains (beta thalassemia major). The reduction or lack of beta globin protein chains leads to an imbalance with the normally-produced alpha globin protein chains and, ultimately, the defective formation of red blood cells, a lack of functional hemoglobin, and the failure to deliver sufficient amounts of oxygen to the body.In individuals with dominant beta thalassemia, the mutated HBB gene creates (synthesizes) an extremely unstable type of hemoglobin. Affected individuals have ineffective red blood cell formation (erythropoiesis).Researchers believe that additional factors influence the severity of beta thalassemia major and intermedia including modifier genes. Modifier genes, unlike the gene that causes beta thalassemia, affect the clinical severity of the disorder. More research is necessary to discover the various modifier genes associated with beta thalassemia and their role in the development of the disorder.Beta thalassemia is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits an abnormal gene from each parent. If an individual receives one normal gene and one abnormal gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the abnormal gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. | 157 | Beta Thalassemia |
nord_157_3 | Affects of Beta Thalassemia | Beta thalassemia is relatively rare in the United States, but is one of the most common autosomal recessive disorders in the world. The incidence of symptomatic cases is estimated to be approximately 1 in 100,000 individuals in the general population. The disorder is particularly prevalent in the Mediterranean, Middle East, Africa, central Asia, the Indian subcontinent, and the Far East. Individuals in other parts of the world whose families are from these regions carry a greater risk of having beta thalassemia. | Affects of Beta Thalassemia. Beta thalassemia is relatively rare in the United States, but is one of the most common autosomal recessive disorders in the world. The incidence of symptomatic cases is estimated to be approximately 1 in 100,000 individuals in the general population. The disorder is particularly prevalent in the Mediterranean, Middle East, Africa, central Asia, the Indian subcontinent, and the Far East. Individuals in other parts of the world whose families are from these regions carry a greater risk of having beta thalassemia. | 157 | Beta Thalassemia |
nord_157_4 | Related disorders of Beta Thalassemia | Symptoms of the following disorders can be similar to those of beta thalassemia. Comparisons may be useful for a differential diagnosis.Various conditions have signs and symptoms similar to those seen in beta thalassemia. Such conditions include sideroblastic anemias and congenital dyserythropoietic anemias. Certain disorders have elevated levels of fetal hemoglobin such as juvenile myelomonocytic leukemia and aplastic anemia. Beta thalassemia can also occur along with other features as part of a larger syndrome such as in X-linked thrombocytopenia with thalassemia or beta thalassemia-trichothiodystrophy. Beta thalassemia may also occur along with another disorder in which there is an abnormality in the structure of hemoglobin (hemoglobinopathy). This includes hemoglobin E (HbE/beta thalassemia), hemoglobin C (HbC/beta thalassemia), and hemoglobin S (HbS/beta thalassemia); a condition that resembles sickle cell anemia and is sometimes referred to as sickle beta thalassemia disease. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | Related disorders of Beta Thalassemia. Symptoms of the following disorders can be similar to those of beta thalassemia. Comparisons may be useful for a differential diagnosis.Various conditions have signs and symptoms similar to those seen in beta thalassemia. Such conditions include sideroblastic anemias and congenital dyserythropoietic anemias. Certain disorders have elevated levels of fetal hemoglobin such as juvenile myelomonocytic leukemia and aplastic anemia. Beta thalassemia can also occur along with other features as part of a larger syndrome such as in X-linked thrombocytopenia with thalassemia or beta thalassemia-trichothiodystrophy. Beta thalassemia may also occur along with another disorder in which there is an abnormality in the structure of hemoglobin (hemoglobinopathy). This includes hemoglobin E (HbE/beta thalassemia), hemoglobin C (HbC/beta thalassemia), and hemoglobin S (HbS/beta thalassemia); a condition that resembles sickle cell anemia and is sometimes referred to as sickle beta thalassemia disease. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | 157 | Beta Thalassemia |
nord_157_5 | Diagnosis of Beta Thalassemia | A diagnosis of beta thalassemia is based upon identification of characteristic symptoms, a clinical evaluation and a variety of specialized tests. With beta thalassemia major, initial symptoms often become apparent during the first two years of life and include failure to thrive, a swollen abdomen and symptoms of anemia. Beta thalassemia intermedia may be suspected in individuals who present with similar (yet milder) symptoms, but at a later age.In many states in the U.S., infants are diagnosed with a hemoglobin disorder through newborn screening. Newborn screening is a public health program that tests newborn infants for a variety of disorders that are treatable, but not readily apparent at birth. Each state’s newborn screening program (and the specific disorders tested for) is different. Clinical Testing and Workup
Individuals suspected of having beta thalassemia will undergo blood tests such as a complete blood count (CBC). A CBC measures several components and aspects of blood including the number, concentration, size, shape and maturity of blood cells. A specialized blood test known as hemoglobin electrophoresis measures the different types of hemoglobin found in blood.A CBC is done to measure the amount of hemoglobin and the number and the size and shape of red blood cells, which are fewer in number and smaller in size than in normal individuals. Red blood cells may also be pale in color (hypochromic) and of varying shapes (poikilocytosis). The distribution of hemoglobin in red blood cells in individuals with beta thalassemia is uneven, giving the cells a distinctive target appearance when viewed under a microscope. A blood sample can be tested to measure the amount of iron in the blood (ferritin), which is often elevated in individuals with beta thalassemia.Molecular genetic testing can confirm a beta thalassemia diagnosis. Molecular genetic testing can detect mutations in the HBB gene known to cause the disorder but is available only as a diagnostic service at specialized laboratories. Molecular genetic testing is not necessary to make a diagnosis of beta thalassemia and is generally used to identify at-risk, asymptomatic relatives, to aid prenatal diagnosis and to attempt to predict the progression or severity of the disease in specific cases. | Diagnosis of Beta Thalassemia. A diagnosis of beta thalassemia is based upon identification of characteristic symptoms, a clinical evaluation and a variety of specialized tests. With beta thalassemia major, initial symptoms often become apparent during the first two years of life and include failure to thrive, a swollen abdomen and symptoms of anemia. Beta thalassemia intermedia may be suspected in individuals who present with similar (yet milder) symptoms, but at a later age.In many states in the U.S., infants are diagnosed with a hemoglobin disorder through newborn screening. Newborn screening is a public health program that tests newborn infants for a variety of disorders that are treatable, but not readily apparent at birth. Each state’s newborn screening program (and the specific disorders tested for) is different. Clinical Testing and Workup
Individuals suspected of having beta thalassemia will undergo blood tests such as a complete blood count (CBC). A CBC measures several components and aspects of blood including the number, concentration, size, shape and maturity of blood cells. A specialized blood test known as hemoglobin electrophoresis measures the different types of hemoglobin found in blood.A CBC is done to measure the amount of hemoglobin and the number and the size and shape of red blood cells, which are fewer in number and smaller in size than in normal individuals. Red blood cells may also be pale in color (hypochromic) and of varying shapes (poikilocytosis). The distribution of hemoglobin in red blood cells in individuals with beta thalassemia is uneven, giving the cells a distinctive target appearance when viewed under a microscope. A blood sample can be tested to measure the amount of iron in the blood (ferritin), which is often elevated in individuals with beta thalassemia.Molecular genetic testing can confirm a beta thalassemia diagnosis. Molecular genetic testing can detect mutations in the HBB gene known to cause the disorder but is available only as a diagnostic service at specialized laboratories. Molecular genetic testing is not necessary to make a diagnosis of beta thalassemia and is generally used to identify at-risk, asymptomatic relatives, to aid prenatal diagnosis and to attempt to predict the progression or severity of the disease in specific cases. | 157 | Beta Thalassemia |
nord_157_6 | Therapies of Beta Thalassemia | Treatment
Individuals with beta thalassemia major and intermedia will benefit from referral to a thalassemia treatment center. These specialized centers provide comprehensive care for individuals with beta thalassemia including the development of specific treatment plans, monitoring and follow up of affected individuals, and state-of-the-art medical care. Treatment at such a center ensures that individuals and their family members will be cared for by a professional healthcare team (physicians, nurses, physical therapists, social workers and genetic counselors) experienced in the treatment of individuals with beta thalassemia. Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as the specific type of beta thalassemia; the progression of the disease; the presence or absence of certain symptoms; severity of the disease upon diagnosis; an individual’s age and general health; and/or other factors. Decisions concerning the use of a particular drug regimen and/or other treatments should be made by physicians and other members of the health care team in 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.Individuals with beta thalassemia minor usually do not develop symptoms and do not require treatment. It is important that individuals with beta thalassemia minor be correctly diagnosed, however, in order to avoid unnecessary treatments for similarly appearing conditions such as iron deficiency anemia. These individuals should not routinely take iron supplements.Individuals with beta thalassemia major require regular blood transfusions. A blood transfusion is a common procedure in which affected individuals receive donated blood to restore the levels of healthy, functioning hemoglobin to their blood. During this procedure, donated blood is delivered to the body through a small, plastic tube inserted into a blood vessel (intravenously). The procedure may take anywhere from 1-4 hours. Individuals with beta thalassemia major require regular blood transfusions, as frequently as every 2-4 weeks in severe cases. Individuals with beta thalassemia intermedia occasionally require blood transfusions such as when suffering from an illness or infection or when planning to undergo surgery.In 2019, the U.S. Food and Drug Administration (FDA) approved Reblozyl (luspatercept-aamt) for the treatment of anemia in adult patients with beta thalassemia who require regular red blood cell transfusions. The medication reduces the need for regular blood transfusions but does not cure the condition.Some individuals may be treated by the surgical removal of the spleen (splenectomy). An abnormally enlarged spleen (splenomegaly) can cause severe pain and contribute to anemia. Splenomegaly can cause low levels of the blood cells (platelets) that allow the blood to clot. An enlarged spleen in individuals with beta thalassemia may occur due to increased destruction of red blood cells, the formation of blood cells outside of the bone marrow (extramedullary hematopoiesis), repeated blood transfusions, or iron overload. If other forms of therapy fail, removal of the spleen may be considered. Splenectomy has led to improvement in certain symptoms associated with beta thalassemia. However, this surgical procedure carries risks, which are weighed against benefits in each individual case. Because of advances in the treatment of beta thalassemia in the past several years, splenectomy is rarely necessary as a treatment for affected individuals.Individuals with beta thalassemia major and intermedia may develop iron overload, which occurs because of two reasons. First, blood transfusions cause the accumulation of excess iron in the body. Second, beta thalassemia can cause increased absorption of dietary iron by the gastrointestinal tract. The body has no normal way to remove excess iron. In individuals who receive regular blood transfusions, iron overload primarily occurs because of treatment. Iron overload causes a variety of symptoms affecting various body organ systems. Iron overload is treated by medications that remove excess iron from the body such as Ferriprox (deferiprone) and Exjade (deferasirox).Treatment of additional complications of beta thalassemia or iron overload is symptomatic and supportive. Special attention is recommended for the early diagnosis and prompt treatment of heart (cardiac) disease potentially associated with iron overload. Cardiac disease is the main life-threatening complication in individuals with beta thalassemia. | Therapies of Beta Thalassemia. Treatment
Individuals with beta thalassemia major and intermedia will benefit from referral to a thalassemia treatment center. These specialized centers provide comprehensive care for individuals with beta thalassemia including the development of specific treatment plans, monitoring and follow up of affected individuals, and state-of-the-art medical care. Treatment at such a center ensures that individuals and their family members will be cared for by a professional healthcare team (physicians, nurses, physical therapists, social workers and genetic counselors) experienced in the treatment of individuals with beta thalassemia. Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as the specific type of beta thalassemia; the progression of the disease; the presence or absence of certain symptoms; severity of the disease upon diagnosis; an individual’s age and general health; and/or other factors. Decisions concerning the use of a particular drug regimen and/or other treatments should be made by physicians and other members of the health care team in 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.Individuals with beta thalassemia minor usually do not develop symptoms and do not require treatment. It is important that individuals with beta thalassemia minor be correctly diagnosed, however, in order to avoid unnecessary treatments for similarly appearing conditions such as iron deficiency anemia. These individuals should not routinely take iron supplements.Individuals with beta thalassemia major require regular blood transfusions. A blood transfusion is a common procedure in which affected individuals receive donated blood to restore the levels of healthy, functioning hemoglobin to their blood. During this procedure, donated blood is delivered to the body through a small, plastic tube inserted into a blood vessel (intravenously). The procedure may take anywhere from 1-4 hours. Individuals with beta thalassemia major require regular blood transfusions, as frequently as every 2-4 weeks in severe cases. Individuals with beta thalassemia intermedia occasionally require blood transfusions such as when suffering from an illness or infection or when planning to undergo surgery.In 2019, the U.S. Food and Drug Administration (FDA) approved Reblozyl (luspatercept-aamt) for the treatment of anemia in adult patients with beta thalassemia who require regular red blood cell transfusions. The medication reduces the need for regular blood transfusions but does not cure the condition.Some individuals may be treated by the surgical removal of the spleen (splenectomy). An abnormally enlarged spleen (splenomegaly) can cause severe pain and contribute to anemia. Splenomegaly can cause low levels of the blood cells (platelets) that allow the blood to clot. An enlarged spleen in individuals with beta thalassemia may occur due to increased destruction of red blood cells, the formation of blood cells outside of the bone marrow (extramedullary hematopoiesis), repeated blood transfusions, or iron overload. If other forms of therapy fail, removal of the spleen may be considered. Splenectomy has led to improvement in certain symptoms associated with beta thalassemia. However, this surgical procedure carries risks, which are weighed against benefits in each individual case. Because of advances in the treatment of beta thalassemia in the past several years, splenectomy is rarely necessary as a treatment for affected individuals.Individuals with beta thalassemia major and intermedia may develop iron overload, which occurs because of two reasons. First, blood transfusions cause the accumulation of excess iron in the body. Second, beta thalassemia can cause increased absorption of dietary iron by the gastrointestinal tract. The body has no normal way to remove excess iron. In individuals who receive regular blood transfusions, iron overload primarily occurs because of treatment. Iron overload causes a variety of symptoms affecting various body organ systems. Iron overload is treated by medications that remove excess iron from the body such as Ferriprox (deferiprone) and Exjade (deferasirox).Treatment of additional complications of beta thalassemia or iron overload is symptomatic and supportive. Special attention is recommended for the early diagnosis and prompt treatment of heart (cardiac) disease potentially associated with iron overload. Cardiac disease is the main life-threatening complication in individuals with beta thalassemia. | 157 | Beta Thalassemia |
nord_158_0 | Overview of Bile Acid Synthesis Disorders | SummaryBile acid synthesis disorders (BASDs) are a group of rare metabolic disorders characterized by defects in the creation (synthesis) of bile acids. Bile acids are chemical compounds found in the liver that have several roles in the body including promoting the flow and excretion of bile and assisting in the intestinal absorption of fat and fat-soluble vitamins. Bile acids are formed from cholesterol and, therefore, bile acid synthesis serves as the main pathway in breaking down and eliminating cholesterol from the body (cholesterol degradation). The failure to produce normal or functional bile acids results in the accumulation of abnormal bile acids and other substances that normally would be broken down (intermediary metabolites) within the body. The resulting accumulation of abnormal bile acids, intermediary metabolites and cholesterol in the body can damage certain organ systems. The main symptom of most (but not all) BASDs is interruption or suppression of the flow of bile from the liver (cholestasis) and fat-soluble vitamin malabsorption. Additional symptoms such as progressive neurological disease may develop in certain cases and can occur in the absence of liver disease. In many cases, symptoms or signs are present at birth or during the newborn period. If untreated, the more severe forms of these disorders can eventually progress to cause life-threatening complications such as scarring of the liver (cirrhosis) and liver failure. Many of these disorders can be successfully treated by replacing the missing bile acids (bile acid replacement therapy). BASDs are caused by mutations in specific genes; most of these mutations are inherited in an autosomal recessive pattern.IntroductionDisorders of bile acid synthesis can be broadly classified as primary or secondary. Primary BASDs involve congenital deficiencies in enzymes required for bringing about chemical reactions (catalyzing) necessary to synthesize the two main bile acids known as cholic acid and chenodeoxycholic acid. Secondary disorders include disorders that are involved in the transport of bile acids such as low gamma-GT familial intrahepatic cholestasis and MDR3 deficiency (known collectively as primary familial intrahepatic cholestasis), Smith-Lemli-Optiz syndrome, which impairs the supply of cholesterol in the body, and Zellweger spectrum disorders, which are classified as peroxisomal disorders, but are involved in bile acid synthesis as well. This report only covers certain primary bile acid synthesis disorders. NORD has individual reports on the secondary types. For more information, choose the specific disorder name as your search term in the Rare Disease Database. | Overview of Bile Acid Synthesis Disorders. SummaryBile acid synthesis disorders (BASDs) are a group of rare metabolic disorders characterized by defects in the creation (synthesis) of bile acids. Bile acids are chemical compounds found in the liver that have several roles in the body including promoting the flow and excretion of bile and assisting in the intestinal absorption of fat and fat-soluble vitamins. Bile acids are formed from cholesterol and, therefore, bile acid synthesis serves as the main pathway in breaking down and eliminating cholesterol from the body (cholesterol degradation). The failure to produce normal or functional bile acids results in the accumulation of abnormal bile acids and other substances that normally would be broken down (intermediary metabolites) within the body. The resulting accumulation of abnormal bile acids, intermediary metabolites and cholesterol in the body can damage certain organ systems. The main symptom of most (but not all) BASDs is interruption or suppression of the flow of bile from the liver (cholestasis) and fat-soluble vitamin malabsorption. Additional symptoms such as progressive neurological disease may develop in certain cases and can occur in the absence of liver disease. In many cases, symptoms or signs are present at birth or during the newborn period. If untreated, the more severe forms of these disorders can eventually progress to cause life-threatening complications such as scarring of the liver (cirrhosis) and liver failure. Many of these disorders can be successfully treated by replacing the missing bile acids (bile acid replacement therapy). BASDs are caused by mutations in specific genes; most of these mutations are inherited in an autosomal recessive pattern.IntroductionDisorders of bile acid synthesis can be broadly classified as primary or secondary. Primary BASDs involve congenital deficiencies in enzymes required for bringing about chemical reactions (catalyzing) necessary to synthesize the two main bile acids known as cholic acid and chenodeoxycholic acid. Secondary disorders include disorders that are involved in the transport of bile acids such as low gamma-GT familial intrahepatic cholestasis and MDR3 deficiency (known collectively as primary familial intrahepatic cholestasis), Smith-Lemli-Optiz syndrome, which impairs the supply of cholesterol in the body, and Zellweger spectrum disorders, which are classified as peroxisomal disorders, but are involved in bile acid synthesis as well. This report only covers certain primary bile acid synthesis disorders. NORD has individual reports on the secondary types. For more information, choose the specific disorder name as your search term in the Rare Disease Database. | 158 | Bile Acid Synthesis Disorders |
nord_158_1 | Symptoms of Bile Acid Synthesis Disorders | Although researchers have been able to establish clear syndromes with characteristic or “core” symptoms, much about bile acid synthesis disorders is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of other genes influencing these disorders prevent physicians from developing a complete picture of associated symptoms and prognosis. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below. Parents should talk to their children’s physician and medical team about their specific case, associated symptoms and overall prognosis.The age of onset, specific symptoms, and rate of progression can vary greatly from one individual to another depending, in part, on the specific underlying defect. Although BASDs are usually detected in newborns or infants, milder forms of these disorders with later onset exist including cases with onset during adulthood.Cholestasis in these disorders is intrahepatic, which means it occurs due to defects in the bile ducts within the liver rather than in the bile ducts outside the liver (extrahepatic). Features of cholestasis may include yellowing of the skin, mucous membranes and whites of the eyes (jaundice), failure to thrive, and growth deficiency. Enlargement of the liver (hepatomegaly) and/or spleen (splenomegaly) may also occur. Persistent, severe itchiness (pruritus) is common to other disorders that cause cholestasis, but rarely occurs in individuals with BASDs. Affected individuals may also exhibit diarrhea, excess fats in the stools (steatorrhea), and pale or clay-colored stools due to the suppression of bile flow (acholic stools).Some of the symptoms of cholestasis result from impairment of the digestive system to properly absorb fat, fat-soluble vitamins, and other nutrients (malabsorption). Malabsorption leads to vitamin deficiency and can result is various symptoms including rickets, a condition marked by softened, weakened bones (vitamin D deficiency), vision problems (vitamin A deficiency), poor coordination and development delays (vitamin E deficiency), and blood clotting problems leading to easy bleeding and bruising (vitamin K deficiency).In some cases, progressive neurological disease has been described that develops later during childhood or during adulthood. Vitamin E deficiency from undiagnosed liver disease may contribute to neurological disease. In other cases, the cause of neurological disease may be different. For example, in CTX neurological disease results from the accumulation or storage of cholesterol-like, fatty substances in nerve cells and the brain.In some cases, without treatment liver abnormalities can progress to cause serious life-threatening complications such as the formation of fibrous, scar tissue (fibrosis) and liver regeneration with scarring (cirrhosis), high blood pressure of the main vein of the liver (portal hypertension), and abnormal fluid retention and swelling in the abdomen (ascites). Eventually, liver disease can progress to cause liver failure.3-BETA-HYDROXY-DELTA-5-C27-STEROID OXIDOREDUCTASE DEFICIENCY
This disorder is sometimes referred to as 3HSD deficiency or bile acid synthesis defect 1. It is believed to be the most common form of BASDs. The clinical picture of this disorder can vary greatly. Generally, affected individuals will develop cholestasis and fat-soluble vitamin malabsorption (and various abnormalities secondary to vitamin deficiency) during infancy. If untreated, progressive liver disease occurs.In recent years, cases of idiopathic cholestasis that develop during adulthood (late onset liver disease) have been attributed to 3beta-dehydrogenase deficiency. Some of these individuals presented with jaundice during infancy, but improved and were not diagnosed with 3beta-dehydrogenase deficiency until later during life.DELTA4 3-OXOSTEROID 5BETA REDUCTASE DEFICIENCY
This disorder is sometimes referred to as 5beta-reductase deficiency or bile acid synthesis defect 2. The clinical picture of this disorder is similar to that of 3beta-dehyddrogenase deficiency, but generally is more severe and, if untreated, can rapidly progress to cirrhosis and liver failure. 5beta-reductase deficiency can present as neonatal cholestasis or as liver failure that resembles liver disease seen in neonatal hemochromatosis (for more information, choose “neonatal hemochromatosis” as your search term in the Rare Disease Database.)OXYSTEROL 7-ALPHA-HYDROXYLASE DEFICIENCY
This disorder is sometimes referred to as bile acid synthesis defect 3. Only a few cases have been reported in the medical literature. Affected infants have exhibited severe neonatal cholestasis, disease affecting the blood’s ability to clot (coagulopathy), hepatosplenomegaly, and, if untreated, cirrhosis and liver failure early in life. Researchers speculate that due to the severity most cases of this disorder prove fatal before birth or shortly after birth.ALPHA-METHYLACYL-COA RACEMASE (AMACR) DEFICIENCY
This disorder is sometimes referred to as 2-methylacyl-CoA racemase deficiency or bile acid synthesis defect 4. The disorder was first reported in three adults presenting with sensory motor neuropathy, a condition in which there is disease of the peripheral nerves (those outside the central nervous system) that control response to pain and temperature and muscle coordination. Sensory motor neuropathy may cause abnormal sensations such as numbness or a feeling of pins and needles in the arms and legs, weakness of the muscles, and problems with balance and coordination. Adults with this disorder may lack symptoms (asymptomatic) until sensory motor neuropathy develops or they may have mild liver disease during childhood. It is not known if asymptomatic adults who develop neurological disease had mild, undiagnosed liver disease that led to fat-soluble vitamin deficiency that eventually caused the neurological findings. This disorder has also been reported in infants who present with severe fat and fat-soluble vitamin deficiencies and mild cholestasis. Fewer than 10 cases have been reported in the medical literature.STEROL 27-HYDROXYLASE DEFICIENCY (CEREBROTENDINOUS XANTHOMATOSIS)
This disorder is also known as cerebrotendinous xanthomatosis (CTX). CTX is highly variable and is associated with a wide range of potential abnormalities. Originally, the disorder was believed only to be a neurological disorder of abnormal fat (lipid) storage not associated with liver disease. It is now know that CTX can present in childhood with cholestatic liver disease that can be severe or can be mild and resolve on its own in individuals who may later develop other complications of the disorder such as neurological disease. Patients with CTX not infrequently also have diarrhea.In CTX, cholestanol deposits accumulate in nerve cells and membranes, causing damage to the brain, spinal cord, tendons, lens of the eyes and arteries. Affected individuals may develop cataracts during childhood and benign, fatty tumors (xanthomas) of the tendons during adolescence. If untreated, progressive neurological problems develop in adulthood potentially causing paralysis, ataxia, and dementia. Coronary heart disease is also common. Many individuals with the adult symptoms of CTX experienced prolonged cholestatic jaundice during infancy.NORD has an individual report on CTX. For more information, choose “cerebrotendinous xanthomatosis” as your search term in the Rare Disease Database.TRIHYDROXYCHOLESTANIC ACID (THCA) COA OXIDASE DEFICIENCY
This form has been reported in several individuals and is characterized primarily by neurological findings including ataxia, which often became apparent by 3 and half years of age. Liver disease has not been described in this form of BSAD.AMIDATION DEFECTS
The final step in bile acid synthesis involves the joining together (conjugation) of two amino acids, glycine and taurine. Disorders involving this step are known as “defective bile acid amidation due to failure to conjugate with glycine and/or taurine” or more simply amidation defects. Two disorders in this subcategory have been identified.Bile Acid CoA Ligase Deficiency
This disorder is characterized by neonatal cholestasis, fat and fat-soluble vitamin malabsorption and growth failure. Fewer than 10 cases have been reported in the medical literature.Amino Acid N-Acyltransferase Deficiency
This disorder was initially described in several individuals within a large Amish kindred. Affected individuals developed pruritus, variable growth deficiency, and fat malabsorption (familial hypercholanemia). More recently a report has appeared that included description of 10 affected patients with only one from an Amish kindred. The presentation was quite varied in this case series with one family member having liver failure in infancy; however, most patients presented with poor growth and fat soluble vitamin deficiencies. | Symptoms of Bile Acid Synthesis Disorders. Although researchers have been able to establish clear syndromes with characteristic or “core” symptoms, much about bile acid synthesis disorders is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of other genes influencing these disorders prevent physicians from developing a complete picture of associated symptoms and prognosis. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below. Parents should talk to their children’s physician and medical team about their specific case, associated symptoms and overall prognosis.The age of onset, specific symptoms, and rate of progression can vary greatly from one individual to another depending, in part, on the specific underlying defect. Although BASDs are usually detected in newborns or infants, milder forms of these disorders with later onset exist including cases with onset during adulthood.Cholestasis in these disorders is intrahepatic, which means it occurs due to defects in the bile ducts within the liver rather than in the bile ducts outside the liver (extrahepatic). Features of cholestasis may include yellowing of the skin, mucous membranes and whites of the eyes (jaundice), failure to thrive, and growth deficiency. Enlargement of the liver (hepatomegaly) and/or spleen (splenomegaly) may also occur. Persistent, severe itchiness (pruritus) is common to other disorders that cause cholestasis, but rarely occurs in individuals with BASDs. Affected individuals may also exhibit diarrhea, excess fats in the stools (steatorrhea), and pale or clay-colored stools due to the suppression of bile flow (acholic stools).Some of the symptoms of cholestasis result from impairment of the digestive system to properly absorb fat, fat-soluble vitamins, and other nutrients (malabsorption). Malabsorption leads to vitamin deficiency and can result is various symptoms including rickets, a condition marked by softened, weakened bones (vitamin D deficiency), vision problems (vitamin A deficiency), poor coordination and development delays (vitamin E deficiency), and blood clotting problems leading to easy bleeding and bruising (vitamin K deficiency).In some cases, progressive neurological disease has been described that develops later during childhood or during adulthood. Vitamin E deficiency from undiagnosed liver disease may contribute to neurological disease. In other cases, the cause of neurological disease may be different. For example, in CTX neurological disease results from the accumulation or storage of cholesterol-like, fatty substances in nerve cells and the brain.In some cases, without treatment liver abnormalities can progress to cause serious life-threatening complications such as the formation of fibrous, scar tissue (fibrosis) and liver regeneration with scarring (cirrhosis), high blood pressure of the main vein of the liver (portal hypertension), and abnormal fluid retention and swelling in the abdomen (ascites). Eventually, liver disease can progress to cause liver failure.3-BETA-HYDROXY-DELTA-5-C27-STEROID OXIDOREDUCTASE DEFICIENCY
This disorder is sometimes referred to as 3HSD deficiency or bile acid synthesis defect 1. It is believed to be the most common form of BASDs. The clinical picture of this disorder can vary greatly. Generally, affected individuals will develop cholestasis and fat-soluble vitamin malabsorption (and various abnormalities secondary to vitamin deficiency) during infancy. If untreated, progressive liver disease occurs.In recent years, cases of idiopathic cholestasis that develop during adulthood (late onset liver disease) have been attributed to 3beta-dehydrogenase deficiency. Some of these individuals presented with jaundice during infancy, but improved and were not diagnosed with 3beta-dehydrogenase deficiency until later during life.DELTA4 3-OXOSTEROID 5BETA REDUCTASE DEFICIENCY
This disorder is sometimes referred to as 5beta-reductase deficiency or bile acid synthesis defect 2. The clinical picture of this disorder is similar to that of 3beta-dehyddrogenase deficiency, but generally is more severe and, if untreated, can rapidly progress to cirrhosis and liver failure. 5beta-reductase deficiency can present as neonatal cholestasis or as liver failure that resembles liver disease seen in neonatal hemochromatosis (for more information, choose “neonatal hemochromatosis” as your search term in the Rare Disease Database.)OXYSTEROL 7-ALPHA-HYDROXYLASE DEFICIENCY
This disorder is sometimes referred to as bile acid synthesis defect 3. Only a few cases have been reported in the medical literature. Affected infants have exhibited severe neonatal cholestasis, disease affecting the blood’s ability to clot (coagulopathy), hepatosplenomegaly, and, if untreated, cirrhosis and liver failure early in life. Researchers speculate that due to the severity most cases of this disorder prove fatal before birth or shortly after birth.ALPHA-METHYLACYL-COA RACEMASE (AMACR) DEFICIENCY
This disorder is sometimes referred to as 2-methylacyl-CoA racemase deficiency or bile acid synthesis defect 4. The disorder was first reported in three adults presenting with sensory motor neuropathy, a condition in which there is disease of the peripheral nerves (those outside the central nervous system) that control response to pain and temperature and muscle coordination. Sensory motor neuropathy may cause abnormal sensations such as numbness or a feeling of pins and needles in the arms and legs, weakness of the muscles, and problems with balance and coordination. Adults with this disorder may lack symptoms (asymptomatic) until sensory motor neuropathy develops or they may have mild liver disease during childhood. It is not known if asymptomatic adults who develop neurological disease had mild, undiagnosed liver disease that led to fat-soluble vitamin deficiency that eventually caused the neurological findings. This disorder has also been reported in infants who present with severe fat and fat-soluble vitamin deficiencies and mild cholestasis. Fewer than 10 cases have been reported in the medical literature.STEROL 27-HYDROXYLASE DEFICIENCY (CEREBROTENDINOUS XANTHOMATOSIS)
This disorder is also known as cerebrotendinous xanthomatosis (CTX). CTX is highly variable and is associated with a wide range of potential abnormalities. Originally, the disorder was believed only to be a neurological disorder of abnormal fat (lipid) storage not associated with liver disease. It is now know that CTX can present in childhood with cholestatic liver disease that can be severe or can be mild and resolve on its own in individuals who may later develop other complications of the disorder such as neurological disease. Patients with CTX not infrequently also have diarrhea.In CTX, cholestanol deposits accumulate in nerve cells and membranes, causing damage to the brain, spinal cord, tendons, lens of the eyes and arteries. Affected individuals may develop cataracts during childhood and benign, fatty tumors (xanthomas) of the tendons during adolescence. If untreated, progressive neurological problems develop in adulthood potentially causing paralysis, ataxia, and dementia. Coronary heart disease is also common. Many individuals with the adult symptoms of CTX experienced prolonged cholestatic jaundice during infancy.NORD has an individual report on CTX. For more information, choose “cerebrotendinous xanthomatosis” as your search term in the Rare Disease Database.TRIHYDROXYCHOLESTANIC ACID (THCA) COA OXIDASE DEFICIENCY
This form has been reported in several individuals and is characterized primarily by neurological findings including ataxia, which often became apparent by 3 and half years of age. Liver disease has not been described in this form of BSAD.AMIDATION DEFECTS
The final step in bile acid synthesis involves the joining together (conjugation) of two amino acids, glycine and taurine. Disorders involving this step are known as “defective bile acid amidation due to failure to conjugate with glycine and/or taurine” or more simply amidation defects. Two disorders in this subcategory have been identified.Bile Acid CoA Ligase Deficiency
This disorder is characterized by neonatal cholestasis, fat and fat-soluble vitamin malabsorption and growth failure. Fewer than 10 cases have been reported in the medical literature.Amino Acid N-Acyltransferase Deficiency
This disorder was initially described in several individuals within a large Amish kindred. Affected individuals developed pruritus, variable growth deficiency, and fat malabsorption (familial hypercholanemia). More recently a report has appeared that included description of 10 affected patients with only one from an Amish kindred. The presentation was quite varied in this case series with one family member having liver failure in infancy; however, most patients presented with poor growth and fat soluble vitamin deficiencies. | 158 | Bile Acid Synthesis Disorders |
nord_158_2 | Causes of Bile Acid Synthesis Disorders | Bile acid synthesis disorders are caused by mutations in specific genes. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body. In all known BASDs, these mutations are believed to be inherited in an autosomal recessive pattern.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.Bile acid synthesis disorders result from improper synthesis of bile acids, particularly the two primary bile acids, cholic acid and chenodeoxycholic acid. The principal bile acids are synthesized by the liver through a series of complex chemical reactions involving at least 17 enzymatic steps. These reactions mainly occur within specialized liver cells known as hepatocytes. Each “step” requires a corresponding specialized protein known as an enzyme. Each gene associated with a bile acid disorder creates (encodes) a specific enzyme. When a gene that encodes a bile acid enzyme is mutated, it leads to low levels of functional versions of the corresponding enzyme. When one enzyme in the process is absent or deficient, it leads to diminished production of bile and potentially a bile acid synthesis disorder.One of the main functions of bile acids is to promote the flow of bile. Abnormal bile acid formation results in improper or hampered bile flow. Bile is created in the liver. Bile is a fluid that contains water, certain minerals that carry an electric charge (electrolytes), and other materials including bile salts, phospholipids, cholesterol, and an orange-yellow pigment (bilirubin) that is a byproduct of the natural breakdown of the hemoglobin of red blood cells. Bile flow accomplishes two important tasks within the body: it aids in digestion and absorption of dietary fats, vitamins, and other nutrients and it aids in the elimination of excess cholesterol, bilirubin, waste, and toxins from the body. Therefore, a problem with normal bile flow often results in malabsorption of vital nutrients and the accumulation of toxic materials in the body.3-beta-hydroxy-delta-5-C27-steroid oxidoreductase deficiency is caused by mutations of the HSD3B7 gene on short arm of chromosome 16 (16p11.2). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered.Delta4-3-oxosteroid 5-beta-reductase deficiency is caused by mutations in the AKR1D1 gene located on the long arm of chromosome 7 (7q33).Oxysterol 7-alpha-hydroxylase deficiency is caused by mutations in the CYP7B1 gene located on the long arm of chromosome 8 (8q12.3).Alpha-methylacyl-CoA racemase deficiency is caused by mutations in the AMACR gene located on the short arm of chromosome 5 (5p13.2).Sterol 27-hydroxylase deficiency (cerebrotendinous xanthomatosis) is caused by mutations in the CYP27A1 gene located on the long arm of chromosome 2 (2q35).Amino acid n-acyltransferase deficiency is caused by mutations in the BAAT gene located on the long arm of chromosome 9 (9q31.1).Bile acid CoA ligase deficiency is caused by mutations in the SLC27A5 gene located on the long arm of chromosome 19 (19q13.43). | Causes of Bile Acid Synthesis Disorders. Bile acid synthesis disorders are caused by mutations in specific genes. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body. In all known BASDs, these mutations are believed to be inherited in an autosomal recessive pattern.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.Bile acid synthesis disorders result from improper synthesis of bile acids, particularly the two primary bile acids, cholic acid and chenodeoxycholic acid. The principal bile acids are synthesized by the liver through a series of complex chemical reactions involving at least 17 enzymatic steps. These reactions mainly occur within specialized liver cells known as hepatocytes. Each “step” requires a corresponding specialized protein known as an enzyme. Each gene associated with a bile acid disorder creates (encodes) a specific enzyme. When a gene that encodes a bile acid enzyme is mutated, it leads to low levels of functional versions of the corresponding enzyme. When one enzyme in the process is absent or deficient, it leads to diminished production of bile and potentially a bile acid synthesis disorder.One of the main functions of bile acids is to promote the flow of bile. Abnormal bile acid formation results in improper or hampered bile flow. Bile is created in the liver. Bile is a fluid that contains water, certain minerals that carry an electric charge (electrolytes), and other materials including bile salts, phospholipids, cholesterol, and an orange-yellow pigment (bilirubin) that is a byproduct of the natural breakdown of the hemoglobin of red blood cells. Bile flow accomplishes two important tasks within the body: it aids in digestion and absorption of dietary fats, vitamins, and other nutrients and it aids in the elimination of excess cholesterol, bilirubin, waste, and toxins from the body. Therefore, a problem with normal bile flow often results in malabsorption of vital nutrients and the accumulation of toxic materials in the body.3-beta-hydroxy-delta-5-C27-steroid oxidoreductase deficiency is caused by mutations of the HSD3B7 gene on short arm of chromosome 16 (16p11.2). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered.Delta4-3-oxosteroid 5-beta-reductase deficiency is caused by mutations in the AKR1D1 gene located on the long arm of chromosome 7 (7q33).Oxysterol 7-alpha-hydroxylase deficiency is caused by mutations in the CYP7B1 gene located on the long arm of chromosome 8 (8q12.3).Alpha-methylacyl-CoA racemase deficiency is caused by mutations in the AMACR gene located on the short arm of chromosome 5 (5p13.2).Sterol 27-hydroxylase deficiency (cerebrotendinous xanthomatosis) is caused by mutations in the CYP27A1 gene located on the long arm of chromosome 2 (2q35).Amino acid n-acyltransferase deficiency is caused by mutations in the BAAT gene located on the long arm of chromosome 9 (9q31.1).Bile acid CoA ligase deficiency is caused by mutations in the SLC27A5 gene located on the long arm of chromosome 19 (19q13.43). | 158 | Bile Acid Synthesis Disorders |
nord_158_3 | Affects of Bile Acid Synthesis Disorders | Bile acid synthesis disorders affect males and females in equal numbers. Individuals of any race or ethnic group can be affected. The incidence and prevalence of BASDs are unknown. These disorders have been estimated to account for as many as 1-2% of all childhood cholestatic disorders. However, many cases go undiagnosed or misdiagnosed making it difficult to determine their true frequency in the general population. CTX has an estimated prevalence of 1 in 70,000 individuals in the general population. It is estimated that BASDs have prevalence of 1 in 50,000 in the general population. | Affects of Bile Acid Synthesis Disorders. Bile acid synthesis disorders affect males and females in equal numbers. Individuals of any race or ethnic group can be affected. The incidence and prevalence of BASDs are unknown. These disorders have been estimated to account for as many as 1-2% of all childhood cholestatic disorders. However, many cases go undiagnosed or misdiagnosed making it difficult to determine their true frequency in the general population. CTX has an estimated prevalence of 1 in 70,000 individuals in the general population. It is estimated that BASDs have prevalence of 1 in 50,000 in the general population. | 158 | Bile Acid Synthesis Disorders |
nord_158_4 | Related disorders of Bile Acid Synthesis Disorders | Symptoms of the following disorders can be similar to those of bile acid synthesis disorders. Comparisons may be useful for a differential diagnosis.Secondary forms of BASDs include low gamma-GT familial intrahepatic cholestasis, also known as progressive familial intrahepatic cholestasis types 1, 2, 4 and 5 and benign recurrent intrahepatic cholestasis types 1 and 2; MDR3 deficiency, also known as progressive familial intrahepatic cholestasis type 3; Zellweger spectrum disorders; and Smith-Lemli-Optiz syndrome. NORD has individual reports on each of these disorders. (For more information, choose the specific disorder name as your search term in the Rare Disease Database.)Neonatal hepatitis is a general term for inflammation of the liver (hepatitis) that occurs shortly after birth in newborns. Despite the name “hepatitis,” most of these disorders are not caused by infections. Neonatal hepatitis may be caused by certain metabolic disorders and other rare diseases that affect or impair the function of the liver. In addition to BASDs, these disorders include certain forms of alpha-1-antitrypsin deficiency, Alagille syndrome, familial hypercholanemia, arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome, cystic fibrosis, and certain metabolic diseases including tyrosinemia type I, galactosemia, hereditary fructose intolerance, and fatty oxidation disorders. In some case, there may be an association with an infectious or viral disease. In some children, the cause of liver inflammation is unknown – these cases are referred to as idiopathic neonatal hepatitis. Symptoms common to liver disease often occur including yellowing of the whites of the eyes and the skin (jaundice), enlargement of the liver (hepatomegaly) and unusually dark urine. (For more information on this disorder, choose “neonatal hepatitis” or the specific disorder name as your search term in the Rare Disease Database.)Biliary atresia is a rare gastrointestinal disorder characterized by destruction or absence of all or a portion of the bile duct that lies outside the liver (extrahepatic bile duct). The bile duct is a tube that allows the passage of bile from the liver into the gall bladder and, eventually, the small intestine. Bile is a liquid secreted by the liver that plays an essential role in carrying waste products from the liver and breaking down fats in the small intestine. In biliary atresia, absence or destruction of the bile ducts results in the abnormal accumulation of bile in the liver. Affected infants may have yellowing of the skin and whites of the eyes (jaundice) and scarring of the liver (cirrhosis). Additional symptoms may include itching, abnormal enlargement of the liver (hepatomegaly), pale, gray stools, and a swollen stomach. In some affected individuals, additional abnormalities may be present, including heart defects and kidney and spleen malformations. The exact cause of biliary atresia is unknown. Biliary atresia patients have high serum GGT. (For more information on this disorder, choose “biliary atresia” as your search term in the Rare Disease Database.) | Related disorders of Bile Acid Synthesis Disorders. Symptoms of the following disorders can be similar to those of bile acid synthesis disorders. Comparisons may be useful for a differential diagnosis.Secondary forms of BASDs include low gamma-GT familial intrahepatic cholestasis, also known as progressive familial intrahepatic cholestasis types 1, 2, 4 and 5 and benign recurrent intrahepatic cholestasis types 1 and 2; MDR3 deficiency, also known as progressive familial intrahepatic cholestasis type 3; Zellweger spectrum disorders; and Smith-Lemli-Optiz syndrome. NORD has individual reports on each of these disorders. (For more information, choose the specific disorder name as your search term in the Rare Disease Database.)Neonatal hepatitis is a general term for inflammation of the liver (hepatitis) that occurs shortly after birth in newborns. Despite the name “hepatitis,” most of these disorders are not caused by infections. Neonatal hepatitis may be caused by certain metabolic disorders and other rare diseases that affect or impair the function of the liver. In addition to BASDs, these disorders include certain forms of alpha-1-antitrypsin deficiency, Alagille syndrome, familial hypercholanemia, arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome, cystic fibrosis, and certain metabolic diseases including tyrosinemia type I, galactosemia, hereditary fructose intolerance, and fatty oxidation disorders. In some case, there may be an association with an infectious or viral disease. In some children, the cause of liver inflammation is unknown – these cases are referred to as idiopathic neonatal hepatitis. Symptoms common to liver disease often occur including yellowing of the whites of the eyes and the skin (jaundice), enlargement of the liver (hepatomegaly) and unusually dark urine. (For more information on this disorder, choose “neonatal hepatitis” or the specific disorder name as your search term in the Rare Disease Database.)Biliary atresia is a rare gastrointestinal disorder characterized by destruction or absence of all or a portion of the bile duct that lies outside the liver (extrahepatic bile duct). The bile duct is a tube that allows the passage of bile from the liver into the gall bladder and, eventually, the small intestine. Bile is a liquid secreted by the liver that plays an essential role in carrying waste products from the liver and breaking down fats in the small intestine. In biliary atresia, absence or destruction of the bile ducts results in the abnormal accumulation of bile in the liver. Affected infants may have yellowing of the skin and whites of the eyes (jaundice) and scarring of the liver (cirrhosis). Additional symptoms may include itching, abnormal enlargement of the liver (hepatomegaly), pale, gray stools, and a swollen stomach. In some affected individuals, additional abnormalities may be present, including heart defects and kidney and spleen malformations. The exact cause of biliary atresia is unknown. Biliary atresia patients have high serum GGT. (For more information on this disorder, choose “biliary atresia” as your search term in the Rare Disease Database.) | 158 | Bile Acid Synthesis Disorders |
nord_158_5 | Diagnosis of Bile Acid Synthesis Disorders | A diagnosis of a bile acid synthesis disorder should be suspected in infants or young children who have jaundice, other symptoms of cholestatic liver disease with an unknown cause, or fat soluble vitamin deficiency and growth failure. The identification of characteristic symptoms, a detailed patient history, and a thorough clinical evaluation can support a suspected diagnosis. However, symptoms of BASDs overlap with numerous other liver disorders. Confirmation of a BASD requires examination by tests performed at or assessed by specialized diagnostic laboratories.Early detection and prompt diagnosis of BASDs is extremely important as many individuals who show a dramatic response to oral bile acid replacement therapy.Clinical Testing and Workup
Certain examinations such as a specific serologic tests and a liver biopsy may be performed to rule out more common causes of cholestasis. For example, serum evaluation of an enzyme known as gamma glutamyl transpeptidase (GGT) can help to identify the cause of cholestasis. This enzyme is often markedly elevated in individuals with cholestasis caused by an underlying liver disease. However, in individuals with BASD and related disorders levels of GGT are normal or low. A liver biopsy involves the surgical removal and microscopic examination of a piece of liver tissue. A liver biopsy can provide important clues to the underlying cause of cholestasis.If more common causes of cholestasis are ruled out, laboratory analysis of certain body fluids (e.g. bile, blood and urine) is necessary. Specialized techniques known as fast atom bombardment-mass spectrometry (FABS-MS), electrospray ionization mass spectrometry (ESI-MS), and gas chromatography-mass spectrometry (GC-MS) may be used. For the most part, these tests are only available at certain laboratories. Mass spectrometry involves creating charged particles (ions) from molecules. These ions can be analyzed to provide information about molecular weight and chemical structure. Each molecule has a unique weight, which is referred to as its mass. A specialized instrument called a spectrometer allows physicians to collect, sort and study these molecules differentiating them by their unique masses. In an individual suspected of having a BASD, a urine sample is used.In FABS-MS, the sample is placed in the spectrometer and is bombarded with an energetic beam of inert gas atoms such as Xenon or Argon. Physicians are able to tell how much of a specific compound is in a sample. The turnaround time for this procedure can sometimes be slow.ESI-MS is similar a procedure. However, this techniques produces multiple charged ions and particularly useful for thermally labile, high molecular mass substances. This procedure is relatively simple and the turnaround rapid.In GC-MS, a sample is inserted into a machine where it is heated. The heated sample will slowly evaporate into a gas. This gas can be separated into its individual components, which can then be analyzed. GC-MS can be a time-consuming technique.Molecular genetic testing can confirm a diagnosis of a BASD in some cases. Molecular genetic testing can detect mutations in specific genes known to cause specific BASDs, but is available only as a diagnostic service at specialized laboratories. Laboratories that provide molecular genetic testing for BSADs include Genetics Labs at Cincinnati Children’s Hospital (www.cincinnatichildrens.org/service/h/hereditary-liver/tests/) and Emory University (http://testcholestasis.com) or other commercial laboratories (https://www.ncbi.nlm.nih.gov/gtr/). Only a limited number of laboratories can perform FAB-MS or ESI-MS. The Mass Spectrometry Laboratory at Cincinnati Children’s Hospital Medical Center https://www.cincinnatichildrens.org/service/p/pathology/mass-spectrometry/tests)can perform these analyses. | Diagnosis of Bile Acid Synthesis Disorders. A diagnosis of a bile acid synthesis disorder should be suspected in infants or young children who have jaundice, other symptoms of cholestatic liver disease with an unknown cause, or fat soluble vitamin deficiency and growth failure. The identification of characteristic symptoms, a detailed patient history, and a thorough clinical evaluation can support a suspected diagnosis. However, symptoms of BASDs overlap with numerous other liver disorders. Confirmation of a BASD requires examination by tests performed at or assessed by specialized diagnostic laboratories.Early detection and prompt diagnosis of BASDs is extremely important as many individuals who show a dramatic response to oral bile acid replacement therapy.Clinical Testing and Workup
Certain examinations such as a specific serologic tests and a liver biopsy may be performed to rule out more common causes of cholestasis. For example, serum evaluation of an enzyme known as gamma glutamyl transpeptidase (GGT) can help to identify the cause of cholestasis. This enzyme is often markedly elevated in individuals with cholestasis caused by an underlying liver disease. However, in individuals with BASD and related disorders levels of GGT are normal or low. A liver biopsy involves the surgical removal and microscopic examination of a piece of liver tissue. A liver biopsy can provide important clues to the underlying cause of cholestasis.If more common causes of cholestasis are ruled out, laboratory analysis of certain body fluids (e.g. bile, blood and urine) is necessary. Specialized techniques known as fast atom bombardment-mass spectrometry (FABS-MS), electrospray ionization mass spectrometry (ESI-MS), and gas chromatography-mass spectrometry (GC-MS) may be used. For the most part, these tests are only available at certain laboratories. Mass spectrometry involves creating charged particles (ions) from molecules. These ions can be analyzed to provide information about molecular weight and chemical structure. Each molecule has a unique weight, which is referred to as its mass. A specialized instrument called a spectrometer allows physicians to collect, sort and study these molecules differentiating them by their unique masses. In an individual suspected of having a BASD, a urine sample is used.In FABS-MS, the sample is placed in the spectrometer and is bombarded with an energetic beam of inert gas atoms such as Xenon or Argon. Physicians are able to tell how much of a specific compound is in a sample. The turnaround time for this procedure can sometimes be slow.ESI-MS is similar a procedure. However, this techniques produces multiple charged ions and particularly useful for thermally labile, high molecular mass substances. This procedure is relatively simple and the turnaround rapid.In GC-MS, a sample is inserted into a machine where it is heated. The heated sample will slowly evaporate into a gas. This gas can be separated into its individual components, which can then be analyzed. GC-MS can be a time-consuming technique.Molecular genetic testing can confirm a diagnosis of a BASD in some cases. Molecular genetic testing can detect mutations in specific genes known to cause specific BASDs, but is available only as a diagnostic service at specialized laboratories. Laboratories that provide molecular genetic testing for BSADs include Genetics Labs at Cincinnati Children’s Hospital (www.cincinnatichildrens.org/service/h/hereditary-liver/tests/) and Emory University (http://testcholestasis.com) or other commercial laboratories (https://www.ncbi.nlm.nih.gov/gtr/). Only a limited number of laboratories can perform FAB-MS or ESI-MS. The Mass Spectrometry Laboratory at Cincinnati Children’s Hospital Medical Center https://www.cincinnatichildrens.org/service/p/pathology/mass-spectrometry/tests)can perform these analyses. | 158 | Bile Acid Synthesis Disorders |
nord_158_6 | Therapies of Bile Acid Synthesis Disorders | TreatmentThe treatment of BASDs is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, liver specialists (hepatologists), nutritionists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Genetic counseling is recommended for affected individuals and their families.Many affected individuals have dramatically responded to treatment by restoring one of the missing primary bile acids to the body (bile acid replacement therapy). This therapy involves the oral administration one of the two primary bile acids, cholic acid or chenodeoxycholic acid. Replacement of the missing bile acids has led to improvement or normalization of liver function in individuals with specific types of BASDs.In 2015, Cholbam (cholic acid) was approved as the first treatment for pediatric and adult patients with bile acid synthesis disorders due to single enzyme defects, and for patients with peroxisomal disorders (including Zellweger spectrum disorders). Cholbam is marketed by Retophin Pharmaceuticals.Cholic acid replacement therapy has proven beneficial in treating individuals with 3-beta-hydroxy-delta-5-C27-steroid oxidoreductase deficiency; delta4-3-oxosteroid 5-beta-reductase deficiency; and alpha-methylacyl-CoA racemase deficiency. Most affected individuals experience a correction of all liver functions over a period of several weeks or months.Cholic acid replacement therapy is not used for amidation defects because these individuals do not lack cholic acid. These two disorders can be treated with commercially available bile acids from health food stores under the name of Ox Bile available in 125 and 500 mg capsules through health food stores or through internet sources. This preparation is approximately 75% glycocholic acid. Glycocholic acid has proven effective in treating individuals with amino acid n-acyltransferase deficiency.Cholic acid replacement therapy is not effective for the treatment of oxysterol 7-alpha-hydroxylase deficiency. Ursodeoxycholic acid worsened the condition. Two infants reported in the medical literature were successfully treated by a liver transplant and one with chenodeoxycholic acid.Chenodeoxycholic and cholic acid have been used to treat individuals with sterol 27-hydroxylase deficiency (cerebrotendinous xanthomatosis). This therapy has led to significant improvement in affected individuals. It tends to be most effective when given in conjunction with a drug that inhibits HMG-CoA reductase, an enzyme that plays a role the creation (biosynthesis) of cholesterol in the liver. There are concerns that treatment with an HMG-CoA reductase inhibitor could boost the activity of receptors for low-density lipoprotein (LDL) cholesterol, thereby increasing cholesterol uptake and potentially worsening CTX.Ursodeoxycholic acid has provided short-term benefit to some individuals with BSADs. However, its long-term benefit is limited because it cannot compensate for the basic underlying defects and ultimately affected individuals experience continued formation of abnormal bile acids and toxic metabolites.Treatment of BASDs is also symptomatic and supportive. For example, supplemental treatment with vitamins and nutrients is essential for individuals with malabsorption. Such treatment may include restoring vitamins A, D, E, and K.Individuals who do not respond to other treatment options may ultimately require a liver transplant. A liver transplant carries risk and may result in post-operative complications. After a liver transplant, affected individuals are required to take medication for the rest of their lives for immunosuppression to prevent rejection. | Therapies of Bile Acid Synthesis Disorders. TreatmentThe treatment of BASDs is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, liver specialists (hepatologists), nutritionists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Genetic counseling is recommended for affected individuals and their families.Many affected individuals have dramatically responded to treatment by restoring one of the missing primary bile acids to the body (bile acid replacement therapy). This therapy involves the oral administration one of the two primary bile acids, cholic acid or chenodeoxycholic acid. Replacement of the missing bile acids has led to improvement or normalization of liver function in individuals with specific types of BASDs.In 2015, Cholbam (cholic acid) was approved as the first treatment for pediatric and adult patients with bile acid synthesis disorders due to single enzyme defects, and for patients with peroxisomal disorders (including Zellweger spectrum disorders). Cholbam is marketed by Retophin Pharmaceuticals.Cholic acid replacement therapy has proven beneficial in treating individuals with 3-beta-hydroxy-delta-5-C27-steroid oxidoreductase deficiency; delta4-3-oxosteroid 5-beta-reductase deficiency; and alpha-methylacyl-CoA racemase deficiency. Most affected individuals experience a correction of all liver functions over a period of several weeks or months.Cholic acid replacement therapy is not used for amidation defects because these individuals do not lack cholic acid. These two disorders can be treated with commercially available bile acids from health food stores under the name of Ox Bile available in 125 and 500 mg capsules through health food stores or through internet sources. This preparation is approximately 75% glycocholic acid. Glycocholic acid has proven effective in treating individuals with amino acid n-acyltransferase deficiency.Cholic acid replacement therapy is not effective for the treatment of oxysterol 7-alpha-hydroxylase deficiency. Ursodeoxycholic acid worsened the condition. Two infants reported in the medical literature were successfully treated by a liver transplant and one with chenodeoxycholic acid.Chenodeoxycholic and cholic acid have been used to treat individuals with sterol 27-hydroxylase deficiency (cerebrotendinous xanthomatosis). This therapy has led to significant improvement in affected individuals. It tends to be most effective when given in conjunction with a drug that inhibits HMG-CoA reductase, an enzyme that plays a role the creation (biosynthesis) of cholesterol in the liver. There are concerns that treatment with an HMG-CoA reductase inhibitor could boost the activity of receptors for low-density lipoprotein (LDL) cholesterol, thereby increasing cholesterol uptake and potentially worsening CTX.Ursodeoxycholic acid has provided short-term benefit to some individuals with BSADs. However, its long-term benefit is limited because it cannot compensate for the basic underlying defects and ultimately affected individuals experience continued formation of abnormal bile acids and toxic metabolites.Treatment of BASDs is also symptomatic and supportive. For example, supplemental treatment with vitamins and nutrients is essential for individuals with malabsorption. Such treatment may include restoring vitamins A, D, E, and K.Individuals who do not respond to other treatment options may ultimately require a liver transplant. A liver transplant carries risk and may result in post-operative complications. After a liver transplant, affected individuals are required to take medication for the rest of their lives for immunosuppression to prevent rejection. | 158 | Bile Acid Synthesis Disorders |
nord_159_0 | Overview of Biliary Atresia | Biliary atresia is a rare gastrointestinal disorder characterized by destruction or absence of all or a portion of the bile duct that lies outside the liver (extrahepatic bile duct). The bile duct is a tube that allows the passage of bile from the liver into the gall bladder and, eventually, the small intestine. Bile is a liquid secreted by the liver that plays an essential role in carrying waste products from the liver and promoting absorption of fats and vitamins by the intestines. In biliary atresia, absence or destruction of the bile ducts results in the abnormal accumulation of bile in the liver. Affected infants have yellowing of the skin and whites of the eyes (jaundice) and scarring of the liver (fibrosis). In some cases, additional abnormalities may be present, including heart defects and intestinal, spleen and kidney malformations. The exact cause of biliary atresia is unknown. | Overview of Biliary Atresia. Biliary atresia is a rare gastrointestinal disorder characterized by destruction or absence of all or a portion of the bile duct that lies outside the liver (extrahepatic bile duct). The bile duct is a tube that allows the passage of bile from the liver into the gall bladder and, eventually, the small intestine. Bile is a liquid secreted by the liver that plays an essential role in carrying waste products from the liver and promoting absorption of fats and vitamins by the intestines. In biliary atresia, absence or destruction of the bile ducts results in the abnormal accumulation of bile in the liver. Affected infants have yellowing of the skin and whites of the eyes (jaundice) and scarring of the liver (fibrosis). In some cases, additional abnormalities may be present, including heart defects and intestinal, spleen and kidney malformations. The exact cause of biliary atresia is unknown. | 159 | Biliary Atresia |
nord_159_1 | Symptoms of Biliary Atresia | The symptoms of biliary atresia usually appear by the age of two to six weeks and include a yellowish coloration of the skin and whites of the eyes (jaundice), abnormally pale stools, and dark urine. Infants may also have swollen (distended) stomach and/or abnormal enlargement of the liver (hepatomegaly). By the age of six to 10 weeks, additional symptoms may also develop including poor weight gain, irritability and/or an increase in blood pressure within the veins that carry blood from the intestine to the liver (portal hypertension). Bile ducts inside the liver (intrahepatic bile ducts) are also involved. If left untreated, biliary atresia may result in permanent scarring of the liver (cirrhosis) and, eventually, liver (hepatic) failure.Some children with biliary atresia may have additional congenital abnormalities including malformations of the heart (e.g., situs inversus, levocardia, and ventricular septal defects) and/or kidneys. Situs inversus is a condition in which the internal organs are on the opposite side of the body from normal. Levocardia is a condition in which the heart is malpositioned. (For more information on ventricular septal defects see the Related Disorders section below.)Additional features may be associated with some cases of biliary atresia including absence of the spleen (asplenia), the presence of more than one spleen (polysplenia), and/or other anatomical abnormalities. | Symptoms of Biliary Atresia. The symptoms of biliary atresia usually appear by the age of two to six weeks and include a yellowish coloration of the skin and whites of the eyes (jaundice), abnormally pale stools, and dark urine. Infants may also have swollen (distended) stomach and/or abnormal enlargement of the liver (hepatomegaly). By the age of six to 10 weeks, additional symptoms may also develop including poor weight gain, irritability and/or an increase in blood pressure within the veins that carry blood from the intestine to the liver (portal hypertension). Bile ducts inside the liver (intrahepatic bile ducts) are also involved. If left untreated, biliary atresia may result in permanent scarring of the liver (cirrhosis) and, eventually, liver (hepatic) failure.Some children with biliary atresia may have additional congenital abnormalities including malformations of the heart (e.g., situs inversus, levocardia, and ventricular septal defects) and/or kidneys. Situs inversus is a condition in which the internal organs are on the opposite side of the body from normal. Levocardia is a condition in which the heart is malpositioned. (For more information on ventricular septal defects see the Related Disorders section below.)Additional features may be associated with some cases of biliary atresia including absence of the spleen (asplenia), the presence of more than one spleen (polysplenia), and/or other anatomical abnormalities. | 159 | Biliary Atresia |
nord_159_2 | Causes of Biliary Atresia | The exact cause of biliary atresia is unknown, but several factors contribute to the development of the disorder, including immunologic, infectious/toxic, and genetic factors. Although the bile ducts may be normal at birth, one or more of these factors initiate epithelial damage (independently or with the help of an activated immune system) and trigger rapid production of fibrous tissue (sclerosis) causing an obstruction of bile ducts. Several viruses, including cytomegalovirus, reovirus type 3 and rotavirus infections are being studied as possible causative agents.A minority of cases may be caused by defects during the development (morphogenesis) of the liver and biliary tree during pregnancy. Some of these cases may be diagnosed during gestation by a prenatal ultrasound that shows a cyst in the biliary system. Biliary atresia is not an inherited disease; rare genetic variants are being reported in children who also have non-liver defects (see above). | Causes of Biliary Atresia. The exact cause of biliary atresia is unknown, but several factors contribute to the development of the disorder, including immunologic, infectious/toxic, and genetic factors. Although the bile ducts may be normal at birth, one or more of these factors initiate epithelial damage (independently or with the help of an activated immune system) and trigger rapid production of fibrous tissue (sclerosis) causing an obstruction of bile ducts. Several viruses, including cytomegalovirus, reovirus type 3 and rotavirus infections are being studied as possible causative agents.A minority of cases may be caused by defects during the development (morphogenesis) of the liver and biliary tree during pregnancy. Some of these cases may be diagnosed during gestation by a prenatal ultrasound that shows a cyst in the biliary system. Biliary atresia is not an inherited disease; rare genetic variants are being reported in children who also have non-liver defects (see above). | 159 | Biliary Atresia |
nord_159_3 | Affects of Biliary Atresia | Biliary atresia is a rare disorder with a slight increased frequency in females. It occurs in approximately 1 in 10,000 to 15,000 births in the United States. Approximately 400-600 new cases of biliary atresia are encountered in the United States each year. According to one estimate, the prevalence of biliary atresia in Europe is approximately 1 in 12,000 births. Biliary atresia is the most common cause of end-stage liver disease and liver transplantation in children. | Affects of Biliary Atresia. Biliary atresia is a rare disorder with a slight increased frequency in females. It occurs in approximately 1 in 10,000 to 15,000 births in the United States. Approximately 400-600 new cases of biliary atresia are encountered in the United States each year. According to one estimate, the prevalence of biliary atresia in Europe is approximately 1 in 12,000 births. Biliary atresia is the most common cause of end-stage liver disease and liver transplantation in children. | 159 | Biliary Atresia |
nord_159_4 | Related disorders of Biliary Atresia | Symptoms of the following disorders can be similar to those of biliary atresia. Comparisons may be useful for a differential diagnosis:Neonatal hepatitis (sometimes referred to as neonatal cholestasis) is a term used to describe a group of disorders that present with jaundice due to inflammation of the liver and/or injury of the bile duct structure within the liver (intrahepatic). Despite the name “hepatitis,” most of these disorders are not caused by infections. Some of the more common disorders are the Alagille syndrome, deficiency of alpha-1-antitrypsin protein, cystic fibrosis, progressive familial intrahepatic cholestasis, and defects in synthesis of bile acids. The cause for neonatal hepatitis in some infants remains unknown. In these infants, some studies suggest an association with an infectious or viral disease. Symptoms of neonatal hepatitis typically appear during the first few weeks of life and may include a yellow discoloration of the skin and whites of the eyes (jaundice), an abnormally enlarged liver (hepatomegaly), poor feeding, slow growth, itchy skin, abdominal discomfort, lightly colored stools, and/or dark urine. (For more information on this disorder, choose “Neonatal Hepatitis” as your search term in the Rare Disease Database.)Primary sclerosing cholangitis (PSC) is a rare progressive disorder characterized by inflammation, thickening, and abnormal formation of fibrous tissue (fibrosis) within the passages that carry bile from the liver (bile ducts). This often results in the decrease of bile flow from the liver (cholestasis). This disorder is more common in older children and adults. The neonatal form of PSC is rare and may share features with biliary atresia and neonatal hepatitis. The cause is not known, but most cases are associated with defects in the immunologic system. Symptoms associated with PSC include fatigue and itching (pruritus), followed by yellowing of the skin, mucous membranes, and whites of the eyes (jaundice). In addition, affected individuals may have dark urine, light-colored stools, abdominal pain, and/or nausea. (For more information on this disorder, choose primary sclerosing cholangitis as your search term in the Rare Disease Database.)The following disorders may be associated with biliary atresia as secondary characteristics. They are not necessary for a differential diagnosis:Ventricular septal defects (VSDs) are heart defects that are present at birth (congenital). The normal heart has four chambers. The two upper chambers, known as atria, are separated from each other by a fibrous partition known as the atrial septum. The two lower chambers are known as ventricles and are separated from each other by the ventricular septum. Valves connect the atria (left and right) to their respective ventricles. The aorta, the main vessel of arterial circulation, carries blood from the left ventricle and away from the heart. VSDs can occur in any portion of the ventricular septum. The size and location of the defect determine the severity of the symptoms. Small ventricular septal defects can close on their own (spontaneously) or become less significant as the child matures and grows. Moderately-sized defects can cause congestive heart failure, which is characterized by an abnormally rapid rate of breathing (tachypnea), wheezing, unusually fast heartbeat (tachycardia), enlarged liver (hepatomegaly), and/or failure to thrive. (For more information on this disorder, choose “ventricular septal defects” as your search term in the Rare Disease Database.) | Related disorders of Biliary Atresia. Symptoms of the following disorders can be similar to those of biliary atresia. Comparisons may be useful for a differential diagnosis:Neonatal hepatitis (sometimes referred to as neonatal cholestasis) is a term used to describe a group of disorders that present with jaundice due to inflammation of the liver and/or injury of the bile duct structure within the liver (intrahepatic). Despite the name “hepatitis,” most of these disorders are not caused by infections. Some of the more common disorders are the Alagille syndrome, deficiency of alpha-1-antitrypsin protein, cystic fibrosis, progressive familial intrahepatic cholestasis, and defects in synthesis of bile acids. The cause for neonatal hepatitis in some infants remains unknown. In these infants, some studies suggest an association with an infectious or viral disease. Symptoms of neonatal hepatitis typically appear during the first few weeks of life and may include a yellow discoloration of the skin and whites of the eyes (jaundice), an abnormally enlarged liver (hepatomegaly), poor feeding, slow growth, itchy skin, abdominal discomfort, lightly colored stools, and/or dark urine. (For more information on this disorder, choose “Neonatal Hepatitis” as your search term in the Rare Disease Database.)Primary sclerosing cholangitis (PSC) is a rare progressive disorder characterized by inflammation, thickening, and abnormal formation of fibrous tissue (fibrosis) within the passages that carry bile from the liver (bile ducts). This often results in the decrease of bile flow from the liver (cholestasis). This disorder is more common in older children and adults. The neonatal form of PSC is rare and may share features with biliary atresia and neonatal hepatitis. The cause is not known, but most cases are associated with defects in the immunologic system. Symptoms associated with PSC include fatigue and itching (pruritus), followed by yellowing of the skin, mucous membranes, and whites of the eyes (jaundice). In addition, affected individuals may have dark urine, light-colored stools, abdominal pain, and/or nausea. (For more information on this disorder, choose primary sclerosing cholangitis as your search term in the Rare Disease Database.)The following disorders may be associated with biliary atresia as secondary characteristics. They are not necessary for a differential diagnosis:Ventricular septal defects (VSDs) are heart defects that are present at birth (congenital). The normal heart has four chambers. The two upper chambers, known as atria, are separated from each other by a fibrous partition known as the atrial septum. The two lower chambers are known as ventricles and are separated from each other by the ventricular septum. Valves connect the atria (left and right) to their respective ventricles. The aorta, the main vessel of arterial circulation, carries blood from the left ventricle and away from the heart. VSDs can occur in any portion of the ventricular septum. The size and location of the defect determine the severity of the symptoms. Small ventricular septal defects can close on their own (spontaneously) or become less significant as the child matures and grows. Moderately-sized defects can cause congestive heart failure, which is characterized by an abnormally rapid rate of breathing (tachypnea), wheezing, unusually fast heartbeat (tachycardia), enlarged liver (hepatomegaly), and/or failure to thrive. (For more information on this disorder, choose “ventricular septal defects” as your search term in the Rare Disease Database.) | 159 | Biliary Atresia |
nord_159_5 | Diagnosis of Biliary Atresia | The diagnosis of biliary atresia requires a direct examination of the bile ducts by abdominal surgery (laparotomy) and the microscopic examination of tissue from the liver (liver biopsy). During the surgery special contrast dye is injected into the gallbladder and x-ray films are taken to outline how the dye fills the major bile ducts (intraoperative cholangiogram). These films show the movement (or lack of movement) of the dye through bile ducts and into the small intestine. The physician/surgeon is then able to evaluate the structure of the bile ducts and to determine the site of the blockage (proximal or distal). Blood tests may demonstrate elevated levels of liver enzymes, gamma-glutamyl transpeptidase, and bilirubin and detect viral agents; high blood levels of matrix metalloproteinase-7 has been discovered to be highly specific for biliary atresia. Ultrasound of the liver may show absence of the gall bladder. | Diagnosis of Biliary Atresia. The diagnosis of biliary atresia requires a direct examination of the bile ducts by abdominal surgery (laparotomy) and the microscopic examination of tissue from the liver (liver biopsy). During the surgery special contrast dye is injected into the gallbladder and x-ray films are taken to outline how the dye fills the major bile ducts (intraoperative cholangiogram). These films show the movement (or lack of movement) of the dye through bile ducts and into the small intestine. The physician/surgeon is then able to evaluate the structure of the bile ducts and to determine the site of the blockage (proximal or distal). Blood tests may demonstrate elevated levels of liver enzymes, gamma-glutamyl transpeptidase, and bilirubin and detect viral agents; high blood levels of matrix metalloproteinase-7 has been discovered to be highly specific for biliary atresia. Ultrasound of the liver may show absence of the gall bladder. | 159 | Biliary Atresia |
nord_159_6 | Therapies of Biliary Atresia | Treatment
No cure exists for biliary atresia, but the timely diagnosis and surgical intervention improves short- and long-term outcomes in most patients. Special attention to the nutritional needs and diet are essential for children with this disorder. Special supplements, formulas, and dietary restrictions may be necessary for affected infants.Surgery must be performed to remove the obstruction and allow bile to flow into the bile ducts and small intestine (also known as “Kasai hepatoportoenterostomy”). In this procedure, the extrahepatic bile ducts are removed and replaced with a portion of the affected infant’s small intestine thereby forming a conduit to allow for bile drainage. The exact surgical procedure may vary according to the location and nature of the obstruction. In the majority of cases, bile drainage can be established with this surgical procedure. However, some children may experience variable degrees of liver dysfunction even after successful surgery. The Kasai procedure may also be used as an early intermediate procedure to support the child’s growth. Despite the Kasai procedure, liver transplantation may ultimately become necessary in many cases. Antibiotics may be used to treat infections of the bile ducts (cholangitis).Genetic counseling may be of benefit for people with biliary atresia and their families. Other treatment is symptomatic and supportive. | Therapies of Biliary Atresia. Treatment
No cure exists for biliary atresia, but the timely diagnosis and surgical intervention improves short- and long-term outcomes in most patients. Special attention to the nutritional needs and diet are essential for children with this disorder. Special supplements, formulas, and dietary restrictions may be necessary for affected infants.Surgery must be performed to remove the obstruction and allow bile to flow into the bile ducts and small intestine (also known as “Kasai hepatoportoenterostomy”). In this procedure, the extrahepatic bile ducts are removed and replaced with a portion of the affected infant’s small intestine thereby forming a conduit to allow for bile drainage. The exact surgical procedure may vary according to the location and nature of the obstruction. In the majority of cases, bile drainage can be established with this surgical procedure. However, some children may experience variable degrees of liver dysfunction even after successful surgery. The Kasai procedure may also be used as an early intermediate procedure to support the child’s growth. Despite the Kasai procedure, liver transplantation may ultimately become necessary in many cases. Antibiotics may be used to treat infections of the bile ducts (cholangitis).Genetic counseling may be of benefit for people with biliary atresia and their families. Other treatment is symptomatic and supportive. | 159 | Biliary Atresia |
nord_160_0 | Overview of Binder Type Nasomaxillary Dysplasia | SummaryBinder type nasomaxillary dysplasia is a rare developmental defect that is present at birth (congenital). The disorder is characterized by the underdevelopment (hypoplasia) of the central portion of the face, particularly the area including the nose and upper jaw (maxillonasal region). The specific symptoms and the severity of the disorder can vary from one person to another. Characteristic symptoms include an abnormally short, flattened nose and underdevelopment of the upper jaw bone (maxillary bone). The exact cause of Binder syndrome is not fully understood. Most cases appear to occur sporadically, but familial cases have been reported as well. Surgical and orthodontic treatment is recommended.IntroductionBinder type nasomaxillary dysplasia was first described in the medical literature as far back 1882. Dr. Noyes described the essential features in a single patient in 1939. Dr. von Binder first identified the condition as a distinct clinical entity in 1962 in a comprehensive report of three children; the disorder now bears his name. There is some debate in the medical literature as to whether Binder type nasomaxillary dysplasia is a syndrome or an association. A syndrome is typically a genetic disorder, in which a group of symptoms consistently occur together. An association is a nonrandom collection of birth defects that may have been caused by a number of factors, including genetic ones, and can potentially be associated with a variety of underlying conditions. | Overview of Binder Type Nasomaxillary Dysplasia. SummaryBinder type nasomaxillary dysplasia is a rare developmental defect that is present at birth (congenital). The disorder is characterized by the underdevelopment (hypoplasia) of the central portion of the face, particularly the area including the nose and upper jaw (maxillonasal region). The specific symptoms and the severity of the disorder can vary from one person to another. Characteristic symptoms include an abnormally short, flattened nose and underdevelopment of the upper jaw bone (maxillary bone). The exact cause of Binder syndrome is not fully understood. Most cases appear to occur sporadically, but familial cases have been reported as well. Surgical and orthodontic treatment is recommended.IntroductionBinder type nasomaxillary dysplasia was first described in the medical literature as far back 1882. Dr. Noyes described the essential features in a single patient in 1939. Dr. von Binder first identified the condition as a distinct clinical entity in 1962 in a comprehensive report of three children; the disorder now bears his name. There is some debate in the medical literature as to whether Binder type nasomaxillary dysplasia is a syndrome or an association. A syndrome is typically a genetic disorder, in which a group of symptoms consistently occur together. An association is a nonrandom collection of birth defects that may have been caused by a number of factors, including genetic ones, and can potentially be associated with a variety of underlying conditions. | 160 | Binder Type Nasomaxillary Dysplasia |
nord_160_1 | Symptoms of Binder Type Nasomaxillary Dysplasia | Although researchers have been able to establish characteristic or “core” symptoms, much about Binder type nasomaxillary l dysplasia is not fully understood. Several factors including the small number of identified affected individuals, the lack of large clinical studies, and the possibility of other genes influencing the disorder prevent physicians from developing an accurate picture of associated symptoms and prognosis.The characteristic finding of the disorder is the abnormal development (dysplasia) of the central or mid portion of the face. The midface appears abnormally flattened. In some patients the frontal sinuses may be underdeveloped or absent. Affected individuals have a short nose and flattened bridge of the nose. The nasal bones may be underdeveloped or abnormally positioned. The bottom of the sheet of cartilage and bone (nasal septum) that separates the right and left nostrils is known as the columella. The columella is abnormally short and the nostrils have a half-moon or comma-shaped appearance. In cases where the columella is severely short, the nostrils may appear triangular. The upper lips may be slanted backward. Despite the various nasal abnormalities, the sense of smell is unaffected.Underdevelopment (hypoplasia) upper jaw (maxillary bone) is another key feature of Binder type nasomaxillary dysplasia. The maxillae are the large bones of that form the upper jaw and assist in the formation of the nasal cavities, the bony cavities of the eyes (orbits), and the roof of the mouth (palate). The maxillae also contain the sockets of the upper teeth. Hypoplasia of the upper jaw may cause the lower jaw (mandible) to appear to protrude or stick out (relative prognathism). However, in some individuals, the mandible may actually be longer than normal (true prognathism). Affected individuals also develop malocclusion, a condition in which the upper teeth are improperly positioned in relation to the lower teeth. More specifically, affected individuals may be predisposed to a reverse overbite (class III malocclusion), in which the lower jaw is too far forward, the cusps of the lower back teeth are abnormally positioned in front of the corresponding upper teeth, and the lower front teeth (incisors) meet or lie in front of the corresponding upper incisors.In some cases, additional symptoms and physical findings have been reported in association with this condition. Individuals with Binder type nasomaxillary dysplasia seem to be at an increased risk of various malformations of the spine (vertebrae). Less often, affected individuals exhibit hearing impairment, incomplete closure of the roof of the mouth (cleft palate), misalignment of the eyes (strabismus), structural malformations of the heart (congenital heart defects), mild intellectual disability, and other features. However, the exact relationship between these findings and Binder type nasomaxillary dysplasia is unknown and they may not represent symptoms of the disorder. | Symptoms of Binder Type Nasomaxillary Dysplasia. Although researchers have been able to establish characteristic or “core” symptoms, much about Binder type nasomaxillary l dysplasia is not fully understood. Several factors including the small number of identified affected individuals, the lack of large clinical studies, and the possibility of other genes influencing the disorder prevent physicians from developing an accurate picture of associated symptoms and prognosis.The characteristic finding of the disorder is the abnormal development (dysplasia) of the central or mid portion of the face. The midface appears abnormally flattened. In some patients the frontal sinuses may be underdeveloped or absent. Affected individuals have a short nose and flattened bridge of the nose. The nasal bones may be underdeveloped or abnormally positioned. The bottom of the sheet of cartilage and bone (nasal septum) that separates the right and left nostrils is known as the columella. The columella is abnormally short and the nostrils have a half-moon or comma-shaped appearance. In cases where the columella is severely short, the nostrils may appear triangular. The upper lips may be slanted backward. Despite the various nasal abnormalities, the sense of smell is unaffected.Underdevelopment (hypoplasia) upper jaw (maxillary bone) is another key feature of Binder type nasomaxillary dysplasia. The maxillae are the large bones of that form the upper jaw and assist in the formation of the nasal cavities, the bony cavities of the eyes (orbits), and the roof of the mouth (palate). The maxillae also contain the sockets of the upper teeth. Hypoplasia of the upper jaw may cause the lower jaw (mandible) to appear to protrude or stick out (relative prognathism). However, in some individuals, the mandible may actually be longer than normal (true prognathism). Affected individuals also develop malocclusion, a condition in which the upper teeth are improperly positioned in relation to the lower teeth. More specifically, affected individuals may be predisposed to a reverse overbite (class III malocclusion), in which the lower jaw is too far forward, the cusps of the lower back teeth are abnormally positioned in front of the corresponding upper teeth, and the lower front teeth (incisors) meet or lie in front of the corresponding upper incisors.In some cases, additional symptoms and physical findings have been reported in association with this condition. Individuals with Binder type nasomaxillary dysplasia seem to be at an increased risk of various malformations of the spine (vertebrae). Less often, affected individuals exhibit hearing impairment, incomplete closure of the roof of the mouth (cleft palate), misalignment of the eyes (strabismus), structural malformations of the heart (congenital heart defects), mild intellectual disability, and other features. However, the exact relationship between these findings and Binder type nasomaxillary dysplasia is unknown and they may not represent symptoms of the disorder. | 160 | Binder Type Nasomaxillary Dysplasia |
nord_160_2 | Causes of Binder Type Nasomaxillary Dysplasia | The exact, underlying cause of Binder type nasomaxillary dysplasia is not fully understood. In many cases, the disorder is believed to occur spontaneously, for no apparent reason (sporadically). However, there have been reports in the medical literature of families in which more than one family member was affected. This suggests that genetic factors play a role in some affected individuals. Some researchers have suggested that Binder type nasomaxillary dysplasia is a genetic disorder inherited in either an autosomal dominant or recessive manner. Other researchers have suggested that the disorder is caused by complex genetic factors, specifically the interaction of many different genes, possibility in combination with environmental factors (multifactorial inheritance).Researchers have identified several environmental factors that may be associated with Binder type nasomaxillary dysplasia including birth trauma, vitamin K deficiency, or exposure of a developing infant to an anti-seizure drug known as Phenytoin or to an anti-blood clotting (anticoagulant) drug known as warfarin. No suspected environmental agent has been conclusively linked to Binder type nasomaxillary dysplasia.Some researchers believe that specific cases of Binder type nasomaxillary dysplasia may actually be mild forms or variants of chondrodysplasia punctata (CDP), a general term for a group of disorders characterized by abnormalities affecting the development of cartilage and bone (skeletal dysplasias). A variety of additional symptoms and physical features can develop. A characteristic finding of CDP is the formation of small, hardened spots of calcium on the “growing portion” or heads of the long bones (stippled epiphyses) or inside other areas of cartilage in the body. However, over time there is loss of epiphyseal stippling. Individuals who receive a diagnosis of Binder type maxillofacial dysplasia until their teen-age years or older may actually have CDP, but the distinctive epiphyseal stippling is gone so that a diagnosis of CDP is not considered. | Causes of Binder Type Nasomaxillary Dysplasia. The exact, underlying cause of Binder type nasomaxillary dysplasia is not fully understood. In many cases, the disorder is believed to occur spontaneously, for no apparent reason (sporadically). However, there have been reports in the medical literature of families in which more than one family member was affected. This suggests that genetic factors play a role in some affected individuals. Some researchers have suggested that Binder type nasomaxillary dysplasia is a genetic disorder inherited in either an autosomal dominant or recessive manner. Other researchers have suggested that the disorder is caused by complex genetic factors, specifically the interaction of many different genes, possibility in combination with environmental factors (multifactorial inheritance).Researchers have identified several environmental factors that may be associated with Binder type nasomaxillary dysplasia including birth trauma, vitamin K deficiency, or exposure of a developing infant to an anti-seizure drug known as Phenytoin or to an anti-blood clotting (anticoagulant) drug known as warfarin. No suspected environmental agent has been conclusively linked to Binder type nasomaxillary dysplasia.Some researchers believe that specific cases of Binder type nasomaxillary dysplasia may actually be mild forms or variants of chondrodysplasia punctata (CDP), a general term for a group of disorders characterized by abnormalities affecting the development of cartilage and bone (skeletal dysplasias). A variety of additional symptoms and physical features can develop. A characteristic finding of CDP is the formation of small, hardened spots of calcium on the “growing portion” or heads of the long bones (stippled epiphyses) or inside other areas of cartilage in the body. However, over time there is loss of epiphyseal stippling. Individuals who receive a diagnosis of Binder type maxillofacial dysplasia until their teen-age years or older may actually have CDP, but the distinctive epiphyseal stippling is gone so that a diagnosis of CDP is not considered. | 160 | Binder Type Nasomaxillary Dysplasia |
nord_160_3 | Affects of Binder Type Nasomaxillary Dysplasia | Binder type nasomaxillary dysplasia is a rare congenital condition that affects males and females in equal numbers. The exact incidence or prevalence is unknown. One estimate suggests that Binder syndrome occurs in less than 1 per 10,000 live births. However, individuals may go undiagnosed or misdiagnosed making it difficult to determine the true frequency in the general population. | Affects of Binder Type Nasomaxillary Dysplasia. Binder type nasomaxillary dysplasia is a rare congenital condition that affects males and females in equal numbers. The exact incidence or prevalence is unknown. One estimate suggests that Binder syndrome occurs in less than 1 per 10,000 live births. However, individuals may go undiagnosed or misdiagnosed making it difficult to determine the true frequency in the general population. | 160 | Binder Type Nasomaxillary Dysplasia |
nord_160_4 | Related disorders of Binder Type Nasomaxillary Dysplasia | Symptoms of the following disorders can be similar to those of Binder type nasomaxillary dysplasia. Comparisons may be useful for a differential diagnosis.Chondrodysplasia punctata, rhizomelic type (CDPR), is a rare, multisystem disorder that has been shown to be associated with impaired peroxisomal functioning. Peroxisomes are tiny, specialized structures (organelles) within cells that play an essential role in various, ongoing chemical and physical processes in the body (metabolism). CDPR is characterized by the appearance of abnormal, dot-like opacities representing an accumulation of calcium salts (calcification) within the growing ends of certain long bones (i.e., stippled epiphyses); shortening of the long bones of the upper arms (humeri) and the thigh bones (femora); and short stature. The disorder is also typically associated with irregularities of certain bones of the spinal column (vertebrae) and fixed bending or extension of multiple joints (contractures). Affected individuals may also have facial abnormalities that resemble those associated with Binder type nasomaxillary dysplasia, such as a flattened midface (midface hypoplasia), with underdevelopment of the nose (nasal hypoplasia), a low nasal bridge, and small nostrils. Additional abnormalities may include an unusually small head (microcephaly); upwardly slanting eyelid folds (palpebral fissures); loss of transparency of the lenses of the eyes (cataracts); abnormal thickening, dryness, and scaling of the skin (ichthyosis); and/or severe intellectual disability. CDPR is inherited in an autosomal recessive pattern. As mentioned above, some researchers suggest that some cases of Binder type nasomaxillary dysplasia should be classified as a mild form of CDPR.Fetal warfarin syndrome refers to a characteristic pattern of birth defects in a newborn resulting from exposure to certain anticlotting drugs (coumarin group), such as warfarin, during pregnancy. Evidence suggests that the greatest period of risk occurs from approximately six to nine weeks following conception. The most consistent feature is midfacial hypoplasia, with an unusually small, flattened nose; a deep groove between the “wings” of the nose (alae) and the tip; and abnormally small nostrils. Additional abnormalities may include growth deficiency before birth; intellectual disability; an abnormally small head (microcephaly); hearing loss; sudden episodes of uncontrolled electrical activity in the brain (seizures); cataracts; abnormal clouding of the normally transparent regions forming the front of the eyeballs (corneal opacities); and/or other features. As noted previously, some individuals diagnosed with Binder type nasomaxillary dysplasia have had a maternal history of warfarin therapy during pregnancy. In addition, maternal use of certain anticlotting agents in early pregnancy may result in features resembling CDPR, including nasal hypoplasia, abnormal accumulation of calcium salts (calcification) within the growing ends of certain long bones (stippled epiphyses), disproportionate short stature, and/or other abnormalities.Several disorders can have symptoms and physical findings that are similar to those seen in individuals with Binder syndrome including acrodysostosis, Apert syndrome, Keutel syndrome, Stickler syndrome, and various metabolic or chromosomal disorders. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | Related disorders of Binder Type Nasomaxillary Dysplasia. Symptoms of the following disorders can be similar to those of Binder type nasomaxillary dysplasia. Comparisons may be useful for a differential diagnosis.Chondrodysplasia punctata, rhizomelic type (CDPR), is a rare, multisystem disorder that has been shown to be associated with impaired peroxisomal functioning. Peroxisomes are tiny, specialized structures (organelles) within cells that play an essential role in various, ongoing chemical and physical processes in the body (metabolism). CDPR is characterized by the appearance of abnormal, dot-like opacities representing an accumulation of calcium salts (calcification) within the growing ends of certain long bones (i.e., stippled epiphyses); shortening of the long bones of the upper arms (humeri) and the thigh bones (femora); and short stature. The disorder is also typically associated with irregularities of certain bones of the spinal column (vertebrae) and fixed bending or extension of multiple joints (contractures). Affected individuals may also have facial abnormalities that resemble those associated with Binder type nasomaxillary dysplasia, such as a flattened midface (midface hypoplasia), with underdevelopment of the nose (nasal hypoplasia), a low nasal bridge, and small nostrils. Additional abnormalities may include an unusually small head (microcephaly); upwardly slanting eyelid folds (palpebral fissures); loss of transparency of the lenses of the eyes (cataracts); abnormal thickening, dryness, and scaling of the skin (ichthyosis); and/or severe intellectual disability. CDPR is inherited in an autosomal recessive pattern. As mentioned above, some researchers suggest that some cases of Binder type nasomaxillary dysplasia should be classified as a mild form of CDPR.Fetal warfarin syndrome refers to a characteristic pattern of birth defects in a newborn resulting from exposure to certain anticlotting drugs (coumarin group), such as warfarin, during pregnancy. Evidence suggests that the greatest period of risk occurs from approximately six to nine weeks following conception. The most consistent feature is midfacial hypoplasia, with an unusually small, flattened nose; a deep groove between the “wings” of the nose (alae) and the tip; and abnormally small nostrils. Additional abnormalities may include growth deficiency before birth; intellectual disability; an abnormally small head (microcephaly); hearing loss; sudden episodes of uncontrolled electrical activity in the brain (seizures); cataracts; abnormal clouding of the normally transparent regions forming the front of the eyeballs (corneal opacities); and/or other features. As noted previously, some individuals diagnosed with Binder type nasomaxillary dysplasia have had a maternal history of warfarin therapy during pregnancy. In addition, maternal use of certain anticlotting agents in early pregnancy may result in features resembling CDPR, including nasal hypoplasia, abnormal accumulation of calcium salts (calcification) within the growing ends of certain long bones (stippled epiphyses), disproportionate short stature, and/or other abnormalities.Several disorders can have symptoms and physical findings that are similar to those seen in individuals with Binder syndrome including acrodysostosis, Apert syndrome, Keutel syndrome, Stickler syndrome, and various metabolic or chromosomal disorders. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | 160 | Binder Type Nasomaxillary Dysplasia |
nord_160_5 | Diagnosis of Binder Type Nasomaxillary Dysplasia | A diagnosis of Binder syndrome is based upon identification of characteristic symptoms, a detailed patient history, and a thorough clinical evaluation. Certain specialized tests can be used to confirm the diagnosis.Clinical Testing and Workup
Specialized imaging techniques may be used to help obtain a diagnosis of Binder syndrome. Such tests include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues.Such exams may yield specific findings including underdevelopment or absence of the bony protrusion that projects from the base of the nasal septum to join with the middle part of the upper jaw (anterior nasal spine); thinness of a portion of the upper jaw known as the alveolar bone, which forms the dental arch over the upper incisors; underdevelopment or absence of the frontal sinuses; and/or certain abnormalities detected with cephalometric studies, which are scientific measurements of particular craniofacial dimensions. | Diagnosis of Binder Type Nasomaxillary Dysplasia. A diagnosis of Binder syndrome is based upon identification of characteristic symptoms, a detailed patient history, and a thorough clinical evaluation. Certain specialized tests can be used to confirm the diagnosis.Clinical Testing and Workup
Specialized imaging techniques may be used to help obtain a diagnosis of Binder syndrome. Such tests include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues.Such exams may yield specific findings including underdevelopment or absence of the bony protrusion that projects from the base of the nasal septum to join with the middle part of the upper jaw (anterior nasal spine); thinness of a portion of the upper jaw known as the alveolar bone, which forms the dental arch over the upper incisors; underdevelopment or absence of the frontal sinuses; and/or certain abnormalities detected with cephalometric studies, which are scientific measurements of particular craniofacial dimensions. | 160 | Binder Type Nasomaxillary Dysplasia |
nord_160_6 | Therapies of Binder Type Nasomaxillary Dysplasia | TreatmentThe treatment of Binder syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians or general internists, oral and plastic surgeons, craniofacial surgeons, specialists in the diagnosis, prevention, and treatment of crooked teeth (orthodontists), specialists in the diagnosis and treatment of disorders of the bones, joints, ligaments and muscles (orthopedists), and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Psychosocial support for the entire family is essential as well.There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with Binder syndrome.Recommended treatment may include various orthodontic and surgical measures to help correct abnormalities of the jaw and nose. The specific therapeutic procedures performed will vary depending upon the nature and severity of the disorder in each individual including the specific anatomical abnormalities present, a patient’s general health, a patient’s age, patient preference, and other factors. Often more than one surgical procedure is necessary. The specific type and timing of an individual surgical procedure is determined based upon disease severity and patient age. Some affected children have been treated during childhood, while others are not treated until the late teen-age years, which is when the bone stops growing.Some individuals may only require treatment with orthodontic devices such as braces that can straighten teeth or reposition the jaw. Nose (nasal) reconstruction can be accomplished with bone or cartilage grafts, or the implantation of alloplastic materials. In some cases, the grafting of cartilage from the ribs has been used successfully to reconstruct the nose (costochondral graft).More severe cases require surgical procedures known as Le Fort I or II osteotomy. During Le Fort I osteotomy, the upper jaw is sectioned and repositioned to treat malocclusion and, if present, cleft palate. Le Fort II osteotomy involves repositioning the upper jaw and nose and correcting the backward displacement (retrusion) of the middle portion of the face.Treatment of the nasal deformity usually involves adding cartilage grafts to the bridge and to support the tip to give more projection and shape. These may be from the ear, but in most cases one needs more cartilage and the rib may be used. The narrow nasal passages may also require treatment. | Therapies of Binder Type Nasomaxillary Dysplasia. TreatmentThe treatment of Binder syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians or general internists, oral and plastic surgeons, craniofacial surgeons, specialists in the diagnosis, prevention, and treatment of crooked teeth (orthodontists), specialists in the diagnosis and treatment of disorders of the bones, joints, ligaments and muscles (orthopedists), and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Psychosocial support for the entire family is essential as well.There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with Binder syndrome.Recommended treatment may include various orthodontic and surgical measures to help correct abnormalities of the jaw and nose. The specific therapeutic procedures performed will vary depending upon the nature and severity of the disorder in each individual including the specific anatomical abnormalities present, a patient’s general health, a patient’s age, patient preference, and other factors. Often more than one surgical procedure is necessary. The specific type and timing of an individual surgical procedure is determined based upon disease severity and patient age. Some affected children have been treated during childhood, while others are not treated until the late teen-age years, which is when the bone stops growing.Some individuals may only require treatment with orthodontic devices such as braces that can straighten teeth or reposition the jaw. Nose (nasal) reconstruction can be accomplished with bone or cartilage grafts, or the implantation of alloplastic materials. In some cases, the grafting of cartilage from the ribs has been used successfully to reconstruct the nose (costochondral graft).More severe cases require surgical procedures known as Le Fort I or II osteotomy. During Le Fort I osteotomy, the upper jaw is sectioned and repositioned to treat malocclusion and, if present, cleft palate. Le Fort II osteotomy involves repositioning the upper jaw and nose and correcting the backward displacement (retrusion) of the middle portion of the face.Treatment of the nasal deformity usually involves adding cartilage grafts to the bridge and to support the tip to give more projection and shape. These may be from the ear, but in most cases one needs more cartilage and the rib may be used. The narrow nasal passages may also require treatment. | 160 | Binder Type Nasomaxillary Dysplasia |
nord_161_0 | Overview of Binswanger Disease | Binswanger disease is a progressive neurological disorder caused by arteriosclerosis and thromboembolism affecting the blood vessels that supply the white-matter (nerve fiber pathways) and clusters of nerve cells (basal ganglia and thalamus) beneath the surface of the brain (cerebral cortex). Most patients experience progressive loss of memory and intellectual abilities (dementia), urinary urgency or incontinence and an abnormally slow, shuffling, unsteady pattern of walking, usually over a 5–10-year period. Due to their vascular etiology, the symptoms and physical findings associated with Binswanger disease may suddenly worsen due to stroke, stabilize and then improve for a brief time, but the patient’s overall condition continues to progress as the blood vessels become increasingly obstructed. | Overview of Binswanger Disease. Binswanger disease is a progressive neurological disorder caused by arteriosclerosis and thromboembolism affecting the blood vessels that supply the white-matter (nerve fiber pathways) and clusters of nerve cells (basal ganglia and thalamus) beneath the surface of the brain (cerebral cortex). Most patients experience progressive loss of memory and intellectual abilities (dementia), urinary urgency or incontinence and an abnormally slow, shuffling, unsteady pattern of walking, usually over a 5–10-year period. Due to their vascular etiology, the symptoms and physical findings associated with Binswanger disease may suddenly worsen due to stroke, stabilize and then improve for a brief time, but the patient’s overall condition continues to progress as the blood vessels become increasingly obstructed. | 161 | Binswanger Disease |
nord_161_1 | Symptoms of Binswanger Disease | Affected individuals often become depressed, uncaring (apathetic), inactive and unable to act or make decisions (abulic). They become withdrawn and exhibit poor judgement, reduced planning and organizational skills, and less spontaneous communication. In addition, affected individuals may have difficulty with speech (dysarthria), swallowing (dysphagia) and urinary bladder control (incontinence). Some patients exhibit abnormalities similar to those seen in Parkinson disease, such as slowness, poor balance and short, shuffling steps (Parkinsonism). Tremor is usually not a feature.Many individuals with Binswanger disease have a history of strokes or transient ischemic attacks. Consequently, some symptoms and signs of this disease may develop in a stuttering or stepwise fashion, but there is also gradual deterioration due to progressive destruction of nerve fiber pathways deep in the brain (subcortical white matter). Therefore, Binswanger disease may be difficult to discern from neurodegenerative diseases like Alzheimer disease and dementia with Lewy bodies, which begin insidiously and progress gradually (see Related Disorders). Furthermore, Binswanger disease and neurodegenerative diseases commonly coexist in the same patient because these conditions are so common in older people. | Symptoms of Binswanger Disease. Affected individuals often become depressed, uncaring (apathetic), inactive and unable to act or make decisions (abulic). They become withdrawn and exhibit poor judgement, reduced planning and organizational skills, and less spontaneous communication. In addition, affected individuals may have difficulty with speech (dysarthria), swallowing (dysphagia) and urinary bladder control (incontinence). Some patients exhibit abnormalities similar to those seen in Parkinson disease, such as slowness, poor balance and short, shuffling steps (Parkinsonism). Tremor is usually not a feature.Many individuals with Binswanger disease have a history of strokes or transient ischemic attacks. Consequently, some symptoms and signs of this disease may develop in a stuttering or stepwise fashion, but there is also gradual deterioration due to progressive destruction of nerve fiber pathways deep in the brain (subcortical white matter). Therefore, Binswanger disease may be difficult to discern from neurodegenerative diseases like Alzheimer disease and dementia with Lewy bodies, which begin insidiously and progress gradually (see Related Disorders). Furthermore, Binswanger disease and neurodegenerative diseases commonly coexist in the same patient because these conditions are so common in older people. | 161 | Binswanger Disease |
nord_161_2 | Causes of Binswanger Disease | Binswanger disease is caused by arteriosclerosis, thromboembolism and other diseases that obstruct blood vessels that supply the deep structures of the brain. Hypertension, smoking, hypercholesterolemia, heart disease and diabetes mellitus are risk factors for Binswanger disease. Rare hereditary diseases such as CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) also cause Binswanger disease. Thus, Binswanger disease is actually a clinical syndrome of vascular dementia with multiple causes, not a specific disease. The reduced blood flow in brain tissue appears to produce secondary inflammation that may be a target for treatment. | Causes of Binswanger Disease. Binswanger disease is caused by arteriosclerosis, thromboembolism and other diseases that obstruct blood vessels that supply the deep structures of the brain. Hypertension, smoking, hypercholesterolemia, heart disease and diabetes mellitus are risk factors for Binswanger disease. Rare hereditary diseases such as CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) also cause Binswanger disease. Thus, Binswanger disease is actually a clinical syndrome of vascular dementia with multiple causes, not a specific disease. The reduced blood flow in brain tissue appears to produce secondary inflammation that may be a target for treatment. | 161 | Binswanger Disease |
nord_161_3 | Affects of Binswanger Disease | Binswanger disease affects males and females in equal numbers and usually occurs in individuals aged 50 years or older. | Affects of Binswanger Disease. Binswanger disease affects males and females in equal numbers and usually occurs in individuals aged 50 years or older. | 161 | Binswanger Disease |
nord_161_4 | Related disorders of Binswanger Disease | Symptoms of the following disorders can be similar to those of Binswanger disease. Comparisons may be useful for a differential diagnosis.Alzheimer Disease
Alzheimer disease is a common progressive disorder of the brain affecting memory, intellect and language function. Alzheimer patients are at increased risk of falling, but most exhibit little or no gross locomotor disturbance until very late in the disease.Dementia with Lewy Bodies (DLB)
Patients with DLB have Parkinsonism and dementia that begin simultaneously. Patients with DLB have difficulty with attention, concentration and multitasking (executive function). They are also prone to depression, visual hallucinations, sleep disturbances and day-to-day fluctuations in cognitive function. Memory is often less affected than in Alzheimer disease. The Parkinsonism in DLB is gradually progressive and consists of slowness (bradykinesia), muscle stiffness (rigidity), stooped posture and slow shuffling gait that is often poorly responsive to levodopa. Tremor is frequently mild or absent, compared to classic Parkinson disease. REM (rapid eye movement) sleep behavior (vocalizations and movement during dreams) is common and may be violent.Frontotemporal Degeneration
Pick disease and other forms of frontotemporal degeneration typically begin before age 65. The initial presentation is often personality change (e.g., impaired judgement, impulsive behavior, and blunted emotions), which may lead to psychiatric consultation. Loss of communication skills is another common presentation. Motor disturbances may occur early or late in the disease. Gradually progressive dementia occurs in all patients. (For more information on this disorder, choose “frontotemporal” as your search term in the Rare Disease Database.)Normal Pressure Hydrocephalus
Binswanger disease may be difficult to distinguish from so-called normal pressure hydrocephalus (NPH). Both conditions are associated with the three clinical features of gait disturbance, dementia and urinary incontinence. However, NPH progresses gradually, not in the stuttering or stepwise fashion of vascular disease. The ventricular system of the brain commonly enlarges in Binswanger disease and neurodegenerative dementias (hydrocephalus ex vacuo), so distinguishing these conditions from NPH is often difficult.There are many other neurological disorders that can cause dementia and memory disturbances. | Related disorders of Binswanger Disease. Symptoms of the following disorders can be similar to those of Binswanger disease. Comparisons may be useful for a differential diagnosis.Alzheimer Disease
Alzheimer disease is a common progressive disorder of the brain affecting memory, intellect and language function. Alzheimer patients are at increased risk of falling, but most exhibit little or no gross locomotor disturbance until very late in the disease.Dementia with Lewy Bodies (DLB)
Patients with DLB have Parkinsonism and dementia that begin simultaneously. Patients with DLB have difficulty with attention, concentration and multitasking (executive function). They are also prone to depression, visual hallucinations, sleep disturbances and day-to-day fluctuations in cognitive function. Memory is often less affected than in Alzheimer disease. The Parkinsonism in DLB is gradually progressive and consists of slowness (bradykinesia), muscle stiffness (rigidity), stooped posture and slow shuffling gait that is often poorly responsive to levodopa. Tremor is frequently mild or absent, compared to classic Parkinson disease. REM (rapid eye movement) sleep behavior (vocalizations and movement during dreams) is common and may be violent.Frontotemporal Degeneration
Pick disease and other forms of frontotemporal degeneration typically begin before age 65. The initial presentation is often personality change (e.g., impaired judgement, impulsive behavior, and blunted emotions), which may lead to psychiatric consultation. Loss of communication skills is another common presentation. Motor disturbances may occur early or late in the disease. Gradually progressive dementia occurs in all patients. (For more information on this disorder, choose “frontotemporal” as your search term in the Rare Disease Database.)Normal Pressure Hydrocephalus
Binswanger disease may be difficult to distinguish from so-called normal pressure hydrocephalus (NPH). Both conditions are associated with the three clinical features of gait disturbance, dementia and urinary incontinence. However, NPH progresses gradually, not in the stuttering or stepwise fashion of vascular disease. The ventricular system of the brain commonly enlarges in Binswanger disease and neurodegenerative dementias (hydrocephalus ex vacuo), so distinguishing these conditions from NPH is often difficult.There are many other neurological disorders that can cause dementia and memory disturbances. | 161 | Binswanger Disease |
nord_161_5 | Diagnosis of Binswanger Disease | The diagnosis of Binswanger disease is usually based on a thorough clinical evaluation, including a detailed patient history, physical examination and magnetic resonance imaging (MRI) or computerized tomography (CT) scanning of the brain. MRI and CT reveal nerve fiber (white matter) degeneration and multiple small strokes in the deep structures of the brain. | Diagnosis of Binswanger Disease. The diagnosis of Binswanger disease is usually based on a thorough clinical evaluation, including a detailed patient history, physical examination and magnetic resonance imaging (MRI) or computerized tomography (CT) scanning of the brain. MRI and CT reveal nerve fiber (white matter) degeneration and multiple small strokes in the deep structures of the brain. | 161 | Binswanger Disease |
nord_161_6 | Therapies of Binswanger Disease | TreatmentThe ischemic brain damage in Binswanger disease is not reversible, so treatment is focused on reducing risk factors for stroke, thereby retarding progression of the disease. Treatment usually involves the use of anti-hypertensive drugs to control blood pressure, antiplatelet drugs (e.g., aspirin) or warfarin to reduce thromboembolism, statins to reduce atherosclerosis, smoking cessation and diabetic control. Inflammation appears to play a role in small vessel damage, but there is no proven way of treating this.It is important to remember that Binswanger disease often coexists with neurodegenerative diseases such as Alzheimer disease, dementia with Lewy bodies and Parkinson disease. Consequently, patients often receive trials of cholinesterase inhibitors (e.g., donepezil, rivastigmine, galantamine) for cognitive impairment and levodopa for motor impairment.Other treatment is symptomatic and supportive. Antidepressant drugs are helpful in the management of depression associated with Binswanger disease. Good sleep hygiene and regular exercise are very important. Speech therapy is helpful in the assessment and treatment of speech and swallowing difficulties. Occupational therapy can perform in-home safety evaluations and recommend useful aids and strategies to improve safety and independence. Patients often benefit from some of the same physical therapy and exercise programs that are useful in Parkinson disease. | Therapies of Binswanger Disease. TreatmentThe ischemic brain damage in Binswanger disease is not reversible, so treatment is focused on reducing risk factors for stroke, thereby retarding progression of the disease. Treatment usually involves the use of anti-hypertensive drugs to control blood pressure, antiplatelet drugs (e.g., aspirin) or warfarin to reduce thromboembolism, statins to reduce atherosclerosis, smoking cessation and diabetic control. Inflammation appears to play a role in small vessel damage, but there is no proven way of treating this.It is important to remember that Binswanger disease often coexists with neurodegenerative diseases such as Alzheimer disease, dementia with Lewy bodies and Parkinson disease. Consequently, patients often receive trials of cholinesterase inhibitors (e.g., donepezil, rivastigmine, galantamine) for cognitive impairment and levodopa for motor impairment.Other treatment is symptomatic and supportive. Antidepressant drugs are helpful in the management of depression associated with Binswanger disease. Good sleep hygiene and regular exercise are very important. Speech therapy is helpful in the assessment and treatment of speech and swallowing difficulties. Occupational therapy can perform in-home safety evaluations and recommend useful aids and strategies to improve safety and independence. Patients often benefit from some of the same physical therapy and exercise programs that are useful in Parkinson disease. | 161 | Binswanger Disease |
nord_162_0 | Overview of Biotinidase Deficiency | SummaryBiotinidase deficiency (BTD) deficiency is a treatable, inherited condition. BTD affects the way the body processes a vitamin called biotin (sometimes called vitamin H). Biotin is an important vitamin that helps the body break down protein, fats, and carbohydrates.Biotinidase is an enzyme that helps recycle biotin to be reused by the body. Bitotinidase deficiency happens when this enzyme this isn’t working properly. BTD is caused by genetic changes (mutations) in the BTD gene.If untreated, BTD can cause health problems such as:BTD can have other features as well, including skin differences like rashes (eczema) and hair loss (alopecia).BTD can be treated by giving people with the condition extra biotin for their body to use. If treated early, people with BTD can avoid all symptoms of the condition and lead a normal, healthy life.IntroductionBiotinidase deficiency is sometimes categorized into groups depending on how much of the biotinidase enzyme is working. These two categories are profound BTD and partial BTD. People with profound BTD tend to have more severe symptoms earlier in life than people with partial BTD. Both forms of BTD can be treated with biotin supplements. Early diagnosis and treatment of BTD can prevent symptoms from happening. Nearly all infants with either profound or partial BTD can be detected in the US by newborn screening. However, not every country has added BTD to its newborn screening program. | Overview of Biotinidase Deficiency. SummaryBiotinidase deficiency (BTD) deficiency is a treatable, inherited condition. BTD affects the way the body processes a vitamin called biotin (sometimes called vitamin H). Biotin is an important vitamin that helps the body break down protein, fats, and carbohydrates.Biotinidase is an enzyme that helps recycle biotin to be reused by the body. Bitotinidase deficiency happens when this enzyme this isn’t working properly. BTD is caused by genetic changes (mutations) in the BTD gene.If untreated, BTD can cause health problems such as:BTD can have other features as well, including skin differences like rashes (eczema) and hair loss (alopecia).BTD can be treated by giving people with the condition extra biotin for their body to use. If treated early, people with BTD can avoid all symptoms of the condition and lead a normal, healthy life.IntroductionBiotinidase deficiency is sometimes categorized into groups depending on how much of the biotinidase enzyme is working. These two categories are profound BTD and partial BTD. People with profound BTD tend to have more severe symptoms earlier in life than people with partial BTD. Both forms of BTD can be treated with biotin supplements. Early diagnosis and treatment of BTD can prevent symptoms from happening. Nearly all infants with either profound or partial BTD can be detected in the US by newborn screening. However, not every country has added BTD to its newborn screening program. | 162 | Biotinidase Deficiency |
nord_162_1 | Symptoms of Biotinidase Deficiency | Infants with BTD may be born without signs of the condition. Symptoms of BTD usually appear after the first few weeks or months of life. Treating BTD with biotin supplements before symptoms show up can prevent them from happening. Below is a list of symptoms that infants and children with profound untreated BTD may have. It is important to know that not every person with BTD will show all of these symptoms.Many of the symptoms of BTD are neurological, which means they affect the brain and nervous system.About 70% of infants with BTD will experience seizures if they are not treated. This is often the first symptom of the condition. Seizures in infants may look different than seizures in adults. Some signs of seizures in infants include:Because the seizures are caused by the body being unable to recycle biotin, they may not stop with seizure medications (anticonvulsants). However, the seizures do respond to biotin therapy and often should stop within minutes to hours of receiving biotin treatment.
Some infants with BTD may have weak muscles and low muscle tone. This is called hypotonia. Infants with hypotonia may look abnormally “floppy.” Hypotonia can affect feeding and motor skills such sitting up without assistance.
Affected infants and children may experience delays in reaching developmental milestones, including holding one’s head up or pulling up to stand.
Infants with BTD may also have problems with vision or hearing. These issues can be prevented if biotin therapy is started early.
Some other common features of BTD include eye infections, like pink eye (conjunctivitis), hair loss (alopecia), and a certain type of skin rash called eczema.
Infants with BTD may have specific molecules in their urine, such as lactic acid (lactic aciduria) or low but noticeable amounts of ammonia.
Some infants may have other symptoms like:Without treatment with biotin, infants with BTD can develop coma and may even die.Children and adults with partial biotinidase who don’t receive biotin supplements may show mild symptoms of the condition during times of stress, like times of illness. | Symptoms of Biotinidase Deficiency. Infants with BTD may be born without signs of the condition. Symptoms of BTD usually appear after the first few weeks or months of life. Treating BTD with biotin supplements before symptoms show up can prevent them from happening. Below is a list of symptoms that infants and children with profound untreated BTD may have. It is important to know that not every person with BTD will show all of these symptoms.Many of the symptoms of BTD are neurological, which means they affect the brain and nervous system.About 70% of infants with BTD will experience seizures if they are not treated. This is often the first symptom of the condition. Seizures in infants may look different than seizures in adults. Some signs of seizures in infants include:Because the seizures are caused by the body being unable to recycle biotin, they may not stop with seizure medications (anticonvulsants). However, the seizures do respond to biotin therapy and often should stop within minutes to hours of receiving biotin treatment.
Some infants with BTD may have weak muscles and low muscle tone. This is called hypotonia. Infants with hypotonia may look abnormally “floppy.” Hypotonia can affect feeding and motor skills such sitting up without assistance.
Affected infants and children may experience delays in reaching developmental milestones, including holding one’s head up or pulling up to stand.
Infants with BTD may also have problems with vision or hearing. These issues can be prevented if biotin therapy is started early.
Some other common features of BTD include eye infections, like pink eye (conjunctivitis), hair loss (alopecia), and a certain type of skin rash called eczema.
Infants with BTD may have specific molecules in their urine, such as lactic acid (lactic aciduria) or low but noticeable amounts of ammonia.
Some infants may have other symptoms like:Without treatment with biotin, infants with BTD can develop coma and may even die.Children and adults with partial biotinidase who don’t receive biotin supplements may show mild symptoms of the condition during times of stress, like times of illness. | 162 | Biotinidase Deficiency |
nord_162_2 | Causes of Biotinidase Deficiency | Biotinidase deficiency is a genetic disorder caused by changes (mutations) in the BTD gene. The BTD gene instructs the body in creating the enzyme biotinidase that helps the body recycle an important vitamin called biotin (vitamin H). When the body is not able to recycle biotin, health concerns like the symptoms above can happen.We all have two copies of every gene. We inherit one copy from out mother and one copy from our father. Genetic diseases are determined by the combination of genes received from our father and mother. Biotinidase deficiency is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits the same non-working 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 non-working 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.All individuals carry 20-30 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. | Causes of Biotinidase Deficiency. Biotinidase deficiency is a genetic disorder caused by changes (mutations) in the BTD gene. The BTD gene instructs the body in creating the enzyme biotinidase that helps the body recycle an important vitamin called biotin (vitamin H). When the body is not able to recycle biotin, health concerns like the symptoms above can happen.We all have two copies of every gene. We inherit one copy from out mother and one copy from our father. Genetic diseases are determined by the combination of genes received from our father and mother. Biotinidase deficiency is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits the same non-working 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 non-working 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.All individuals carry 20-30 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. | 162 | Biotinidase Deficiency |
nord_162_3 | Affects of Biotinidase Deficiency | Biotinidase deficiency is a rare disorder. The early-onset form (profound BTD) usually begins during the newborn (neonatal) period. The juvenile form (partial BTD) usually begins at about three months of age. Both males and females are affected in equal numbers.One in 140,000 people have profound biotinidase deficiency.
One in 110,000 people have partial biotinidase deficiency.
One in 60,000 people have either profound or partial biotinidase deficiency.Approximately 1 in 120 people are carriers of one gene for BTD, but this number may be higher in the Hispanic population and lower in the African American population. | Affects of Biotinidase Deficiency. Biotinidase deficiency is a rare disorder. The early-onset form (profound BTD) usually begins during the newborn (neonatal) period. The juvenile form (partial BTD) usually begins at about three months of age. Both males and females are affected in equal numbers.One in 140,000 people have profound biotinidase deficiency.
One in 110,000 people have partial biotinidase deficiency.
One in 60,000 people have either profound or partial biotinidase deficiency.Approximately 1 in 120 people are carriers of one gene for BTD, but this number may be higher in the Hispanic population and lower in the African American population. | 162 | Biotinidase Deficiency |
nord_162_4 | Related disorders of Biotinidase Deficiency | Symptoms of the following disorders can be similar to those of biotinidase deficiency. Comparisons may be useful for a differential diagnosis.Other conditions involve breaking down (metabolizing) body chemicals, but unlike BTD, some of these conditions may not be identified by newborn screening. Holocarboxylase Synthetase Deficiency (HCSD)Physicians may have difficulty distinguishing between BTD and HCDS. Many of the symptoms are similar and each is responsive to treatment with biotin. Both conditions are genetic and inherited in an autosomal recessive manner. The term holocarboxylase refers to an enzymatic chemical process in which any of three complex organic acids may be involved. These three complex organic acids are normal body metabolites that require biotin as a co-factor. Because the chemical process involved is the same for each of the three organic acids, the disorder was termed “multiple carboxylase deficiency”.Isolated Carboxylase DeficiencyAs noted above, biotin is required to build up or metabolize any of three complex organic acids. If a mutation occurs in a gene, such that the reaction involving one of these organic acids fails, then the resulting disorder is known as an “isolated carboxylase deficiency”. Many of the symptoms and signs of these isolated carboxylase reactions are similar to those exhibited by patients with BTD and HCSD. | Related disorders of Biotinidase Deficiency. Symptoms of the following disorders can be similar to those of biotinidase deficiency. Comparisons may be useful for a differential diagnosis.Other conditions involve breaking down (metabolizing) body chemicals, but unlike BTD, some of these conditions may not be identified by newborn screening. Holocarboxylase Synthetase Deficiency (HCSD)Physicians may have difficulty distinguishing between BTD and HCDS. Many of the symptoms are similar and each is responsive to treatment with biotin. Both conditions are genetic and inherited in an autosomal recessive manner. The term holocarboxylase refers to an enzymatic chemical process in which any of three complex organic acids may be involved. These three complex organic acids are normal body metabolites that require biotin as a co-factor. Because the chemical process involved is the same for each of the three organic acids, the disorder was termed “multiple carboxylase deficiency”.Isolated Carboxylase DeficiencyAs noted above, biotin is required to build up or metabolize any of three complex organic acids. If a mutation occurs in a gene, such that the reaction involving one of these organic acids fails, then the resulting disorder is known as an “isolated carboxylase deficiency”. Many of the symptoms and signs of these isolated carboxylase reactions are similar to those exhibited by patients with BTD and HCSD. | 162 | Biotinidase Deficiency |
nord_162_5 | Diagnosis of Biotinidase Deficiency | Biotinidase deficiency can be diagnosed in newborns through newborn screening. Newborn screening is a special type of screening test that newborns receive to see if they have certain diseases. Because the newborn screen is a screening test, a positive result does not mean that an infant definitely has the disease. Often, a repeat test must be done to confirm the diagnosis. A clinical diagnosis is possible after birth by testing for biotinidase activity in the blood. Usually, this is performed when signs and symptoms of BTD become clearer. In some infants, a genetic test may be ordered to identify the specific gene changes (mutation) that are causing BTD. Prenatal testing of sample fluid from the womb for biotinidase activity is available as early as 12 weeks of pregnancy (this includes chorionic villi sampling and amniocentesis). | Diagnosis of Biotinidase Deficiency. Biotinidase deficiency can be diagnosed in newborns through newborn screening. Newborn screening is a special type of screening test that newborns receive to see if they have certain diseases. Because the newborn screen is a screening test, a positive result does not mean that an infant definitely has the disease. Often, a repeat test must be done to confirm the diagnosis. A clinical diagnosis is possible after birth by testing for biotinidase activity in the blood. Usually, this is performed when signs and symptoms of BTD become clearer. In some infants, a genetic test may be ordered to identify the specific gene changes (mutation) that are causing BTD. Prenatal testing of sample fluid from the womb for biotinidase activity is available as early as 12 weeks of pregnancy (this includes chorionic villi sampling and amniocentesis). | 162 | Biotinidase Deficiency |
nord_162_6 | Therapies of Biotinidase Deficiency | TreatmentBiotinidase deficiency is treated with oral biotin (vitamin H; coenzyme R, part of vitamin B complex) supplements. Treatment should begin as soon as the diagnosis is made. With biotin treatment, symptoms of the disorder may disappear. However, a person with biotinidase deficiency may have to take biotin for his/her entire lifetime. Genetic counseling is recommended for families of a child with biotinidase deficiency. Genetic counselors are healthcare providers that help families understand genetic conditions and make genetic testing decisions. | Therapies of Biotinidase Deficiency. TreatmentBiotinidase deficiency is treated with oral biotin (vitamin H; coenzyme R, part of vitamin B complex) supplements. Treatment should begin as soon as the diagnosis is made. With biotin treatment, symptoms of the disorder may disappear. However, a person with biotinidase deficiency may have to take biotin for his/her entire lifetime. Genetic counseling is recommended for families of a child with biotinidase deficiency. Genetic counselors are healthcare providers that help families understand genetic conditions and make genetic testing decisions. | 162 | Biotinidase Deficiency |
nord_163_0 | Overview of Birt-Hogg-Dubé Syndrome | Summary
Birt-Hogg-Dubé (BHD) syndrome is a rare complex genetic skin disorder (genodermatosis) characterized by the development of skin papules generally located on the head, face and upper torso. These benign (noncancerous) tumors of the hair follicle are called fibrofolliculomas. BHD syndrome also predisposes individuals to the development of benign cysts in the lungs, repeated episodes of a collapsed lung (pneumothorax) and increased risk for developing kidney neoplasia. BHD syndrome is caused by changes (pathogenic variants or mutations) in the FLCN gene and is inherited in an autosomal dominant pattern.Introduction
BHD syndrome was first described in the medical literature in 1977 by three Canadian physicians (Drs. Birt, Hogg and Dubé) for whom the disease was named. | Overview of Birt-Hogg-Dubé Syndrome. Summary
Birt-Hogg-Dubé (BHD) syndrome is a rare complex genetic skin disorder (genodermatosis) characterized by the development of skin papules generally located on the head, face and upper torso. These benign (noncancerous) tumors of the hair follicle are called fibrofolliculomas. BHD syndrome also predisposes individuals to the development of benign cysts in the lungs, repeated episodes of a collapsed lung (pneumothorax) and increased risk for developing kidney neoplasia. BHD syndrome is caused by changes (pathogenic variants or mutations) in the FLCN gene and is inherited in an autosomal dominant pattern.Introduction
BHD syndrome was first described in the medical literature in 1977 by three Canadian physicians (Drs. Birt, Hogg and Dubé) for whom the disease was named. | 163 | Birt-Hogg-Dubé Syndrome |
nord_163_1 | Symptoms of Birt-Hogg-Dubé Syndrome | The symptoms of Birt-Hogg-Dubé syndrome vary from person to person. The most common symptoms are multiple, benign skin lesions, lung (pulmonary) cysts, increased risk of repeated collapsed lungs (pneumothorax) and kidney (renal) neoplasia (malignant and benign tumors). Skin papules are the most frequent symptom occurring in up to 85% of individuals with BHD, but some affected individuals may develop lung cysts/pneumothorax and renal neoplasia without skin lesions. Symptoms of BHD may vary in affected members of a single BHD family who inherit the same FLCN gene variant, and patients may develop one, two or all three of the characteristic features in any combination.The skin papules known as fibrofolliculomas that are associated with BHD syndrome commonly occur on the scalp, face and neck, but can also be found on the ear lobes and in the oral mucosa. They are generally 2-3mm in size, dome shaped, flesh-colored and are not associated with any pain or discomfort. The onset is usually after the age of 20. Skin lesions may increase in number as affected individuals age. The number of skin lesions can vary dramatically; some individuals may only have a few skin lesions, while others may have a hundred or more.In the original description of BHD syndrome, two other skin lesions were noted: trichodiscomas, benign tumors of the hair disc, and acrochordons or skin tags that appear as soft small growths that hang off the skin and are common in the general population. Some researchers believe that trichodiscomas and fibrofolliculomas are the same lesion despite different surface appearances.
Individuals with BHD syndrome may also develop multiple lung (pulmonary) cysts in both lungs, which occur in greater than 80% of individuals affected with BHD. These cysts usually do not cause symptoms (asymptomatic) and lung function is generally normal, but up to one-third of affected individuals may experience repeated occurrences of a collapsed lung (spontaneous pneumothorax). A collapsed lung occurs when air or gas is trapped in the space surrounding the lungs. When the cause is not known (e.g., trauma, injury), it is referred to as spontaneous. Pneumothorax in BHD syndrome occurs more often in younger individuals and has been reported in children as young as 7 years old. Individuals in a BHD family who inherit the diseae-causing FLCN variant have a 50-fold greater risk of developing spontaneous pneumothorax than their unaffected siblings.Approximately 15-30 % of individuals with BHD syndrome may develop multiple kidney (renal) neoplasms. These are usually slow growing and can affect both kidneys (bilateral). The mean age of diagnosis for renal neoplasia is 48-50 years old. The most common tumor types are the hybrid oncocytic tumor (a hybrid consisting of both oncocytoma and chromophobe histologic cell types), and chromophobe renal cell carcinoma, both of which are malignant (cancerous). Renal oncocytomas, which are benign tumors, can also develop but occur only rarely. Individuals affected with BHD have a 7-fold greater risk of developing renal neoplasia than siblings who do not inherit the FLCN variant.In 1975, two researchers reported on a disorder that became known as Hornstein-Knickenberg syndrome. This disorder is now considered to be the same as BHD syndrome. Affected individuals with Hornstein-Knickenberg syndrome had polyps in the colon in addition to skin lesions. Some researchers believe that colonic polyps are a coincidental finding in individuals with BHD syndrome and not part of the disorder; more family studies are needed to determine whether colon polyps are an additional symptom of BHD.Other findings have been reported in a few cases of BHD syndrome including oral papules in the mouth, benign tumors consisting of fatty tissue (lipomas), benign tumors consisting of fatty tissue and an abnormally large number of blood vessels (angiolipomas), a benign tumor of the parathyroid glands (parathyroid adenoma), a benign tumor of the salivary gland (parotid oncocytoma) and a lesion or birthmark consisting of thickened, abnormally firm connective tissue (connective tissue nevus). Researchers do not know whether these findings are incidental or true manifestations of BHD syndrome. | Symptoms of Birt-Hogg-Dubé Syndrome. The symptoms of Birt-Hogg-Dubé syndrome vary from person to person. The most common symptoms are multiple, benign skin lesions, lung (pulmonary) cysts, increased risk of repeated collapsed lungs (pneumothorax) and kidney (renal) neoplasia (malignant and benign tumors). Skin papules are the most frequent symptom occurring in up to 85% of individuals with BHD, but some affected individuals may develop lung cysts/pneumothorax and renal neoplasia without skin lesions. Symptoms of BHD may vary in affected members of a single BHD family who inherit the same FLCN gene variant, and patients may develop one, two or all three of the characteristic features in any combination.The skin papules known as fibrofolliculomas that are associated with BHD syndrome commonly occur on the scalp, face and neck, but can also be found on the ear lobes and in the oral mucosa. They are generally 2-3mm in size, dome shaped, flesh-colored and are not associated with any pain or discomfort. The onset is usually after the age of 20. Skin lesions may increase in number as affected individuals age. The number of skin lesions can vary dramatically; some individuals may only have a few skin lesions, while others may have a hundred or more.In the original description of BHD syndrome, two other skin lesions were noted: trichodiscomas, benign tumors of the hair disc, and acrochordons or skin tags that appear as soft small growths that hang off the skin and are common in the general population. Some researchers believe that trichodiscomas and fibrofolliculomas are the same lesion despite different surface appearances.
Individuals with BHD syndrome may also develop multiple lung (pulmonary) cysts in both lungs, which occur in greater than 80% of individuals affected with BHD. These cysts usually do not cause symptoms (asymptomatic) and lung function is generally normal, but up to one-third of affected individuals may experience repeated occurrences of a collapsed lung (spontaneous pneumothorax). A collapsed lung occurs when air or gas is trapped in the space surrounding the lungs. When the cause is not known (e.g., trauma, injury), it is referred to as spontaneous. Pneumothorax in BHD syndrome occurs more often in younger individuals and has been reported in children as young as 7 years old. Individuals in a BHD family who inherit the diseae-causing FLCN variant have a 50-fold greater risk of developing spontaneous pneumothorax than their unaffected siblings.Approximately 15-30 % of individuals with BHD syndrome may develop multiple kidney (renal) neoplasms. These are usually slow growing and can affect both kidneys (bilateral). The mean age of diagnosis for renal neoplasia is 48-50 years old. The most common tumor types are the hybrid oncocytic tumor (a hybrid consisting of both oncocytoma and chromophobe histologic cell types), and chromophobe renal cell carcinoma, both of which are malignant (cancerous). Renal oncocytomas, which are benign tumors, can also develop but occur only rarely. Individuals affected with BHD have a 7-fold greater risk of developing renal neoplasia than siblings who do not inherit the FLCN variant.In 1975, two researchers reported on a disorder that became known as Hornstein-Knickenberg syndrome. This disorder is now considered to be the same as BHD syndrome. Affected individuals with Hornstein-Knickenberg syndrome had polyps in the colon in addition to skin lesions. Some researchers believe that colonic polyps are a coincidental finding in individuals with BHD syndrome and not part of the disorder; more family studies are needed to determine whether colon polyps are an additional symptom of BHD.Other findings have been reported in a few cases of BHD syndrome including oral papules in the mouth, benign tumors consisting of fatty tissue (lipomas), benign tumors consisting of fatty tissue and an abnormally large number of blood vessels (angiolipomas), a benign tumor of the parathyroid glands (parathyroid adenoma), a benign tumor of the salivary gland (parotid oncocytoma) and a lesion or birthmark consisting of thickened, abnormally firm connective tissue (connective tissue nevus). Researchers do not know whether these findings are incidental or true manifestations of BHD syndrome. | 163 | Birt-Hogg-Dubé Syndrome |
nord_163_2 | Causes of Birt-Hogg-Dubé Syndrome | BHD syndrome is caused by changes (pathogenic variant or mutations) in the FLCN gene. The FLCN gene carries the instructions to produce (encode) folliculin, a protein whose precise function is not known, but which interacts with proteins that function in cellular pathways involved in cell growth, energy production and metabolism. The FLCN gene is a tumor suppressor gene, a gene that keeps cell growth in check or slows its growth, repairs damage to the DNA of cells and tells cells when to die, a normal process called apoptosis. Variants in a tumor suppressor gene often predispose individuals to develop cancer, but having a gene variant does not absolutely guarantee development of the disease.The predisposition to develop Birt-Hogg-Dubé syndrome is inherited in an autosomal dominant pattern. 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 gene change in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.In some individuals, the predisposition to the disorder is due to a spontaneous (de novo) gene change that occurs in the egg or sperm cell. In such situations, the disorder is not inherited from the parents. | Causes of Birt-Hogg-Dubé Syndrome. BHD syndrome is caused by changes (pathogenic variant or mutations) in the FLCN gene. The FLCN gene carries the instructions to produce (encode) folliculin, a protein whose precise function is not known, but which interacts with proteins that function in cellular pathways involved in cell growth, energy production and metabolism. The FLCN gene is a tumor suppressor gene, a gene that keeps cell growth in check or slows its growth, repairs damage to the DNA of cells and tells cells when to die, a normal process called apoptosis. Variants in a tumor suppressor gene often predispose individuals to develop cancer, but having a gene variant does not absolutely guarantee development of the disease.The predisposition to develop Birt-Hogg-Dubé syndrome is inherited in an autosomal dominant pattern. 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 gene change in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.In some individuals, the predisposition to the disorder is due to a spontaneous (de novo) gene change that occurs in the egg or sperm cell. In such situations, the disorder is not inherited from the parents. | 163 | Birt-Hogg-Dubé Syndrome |
nord_163_3 | Affects of Birt-Hogg-Dubé Syndrome | Birt-Hogg-Dubé syndrome is a rare disorder that affects males and females in equal numbers. About 600 families (kindreds) affected with BHD have been described to date in the medical literature. Some researchers believe BHD syndrome is under-diagnosed, making it difficult to determine its true frequency in the general population. | Affects of Birt-Hogg-Dubé Syndrome. Birt-Hogg-Dubé syndrome is a rare disorder that affects males and females in equal numbers. About 600 families (kindreds) affected with BHD have been described to date in the medical literature. Some researchers believe BHD syndrome is under-diagnosed, making it difficult to determine its true frequency in the general population. | 163 | Birt-Hogg-Dubé Syndrome |
nord_163_4 | Related disorders of Birt-Hogg-Dubé Syndrome | Symptoms of the following disorders can be similar to those of Birt-Hogg-Dubé syndrome. Comparisons may be useful for a differential diagnosis.The PTEN hamartoma tumor syndrome (PHTS) is a spectrum of disorders caused by variants in the PTEN gene. These disorders are characterized by multiple hamartomas that can affect various areas of the body. Hamartoma is a general term for benign tumor-like malformations that can affect any area of the body. Hamartomas are composed of mature cells and tissue normally found in the affected area. PHTS includes virtually all cases of Cowden syndrome (also known as multiple hamartoma syndrome) and a percentage of cases of Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome and Proteus-like syndrome (i.e., those associated with variants in the PTEN gene). Cowden syndrome is a difficult to recognize, under-diagnosed genetic disorder characterized by the development of multiple, benign tumor-like malformations (hamartomas) in various areas of the body. Affected individuals also have a predisposition to developing certain cancers, especially cancer of the breast, thyroid or mucous membrane lining the uterus (endometrium). The specific symptoms of Cowden syndrome vary from person to person. (For more information on this disorder, choose “PTEN hamartoma tumor syndrome” as your search term in the Rare Disease Database.)Some researchers think symptoms of tuberous sclerosis complex including skin and lung hamartomas and angiomyolipomas of the kidney (and rare renal neoplasia) are similar to BHD. (For more information on this disorder, choose “tuberous sclerosis” as your search term in the Rare Disease Database.)Recently, germline variants in the FLCN gene have been identified in families with familial spontaneous pneumothorax, in which affected family members develop frequent lung collapse without other typical BHD skin lesions or renal neoplasia. | Related disorders of Birt-Hogg-Dubé Syndrome. Symptoms of the following disorders can be similar to those of Birt-Hogg-Dubé syndrome. Comparisons may be useful for a differential diagnosis.The PTEN hamartoma tumor syndrome (PHTS) is a spectrum of disorders caused by variants in the PTEN gene. These disorders are characterized by multiple hamartomas that can affect various areas of the body. Hamartoma is a general term for benign tumor-like malformations that can affect any area of the body. Hamartomas are composed of mature cells and tissue normally found in the affected area. PHTS includes virtually all cases of Cowden syndrome (also known as multiple hamartoma syndrome) and a percentage of cases of Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome and Proteus-like syndrome (i.e., those associated with variants in the PTEN gene). Cowden syndrome is a difficult to recognize, under-diagnosed genetic disorder characterized by the development of multiple, benign tumor-like malformations (hamartomas) in various areas of the body. Affected individuals also have a predisposition to developing certain cancers, especially cancer of the breast, thyroid or mucous membrane lining the uterus (endometrium). The specific symptoms of Cowden syndrome vary from person to person. (For more information on this disorder, choose “PTEN hamartoma tumor syndrome” as your search term in the Rare Disease Database.)Some researchers think symptoms of tuberous sclerosis complex including skin and lung hamartomas and angiomyolipomas of the kidney (and rare renal neoplasia) are similar to BHD. (For more information on this disorder, choose “tuberous sclerosis” as your search term in the Rare Disease Database.)Recently, germline variants in the FLCN gene have been identified in families with familial spontaneous pneumothorax, in which affected family members develop frequent lung collapse without other typical BHD skin lesions or renal neoplasia. | 163 | Birt-Hogg-Dubé Syndrome |
nord_163_5 | Diagnosis of Birt-Hogg-Dubé Syndrome | A diagnosis of Birt-Hogg-Dubé syndrome is made based upon a thorough clinical evaluation, detailed patient history and identification of characteristic symptoms including two or more fibrofolliculomas, history of spontaneous pneumothorax or bilateral, multiple chromophobe or hybrid oncocytic renal tumors. Surgical removal and microscopic evaluation (biopsy) of affected skin tissue is performed to determine the type of skin lesion present. Detection of a pathogenic (disease-causing) FLCN variant in a DNA-based genetic test confirms the diagnosis of BHD. Since renal neoplasia has been reported in individuals with BHD as young as 14, genetic testing is recommended starting at age 21 in at-risk family members.Clinical Testing and Work-up
If a diagnosis of BHD syndrome is made, computed tomography (CT) scans of the lungs are recommended to detect pulmonary cysts/pneumothorax. Individuals with BHD have a lifelong risk for developing renal tumors and therefore, should undergo periodic surveillance by abdominal imaging (CT or magnetic resonance imaging to reduce radiation exposure is recommended) for early detection of renal tumors. | Diagnosis of Birt-Hogg-Dubé Syndrome. A diagnosis of Birt-Hogg-Dubé syndrome is made based upon a thorough clinical evaluation, detailed patient history and identification of characteristic symptoms including two or more fibrofolliculomas, history of spontaneous pneumothorax or bilateral, multiple chromophobe or hybrid oncocytic renal tumors. Surgical removal and microscopic evaluation (biopsy) of affected skin tissue is performed to determine the type of skin lesion present. Detection of a pathogenic (disease-causing) FLCN variant in a DNA-based genetic test confirms the diagnosis of BHD. Since renal neoplasia has been reported in individuals with BHD as young as 14, genetic testing is recommended starting at age 21 in at-risk family members.Clinical Testing and Work-up
If a diagnosis of BHD syndrome is made, computed tomography (CT) scans of the lungs are recommended to detect pulmonary cysts/pneumothorax. Individuals with BHD have a lifelong risk for developing renal tumors and therefore, should undergo periodic surveillance by abdominal imaging (CT or magnetic resonance imaging to reduce radiation exposure is recommended) for early detection of renal tumors. | 163 | Birt-Hogg-Dubé Syndrome |
nord_163_6 | Therapies of Birt-Hogg-Dubé Syndrome | Treatment
The treatment of BHD syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may include the use of a laser beam to destroy affected skin tissue (laser ablation). This treatment is highly successful in treating the skin lesions associated with BHD syndrome, but the lesions often return (relapse).Some instances of a lung collapse do not require treatment and the air is absorbed over several days. In some patients, treatment is necessary. Treatment of a collapsed lung is intended to remove the air surrounding the lungs, allowing the lungs to re-inflate. A tube is inserted into the chest to allow the air or gas to escape (aspiration). In cases where repeated lung collapses occur, surgery may be necessary.Surgery may also be necessary in individuals with renal neoplasia. Surgeons need to remove the kidney neoplasm, so it does not grow larger and spread (metastasis). They may also remove part or all of a kidney (nephrectomy) if the tumor burden is extensive. The main objective of surgery in individuals with renal neoplasia is to preserve as much kidney tissue as possible, thereby preserving as much of the kidney function as possible. Since individuals with BHD may have multiple surgeries for multiple tumors over their lifetime, one effective management practice has been to wait and remove the largest tumor when it reaches 3 cm in diameter by nephron-sparing surgery.Individuals with BHD syndrome without renal neoplasia should be periodically imaged to monitor tumor development (recommended at 2-to-3-year intervals). Genetic counseling is recommended for affected individuals and their families. | Therapies of Birt-Hogg-Dubé Syndrome. Treatment
The treatment of BHD syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may include the use of a laser beam to destroy affected skin tissue (laser ablation). This treatment is highly successful in treating the skin lesions associated with BHD syndrome, but the lesions often return (relapse).Some instances of a lung collapse do not require treatment and the air is absorbed over several days. In some patients, treatment is necessary. Treatment of a collapsed lung is intended to remove the air surrounding the lungs, allowing the lungs to re-inflate. A tube is inserted into the chest to allow the air or gas to escape (aspiration). In cases where repeated lung collapses occur, surgery may be necessary.Surgery may also be necessary in individuals with renal neoplasia. Surgeons need to remove the kidney neoplasm, so it does not grow larger and spread (metastasis). They may also remove part or all of a kidney (nephrectomy) if the tumor burden is extensive. The main objective of surgery in individuals with renal neoplasia is to preserve as much kidney tissue as possible, thereby preserving as much of the kidney function as possible. Since individuals with BHD may have multiple surgeries for multiple tumors over their lifetime, one effective management practice has been to wait and remove the largest tumor when it reaches 3 cm in diameter by nephron-sparing surgery.Individuals with BHD syndrome without renal neoplasia should be periodically imaged to monitor tumor development (recommended at 2-to-3-year intervals). Genetic counseling is recommended for affected individuals and their families. | 163 | Birt-Hogg-Dubé Syndrome |
nord_164_0 | Overview of Björnstad Syndrome | SummaryBjornstad syndrome (BS) is an extremely rare autosomal recessive genetic disorder characterized by abnormally flattened, twisted hair shafts (pili torti) and, in most patients, deafness (congenital sensorineural hearing loss). Hearing loss at birth is variable in severity, but typically affects both ears (bilateral). Individuals with this disorder usually have dry, fragile, lusterless and/or coarse scalp hair as well as areas of patchy hair loss (alopecia).IntroductionProfessor Roar Bjornstad first identified this syndrome in 1965 when he noted pili torti in eight patients and five of them also had sensorineural deafness. Since then, several other cases have been described, defining the clinical features of the syndrome. | Overview of Björnstad Syndrome. SummaryBjornstad syndrome (BS) is an extremely rare autosomal recessive genetic disorder characterized by abnormally flattened, twisted hair shafts (pili torti) and, in most patients, deafness (congenital sensorineural hearing loss). Hearing loss at birth is variable in severity, but typically affects both ears (bilateral). Individuals with this disorder usually have dry, fragile, lusterless and/or coarse scalp hair as well as areas of patchy hair loss (alopecia).IntroductionProfessor Roar Bjornstad first identified this syndrome in 1965 when he noted pili torti in eight patients and five of them also had sensorineural deafness. Since then, several other cases have been described, defining the clinical features of the syndrome. | 164 | Björnstad Syndrome |
nord_164_1 | Symptoms of Björnstad Syndrome | Bjornstad syndrome is characterized by the presence of abnormally flat and twisted hair shafts defined as pili torti. BS patients usually present with dry, fragile, lusterless, and/or coarse scalp hair. When studied under an electron microscope, hair shafts from the scalp appear flattened and/or twisted (torti) at regular intervals. Body hair may exhibit the same characteristic twisting (pili torti) as scalp hair. In some patients, patchy areas of hair loss (alopecia) may be present on the scalp as well as on other areas of the body. However, the eyebrows and eyelashes are typically not affected. Light colored eyes and hair could be associated with BS and some individuals may also experience a lack of sweating (anhidrosis). Most BS patients have deafness due to an impaired ability of the auditory nerves to transmit sensory input to the brain (sensorineural hearing loss). Hair loss typically begins during the first two years of life and, although severity of symptoms and age of onset are variable, the hair abnormality may become milder with age. Hearing loss typically develops by 3 or 4 years of age and hearing impairment may lead to speech difficulties. Intellectual disability is not a typical feature of the syndrome but has been reported occasionally. Hypogonadism, characterized by underdevelopment of the ovaries in females and of testes in males, has been described in some BS patients, but this is not typical. | Symptoms of Björnstad Syndrome. Bjornstad syndrome is characterized by the presence of abnormally flat and twisted hair shafts defined as pili torti. BS patients usually present with dry, fragile, lusterless, and/or coarse scalp hair. When studied under an electron microscope, hair shafts from the scalp appear flattened and/or twisted (torti) at regular intervals. Body hair may exhibit the same characteristic twisting (pili torti) as scalp hair. In some patients, patchy areas of hair loss (alopecia) may be present on the scalp as well as on other areas of the body. However, the eyebrows and eyelashes are typically not affected. Light colored eyes and hair could be associated with BS and some individuals may also experience a lack of sweating (anhidrosis). Most BS patients have deafness due to an impaired ability of the auditory nerves to transmit sensory input to the brain (sensorineural hearing loss). Hair loss typically begins during the first two years of life and, although severity of symptoms and age of onset are variable, the hair abnormality may become milder with age. Hearing loss typically develops by 3 or 4 years of age and hearing impairment may lead to speech difficulties. Intellectual disability is not a typical feature of the syndrome but has been reported occasionally. Hypogonadism, characterized by underdevelopment of the ovaries in females and of testes in males, has been described in some BS patients, but this is not typical. | 164 | Björnstad Syndrome |
nord_164_2 | Causes of Björnstad Syndrome | Bjornstad syndrome is caused by changes (mutations) in the BCS1L gene. This gene codes for a chaperone protein that is a member of the AAA family of ATPases. An ATPase is an enzyme that uses ATP (adenosine triphosphate), the main energy source in cells, to drive chemical reactions. This particular ATPase is involved in the assembly of complex III in the mitochondrial electron transport chain. The electron transport chain is responsible for generating the energy that cells require. Complex III also produces reactive oxygen species. When present in high numbers, these reactive compounds will cause damage to tissue. Even though this abnormal protein leads to a decrease in the activity of complex III, the complex will produce more reactive oxygen species. The hair follicles and cells of the inner ear are particularly sensitive to these reactive oxygen species. This is thought to be the reason why hair changes and hearing loss are part of this syndrome. Bjornstad syndrome is 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% for 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. | Causes of Björnstad Syndrome. Bjornstad syndrome is caused by changes (mutations) in the BCS1L gene. This gene codes for a chaperone protein that is a member of the AAA family of ATPases. An ATPase is an enzyme that uses ATP (adenosine triphosphate), the main energy source in cells, to drive chemical reactions. This particular ATPase is involved in the assembly of complex III in the mitochondrial electron transport chain. The electron transport chain is responsible for generating the energy that cells require. Complex III also produces reactive oxygen species. When present in high numbers, these reactive compounds will cause damage to tissue. Even though this abnormal protein leads to a decrease in the activity of complex III, the complex will produce more reactive oxygen species. The hair follicles and cells of the inner ear are particularly sensitive to these reactive oxygen species. This is thought to be the reason why hair changes and hearing loss are part of this syndrome. Bjornstad syndrome is 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% for 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. | 164 | Björnstad Syndrome |
nord_164_3 | Affects of Björnstad Syndrome | Bjornstad syndrome is an extremely rare disorder. In theory, it affects males and females in equal numbers. However, in observed cases, more females than males have been identified. Less than 50 cases are reported in the medical literature. | Affects of Björnstad Syndrome. Bjornstad syndrome is an extremely rare disorder. In theory, it affects males and females in equal numbers. However, in observed cases, more females than males have been identified. Less than 50 cases are reported in the medical literature. | 164 | Björnstad Syndrome |
nord_164_4 | Related disorders of Björnstad Syndrome | Some genetic disorders present symptoms that can be similar to those of Bjornstad syndrome. Comparisons may be useful for a differential diagnosis:Menkes disease is an inherited X-linked recessive genetic disorder caused by disruption of copper metabolism and affects many systems in the body. Affected infants are often born prematurely and may have non-specific symptoms such as hypothermia, hypoglycemia, and prolonged jaundice. One obvious and specific physical sign is “steely” or “kinky” hair that usually develops by several months of age. Menkes disease is also associated with seizures, stunted growth, failure to thrive, unstable body temperature and intellectual disability. (For more information on this disorder, choose “Menkes” as your search term in the Rare Disease Database.)Twisted hair (pili torti) and sensorineural deafness may be findings associated with other rare disorders, such as a group of diseases known as the ectodermal dysplasias. However, these conditions present several particular clinical findings that can facilitate differential diagnosis (For more information on these disorders, choose “ectodermal dysplasia” as your search term in the Rare Disease Database.)Other genetic diseases, GRACILE syndrome and complex III deficiency syndrome, are also caused by mutations in BCS1L gene but present more severe clinical features than Bjornstad syndrome. GRACILE syndrome is an inherited lethal metabolic disease. GRACILE stands for growth retardation, aminoaciduria, cholestasis, iron overload, lactacidosis and early death. Infants are very small at birth and quickly develop life-threatening complications. Complex III deficiency syndrome is a rare genetic disorder that affects multiple organ systems including the brain, kidney, liver, heart and skeletal muscles. Severity of this syndrome varies among affected individuals. | Related disorders of Björnstad Syndrome. Some genetic disorders present symptoms that can be similar to those of Bjornstad syndrome. Comparisons may be useful for a differential diagnosis:Menkes disease is an inherited X-linked recessive genetic disorder caused by disruption of copper metabolism and affects many systems in the body. Affected infants are often born prematurely and may have non-specific symptoms such as hypothermia, hypoglycemia, and prolonged jaundice. One obvious and specific physical sign is “steely” or “kinky” hair that usually develops by several months of age. Menkes disease is also associated with seizures, stunted growth, failure to thrive, unstable body temperature and intellectual disability. (For more information on this disorder, choose “Menkes” as your search term in the Rare Disease Database.)Twisted hair (pili torti) and sensorineural deafness may be findings associated with other rare disorders, such as a group of diseases known as the ectodermal dysplasias. However, these conditions present several particular clinical findings that can facilitate differential diagnosis (For more information on these disorders, choose “ectodermal dysplasia” as your search term in the Rare Disease Database.)Other genetic diseases, GRACILE syndrome and complex III deficiency syndrome, are also caused by mutations in BCS1L gene but present more severe clinical features than Bjornstad syndrome. GRACILE syndrome is an inherited lethal metabolic disease. GRACILE stands for growth retardation, aminoaciduria, cholestasis, iron overload, lactacidosis and early death. Infants are very small at birth and quickly develop life-threatening complications. Complex III deficiency syndrome is a rare genetic disorder that affects multiple organ systems including the brain, kidney, liver, heart and skeletal muscles. Severity of this syndrome varies among affected individuals. | 164 | Björnstad Syndrome |
nord_164_5 | Diagnosis of Björnstad Syndrome | The diagnosis of BS may be suspected in individuals that have twisted hair, which may be obvious at birth or in the first months of life. The diagnosis is confirmed by examination of hair shafts from affected individuals under an electron microscope, demonstrating characteristic twisting of the hair shafts at regular intervals. Since the presence of this hair abnormality is suggestive of BS, all infants with this finding should be evaluated for possible sensorineural deafness that may be confirmed through a variety of specialized hearing (auditory) tests. Diagnosis is confirmed by molecular genetic testing for mutations in the BCS1L gene. | Diagnosis of Björnstad Syndrome. The diagnosis of BS may be suspected in individuals that have twisted hair, which may be obvious at birth or in the first months of life. The diagnosis is confirmed by examination of hair shafts from affected individuals under an electron microscope, demonstrating characteristic twisting of the hair shafts at regular intervals. Since the presence of this hair abnormality is suggestive of BS, all infants with this finding should be evaluated for possible sensorineural deafness that may be confirmed through a variety of specialized hearing (auditory) tests. Diagnosis is confirmed by molecular genetic testing for mutations in the BCS1L gene. | 164 | Björnstad Syndrome |
nord_164_6 | Therapies of Björnstad Syndrome | There is no specific therapy for BS patients. Treatment is symptomatic and supportive and directed toward the specific symptoms present in each child. Care may require the skills of a team of specialists. Pediatricians, specialists who assess and treat hearing loss (audiologists) and physicians who specialize in diagnosing and treating disorders involving the skin (dermatologists) may coordinate their efforts to ensure the comprehensive, systematic treatment of affected children.The treatment of patchy hair loss (alopecia) may include the use of wigs and/or other hair replacement therapies. Early detection and treatment of sensorineural deafness is essential to help avoid possible speech problems and assisted hearing devices may be prescribed to treat hearing loss. Early intervention is important in ensuring that children with BS reach their full potential. Services that may be beneficial may include special remedial education, special services for children with congenital sensorineural deafness, and other medical, social, and/or vocational services.Genetic counseling is recommended for affected individuals and their families. | Therapies of Björnstad Syndrome. There is no specific therapy for BS patients. Treatment is symptomatic and supportive and directed toward the specific symptoms present in each child. Care may require the skills of a team of specialists. Pediatricians, specialists who assess and treat hearing loss (audiologists) and physicians who specialize in diagnosing and treating disorders involving the skin (dermatologists) may coordinate their efforts to ensure the comprehensive, systematic treatment of affected children.The treatment of patchy hair loss (alopecia) may include the use of wigs and/or other hair replacement therapies. Early detection and treatment of sensorineural deafness is essential to help avoid possible speech problems and assisted hearing devices may be prescribed to treat hearing loss. Early intervention is important in ensuring that children with BS reach their full potential. Services that may be beneficial may include special remedial education, special services for children with congenital sensorineural deafness, and other medical, social, and/or vocational services.Genetic counseling is recommended for affected individuals and their families. | 164 | Björnstad Syndrome |
nord_165_0 | Overview of Bladder Exstrophy-Epispadias-Cloacal Exstrophy Complex | Bladder exstrophy-epispadias-cloacal exstrophy complex is a spectrum of anomalies involving the urinary tract, genital tract, musculoskeletal system and sometimes the intestinal tract. In classic bladder exstrophy, most anomalies are related to defects of the abdominal wall, bladder, genitalia, pelvic bones, rectum and anus.Bladder exstrophy is a rare developmental abnormality that is present at birth (congenital) in which the bladder and related structures are turned inside out. The rear portion of the bladder wall (posterior vesical wall) turns outward (exstrophy) through an opening in the abdominal wall and urine is excreted through this opening. The extent of the exstrophy depends on how large the opening is. The mildest form is when there is a defect or opening in the tube that carries urine out of the body from the bladder (urethra) and is termed epispadias.The most severe form is when there is a defect in the urethra, bladder and bowel (cloacal exstrophy). Classic bladder exstrophy is when there is a defect in the urethra and bladder and is intermediate in severity. The underlying cause of this complex is not known. The physical characteristics are the result of a developmental abnormality during embryonic growth in which the cloacal membrane is not replaced by tissue that will form the abdominal muscles. | Overview of Bladder Exstrophy-Epispadias-Cloacal Exstrophy Complex. Bladder exstrophy-epispadias-cloacal exstrophy complex is a spectrum of anomalies involving the urinary tract, genital tract, musculoskeletal system and sometimes the intestinal tract. In classic bladder exstrophy, most anomalies are related to defects of the abdominal wall, bladder, genitalia, pelvic bones, rectum and anus.Bladder exstrophy is a rare developmental abnormality that is present at birth (congenital) in which the bladder and related structures are turned inside out. The rear portion of the bladder wall (posterior vesical wall) turns outward (exstrophy) through an opening in the abdominal wall and urine is excreted through this opening. The extent of the exstrophy depends on how large the opening is. The mildest form is when there is a defect or opening in the tube that carries urine out of the body from the bladder (urethra) and is termed epispadias.The most severe form is when there is a defect in the urethra, bladder and bowel (cloacal exstrophy). Classic bladder exstrophy is when there is a defect in the urethra and bladder and is intermediate in severity. The underlying cause of this complex is not known. The physical characteristics are the result of a developmental abnormality during embryonic growth in which the cloacal membrane is not replaced by tissue that will form the abdominal muscles. | 165 | Bladder Exstrophy-Epispadias-Cloacal Exstrophy Complex |
nord_165_1 | Symptoms of Bladder Exstrophy-Epispadias-Cloacal Exstrophy Complex | The bladder-exstrophy-epispadias-cloacal exstrophy complex can take many forms depending on the extent of the developmental abnormality that causes it. The mildest form is when there is an opening in the urethra (epispadias). The most severe form is when there is an opening in the urethra, bladder and bowel (cloacal exstrophy). The most common form is classic bladder exstrophy in which the bladder and related structures are turned inside out through an opening in the abdominal wall. Classic bladder exstrophy is intermediate in severity and the bladder is open from the top of the bladder through the urethra and to the tip of the penis. Boys with epispadias have a urethra that is extremely short and split and the opening is on the upper surface of the penis. Girls with epispadias have a urethral opening located between a split clitoris and labia minor. Cloacal exstrophy is a severe birth defect in which there is usually a membrane-covered area on the abdominal wall that contains the abdominal contents (omphalocele). The bladder is divided in two halves and males have a penis split in two halves. Females have a clitoris divided in two halves and may have two vaginal openings. The opening of the rectum to the outside of the body is usually missing or abnormally small. Other abnormalities are sometimes associated with the complex. These include a separation of the pubic bones, absence of the lower portion of the bladder causing lack of bladder control (incontinence) and abnormal position of the tubes that carry urine from the kidneys to the bladder (ureters) causing back up of urine in the kidneys (reflux), | Symptoms of Bladder Exstrophy-Epispadias-Cloacal Exstrophy Complex. The bladder-exstrophy-epispadias-cloacal exstrophy complex can take many forms depending on the extent of the developmental abnormality that causes it. The mildest form is when there is an opening in the urethra (epispadias). The most severe form is when there is an opening in the urethra, bladder and bowel (cloacal exstrophy). The most common form is classic bladder exstrophy in which the bladder and related structures are turned inside out through an opening in the abdominal wall. Classic bladder exstrophy is intermediate in severity and the bladder is open from the top of the bladder through the urethra and to the tip of the penis. Boys with epispadias have a urethra that is extremely short and split and the opening is on the upper surface of the penis. Girls with epispadias have a urethral opening located between a split clitoris and labia minor. Cloacal exstrophy is a severe birth defect in which there is usually a membrane-covered area on the abdominal wall that contains the abdominal contents (omphalocele). The bladder is divided in two halves and males have a penis split in two halves. Females have a clitoris divided in two halves and may have two vaginal openings. The opening of the rectum to the outside of the body is usually missing or abnormally small. Other abnormalities are sometimes associated with the complex. These include a separation of the pubic bones, absence of the lower portion of the bladder causing lack of bladder control (incontinence) and abnormal position of the tubes that carry urine from the kidneys to the bladder (ureters) causing back up of urine in the kidneys (reflux), | 165 | Bladder Exstrophy-Epispadias-Cloacal Exstrophy Complex |
nord_165_2 | Causes of Bladder Exstrophy-Epispadias-Cloacal Exstrophy Complex | In normal development, the cloacal membrane temporarily separates the urogenital and anal structures and them breaks when tissue that will form abdominal muscles begins to grow in its place. The bladder exstrophy-epispadias-cloacal exstrophy complex is caused by a developmental abnormality that occurs 4-5 weeks after conception in which the cloacal membrane is not replaced by tissue that will form the abdominal muscles. The underlying cause of this error in development is not known. | Causes of Bladder Exstrophy-Epispadias-Cloacal Exstrophy Complex. In normal development, the cloacal membrane temporarily separates the urogenital and anal structures and them breaks when tissue that will form abdominal muscles begins to grow in its place. The bladder exstrophy-epispadias-cloacal exstrophy complex is caused by a developmental abnormality that occurs 4-5 weeks after conception in which the cloacal membrane is not replaced by tissue that will form the abdominal muscles. The underlying cause of this error in development is not known. | 165 | Bladder Exstrophy-Epispadias-Cloacal Exstrophy Complex |
nord_165_3 | Affects of Bladder Exstrophy-Epispadias-Cloacal Exstrophy Complex | The birth prevalence of classic bladder exstrophy has been estimated to be between 1 in 10,000 and 1 in 50,000 livebirths. Males are affected 2-3 times more often than females. Isolated epispadias occurs in approximately 1 in 112,000 live male births and 1 in 400,000 live female births. Cloacal exstrophy occurs in approximately 1 in 400,000 live births. | Affects of Bladder Exstrophy-Epispadias-Cloacal Exstrophy Complex. The birth prevalence of classic bladder exstrophy has been estimated to be between 1 in 10,000 and 1 in 50,000 livebirths. Males are affected 2-3 times more often than females. Isolated epispadias occurs in approximately 1 in 112,000 live male births and 1 in 400,000 live female births. Cloacal exstrophy occurs in approximately 1 in 400,000 live births. | 165 | Bladder Exstrophy-Epispadias-Cloacal Exstrophy Complex |
nord_165_4 | Related disorders of Bladder Exstrophy-Epispadias-Cloacal Exstrophy Complex | Related disorders of Bladder Exstrophy-Epispadias-Cloacal Exstrophy Complex. | 165 | Bladder Exstrophy-Epispadias-Cloacal Exstrophy Complex |
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nord_165_5 | Diagnosis of Bladder Exstrophy-Epispadias-Cloacal Exstrophy Complex | Prenatal ultrasound examination of a fetus with the complex may reveal absence of bladder filling, low-set umbilical cord, separation of pubic bones, small genitals and an abdominal mass that increases in size as the pregnancy progresses. | Diagnosis of Bladder Exstrophy-Epispadias-Cloacal Exstrophy Complex. Prenatal ultrasound examination of a fetus with the complex may reveal absence of bladder filling, low-set umbilical cord, separation of pubic bones, small genitals and an abdominal mass that increases in size as the pregnancy progresses. | 165 | Bladder Exstrophy-Epispadias-Cloacal Exstrophy Complex |
nord_165_6 | Therapies of Bladder Exstrophy-Epispadias-Cloacal Exstrophy Complex | TreatmentThe treatment of bladder exstrophy consists of a series of corrective surgeries performed over several years. The first surgery is closure of the bladder to allow it to hold urine, placement of the bladder inside the pelvis and closure of the abdominal wall. In some cases, children with bladder exstrophy may also require a series of surgical procedures to reconstruct the external genitalia. These surgeries are usually performed before the age of 2 years. Bladder neck reconstruction is performed at approximately 5 years of age to allow control of urine and ureters are repositioned to prevent urine from backing up into the kidneys.The outlook for maintaining normal kidney function after surgical correction and reconstruction is good. However, some individuals with this disorder may experience long-term urinary problems such as kidney stones, kidney infections, and varying degrees of urinary incontinence. Other treatment is symptomatic and supportive. | Therapies of Bladder Exstrophy-Epispadias-Cloacal Exstrophy Complex. TreatmentThe treatment of bladder exstrophy consists of a series of corrective surgeries performed over several years. The first surgery is closure of the bladder to allow it to hold urine, placement of the bladder inside the pelvis and closure of the abdominal wall. In some cases, children with bladder exstrophy may also require a series of surgical procedures to reconstruct the external genitalia. These surgeries are usually performed before the age of 2 years. Bladder neck reconstruction is performed at approximately 5 years of age to allow control of urine and ureters are repositioned to prevent urine from backing up into the kidneys.The outlook for maintaining normal kidney function after surgical correction and reconstruction is good. However, some individuals with this disorder may experience long-term urinary problems such as kidney stones, kidney infections, and varying degrees of urinary incontinence. Other treatment is symptomatic and supportive. | 165 | Bladder Exstrophy-Epispadias-Cloacal Exstrophy Complex |
nord_166_0 | Overview of Blastomycosis | Blastomycosis is a rare infectious multisystem disease that is caused by the fungus Blastomyces dermatitidis. The symptoms vary greatly according the affected organ system. It is characterized by fever, chills, cough, and/or difficulty breathing (dyspnea). In the chronic phase of the disease, the lungs and skin are most frequently affected. The genitourinary tract and bones may also be involved. | Overview of Blastomycosis. Blastomycosis is a rare infectious multisystem disease that is caused by the fungus Blastomyces dermatitidis. The symptoms vary greatly according the affected organ system. It is characterized by fever, chills, cough, and/or difficulty breathing (dyspnea). In the chronic phase of the disease, the lungs and skin are most frequently affected. The genitourinary tract and bones may also be involved. | 166 | Blastomycosis |
nord_166_1 | Symptoms of Blastomycosis | Blastomycosis is an infectious disease characterized by fever, chills, headaches, chest pain, weight loss, night sweats, cough, and/or difficulty breathing (dyspnea). Some affected individuals do not experience these symptoms although they are actively infected (asymptomatic). Muscle and joint pain may occur during the acute stage which typically lasts less than three weeks. The disease may resolve on its own or persist into the chronic form of the infection. Chronic Blastomycosis, which lasts more than three weeks, may affect the lungs, skin, bones, joints, genitourinary tract, and/or central nervous system.Involvement of the skin is very common in individuals with Blastomycosis. Wart-like (verrucous) and small raised pus-filled (papulopustular) lesions are common. They may be violet colored and have very small abscesses around the borders of the lesions. Nodular lesions may be present under the skin (subcutaneous) and are usually accompanied by active fungal infection of the lungs.When Blastomycosis affects the lungs, which are common sites of fungal involvement, it usually takes the form of chronic pneumonia. Symptoms may include a cough ccompanied by thick sputum, chest pain, difficulty breathing, and/or rapid heartbeat. In some severe cases of Blastomycosis, Respiratory Distress Syndrome may develop, characterized by excessive deep and rapid breathing (hyperventilation) and insufficient levels of oxygen in the circulating blood (hypoxemia). Affected individuals typically require mechanical ventilation to assist breathing. (For more information on this disorder, choose “Respiratory Distress” as your search term in the Rare Disease Database.)Blastomycosis may also affect the bones and cause lesions that destroy bone tissue (osteolytic). The ribs, vertebrae of the spine, and the long bones of the arms and legs are most frequently involved. In many cases these lesions are painless but may develop an overlying abscess.Involvement of the urogenital tract is common in males with Blastomycosis. In about 30 percent of cases, the prostate gland and the tubes that carry sperm from the testes (epididymis) are infected by the fungus. Symptoms may include inflammation, swelling, and/or pain in the groin. Involvement of the central nervous system, liver, spleen, gastrointestinal tract, thyroid, adrenal glands, and other organs has also been reported in chronic cases of Blastomycosis. | Symptoms of Blastomycosis. Blastomycosis is an infectious disease characterized by fever, chills, headaches, chest pain, weight loss, night sweats, cough, and/or difficulty breathing (dyspnea). Some affected individuals do not experience these symptoms although they are actively infected (asymptomatic). Muscle and joint pain may occur during the acute stage which typically lasts less than three weeks. The disease may resolve on its own or persist into the chronic form of the infection. Chronic Blastomycosis, which lasts more than three weeks, may affect the lungs, skin, bones, joints, genitourinary tract, and/or central nervous system.Involvement of the skin is very common in individuals with Blastomycosis. Wart-like (verrucous) and small raised pus-filled (papulopustular) lesions are common. They may be violet colored and have very small abscesses around the borders of the lesions. Nodular lesions may be present under the skin (subcutaneous) and are usually accompanied by active fungal infection of the lungs.When Blastomycosis affects the lungs, which are common sites of fungal involvement, it usually takes the form of chronic pneumonia. Symptoms may include a cough ccompanied by thick sputum, chest pain, difficulty breathing, and/or rapid heartbeat. In some severe cases of Blastomycosis, Respiratory Distress Syndrome may develop, characterized by excessive deep and rapid breathing (hyperventilation) and insufficient levels of oxygen in the circulating blood (hypoxemia). Affected individuals typically require mechanical ventilation to assist breathing. (For more information on this disorder, choose “Respiratory Distress” as your search term in the Rare Disease Database.)Blastomycosis may also affect the bones and cause lesions that destroy bone tissue (osteolytic). The ribs, vertebrae of the spine, and the long bones of the arms and legs are most frequently involved. In many cases these lesions are painless but may develop an overlying abscess.Involvement of the urogenital tract is common in males with Blastomycosis. In about 30 percent of cases, the prostate gland and the tubes that carry sperm from the testes (epididymis) are infected by the fungus. Symptoms may include inflammation, swelling, and/or pain in the groin. Involvement of the central nervous system, liver, spleen, gastrointestinal tract, thyroid, adrenal glands, and other organs has also been reported in chronic cases of Blastomycosis. | 166 | Blastomycosis |
nord_166_2 | Causes of Blastomycosis | Blastomycosis is a rare infectious disease caused by the fungus Blastomyces dermatitidis. This fungus grows and is inhaled through mold spores. In the body the fungus converts to yeasts and invades the lungs. It travels throughout the body through the blood. Blastomycosis usually affects people with a compromised immune system. | Causes of Blastomycosis. Blastomycosis is a rare infectious disease caused by the fungus Blastomyces dermatitidis. This fungus grows and is inhaled through mold spores. In the body the fungus converts to yeasts and invades the lungs. It travels throughout the body through the blood. Blastomycosis usually affects people with a compromised immune system. | 166 | Blastomycosis |
nord_166_3 | Affects of Blastomycosis | Blastomycosis affects males and females in equal numbers. The organism that causes this disease (Blastomyces dermatitidis) is most common (endemic) in the south central and southeastern portions of the United States. It may also be found around the perimeter of the Great Lakes, and along the St. Lawrence River in Canada. Blastomycosis has also been reported in Mexico, the Middle East, Africa, India, and South and Central America.The natural habitat of this fungus is unclear but it is suspected to come from the soil. Farmers, construction workers, and others who work with soil appear to be at increased risk for Blastomycosis. Also at increased risk for severe chronic Blastomycosis are individuals who have a compromised immune system such as people with Acquired Immunodeficiency Syndrome (AIDS), these taking medications that suppress the immune system, and the elderly. | Affects of Blastomycosis. Blastomycosis affects males and females in equal numbers. The organism that causes this disease (Blastomyces dermatitidis) is most common (endemic) in the south central and southeastern portions of the United States. It may also be found around the perimeter of the Great Lakes, and along the St. Lawrence River in Canada. Blastomycosis has also been reported in Mexico, the Middle East, Africa, India, and South and Central America.The natural habitat of this fungus is unclear but it is suspected to come from the soil. Farmers, construction workers, and others who work with soil appear to be at increased risk for Blastomycosis. Also at increased risk for severe chronic Blastomycosis are individuals who have a compromised immune system such as people with Acquired Immunodeficiency Syndrome (AIDS), these taking medications that suppress the immune system, and the elderly. | 166 | Blastomycosis |
nord_166_4 | Related disorders of Blastomycosis | Symptoms of the following disorders can be similar to those of Blastomycosis. Comparisons may be useful for a differential diagnosis:Paracoccidioidomycosis (PCM) is a chronic infectious tropical disease caused by the fungus Paracoccidioides brasiliensis. The initial infection usually occurs in the lungs, but may also spread to the skin, mucous membranes, and other parts of the body. The symptoms generally develop about five years after the initial exposure to the fungus and vary according to the area of the body that is infected. In Mucocutaneous Paracoccidioidomycosis, ulcers appear on the mucous membranes, especially those of the mouth and nose. When the lungs are affected, symptoms may include cough, difficulty breathing (dyspnea), fatigue, and/or chest pain. (For more information on this disorder, choose “Paracoccidioidomycosis” as your search term in the Rare Disease Database.)Tuberculosis is a bacterial disease caused by Mycobacterium tuberculosis or Mycobacterium bovis. It is characterized by an initial period without symptoms. Pneumonia may be the first symptom in some people with Tuberculosis. Other symptoms may include coughing, weight loss, night sweats, fever, and/or fatigue. Chest x-rays typically reveal cavities in the lungs caused by chronic infection. The major symptom at this stage is coughing and the production of phlegm. (For more information on this disorder, choose “Tuberculosis” as your search term in the Rare Disease Database.)Nocardiosis is a rare infectious disease caused by the bacteria Nocardia asteroides and is characterized by acute inflammation of the lungs (pneumonia) and abscesses in the lungs. Symptoms include the profound loss of appetite (anorexia), generalized weakness, cough, and/or chest pain. Some affected individuals may also have abscesses in the brain, kidneys, intestines, and/or other organs of the body. Symptoms associated with brain abscesses may include severe headaches and other neurological difficulties. (For more information on this disorder, choose “Nocardiosis” as your search term in the Rare Disease Database.)Toxoplasmosis is an infectious disorder that is caused by a parasite (Toxoplasma gondii) that is found in the feces of cats. This infection is found worldwide and may be either acquired or transmitted to a fetus from an infected mother. When the disorder is acquired, the symptoms are similar to mononucleosis or involve lesions of the lungs, liver, heart, skin, muscle, brain, and spinal cord membranes. Lesions are often accompanied by inflammation and in some cases hepatitis. Acute cases are often characterized by rash, high fever, chills, and fatigue. To avoid this disease, pregnant women and people with an impaired immune system should wear a protective mask when emptying litter boxes containing cat feces. The prognosis for the acquired forms of Toxoplasmosis is usually good with treatment, and complications are uncommon. Without treatment this disorder may persist for many months. (For more information on this disorder, choose “Toxoplasmosis” as your search term in the Rare Disease Database.) | Related disorders of Blastomycosis. Symptoms of the following disorders can be similar to those of Blastomycosis. Comparisons may be useful for a differential diagnosis:Paracoccidioidomycosis (PCM) is a chronic infectious tropical disease caused by the fungus Paracoccidioides brasiliensis. The initial infection usually occurs in the lungs, but may also spread to the skin, mucous membranes, and other parts of the body. The symptoms generally develop about five years after the initial exposure to the fungus and vary according to the area of the body that is infected. In Mucocutaneous Paracoccidioidomycosis, ulcers appear on the mucous membranes, especially those of the mouth and nose. When the lungs are affected, symptoms may include cough, difficulty breathing (dyspnea), fatigue, and/or chest pain. (For more information on this disorder, choose “Paracoccidioidomycosis” as your search term in the Rare Disease Database.)Tuberculosis is a bacterial disease caused by Mycobacterium tuberculosis or Mycobacterium bovis. It is characterized by an initial period without symptoms. Pneumonia may be the first symptom in some people with Tuberculosis. Other symptoms may include coughing, weight loss, night sweats, fever, and/or fatigue. Chest x-rays typically reveal cavities in the lungs caused by chronic infection. The major symptom at this stage is coughing and the production of phlegm. (For more information on this disorder, choose “Tuberculosis” as your search term in the Rare Disease Database.)Nocardiosis is a rare infectious disease caused by the bacteria Nocardia asteroides and is characterized by acute inflammation of the lungs (pneumonia) and abscesses in the lungs. Symptoms include the profound loss of appetite (anorexia), generalized weakness, cough, and/or chest pain. Some affected individuals may also have abscesses in the brain, kidneys, intestines, and/or other organs of the body. Symptoms associated with brain abscesses may include severe headaches and other neurological difficulties. (For more information on this disorder, choose “Nocardiosis” as your search term in the Rare Disease Database.)Toxoplasmosis is an infectious disorder that is caused by a parasite (Toxoplasma gondii) that is found in the feces of cats. This infection is found worldwide and may be either acquired or transmitted to a fetus from an infected mother. When the disorder is acquired, the symptoms are similar to mononucleosis or involve lesions of the lungs, liver, heart, skin, muscle, brain, and spinal cord membranes. Lesions are often accompanied by inflammation and in some cases hepatitis. Acute cases are often characterized by rash, high fever, chills, and fatigue. To avoid this disease, pregnant women and people with an impaired immune system should wear a protective mask when emptying litter boxes containing cat feces. The prognosis for the acquired forms of Toxoplasmosis is usually good with treatment, and complications are uncommon. Without treatment this disorder may persist for many months. (For more information on this disorder, choose “Toxoplasmosis” as your search term in the Rare Disease Database.) | 166 | Blastomycosis |
nord_166_5 | Diagnosis of Blastomycosis | The diagnosis of Blastomycosis is confirmed by clinical evaluation that includes chest X-ray studies which may reveal findings that are consistent with fungal pneumonia (i.e., consolidation or cavitation). The direct microscopic examination of infected material (i.e., pus, sputum, or urine) is also performed. The tissue samples are prepared with potassium hydroxide which makes the yeast cells easily visible. Growing tissue samples and then isolating Blastomyces dermatitidis from the culture also confirms the diagnosis of Blastomycosis. Skin testing and blood tests are not helpful in the diagnosing of Blastomycosis.Pulmonary Blastomycosis may be mistaken for a malignancy such as lung cancer. Examination of the throat with a special instrument (bronchoscopy) may be required to confirm the diagnosis of Blastomycosis. Cutaneous Blastomycosis of the skin may also resemble certain forms of skin cancer. | Diagnosis of Blastomycosis. The diagnosis of Blastomycosis is confirmed by clinical evaluation that includes chest X-ray studies which may reveal findings that are consistent with fungal pneumonia (i.e., consolidation or cavitation). The direct microscopic examination of infected material (i.e., pus, sputum, or urine) is also performed. The tissue samples are prepared with potassium hydroxide which makes the yeast cells easily visible. Growing tissue samples and then isolating Blastomyces dermatitidis from the culture also confirms the diagnosis of Blastomycosis. Skin testing and blood tests are not helpful in the diagnosing of Blastomycosis.Pulmonary Blastomycosis may be mistaken for a malignancy such as lung cancer. Examination of the throat with a special instrument (bronchoscopy) may be required to confirm the diagnosis of Blastomycosis. Cutaneous Blastomycosis of the skin may also resemble certain forms of skin cancer. | 166 | Blastomycosis |
nord_166_6 | Therapies of Blastomycosis | TreatmentThe treatment of choice for both acute and chronic forms of Blastomycosis, especially those involving the central nervous system, is the oral administration of the antibiotic drug amphotericin B. If the disease is mild to moderate, then ketoconazole may be the drug of choice. Prolonged therapy may be necessary in some cases and relapses may occur. When the central nervous system is involved, the drug amphotericin B is usually administered. Affected individuals who cannot tolerate amphotericin B may be treated with hydroxystilbamidine isethionate. This drug is difficult to administer and may have various side effects. Other treatment is symptomatic and supportive. Other newer antifungal drugs such as fluconazole and itraconazole appear to be effective for the treatment of mild or moderate cases. | Therapies of Blastomycosis. TreatmentThe treatment of choice for both acute and chronic forms of Blastomycosis, especially those involving the central nervous system, is the oral administration of the antibiotic drug amphotericin B. If the disease is mild to moderate, then ketoconazole may be the drug of choice. Prolonged therapy may be necessary in some cases and relapses may occur. When the central nervous system is involved, the drug amphotericin B is usually administered. Affected individuals who cannot tolerate amphotericin B may be treated with hydroxystilbamidine isethionate. This drug is difficult to administer and may have various side effects. Other treatment is symptomatic and supportive. Other newer antifungal drugs such as fluconazole and itraconazole appear to be effective for the treatment of mild or moderate cases. | 166 | Blastomycosis |
nord_167_0 | Overview of Blepharophimosis, Ptosis, Epicanthus Inversus Syndrome | Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) is a rare developmental condition affecting the eyelids and ovary. Typically, four major facial features are present at birth: narrow eyes, droopy eyelids, an upward fold of skin of the inner lower eyelids and widely set eyes. These features cause difficulty in opening the eyes fully and may affect an affected individual’s quality of vision. BPES type I involves premature ovarian insufficiency (POI) in females as well as the characteristic facial features, whereas BPES type II is characterized by these facial features alone. Potential treatments include corrective eyelid surgery, hormone replacement therapy for premature ovarian insufficiency and embryo/egg donation for consequent problems with fertility. | Overview of Blepharophimosis, Ptosis, Epicanthus Inversus Syndrome. Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) is a rare developmental condition affecting the eyelids and ovary. Typically, four major facial features are present at birth: narrow eyes, droopy eyelids, an upward fold of skin of the inner lower eyelids and widely set eyes. These features cause difficulty in opening the eyes fully and may affect an affected individual’s quality of vision. BPES type I involves premature ovarian insufficiency (POI) in females as well as the characteristic facial features, whereas BPES type II is characterized by these facial features alone. Potential treatments include corrective eyelid surgery, hormone replacement therapy for premature ovarian insufficiency and embryo/egg donation for consequent problems with fertility. | 167 | Blepharophimosis, Ptosis, Epicanthus Inversus Syndrome |
nord_167_1 | Symptoms of Blepharophimosis, Ptosis, Epicanthus Inversus Syndrome | The four major features that are characteristic symptoms of BPES are present at birth: narrowing of the eye opening (blepharophimosis), droopy eyelids (ptosis), formation of an upward fold of the inner lower eyelid (epicanthus inversus) and increased distance between the eyes (telecanthus). There are two types of BPES, BPES type I and type II, which are both characterized by the typical eyelid malformation. However, BPES type I is also associated with loss of ovarian function or premature ovarian insufficiency (POI). Menstrual periods in women with POI become less frequent over time and stop before the age of 40 thus leading to either difficulty (subfertility) or inability to conceive (infertility). Other minor facial features frequently observed in both types include “lazy” eye (amblyopia), crossed eyes (strabismus), low-set ears, a short distance between the upper lip and nose, and a broad nasal bridge. | Symptoms of Blepharophimosis, Ptosis, Epicanthus Inversus Syndrome. The four major features that are characteristic symptoms of BPES are present at birth: narrowing of the eye opening (blepharophimosis), droopy eyelids (ptosis), formation of an upward fold of the inner lower eyelid (epicanthus inversus) and increased distance between the eyes (telecanthus). There are two types of BPES, BPES type I and type II, which are both characterized by the typical eyelid malformation. However, BPES type I is also associated with loss of ovarian function or premature ovarian insufficiency (POI). Menstrual periods in women with POI become less frequent over time and stop before the age of 40 thus leading to either difficulty (subfertility) or inability to conceive (infertility). Other minor facial features frequently observed in both types include “lazy” eye (amblyopia), crossed eyes (strabismus), low-set ears, a short distance between the upper lip and nose, and a broad nasal bridge. | 167 | Blepharophimosis, Ptosis, Epicanthus Inversus Syndrome |
nord_167_2 | Causes of Blepharophimosis, Ptosis, Epicanthus Inversus Syndrome | FOXL2 is the only gene known to cause BPES. This gene controls the production of the FOXL2 protein, which is involved in the development of the muscles in the eyelid as well as the growth and development of ovarian cells. Disease-causing changes (mutations) in the FOXL2 gene result in the signs and symptoms described above.This syndrome is almost always inherited in an autosomal dominant manner. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Dominant genetic disorders occur when only a single copy of an altered gene is necessary to cause a particular disease. The altered gene can be inherited from either parent or can be the result of a new mutation in the affected individual. The risk of passing the altered gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females. In some individuals, the disorder is due to a spontaneous (de novo) genetic mutation that occurs in the egg or sperm cell. In such situations, the disorder is not inherited from the parents. | Causes of Blepharophimosis, Ptosis, Epicanthus Inversus Syndrome. FOXL2 is the only gene known to cause BPES. This gene controls the production of the FOXL2 protein, which is involved in the development of the muscles in the eyelid as well as the growth and development of ovarian cells. Disease-causing changes (mutations) in the FOXL2 gene result in the signs and symptoms described above.This syndrome is almost always inherited in an autosomal dominant manner. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Dominant genetic disorders occur when only a single copy of an altered gene is necessary to cause a particular disease. The altered gene can be inherited from either parent or can be the result of a new mutation in the affected individual. The risk of passing the altered gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females. In some individuals, the disorder is due to a spontaneous (de novo) genetic mutation that occurs in the egg or sperm cell. In such situations, the disorder is not inherited from the parents. | 167 | Blepharophimosis, Ptosis, Epicanthus Inversus Syndrome |
nord_167_3 | Affects of Blepharophimosis, Ptosis, Epicanthus Inversus Syndrome | The prevalence of BPES is unknown, but there are no differences in prevalence based on ethnicity, sex, race or age. | Affects of Blepharophimosis, Ptosis, Epicanthus Inversus Syndrome. The prevalence of BPES is unknown, but there are no differences in prevalence based on ethnicity, sex, race or age. | 167 | Blepharophimosis, Ptosis, Epicanthus Inversus Syndrome |
nord_167_4 | Related disorders of Blepharophimosis, Ptosis, Epicanthus Inversus Syndrome | As POI is part of the phenotypic spectrum of BPES type I, FOXL2 was assumed to be a possible candidate gene for nonsyndromic POI. However, only a handful of mutations in FOXL2 have been described in patients with nonsyndromic POI. Other differential diagnoses of BPES include disorders in which either droopy eyelids (ptosis) or narrowing of the eyes (blepharophimosis) is a major feature. These disorders include hereditary congenital ptosis 1 and 2 (PTOS1 and PTOS2), Ohdo blepharophimosis syndrome, Michels syndrome, Ptosis with external opthalmoplegia, Noonan syndrome, Marden-Walker syndrome, Schwartz-Jampel syndrome, Dubowitz syndrome, Smith-Lemli-Opitz syndrome and KANSL1-related intellectual disability syndrome. For more information about these conditions, please visit the Rare Disease Database and use the respective disease name as your search term. | Related disorders of Blepharophimosis, Ptosis, Epicanthus Inversus Syndrome. As POI is part of the phenotypic spectrum of BPES type I, FOXL2 was assumed to be a possible candidate gene for nonsyndromic POI. However, only a handful of mutations in FOXL2 have been described in patients with nonsyndromic POI. Other differential diagnoses of BPES include disorders in which either droopy eyelids (ptosis) or narrowing of the eyes (blepharophimosis) is a major feature. These disorders include hereditary congenital ptosis 1 and 2 (PTOS1 and PTOS2), Ohdo blepharophimosis syndrome, Michels syndrome, Ptosis with external opthalmoplegia, Noonan syndrome, Marden-Walker syndrome, Schwartz-Jampel syndrome, Dubowitz syndrome, Smith-Lemli-Opitz syndrome and KANSL1-related intellectual disability syndrome. For more information about these conditions, please visit the Rare Disease Database and use the respective disease name as your search term. | 167 | Blepharophimosis, Ptosis, Epicanthus Inversus Syndrome |
nord_167_5 | Diagnosis of Blepharophimosis, Ptosis, Epicanthus Inversus Syndrome | The diagnosis of BPES is based on four clinical findings which are present at the time of birth. The first of these findings is narrowing of the eyelids (blepharophimosis). The second finding is drooping of the upper eyelid (ptosis). With this condition, affected individuals usually compensate by tilting their heads backward with their chin up and wrinkling their foreheads to pull the eyebrows upward to maintain full vision. These compensatory mechanisms result in a characteristic facial appearance. The third clinical finding is a skin fold that arises from the lower eyelid and runs inwards and upwards (epicanthus inversus). The final clinical finding used for diagnosis is widely set eyes (telecanthus). There are two types of BPES. Type I is diagnosed based on the four major features mentioned as well as premature ovarian insufficiency causing infertility or subfertility in females. Type II is diagnosed based on the presence of the four major features alone.Clinical Testing and Work-UpFemale BPES patients can also be tested for premature ovarian insufficiency. Clinical signs of this are endocrinologic or hormonal, including elevated serum levels of FSH and LH and decreased serum concentrations of estradiol and progesterone (important hormones in the female reproductive system). In addition, the size of the uterus and clinical features observable upon pelvic ultrasound can be telltale signs of POI.To confirm the clinical diagnosis on the molecular level, several genetic tests can be performed. Molecular genetic testing of FOXL2, includes sequence analysis and deletion/duplication analysis. In addition, chromosome analysis may be performed to screen for cytogenetic rearrangements involving 3q23 (band 23 on short arm of chromosome 3). | Diagnosis of Blepharophimosis, Ptosis, Epicanthus Inversus Syndrome. The diagnosis of BPES is based on four clinical findings which are present at the time of birth. The first of these findings is narrowing of the eyelids (blepharophimosis). The second finding is drooping of the upper eyelid (ptosis). With this condition, affected individuals usually compensate by tilting their heads backward with their chin up and wrinkling their foreheads to pull the eyebrows upward to maintain full vision. These compensatory mechanisms result in a characteristic facial appearance. The third clinical finding is a skin fold that arises from the lower eyelid and runs inwards and upwards (epicanthus inversus). The final clinical finding used for diagnosis is widely set eyes (telecanthus). There are two types of BPES. Type I is diagnosed based on the four major features mentioned as well as premature ovarian insufficiency causing infertility or subfertility in females. Type II is diagnosed based on the presence of the four major features alone.Clinical Testing and Work-UpFemale BPES patients can also be tested for premature ovarian insufficiency. Clinical signs of this are endocrinologic or hormonal, including elevated serum levels of FSH and LH and decreased serum concentrations of estradiol and progesterone (important hormones in the female reproductive system). In addition, the size of the uterus and clinical features observable upon pelvic ultrasound can be telltale signs of POI.To confirm the clinical diagnosis on the molecular level, several genetic tests can be performed. Molecular genetic testing of FOXL2, includes sequence analysis and deletion/duplication analysis. In addition, chromosome analysis may be performed to screen for cytogenetic rearrangements involving 3q23 (band 23 on short arm of chromosome 3). | 167 | Blepharophimosis, Ptosis, Epicanthus Inversus Syndrome |
nord_167_6 | Therapies of Blepharophimosis, Ptosis, Epicanthus Inversus Syndrome | Treatment
Treatment for BPES needs to address both the eyelid malformation and the premature ovarian insufficienty in type I patients. To manage the eyelid malformation, surgery is performed with the purpose of correcting the blepharophimosis, epicanthis inversus, telecanthus and ptosis. These procedures are traditionally done in two stages, though it is possible to do them simultaneously. Traditionally, correction of blepharophimosis, epicanthus inversus and telecanthus is done between the ages of three to five years, followed by ptosis correction after about one year. Timing of surgery is important, as this determines the balance of maintaining visual function while also producing the best cosmetic outcome. To manage premature ovarian insufficiency associated with BPES type I, hormone replacement therapy is recommended. More specific, estrogen replacement is given to manage the insufficiency of hormones experienced with POI. It should however be noted that no therapies have been shown to restore fertility or ovarian function thus far. As such, other reproductive options may be explored including adoption, foster parenthood, embryo donation, and egg donation. Follow-up is important in the management of BPES. Ophthalmic follow-up is individualized based on the affected individual’s visual acuity testing results, past procedures and age. Females who have BPES (type I especially) are encouraged for endocrinologic and gynecologic follow up to monitor ovarian function. This may include procedures such as pelvic ultrasounds, measuring serum FSH levels and menstrual pattern assessment. | Therapies of Blepharophimosis, Ptosis, Epicanthus Inversus Syndrome. Treatment
Treatment for BPES needs to address both the eyelid malformation and the premature ovarian insufficienty in type I patients. To manage the eyelid malformation, surgery is performed with the purpose of correcting the blepharophimosis, epicanthis inversus, telecanthus and ptosis. These procedures are traditionally done in two stages, though it is possible to do them simultaneously. Traditionally, correction of blepharophimosis, epicanthus inversus and telecanthus is done between the ages of three to five years, followed by ptosis correction after about one year. Timing of surgery is important, as this determines the balance of maintaining visual function while also producing the best cosmetic outcome. To manage premature ovarian insufficiency associated with BPES type I, hormone replacement therapy is recommended. More specific, estrogen replacement is given to manage the insufficiency of hormones experienced with POI. It should however be noted that no therapies have been shown to restore fertility or ovarian function thus far. As such, other reproductive options may be explored including adoption, foster parenthood, embryo donation, and egg donation. Follow-up is important in the management of BPES. Ophthalmic follow-up is individualized based on the affected individual’s visual acuity testing results, past procedures and age. Females who have BPES (type I especially) are encouraged for endocrinologic and gynecologic follow up to monitor ovarian function. This may include procedures such as pelvic ultrasounds, measuring serum FSH levels and menstrual pattern assessment. | 167 | Blepharophimosis, Ptosis, Epicanthus Inversus Syndrome |
nord_168_0 | Overview of Bloom Syndrome | Bloom syndrome (BSyn) is a rare genetic disorder characterized by short stature; a sun-sensitive, red rash that occurs primarily over the nose and cheeks; mild immune deficiency with increased susceptibility to infections; insulin resistance that resembles type 2 diabetes; and most importantly, a markedly increased susceptibility to many types of cancer, especially leukemia, lymphoma and gastrointestinal tract tumors. Diagnosis typically involves identification of the characteristic clinical features and/or molecular testing to identify changes to the BLM gene. BSyn is inherited in an autosomal recessive pattern, meaning that it occurs when a person inherits two changed (mutated) copies of the BLM gene. Because the most common BLM mutation is present at a high frequency in the Eastern European Jewish (Ashkenazi) population, it is often included among the Jewish genetic diseases. The genetic abnormality in Bloom syndrome causes problems with DNA repair, resulting in a high number of chromosome breaks and rearrangements. The abnormal DNA repair is responsible for the increased risk for cancer. | Overview of Bloom Syndrome. Bloom syndrome (BSyn) is a rare genetic disorder characterized by short stature; a sun-sensitive, red rash that occurs primarily over the nose and cheeks; mild immune deficiency with increased susceptibility to infections; insulin resistance that resembles type 2 diabetes; and most importantly, a markedly increased susceptibility to many types of cancer, especially leukemia, lymphoma and gastrointestinal tract tumors. Diagnosis typically involves identification of the characteristic clinical features and/or molecular testing to identify changes to the BLM gene. BSyn is inherited in an autosomal recessive pattern, meaning that it occurs when a person inherits two changed (mutated) copies of the BLM gene. Because the most common BLM mutation is present at a high frequency in the Eastern European Jewish (Ashkenazi) population, it is often included among the Jewish genetic diseases. The genetic abnormality in Bloom syndrome causes problems with DNA repair, resulting in a high number of chromosome breaks and rearrangements. The abnormal DNA repair is responsible for the increased risk for cancer. | 168 | Bloom Syndrome |
nord_168_1 | Symptoms of Bloom Syndrome | The most consistent clinical feature of BSyn, seen throughout all stages of life, is poor growth that affects height, weight and head circumference. This growth deficiency begins before birth, and the affected fetus is typically smaller than normal for gestational age. The average birth weight of affected males is 1760 g (range 900-3189 g) and of affected females, 1754 g (range 700-2892 g). Body proportions are nonetheless normal. The average adult height of affected males and females is 149 cm (range 128-164 cm) and 138 cm (range 115-160 cm), respectively.While the facial appearance of people with BSyn is variable and may be undistinguishable from unaffected persons of similar age and size, infants and adults with Bloom syndrome usually present with a distinctively narrow head and face, but they have normal body proportions. Sparse subcutaneous fat may cause the nose and/or ears to appear prominent. Despite their very small head circumference, most affected individuals have normal intellectual ability. Feeding difficulties are commonly reported in newborns, infants, and young children with BSyn. The child with BSyn characteristically feeds slowly, has a decreased appetite and eats a limited variety of foods. Some infants have had feeding tubes placed. Despite these interventions, weight gain continues to be modest, and children are rarely in the normal range for growth, even though their growth hormone levels are normal. Gastroesophageal reflux is common and may contribute to feeding issues. Skin lesions are another hallmark of BSyn. Although the skin at birth and in infancy appears normal, a red rash later appears on the nose and cheeks in a “butterfly” shape, and sometimes on the hands and forearms due to the dilation of small blood vessels, called telangiectasia. The skin is highly sensitive to sunlight (photosensitive), and this rash often occurs for the first time following sun exposure in the first or second year of life. Areas of abnormal brown or gray skin coloration (cafe-au-lait spots) may occur on other parts of the body. Male sterility is common because, for reasons that are not well understood, men with Bloom syndrome are unable to produce normal amounts of sperm. There has been one confirmed case of paternity in men with BSyn. Female infertility is also common because menstruation ceases at an abnormally early age among women with Bloom syndrome. Eleven women in the Bloom Syndrome Registry have become pregnant at least once, seven of whom have delivered a total of eleven healthy babies of normal size.Many people with BSyn may show signs of immune deficiency. As a result, those affected can experience recurrent infections, primarily ear infections and respiratory infections. Additionally, about 10% of people with BSyn will develop diabetes.At least 50% of people with this disorder eventually develop any one of a variety of cancers, especially leukemia and cancers of the gastrointestinal tract such as the colon. The types and locations in the body of cancer mimic those seen in the general population, but cancer occurs more frequently and at earlier ages among those with BSyn. Of the 283 persons in the Bloom Syndrome Registry, 148 individuals (52%) have developed a total of 240 cancers. Solid tumors account for 66.3% of all cancers, compared to 33.6% being leukemia/lymphoma. Among solid tumors, colorectal cancer is most common at 29 cases to date, followed by skin cancer (25 cases), then breast and oropharyngeal cancers (24 cases each). One-third of the people who have developed cancer develop multiple cancers.People with Bloom syndrome appear to have 150-300 times the risk of developing cancerous growths as do people without this disorder. Most people with Bloom syndrome are likely to develop cancer over their lifetimes. | Symptoms of Bloom Syndrome. The most consistent clinical feature of BSyn, seen throughout all stages of life, is poor growth that affects height, weight and head circumference. This growth deficiency begins before birth, and the affected fetus is typically smaller than normal for gestational age. The average birth weight of affected males is 1760 g (range 900-3189 g) and of affected females, 1754 g (range 700-2892 g). Body proportions are nonetheless normal. The average adult height of affected males and females is 149 cm (range 128-164 cm) and 138 cm (range 115-160 cm), respectively.While the facial appearance of people with BSyn is variable and may be undistinguishable from unaffected persons of similar age and size, infants and adults with Bloom syndrome usually present with a distinctively narrow head and face, but they have normal body proportions. Sparse subcutaneous fat may cause the nose and/or ears to appear prominent. Despite their very small head circumference, most affected individuals have normal intellectual ability. Feeding difficulties are commonly reported in newborns, infants, and young children with BSyn. The child with BSyn characteristically feeds slowly, has a decreased appetite and eats a limited variety of foods. Some infants have had feeding tubes placed. Despite these interventions, weight gain continues to be modest, and children are rarely in the normal range for growth, even though their growth hormone levels are normal. Gastroesophageal reflux is common and may contribute to feeding issues. Skin lesions are another hallmark of BSyn. Although the skin at birth and in infancy appears normal, a red rash later appears on the nose and cheeks in a “butterfly” shape, and sometimes on the hands and forearms due to the dilation of small blood vessels, called telangiectasia. The skin is highly sensitive to sunlight (photosensitive), and this rash often occurs for the first time following sun exposure in the first or second year of life. Areas of abnormal brown or gray skin coloration (cafe-au-lait spots) may occur on other parts of the body. Male sterility is common because, for reasons that are not well understood, men with Bloom syndrome are unable to produce normal amounts of sperm. There has been one confirmed case of paternity in men with BSyn. Female infertility is also common because menstruation ceases at an abnormally early age among women with Bloom syndrome. Eleven women in the Bloom Syndrome Registry have become pregnant at least once, seven of whom have delivered a total of eleven healthy babies of normal size.Many people with BSyn may show signs of immune deficiency. As a result, those affected can experience recurrent infections, primarily ear infections and respiratory infections. Additionally, about 10% of people with BSyn will develop diabetes.At least 50% of people with this disorder eventually develop any one of a variety of cancers, especially leukemia and cancers of the gastrointestinal tract such as the colon. The types and locations in the body of cancer mimic those seen in the general population, but cancer occurs more frequently and at earlier ages among those with BSyn. Of the 283 persons in the Bloom Syndrome Registry, 148 individuals (52%) have developed a total of 240 cancers. Solid tumors account for 66.3% of all cancers, compared to 33.6% being leukemia/lymphoma. Among solid tumors, colorectal cancer is most common at 29 cases to date, followed by skin cancer (25 cases), then breast and oropharyngeal cancers (24 cases each). One-third of the people who have developed cancer develop multiple cancers.People with Bloom syndrome appear to have 150-300 times the risk of developing cancerous growths as do people without this disorder. Most people with Bloom syndrome are likely to develop cancer over their lifetimes. | 168 | Bloom Syndrome |
nord_168_2 | Causes of Bloom Syndrome | Bloom syndrome is inherited in an autosomal recessive pattern. This means that there is a mutation of both copies of the BLM gene in people with Bloom syndrome; and each parent carries one mutant copy and one normal copy. The causative gene has been mapped to chromosomal location 15q26.1 and is responsible for making a protein known as BLM. A single mutation, known as BLMAsh, is responsible for over 90% cases of Bloom syndrome among Ashkenazi Jews. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. This means that to be affected with Bloom syndrome, a person receives one mutated gene copy from his or her mother and one mutated gene copy from his or her father. The risk for two carrier parents to both pass down the disease-causing gene and therefore to 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.Bloom syndrome is of special interest to geneticists because patients with this condition bear chromosomes that are highly unstable, so gene mutations are frequently encountered. In addition, the recombination of chromosomes in Bloom syndrome patients occurs with much greater frequency and seemingly with much greater ease than normal. Most clinicians engaged in studies of Bloom syndrome consider the volatility of the chromosomes to be a major contributor to both short stature and a predisposition to cancer.One of the types of chromosomal recombination that occurs in Bloom syndrome because of mutations in the BLM gene is known as sister-chromatid exchange (SCE). This means that portions of the chromosomal-DNA are exchanged among paired (sister) chromosomes. Whereas persons without BSyn have an average SCE rate of RMI1, RMI2 and TOP3A genes (Hudson et al 2016, Martin et al 2018). Nonetheless, SCE analysis may be useful for diagnosis of BSyn in circumstances where only one BLM mutation is identified and molecular genetic testing finds no mutations in RMI1, RMI2 or TOP3A.The BLM protein that is abnormal in people with Bloom syndrome is a RECQ helicase. Helicases help in DNA replication and repair by temporarily “unzipping” or “unwinding” the double helix of DNA so that it can be replicated. When this helicase is defective, as is the case in BSyn, a cell cannot detect and repair errors as effectively. This means that DNA damage during the course of a cell’s life is not found and repaired, so the cell cannot continue to function. The cell may die, or in some cases the damaged cells may continue to grow in an abnormal fashion and result in cancer. | Causes of Bloom Syndrome. Bloom syndrome is inherited in an autosomal recessive pattern. This means that there is a mutation of both copies of the BLM gene in people with Bloom syndrome; and each parent carries one mutant copy and one normal copy. The causative gene has been mapped to chromosomal location 15q26.1 and is responsible for making a protein known as BLM. A single mutation, known as BLMAsh, is responsible for over 90% cases of Bloom syndrome among Ashkenazi Jews. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. This means that to be affected with Bloom syndrome, a person receives one mutated gene copy from his or her mother and one mutated gene copy from his or her father. The risk for two carrier parents to both pass down the disease-causing gene and therefore to 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.Bloom syndrome is of special interest to geneticists because patients with this condition bear chromosomes that are highly unstable, so gene mutations are frequently encountered. In addition, the recombination of chromosomes in Bloom syndrome patients occurs with much greater frequency and seemingly with much greater ease than normal. Most clinicians engaged in studies of Bloom syndrome consider the volatility of the chromosomes to be a major contributor to both short stature and a predisposition to cancer.One of the types of chromosomal recombination that occurs in Bloom syndrome because of mutations in the BLM gene is known as sister-chromatid exchange (SCE). This means that portions of the chromosomal-DNA are exchanged among paired (sister) chromosomes. Whereas persons without BSyn have an average SCE rate of RMI1, RMI2 and TOP3A genes (Hudson et al 2016, Martin et al 2018). Nonetheless, SCE analysis may be useful for diagnosis of BSyn in circumstances where only one BLM mutation is identified and molecular genetic testing finds no mutations in RMI1, RMI2 or TOP3A.The BLM protein that is abnormal in people with Bloom syndrome is a RECQ helicase. Helicases help in DNA replication and repair by temporarily “unzipping” or “unwinding” the double helix of DNA so that it can be replicated. When this helicase is defective, as is the case in BSyn, a cell cannot detect and repair errors as effectively. This means that DNA damage during the course of a cell’s life is not found and repaired, so the cell cannot continue to function. The cell may die, or in some cases the damaged cells may continue to grow in an abnormal fashion and result in cancer. | 168 | Bloom Syndrome |
nord_168_3 | Affects of Bloom Syndrome | Bloom syndrome is rare, with about 283 cases reported to the Bloom Syndrome Registry. Although it occurs in many ethnic groups, it is more prevalent in people of Ashkenazi Jewish heritage whose ancestors were from Poland or the Ukraine. Among Ashkenazi Jews in either New York City or Israel, the carrier frequency for Bloom syndrome is about 1 in 100. Among Ashkenazi Jews living in Israel, all four of whose grandparents were from Poland, the relative carrier rate is 1 in 37 (Shahrabani-Gargir, et al 1998). Bloom syndrome has been seen in many other persons from throughout the world however, and about 75% of cases occur in people who are not of Jewish ancestry. | Affects of Bloom Syndrome. Bloom syndrome is rare, with about 283 cases reported to the Bloom Syndrome Registry. Although it occurs in many ethnic groups, it is more prevalent in people of Ashkenazi Jewish heritage whose ancestors were from Poland or the Ukraine. Among Ashkenazi Jews in either New York City or Israel, the carrier frequency for Bloom syndrome is about 1 in 100. Among Ashkenazi Jews living in Israel, all four of whose grandparents were from Poland, the relative carrier rate is 1 in 37 (Shahrabani-Gargir, et al 1998). Bloom syndrome has been seen in many other persons from throughout the world however, and about 75% of cases occur in people who are not of Jewish ancestry. | 168 | Bloom Syndrome |
nord_168_4 | Related disorders of Bloom Syndrome | Symptoms of the following disorders can be similar to those of Bloom syndrome. Comparisons may be useful for a differential diagnosis:Previously, BSyn was thought to be the only syndrome that shows increased SCE. However, three recently discovered disorders also show increased SCE and have other clinical features that overlap with those of BSyn. These disorders involve genes (RMI1, RMI2, and TOP3A) that code for proteins that interact with the BLM protein to repair DNA.Chromosomal instability syndromes are autosomal recessive inherited disorders that are associated with increased chromosomal breakage and genetic instability. These chromosomal changes place affected individuals at a higher than average risk for certain cancers, especially leukemia. Chromosomal instability syndromes include Fanconi anemia, ataxia telangiectasia, and xeroderma pigmentosum. (For more information on these disorders choose “Fanconi,” “ataxia telangiectasia,” and “xeroderma pigmentosum” as your search terms in the Rare Disease Database.)Cockayne syndrome (CS) is a variable genetic condition with cardinal features of growth deficiency and progressive neurological deterioration. Like BSyn, it is also marked by growth deficiency and sensitivity to sunlight. However, Individuals with Cockayne syndrome are more likely to experience hearing and vision loss than people with BSyn, and do not demonstrate an increased incidence of cancer. In the classical form of Cockayne syndrome (CS type I), the growth and neurological problems typically become apparent after the age of one year. A more severe form of Cockayne syndrome (CS type II) is apparent at birth (congenital) or in the early newborn period. There is a third form, known as Cockayne syndrome Type III (CS type III), that presents later in the child’s development and is generally a milder form. A fourth form, now recognized as xeroderma pigmentosa-Cockayne syndrome (XP-CS), combines features of both of these disorders. (For more information on this disorder choose “Cockayne syndrome” as your search term in the Rare Disease Database.)Two other conditions — Nijmegen breakage syndrome and Russell-Silver syndrome — share hallmark clinical features with BSyn. Persons with Nijmegen breakage syndrome and BSyn both present with small stature, evidence of excessive genomic instability, increased immunodeficiency, greater size and frequency of café-au-lait spots, and a predisposition to lymphoid cancers. However, a decline in intellectual performance is common in Nijmegen breakage syndrome, but absent in BSyn; additionally, persons with Nijmegen breakage syndrome demonstrate skin abnormalities like small, dilated blood vessels that are common in BSyn. Russell-Silver syndrome resembles BSyn in that both conditions cause growth deficiency, but those with Russel-Silver syndrome often have ophthalmological abnormalities that are not commonly seen in BSyn. Two other autosomal recessive disorders caused by defects in DNA repair that disrupt a RECQ helicase are Werner syndrome and Rothmund-Thomson syndrome. As is the case with BSyn, persons with Werner syndrome and Rothmund-Thomson syndrome generally have short stature and DNA instability. Both conditions have clinical features that overlap with those of BSyn: persons with Werner syndrome also demonstrate increased incidence of diabetes, while persons with Rothmund-Thomson syndrome also present with a sun-sensitive rash in the first years of life. And, although people with Rothmund-Thomson syndrome have a high risk to develop osteogenic sarcoma (a rare bone tumor) and a lower but still substantially increased risk for lymphoma, they do not develop the wide spectrum of tumors seen in persons with BSyn. The risk for tumors is not increased in persons with Werner syndrome. People with Rothmund-Thomson syndrome and Werner syndrome often have a prematurely aged appearance, and those with Werner syndrome often have premature atherosclerosis – these features are not generally present in people with BSyn. And finally, people with Rothmund-Thomson syndrome may experience dental or skeletal abnormalities and sparse hair, which are not seen in persons with BSyn. | Related disorders of Bloom Syndrome. Symptoms of the following disorders can be similar to those of Bloom syndrome. Comparisons may be useful for a differential diagnosis:Previously, BSyn was thought to be the only syndrome that shows increased SCE. However, three recently discovered disorders also show increased SCE and have other clinical features that overlap with those of BSyn. These disorders involve genes (RMI1, RMI2, and TOP3A) that code for proteins that interact with the BLM protein to repair DNA.Chromosomal instability syndromes are autosomal recessive inherited disorders that are associated with increased chromosomal breakage and genetic instability. These chromosomal changes place affected individuals at a higher than average risk for certain cancers, especially leukemia. Chromosomal instability syndromes include Fanconi anemia, ataxia telangiectasia, and xeroderma pigmentosum. (For more information on these disorders choose “Fanconi,” “ataxia telangiectasia,” and “xeroderma pigmentosum” as your search terms in the Rare Disease Database.)Cockayne syndrome (CS) is a variable genetic condition with cardinal features of growth deficiency and progressive neurological deterioration. Like BSyn, it is also marked by growth deficiency and sensitivity to sunlight. However, Individuals with Cockayne syndrome are more likely to experience hearing and vision loss than people with BSyn, and do not demonstrate an increased incidence of cancer. In the classical form of Cockayne syndrome (CS type I), the growth and neurological problems typically become apparent after the age of one year. A more severe form of Cockayne syndrome (CS type II) is apparent at birth (congenital) or in the early newborn period. There is a third form, known as Cockayne syndrome Type III (CS type III), that presents later in the child’s development and is generally a milder form. A fourth form, now recognized as xeroderma pigmentosa-Cockayne syndrome (XP-CS), combines features of both of these disorders. (For more information on this disorder choose “Cockayne syndrome” as your search term in the Rare Disease Database.)Two other conditions — Nijmegen breakage syndrome and Russell-Silver syndrome — share hallmark clinical features with BSyn. Persons with Nijmegen breakage syndrome and BSyn both present with small stature, evidence of excessive genomic instability, increased immunodeficiency, greater size and frequency of café-au-lait spots, and a predisposition to lymphoid cancers. However, a decline in intellectual performance is common in Nijmegen breakage syndrome, but absent in BSyn; additionally, persons with Nijmegen breakage syndrome demonstrate skin abnormalities like small, dilated blood vessels that are common in BSyn. Russell-Silver syndrome resembles BSyn in that both conditions cause growth deficiency, but those with Russel-Silver syndrome often have ophthalmological abnormalities that are not commonly seen in BSyn. Two other autosomal recessive disorders caused by defects in DNA repair that disrupt a RECQ helicase are Werner syndrome and Rothmund-Thomson syndrome. As is the case with BSyn, persons with Werner syndrome and Rothmund-Thomson syndrome generally have short stature and DNA instability. Both conditions have clinical features that overlap with those of BSyn: persons with Werner syndrome also demonstrate increased incidence of diabetes, while persons with Rothmund-Thomson syndrome also present with a sun-sensitive rash in the first years of life. And, although people with Rothmund-Thomson syndrome have a high risk to develop osteogenic sarcoma (a rare bone tumor) and a lower but still substantially increased risk for lymphoma, they do not develop the wide spectrum of tumors seen in persons with BSyn. The risk for tumors is not increased in persons with Werner syndrome. People with Rothmund-Thomson syndrome and Werner syndrome often have a prematurely aged appearance, and those with Werner syndrome often have premature atherosclerosis – these features are not generally present in people with BSyn. And finally, people with Rothmund-Thomson syndrome may experience dental or skeletal abnormalities and sparse hair, which are not seen in persons with BSyn. | 168 | Bloom Syndrome |
nord_168_5 | Diagnosis of Bloom Syndrome | Diagnosis of Bloom Syndrome. | 168 | Bloom Syndrome |
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nord_168_6 | Therapies of Bloom Syndrome | The treatment of Bloom syndrome is symptomatic and supportive. Health supervision recommendations that address diagnosis, treatment and surveillance for complications in persons with Bloom syndrome have been published [Cunniff et al. 2018]. Both to prevent skin cancer and the typical red rash that is common in BSyn, persons with Bloom syndrome should limit contact with direct sunlight by seeking shade, especially between 10 a.m. and 4 p.m. Health recommendations also suggest covering exposed skin with clothing, including a broad-brimmed hat and UV-blocking sunglasses, and applying a broad-spectrum sunscreen with SPF of 30 twice daily, or every 2-3 hours if outdoors. Annual evaluation by a dermatologist is also advised. Family members, friends and teachers are encouraged to relate to persons with BSyn appropriately for their chronologic age rather than the younger age suggested by their unusually small size. Nonetheless, infants, toddlers, and preschool-age children with BSyn should have close developmental monitoring and referral for early intervention services. If developmental delays are present, physical, occupational, and speech therapy can help. School performance should be assessed regularly, and parents should be aware of educational support available.Growth hormone administration to children with BSyn has not consistently increased growth rate in most persons, but some have experienced improved linear growth. Use of growth hormone has been approached cautiously in this population, because of concerns regarding an increased risk to develop tumors as a result of their treatment. If growth hormone is prescribed, the growth response and serum IGF-1 and IGFBP-3 levels should be closely monitored, and unless there is an increase in growth velocity while under treatment, it should be discontinued. Because of an increased incidence of hypothyroidism among the BSyn population, serum TSH with reflex to T4 should be measured annually beginning at 10 years. Additionally, recent health supervision guidelines suggest screening and family education on the signs and symptoms of hypothyroidism, including fatigue, constipation, cold sensitivity, and weight gain.Until additional information is available regarding treatment of problematic feeding behaviors and gastrointestinal symptoms, standard treatment for these concerns is recommended. This may include consultation with a gastroenterologist or feeding specialist, use of high calorie diets, institution of reflux precautions and use of anti-reflux medications. While supplemental feeding may result in increased fat deposition, it does not necessarily result in improved linear growth. Because abnormalities have been identified in the lipid profile of persons with BSyn, caution should be exercised in the use of high fat and/or high cholesterol diets. A lipid profile to detect dyslipidemia is recommended annually beginning at 10 years; for those with dyslipidemia, dietary treatment according to standard protocols is recommended. Diabetes mellitus is also prevalent among the BSyn population, so fasting blood glucose and hemoglobin A1C should be measured annually beginning at 10 years, and patients, their families, and their doctors should be alert for signs and symptoms such as increased thirst, increased urination, and weight loss. Treatment of diabetes mellitus in BSyn is the same as in other persons. For those with defects in humoral immunity, weekly subcutaneous or monthly intravenous infusions of gamma globulin may be beneficial. Cough assist devices, vibration vests, and daily nasal lavage can be used to for mucociliary clearance for bronchiectasis. If an individual with BSyn experiences recurrent, severe, or opportunistic infection, then immunodeficiency screening, including immunoglobulin level, antibody responses to vaccines, and quantitative B and T lymphocyte measurements, are recommended. Physicians must be conscientious in watching for indications of cancer, especially with patients who reach adulthood. A timeline for when to begin the suggested screenings and how often they should recur has been published [Cunniff et al. 2018]. It should be recognized however, that these recommendations are based on limited data from the Bloom Syndrome Registry and on expert opinion. There are currently no clinical trials or case control studies that address outcomes in people with BSyn. Because of the unusually high risk for early development of cancer, much of the health supervision effort is directed to early detection and treatment. For pediatric patients, recent health supervision guidelines suggest screening for Wilms tumor by performing an abdominal ultrasound every 3 months from the age of diagnosis until 8 years, in addition to screening for signs and symptoms such as hematuria and a painless abdominal mass. Surveillance for hematological cancers largely depends on awareness of sign/symptoms, including unintentional weight loss and fatigue; additionally, pallor, abnormal bleeding, and petechiae when surveilling for leukemia and enlarged lymph nodes, unexplained fevers, and drenching night sweats for lymphoma. Screening for colorectal cancer begins at 10-12 years, with an annual colonoscopy and fecal immunochemical testing (FIT) every 6 months. In affected females over the age of 18, a breast MRI to detect breast cancer is recommended annually. The most recent guidelines also recommend a whole-body MRI every 1-2 years beginning at age 12 or 13 to detect other solid tumors or lymphomas.When treating cancer, the hypersensitivity of persons with BSyn to both DNA-damaging chemicals and ionizing radiation ordinarily necessitates modification of standard cancer treatment regimens, which usually includes a reduction of both dosage and duration. Individuals with BSyn have usually tolerated doses at or below 50% of the standard chemotherapy dosage, with no clear evidence that this has resulted in poorer outcomes. However, full weight-based dosing may be appropriate for some chemotherapeutic drugs such as steroids and tyrosine kinase inhibitors. Absence of information as to the ideal dosages makes such treatment particularly challenging to the physician; nevertheless, the fact that the cancers themselves often appear unusually responsive to the treatment justifies the special effort. If HSCT is being contemplated, nonmyeloablative transplantation is likely to be tolerated more readily than other regimens. Additionally, the required ablative therapy prior to BMT often may require modification of standard protocols because of the hypersensitivity of persons with BSyn to DNA-damaging agents. Because infertility is a common issue, men with BSyn can undergo semen analysis to assess for abnormalities in the quantity and motility of sperm (azoospermia, oligospermia, or asthenospermia). Women with BSyn should be aware of signs of early menopause and may also consider oocyte (egg) freezing (cryopreservation). Additionally, assisted reproductive technology (ART) may be beneficial if natural conception is not possible, but there are currently no reports of ART in this population. Those who wish to conceive should consider consulting with a fertility specialist. Genetic counseling is recommended for people with Bloom syndrome and their families. Preimplantation and prenatal diagnosis are possible if the BLM mutations have been identified in the at-risk couple. | Therapies of Bloom Syndrome. The treatment of Bloom syndrome is symptomatic and supportive. Health supervision recommendations that address diagnosis, treatment and surveillance for complications in persons with Bloom syndrome have been published [Cunniff et al. 2018]. Both to prevent skin cancer and the typical red rash that is common in BSyn, persons with Bloom syndrome should limit contact with direct sunlight by seeking shade, especially between 10 a.m. and 4 p.m. Health recommendations also suggest covering exposed skin with clothing, including a broad-brimmed hat and UV-blocking sunglasses, and applying a broad-spectrum sunscreen with SPF of 30 twice daily, or every 2-3 hours if outdoors. Annual evaluation by a dermatologist is also advised. Family members, friends and teachers are encouraged to relate to persons with BSyn appropriately for their chronologic age rather than the younger age suggested by their unusually small size. Nonetheless, infants, toddlers, and preschool-age children with BSyn should have close developmental monitoring and referral for early intervention services. If developmental delays are present, physical, occupational, and speech therapy can help. School performance should be assessed regularly, and parents should be aware of educational support available.Growth hormone administration to children with BSyn has not consistently increased growth rate in most persons, but some have experienced improved linear growth. Use of growth hormone has been approached cautiously in this population, because of concerns regarding an increased risk to develop tumors as a result of their treatment. If growth hormone is prescribed, the growth response and serum IGF-1 and IGFBP-3 levels should be closely monitored, and unless there is an increase in growth velocity while under treatment, it should be discontinued. Because of an increased incidence of hypothyroidism among the BSyn population, serum TSH with reflex to T4 should be measured annually beginning at 10 years. Additionally, recent health supervision guidelines suggest screening and family education on the signs and symptoms of hypothyroidism, including fatigue, constipation, cold sensitivity, and weight gain.Until additional information is available regarding treatment of problematic feeding behaviors and gastrointestinal symptoms, standard treatment for these concerns is recommended. This may include consultation with a gastroenterologist or feeding specialist, use of high calorie diets, institution of reflux precautions and use of anti-reflux medications. While supplemental feeding may result in increased fat deposition, it does not necessarily result in improved linear growth. Because abnormalities have been identified in the lipid profile of persons with BSyn, caution should be exercised in the use of high fat and/or high cholesterol diets. A lipid profile to detect dyslipidemia is recommended annually beginning at 10 years; for those with dyslipidemia, dietary treatment according to standard protocols is recommended. Diabetes mellitus is also prevalent among the BSyn population, so fasting blood glucose and hemoglobin A1C should be measured annually beginning at 10 years, and patients, their families, and their doctors should be alert for signs and symptoms such as increased thirst, increased urination, and weight loss. Treatment of diabetes mellitus in BSyn is the same as in other persons. For those with defects in humoral immunity, weekly subcutaneous or monthly intravenous infusions of gamma globulin may be beneficial. Cough assist devices, vibration vests, and daily nasal lavage can be used to for mucociliary clearance for bronchiectasis. If an individual with BSyn experiences recurrent, severe, or opportunistic infection, then immunodeficiency screening, including immunoglobulin level, antibody responses to vaccines, and quantitative B and T lymphocyte measurements, are recommended. Physicians must be conscientious in watching for indications of cancer, especially with patients who reach adulthood. A timeline for when to begin the suggested screenings and how often they should recur has been published [Cunniff et al. 2018]. It should be recognized however, that these recommendations are based on limited data from the Bloom Syndrome Registry and on expert opinion. There are currently no clinical trials or case control studies that address outcomes in people with BSyn. Because of the unusually high risk for early development of cancer, much of the health supervision effort is directed to early detection and treatment. For pediatric patients, recent health supervision guidelines suggest screening for Wilms tumor by performing an abdominal ultrasound every 3 months from the age of diagnosis until 8 years, in addition to screening for signs and symptoms such as hematuria and a painless abdominal mass. Surveillance for hematological cancers largely depends on awareness of sign/symptoms, including unintentional weight loss and fatigue; additionally, pallor, abnormal bleeding, and petechiae when surveilling for leukemia and enlarged lymph nodes, unexplained fevers, and drenching night sweats for lymphoma. Screening for colorectal cancer begins at 10-12 years, with an annual colonoscopy and fecal immunochemical testing (FIT) every 6 months. In affected females over the age of 18, a breast MRI to detect breast cancer is recommended annually. The most recent guidelines also recommend a whole-body MRI every 1-2 years beginning at age 12 or 13 to detect other solid tumors or lymphomas.When treating cancer, the hypersensitivity of persons with BSyn to both DNA-damaging chemicals and ionizing radiation ordinarily necessitates modification of standard cancer treatment regimens, which usually includes a reduction of both dosage and duration. Individuals with BSyn have usually tolerated doses at or below 50% of the standard chemotherapy dosage, with no clear evidence that this has resulted in poorer outcomes. However, full weight-based dosing may be appropriate for some chemotherapeutic drugs such as steroids and tyrosine kinase inhibitors. Absence of information as to the ideal dosages makes such treatment particularly challenging to the physician; nevertheless, the fact that the cancers themselves often appear unusually responsive to the treatment justifies the special effort. If HSCT is being contemplated, nonmyeloablative transplantation is likely to be tolerated more readily than other regimens. Additionally, the required ablative therapy prior to BMT often may require modification of standard protocols because of the hypersensitivity of persons with BSyn to DNA-damaging agents. Because infertility is a common issue, men with BSyn can undergo semen analysis to assess for abnormalities in the quantity and motility of sperm (azoospermia, oligospermia, or asthenospermia). Women with BSyn should be aware of signs of early menopause and may also consider oocyte (egg) freezing (cryopreservation). Additionally, assisted reproductive technology (ART) may be beneficial if natural conception is not possible, but there are currently no reports of ART in this population. Those who wish to conceive should consider consulting with a fertility specialist. Genetic counseling is recommended for people with Bloom syndrome and their families. Preimplantation and prenatal diagnosis are possible if the BLM mutations have been identified in the at-risk couple. | 168 | Bloom Syndrome |
nord_169_0 | Overview of Blue Diaper Syndrome | Blue diaper syndrome is a rare, genetic metabolic disorder characterized by the incomplete intestinal breakdown of tryptophan, a dietary nutrient. Symptoms typically include digestive disturbances, fever, irritability and visual difficulties. Some children with blue diaper syndrome may also develop kidney disease. Infants with this disorder may have bluish urine-stained diapers. Blue diaper syndrome is inherited as an autosomal or X-linked recessive trait. | Overview of Blue Diaper Syndrome. Blue diaper syndrome is a rare, genetic metabolic disorder characterized by the incomplete intestinal breakdown of tryptophan, a dietary nutrient. Symptoms typically include digestive disturbances, fever, irritability and visual difficulties. Some children with blue diaper syndrome may also develop kidney disease. Infants with this disorder may have bluish urine-stained diapers. Blue diaper syndrome is inherited as an autosomal or X-linked recessive trait. | 169 | Blue Diaper Syndrome |
nord_169_1 | Symptoms of Blue Diaper Syndrome | Blue diaper syndrome is a rare inborn error metabolism that is usually detected when urine produces unusual blue stains on an infant's diapers (indoluria). This occurs when intestinal bacteria break down excessive amounts of unabsorbed tryptophan.Symptoms of blue diaper syndrome may include irritability, constipation, poor appetite, vomiting, and the failure to grow and gain weight at the expected rate (failure to thrive). Some children with Blue diaper syndrome may have frequent fevers and intestinal infections. Additional symptoms may include poor vision and abnormally high levels of calcium in the blood (hypercalcemia). Excessive calcium may accumulate in the kidneys (nephrocalcinosis) leading to impaired kidney function and possible kidney failure.Some infants may have eye abnormalities including underdevelopment (hypoplasia) of the optic disc, abnormal eye movements, and an abnormally small cornea (microcornea), the front, clear portion of the eye through which light passes. | Symptoms of Blue Diaper Syndrome. Blue diaper syndrome is a rare inborn error metabolism that is usually detected when urine produces unusual blue stains on an infant's diapers (indoluria). This occurs when intestinal bacteria break down excessive amounts of unabsorbed tryptophan.Symptoms of blue diaper syndrome may include irritability, constipation, poor appetite, vomiting, and the failure to grow and gain weight at the expected rate (failure to thrive). Some children with Blue diaper syndrome may have frequent fevers and intestinal infections. Additional symptoms may include poor vision and abnormally high levels of calcium in the blood (hypercalcemia). Excessive calcium may accumulate in the kidneys (nephrocalcinosis) leading to impaired kidney function and possible kidney failure.Some infants may have eye abnormalities including underdevelopment (hypoplasia) of the optic disc, abnormal eye movements, and an abnormally small cornea (microcornea), the front, clear portion of the eye through which light passes. | 169 | Blue Diaper Syndrome |
nord_169_2 | Causes of Blue Diaper Syndrome | Blue diaper syndrome is a rare disorder inherited as an autosomal recessive trait although X-linked recessive inheritance has not been completely ruled out. 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%. X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females have two X chromosomes but one of the X chromosomes is “turned off” and all of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is “turned off”. Males have one X chromosome and if they inherit an X chromosome that contains a disease gene, they will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers. Males can not pass an X-linked gene to their sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% to have a son affected with the disease, and a 25% chance to have an unaffected son.Symptoms, such as the blue urine stains on diapers, develop due to the intestinal breakdown of excessive amounts of tryptophan and the accumulation of indican and related compounds (e.g., indigotin) in the urine (indicanuria). When tryptophan is broken down by intestinal bacteria, it is converted into an organic compound called indole. Indole is absorbed and broken down into another organic compound called indican. When exposed to air, indican converts into indigo blue dye giving the urine a distinctive blue color. Although the exact nature of the biochemical defect remains uncertain, it is believed to be related to a defect in the intestinal absorption and transport of tryptophan. | Causes of Blue Diaper Syndrome. Blue diaper syndrome is a rare disorder inherited as an autosomal recessive trait although X-linked recessive inheritance has not been completely ruled out. 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%. X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females have two X chromosomes but one of the X chromosomes is “turned off” and all of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is “turned off”. Males have one X chromosome and if they inherit an X chromosome that contains a disease gene, they will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers. Males can not pass an X-linked gene to their sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% to have a son affected with the disease, and a 25% chance to have an unaffected son.Symptoms, such as the blue urine stains on diapers, develop due to the intestinal breakdown of excessive amounts of tryptophan and the accumulation of indican and related compounds (e.g., indigotin) in the urine (indicanuria). When tryptophan is broken down by intestinal bacteria, it is converted into an organic compound called indole. Indole is absorbed and broken down into another organic compound called indican. When exposed to air, indican converts into indigo blue dye giving the urine a distinctive blue color. Although the exact nature of the biochemical defect remains uncertain, it is believed to be related to a defect in the intestinal absorption and transport of tryptophan. | 169 | Blue Diaper Syndrome |
nord_169_3 | Affects of Blue Diaper Syndrome | Blue diaper syndrome is an extremely rare metabolic disorder that affects males and females in equal numbers. The incidence of the disorder in the general population is unknown. | Affects of Blue Diaper Syndrome. Blue diaper syndrome is an extremely rare metabolic disorder that affects males and females in equal numbers. The incidence of the disorder in the general population is unknown. | 169 | Blue Diaper Syndrome |
nord_169_4 | Related disorders of Blue Diaper Syndrome | Symptoms of the following disorder can be similar to those of blue diaper syndrome. Comparison may be useful for a differential diagnosis.Intestinal infections with the bacteria Pseudomonas aeruginosa can produce a blue discoloration of the stools. This can lead to a bluish appearance on a diaper and may be confused initially with blue diaper syndrome. Symptoms may include diarrhea, poor feeding habits, and irritability. | Related disorders of Blue Diaper Syndrome. Symptoms of the following disorder can be similar to those of blue diaper syndrome. Comparison may be useful for a differential diagnosis.Intestinal infections with the bacteria Pseudomonas aeruginosa can produce a blue discoloration of the stools. This can lead to a bluish appearance on a diaper and may be confused initially with blue diaper syndrome. Symptoms may include diarrhea, poor feeding habits, and irritability. | 169 | Blue Diaper Syndrome |
nord_169_5 | Diagnosis of Blue Diaper Syndrome | A diagnosis of blue diaper syndrome is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic symptoms, and the demonstration of indican in a fresh urine sample (indicanuria). | Diagnosis of Blue Diaper Syndrome. A diagnosis of blue diaper syndrome is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic symptoms, and the demonstration of indican in a fresh urine sample (indicanuria). | 169 | Blue Diaper Syndrome |
nord_169_6 | Therapies of Blue Diaper Syndrome | TreatmentChildren with blue diaper syndrome may be put on a diet that restricts their intake of calcium. It is hoped that a calcium restricted diet may help to prevent kidney damage. The diet should also be low in protein and the amount of vitamin D should be limited. Antibiotics may be administered to reduce or eliminate certain intestinal bacteria. Nicotinic acid may also be beneficial to control intestinal infections. Foods with high levels of tryptophan should be avoided, such as turkey and warm milk.Genetic counseling will of benefit for affected individuals and their families. Other treatment is symptomatic and supportive. | Therapies of Blue Diaper Syndrome. TreatmentChildren with blue diaper syndrome may be put on a diet that restricts their intake of calcium. It is hoped that a calcium restricted diet may help to prevent kidney damage. The diet should also be low in protein and the amount of vitamin D should be limited. Antibiotics may be administered to reduce or eliminate certain intestinal bacteria. Nicotinic acid may also be beneficial to control intestinal infections. Foods with high levels of tryptophan should be avoided, such as turkey and warm milk.Genetic counseling will of benefit for affected individuals and their families. Other treatment is symptomatic and supportive. | 169 | Blue Diaper Syndrome |
nord_170_0 | Overview of Blue Rubber Bleb Nevus syndrome | Blue rubber bleb nevus syndrome (BRBNS) is a rare blood vessel (vascular) disorder that affects the skin and internal organs of the body. Multiple distinctive skin lesions are usually characteristic of this disorder and are often present at birth or present during early childhood. Lesions in the gastrointestinal tract frequently become apparent during childhood or early adulthood. The lesions are multifocal venous malformations, resulting from abnormal embryonic blood vessel development. | Overview of Blue Rubber Bleb Nevus syndrome. Blue rubber bleb nevus syndrome (BRBNS) is a rare blood vessel (vascular) disorder that affects the skin and internal organs of the body. Multiple distinctive skin lesions are usually characteristic of this disorder and are often present at birth or present during early childhood. Lesions in the gastrointestinal tract frequently become apparent during childhood or early adulthood. The lesions are multifocal venous malformations, resulting from abnormal embryonic blood vessel development. | 170 | Blue Rubber Bleb Nevus syndrome |
nord_170_1 | Symptoms of Blue Rubber Bleb Nevus syndrome | BRBNS is characterized by soft, elevated lesions on the skin or just under the skin that are dark blue, red, purple-red or black in color. The venous malformations may be tender, contain blood and be easily compressed and are usually located on the upper limbs, trunk and soles of the feet but can occur anywhere. The lesions increase in size and become more apparent over time but have not been reported to become cancerous. The organ system most commonly affected by BRBNS is the gastrointestinal (GI) tract, particularly the small intestine. The lesions in the GI tract often bleed and can lead to mild or severe anemia. Iron replacement and/or frequent blood transfusions may be required. The GI lesions can also cause an obstruction or blockage (intussusception) of part of the bowel. Skeletal abnormalities and venous malformations in muscle are sometimes associated with BRBNS. | Symptoms of Blue Rubber Bleb Nevus syndrome. BRBNS is characterized by soft, elevated lesions on the skin or just under the skin that are dark blue, red, purple-red or black in color. The venous malformations may be tender, contain blood and be easily compressed and are usually located on the upper limbs, trunk and soles of the feet but can occur anywhere. The lesions increase in size and become more apparent over time but have not been reported to become cancerous. The organ system most commonly affected by BRBNS is the gastrointestinal (GI) tract, particularly the small intestine. The lesions in the GI tract often bleed and can lead to mild or severe anemia. Iron replacement and/or frequent blood transfusions may be required. The GI lesions can also cause an obstruction or blockage (intussusception) of part of the bowel. Skeletal abnormalities and venous malformations in muscle are sometimes associated with BRBNS. | 170 | Blue Rubber Bleb Nevus syndrome |
nord_170_2 | Causes of Blue Rubber Bleb Nevus syndrome | Blue rubber bleb nevus syndrome is sporadic. Although families have been described in which the condition follows autosomal dominant inheritance, these families actually have other multifocal venous malformations. | Causes of Blue Rubber Bleb Nevus syndrome. Blue rubber bleb nevus syndrome is sporadic. Although families have been described in which the condition follows autosomal dominant inheritance, these families actually have other multifocal venous malformations. | 170 | Blue Rubber Bleb Nevus syndrome |
nord_170_3 | Affects of Blue Rubber Bleb Nevus syndrome | Blue Rubber Bleb Nevus Syndrome affects males and females in equal numbers. Approximately 150 cases have been reported in the medical literature. | Affects of Blue Rubber Bleb Nevus syndrome. Blue Rubber Bleb Nevus Syndrome affects males and females in equal numbers. Approximately 150 cases have been reported in the medical literature. | 170 | Blue Rubber Bleb Nevus syndrome |
nord_170_4 | Related disorders of Blue Rubber Bleb Nevus syndrome | Arteriovenous malformation (AVM) is a congenital defect in which arteries and veins are tangled and not connected by capillaries. The lack of capillaries allows blood traveling through the abnormal vessels to flow rapidly and under high pressure and prevents the nutrient rich blood in the arteries from reaching the tissues. AVM can occur in many different parts of the body, but those located in the brain, brainstem and spinal cord (neurological AVM) can affect the entire body. (For more information about arteriovenous malformation, choose “arteriovenous malformation” as your search term in the Rare Disease Database).Capillary malformations are birthmarks that involve the skin only and not the underlying tissues. Most capillary malformations do not cause health problems.Hereditary hemorrhagic telangiectasia (HHT or Osler-Weber-Rendu syndrome) is a rare inherited disorder characterized by malformations of various blood vessels (vascular dysplasia), usually resulting in excessive bleeding (hemorrhaging). Chronic nosebleeds are often the first apparent symptom associated with hereditary hemorrhagic telangiectasia. Malformation of various blood vessels may result in abnormalities affecting various organ systems of the body including the lungs, brain, intestine and liver. Hereditary hemorrhagic telangiectasia is inherited as an autosomal dominant trait. (For more information about hereditary hemorrhagic telangiectasia, choose “hemorrhagic” as your search term in the Rare Disease Database).Maffucci syndrome is a rare genetic disorder characterized by benign overgrowths of cartilage (enchondromas), skeletal deformities, and dark red irregularly shaped patches of skin (venous malformations). Enchondromas are most often found in certain bones (phalanges) of the hands and feet. Skeletal malformations may include legs that are disproportionate in length and/or abnormal side-to-side curvature of the spine (scoliosis). In many cases, bones may tend to fracture easily. In most cases, venous malformations appear at birth or during early childhood and may be progressive. Maffucci syndrome is inherited as an autosomal dominant genetic trait. (For more information about Maffucci syndrome, choose “Maffucci” as your search term in the Rare Disease Database).Klippel-Trenaunay syndrome, a rare disorder that is present at birth (congenital), is characterized by abnormal benign growths on the skin (cutaneous) consisting of masses of blood vessels (capillary, venous and lymphatic malformations), and excessive growth (hypertrophy) of the soft tissue and bone of a leg and/or arm (limb). (In individuals with the disorder, such hypertrophy typically affects one side of the body [hemihypertrophy].) In many cases vascular malformations may include distinctive purplish-reddish birthmarks (“port wine stain”) on certain areas of the skin. The symptoms and findings associated with the disorder may vary in range and severity from case to case. . (For more information about Klippel-Trenaunay syndrome, choose “Klippel-Trenaunay” as your search term in the Rare Disease Database). | Related disorders of Blue Rubber Bleb Nevus syndrome. Arteriovenous malformation (AVM) is a congenital defect in which arteries and veins are tangled and not connected by capillaries. The lack of capillaries allows blood traveling through the abnormal vessels to flow rapidly and under high pressure and prevents the nutrient rich blood in the arteries from reaching the tissues. AVM can occur in many different parts of the body, but those located in the brain, brainstem and spinal cord (neurological AVM) can affect the entire body. (For more information about arteriovenous malformation, choose “arteriovenous malformation” as your search term in the Rare Disease Database).Capillary malformations are birthmarks that involve the skin only and not the underlying tissues. Most capillary malformations do not cause health problems.Hereditary hemorrhagic telangiectasia (HHT or Osler-Weber-Rendu syndrome) is a rare inherited disorder characterized by malformations of various blood vessels (vascular dysplasia), usually resulting in excessive bleeding (hemorrhaging). Chronic nosebleeds are often the first apparent symptom associated with hereditary hemorrhagic telangiectasia. Malformation of various blood vessels may result in abnormalities affecting various organ systems of the body including the lungs, brain, intestine and liver. Hereditary hemorrhagic telangiectasia is inherited as an autosomal dominant trait. (For more information about hereditary hemorrhagic telangiectasia, choose “hemorrhagic” as your search term in the Rare Disease Database).Maffucci syndrome is a rare genetic disorder characterized by benign overgrowths of cartilage (enchondromas), skeletal deformities, and dark red irregularly shaped patches of skin (venous malformations). Enchondromas are most often found in certain bones (phalanges) of the hands and feet. Skeletal malformations may include legs that are disproportionate in length and/or abnormal side-to-side curvature of the spine (scoliosis). In many cases, bones may tend to fracture easily. In most cases, venous malformations appear at birth or during early childhood and may be progressive. Maffucci syndrome is inherited as an autosomal dominant genetic trait. (For more information about Maffucci syndrome, choose “Maffucci” as your search term in the Rare Disease Database).Klippel-Trenaunay syndrome, a rare disorder that is present at birth (congenital), is characterized by abnormal benign growths on the skin (cutaneous) consisting of masses of blood vessels (capillary, venous and lymphatic malformations), and excessive growth (hypertrophy) of the soft tissue and bone of a leg and/or arm (limb). (In individuals with the disorder, such hypertrophy typically affects one side of the body [hemihypertrophy].) In many cases vascular malformations may include distinctive purplish-reddish birthmarks (“port wine stain”) on certain areas of the skin. The symptoms and findings associated with the disorder may vary in range and severity from case to case. . (For more information about Klippel-Trenaunay syndrome, choose “Klippel-Trenaunay” as your search term in the Rare Disease Database). | 170 | Blue Rubber Bleb Nevus syndrome |
nord_170_5 | Diagnosis of Blue Rubber Bleb Nevus syndrome | BRBNS is diagnosed by physical examination and a procedure in which the GI tract is illuminated and visualized (endoscopy). Genetic testing for BRBNS is available on a research basis only. | Diagnosis of Blue Rubber Bleb Nevus syndrome. BRBNS is diagnosed by physical examination and a procedure in which the GI tract is illuminated and visualized (endoscopy). Genetic testing for BRBNS is available on a research basis only. | 170 | Blue Rubber Bleb Nevus syndrome |
nord_170_6 | Therapies of Blue Rubber Bleb Nevus syndrome | TreatmentIron therapy and blood transfusions are used to conservatively manage BRBNS. The skin lesions associated with BRBNS can be treated with laser therapy, injection of chemicals that collapse the lesion (sclerotherapy) or surgical removal. Lesions in the gastrointestinal system are usually not removed unless bleeding leads to anemia and necessitates repeated blood transfusions. Gastrointestinal lesions can be safely removed surgically, but one or several lengthy operations may be required. | Therapies of Blue Rubber Bleb Nevus syndrome. TreatmentIron therapy and blood transfusions are used to conservatively manage BRBNS. The skin lesions associated with BRBNS can be treated with laser therapy, injection of chemicals that collapse the lesion (sclerotherapy) or surgical removal. Lesions in the gastrointestinal system are usually not removed unless bleeding leads to anemia and necessitates repeated blood transfusions. Gastrointestinal lesions can be safely removed surgically, but one or several lengthy operations may be required. | 170 | Blue Rubber Bleb Nevus syndrome |
nord_171_0 | Overview of Bohring-Opitz Syndrome | SummaryBohring-Opitz syndrome (BOS) is a rare, multiple anomaly syndrome that most often is evident at birth (congenital) and affects an individual’s growth, development, and variable organ-systems. Individuals with BOS often have severe growth restriction and are therefore quite small; they may have feeding difficulties, characteristic facial features, and the presence of a red or pink birthmark (nevus flammeus) on the forehead or eyelids. Individuals may also have seizures, heart anomalies, and a characteristic ‘BOS posture’ where the elbows are bent and wrists angle outwards. Additional abnormalities may include a smaller than average head size (microcephaly), a visible ridge over the forehead (metopic ridge), a cleft lip and/or palate, eye abnormalities, recurrent infections, and pauses during breathing while asleep (sleep apnea), as well as sleep difficulties. Children with BOS may have varying degrees of learning differences, but these are generally severe, and most children do not attain typical speech or ambulation. Bohring-Opitz syndrome is caused by mutations in the ASXL1 gene. There are currently no known medications or disease-specific therapies, but supportive treatment involving physical/occupational/speech therapy and specific management of an individual’s symptoms are considered the standard of care. BOS can theoretically be transmitted in an autosomal dominant manner (where 50% of an individual’s children are at risk of inheriting the gene), but most individuals do not reproduce due to developmental and neurologic impairments. There are no reports of BOS mutations being passed down from parent to child. All reports of BOS indicate that neither parent carries the same mutation and the mutation was new in the child (de novo).IntroductionBOS was first described in 1999 by Bohring, et al. to describe four individuals with severe prenatal growth restriction, microcephaly, cleft lip, characteristic positioning of the elbows and wrists, and additional organ-system anomalies. Two prior reports described similar individuals with abnormalities to their skull shape who were felt to have Opitz trigonencephaly syndrome (C syndrome). Mutations in the ASXL1 gene were found in individuals with clinical features of BOS and reported in 2011. | Overview of Bohring-Opitz Syndrome. SummaryBohring-Opitz syndrome (BOS) is a rare, multiple anomaly syndrome that most often is evident at birth (congenital) and affects an individual’s growth, development, and variable organ-systems. Individuals with BOS often have severe growth restriction and are therefore quite small; they may have feeding difficulties, characteristic facial features, and the presence of a red or pink birthmark (nevus flammeus) on the forehead or eyelids. Individuals may also have seizures, heart anomalies, and a characteristic ‘BOS posture’ where the elbows are bent and wrists angle outwards. Additional abnormalities may include a smaller than average head size (microcephaly), a visible ridge over the forehead (metopic ridge), a cleft lip and/or palate, eye abnormalities, recurrent infections, and pauses during breathing while asleep (sleep apnea), as well as sleep difficulties. Children with BOS may have varying degrees of learning differences, but these are generally severe, and most children do not attain typical speech or ambulation. Bohring-Opitz syndrome is caused by mutations in the ASXL1 gene. There are currently no known medications or disease-specific therapies, but supportive treatment involving physical/occupational/speech therapy and specific management of an individual’s symptoms are considered the standard of care. BOS can theoretically be transmitted in an autosomal dominant manner (where 50% of an individual’s children are at risk of inheriting the gene), but most individuals do not reproduce due to developmental and neurologic impairments. There are no reports of BOS mutations being passed down from parent to child. All reports of BOS indicate that neither parent carries the same mutation and the mutation was new in the child (de novo).IntroductionBOS was first described in 1999 by Bohring, et al. to describe four individuals with severe prenatal growth restriction, microcephaly, cleft lip, characteristic positioning of the elbows and wrists, and additional organ-system anomalies. Two prior reports described similar individuals with abnormalities to their skull shape who were felt to have Opitz trigonencephaly syndrome (C syndrome). Mutations in the ASXL1 gene were found in individuals with clinical features of BOS and reported in 2011. | 171 | Bohring-Opitz Syndrome |
nord_171_1 | Symptoms of Bohring-Opitz Syndrome | BOS presents typically at birth, but not all signs may be evident immediately. Infants with BOS may display poor growth prenatally (intrauterine growth restriction), and may have brain abnormalities evident on prenatal ultrasound, including but not limited to agenesis of the corpus callosum, enlarged ventricles, or Dandy-Walker malformation. Infants with BOS may have feeding issues which may necessitate the use of a feeding tube (G-tube or gastrostomy tube), as well as cyclic vomiting, gastroesophageal reflux, or oral aversion. Feeding issues may improve or resolve as children get older. Some children with BOS may have a cleft lip or palate which may further complicate feeding and swallowing. Individuals may have cardiac anomalies involving structure of the heart or heart rhythm abnormalities. Frequent infections may be common, and may be exacerbated by low tone and inability to clear secretions. Some children may need a breathing tube through the neck (tracheostomy) if they have significant airway issues or need help breathing. Although children with BOS are more susceptible to common respiratory infections, there have been no documentations of immunodeficiency in BOS. Some children may have sleep problems related to falling or staying asleep, and some may also have pauses in their breathing during sleep (sleep apnea). Children may also have eye abnormalities including difficulty seeing far away (myopia) or problems with eye muscles (strabismus).All individuals with BOS have learning and developmental differences, which are often severe. Most children do not attain speech, although many are able to use various adaptive communication devices. Although few individuals with BOS walk independently, many also benefit from adaptive walkers, strollers, and leg bracing to assist with mobility. There are some individuals with BOS who have been reported to have a type of childhood kidney cancer called Wilms tumor; while there may be an increased risk for children with BOS to have Wilms tumor, and certain screening recommendations exist, not all children with BOS develop cancer. | Symptoms of Bohring-Opitz Syndrome. BOS presents typically at birth, but not all signs may be evident immediately. Infants with BOS may display poor growth prenatally (intrauterine growth restriction), and may have brain abnormalities evident on prenatal ultrasound, including but not limited to agenesis of the corpus callosum, enlarged ventricles, or Dandy-Walker malformation. Infants with BOS may have feeding issues which may necessitate the use of a feeding tube (G-tube or gastrostomy tube), as well as cyclic vomiting, gastroesophageal reflux, or oral aversion. Feeding issues may improve or resolve as children get older. Some children with BOS may have a cleft lip or palate which may further complicate feeding and swallowing. Individuals may have cardiac anomalies involving structure of the heart or heart rhythm abnormalities. Frequent infections may be common, and may be exacerbated by low tone and inability to clear secretions. Some children may need a breathing tube through the neck (tracheostomy) if they have significant airway issues or need help breathing. Although children with BOS are more susceptible to common respiratory infections, there have been no documentations of immunodeficiency in BOS. Some children may have sleep problems related to falling or staying asleep, and some may also have pauses in their breathing during sleep (sleep apnea). Children may also have eye abnormalities including difficulty seeing far away (myopia) or problems with eye muscles (strabismus).All individuals with BOS have learning and developmental differences, which are often severe. Most children do not attain speech, although many are able to use various adaptive communication devices. Although few individuals with BOS walk independently, many also benefit from adaptive walkers, strollers, and leg bracing to assist with mobility. There are some individuals with BOS who have been reported to have a type of childhood kidney cancer called Wilms tumor; while there may be an increased risk for children with BOS to have Wilms tumor, and certain screening recommendations exist, not all children with BOS develop cancer. | 171 | Bohring-Opitz Syndrome |
nord_171_2 | Causes of Bohring-Opitz Syndrome | BOS is thought to be caused by changes (mutations) in the ASXL1 gene. This gene is thought to play a role in chromatin remodeling, which is responsible in part for the packaging of genetic material in the body. The ASXL1 gene is also thought to be involved in activating and silencing other genes in the HOX family. All individuals who have been reported to have a mutation in the ASXL1 gene appear to have developed it spontaneously, and not inherited it from a parent. If BOS were to be inherited, it is theorized that it would be in an autosomal dominant manner, meaning that the individual with BOS would have a 50% chance of passing down the affected gene change to any offspring. In some disorders which are dominant, individuals may have varying expression of certain signs and symptoms. Therefore, not all individuals with BOS may be identical in regards to their medical issues, although many do share similar characteristics. | Causes of Bohring-Opitz Syndrome. BOS is thought to be caused by changes (mutations) in the ASXL1 gene. This gene is thought to play a role in chromatin remodeling, which is responsible in part for the packaging of genetic material in the body. The ASXL1 gene is also thought to be involved in activating and silencing other genes in the HOX family. All individuals who have been reported to have a mutation in the ASXL1 gene appear to have developed it spontaneously, and not inherited it from a parent. If BOS were to be inherited, it is theorized that it would be in an autosomal dominant manner, meaning that the individual with BOS would have a 50% chance of passing down the affected gene change to any offspring. In some disorders which are dominant, individuals may have varying expression of certain signs and symptoms. Therefore, not all individuals with BOS may be identical in regards to their medical issues, although many do share similar characteristics. | 171 | Bohring-Opitz Syndrome |
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