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nord_371_3 | Affects of Diamond Blackfan Anemia | Diamond Blackfan anemia affects approximately 5 to 7 people per million live births per year. Thus in the United States, with 4 million livebirths per year, there are approximately 25-35 new patients born per year. There are several approximately 5000 cases world-wide. There are an equal number of males and females with the disease. | Affects of Diamond Blackfan Anemia. Diamond Blackfan anemia affects approximately 5 to 7 people per million live births per year. Thus in the United States, with 4 million livebirths per year, there are approximately 25-35 new patients born per year. There are several approximately 5000 cases world-wide. There are an equal number of males and females with the disease. | 371 | Diamond Blackfan Anemia |
nord_371_4 | Related disorders of Diamond Blackfan Anemia | Symptoms of the following disorders can be similar to those of DBA. Comparisons may be useful for a differential diagnosis.Aplastic anemia is characterized by bone marrow failure. A total suppression or aplasia of the bone marrow is typical of aplastic anemia. The disorder may occur for unknown reasons or as the result of an infection or a toxic reaction to radiation, certain drugs, or chemicals. In rare cases, a tumor in the thymus may cause this disorder. The bone marrow may be classified as hypoplastic or aplastic. Hypoplasia occurs when the marrow is defective or only partially working, while in aplasia the bone marrow ceases developing any new blood cells.Fanconi anemia is another rare inherited bone marrow failure syndrome. It is characterized by congenital anomalies including bone abnormalities, small head size, small genitalia and abnormal pigmentation of the skin. Complications include low white blood counts which can lead to infections such as pneumonia and meningitis; and, low platelet counts causing abnormal bleeding. These patients are at high risk for developing leukemia and other cancers.(For more information on these disorders, choose “aplastic” and “Fanconi” as your search terms in the Rare Disease Database.) | Related disorders of Diamond Blackfan Anemia. Symptoms of the following disorders can be similar to those of DBA. Comparisons may be useful for a differential diagnosis.Aplastic anemia is characterized by bone marrow failure. A total suppression or aplasia of the bone marrow is typical of aplastic anemia. The disorder may occur for unknown reasons or as the result of an infection or a toxic reaction to radiation, certain drugs, or chemicals. In rare cases, a tumor in the thymus may cause this disorder. The bone marrow may be classified as hypoplastic or aplastic. Hypoplasia occurs when the marrow is defective or only partially working, while in aplasia the bone marrow ceases developing any new blood cells.Fanconi anemia is another rare inherited bone marrow failure syndrome. It is characterized by congenital anomalies including bone abnormalities, small head size, small genitalia and abnormal pigmentation of the skin. Complications include low white blood counts which can lead to infections such as pneumonia and meningitis; and, low platelet counts causing abnormal bleeding. These patients are at high risk for developing leukemia and other cancers.(For more information on these disorders, choose “aplastic” and “Fanconi” as your search terms in the Rare Disease Database.) | 371 | Diamond Blackfan Anemia |
nord_371_5 | Diagnosis of Diamond Blackfan Anemia | The average age of presenting with anemia is two months and the average age of diagnosis with DBA is 3-4 months. Some tests that aid in diagnosing DBA are: | Diagnosis of Diamond Blackfan Anemia. The average age of presenting with anemia is two months and the average age of diagnosis with DBA is 3-4 months. Some tests that aid in diagnosing DBA are: | 371 | Diamond Blackfan Anemia |
nord_371_6 | Therapies of Diamond Blackfan Anemia | Treatment
When the patient presents with anemia, the usual initial treatment includes a red cell transfusion. If available, transfusions are usually the mainstay of treatment for the first year of life for the anemia of DBA. After the first year patients are started on a course of treatment with corticosteroids. This treatment can initially improve the red blood cell count in approximately 80% of people with DBA.Red blood transfusions are used for those patients who do not respond to corticosteroid treatment. If the patient remains on chronic transfusion therapy (usually required every 3-4 weeks) then the patient will also require iron chelation. Iron chelation is necessary to unload the extra iron that accumulates when a person receives transfusions. If the iron is not removed then the person can develop iron overload in the heart, liver and endocrine organs and develop heart arrhythmias (abnormal heart rhythms), congestive heart failure, liver abnormalities and cirrhosis, diabetes, hypothyroidism, gonadal dysfunction, and other issues.Some people have such mild signs and symptoms that they do not require treatment.
The only curative treatment for the anemia of DBA is bone marrow/stem cell transplantation. This treatment replaces damaged bone marrow with healthy stem cells from a donor. This can be done using an unaffected sibling or an unrelated donor. | Therapies of Diamond Blackfan Anemia. Treatment
When the patient presents with anemia, the usual initial treatment includes a red cell transfusion. If available, transfusions are usually the mainstay of treatment for the first year of life for the anemia of DBA. After the first year patients are started on a course of treatment with corticosteroids. This treatment can initially improve the red blood cell count in approximately 80% of people with DBA.Red blood transfusions are used for those patients who do not respond to corticosteroid treatment. If the patient remains on chronic transfusion therapy (usually required every 3-4 weeks) then the patient will also require iron chelation. Iron chelation is necessary to unload the extra iron that accumulates when a person receives transfusions. If the iron is not removed then the person can develop iron overload in the heart, liver and endocrine organs and develop heart arrhythmias (abnormal heart rhythms), congestive heart failure, liver abnormalities and cirrhosis, diabetes, hypothyroidism, gonadal dysfunction, and other issues.Some people have such mild signs and symptoms that they do not require treatment.
The only curative treatment for the anemia of DBA is bone marrow/stem cell transplantation. This treatment replaces damaged bone marrow with healthy stem cells from a donor. This can be done using an unaffected sibling or an unrelated donor. | 371 | Diamond Blackfan Anemia |
nord_372_0 | Overview of Diastrophic Dysplasia | Diastrophic dysplasia, which is also known as disastrophic dwarfism, is a rare disorder that is present at birth (congenital). The range and severity of associated symptoms and physical findings may vary greatly from case to case. However, the disorder is often characterized by short stature and unusually short arms and legs (short-limbed dwarfism); abnormal development of bones (skeletal dysplasia) and joints (joint dysplasia) in many areas of the body; progressive abnormal curvature of the spine (scoliosis and/or kyphosis); abnormal tissue changes of the outer, visible portions of the ears (pinnae); and/or, in some cases, malformations of the head and facial (craniofacial) area.In most infants with diastrophic dysplasia, the first bone within the body of each hand (first metacarpals) may be unusually small and “oval shaped,” causing the thumbs to deviate away (abduction) from the body (“hitchhiker thumbs”). Other fingers may also be abnormally short (brachydactyly) and joints between certain bones of the fingers (proximal interphalangeal joints) may become fused (symphalangism), causing limited flexion and restricted movement of the finger joints. Affected infants also typically have severe foot deformities (talipes or “clubfeet”) due to abnormal deviation and fusion of certain bones within the body of each foot (metatarsals). In addition, many children with the disorder experience limited extension, partial (subluxation) or complete dislocation, and/or permanent flexion and immobilization (contractures) of certain joints.In most infants with diastrophic dysplasia, there is also incomplete closure of bones of the spinal column (spina bifida occulta) within the neck area and the upper portion of the back (lower cervical and upper thoracic vertebrae). In addition, during the first year of life, some affected children may begin to develop progressive abnormal sideways curvature of the spine (scoliosis). During adolescence, individuals with the disorder may also develop abnormal front-to-back curvature of the spine (kyphosis), particularly affecting vertebrae within the neck area (cervical vertebrae). In severe cases, progressive kyphosis may lead to difficulties breathing (respiratory distress). Some individuals may also be prone to experiencing partial dislocation (subluxation) of joints between the central areas (bodies) of cervical vertebrae, potentially resulting in spinal cord injury. Such injury may cause muscle weakness (paresis) or paralysis and/or life-threatening complications.In addition, most newborns with diastrophic dysplasia have or develop abnormal fluid-filled sacs (cysts) within the outer, visible portions of the ears (pinnae). Within the first weeks of life, the pinnae become swollen and inflamed and unusually firm, thick, and abnormal in shape. Over time, the abnormal areas of tissue (lesions) may accumulate deposits of calcium salts (calcification) and eventually develop into bone (ossification). Some affected infants may also have abnormalities of the head and facial (craniofacial) area including incomplete closure of the roof of the mouth (cleft palate) and/or abnormal smallness of the jaws (micrognathia). In addition, in some affected infants, abnormalities of supportive connective tissue (cartilage) within the windpipe (trachea), voice box (larynx), and certain air passages in the lungs (bronchi) may result in collapse of these airways, causing life-threatening complications such as respiratory obstruction and difficulties breathing. In some individuals with the disorder, additional symptoms and physical findings may also be present. Diastrophic dysplasia is inherited as an autosomal recessive trait. | Overview of Diastrophic Dysplasia. Diastrophic dysplasia, which is also known as disastrophic dwarfism, is a rare disorder that is present at birth (congenital). The range and severity of associated symptoms and physical findings may vary greatly from case to case. However, the disorder is often characterized by short stature and unusually short arms and legs (short-limbed dwarfism); abnormal development of bones (skeletal dysplasia) and joints (joint dysplasia) in many areas of the body; progressive abnormal curvature of the spine (scoliosis and/or kyphosis); abnormal tissue changes of the outer, visible portions of the ears (pinnae); and/or, in some cases, malformations of the head and facial (craniofacial) area.In most infants with diastrophic dysplasia, the first bone within the body of each hand (first metacarpals) may be unusually small and “oval shaped,” causing the thumbs to deviate away (abduction) from the body (“hitchhiker thumbs”). Other fingers may also be abnormally short (brachydactyly) and joints between certain bones of the fingers (proximal interphalangeal joints) may become fused (symphalangism), causing limited flexion and restricted movement of the finger joints. Affected infants also typically have severe foot deformities (talipes or “clubfeet”) due to abnormal deviation and fusion of certain bones within the body of each foot (metatarsals). In addition, many children with the disorder experience limited extension, partial (subluxation) or complete dislocation, and/or permanent flexion and immobilization (contractures) of certain joints.In most infants with diastrophic dysplasia, there is also incomplete closure of bones of the spinal column (spina bifida occulta) within the neck area and the upper portion of the back (lower cervical and upper thoracic vertebrae). In addition, during the first year of life, some affected children may begin to develop progressive abnormal sideways curvature of the spine (scoliosis). During adolescence, individuals with the disorder may also develop abnormal front-to-back curvature of the spine (kyphosis), particularly affecting vertebrae within the neck area (cervical vertebrae). In severe cases, progressive kyphosis may lead to difficulties breathing (respiratory distress). Some individuals may also be prone to experiencing partial dislocation (subluxation) of joints between the central areas (bodies) of cervical vertebrae, potentially resulting in spinal cord injury. Such injury may cause muscle weakness (paresis) or paralysis and/or life-threatening complications.In addition, most newborns with diastrophic dysplasia have or develop abnormal fluid-filled sacs (cysts) within the outer, visible portions of the ears (pinnae). Within the first weeks of life, the pinnae become swollen and inflamed and unusually firm, thick, and abnormal in shape. Over time, the abnormal areas of tissue (lesions) may accumulate deposits of calcium salts (calcification) and eventually develop into bone (ossification). Some affected infants may also have abnormalities of the head and facial (craniofacial) area including incomplete closure of the roof of the mouth (cleft palate) and/or abnormal smallness of the jaws (micrognathia). In addition, in some affected infants, abnormalities of supportive connective tissue (cartilage) within the windpipe (trachea), voice box (larynx), and certain air passages in the lungs (bronchi) may result in collapse of these airways, causing life-threatening complications such as respiratory obstruction and difficulties breathing. In some individuals with the disorder, additional symptoms and physical findings may also be present. Diastrophic dysplasia is inherited as an autosomal recessive trait. | 372 | Diastrophic Dysplasia |
nord_372_1 | Symptoms of Diastrophic Dysplasia | The symptoms and physical findings associated with diastrophic dysplasia may be extremely variable, differing in range and severity even among affected family members (kindreds). However, in all individuals with the disorder, there is abnormal development of bones and joints of the body (skeletal and joint dysplasia).During normal development before birth (embryonic and fetal development) as well as development during early childhood, cartilage in many areas of the body is gradually replaced by bone (ossification). In addition, a layer of cartilage (epiphyseal cartilage [growth plate]) separates the shafts (diaphyses) of long bones (e.g., bones of the arms and legs) from their ends (epiphyses), allowing long bones to grow until the cartilage is no longer present. In those affected by diastrophic dysplasia, however, there is delayed growth before and after birth (prenatal and postnatal growth retardation), the development of the ends of the long bones (epiphyses) is irregular, and the ossification of the epiphyses is delayed. Thus, affected newborns and children typically have markedly short, bowed arms and legs and short stature (short-limbed dwarfism). In addition, in such cases, growth failure is typically progressive, in part due to absence of the “growth spurt” that usually occurs during puberty. The severity of such growth failure may vary greatly from case to case, including among affected siblings.Due to abnormalities of skeletal development, infants and children with diastrophic dysplasia also have additional distinctive malformations of bones of the hands, feet, and other areas of the body. For example, the first bone within the body of each hand (first metacarpals) may be unusually small, short, and “oval shaped.” As a result, the thumbs deviate away (abduction) from the body (“hitchhiker thumbs”). In addition, other fingers may be abnormally short (brachydactyly) and joints between particular bones of the fingers (proximal interphalangeal joints) may become fused (symphalangism), causing limited flexion and restricted movement (reduced mobility) of the finger joints. In some cases, bones of the wrists may also be malformed due to premature ossification.Infants with the disorder also typically have severe foot deformities (talipes or “clubfeet”) due to abnormal fusion and deviation of bones within the body of each foot (metatarsals). In most cases, the heels turn outward (talipes valgus) while the fore part of each foot deviates inward (metatarsus adductus). In other infants, the soles of the feet may be flexed (talipes equinus) and, in some cases, the heels may also turn inward (talipes equinovarus). The great toes, like the thumbs, may also deviate away (abduction) from the body. In addition to having limited flexion of finger joints, many affected infants and children also experience partial dislocation (subluxation) and/or complete dislocation of particular joints of the body. For example, in many cases, dislocations of the knees and hips occur upon weightbearing. Affected individuals may also have abnormally loose and/or stiff joints; experience limited extension of joints at the elbows and/or knees; and/or develop permanent flexion and immobilization (contracture) of certain joints (e.g., knees). Due to joint and bone abnormalities such as those affecting the feet, many individuals with diastrophic dysplasia have a tendency to walk on tiptoe. In addition, affected individuals may be predisposed to degenerative changes (osteoarthrosis) of particular joints (e.g. of the hips), resulting in pain with use of the joint, tenderness, stiffness, and, in some cases, deformity. Many infants with diastrophic dysplasia also have abnormalities of bones within the spinal column (vertebrae). For example, in most affected infants, there may be incomplete closure of vertebrae (spina bifida occulta) within the neck area and the upper portion of the back (lower cervical and upper thoracic vertebrae) and/or abnormal narrowing of portions of the vertebrae of the lower back (interpedicular narrowing in lumbar vertebrae). During the first year of life, some infants may begin to develop progressive abnormal sideways curvature of the spine (scoliosis). In addition, during adolescence, individuals with diastrophic dysplasia may also develop abnormal front-to-back curvature of the spine (kyphosis), particularly affecting vertebrae of the neck region (cervical vertebrae). In severe cases, progressive kyphosis may result in difficulties breathing (respiratory distress). Some individuals with the disorder may also be prone to experiencing partial dislocation of joints between the central areas (bodies) of cervical vertebrae (cervical subluxation), potentially resulting in compression of the spinal cord. (This cylindrical structure of nerve tissue extends from the lower portion of the brain and is located inside the central canal within the spinal column [spinal cavity].) Such spinal cord injury may result in muscle weakness (paresis) or paralysis and/or life-threatening complications. Most newborns with diastrophic dysplasia also have or develop fluid-filled sacs (cysts) within the outer, visible portions of the ears (pinnae). Within approximately two to five weeks after birth, the pinnae become swollen and inflamed. When such swelling and inflammation subside, the pinnae remain unusually thick, hard, and abnormal in shape. The abnormal areas of tissue (lesions) may gradually accumulate deposits of calcium salts (calcification) and eventually be replaced by bone (ossification). Although affected infants may experience associated abnormal narrowing (stenosis) of the external ear canal (external auditory canal), hearing is usually normal. However, according to reports in the literature, other affected infants and children may experience hearing impairment due to such auditory canal stenosis or abnormal fusion or absence of the three tiny bones (auditory ossicles) in the middle ear that conduct sound to the inner ear. Some infants with diastrophic dysplasia also have characteristic malformations of the head and facial (craniofacial) area, such as an unusually high, prominent forehead; abnormal smallness of the jaws (micrognathia); and/or a broad, highly arched roof of the mouth (palate) or incomplete closure of the palate (cleft palate). Cleft palate has been reported to occur in anywhere from 25 to 60% of affected infants, and may cause difficulties with feeding and/or breathing. In addition, in some infants with diastrophic dysplasia, abnormalities of supportive connective tissue (cartilage) within the windpipe (trachea), voice box (larynx), and air passages in the lungs (bronchi) may cause abnormal narrowing (e.g., laryngotracheal stenosis) and collapse of such airways. In such cases, life-threatening complications such as respiratory obstruction and difficulties breathing (respiratory distress) may result. However, in many cases nasal speech (hyponasality) occurs as a result of the abnormally shaped vocal tract.Approximately one third of infants and children with diastrophic dysplasia also have dental abnormalities, such as abnormally small teeth and dental crowding. In addition, in some cases, affected infants may have benign, reddish purple growths in the midportion of the face (midline frontal hemangioma) due to an abnormal distribution of tiny blood vessels (capillaries). Some individuals with the disorder may also have additional symptoms and physical findings. | Symptoms of Diastrophic Dysplasia. The symptoms and physical findings associated with diastrophic dysplasia may be extremely variable, differing in range and severity even among affected family members (kindreds). However, in all individuals with the disorder, there is abnormal development of bones and joints of the body (skeletal and joint dysplasia).During normal development before birth (embryonic and fetal development) as well as development during early childhood, cartilage in many areas of the body is gradually replaced by bone (ossification). In addition, a layer of cartilage (epiphyseal cartilage [growth plate]) separates the shafts (diaphyses) of long bones (e.g., bones of the arms and legs) from their ends (epiphyses), allowing long bones to grow until the cartilage is no longer present. In those affected by diastrophic dysplasia, however, there is delayed growth before and after birth (prenatal and postnatal growth retardation), the development of the ends of the long bones (epiphyses) is irregular, and the ossification of the epiphyses is delayed. Thus, affected newborns and children typically have markedly short, bowed arms and legs and short stature (short-limbed dwarfism). In addition, in such cases, growth failure is typically progressive, in part due to absence of the “growth spurt” that usually occurs during puberty. The severity of such growth failure may vary greatly from case to case, including among affected siblings.Due to abnormalities of skeletal development, infants and children with diastrophic dysplasia also have additional distinctive malformations of bones of the hands, feet, and other areas of the body. For example, the first bone within the body of each hand (first metacarpals) may be unusually small, short, and “oval shaped.” As a result, the thumbs deviate away (abduction) from the body (“hitchhiker thumbs”). In addition, other fingers may be abnormally short (brachydactyly) and joints between particular bones of the fingers (proximal interphalangeal joints) may become fused (symphalangism), causing limited flexion and restricted movement (reduced mobility) of the finger joints. In some cases, bones of the wrists may also be malformed due to premature ossification.Infants with the disorder also typically have severe foot deformities (talipes or “clubfeet”) due to abnormal fusion and deviation of bones within the body of each foot (metatarsals). In most cases, the heels turn outward (talipes valgus) while the fore part of each foot deviates inward (metatarsus adductus). In other infants, the soles of the feet may be flexed (talipes equinus) and, in some cases, the heels may also turn inward (talipes equinovarus). The great toes, like the thumbs, may also deviate away (abduction) from the body. In addition to having limited flexion of finger joints, many affected infants and children also experience partial dislocation (subluxation) and/or complete dislocation of particular joints of the body. For example, in many cases, dislocations of the knees and hips occur upon weightbearing. Affected individuals may also have abnormally loose and/or stiff joints; experience limited extension of joints at the elbows and/or knees; and/or develop permanent flexion and immobilization (contracture) of certain joints (e.g., knees). Due to joint and bone abnormalities such as those affecting the feet, many individuals with diastrophic dysplasia have a tendency to walk on tiptoe. In addition, affected individuals may be predisposed to degenerative changes (osteoarthrosis) of particular joints (e.g. of the hips), resulting in pain with use of the joint, tenderness, stiffness, and, in some cases, deformity. Many infants with diastrophic dysplasia also have abnormalities of bones within the spinal column (vertebrae). For example, in most affected infants, there may be incomplete closure of vertebrae (spina bifida occulta) within the neck area and the upper portion of the back (lower cervical and upper thoracic vertebrae) and/or abnormal narrowing of portions of the vertebrae of the lower back (interpedicular narrowing in lumbar vertebrae). During the first year of life, some infants may begin to develop progressive abnormal sideways curvature of the spine (scoliosis). In addition, during adolescence, individuals with diastrophic dysplasia may also develop abnormal front-to-back curvature of the spine (kyphosis), particularly affecting vertebrae of the neck region (cervical vertebrae). In severe cases, progressive kyphosis may result in difficulties breathing (respiratory distress). Some individuals with the disorder may also be prone to experiencing partial dislocation of joints between the central areas (bodies) of cervical vertebrae (cervical subluxation), potentially resulting in compression of the spinal cord. (This cylindrical structure of nerve tissue extends from the lower portion of the brain and is located inside the central canal within the spinal column [spinal cavity].) Such spinal cord injury may result in muscle weakness (paresis) or paralysis and/or life-threatening complications. Most newborns with diastrophic dysplasia also have or develop fluid-filled sacs (cysts) within the outer, visible portions of the ears (pinnae). Within approximately two to five weeks after birth, the pinnae become swollen and inflamed. When such swelling and inflammation subside, the pinnae remain unusually thick, hard, and abnormal in shape. The abnormal areas of tissue (lesions) may gradually accumulate deposits of calcium salts (calcification) and eventually be replaced by bone (ossification). Although affected infants may experience associated abnormal narrowing (stenosis) of the external ear canal (external auditory canal), hearing is usually normal. However, according to reports in the literature, other affected infants and children may experience hearing impairment due to such auditory canal stenosis or abnormal fusion or absence of the three tiny bones (auditory ossicles) in the middle ear that conduct sound to the inner ear. Some infants with diastrophic dysplasia also have characteristic malformations of the head and facial (craniofacial) area, such as an unusually high, prominent forehead; abnormal smallness of the jaws (micrognathia); and/or a broad, highly arched roof of the mouth (palate) or incomplete closure of the palate (cleft palate). Cleft palate has been reported to occur in anywhere from 25 to 60% of affected infants, and may cause difficulties with feeding and/or breathing. In addition, in some infants with diastrophic dysplasia, abnormalities of supportive connective tissue (cartilage) within the windpipe (trachea), voice box (larynx), and air passages in the lungs (bronchi) may cause abnormal narrowing (e.g., laryngotracheal stenosis) and collapse of such airways. In such cases, life-threatening complications such as respiratory obstruction and difficulties breathing (respiratory distress) may result. However, in many cases nasal speech (hyponasality) occurs as a result of the abnormally shaped vocal tract.Approximately one third of infants and children with diastrophic dysplasia also have dental abnormalities, such as abnormally small teeth and dental crowding. In addition, in some cases, affected infants may have benign, reddish purple growths in the midportion of the face (midline frontal hemangioma) due to an abnormal distribution of tiny blood vessels (capillaries). Some individuals with the disorder may also have additional symptoms and physical findings. | 372 | Diastrophic Dysplasia |
nord_372_2 | Causes of Diastrophic Dysplasia | Diastrophic dysplasia is inherited as an autosomal recessive trait. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother.In recessive disorders, the condition does not appear unless a person inherits the same defective gene for the same trait from each parent. If an individual receives one normal copy of the gene and one mutated copy of the gene, the person will be a carrier for the disease but usually will not show symptoms. The risk of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy. Parents of some individuals with diastrophic dysplasia have been closely related by blood (consanguineous). If both parents carry an altered gene for the disorder, there is a higher than normal risk that their children may inherit the two genes necessary for the development of the disease.A gene responsible for diastrophic dysplasia, known as DTDST (for “diastrophic dysplasia sulfate transporter” gene), has been located on the long arm (q) of chromosome 5 (5q32-q33.1). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q.” Chromosomes are further subdivided into bands that are numbered. For example, 5q32 refers to band 32 on the long arm of chromosome 5. The symptoms and findings associated with diastrophic dysplasia are thought to result due to abnormalities in the formation of cartilage, thus affecting skeletal development. Early during normal embryonic development, the skeleton mainly consists of cartilage that is gradually replaced by bone (ossification). After birth, many bones of the skeleton still consist primarily of cartilage that will eventually ossify. However, researchers suspect that certain changes (mutations) of the DTDST gene result in abnormalities of cartilage cells (chondrocytes) and the substance (matrix) that lies between such cells, ultimately causing the symptoms and findings associated with the disorder. For example, in individuals with diastrophic dysplasia, the growth plate of long bones may contain an abnormal distribution of cartilage cells (chondrocytes) and abnormal fibrous and cystic areas within its matrix.As discussed below (see “Affected Population”), diastrophic dysplasia is particularly frequent in Finland. Genetic analysis has revealed that a specific mutation, designated as “DTDST(Fin),” is present in affected members of many Finnish families (kindreds) and suggests that a single mutation event may have occurred in a common ancestor (i.e., founder mutation) in the past. However, in some Finnish kindreds, the disorder has been shown to result from different DTDST gene mutations (DTD-causing alleles) that do not descend from the common ancestral (founder) mutation. In addition, different mutations of the DTDST gene have been identified in some non-Finnish individuals with the disorder. | Causes of Diastrophic Dysplasia. Diastrophic dysplasia is inherited as an autosomal recessive trait. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother.In recessive disorders, the condition does not appear unless a person inherits the same defective gene for the same trait from each parent. If an individual receives one normal copy of the gene and one mutated copy of the gene, the person will be a carrier for the disease but usually will not show symptoms. The risk of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy. Parents of some individuals with diastrophic dysplasia have been closely related by blood (consanguineous). If both parents carry an altered gene for the disorder, there is a higher than normal risk that their children may inherit the two genes necessary for the development of the disease.A gene responsible for diastrophic dysplasia, known as DTDST (for “diastrophic dysplasia sulfate transporter” gene), has been located on the long arm (q) of chromosome 5 (5q32-q33.1). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q.” Chromosomes are further subdivided into bands that are numbered. For example, 5q32 refers to band 32 on the long arm of chromosome 5. The symptoms and findings associated with diastrophic dysplasia are thought to result due to abnormalities in the formation of cartilage, thus affecting skeletal development. Early during normal embryonic development, the skeleton mainly consists of cartilage that is gradually replaced by bone (ossification). After birth, many bones of the skeleton still consist primarily of cartilage that will eventually ossify. However, researchers suspect that certain changes (mutations) of the DTDST gene result in abnormalities of cartilage cells (chondrocytes) and the substance (matrix) that lies between such cells, ultimately causing the symptoms and findings associated with the disorder. For example, in individuals with diastrophic dysplasia, the growth plate of long bones may contain an abnormal distribution of cartilage cells (chondrocytes) and abnormal fibrous and cystic areas within its matrix.As discussed below (see “Affected Population”), diastrophic dysplasia is particularly frequent in Finland. Genetic analysis has revealed that a specific mutation, designated as “DTDST(Fin),” is present in affected members of many Finnish families (kindreds) and suggests that a single mutation event may have occurred in a common ancestor (i.e., founder mutation) in the past. However, in some Finnish kindreds, the disorder has been shown to result from different DTDST gene mutations (DTD-causing alleles) that do not descend from the common ancestral (founder) mutation. In addition, different mutations of the DTDST gene have been identified in some non-Finnish individuals with the disorder. | 372 | Diastrophic Dysplasia |
nord_372_3 | Affects of Diastrophic Dysplasia | Diastrophic dysplasia affects males and females in equal numbers. Although the disorder is extremely rare, the percentage of carriers in certain groups is high. In Finland, 1-2% of the general population are carriers and a total of 183 cases have been diagnosed, with a prevalence ratio of 1 in 30,000. Diastrophic dysplasia has been observed in most white populations | Affects of Diastrophic Dysplasia. Diastrophic dysplasia affects males and females in equal numbers. Although the disorder is extremely rare, the percentage of carriers in certain groups is high. In Finland, 1-2% of the general population are carriers and a total of 183 cases have been diagnosed, with a prevalence ratio of 1 in 30,000. Diastrophic dysplasia has been observed in most white populations | 372 | Diastrophic Dysplasia |
nord_372_4 | Related disorders of Diastrophic Dysplasia | Symptoms of the following disorders may be similar to those of diastrophic dysplasia. Comparisons may be useful for a differential diagnosis: Atelosteogenesis type II, also known as neonatal osseous dysplasia I, is a rare genetic disorder caused by abnormal changes (mutations) of the disease gene (DTDST) that is also responsible for diastrophic dysplasia (allelic disorder). Although the disorder has many symptoms and findings similar to those associated with diastrophic dysplasia, it is typically more severe. Atelosteogenesis type II is characterized by marked shortness of the arms and legs (micromelia), outward deviation (abduction) of the thumbs and great toes, and severe deformity of the feet (talipes or “clubfeet”) in which the soles are flexed and the heels are turned inward (talipes equinovarus). Additional characteristic features include an unusually small chest (thorax), abnormal flatness of certain bones in the spinal column (vertebrae), abnormal sideways curvature of the spine (scoliosis), front-to-back curvature of vertebrae within the neck area of the spine (cervical kyphosis), and/or incomplete closure of the roof of the mouth (cleft palate). Due to abnormalities of cartilage within the voice box (larynx), windpipe (trachea), and air passages in the lungs (bronchi), affected infants may experience narrowing of the larynx (laryngeal stenosis), abnormal softness of cartilage in the trachea and bronchi (tracheobronchomalacia), and underdevelopment of the lungs (pulmonary hypoplasia). Such abnormalities may result in collapse of such airways, causing life-threatening complications shortly after birth, such as respiratory obstruction and difficulties breathing (respiratory distress). Atelosteogenesis type II is inherited as an autosomal recessive trait.Achondrogenesis type IB is a rare genetic disorder that is also thought to be caused by mutations of the disease gene responsible for diastrophic dysplasia (allelic disorder). According to reports in the literature, the disorder is more severe than diastrophic dysplasia and atelosteogenesis type II. Achondrogenesis type IB is characterized by marked shortness of the arms and legs (micromelia) and short stature (short-limbed dwarfism), abnormally thin ribs, and a susceptibility to rib fractures. Additional characteristic features include impaired ossification of vertebrae of the lower back (lumbar vertebrae); the five fused bones forming the large triangular bone (sacrum) of the lower spine (sacral vertebrae); and certain bones that form the hip bones (pubic and ischial bones). Achondrogenesis type IB is inherited as an autosomal recessive trait.Pseudodiastrophic dysplasia is a rare genetic disorder characterized by abnormally short arms and legs and short stature (short-limbed dwarfism) and severe deformities of the feet (talipes or “clubfeet”) that tend to respond well to surgical treatment and physical therapy. Additional features may include dislocations of certain joints in the fingers (proximal interphalangeal joints), dislocations of the elbows, flattening of the central regions of bones in the spinal column (platyspondyly), abnormal sideways curvature of the spine (scoliosis), and/or other abnormalities. In contrast to individuals with diastrophic dysplasia, the first bones within the body of each hand (first metacarpals) have a normal appearance and the outer, visible portions of the ears (pinnae) do not experience the inflammation and cystic enlargement often seen in those with diastrophic dysplasia in the first weeks of life. Pseudodiastrophic dysplasia is inherited as an autosomal recessive trait.Achondroplasia is a rare genetic disorder characterized by distinctive abnormalities of the head and facial (craniofacial) area; unusually short upper arms and legs and short stature (short-limbed dwarfism); and short hands with fingers that assume a “trident” or three-pronged position during extension. Affected individuals may also have limited extension of the elbows and hips, bowing of the legs, and abnormally increased curvature of the bones of the lower spine (lumbar lordosis). In addition, many individuals with achondroplasia have an abnormally enlarged brain (macrencephaly), a prominent forehead (frontal bossing), and a flat (depressed) nasal bridge. In some cases, affected individuals may experience inhibition of the normal flow of cerebrospinal fluid (CSF), potentially causing increased pressure on brain tissue. In most cases, achondroplasia appears to occur randomly (sporadically) due to new genetic changes (mutations). In other cases, the disorder may be inherited as an autosomal dominant trait. (For more information on this disorder, choose “Achondroplasia” as your search term in the Rare Disease Database.) Arthrogryposis multiplex congenita is a group of disorders present at birth (congenital) that are characterized by limited movement or immobility of several joints and partial or complete replacement of muscle with fibrous tissue in affected areas. Affected joints may be permanently flexed or extended in various fixed postures (joint contractures). In many cases, the term arthrogryposis multiplex congenita refers to a form of the disorder in which joint contractures result in abnormal extension of the elbows, flexion of the wrists, and internal rotation of the shoulders. In addition, many affected individuals may have severe clubfoot (talipes equinovarus), a deformity in which the heel is turned inward and the sole is flexed (plantar flexion). Additional associated abnormalities may include a rounded face and a slightly small jaw. This form of the disorder appears to occur randomly (sporadically), for unknown reasons. Another form of the disorder, known as a distal arthrogryposis (type 1), may be characterized by joint contractures primarily affecting the hands and feet (distal limbs). Such contractures result in characteristic positioning including permanent flexion (camptodactyly) and overlapping of fingers, deviation of fingers toward the “pinky” side of the hand (ulnar deviation), clenching of the fists, and clubfeet. This form of the disorder is inherited as an autosomal dominant trait. The causes of other forms of arthrogryposis multiplex congenita are variable. (For more information on this disorder, choose “arthrogryposis multiplex congenita” as your search term in the Rare Disease Database.) There may be additional disorders that are characterized by growth delays before and after birth (prenatal and postnatal growth retardation); abnormally short arms and legs and short stature (short-limbed dwarfism); distinctive malformations of bones of the fingers and hands; clubfeet; partial (subluxation) or complete dislocation and/or permanent flexion and immobilization (contractures) of certain joints; abnormal progressive curvature of the spine (e.g., scoliosis and/or kyphosis); and/or other abnormalities similar to those potentially associated with diastrophic dysplasia. (For more information on such disorders, choose the exact disease name in question as your search term in the Rare Disease Database.) | Related disorders of Diastrophic Dysplasia. Symptoms of the following disorders may be similar to those of diastrophic dysplasia. Comparisons may be useful for a differential diagnosis: Atelosteogenesis type II, also known as neonatal osseous dysplasia I, is a rare genetic disorder caused by abnormal changes (mutations) of the disease gene (DTDST) that is also responsible for diastrophic dysplasia (allelic disorder). Although the disorder has many symptoms and findings similar to those associated with diastrophic dysplasia, it is typically more severe. Atelosteogenesis type II is characterized by marked shortness of the arms and legs (micromelia), outward deviation (abduction) of the thumbs and great toes, and severe deformity of the feet (talipes or “clubfeet”) in which the soles are flexed and the heels are turned inward (talipes equinovarus). Additional characteristic features include an unusually small chest (thorax), abnormal flatness of certain bones in the spinal column (vertebrae), abnormal sideways curvature of the spine (scoliosis), front-to-back curvature of vertebrae within the neck area of the spine (cervical kyphosis), and/or incomplete closure of the roof of the mouth (cleft palate). Due to abnormalities of cartilage within the voice box (larynx), windpipe (trachea), and air passages in the lungs (bronchi), affected infants may experience narrowing of the larynx (laryngeal stenosis), abnormal softness of cartilage in the trachea and bronchi (tracheobronchomalacia), and underdevelopment of the lungs (pulmonary hypoplasia). Such abnormalities may result in collapse of such airways, causing life-threatening complications shortly after birth, such as respiratory obstruction and difficulties breathing (respiratory distress). Atelosteogenesis type II is inherited as an autosomal recessive trait.Achondrogenesis type IB is a rare genetic disorder that is also thought to be caused by mutations of the disease gene responsible for diastrophic dysplasia (allelic disorder). According to reports in the literature, the disorder is more severe than diastrophic dysplasia and atelosteogenesis type II. Achondrogenesis type IB is characterized by marked shortness of the arms and legs (micromelia) and short stature (short-limbed dwarfism), abnormally thin ribs, and a susceptibility to rib fractures. Additional characteristic features include impaired ossification of vertebrae of the lower back (lumbar vertebrae); the five fused bones forming the large triangular bone (sacrum) of the lower spine (sacral vertebrae); and certain bones that form the hip bones (pubic and ischial bones). Achondrogenesis type IB is inherited as an autosomal recessive trait.Pseudodiastrophic dysplasia is a rare genetic disorder characterized by abnormally short arms and legs and short stature (short-limbed dwarfism) and severe deformities of the feet (talipes or “clubfeet”) that tend to respond well to surgical treatment and physical therapy. Additional features may include dislocations of certain joints in the fingers (proximal interphalangeal joints), dislocations of the elbows, flattening of the central regions of bones in the spinal column (platyspondyly), abnormal sideways curvature of the spine (scoliosis), and/or other abnormalities. In contrast to individuals with diastrophic dysplasia, the first bones within the body of each hand (first metacarpals) have a normal appearance and the outer, visible portions of the ears (pinnae) do not experience the inflammation and cystic enlargement often seen in those with diastrophic dysplasia in the first weeks of life. Pseudodiastrophic dysplasia is inherited as an autosomal recessive trait.Achondroplasia is a rare genetic disorder characterized by distinctive abnormalities of the head and facial (craniofacial) area; unusually short upper arms and legs and short stature (short-limbed dwarfism); and short hands with fingers that assume a “trident” or three-pronged position during extension. Affected individuals may also have limited extension of the elbows and hips, bowing of the legs, and abnormally increased curvature of the bones of the lower spine (lumbar lordosis). In addition, many individuals with achondroplasia have an abnormally enlarged brain (macrencephaly), a prominent forehead (frontal bossing), and a flat (depressed) nasal bridge. In some cases, affected individuals may experience inhibition of the normal flow of cerebrospinal fluid (CSF), potentially causing increased pressure on brain tissue. In most cases, achondroplasia appears to occur randomly (sporadically) due to new genetic changes (mutations). In other cases, the disorder may be inherited as an autosomal dominant trait. (For more information on this disorder, choose “Achondroplasia” as your search term in the Rare Disease Database.) Arthrogryposis multiplex congenita is a group of disorders present at birth (congenital) that are characterized by limited movement or immobility of several joints and partial or complete replacement of muscle with fibrous tissue in affected areas. Affected joints may be permanently flexed or extended in various fixed postures (joint contractures). In many cases, the term arthrogryposis multiplex congenita refers to a form of the disorder in which joint contractures result in abnormal extension of the elbows, flexion of the wrists, and internal rotation of the shoulders. In addition, many affected individuals may have severe clubfoot (talipes equinovarus), a deformity in which the heel is turned inward and the sole is flexed (plantar flexion). Additional associated abnormalities may include a rounded face and a slightly small jaw. This form of the disorder appears to occur randomly (sporadically), for unknown reasons. Another form of the disorder, known as a distal arthrogryposis (type 1), may be characterized by joint contractures primarily affecting the hands and feet (distal limbs). Such contractures result in characteristic positioning including permanent flexion (camptodactyly) and overlapping of fingers, deviation of fingers toward the “pinky” side of the hand (ulnar deviation), clenching of the fists, and clubfeet. This form of the disorder is inherited as an autosomal dominant trait. The causes of other forms of arthrogryposis multiplex congenita are variable. (For more information on this disorder, choose “arthrogryposis multiplex congenita” as your search term in the Rare Disease Database.) There may be additional disorders that are characterized by growth delays before and after birth (prenatal and postnatal growth retardation); abnormally short arms and legs and short stature (short-limbed dwarfism); distinctive malformations of bones of the fingers and hands; clubfeet; partial (subluxation) or complete dislocation and/or permanent flexion and immobilization (contractures) of certain joints; abnormal progressive curvature of the spine (e.g., scoliosis and/or kyphosis); and/or other abnormalities similar to those potentially associated with diastrophic dysplasia. (For more information on such disorders, choose the exact disease name in question as your search term in the Rare Disease Database.) | 372 | Diastrophic Dysplasia |
nord_372_5 | Diagnosis of Diastrophic Dysplasia | In some families with a previous history of diastrophic dysplasia, it is possible that the disorder may be detected before birth (prenatally) during early pregnancy (e.g., first trimester) based upon the results of specialized genetic (i.e., DNA marker) testing. In addition, in some cases, the disorder may be detected during mid pregnancy (e.g., second trimester) through fetal ultrasonography, a specialized imaging technique in which sound waves are used to create an image of the developing fetus. In such cases, diagnosis is most easily established when a clear family history is present. During fetal ultrasonography, a diagnosis of diastrophic dysplasia may be considered due to detection of certain characteristic findings, such as marked shortening of bones of the fingers (phalanges), arms, and legs; abnormal deviation (abduction) of the thumbs ("hitchhiker thumbs") and great toes; severe deformities of both feet (talipes or "clubfeet"); and/or other findings.In most cases, diastrophic dysplasia is diagnosed and/or confirmed at birth based upon a thorough clinical evaluation, identification of characteristic physical findings, and a variety of specializing tests, such as advanced imaging techniques. For example, specialized x-ray studies such as computerized tomography (CT) scanning and magnetic resonance imaging (MRI) may be used to detect, confirm, and/or characterize certain skeletal abnormalities that may be associated with diastrophic dysplasia. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of internal structures. During MRI, a magnetic field and radio waves are used to create cross-sectional images of organs and structures in the body.Specialized diagnostic testing (i.e., audiological tests) may also be performed to help detect hearing deficits that may occur in some children with diastrophic dysplasia. | Diagnosis of Diastrophic Dysplasia. In some families with a previous history of diastrophic dysplasia, it is possible that the disorder may be detected before birth (prenatally) during early pregnancy (e.g., first trimester) based upon the results of specialized genetic (i.e., DNA marker) testing. In addition, in some cases, the disorder may be detected during mid pregnancy (e.g., second trimester) through fetal ultrasonography, a specialized imaging technique in which sound waves are used to create an image of the developing fetus. In such cases, diagnosis is most easily established when a clear family history is present. During fetal ultrasonography, a diagnosis of diastrophic dysplasia may be considered due to detection of certain characteristic findings, such as marked shortening of bones of the fingers (phalanges), arms, and legs; abnormal deviation (abduction) of the thumbs ("hitchhiker thumbs") and great toes; severe deformities of both feet (talipes or "clubfeet"); and/or other findings.In most cases, diastrophic dysplasia is diagnosed and/or confirmed at birth based upon a thorough clinical evaluation, identification of characteristic physical findings, and a variety of specializing tests, such as advanced imaging techniques. For example, specialized x-ray studies such as computerized tomography (CT) scanning and magnetic resonance imaging (MRI) may be used to detect, confirm, and/or characterize certain skeletal abnormalities that may be associated with diastrophic dysplasia. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of internal structures. During MRI, a magnetic field and radio waves are used to create cross-sectional images of organs and structures in the body.Specialized diagnostic testing (i.e., audiological tests) may also be performed to help detect hearing deficits that may occur in some children with diastrophic dysplasia. | 372 | Diastrophic Dysplasia |
nord_372_6 | Therapies of Diastrophic Dysplasia | TreatmentThe treatment of diastrophic dysplasia is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists who may need to work together to systematically and comprehensively plan an affected child's treatment. Such specialists may include pediatricians; physicians who diagnose and treat abnormalities of the skeleton, joints, muscles, and related tissues (orthopedists); surgeons; physical therapists; dental specialists (orthodontists); specialists who assess and treat hearing problems (audiologists); and/or other health care professionals.Specific therapies for the treatment of diastrophic dysplasia are symptomatic and supportive. Physicians may carefully monitor affected infants to ensure prompt detection and appropriate preventive or corrective treatment of respiratory obstruction and distress that may result due to certain abnormalities potentially associated with the disorder (e.g., laryngotracheal stenosis). In addition, special supportive measures may be used to help ensure an appropriate intake of nutrients in infants who experience feeding difficulties due to cleft palate. In some cases, surgical procedures may be performed to correct malformations resulting in breathing and/or feeding difficulties. The specific procedures performed will depend upon the location, severity, and combination of such anatomical abnormalities.In addition, various orthopedic techniques, including surgery, may also be used to help prevent, treat, and/or correct certain skeletal deformities associated with diastrophic dysplasia. In some cases, physical therapy in combination with surgical and supportive measures may be helpful in improving an affected individual's ability to walk and perform other movements (mobility). According to the medical literature, although the foot deformities (i.e., talipes or clubfeet) associated with the disorder may be resistant to treatment, early, persistent therapy may be helpful in achieving beneficial results. In addition, because particular skeletal changes associated with diastrophic dysplasia are progressive (e.g., kyphosis) and, in some cases, may lead to severe complications (e.g., respiratory distress, compression of the spine, potential paresis or paralysis), physicians may perform ongoing monitoring to ensure prompt detection of and appropriate preventive and/or corrective measures for such abnormalities.In affected children with dental abnormalities, braces (orthodontics), dental surgery, and/or other corrective procedures may be undertaken to correct such malformations. Steroid injections and/or other measures may also be used to help decrease the ear deformity that often affects infants with the disorder.Genetic counseling will be of benefit for affected individuals and their families. Other treatment for this disorder is symptomatic and supportive. | Therapies of Diastrophic Dysplasia. TreatmentThe treatment of diastrophic dysplasia is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists who may need to work together to systematically and comprehensively plan an affected child's treatment. Such specialists may include pediatricians; physicians who diagnose and treat abnormalities of the skeleton, joints, muscles, and related tissues (orthopedists); surgeons; physical therapists; dental specialists (orthodontists); specialists who assess and treat hearing problems (audiologists); and/or other health care professionals.Specific therapies for the treatment of diastrophic dysplasia are symptomatic and supportive. Physicians may carefully monitor affected infants to ensure prompt detection and appropriate preventive or corrective treatment of respiratory obstruction and distress that may result due to certain abnormalities potentially associated with the disorder (e.g., laryngotracheal stenosis). In addition, special supportive measures may be used to help ensure an appropriate intake of nutrients in infants who experience feeding difficulties due to cleft palate. In some cases, surgical procedures may be performed to correct malformations resulting in breathing and/or feeding difficulties. The specific procedures performed will depend upon the location, severity, and combination of such anatomical abnormalities.In addition, various orthopedic techniques, including surgery, may also be used to help prevent, treat, and/or correct certain skeletal deformities associated with diastrophic dysplasia. In some cases, physical therapy in combination with surgical and supportive measures may be helpful in improving an affected individual's ability to walk and perform other movements (mobility). According to the medical literature, although the foot deformities (i.e., talipes or clubfeet) associated with the disorder may be resistant to treatment, early, persistent therapy may be helpful in achieving beneficial results. In addition, because particular skeletal changes associated with diastrophic dysplasia are progressive (e.g., kyphosis) and, in some cases, may lead to severe complications (e.g., respiratory distress, compression of the spine, potential paresis or paralysis), physicians may perform ongoing monitoring to ensure prompt detection of and appropriate preventive and/or corrective measures for such abnormalities.In affected children with dental abnormalities, braces (orthodontics), dental surgery, and/or other corrective procedures may be undertaken to correct such malformations. Steroid injections and/or other measures may also be used to help decrease the ear deformity that often affects infants with the disorder.Genetic counseling will be of benefit for affected individuals and their families. Other treatment for this disorder is symptomatic and supportive. | 372 | Diastrophic Dysplasia |
nord_373_0 | Overview of Diencephalic Syndrome | Diencephalic syndrome is a rare disorder caused by a tumor that is usually located in the diencephalon, a portion of the brain just above the brainstem. The diencephalon includes the hypothalamus and the thalamus. Affected infants and young children may develop symptoms that include the failure to gain weight and grow as would be expected based upon age and gender (failure to thrive) and abnormal progressive thinness and weakness (emaciation). Affected infants and children may behave in an alert, happy and outgoing manner, which contrasts with their physical appearance. However, more frequently, infants and young children are irritable. Additional symptoms such as vomiting, vision abnormalities, nystagmus, headaches and pallor can also develop. Diencephalic syndrome can progress to cause severe, life-threatening complications. Diencephalic syndrome is treated by surgery, radiation, chemotherapy and/or molecular-targeted therapy. The reason for the development of the tumor that causes diencephalic syndrome is unknown. Diencephalic syndrome was first described in the medical literature in 1951 by Dr. Russell. | Overview of Diencephalic Syndrome. Diencephalic syndrome is a rare disorder caused by a tumor that is usually located in the diencephalon, a portion of the brain just above the brainstem. The diencephalon includes the hypothalamus and the thalamus. Affected infants and young children may develop symptoms that include the failure to gain weight and grow as would be expected based upon age and gender (failure to thrive) and abnormal progressive thinness and weakness (emaciation). Affected infants and children may behave in an alert, happy and outgoing manner, which contrasts with their physical appearance. However, more frequently, infants and young children are irritable. Additional symptoms such as vomiting, vision abnormalities, nystagmus, headaches and pallor can also develop. Diencephalic syndrome can progress to cause severe, life-threatening complications. Diencephalic syndrome is treated by surgery, radiation, chemotherapy and/or molecular-targeted therapy. The reason for the development of the tumor that causes diencephalic syndrome is unknown. Diencephalic syndrome was first described in the medical literature in 1951 by Dr. Russell. | 373 | Diencephalic Syndrome |
nord_373_1 | Symptoms of Diencephalic Syndrome | The specific symptoms and severity of diencephalic syndrome can vary from one person to another. The disorder can potentially cause severe, even life-threatening complications. Onset is usually in infancy or early childhood. Usually, there is a period of normal development and weight gain, followed by a prolonged period of failure to gain weight and weight loss.The most striking feature of diencephalic syndrome is profound emaciation including a uniform loss of body fat (adipose tissue). Emaciation occurs despite normal or near normal caloric intake. Emaciation may progressively worsen. Because of the loss of body fat, affected children may appear muscular. Although weight is affected, length (linear growth) may be normal. Emaciation and failure to thrive may occur following an initial period of normal growth.Although overall development is slowed, neurological development may be normal. However, detailed neurologic examination often discloses subtle abnormalities. Affected children are usually mentally alert. Some children are overactive and restless (hyperkinesia); others are happy and outgoing, which is not in keeping with their outward appearance. Some affected children are described as intensely excited or happy (euphoric). Others may, in contrast, act irritable.Rapid, involuntary, “jerky” movements of the eyes (nystagmus) can be seen in children with diencephalic syndrome. Nystagmus is a notable feature of this disorder but does not occur in all patients. It may affect one or both eyes. Additional nonspecific symptoms include pallor, vomiting (emesis) and headaches. Degeneration of the nerve that transmits visual stimuli from the eyes to the brain (optic nerve) may also occur (optic atrophy). Vision loss can potentially occur in some patients.Some affected infants and children develop hydrocephalus, a condition in which excessive cerebrospinal fluid (CSF) in the skull causes pressure on the brain, resulting in a variety of symptoms including a head that appears large in comparison to the rest of the body, swelling of the optic disk (papilledema).Less often, additional symptoms have been reported including low blood sugar (hypoglycemia), excessive sweating (hyperhidrosis) and high blood pressure (hypertension). In rare instances, disproportionately large hands and feet have developed. | Symptoms of Diencephalic Syndrome. The specific symptoms and severity of diencephalic syndrome can vary from one person to another. The disorder can potentially cause severe, even life-threatening complications. Onset is usually in infancy or early childhood. Usually, there is a period of normal development and weight gain, followed by a prolonged period of failure to gain weight and weight loss.The most striking feature of diencephalic syndrome is profound emaciation including a uniform loss of body fat (adipose tissue). Emaciation occurs despite normal or near normal caloric intake. Emaciation may progressively worsen. Because of the loss of body fat, affected children may appear muscular. Although weight is affected, length (linear growth) may be normal. Emaciation and failure to thrive may occur following an initial period of normal growth.Although overall development is slowed, neurological development may be normal. However, detailed neurologic examination often discloses subtle abnormalities. Affected children are usually mentally alert. Some children are overactive and restless (hyperkinesia); others are happy and outgoing, which is not in keeping with their outward appearance. Some affected children are described as intensely excited or happy (euphoric). Others may, in contrast, act irritable.Rapid, involuntary, “jerky” movements of the eyes (nystagmus) can be seen in children with diencephalic syndrome. Nystagmus is a notable feature of this disorder but does not occur in all patients. It may affect one or both eyes. Additional nonspecific symptoms include pallor, vomiting (emesis) and headaches. Degeneration of the nerve that transmits visual stimuli from the eyes to the brain (optic nerve) may also occur (optic atrophy). Vision loss can potentially occur in some patients.Some affected infants and children develop hydrocephalus, a condition in which excessive cerebrospinal fluid (CSF) in the skull causes pressure on the brain, resulting in a variety of symptoms including a head that appears large in comparison to the rest of the body, swelling of the optic disk (papilledema).Less often, additional symptoms have been reported including low blood sugar (hypoglycemia), excessive sweating (hyperhidrosis) and high blood pressure (hypertension). In rare instances, disproportionately large hands and feet have developed. | 373 | Diencephalic Syndrome |
nord_373_2 | Causes of Diencephalic Syndrome | Diencephalic syndrome is caused by a tumor, most commonly located in the hypothalamus or the optic chiasm. The hypothalamus is a special area in the brain that is divided into several regions that have different functions. The hypothalamus controls the pituitary gland by controlling the gland’s release of certain hormones. The hypothalamus also helps regulate basic functions of the body including sleep, hunger, thirst and body temperature. The optic chiasm is the region where the optic nerves pass through to the brain.A glioma or astrocytoma is the most common tumor associated with diencephalic syndrome. An astrocytoma is a tumor that arises from the star-shaped cells (astrocytes) that form the supportive tissue of the brain. Other supportive tissue of the brain includes oligodendrocytes and ependymal cells. Collectively, these cells are known as glial cells and the tissue they form is known as glial tissue. Tumors that arise from the glial tissue are collectively referred to as gliomas. Technically, an astrocytoma is a subtype of gliomas, but occasionally the terms are used interchangeably. Astrocytoma that occurs in association with diencephalic syndrome tends to be more aggressive and to develop at an earlier age than other astrocytoma arising in the same area. Juvenile pilocytic astrocytoma is the most common cause of diencephalic syndrome. NORD has a report on this tumor. For more information, choose “juvenile pilocytic astrocytoma” as your search term in the Rare Disease Database.Pediatric low-grade gliomas frequently demonstrate specific molecular genetic alterations, such as BRAF V600E variants, activating BRAF-fusions, NF1 gene variants and FGFR variants. All these abnormalities increase signaling through the RAS-MAPK signaling pathway and are the cause of tumor growth. CDKN2A/B loss or ATRX variants may occur at the same time the more frequent genetic abnormalities are seen and are associated with more aggressive tumor growth.Gliomas in the hypothalamus or optic chiasm can sometimes be associated with neurofibromatosis type 1, a rare genetic disorder characterized by the development of multiple noncancerous (benign) tumors of the skin and nerves (neurofibromas). The development of a tumor in the hypothalamus and optic chiasm in neurofibromatosis type 1 and the subsequent development of diencephalic syndrome is not common but does occur. For more information, choose “neurofibromatosis” as your search term in the Rare Disease Database.In some instances, the causative tumor is unclassified. In extremely rare cases, a different type of tumor such as an ependymoma, dysgerminoma or ganglioma has been associated with diencephalic syndrome.The exact underlying way these tumors cause the symptoms of diencephalic syndrome is not fully understood. | Causes of Diencephalic Syndrome. Diencephalic syndrome is caused by a tumor, most commonly located in the hypothalamus or the optic chiasm. The hypothalamus is a special area in the brain that is divided into several regions that have different functions. The hypothalamus controls the pituitary gland by controlling the gland’s release of certain hormones. The hypothalamus also helps regulate basic functions of the body including sleep, hunger, thirst and body temperature. The optic chiasm is the region where the optic nerves pass through to the brain.A glioma or astrocytoma is the most common tumor associated with diencephalic syndrome. An astrocytoma is a tumor that arises from the star-shaped cells (astrocytes) that form the supportive tissue of the brain. Other supportive tissue of the brain includes oligodendrocytes and ependymal cells. Collectively, these cells are known as glial cells and the tissue they form is known as glial tissue. Tumors that arise from the glial tissue are collectively referred to as gliomas. Technically, an astrocytoma is a subtype of gliomas, but occasionally the terms are used interchangeably. Astrocytoma that occurs in association with diencephalic syndrome tends to be more aggressive and to develop at an earlier age than other astrocytoma arising in the same area. Juvenile pilocytic astrocytoma is the most common cause of diencephalic syndrome. NORD has a report on this tumor. For more information, choose “juvenile pilocytic astrocytoma” as your search term in the Rare Disease Database.Pediatric low-grade gliomas frequently demonstrate specific molecular genetic alterations, such as BRAF V600E variants, activating BRAF-fusions, NF1 gene variants and FGFR variants. All these abnormalities increase signaling through the RAS-MAPK signaling pathway and are the cause of tumor growth. CDKN2A/B loss or ATRX variants may occur at the same time the more frequent genetic abnormalities are seen and are associated with more aggressive tumor growth.Gliomas in the hypothalamus or optic chiasm can sometimes be associated with neurofibromatosis type 1, a rare genetic disorder characterized by the development of multiple noncancerous (benign) tumors of the skin and nerves (neurofibromas). The development of a tumor in the hypothalamus and optic chiasm in neurofibromatosis type 1 and the subsequent development of diencephalic syndrome is not common but does occur. For more information, choose “neurofibromatosis” as your search term in the Rare Disease Database.In some instances, the causative tumor is unclassified. In extremely rare cases, a different type of tumor such as an ependymoma, dysgerminoma or ganglioma has been associated with diencephalic syndrome.The exact underlying way these tumors cause the symptoms of diencephalic syndrome is not fully understood. | 373 | Diencephalic Syndrome |
nord_373_3 | Affects of Diencephalic Syndrome | Diencephalic syndrome is an extremely rare disorder that affects both males and females. The incidence and prevalence of this disorder in the general population is unknown. The disorder is most often seen in infants or young children but has also been reported in older children and adults. | Affects of Diencephalic Syndrome. Diencephalic syndrome is an extremely rare disorder that affects both males and females. The incidence and prevalence of this disorder in the general population is unknown. The disorder is most often seen in infants or young children but has also been reported in older children and adults. | 373 | Diencephalic Syndrome |
nord_373_4 | Related disorders of Diencephalic Syndrome | Symptoms of the following disorders can be similar to those of diencephalic syndrome. Comparisons may be useful for a differential diagnosis.Brain tumors are abnormal growths in the brain that can be either cancerous (malignant) or noncancerous (benign). There are many different types of brain tumors. The classification of brain tumors is based on the cells that the tumor originated from and the likelihood that it will spread to other tissues. The symptoms of brain tumors can be very similar. Depending upon the type of tumor and where it is located in the brain, a tumor can cause swelling and compression of nearby structures resulting in various symptoms. (For more information, choose the specific tumor name as your search term in the Rare Disease Database.) | Related disorders of Diencephalic Syndrome. Symptoms of the following disorders can be similar to those of diencephalic syndrome. Comparisons may be useful for a differential diagnosis.Brain tumors are abnormal growths in the brain that can be either cancerous (malignant) or noncancerous (benign). There are many different types of brain tumors. The classification of brain tumors is based on the cells that the tumor originated from and the likelihood that it will spread to other tissues. The symptoms of brain tumors can be very similar. Depending upon the type of tumor and where it is located in the brain, a tumor can cause swelling and compression of nearby structures resulting in various symptoms. (For more information, choose the specific tumor name as your search term in the Rare Disease Database.) | 373 | Diencephalic Syndrome |
nord_373_5 | Diagnosis of Diencephalic Syndrome | The diagnosis of diencephalic syndrome is suspected in a child who has failed to thrive despite eating an apparently normal diet. A history of relatively normal development followed by a period of weight loss and lack of clear-cut stomach or intestinal problems is suggestive of diencephalic syndrome. A detailed patient history, a thorough clinical evaluation and a variety of specialized imaging techniques are used to establish a diagnosis. Clinical Testing and WorkupImaging techniques may include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of organs and bodily tissues such as brain tissue.Examination of cerebrospinal fluid can show elevated protein levels, as well as the presence of abnormal cells in cases of tumor dissemination. Lumbar cerebrospinal fluid sampling should not be done when there is a major mass effect by the tumor or untreated obstructive hydrocephalus. MRI of the entire neuro-axis is needed, in most cases, to rule out tumor dissemination and should be performed in at least 2 planes with and without contrast agents (i.e., gadolinium).Most patients will require at least a biopsy to confirm the diagnosis. Increasingly, the tissue removed at the time of surgery will also be sent for molecular analysis to help guide therapy. The exception to this is in patients with NF1 in whom biopsy is often not needed. | Diagnosis of Diencephalic Syndrome. The diagnosis of diencephalic syndrome is suspected in a child who has failed to thrive despite eating an apparently normal diet. A history of relatively normal development followed by a period of weight loss and lack of clear-cut stomach or intestinal problems is suggestive of diencephalic syndrome. A detailed patient history, a thorough clinical evaluation and a variety of specialized imaging techniques are used to establish a diagnosis. Clinical Testing and WorkupImaging techniques may include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of organs and bodily tissues such as brain tissue.Examination of cerebrospinal fluid can show elevated protein levels, as well as the presence of abnormal cells in cases of tumor dissemination. Lumbar cerebrospinal fluid sampling should not be done when there is a major mass effect by the tumor or untreated obstructive hydrocephalus. MRI of the entire neuro-axis is needed, in most cases, to rule out tumor dissemination and should be performed in at least 2 planes with and without contrast agents (i.e., gadolinium).Most patients will require at least a biopsy to confirm the diagnosis. Increasingly, the tissue removed at the time of surgery will also be sent for molecular analysis to help guide therapy. The exception to this is in patients with NF1 in whom biopsy is often not needed. | 373 | Diencephalic Syndrome |
nord_373_6 | Therapies of Diencephalic Syndrome | Treatment
The treatment of diencephalic 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, surgeons, neurologists, oncologists, radiation oncologists and other healthcare professionals may need to plan an affect child’s treatment systematically and comprehensively.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease stage; tumor size and specific location; specific tumor type; the presence or absence of certain symptoms; an individual’s age and general health; and/or other elements. Decisions concerning the use of drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of their case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors. Psychosocial support for the entire family is essential as well.There is no agreed upon consensus for the best treatment for individuals with diencephalic syndrome and there are no standardized treatment protocols or guidelines. However, protocols and often clinical trials are available for specific tumor types that cause the syndrome. Various treatments have been reported in the medical literature as part of single patient reports, small series of patients or more extensive, tumor-type based studies. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with diencephalic syndrome.Surgery, radiation, chemotherapy, and molecular-targeted therapy alone or in various combinations have been used to treat the diencephalic syndrome. In some patients, physicians may recommend surgical excision and removal of as much of the tumor as possible (resection). However, because of the area of the brain that is usually affected, surgical removal of the entire tumor is rarely possible. Additionally, surgery, even to remove only a portion of the tumor, carries risks due to the tumor’s location deep within the brain. However, as noted previously, biopsy is usually indicated to not only determine the histological subtype of the tumor, but its molecular subtype; this is especially useful in low-grade gliomas where molecular findings can guide therapy.Radiation therapy can be used to directly destroy cancer cells or to destroy cancer cells left over after surgery. However, the potential for serious short and long-term side effects exists. Radiation therapy is especially avoided in children less than 5 years of age because of the potential for serious side effects.Chemotherapy, the use of one or more anti-cancer drugs, has also been used to treat individuals with diencephalic syndrome, particularly those with low grade gliomas. Chemotherapy may be used instead of radiation in very young children to avoid damage to the developing brain. Chemotherapy may also be administered after radiation to destroy any cells that remain or may be given during radiation treatment. The type of chemotherapeutic drug therapy used is determined by a neuro-oncologist who examines the grade of tumor, previous treatment and current health status of the affected individual. Chemotherapeutic drugs that have been used for diencephalic syndrome include carboplatin, carboplatin-vincristine, carboplatin-vincristine-temador, low dose cisplatin-etoposide and other drug regimens.Recently, molecularly targeted therapies (biologic therapy) have become available for treatment of low-grade pediatric gliomas.
Bevacizumab, which targets vascular endothelial growth factor, has been successfully used for some patients with diencephalic gliomas. Agents interfering with RAS-MAPK signaling have shown great promise for treatment of diencephalic tumors. Doctors have used oral MEK inhibitors for BRAF-fusion associated tumors and BRAF inhibitors, alone or in combination with MEK inhibitors, for tumors with BRAF variants. These trials require molecular characterization of the tumor for a patient to be eligible.Prospective, randomized trials have demonstrated the superiority of dabrafenib and trametinib compared to standard chemotherapy for gliomas with BRAF. variants. Prospective, randomized trials are underway comparing a MEK inhibitor to chemotherapy for both patients with NF-1 associated tumors and BRAF-fusion associated low-grade gliomas. | Therapies of Diencephalic Syndrome. Treatment
The treatment of diencephalic 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, surgeons, neurologists, oncologists, radiation oncologists and other healthcare professionals may need to plan an affect child’s treatment systematically and comprehensively.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease stage; tumor size and specific location; specific tumor type; the presence or absence of certain symptoms; an individual’s age and general health; and/or other elements. Decisions concerning the use of drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of their case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors. Psychosocial support for the entire family is essential as well.There is no agreed upon consensus for the best treatment for individuals with diencephalic syndrome and there are no standardized treatment protocols or guidelines. However, protocols and often clinical trials are available for specific tumor types that cause the syndrome. Various treatments have been reported in the medical literature as part of single patient reports, small series of patients or more extensive, tumor-type based studies. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with diencephalic syndrome.Surgery, radiation, chemotherapy, and molecular-targeted therapy alone or in various combinations have been used to treat the diencephalic syndrome. In some patients, physicians may recommend surgical excision and removal of as much of the tumor as possible (resection). However, because of the area of the brain that is usually affected, surgical removal of the entire tumor is rarely possible. Additionally, surgery, even to remove only a portion of the tumor, carries risks due to the tumor’s location deep within the brain. However, as noted previously, biopsy is usually indicated to not only determine the histological subtype of the tumor, but its molecular subtype; this is especially useful in low-grade gliomas where molecular findings can guide therapy.Radiation therapy can be used to directly destroy cancer cells or to destroy cancer cells left over after surgery. However, the potential for serious short and long-term side effects exists. Radiation therapy is especially avoided in children less than 5 years of age because of the potential for serious side effects.Chemotherapy, the use of one or more anti-cancer drugs, has also been used to treat individuals with diencephalic syndrome, particularly those with low grade gliomas. Chemotherapy may be used instead of radiation in very young children to avoid damage to the developing brain. Chemotherapy may also be administered after radiation to destroy any cells that remain or may be given during radiation treatment. The type of chemotherapeutic drug therapy used is determined by a neuro-oncologist who examines the grade of tumor, previous treatment and current health status of the affected individual. Chemotherapeutic drugs that have been used for diencephalic syndrome include carboplatin, carboplatin-vincristine, carboplatin-vincristine-temador, low dose cisplatin-etoposide and other drug regimens.Recently, molecularly targeted therapies (biologic therapy) have become available for treatment of low-grade pediatric gliomas.
Bevacizumab, which targets vascular endothelial growth factor, has been successfully used for some patients with diencephalic gliomas. Agents interfering with RAS-MAPK signaling have shown great promise for treatment of diencephalic tumors. Doctors have used oral MEK inhibitors for BRAF-fusion associated tumors and BRAF inhibitors, alone or in combination with MEK inhibitors, for tumors with BRAF variants. These trials require molecular characterization of the tumor for a patient to be eligible.Prospective, randomized trials have demonstrated the superiority of dabrafenib and trametinib compared to standard chemotherapy for gliomas with BRAF. variants. Prospective, randomized trials are underway comparing a MEK inhibitor to chemotherapy for both patients with NF-1 associated tumors and BRAF-fusion associated low-grade gliomas. | 373 | Diencephalic Syndrome |
nord_374_0 | Overview of Diffuse Pulmonary Lymphangiomatosis | Summary
Diffuse pulmonary lymphangiomatosis (DPL) is a disease in which the overgrowth (proliferation) of lymphatic vessels (lymphangiomatosis) occurs in the lungs, pleura and typically the surrounding soft tissue of the chest (mediastinum). Lymphatic vessels are part of the lymphatic system, which includes lymph nodes, the small nodules where certain white blood cells (lymphocytes) and other cells participate in the immune regulatory system of the body. When fluid leaves arteries and enters the soft tissue and organs of the body, it does so without red or white blood cells. This thin watery fluid is known as lymph. The lymphatic system consists of a network of tubular channels (lymph vessels) that transport lymph back into the bloodstream. Lymph accumulates between tissue cells and contains proteins, fats, and lymphocytes. As lymph moves through the lymphatic system, it passes through the network of lymph nodes that help the body to deactivate sources of infection (e.g., viruses, bacteria, etc.) and other potentially injurious substances and toxins. Groups of lymph nodes are located throughout the body, including in the neck, under the arms (axillae), at the elbows, and in the chest, abdomen and groin. The lymphatic system also includes the spleen, which filters worn-out red blood cells and produces lymphocytes; and bone marrow, which is the spongy tissue inside the cavities of bones that manufactures blood cells.Lymphangiomatosis can potentially affect any part of the body except the brain. The disorder can be widespread, affecting multiple areas simultaneously, or be isolated to one area (e.g. the lungs and chest). The specific symptoms and severity vary, depending in part upon the size and the specific location of the abnormalities. Diffuse pulmonary lymphangiomatosis causes functional impairment of the lungs and when the chest wall is involved, may be associated with disfigurement. The exact cause of diffuse pulmonary lymphangiomatosis is unknown.Introduction
There is a lack of consensus among the medical community as to the proper terminology for disorders and malformations associated with lymphatics. In general, however, a lymphangioma is a relatively localized collection of abnormal lymphatic vessels, lymphangiectasis refers to dilatation of lymphatics and lymphangiomatosis refers to an increase in lymphatic number. In some patients there is overlap between these and so exact classification becomes challenging. Lymphangiomatosis may also occur in association with better-characterized diseases such as Gorham’s disease. Gorham’s disease is a form of lymphangiomatosis in which the lymphatics proliferate in bone, resulting in progressive bone loss. Another disease, which has a similar sounding name, is lymphangioleiomyomatosis (LAM), a distinct disorder caused by proliferation of smooth muscle-like cells that, despite the similarity in the names, is unrelated to lymphangiomatosis. LAM occurs almost exclusively in women, while lymphangiomatosis is not as gender restricted.NORD has separate reports on other lymphatic malformations, Gorham’s disease, lymphangioleiomyomatosis and several types of lymphangiectasia. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.). Lymphatic disorders are a rapidly growing disease family and information about these disorders and the terminology used to describe them are constantly changing. Physicians and researchers are working to create a standardized classification and nomenclature system for these disorders. | Overview of Diffuse Pulmonary Lymphangiomatosis. Summary
Diffuse pulmonary lymphangiomatosis (DPL) is a disease in which the overgrowth (proliferation) of lymphatic vessels (lymphangiomatosis) occurs in the lungs, pleura and typically the surrounding soft tissue of the chest (mediastinum). Lymphatic vessels are part of the lymphatic system, which includes lymph nodes, the small nodules where certain white blood cells (lymphocytes) and other cells participate in the immune regulatory system of the body. When fluid leaves arteries and enters the soft tissue and organs of the body, it does so without red or white blood cells. This thin watery fluid is known as lymph. The lymphatic system consists of a network of tubular channels (lymph vessels) that transport lymph back into the bloodstream. Lymph accumulates between tissue cells and contains proteins, fats, and lymphocytes. As lymph moves through the lymphatic system, it passes through the network of lymph nodes that help the body to deactivate sources of infection (e.g., viruses, bacteria, etc.) and other potentially injurious substances and toxins. Groups of lymph nodes are located throughout the body, including in the neck, under the arms (axillae), at the elbows, and in the chest, abdomen and groin. The lymphatic system also includes the spleen, which filters worn-out red blood cells and produces lymphocytes; and bone marrow, which is the spongy tissue inside the cavities of bones that manufactures blood cells.Lymphangiomatosis can potentially affect any part of the body except the brain. The disorder can be widespread, affecting multiple areas simultaneously, or be isolated to one area (e.g. the lungs and chest). The specific symptoms and severity vary, depending in part upon the size and the specific location of the abnormalities. Diffuse pulmonary lymphangiomatosis causes functional impairment of the lungs and when the chest wall is involved, may be associated with disfigurement. The exact cause of diffuse pulmonary lymphangiomatosis is unknown.Introduction
There is a lack of consensus among the medical community as to the proper terminology for disorders and malformations associated with lymphatics. In general, however, a lymphangioma is a relatively localized collection of abnormal lymphatic vessels, lymphangiectasis refers to dilatation of lymphatics and lymphangiomatosis refers to an increase in lymphatic number. In some patients there is overlap between these and so exact classification becomes challenging. Lymphangiomatosis may also occur in association with better-characterized diseases such as Gorham’s disease. Gorham’s disease is a form of lymphangiomatosis in which the lymphatics proliferate in bone, resulting in progressive bone loss. Another disease, which has a similar sounding name, is lymphangioleiomyomatosis (LAM), a distinct disorder caused by proliferation of smooth muscle-like cells that, despite the similarity in the names, is unrelated to lymphangiomatosis. LAM occurs almost exclusively in women, while lymphangiomatosis is not as gender restricted.NORD has separate reports on other lymphatic malformations, Gorham’s disease, lymphangioleiomyomatosis and several types of lymphangiectasia. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.). Lymphatic disorders are a rapidly growing disease family and information about these disorders and the terminology used to describe them are constantly changing. Physicians and researchers are working to create a standardized classification and nomenclature system for these disorders. | 374 | Diffuse Pulmonary Lymphangiomatosis |
nord_374_1 | Symptoms of Diffuse Pulmonary Lymphangiomatosis | The symptoms and severity of DPL are variable and there is no typical or standard presentation for the disorder. Generally, pulmonary lymphangiomatosis progresses faster in children than adults. Some individuals may eventually experience life-threatening complications, while others have mild symptoms that can go undiagnosed well until adulthood. Consequently, it is important to note that one person’s experience can vary dramatically from another’s. Affected individuals and parents of affected children should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.The specific symptoms associated with diffuse pulmonary lymphangiomatosis depend upon the size and exact location of affected lymphatic vessels. The disorder often causes a variety of general, nonspecific symptoms including fatigue and nausea as well as symptoms more directly related to the chest, including chest pain, wheezing, shortness of breath (dyspnea), chronic cough and coughing up blood (hemoptysis). Chest tightness, recurrent respiratory infections and recurrent pneumonia have also been reported in individuals with diffuse pulmonary lymphangiomatosis. Some individuals give a history of asthma, but the symptoms may be secondary to lymphangiomatosis rather than true asthma.Diffuse pulmonary lymphangiomatosis can eventually cause compression of nearby structures in the chest, bony destruction leading to the appearance of “holes” in adjacent bones (lytic bone lesions), and other complications such as the accumulation of lymph fluid (chyle) in the space between the lung surface and chest wall (pleural space), a condition known as chylous pleural effusions. A collapsed lung (pneumothorax) can also occur. Some of these complications can be life-threatening e.g., when chylous pleural effusions become large enough to make breathing difficult, and when chyle accumulates in the sac around the heart (pericardial effusion) and makes it difficult for the heart to pump blood. The excess fluid in the lungs and other spaces also can lead to severe infection, as bacteria can grow in these excess fluid pockets. | Symptoms of Diffuse Pulmonary Lymphangiomatosis. The symptoms and severity of DPL are variable and there is no typical or standard presentation for the disorder. Generally, pulmonary lymphangiomatosis progresses faster in children than adults. Some individuals may eventually experience life-threatening complications, while others have mild symptoms that can go undiagnosed well until adulthood. Consequently, it is important to note that one person’s experience can vary dramatically from another’s. Affected individuals and parents of affected children should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.The specific symptoms associated with diffuse pulmonary lymphangiomatosis depend upon the size and exact location of affected lymphatic vessels. The disorder often causes a variety of general, nonspecific symptoms including fatigue and nausea as well as symptoms more directly related to the chest, including chest pain, wheezing, shortness of breath (dyspnea), chronic cough and coughing up blood (hemoptysis). Chest tightness, recurrent respiratory infections and recurrent pneumonia have also been reported in individuals with diffuse pulmonary lymphangiomatosis. Some individuals give a history of asthma, but the symptoms may be secondary to lymphangiomatosis rather than true asthma.Diffuse pulmonary lymphangiomatosis can eventually cause compression of nearby structures in the chest, bony destruction leading to the appearance of “holes” in adjacent bones (lytic bone lesions), and other complications such as the accumulation of lymph fluid (chyle) in the space between the lung surface and chest wall (pleural space), a condition known as chylous pleural effusions. A collapsed lung (pneumothorax) can also occur. Some of these complications can be life-threatening e.g., when chylous pleural effusions become large enough to make breathing difficult, and when chyle accumulates in the sac around the heart (pericardial effusion) and makes it difficult for the heart to pump blood. The excess fluid in the lungs and other spaces also can lead to severe infection, as bacteria can grow in these excess fluid pockets. | 374 | Diffuse Pulmonary Lymphangiomatosis |
nord_374_2 | Causes of Diffuse Pulmonary Lymphangiomatosis | The exact cause of diffuse pulmonary lymphangiomatosis is unknown. Lymphangiomatosis in general is believed to result from abnormalities in the development of the lymphatic vascular system during embryonic growth. No environmental, immunological or genetic risk factors that may play a role in the development of the disorder have been identified.The symptoms of diffuse pulmonary lymphangiomatosis are caused by complications due to the overproduction (proliferation), widening (dilation), and thickening of lymphatic vessels throughout the lungs.Researchers are studying whether vascular endothelial growth factor receptor 3 (VEGFR-3) plays a role in the development of lymphangiomatosis. Researchers have determined that affected tissue in individuals with lymphangiomatosis have high levels of VEGFR-3, a chemical that most likely promotes the growth of lymphatic vessels. A better understanding of such underlying mechanisms should lead to targeted therapies for individuals with lymphangiomatosis. | Causes of Diffuse Pulmonary Lymphangiomatosis. The exact cause of diffuse pulmonary lymphangiomatosis is unknown. Lymphangiomatosis in general is believed to result from abnormalities in the development of the lymphatic vascular system during embryonic growth. No environmental, immunological or genetic risk factors that may play a role in the development of the disorder have been identified.The symptoms of diffuse pulmonary lymphangiomatosis are caused by complications due to the overproduction (proliferation), widening (dilation), and thickening of lymphatic vessels throughout the lungs.Researchers are studying whether vascular endothelial growth factor receptor 3 (VEGFR-3) plays a role in the development of lymphangiomatosis. Researchers have determined that affected tissue in individuals with lymphangiomatosis have high levels of VEGFR-3, a chemical that most likely promotes the growth of lymphatic vessels. A better understanding of such underlying mechanisms should lead to targeted therapies for individuals with lymphangiomatosis. | 374 | Diffuse Pulmonary Lymphangiomatosis |
nord_374_3 | Affects of Diffuse Pulmonary Lymphangiomatosis | Diffuse pulmonary lymphangiomatosis affects males and females in equal numbers. Most cases have been reported in infants and children, but the disorder has occurred in adults as well. The disorder has been reported in individuals of every race and ethnicity. The exact incidence or prevalence is unknown. The disorder often goes misdiagnosed or undiagnosed, making it difficult to determine true frequency of diffuse pulmonary lymphangiomatosis in the general population. | Affects of Diffuse Pulmonary Lymphangiomatosis. Diffuse pulmonary lymphangiomatosis affects males and females in equal numbers. Most cases have been reported in infants and children, but the disorder has occurred in adults as well. The disorder has been reported in individuals of every race and ethnicity. The exact incidence or prevalence is unknown. The disorder often goes misdiagnosed or undiagnosed, making it difficult to determine true frequency of diffuse pulmonary lymphangiomatosis in the general population. | 374 | Diffuse Pulmonary Lymphangiomatosis |
nord_374_4 | Related disorders of Diffuse Pulmonary Lymphangiomatosis | Symptoms of the following disorders can be like those of diffuse pulmonary lymphangiomatosis. Comparisons may be useful for a differential diagnosis.A wide variety of conditions may have symptoms that are like those found in individuals with diffuse pulmonary lymphangiomatosis. Such conditions include congenital pulmonary lymphangiectasia, lymphangioleiomyomatosis (LAM), hemangiomatosis (proliferation of blood vessels as opposed to lymphatics), various disorders associated with bone loss (osteolysis) such as Hadju-Cheney disease and various tumors or malignancies including kaposiform hemangioendothelioma and Kaposi’s sarcoma of the lung. Several different obstructive lung diseases can also cause similar symptoms to those seen in pulmonary lymphangiomatosis. Such disorders include asthma, chronic obstructive pulmonary disease (COPD), emphysema and chronic bronchitis and interstitial lung disease. Recurrent respiratory infections can also cause similar symptoms. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Gorham’s disease, which is also known as vanishing bone disease, is a rare bone disorder characterized by bone loss (osteolysis) associated with overgrowth (proliferation) of small blood (vascular) or lymphatic vessels. Affected individuals experience progressive destruction and resorption of bone. Multiple bones may become involved. Areas commonly affected by Gorham’s disease include the pelvis, shoulder, spine, ribs, jaws and skull. Pain and swelling in the affected area may occur. Bones affected by Gorham’s disease are prone to fracture. The severity of Gorham’s disease can vary from one individual to another and can cause disfigurement and functional disability. The exact cause of Gorham’s disease is unknown. (For more information on this disorder, choose “Gorham’s” as your search term in the Rare Disease Database.) | Related disorders of Diffuse Pulmonary Lymphangiomatosis. Symptoms of the following disorders can be like those of diffuse pulmonary lymphangiomatosis. Comparisons may be useful for a differential diagnosis.A wide variety of conditions may have symptoms that are like those found in individuals with diffuse pulmonary lymphangiomatosis. Such conditions include congenital pulmonary lymphangiectasia, lymphangioleiomyomatosis (LAM), hemangiomatosis (proliferation of blood vessels as opposed to lymphatics), various disorders associated with bone loss (osteolysis) such as Hadju-Cheney disease and various tumors or malignancies including kaposiform hemangioendothelioma and Kaposi’s sarcoma of the lung. Several different obstructive lung diseases can also cause similar symptoms to those seen in pulmonary lymphangiomatosis. Such disorders include asthma, chronic obstructive pulmonary disease (COPD), emphysema and chronic bronchitis and interstitial lung disease. Recurrent respiratory infections can also cause similar symptoms. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Gorham’s disease, which is also known as vanishing bone disease, is a rare bone disorder characterized by bone loss (osteolysis) associated with overgrowth (proliferation) of small blood (vascular) or lymphatic vessels. Affected individuals experience progressive destruction and resorption of bone. Multiple bones may become involved. Areas commonly affected by Gorham’s disease include the pelvis, shoulder, spine, ribs, jaws and skull. Pain and swelling in the affected area may occur. Bones affected by Gorham’s disease are prone to fracture. The severity of Gorham’s disease can vary from one individual to another and can cause disfigurement and functional disability. The exact cause of Gorham’s disease is unknown. (For more information on this disorder, choose “Gorham’s” as your search term in the Rare Disease Database.) | 374 | Diffuse Pulmonary Lymphangiomatosis |
nord_374_5 | Diagnosis of Diffuse Pulmonary Lymphangiomatosis | The diagnosis of diffuse pulmonary lymphangiomatosis is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Because of the disorder’s rarity and varying presentation, obtaining a correct diagnosis can be challenging.Clinical Testing and Workup
Pulmonary function tests may be used to help diagnose diffuse pulmonary lymphangiomatosis. This group of tests evaluate how well the lungs are functioning. Affected individuals often have a restrictive pattern or a mixed restrictive and obstructive pattern of lung function.Lymphoscintigraphy is a specialized procedure in which small amounts of radioactive material is used to help create pictures (called scintigrams) of the lymphatic system. Lymphoscintigraphy is used to help obtain a diagnosis of lymphatic disease and/or to assess the extent of the disease.Surgical removal and microscopic examination of affected lung tissue (lung biopsy) may be used to confirm a diagnosis of diffuse pulmonary lymphangiomatosis. However, a lung biopsy is not always possible and can be associated with complications such as the accumulation of chyle within the thoracic cavity and around the lungs (chylothorax). If an area of bone is affected, a bone biopsy may be performed.Various imaging techniques including plain x-rays, ultrasound, computerized tomography (CT) scanning and magnetic resonance imaging (MRI) may be used to determine the location, behavior and extent of the disorder. Plain x-rays can reveal snow-white patches (infiltrates) or chylous effusions. During ultrasound, high-frequency radio waves are used to create a picture of internal organs. 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 organs and other tissues. | Diagnosis of Diffuse Pulmonary Lymphangiomatosis. The diagnosis of diffuse pulmonary lymphangiomatosis is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Because of the disorder’s rarity and varying presentation, obtaining a correct diagnosis can be challenging.Clinical Testing and Workup
Pulmonary function tests may be used to help diagnose diffuse pulmonary lymphangiomatosis. This group of tests evaluate how well the lungs are functioning. Affected individuals often have a restrictive pattern or a mixed restrictive and obstructive pattern of lung function.Lymphoscintigraphy is a specialized procedure in which small amounts of radioactive material is used to help create pictures (called scintigrams) of the lymphatic system. Lymphoscintigraphy is used to help obtain a diagnosis of lymphatic disease and/or to assess the extent of the disease.Surgical removal and microscopic examination of affected lung tissue (lung biopsy) may be used to confirm a diagnosis of diffuse pulmonary lymphangiomatosis. However, a lung biopsy is not always possible and can be associated with complications such as the accumulation of chyle within the thoracic cavity and around the lungs (chylothorax). If an area of bone is affected, a bone biopsy may be performed.Various imaging techniques including plain x-rays, ultrasound, computerized tomography (CT) scanning and magnetic resonance imaging (MRI) may be used to determine the location, behavior and extent of the disorder. Plain x-rays can reveal snow-white patches (infiltrates) or chylous effusions. During ultrasound, high-frequency radio waves are used to create a picture of internal organs. 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 organs and other tissues. | 374 | Diffuse Pulmonary Lymphangiomatosis |
nord_374_6 | Therapies of Diffuse Pulmonary Lymphangiomatosis | Treatment
The treatment of diffuse pulmonary lymphangiomatosis is directed toward the specific symptoms that dominate in an individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, pulmonologists, radiologists and other healthcare professionals may need to systematically and comprehensively plan effective treatment. In extremely rare cases, spontaneous remission, in which symptoms go away on their own, has been reported.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease severity; the size and location of the lymphatic abnormalities; the presence or absence of certain symptoms; an individual’s age and general health; and/or other elements. Decisions concerning the use of drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient or parents based upon the specifics of the case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference and other appropriate factors.A wide variety of potential therapies have been tried in individuals with diffuse pulmonary lymphangiomatosis. 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 diffuse pulmonary lymphangiomatosis.Surgical removal (excision) of affected tissue can be performed and has been effective in some cases when the disease is more localized. However, this is typically not the case in diffuse pulmonary lymphangiomatosis. When surgery is attempted, diseased lymphatic tissue is often difficult to distinguish from healthy tissue, making it challenging to completely remove all affected tissue. Any diseased tissue left behind can cause recurrence of the disorder. In addition, it may be impossible to remove all the diseased lymphatic tissue because of its location near or around vital organs.Sclerotherapy is a procedure in which a solution, called a sclerosant or sclerosing agent, is injected directly into the lesion. This solution causes scarring within the lesion, eventually causing it to shrink or collapse. In most patients, the antibiotic doxycycline is the sclerosing agent used. Sclerotherapy may require multiple sessions to be effective and has demonstrated good results in some cases. Again, however, this is of limited value in a widespread disease such as diffuse pulmonary lymphangiomatosis but could for example be used to partially treat pleural effusions, or the build-up of chyle in the space between the lungs and chest wall.A variety of drugs have been reported in the medical literature for the treatment of individuals with diffuse pulmonary lymphangiomatosis. Two commonly used drugs are interferon alfa 2b and glucocorticoids. Other medications that have been tried include bisphosphates, thalidomide and rapamycin. Recently, researchers have reported encouraging results with drugs that inhibit, either directly or indirectly, the production of vascular endothelial growth factor receptor 3 (VEGFR-3), specifically the drugs propranolol, bevacizumab and sirolimus.Radiotherapy, or the use of radiation to destroy affected tissue, has also been tried in individuals with diffuse pulmonary lymphangiomatosis where surgery is not an option.Some individuals have been treated by dietary adjustments such as restricting fat, except for a particular type of fat known as medium chain triglycerides. Dietary treatments, however, have generally proven ineffective. Drainage of fluid around lungs and heart may be necessary in some cases (pleural or pericardial drainage). Some individuals have also undergone artificial destruction of the pleural space (pleurodesis) to prevent fluid accumulation there. Surgical removal of part of the pleura has also been tried (pleurectomy). Lung transplantation has been used to treat some patients with severe disease that has not responded to any other therapy, but due to the extensive nature of the disease in the chest, this surgery can be very challenging. | Therapies of Diffuse Pulmonary Lymphangiomatosis. Treatment
The treatment of diffuse pulmonary lymphangiomatosis is directed toward the specific symptoms that dominate in an individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, pulmonologists, radiologists and other healthcare professionals may need to systematically and comprehensively plan effective treatment. In extremely rare cases, spontaneous remission, in which symptoms go away on their own, has been reported.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease severity; the size and location of the lymphatic abnormalities; the presence or absence of certain symptoms; an individual’s age and general health; and/or other elements. Decisions concerning the use of drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient or parents based upon the specifics of the case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference and other appropriate factors.A wide variety of potential therapies have been tried in individuals with diffuse pulmonary lymphangiomatosis. 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 diffuse pulmonary lymphangiomatosis.Surgical removal (excision) of affected tissue can be performed and has been effective in some cases when the disease is more localized. However, this is typically not the case in diffuse pulmonary lymphangiomatosis. When surgery is attempted, diseased lymphatic tissue is often difficult to distinguish from healthy tissue, making it challenging to completely remove all affected tissue. Any diseased tissue left behind can cause recurrence of the disorder. In addition, it may be impossible to remove all the diseased lymphatic tissue because of its location near or around vital organs.Sclerotherapy is a procedure in which a solution, called a sclerosant or sclerosing agent, is injected directly into the lesion. This solution causes scarring within the lesion, eventually causing it to shrink or collapse. In most patients, the antibiotic doxycycline is the sclerosing agent used. Sclerotherapy may require multiple sessions to be effective and has demonstrated good results in some cases. Again, however, this is of limited value in a widespread disease such as diffuse pulmonary lymphangiomatosis but could for example be used to partially treat pleural effusions, or the build-up of chyle in the space between the lungs and chest wall.A variety of drugs have been reported in the medical literature for the treatment of individuals with diffuse pulmonary lymphangiomatosis. Two commonly used drugs are interferon alfa 2b and glucocorticoids. Other medications that have been tried include bisphosphates, thalidomide and rapamycin. Recently, researchers have reported encouraging results with drugs that inhibit, either directly or indirectly, the production of vascular endothelial growth factor receptor 3 (VEGFR-3), specifically the drugs propranolol, bevacizumab and sirolimus.Radiotherapy, or the use of radiation to destroy affected tissue, has also been tried in individuals with diffuse pulmonary lymphangiomatosis where surgery is not an option.Some individuals have been treated by dietary adjustments such as restricting fat, except for a particular type of fat known as medium chain triglycerides. Dietary treatments, however, have generally proven ineffective. Drainage of fluid around lungs and heart may be necessary in some cases (pleural or pericardial drainage). Some individuals have also undergone artificial destruction of the pleural space (pleurodesis) to prevent fluid accumulation there. Surgical removal of part of the pleura has also been tried (pleurectomy). Lung transplantation has been used to treat some patients with severe disease that has not responded to any other therapy, but due to the extensive nature of the disease in the chest, this surgery can be very challenging. | 374 | Diffuse Pulmonary Lymphangiomatosis |
nord_375_0 | Overview of Dilatation of the Pulmonary Artery, Idiopathic | Idiopathic dilatation of the pulmonary artery (IDPA) is a rare congenital defect characterized by a wider than normal main pulmonary artery in the absence of any apparent anatomical or physiological cause. | Overview of Dilatation of the Pulmonary Artery, Idiopathic. Idiopathic dilatation of the pulmonary artery (IDPA) is a rare congenital defect characterized by a wider than normal main pulmonary artery in the absence of any apparent anatomical or physiological cause. | 375 | Dilatation of the Pulmonary Artery, Idiopathic |
nord_375_1 | Symptoms of Dilatation of the Pulmonary Artery, Idiopathic | Idiopathic dilatation of the pulmonary artery commonly does not produce symptoms because there is no circulatory abnormality. Clinical signs are minimal, and usually consist of a palpable pulmonary ejection sound that disappears when the patient inhales, a soft pulmonary ejection systolic murmur (abnormal heart sound), and splitting of the second sound on breathing in. IDPA does not cause pulmonary valve disease, nor does bacterial endocarditis occur in patients with this condition. The electrocardiogram is normal, and diagnosis is made when chest X-rays reveal a dilated pulmonary artery without cardiac chamber enlargement. | Symptoms of Dilatation of the Pulmonary Artery, Idiopathic. Idiopathic dilatation of the pulmonary artery commonly does not produce symptoms because there is no circulatory abnormality. Clinical signs are minimal, and usually consist of a palpable pulmonary ejection sound that disappears when the patient inhales, a soft pulmonary ejection systolic murmur (abnormal heart sound), and splitting of the second sound on breathing in. IDPA does not cause pulmonary valve disease, nor does bacterial endocarditis occur in patients with this condition. The electrocardiogram is normal, and diagnosis is made when chest X-rays reveal a dilated pulmonary artery without cardiac chamber enlargement. | 375 | Dilatation of the Pulmonary Artery, Idiopathic |
nord_375_2 | Causes of Dilatation of the Pulmonary Artery, Idiopathic | The cause of idiopathic dilatation of the pulmonary artery is unknown. A defect in the normal development of pulmonary artery elastic tissue before or after birth has been postulated. The dilatation may also be a consequence of a generalized connective tissue disease as it is occasionally found in Marfan's syndrome or Ehlers-Danlos syndrome. (For more information on these disorders, choose “Marfan” and Ehlers-Danlos” as your search terms in the Rare Disease Database. | Causes of Dilatation of the Pulmonary Artery, Idiopathic. The cause of idiopathic dilatation of the pulmonary artery is unknown. A defect in the normal development of pulmonary artery elastic tissue before or after birth has been postulated. The dilatation may also be a consequence of a generalized connective tissue disease as it is occasionally found in Marfan's syndrome or Ehlers-Danlos syndrome. (For more information on these disorders, choose “Marfan” and Ehlers-Danlos” as your search terms in the Rare Disease Database. | 375 | Dilatation of the Pulmonary Artery, Idiopathic |
nord_375_3 | Affects of Dilatation of the Pulmonary Artery, Idiopathic | The incidence and prevalence of IDPA are not known. Because the disorder is benign in most instances, neither clinicians nor epidemiologists are able to measure the distribution of the disease with confidence. | Affects of Dilatation of the Pulmonary Artery, Idiopathic. The incidence and prevalence of IDPA are not known. Because the disorder is benign in most instances, neither clinicians nor epidemiologists are able to measure the distribution of the disease with confidence. | 375 | Dilatation of the Pulmonary Artery, Idiopathic |
nord_375_4 | Related disorders of Dilatation of the Pulmonary Artery, Idiopathic | Related disorders of Dilatation of the Pulmonary Artery, Idiopathic. | 375 | Dilatation of the Pulmonary Artery, Idiopathic |
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nord_375_5 | Diagnosis of Dilatation of the Pulmonary Artery, Idiopathic | Diagnosis of Dilatation of the Pulmonary Artery, Idiopathic. | 375 | Dilatation of the Pulmonary Artery, Idiopathic |
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nord_375_6 | Therapies of Dilatation of the Pulmonary Artery, Idiopathic | Treatment for idiopathic dilatation of the pulmonary artery is not required. People with this condition have a normal life expectancy, provided they have no cardiac lesions. | Therapies of Dilatation of the Pulmonary Artery, Idiopathic. Treatment for idiopathic dilatation of the pulmonary artery is not required. People with this condition have a normal life expectancy, provided they have no cardiac lesions. | 375 | Dilatation of the Pulmonary Artery, Idiopathic |
nord_376_0 | Overview of Distal Myopathy | Distal myopathy (or distal muscular dystrophy) is a general term for a group of rare progressive genetic disorders characterized by wasting (atrophy) and weakness of the voluntary distal muscles. The distal muscles are those farther from the center of the body and include the muscles of the lower arms and legs and the hands and feet. Conversely, the proximal muscles are the muscles closest to the center of the body such as the muscles of the shoulder, pelvis, and upper arms and legs. Although age of onset can occur anytime from infancy to adulthood, most forms develop later in life and are slowly progressive. Inheritance is autosomal dominant or recessive.The distal myopathies belong to a larger group of disorders known as the muscular dystrophies. The muscular dystrophies are characterized by weakness and degeneration of various voluntary muscles of the body. Approximately 30 different disorders make up the muscular dystrophies. The disorders affect different muscles and have different ages of onset, severity and inheritance patterns. | Overview of Distal Myopathy. Distal myopathy (or distal muscular dystrophy) is a general term for a group of rare progressive genetic disorders characterized by wasting (atrophy) and weakness of the voluntary distal muscles. The distal muscles are those farther from the center of the body and include the muscles of the lower arms and legs and the hands and feet. Conversely, the proximal muscles are the muscles closest to the center of the body such as the muscles of the shoulder, pelvis, and upper arms and legs. Although age of onset can occur anytime from infancy to adulthood, most forms develop later in life and are slowly progressive. Inheritance is autosomal dominant or recessive.The distal myopathies belong to a larger group of disorders known as the muscular dystrophies. The muscular dystrophies are characterized by weakness and degeneration of various voluntary muscles of the body. Approximately 30 different disorders make up the muscular dystrophies. The disorders affect different muscles and have different ages of onset, severity and inheritance patterns. | 376 | Distal Myopathy |
nord_376_1 | Symptoms of Distal Myopathy | The severity, specific symptoms, and progression of the distal myopathies vary greatly, even among members of the same family. Slowly progressive weakness and degeneration of the voluntary distal muscles characterizes these disorders. In some cases, additional muscles including various proximal muscles may become involved. Welander Distal MyopathyMost cases of this form of distal myopathy occur in individuals greater than 40 years of age. Certain muscles of the hands and feet (intrinsic muscles and long extensors) and certain muscles of the fingers and toes (extensors) are predominantly affected. Muscle weakness and degeneration ranges from mild to severe. The progression of muscle weakness is slow. Muscles in the hands are affected first with the muscles in the legs becoming involved later on or not at all. Welander distal myopathy has been identified with greater frequency in Sweden and Finland. Udd Distal Myopathy (Tibial Distal Myopathy)This form of distal myopathy is characterized by muscle weakness affecting the ankles that may spread to affect the muscles of the shinbone (tibia). Onset is usually after 35 years of age and progression is slow. Eventually the long extensors of the toes may become involved resulting in clumsiness and an inability to turn the feet and toes upward (foot drop), which may make it difficult to pick up the front of the foot when walking. In most cases, Udd distal myopathy only affects the lower limbs. By the mid seventies, some individuals may have involvement of the upper legs muscles (proximal muscles) and may experience mild to moderate difficulty walking. Laing Distal Myopathy (Laing Early-Onset Distal Myopathy; Distal Myopathy 1; MPD1)In most cases, Laing distal myopathy onset occurs before the age of 5 and has a distinct pattern of muscle weakness and degeneration. Initially, specific muscles of the ankles and great toes are affected. Muscles of the fingers may also be affected with the third and fourth fingers affected most severely. Additional findings may occur including weakness of neck flexion and mild weakness of certain facial muscles. In some cases, onset of Laing distal myopathy may be early enough to cause delays in walking in affected infants. In other cases, no symptoms are apparent until the twenties. Approximately 10 years after the onset of distal muscle weakness, the proximal muscles may become mildly affected. Progression of Laing distal myopathy is extremely slow and no affected individuals have required a wheelchair even into their sixties. Inclusion Body Myopathy Type 2 (IBM2; Distal Myopathy with Rimmed Vacuoles (DMRV); Nonaka Myopathy)Inclusion body myopathy type 2 (IBM2) is characterized by progressive weakness and degeneration of the distal muscles of the legs. Onset ranges from 10 to 40 years of age, but is most common in the late teens to early twenties. Affected individuals may experience gait disturbances and foot drop. Muscle weakness eventually spreads to affect the hands and certain proximal muscles of the upper legs including the thigh and hamstrings. Approximately 20 years after the onset of IBM2, some affected individuals may eventually require a wheelchair. The muscles of the shoulders and neck may become involved in some case. In rare cases, weakness of certain facial muscles may occur. Miyoshi Myopathy Onset of this form of distal myopathy is usually between 15-30 years of age. Affected individuals experience weakness and degeneration of the leg muscles, including the calves, which at first may appear bulky or abnormally large (pseudohypertrophy). Two muscles found in the calf, the gastrocnemius and soleus, are most often first affected by Miyoshi myopathy. Initially, affected individuals may be unable to stand on their toes. Eventually, muscle weakness spreads to affect the proximal muscles of the upper legs often causing difficulties climbing stairs, standing or walking. Muscles in the hands, forearms, and shoulder area may also become affected. As the disease progresses, affected individuals may eventually have significant difficulty walking and require a wheelchair. The specific symptoms and severity of Miyoshi myopathy vary greatly. The disorder is caused by mutations of a gene, dysferlin, that also causes limb-girdle muscular dystrophy type 2B (LGMD2B), a rare muscle disorder characterized by weakness of the proximal muscles of the of the hip and shoulder areas (limb-girdle area). Families have been reported in which some members develop Miyoshi myopathy and others LGMD2B. In addition, some patients with dysferlin mutations can have an anterior tibial distribution of weakness. (For more information on this disorder, choose “limb-girdle muscular dystrophy” as your search term in the Rare Disease Database.)Distal Myopathy with Vocal Cord and Pharyngeal Signs (Distal Myopathy 2; MPD2)This form of distal myopathy has only been described in one family. It is characterized by weakness and degeneration of the distal muscles of the hands and feet. In some cases, muscles of the shoulder area may become involved. Weakness of the vocal cord muscles and certain muscles of the throat (pharyngeal muscle) may also occur potentially resulting in difficulty swallowing (dysphagia) or the ingestion of food or liquids into the lungs (aspiration).Distal Myopathy 3 (MPD3)This extremely rare form of distal myopathy is characterized by muscle weakness and atrophy that can begin in the distal muscles of the arms or legs. Affected individuals may be clumsy with their hands or experience gait abnormalities (e.g., frequent stumbling). The disease will progress to affect additional muscles such as the proximal muscles of the upper legs. Mild contractures of the hands may be present. Onset has ranged from 32-45 years of age. | Symptoms of Distal Myopathy. The severity, specific symptoms, and progression of the distal myopathies vary greatly, even among members of the same family. Slowly progressive weakness and degeneration of the voluntary distal muscles characterizes these disorders. In some cases, additional muscles including various proximal muscles may become involved. Welander Distal MyopathyMost cases of this form of distal myopathy occur in individuals greater than 40 years of age. Certain muscles of the hands and feet (intrinsic muscles and long extensors) and certain muscles of the fingers and toes (extensors) are predominantly affected. Muscle weakness and degeneration ranges from mild to severe. The progression of muscle weakness is slow. Muscles in the hands are affected first with the muscles in the legs becoming involved later on or not at all. Welander distal myopathy has been identified with greater frequency in Sweden and Finland. Udd Distal Myopathy (Tibial Distal Myopathy)This form of distal myopathy is characterized by muscle weakness affecting the ankles that may spread to affect the muscles of the shinbone (tibia). Onset is usually after 35 years of age and progression is slow. Eventually the long extensors of the toes may become involved resulting in clumsiness and an inability to turn the feet and toes upward (foot drop), which may make it difficult to pick up the front of the foot when walking. In most cases, Udd distal myopathy only affects the lower limbs. By the mid seventies, some individuals may have involvement of the upper legs muscles (proximal muscles) and may experience mild to moderate difficulty walking. Laing Distal Myopathy (Laing Early-Onset Distal Myopathy; Distal Myopathy 1; MPD1)In most cases, Laing distal myopathy onset occurs before the age of 5 and has a distinct pattern of muscle weakness and degeneration. Initially, specific muscles of the ankles and great toes are affected. Muscles of the fingers may also be affected with the third and fourth fingers affected most severely. Additional findings may occur including weakness of neck flexion and mild weakness of certain facial muscles. In some cases, onset of Laing distal myopathy may be early enough to cause delays in walking in affected infants. In other cases, no symptoms are apparent until the twenties. Approximately 10 years after the onset of distal muscle weakness, the proximal muscles may become mildly affected. Progression of Laing distal myopathy is extremely slow and no affected individuals have required a wheelchair even into their sixties. Inclusion Body Myopathy Type 2 (IBM2; Distal Myopathy with Rimmed Vacuoles (DMRV); Nonaka Myopathy)Inclusion body myopathy type 2 (IBM2) is characterized by progressive weakness and degeneration of the distal muscles of the legs. Onset ranges from 10 to 40 years of age, but is most common in the late teens to early twenties. Affected individuals may experience gait disturbances and foot drop. Muscle weakness eventually spreads to affect the hands and certain proximal muscles of the upper legs including the thigh and hamstrings. Approximately 20 years after the onset of IBM2, some affected individuals may eventually require a wheelchair. The muscles of the shoulders and neck may become involved in some case. In rare cases, weakness of certain facial muscles may occur. Miyoshi Myopathy Onset of this form of distal myopathy is usually between 15-30 years of age. Affected individuals experience weakness and degeneration of the leg muscles, including the calves, which at first may appear bulky or abnormally large (pseudohypertrophy). Two muscles found in the calf, the gastrocnemius and soleus, are most often first affected by Miyoshi myopathy. Initially, affected individuals may be unable to stand on their toes. Eventually, muscle weakness spreads to affect the proximal muscles of the upper legs often causing difficulties climbing stairs, standing or walking. Muscles in the hands, forearms, and shoulder area may also become affected. As the disease progresses, affected individuals may eventually have significant difficulty walking and require a wheelchair. The specific symptoms and severity of Miyoshi myopathy vary greatly. The disorder is caused by mutations of a gene, dysferlin, that also causes limb-girdle muscular dystrophy type 2B (LGMD2B), a rare muscle disorder characterized by weakness of the proximal muscles of the of the hip and shoulder areas (limb-girdle area). Families have been reported in which some members develop Miyoshi myopathy and others LGMD2B. In addition, some patients with dysferlin mutations can have an anterior tibial distribution of weakness. (For more information on this disorder, choose “limb-girdle muscular dystrophy” as your search term in the Rare Disease Database.)Distal Myopathy with Vocal Cord and Pharyngeal Signs (Distal Myopathy 2; MPD2)This form of distal myopathy has only been described in one family. It is characterized by weakness and degeneration of the distal muscles of the hands and feet. In some cases, muscles of the shoulder area may become involved. Weakness of the vocal cord muscles and certain muscles of the throat (pharyngeal muscle) may also occur potentially resulting in difficulty swallowing (dysphagia) or the ingestion of food or liquids into the lungs (aspiration).Distal Myopathy 3 (MPD3)This extremely rare form of distal myopathy is characterized by muscle weakness and atrophy that can begin in the distal muscles of the arms or legs. Affected individuals may be clumsy with their hands or experience gait abnormalities (e.g., frequent stumbling). The disease will progress to affect additional muscles such as the proximal muscles of the upper legs. Mild contractures of the hands may be present. Onset has ranged from 32-45 years of age. | 376 | Distal Myopathy |
nord_376_2 | Causes of Distal Myopathy | The distal myopathies are inherited as either autosomal dominant or recessive traits. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.Autosomal recessive genetic disorders occur when an individual inherits an 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, and usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. The distal myopathies are caused by deficiency or lack of specific proteins that play an essential role in the proper function and health of muscle cells. Laing distal myopathy is caused by mutations in the beta cardiac myosin (MYH7) gene located on the long arm (q) of chromosome 14 (14q12). The MYH7 gene contains instructions to create (encode) the muscle protein, myosin. 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 (in most cases). Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 14q12” refers to a specific band on the long arm of chromosome 14. The numbered bands specify the location of the thousands of genes that are present on each chromosome. Laing distal myopathy is inherited as an autosomal dominant trait. Udd distal myopathy is caused by mutations of the titin (TTN) located on the long arm of chromosome 2 (2q24.3). The TTN gene encodes the muscle protein, titin, found in both skeletal and heart (cardiac) muscles. Udd distal myopathy is inherited as an autosomal dominant trait.Inclusion body myopathy type 2 (DMRV) is caused by mutations of GNE gene located on the short arm of chromosome 9 (9p12-p11). The GNE gene encodes the protein UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase. IBM2 is inherited as an autosomal recessive trait.Miyoshi myopathy is caused by mutations of the dysferlin (DYSF) gene located on the short arm of chromosome 2 (2p13.3-p13.1). Miyoshi myopathy is inherited as an autosomal recessive trait. Researchers have linked other forms of distal myopathy to specific chromosomes, but have not yet identified the causative genes. Welander distal myopathy has been linked to the short arm of chromosome 2 (2p13). Distal myopathy with vocal cord and pharyngeal signs has been linked to the long arm of chromosome 5 (5q). Distal myopathy 3 has been linked to the short or long arm of chromosome 8 (8p22-q12) or the long arm of chromosome 12 (12q13-q22). These three forms of distal myopathy are inherited as autosomal dominant traits. | Causes of Distal Myopathy. The distal myopathies are inherited as either autosomal dominant or recessive traits. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.Autosomal recessive genetic disorders occur when an individual inherits an 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, and usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. The distal myopathies are caused by deficiency or lack of specific proteins that play an essential role in the proper function and health of muscle cells. Laing distal myopathy is caused by mutations in the beta cardiac myosin (MYH7) gene located on the long arm (q) of chromosome 14 (14q12). The MYH7 gene contains instructions to create (encode) the muscle protein, myosin. 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 (in most cases). Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 14q12” refers to a specific band on the long arm of chromosome 14. The numbered bands specify the location of the thousands of genes that are present on each chromosome. Laing distal myopathy is inherited as an autosomal dominant trait. Udd distal myopathy is caused by mutations of the titin (TTN) located on the long arm of chromosome 2 (2q24.3). The TTN gene encodes the muscle protein, titin, found in both skeletal and heart (cardiac) muscles. Udd distal myopathy is inherited as an autosomal dominant trait.Inclusion body myopathy type 2 (DMRV) is caused by mutations of GNE gene located on the short arm of chromosome 9 (9p12-p11). The GNE gene encodes the protein UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase. IBM2 is inherited as an autosomal recessive trait.Miyoshi myopathy is caused by mutations of the dysferlin (DYSF) gene located on the short arm of chromosome 2 (2p13.3-p13.1). Miyoshi myopathy is inherited as an autosomal recessive trait. Researchers have linked other forms of distal myopathy to specific chromosomes, but have not yet identified the causative genes. Welander distal myopathy has been linked to the short arm of chromosome 2 (2p13). Distal myopathy with vocal cord and pharyngeal signs has been linked to the long arm of chromosome 5 (5q). Distal myopathy 3 has been linked to the short or long arm of chromosome 8 (8p22-q12) or the long arm of chromosome 12 (12q13-q22). These three forms of distal myopathy are inherited as autosomal dominant traits. | 376 | Distal Myopathy |
nord_376_3 | Affects of Distal Myopathy | Since no distal myopathy has been linked to the X-chromosome, distal myopathies affect males and females in equal numbers. The exact incidence of the distal myopathies is unknown. Some forms have been identified with greater frequency in certain populations. Udd distal myopathy occurs with greater frequency in Finland where the prevalence is estimated to be 7 in 100,000 individuals. Welander distal myopathy occurs with greater frequency in Sweden where the prevalence is estimated to be 1 in 1,000 individuals. Approximately 220 cases of IBM2 have been identified in the medical literature. The muscular dystrophies as a whole are estimated to affect 250,000 individuals in the United States. | Affects of Distal Myopathy. Since no distal myopathy has been linked to the X-chromosome, distal myopathies affect males and females in equal numbers. The exact incidence of the distal myopathies is unknown. Some forms have been identified with greater frequency in certain populations. Udd distal myopathy occurs with greater frequency in Finland where the prevalence is estimated to be 7 in 100,000 individuals. Welander distal myopathy occurs with greater frequency in Sweden where the prevalence is estimated to be 1 in 1,000 individuals. Approximately 220 cases of IBM2 have been identified in the medical literature. The muscular dystrophies as a whole are estimated to affect 250,000 individuals in the United States. | 376 | Distal Myopathy |
nord_376_4 | Related disorders of Distal Myopathy | Symptoms of the following disorders can be similar to those of distal myopathies. Comparisons may be useful for a differential diagnosis.Limb-girdle muscular dystrophy (LGMD) is a generic term for a group of rare progressive genetic disorders that are characterized by wasting (atrophy) and weakness of the voluntary muscles of the hip and shoulder areas (limb-girdle area). Muscle weakness and atrophy are progressive and may spread to affect other muscles of the body. Approximately 15 different subtypes have been identified based upon abnormal changes (mutations) of certain genes. The age of onset, severity, and progression of symptoms of these subtypes varies greatly even among individuals in the same family. Some individuals may have a mild, slowly progressive form of the disorders; other may have a rapidly progressive form of the disorder that causes severe disability. Additional forms of muscle disease (myopathy) may be considered differential diagnoses for distal myopathy including metabolic myopathies such as Pompe disease; inflammatory myopathies such as dermatomyositis or polymyositis; and distinct congenital myopathies such as nemaline myopathy. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) Distal myopathies may also be mistaken for peripheral neuropathies, which can have a similar distribution of muscle weakness. | Related disorders of Distal Myopathy. Symptoms of the following disorders can be similar to those of distal myopathies. Comparisons may be useful for a differential diagnosis.Limb-girdle muscular dystrophy (LGMD) is a generic term for a group of rare progressive genetic disorders that are characterized by wasting (atrophy) and weakness of the voluntary muscles of the hip and shoulder areas (limb-girdle area). Muscle weakness and atrophy are progressive and may spread to affect other muscles of the body. Approximately 15 different subtypes have been identified based upon abnormal changes (mutations) of certain genes. The age of onset, severity, and progression of symptoms of these subtypes varies greatly even among individuals in the same family. Some individuals may have a mild, slowly progressive form of the disorders; other may have a rapidly progressive form of the disorder that causes severe disability. Additional forms of muscle disease (myopathy) may be considered differential diagnoses for distal myopathy including metabolic myopathies such as Pompe disease; inflammatory myopathies such as dermatomyositis or polymyositis; and distinct congenital myopathies such as nemaline myopathy. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) Distal myopathies may also be mistaken for peripheral neuropathies, which can have a similar distribution of muscle weakness. | 376 | Distal Myopathy |
nord_376_5 | Diagnosis of Distal Myopathy | A diagnosis of distal myopathy is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic findings and a variety of tests including a test that assesses the health of muscles and the nerves that control muscles (electromyography); specialized blood tests; magnetic resonance imaging (MRI) of muscle tissue; and surgical removal and microscopic examination (biopsy) of affected muscle tissue that may reveal characteristic changes to muscle fibers.During an electromyography, a needle electrode is inserted through the skin into an affected muscle. The electrode records the electrical activity of the muscle. This record shows how well a muscle responds to the nerves and can determine whether muscle weakness is caused by the muscle themselves or by the nerves that control the muscles. An electromyography can rule out nerve disorders such as motor neuron disease and peripheral neuropathy.Blood tests may reveal elevated levels of the creatine kinase (CK), an enzyme that is often found in abnormally high levels when muscle is damaged. Elevated CK levels occur in some, but not all cases of distal myopathy, except for cases of Miyoshi myopathy where it is significantly elevated. The detection of elevated CK levels can confirm that muscle is damaged or inflamed, but cannot confirm a diagnosis of distal myopathy.MRIs of muscle tissue may reveal a distinct pattern of muscle damage or involvement. Distinct patterns have been identified in individuals with Welander, Udd and other distal myopathies.Biopsy of affected muscle tissue may reveal characteristic changes such as increased connective tissue and fat. In some forms of distal myopathy, numerous sub-cellular compartments known as rimmed vacuoles can be detected on muscle biopsy. | Diagnosis of Distal Myopathy. A diagnosis of distal myopathy is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic findings and a variety of tests including a test that assesses the health of muscles and the nerves that control muscles (electromyography); specialized blood tests; magnetic resonance imaging (MRI) of muscle tissue; and surgical removal and microscopic examination (biopsy) of affected muscle tissue that may reveal characteristic changes to muscle fibers.During an electromyography, a needle electrode is inserted through the skin into an affected muscle. The electrode records the electrical activity of the muscle. This record shows how well a muscle responds to the nerves and can determine whether muscle weakness is caused by the muscle themselves or by the nerves that control the muscles. An electromyography can rule out nerve disorders such as motor neuron disease and peripheral neuropathy.Blood tests may reveal elevated levels of the creatine kinase (CK), an enzyme that is often found in abnormally high levels when muscle is damaged. Elevated CK levels occur in some, but not all cases of distal myopathy, except for cases of Miyoshi myopathy where it is significantly elevated. The detection of elevated CK levels can confirm that muscle is damaged or inflamed, but cannot confirm a diagnosis of distal myopathy.MRIs of muscle tissue may reveal a distinct pattern of muscle damage or involvement. Distinct patterns have been identified in individuals with Welander, Udd and other distal myopathies.Biopsy of affected muscle tissue may reveal characteristic changes such as increased connective tissue and fat. In some forms of distal myopathy, numerous sub-cellular compartments known as rimmed vacuoles can be detected on muscle biopsy. | 376 | Distal Myopathy |
nord_376_6 | Therapies of Distal Myopathy | TreatmentNo cure exists for the distal myopathies. Treatment is aimed at the specific symptoms present in each individual. Specific treatment options may include physical and occupational therapy to improve muscle strength and, when necessary, the use of various devices including braces (e.g., ankle-foot orthosis) or wheelchairs to assist with walking (ambulation).Genetic counseling may be of benefit for affected individuals and their families. | Therapies of Distal Myopathy. TreatmentNo cure exists for the distal myopathies. Treatment is aimed at the specific symptoms present in each individual. Specific treatment options may include physical and occupational therapy to improve muscle strength and, when necessary, the use of various devices including braces (e.g., ankle-foot orthosis) or wheelchairs to assist with walking (ambulation).Genetic counseling may be of benefit for affected individuals and their families. | 376 | Distal Myopathy |
nord_377_0 | Overview of Dominant Multiple Epiphyseal Dysplasia | SummaryDominant multiple epiphyseal dysplasia is a general term for a group of genetic disorders characterized by skeletal malformations (dysplasia) including those affecting bones of the hands, feet, and knees. Joint pain, particularly of the hips or knees, is also common and often develops during childhood. Initial signs may include pain in the hips and knees following exercise. Progressive joint disease, particularly of the large weight-bearing bones, is common. Dominant multiple epiphyseal dysplasia is caused by mutations in certain genes. Five different genes are known to cause the disorder.IntroductionMultiple epiphyseal dysplasia is a broad term for a group of disorders characterized by abnormal development of the bone and cartilage of the epiphyses, which are the rounded ends or “heads” of the long bones of the arms or legs. In the past, the disorder was subdivided into the milder Ribbing type and the more severe Fairbank type. These terms are no longer used. Researchers now know that multiple epiphyseal dysplasia represents a group or family of at least six disorders that are separated by the underlying genetic mutation that causes each subtype. Most subtypes are inherited in an autosomal dominant manner. One form, multiple epiphyseal dysplasia type 4, is inherited in an autosomal recessive manner. (NORD has a separate report on this disorder.) | Overview of Dominant Multiple Epiphyseal Dysplasia. SummaryDominant multiple epiphyseal dysplasia is a general term for a group of genetic disorders characterized by skeletal malformations (dysplasia) including those affecting bones of the hands, feet, and knees. Joint pain, particularly of the hips or knees, is also common and often develops during childhood. Initial signs may include pain in the hips and knees following exercise. Progressive joint disease, particularly of the large weight-bearing bones, is common. Dominant multiple epiphyseal dysplasia is caused by mutations in certain genes. Five different genes are known to cause the disorder.IntroductionMultiple epiphyseal dysplasia is a broad term for a group of disorders characterized by abnormal development of the bone and cartilage of the epiphyses, which are the rounded ends or “heads” of the long bones of the arms or legs. In the past, the disorder was subdivided into the milder Ribbing type and the more severe Fairbank type. These terms are no longer used. Researchers now know that multiple epiphyseal dysplasia represents a group or family of at least six disorders that are separated by the underlying genetic mutation that causes each subtype. Most subtypes are inherited in an autosomal dominant manner. One form, multiple epiphyseal dysplasia type 4, is inherited in an autosomal recessive manner. (NORD has a separate report on this disorder.) | 377 | Dominant Multiple Epiphyseal Dysplasia |
nord_377_1 | Symptoms of Dominant Multiple Epiphyseal Dysplasia | The specific signs and symptoms of these disorders can vary from one person to another, even among those with the same subtype. Onset is usually in early childhood. Pain in the hips and knees following exercise is usually the initial sign of these disorders. Affected children may fatigue easily. Some affected children develop a waddling manner of walking (abnormal gait). Growth deficiency occurs in childhood and some children may be short for their age (mild to moderate short stature). Adult height is usually normal, but in the shorter range. An individual’s arms and legs may be short in comparison to the torso, which can become apparent during childhood. These growth features may be mild and difficult to appreciate.Some young children may exhibit low muscle tone and reduced muscle strength (muscular hypotonia), knee and finger joints that stretch farther than normal (hypermobility), and restricted movement of the elbows.Affected individuals also experience early onset of inflammation, pain and stiffness in affected joints (early-onset arthritis) that can develop into chronic joint pain (arthralgia). Joint problems can begin as early as 5 or 6 years of age, but is more likely to occur in the 30s. Multiple joints may be affected, particularly in adolescents. The knees and hips are commonly affected and deformation of the hips may occur. Joint pain is usually worse after physical exercise. Pain and loss of motion in the shoulders may occur in adulthood. Some individuals develop deformity or rigidity of affected joints due to shortening or hardening of muscles, tendons or other tissue (contractures). In severe cases, progressive joint damage can potentially result in significant disability and the need for joint replacement in the 30s or 40s.In rare cases, additional symptoms may occur including a hip deformity in which the thigh bone is angled toward the center of the body (cox vara), bowed legs (genu varum), and ‘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 apart. Another rare finding, known as a double-layered or double patella, may be associated with certain forms of dominant multiple epiphyseal dysplasia. The patella, or the kneecap, is the triangular bone that protects the front of the knee joint. A double patella has two bony (osseous) layers instead of one with cartilage in between. A double patella may not be associated with any symptoms (asymptomatic) or may lead to frequent dislocations, knee pain, and potentially functional disability of the knee. | Symptoms of Dominant Multiple Epiphyseal Dysplasia. The specific signs and symptoms of these disorders can vary from one person to another, even among those with the same subtype. Onset is usually in early childhood. Pain in the hips and knees following exercise is usually the initial sign of these disorders. Affected children may fatigue easily. Some affected children develop a waddling manner of walking (abnormal gait). Growth deficiency occurs in childhood and some children may be short for their age (mild to moderate short stature). Adult height is usually normal, but in the shorter range. An individual’s arms and legs may be short in comparison to the torso, which can become apparent during childhood. These growth features may be mild and difficult to appreciate.Some young children may exhibit low muscle tone and reduced muscle strength (muscular hypotonia), knee and finger joints that stretch farther than normal (hypermobility), and restricted movement of the elbows.Affected individuals also experience early onset of inflammation, pain and stiffness in affected joints (early-onset arthritis) that can develop into chronic joint pain (arthralgia). Joint problems can begin as early as 5 or 6 years of age, but is more likely to occur in the 30s. Multiple joints may be affected, particularly in adolescents. The knees and hips are commonly affected and deformation of the hips may occur. Joint pain is usually worse after physical exercise. Pain and loss of motion in the shoulders may occur in adulthood. Some individuals develop deformity or rigidity of affected joints due to shortening or hardening of muscles, tendons or other tissue (contractures). In severe cases, progressive joint damage can potentially result in significant disability and the need for joint replacement in the 30s or 40s.In rare cases, additional symptoms may occur including a hip deformity in which the thigh bone is angled toward the center of the body (cox vara), bowed legs (genu varum), and ‘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 apart. Another rare finding, known as a double-layered or double patella, may be associated with certain forms of dominant multiple epiphyseal dysplasia. The patella, or the kneecap, is the triangular bone that protects the front of the knee joint. A double patella has two bony (osseous) layers instead of one with cartilage in between. A double patella may not be associated with any symptoms (asymptomatic) or may lead to frequent dislocations, knee pain, and potentially functional disability of the knee. | 377 | Dominant Multiple Epiphyseal Dysplasia |
nord_377_2 | Causes of Dominant Multiple Epiphyseal Dysplasia | Dominant multiple epiphyseal dysplasia is caused by a mutation 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, many organ systems of the body can be affected.Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.Dominant multiple epiphyseal dysplasia type 1 is caused by mutations in the cartilage oligomeric matrix protein (COMP) gene. The majority of cases (more than 70%) of multiple epiphyseal dysplasia are caused by mutations in the COMP gene. Investigators have determined that the gene is located on the short arm (p) of chromosome 19 (19p13.11). 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.Dominant multiple epiphyseal dysplasia type 2 is caused by mutations in the collagen type IX alpha-2 (COL9A2) gene. The gene is located on the short arm of chromosome 1 (1p34.2).Dominant multiple epiphyseal dysplasia type 3 is caused by mutations in the collagen type IX alpha-3 (COL9A3) gene. The gene is located on the long arm 20q13.33.Dominant multiple epiphyseal dysplasia type 5 gene is caused by mutations in the matrilin 3 (MATN3) gene. The gene is located on the short arm of chromosome 2 (2p24.1).Dominant multiple epiphyseal dysplasia type 6 is caused by mutations in the collagen type IX alpha-1 (COL9A1) gene. The gene is located on the long arm of chromosome 6 (6q13).The COMP and MATN3 genes create (encode) proteins that are found in the extracellular matrix, which is a network of tissue that provides support to cells. The proteins encoded by these genes are found in the part of the extracellular matrix surrounding cells that make up the ligaments or tendons, as well as nearby cartilage-forming cells known as chondrocytes. The exact functions of these proteins are not fully understood.The COL9A2, COL9A3, and COL9A1 genes create (encode) various parts of type IX collagen, a protein that is essential to the development and strengthening of connective tissue. Connective tissue, which is the material between cells of the body, is made up of collagen of which there are several different varieties found in the body. Type IX collagen is an important part of cartilage.Researchers have determined that the progression and severity of dominant multiple epiphyseal dysplasia may vary based upon the gene involved and the specific mutation present in a gene as well as the specific location of the mutation in the gene. This is known as genotype-phenotype correlation. For example, the three genes associated with type IX collagen are more likely to have severe joint involvement with the knees, while the hips are spared or only mildly affected. MATN3 mutations are associated with hip abnormalities that are more severe than those seen in individuals with a COL9A2 mutation, but less severe than those seen in individuals in a COMP mutation. Significant involvement of the head of the thigh bone (femoral epiphysis) is more likely with COMP mutations than other mutations. Researchers are studying these disorders to further understand the specific genotype-phenotype correlations.Although five different genes known to cause dominant multiple epiphyseal dysplasia, many cases cannot be linked to any of these genes suggesting that additional, as-yet-unidentified genes may also cause the disorder. The known genes are estimated to account for less than half of the overall cases of this disorder. | Causes of Dominant Multiple Epiphyseal Dysplasia. Dominant multiple epiphyseal dysplasia is caused by a mutation 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, many organ systems of the body can be affected.Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.Dominant multiple epiphyseal dysplasia type 1 is caused by mutations in the cartilage oligomeric matrix protein (COMP) gene. The majority of cases (more than 70%) of multiple epiphyseal dysplasia are caused by mutations in the COMP gene. Investigators have determined that the gene is located on the short arm (p) of chromosome 19 (19p13.11). 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.Dominant multiple epiphyseal dysplasia type 2 is caused by mutations in the collagen type IX alpha-2 (COL9A2) gene. The gene is located on the short arm of chromosome 1 (1p34.2).Dominant multiple epiphyseal dysplasia type 3 is caused by mutations in the collagen type IX alpha-3 (COL9A3) gene. The gene is located on the long arm 20q13.33.Dominant multiple epiphyseal dysplasia type 5 gene is caused by mutations in the matrilin 3 (MATN3) gene. The gene is located on the short arm of chromosome 2 (2p24.1).Dominant multiple epiphyseal dysplasia type 6 is caused by mutations in the collagen type IX alpha-1 (COL9A1) gene. The gene is located on the long arm of chromosome 6 (6q13).The COMP and MATN3 genes create (encode) proteins that are found in the extracellular matrix, which is a network of tissue that provides support to cells. The proteins encoded by these genes are found in the part of the extracellular matrix surrounding cells that make up the ligaments or tendons, as well as nearby cartilage-forming cells known as chondrocytes. The exact functions of these proteins are not fully understood.The COL9A2, COL9A3, and COL9A1 genes create (encode) various parts of type IX collagen, a protein that is essential to the development and strengthening of connective tissue. Connective tissue, which is the material between cells of the body, is made up of collagen of which there are several different varieties found in the body. Type IX collagen is an important part of cartilage.Researchers have determined that the progression and severity of dominant multiple epiphyseal dysplasia may vary based upon the gene involved and the specific mutation present in a gene as well as the specific location of the mutation in the gene. This is known as genotype-phenotype correlation. For example, the three genes associated with type IX collagen are more likely to have severe joint involvement with the knees, while the hips are spared or only mildly affected. MATN3 mutations are associated with hip abnormalities that are more severe than those seen in individuals with a COL9A2 mutation, but less severe than those seen in individuals in a COMP mutation. Significant involvement of the head of the thigh bone (femoral epiphysis) is more likely with COMP mutations than other mutations. Researchers are studying these disorders to further understand the specific genotype-phenotype correlations.Although five different genes known to cause dominant multiple epiphyseal dysplasia, many cases cannot be linked to any of these genes suggesting that additional, as-yet-unidentified genes may also cause the disorder. The known genes are estimated to account for less than half of the overall cases of this disorder. | 377 | Dominant Multiple Epiphyseal Dysplasia |
nord_377_3 | Affects of Dominant Multiple Epiphyseal Dysplasia | Dominant multiple epiphyseal dysplasia affects males and females in equal numbers. The exact incidence and prevalence is unknown, but multiple epiphyseal dysplasia, collectively, has been estimated to occur in approximately 1 in 20,000 people in the general population. Because some cases go undiagnosed or misdiagnosed, determining the true frequency these disorders in the general population is difficult. Dominant multiple epiphyseal dysplasia type 1 accounts for approximately 70% of cases. Gene alterations of MATN3 are seen in roughly 20% of molecularly diagnosed cases and alterations of the three different COL9 genes account for another 10%. | Affects of Dominant Multiple Epiphyseal Dysplasia. Dominant multiple epiphyseal dysplasia affects males and females in equal numbers. The exact incidence and prevalence is unknown, but multiple epiphyseal dysplasia, collectively, has been estimated to occur in approximately 1 in 20,000 people in the general population. Because some cases go undiagnosed or misdiagnosed, determining the true frequency these disorders in the general population is difficult. Dominant multiple epiphyseal dysplasia type 1 accounts for approximately 70% of cases. Gene alterations of MATN3 are seen in roughly 20% of molecularly diagnosed cases and alterations of the three different COL9 genes account for another 10%. | 377 | Dominant Multiple Epiphyseal Dysplasia |
nord_377_4 | Related disorders of Dominant Multiple Epiphyseal Dysplasia | Symptoms of the following disorders can be similar to those of dominant multiple epiphyseal dysplasia. Comparisons may be useful for a differential diagnosis.Skeletal dysplasias (osteochondrodysplasias) are a general term for a group of disorders characterized by abnormal growth or development or cartilage and bone. Some forms cause life-threatening complications shortly after birth, while others are only may or may not cause life-threatening complications. Some forms do not cause life-threatening complications early in life. Skeletal dysplasias can be associated with short-limbed short stature or with more proportional shortening of the trunk and limbs. Various additional abnormalities may be present depending upon the specific disorder. There are approximately 500 types of skeletal dysplasias with more than 300 causative genes.Pseudoachondroplasia is a rare genetic disorder characterized by delayed growth, a waddling manner of walking (waddling gait), and joint disease, particularly in the large joints of the legs. Affected individuals may be shorter than normal (short stature) with shortened arms and legs (short-limbed dwarfism). Affected individuals may have loose ligaments and certain joints may be able to be stretched to greater degree than normal. Joint disease is progressive and can cause joint pain and degeneration of affected joints (osteoarthritis). Some individuals exhibit abnormal curvature of the spine (scoliosis). Pseudoachondroplasia is caused by a mutation in the same gene that causes dominant multiple epiphyseal dysplasia type 1 (allelic disorders). These disorders are part of a spectrum of disease involving the COMP gene. Pseudoachondroplasia is the severe end of the spectrum. Pseudoachondroplasia is inherited in an autosomal dominant manner. (For more information on this disorder, choose “pseudoachondroplasia” as your search term in the Rare Disease Database.)Recessive multiple epiphyseal dysplasia (rMED) is a rare genetic disorder characterized by skeletal malformations (dysplasia) including those affecting bones of the hands, feet, and knees. Joint pain, particularly of the hips or knees, is also common and develops during childhood. Affected individuals may exhibit additional abnormalities such as mild sideways curvature of the spine (scoliosis). Certain malformations such as clubfoot can be present at birth (congenital). rMED is caused by mutations in the SLC26A2 gene. This gene is also known as the diastrophic dysplasia sulfate transport or DTDST gene. The term ‘recessive’ in the disorder’s name refers to the how the disorder is inherited (autosomal recessive inheritance). The disorder is also known as multiple epiphyseal dysplasia type 4. (For more information on this disorder, choose “recessive multiple epiphyseal dysplasia” as your search term in the Rare Disease Database.)Legg-Calvé-Perthes disease (LCPD) is one of a group of disorders known as the osteochondroses. The Osteochondroses typically are characterized by degeneration (avascular necrosis) and subsequent regeneration of the growing end or ‘head’ of a long bone (epiphyses). In Legg-Calvé-Perthes disease, the growing end (epiphysis) of the upper portion (capital) of the thigh bone (femur) is affected. Researchers believe that an unexplained interruption of the blood supply (ischemia) to the capital femoral epiphysis results in degeneration (avascular necrosis) and deformity of the thigh bone in this area. Symptoms may include a limp with or without pain in the hip, knee, thigh, and/or groin; muscle spasms; delayed maturation of the femur (delayed bone age); mild short stature; and/or limited movements of the affected hip. The disease process seems to be self-limiting as new blood supplies are established (revascularization) and new healthy bone forms (reossifies) in the affected area. Most cases of Legg-Calvé-Perthes disease occur randomly for no apparent reason (sporadically). (For more information on this disorder, choose “Legg-Calvé-Perthes disease” as your search term in the Rare Disease Database.)Meyer dysplasia is a rare condition that primarily affects the epiphyses of the thigh bone (femur) in young children. Meyer dysplasia may not cause any symptoms (asymptomatic), but can result in pain in both hips and cause young children to limp. Affected children may have limited range of motion in the hips and a waddling gait. In most cases, both hips are affected. The disorder usually begins during the second year of life and often resolves without treatment by the age of six. During this time the epiphyses continue to grow and unify. It is important to distinguish Meyer dysplasia from more serious causes of hip dysplasia. Many cases do not require treatment. In some cases, flattening of the epiphyses of the femur (femoral head) occurs and may possibly represent a mild form of multiple epiphyseal dysplasia. | Related disorders of Dominant Multiple Epiphyseal Dysplasia. Symptoms of the following disorders can be similar to those of dominant multiple epiphyseal dysplasia. Comparisons may be useful for a differential diagnosis.Skeletal dysplasias (osteochondrodysplasias) are a general term for a group of disorders characterized by abnormal growth or development or cartilage and bone. Some forms cause life-threatening complications shortly after birth, while others are only may or may not cause life-threatening complications. Some forms do not cause life-threatening complications early in life. Skeletal dysplasias can be associated with short-limbed short stature or with more proportional shortening of the trunk and limbs. Various additional abnormalities may be present depending upon the specific disorder. There are approximately 500 types of skeletal dysplasias with more than 300 causative genes.Pseudoachondroplasia is a rare genetic disorder characterized by delayed growth, a waddling manner of walking (waddling gait), and joint disease, particularly in the large joints of the legs. Affected individuals may be shorter than normal (short stature) with shortened arms and legs (short-limbed dwarfism). Affected individuals may have loose ligaments and certain joints may be able to be stretched to greater degree than normal. Joint disease is progressive and can cause joint pain and degeneration of affected joints (osteoarthritis). Some individuals exhibit abnormal curvature of the spine (scoliosis). Pseudoachondroplasia is caused by a mutation in the same gene that causes dominant multiple epiphyseal dysplasia type 1 (allelic disorders). These disorders are part of a spectrum of disease involving the COMP gene. Pseudoachondroplasia is the severe end of the spectrum. Pseudoachondroplasia is inherited in an autosomal dominant manner. (For more information on this disorder, choose “pseudoachondroplasia” as your search term in the Rare Disease Database.)Recessive multiple epiphyseal dysplasia (rMED) is a rare genetic disorder characterized by skeletal malformations (dysplasia) including those affecting bones of the hands, feet, and knees. Joint pain, particularly of the hips or knees, is also common and develops during childhood. Affected individuals may exhibit additional abnormalities such as mild sideways curvature of the spine (scoliosis). Certain malformations such as clubfoot can be present at birth (congenital). rMED is caused by mutations in the SLC26A2 gene. This gene is also known as the diastrophic dysplasia sulfate transport or DTDST gene. The term ‘recessive’ in the disorder’s name refers to the how the disorder is inherited (autosomal recessive inheritance). The disorder is also known as multiple epiphyseal dysplasia type 4. (For more information on this disorder, choose “recessive multiple epiphyseal dysplasia” as your search term in the Rare Disease Database.)Legg-Calvé-Perthes disease (LCPD) is one of a group of disorders known as the osteochondroses. The Osteochondroses typically are characterized by degeneration (avascular necrosis) and subsequent regeneration of the growing end or ‘head’ of a long bone (epiphyses). In Legg-Calvé-Perthes disease, the growing end (epiphysis) of the upper portion (capital) of the thigh bone (femur) is affected. Researchers believe that an unexplained interruption of the blood supply (ischemia) to the capital femoral epiphysis results in degeneration (avascular necrosis) and deformity of the thigh bone in this area. Symptoms may include a limp with or without pain in the hip, knee, thigh, and/or groin; muscle spasms; delayed maturation of the femur (delayed bone age); mild short stature; and/or limited movements of the affected hip. The disease process seems to be self-limiting as new blood supplies are established (revascularization) and new healthy bone forms (reossifies) in the affected area. Most cases of Legg-Calvé-Perthes disease occur randomly for no apparent reason (sporadically). (For more information on this disorder, choose “Legg-Calvé-Perthes disease” as your search term in the Rare Disease Database.)Meyer dysplasia is a rare condition that primarily affects the epiphyses of the thigh bone (femur) in young children. Meyer dysplasia may not cause any symptoms (asymptomatic), but can result in pain in both hips and cause young children to limp. Affected children may have limited range of motion in the hips and a waddling gait. In most cases, both hips are affected. The disorder usually begins during the second year of life and often resolves without treatment by the age of six. During this time the epiphyses continue to grow and unify. It is important to distinguish Meyer dysplasia from more serious causes of hip dysplasia. Many cases do not require treatment. In some cases, flattening of the epiphyses of the femur (femoral head) occurs and may possibly represent a mild form of multiple epiphyseal dysplasia. | 377 | Dominant Multiple Epiphyseal Dysplasia |
nord_377_5 | Diagnosis of Dominant Multiple Epiphyseal Dysplasia | A diagnosis of dominant multiple epiphyseal dysplasia is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. The disorder may be suspected in individuals with joint pain, particularly in the hips and knees, skeletal malformation of the hands, feet and knees, and scoliosis.Clinical Testing and Workup
Basic x-rays (radiographs) can help to establish a diagnosis by revealing abnormal epiphyses and other characteristic skeletal findings.Molecular genetic testing can support a diagnosis of multiple epiphyseal dysplasia. Molecular genetic testing can detect mutations in the specific genes known to cause the disorder, but it is only available as a diagnostic service at specialized laboratories. | Diagnosis of Dominant Multiple Epiphyseal Dysplasia. A diagnosis of dominant multiple epiphyseal dysplasia is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. The disorder may be suspected in individuals with joint pain, particularly in the hips and knees, skeletal malformation of the hands, feet and knees, and scoliosis.Clinical Testing and Workup
Basic x-rays (radiographs) can help to establish a diagnosis by revealing abnormal epiphyses and other characteristic skeletal findings.Molecular genetic testing can support a diagnosis of multiple epiphyseal dysplasia. Molecular genetic testing can detect mutations in the specific genes known to cause the disorder, but it is only available as a diagnostic service at specialized laboratories. | 377 | Dominant Multiple Epiphyseal Dysplasia |
nord_377_6 | Therapies of Dominant Multiple Epiphyseal Dysplasia | Treatment
Treatment is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, specialists in diagnosing and treating skeletal disorders (orthopedists and orthopedic surgeons), rheumatologists, physical therapists and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Genetic counseling may be of benefit for affected individuals and their families. Psychosocial support for the entire family is essential as well.Standard physical therapy, which can improve joint motion and avoid muscle degeneration (atrophy), is beneficial. Physical therapy in a pool (hydrotherapy) can be beneficial for individuals with arthritis. Pain management can be challenging. Cautious use of pain (analgesic) medications such as nonsteroidal anti-inflammatory drugs (NSAIDs) is recommended.In some cases, surgery may be necessary to achieve better positioning and to increase the range of motion in certain joints. Surgery may be necessary to treat malformation of the hips and, in some cases, total hip replacement surgery (total hip arthroplasty) may be necessary. Surgical procedures may be recommended to treat abnormalities of the knee. | Therapies of Dominant Multiple Epiphyseal Dysplasia. Treatment
Treatment is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, specialists in diagnosing and treating skeletal disorders (orthopedists and orthopedic surgeons), rheumatologists, physical therapists and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Genetic counseling may be of benefit for affected individuals and their families. Psychosocial support for the entire family is essential as well.Standard physical therapy, which can improve joint motion and avoid muscle degeneration (atrophy), is beneficial. Physical therapy in a pool (hydrotherapy) can be beneficial for individuals with arthritis. Pain management can be challenging. Cautious use of pain (analgesic) medications such as nonsteroidal anti-inflammatory drugs (NSAIDs) is recommended.In some cases, surgery may be necessary to achieve better positioning and to increase the range of motion in certain joints. Surgery may be necessary to treat malformation of the hips and, in some cases, total hip replacement surgery (total hip arthroplasty) may be necessary. Surgical procedures may be recommended to treat abnormalities of the knee. | 377 | Dominant Multiple Epiphyseal Dysplasia |
nord_378_0 | Overview of DOORS Syndrome | DOORS syndrome is a rare multisystem genetic disorder that is typically recognized shortly after birth. DOORS is an acronym for the abnormalities that characterize the disorder: (D)eafness (sensorineural hearing loss); (O)nychodystrophy (malformation of the nails); (O)steodystrophy (malformation of certain bones); intellectual disability (previously referred to as mental (R)etardation), and in many cases, affected infants may experience (S)eizures (sudden episodes of uncontrolled electrical activity in the brain). DOORS syndrome is inherited in an autosomal recessive pattern. Treatments are directed toward specific symptoms of affected individuals. | Overview of DOORS Syndrome. DOORS syndrome is a rare multisystem genetic disorder that is typically recognized shortly after birth. DOORS is an acronym for the abnormalities that characterize the disorder: (D)eafness (sensorineural hearing loss); (O)nychodystrophy (malformation of the nails); (O)steodystrophy (malformation of certain bones); intellectual disability (previously referred to as mental (R)etardation), and in many cases, affected infants may experience (S)eizures (sudden episodes of uncontrolled electrical activity in the brain). DOORS syndrome is inherited in an autosomal recessive pattern. Treatments are directed toward specific symptoms of affected individuals. | 378 | DOORS Syndrome |
nord_378_1 | Symptoms of DOORS Syndrome | DOORS syndrome is typically identified at birth by these symptoms: deafness, malformation of the fingernails and toenails (onychodystrophy) and defective formation of certain bones (osteodystrophy) of the fingers and toes. The syndrome may also be associated with seizure disorders.Most infants with DOORS syndrome have congenital deafness in both ears due to sensorineural hearing loss. This means that sound vibrations are not properly transmitted to the brain due to a defect of the inner ear or the auditory nerve, resulting in hearing loss. With normal hearing, a portion of the inner ear serves to convert sound vibrations to nerve impulses, which are then transmitted via the auditory nerve to the brain. Hearing loss may not be detected until later during infancy. Deafness may cause delays in speech or impaired development of speech.Infants with DOORS syndrome also typically have abnormalities of the structure, texture and color of the fingernails and toenails (onychodystrophy). These abnormalities may include misshapen, discolored, underdeveloped and/or rudimentary nails. In some affected infants, some of the fingernails and/or toenails may be absent.Various bone deformities of the fingers and/or toes (digits) may also be present (osteodystrophy). The thumbs and/or great toes are often long, with abnormally large bones at the ends of the digits. In addition, an extra third bone (rather than the normal two) may be present in the thumbs and/or great toes (triphalangeal thumb/great toe). In some patients, this extra bone may not be fully developed and/or may be malformed. Patients may have a permanent curving of the fifth finger (clinodactyly). There may also be underdevelopment or absence of the bones at the ends of the other fingers and/or toes. In addition, affected infants may have distinctive, abnormal skin ridge patterns (dermatoglyphics) in which there are arch patterns on every finger.Infants with DOORS syndrome may also have varying degrees of intellectual disability, ranging from mild to profound. Some children may have variable delays in achieving developmental milestones (e.g., sitting, walking, etc.) as well as speech delay. Intellectual disabilities can vary significantly between patients but are often severe and require intervention.During the first year of life, some affected infants may also begin to experience sudden episodes of uncontrolled electrical activity in the brain (seizures). Without sufficient management of seizures, this may result in further deterioration of intellectual functioning. During the most common type of seizure, a grand mal (generalized tonic-clonic) seizure, affected individuals may experience an abrupt loss of consciousness, generalized stiffening of muscles, rhythmic contraction and relaxation or uncontrollable jerking of muscle groups, and other findings. In addition, some may experience certain “warning symptoms” before a seizure. Severely affected children may have a prolonged series of such seizures, without fully regaining consciousness between attacks or experience a prolonged, continuous seizure attack while unconscious (status epilepticus). Some patients experience seizures that are difficult to control even with multiple antiepileptic medications, which have led to status epilepticus and can be life threatening.Other possible symptoms include a wide nasal base, wide nasal bridge, gum enlargement (gingival overgrowth), low set ears, wide set eyes (hypertelorism), coarse facial features, downturned corners of mouth and a bulbous nose. | Symptoms of DOORS Syndrome. DOORS syndrome is typically identified at birth by these symptoms: deafness, malformation of the fingernails and toenails (onychodystrophy) and defective formation of certain bones (osteodystrophy) of the fingers and toes. The syndrome may also be associated with seizure disorders.Most infants with DOORS syndrome have congenital deafness in both ears due to sensorineural hearing loss. This means that sound vibrations are not properly transmitted to the brain due to a defect of the inner ear or the auditory nerve, resulting in hearing loss. With normal hearing, a portion of the inner ear serves to convert sound vibrations to nerve impulses, which are then transmitted via the auditory nerve to the brain. Hearing loss may not be detected until later during infancy. Deafness may cause delays in speech or impaired development of speech.Infants with DOORS syndrome also typically have abnormalities of the structure, texture and color of the fingernails and toenails (onychodystrophy). These abnormalities may include misshapen, discolored, underdeveloped and/or rudimentary nails. In some affected infants, some of the fingernails and/or toenails may be absent.Various bone deformities of the fingers and/or toes (digits) may also be present (osteodystrophy). The thumbs and/or great toes are often long, with abnormally large bones at the ends of the digits. In addition, an extra third bone (rather than the normal two) may be present in the thumbs and/or great toes (triphalangeal thumb/great toe). In some patients, this extra bone may not be fully developed and/or may be malformed. Patients may have a permanent curving of the fifth finger (clinodactyly). There may also be underdevelopment or absence of the bones at the ends of the other fingers and/or toes. In addition, affected infants may have distinctive, abnormal skin ridge patterns (dermatoglyphics) in which there are arch patterns on every finger.Infants with DOORS syndrome may also have varying degrees of intellectual disability, ranging from mild to profound. Some children may have variable delays in achieving developmental milestones (e.g., sitting, walking, etc.) as well as speech delay. Intellectual disabilities can vary significantly between patients but are often severe and require intervention.During the first year of life, some affected infants may also begin to experience sudden episodes of uncontrolled electrical activity in the brain (seizures). Without sufficient management of seizures, this may result in further deterioration of intellectual functioning. During the most common type of seizure, a grand mal (generalized tonic-clonic) seizure, affected individuals may experience an abrupt loss of consciousness, generalized stiffening of muscles, rhythmic contraction and relaxation or uncontrollable jerking of muscle groups, and other findings. In addition, some may experience certain “warning symptoms” before a seizure. Severely affected children may have a prolonged series of such seizures, without fully regaining consciousness between attacks or experience a prolonged, continuous seizure attack while unconscious (status epilepticus). Some patients experience seizures that are difficult to control even with multiple antiepileptic medications, which have led to status epilepticus and can be life threatening.Other possible symptoms include a wide nasal base, wide nasal bridge, gum enlargement (gingival overgrowth), low set ears, wide set eyes (hypertelorism), coarse facial features, downturned corners of mouth and a bulbous nose. | 378 | DOORS Syndrome |
nord_378_2 | Causes of DOORS Syndrome | In most patients, DOORS syndrome is caused by harmful changes (variants) in the TBC1D24 gene. Some patients with DOORS syndrome have variants in the ATP6V1B2 gene.DOORS 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% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females. | Causes of DOORS Syndrome. In most patients, DOORS syndrome is caused by harmful changes (variants) in the TBC1D24 gene. Some patients with DOORS syndrome have variants in the ATP6V1B2 gene.DOORS 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% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females. | 378 | DOORS Syndrome |
nord_378_3 | Affects of DOORS Syndrome | Approximately 50 cases of DOORS syndrome have been reported in the medical literature, most often diagnosed at birth. DOORS syndrome appears to affect males and females in equal numbers. | Affects of DOORS Syndrome. Approximately 50 cases of DOORS syndrome have been reported in the medical literature, most often diagnosed at birth. DOORS syndrome appears to affect males and females in equal numbers. | 378 | DOORS Syndrome |
nord_378_4 | Related disorders of DOORS Syndrome | Symptoms of the following disorders may be similar to those of DOORS syndrome. Comparisons may be useful for a differential diagnosis:DOORS syndrome is in a group of conditions called TBC1D24-related disorders. Other conditions in this group include familial infantile myoclonic epilepsy (FIME), progressive myoclonus epilepsy (PME), early infantile epileptic encephalopathy 16 (EIEE16), autosomal recessive nonsyndromic hearing loss, DFNB86 and autosomal dominant nonsyndromic hearing loss, DFNA65. These conditions have similar signs and symptoms.Deafness and onychodystrophy, dominant form (DDOD), is an autosomal dominant disorder characterized by sensorineural deafness occurring in association with malformation of the nails. Nail abnormalities may include unusually small fingernails and toenails that may be grooved, discolored and/or malformed. Additional features may also be present, such as webbing of toes (syndactyly), delayed development and delayed eruption of primary and secondary teeth and malformation and/or absence of certain teeth. DDOD has sometimes been described as an autosomal dominant form of DOORS syndrome. However, the designation of “DOORS syndrome” is reserved for the association of deafness and onychodystrophy with osteodystrophy, intellectual disability and possible seizure disorder with an autosomal recessive inheritance.Individuals with Coffin-Siris syndrome, Nicolaides-Baraitser syndrome, Temple-Baraitser syndrome, Zimmermann-Laband syndrome, Mabry syndrome, Kaufman oculocerebrofacial syndrome, fetal anticonvulsant syndrome, and disorders with mutations in the KCNH1, KCNN3, PIGF (GPI deficiency disorders), and PDPK1 genes can also have similar symptoms.Other congenital disorders may be characterized by sensorineural deafness, nail malformations, bone abnormalities and/or other findings similar to those associated with DOORS syndrome. | Related disorders of DOORS Syndrome. Symptoms of the following disorders may be similar to those of DOORS syndrome. Comparisons may be useful for a differential diagnosis:DOORS syndrome is in a group of conditions called TBC1D24-related disorders. Other conditions in this group include familial infantile myoclonic epilepsy (FIME), progressive myoclonus epilepsy (PME), early infantile epileptic encephalopathy 16 (EIEE16), autosomal recessive nonsyndromic hearing loss, DFNB86 and autosomal dominant nonsyndromic hearing loss, DFNA65. These conditions have similar signs and symptoms.Deafness and onychodystrophy, dominant form (DDOD), is an autosomal dominant disorder characterized by sensorineural deafness occurring in association with malformation of the nails. Nail abnormalities may include unusually small fingernails and toenails that may be grooved, discolored and/or malformed. Additional features may also be present, such as webbing of toes (syndactyly), delayed development and delayed eruption of primary and secondary teeth and malformation and/or absence of certain teeth. DDOD has sometimes been described as an autosomal dominant form of DOORS syndrome. However, the designation of “DOORS syndrome” is reserved for the association of deafness and onychodystrophy with osteodystrophy, intellectual disability and possible seizure disorder with an autosomal recessive inheritance.Individuals with Coffin-Siris syndrome, Nicolaides-Baraitser syndrome, Temple-Baraitser syndrome, Zimmermann-Laband syndrome, Mabry syndrome, Kaufman oculocerebrofacial syndrome, fetal anticonvulsant syndrome, and disorders with mutations in the KCNH1, KCNN3, PIGF (GPI deficiency disorders), and PDPK1 genes can also have similar symptoms.Other congenital disorders may be characterized by sensorineural deafness, nail malformations, bone abnormalities and/or other findings similar to those associated with DOORS syndrome. | 378 | DOORS Syndrome |
nord_378_5 | Diagnosis of DOORS Syndrome | DOORS syndrome may be suspected shortly after birth by the identification of certain physical features (i.e., bone, dermatoglyphic, and nail abnormalities). X-ray studies may show an extra bone in the thumbs and/or great toes as well as underdevelopment of bones in other fingers and/or toes. Genetic testing for variants in the TBC1D24 or ATP6V1B2 genes can confirm the diagnosis.Clinical Testing and Work-UpInfants with these characteristic abnormalities should be tested for sensorineural deafness. Deafness may be suspected within the first few months of life and confirmed through a variety of specialized hearing (auditory) tests. Intellectual disability may also be present at birth but may not be detected until an affected infant is old enough to be thoroughly evaluated.Seizure episodes usually begin during the first year of life. Diagnostic evaluation includes certain advanced imaging techniques. Electroencephalography (EEG) records the electrical impulses produced by brain activity. Computerized tomography (CT) scanning is where a computer and x-rays are used to create a film showing cross-sectional images of the brain’s tissue structure. Magnetic resonance imaging (MRI) uses a magnetic field and radio waves are used to create cross-sectional images of the brain.According to reports in the medical literature, some individuals with DOORS syndrome may also have elevated levels of the organic acid 2-oxoglutarate in the urine and fluid portion of the blood (plasma). The implications of this finding are still being researched. | Diagnosis of DOORS Syndrome. DOORS syndrome may be suspected shortly after birth by the identification of certain physical features (i.e., bone, dermatoglyphic, and nail abnormalities). X-ray studies may show an extra bone in the thumbs and/or great toes as well as underdevelopment of bones in other fingers and/or toes. Genetic testing for variants in the TBC1D24 or ATP6V1B2 genes can confirm the diagnosis.Clinical Testing and Work-UpInfants with these characteristic abnormalities should be tested for sensorineural deafness. Deafness may be suspected within the first few months of life and confirmed through a variety of specialized hearing (auditory) tests. Intellectual disability may also be present at birth but may not be detected until an affected infant is old enough to be thoroughly evaluated.Seizure episodes usually begin during the first year of life. Diagnostic evaluation includes certain advanced imaging techniques. Electroencephalography (EEG) records the electrical impulses produced by brain activity. Computerized tomography (CT) scanning is where a computer and x-rays are used to create a film showing cross-sectional images of the brain’s tissue structure. Magnetic resonance imaging (MRI) uses a magnetic field and radio waves are used to create cross-sectional images of the brain.According to reports in the medical literature, some individuals with DOORS syndrome may also have elevated levels of the organic acid 2-oxoglutarate in the urine and fluid portion of the blood (plasma). The implications of this finding are still being researched. | 378 | DOORS Syndrome |
nord_378_6 | Therapies of DOORS Syndrome | TreatmentThe treatment for DOORS syndrome is directed toward the specific symptoms apparent in each individual. Treatment requires the coordinated efforts of a team of medical professionals such as pediatricians, surgeons, specialists who assess and treat hearing problems, dentists, physicians who diagnose and treat neurological disorders (neurologists), therapists and/or other health care professionals.Treatment for seizures may include various medications that may help to prevent, reduce, or control seizures (anticonvulsants). Prolonged seizures accompanied by unconsciousness (status epilepticus) require immediate medical intervention.Hearing impairment should be assessed and treated through audiologic evaluation and/or cochlear implants, as early as possible to help minimize possible speech difficulties or improve communication ability. In addition, clinical evaluation should be conducted early in development and on a continuing basis to help determine the extent of intellectual disability. Early educational intervention and physical, occupational and speech therapy can benefit the patient in this regard. Additional special services that may be beneficial include special remedial education, special social support and other medical, social, and/or vocational services. Other treatment is symptomatic and supportive.Genetic counseling is recommended for affected individuals and their families. | Therapies of DOORS Syndrome. TreatmentThe treatment for DOORS syndrome is directed toward the specific symptoms apparent in each individual. Treatment requires the coordinated efforts of a team of medical professionals such as pediatricians, surgeons, specialists who assess and treat hearing problems, dentists, physicians who diagnose and treat neurological disorders (neurologists), therapists and/or other health care professionals.Treatment for seizures may include various medications that may help to prevent, reduce, or control seizures (anticonvulsants). Prolonged seizures accompanied by unconsciousness (status epilepticus) require immediate medical intervention.Hearing impairment should be assessed and treated through audiologic evaluation and/or cochlear implants, as early as possible to help minimize possible speech difficulties or improve communication ability. In addition, clinical evaluation should be conducted early in development and on a continuing basis to help determine the extent of intellectual disability. Early educational intervention and physical, occupational and speech therapy can benefit the patient in this regard. Additional special services that may be beneficial include special remedial education, special social support and other medical, social, and/or vocational services. Other treatment is symptomatic and supportive.Genetic counseling is recommended for affected individuals and their families. | 378 | DOORS Syndrome |
nord_379_0 | Overview of Dracunculosis | Dracunculosis is an infection caused by a parasitic worm known as Dracunculus medinensis, the guinea worm. Infected water fleas release the larvae of the worm into drinking water. Ingestion of contaminated water causes the larvae to migrate from the intestines via the abdominal cavity to the tissue under the skin. The larvae mature and release a toxic substance that makes the overlying skin ulcerate. After treatment, symptoms disappear and the worms can be safely removed from the skin. | Overview of Dracunculosis. Dracunculosis is an infection caused by a parasitic worm known as Dracunculus medinensis, the guinea worm. Infected water fleas release the larvae of the worm into drinking water. Ingestion of contaminated water causes the larvae to migrate from the intestines via the abdominal cavity to the tissue under the skin. The larvae mature and release a toxic substance that makes the overlying skin ulcerate. After treatment, symptoms disappear and the worms can be safely removed from the skin. | 379 | Dracunculosis |
nord_379_1 | Symptoms of Dracunculosis | Dracunculosis is characterized by chronic skin ulcers. Tissue under the skin is infiltrated by developing larvae of the parasitic worm known as Dracunculus medinensis, or Guinea worm. A female worm ready to release larvae produces stinging elevated spots (papules), causing redness and itching of the skin. These symptoms may be an allergic reaction to the parasite. The spots form blisters and later rupture, developing into painful ulcers. Multiple ulcers (usually on the legs) are common. Without treatment, the worms are absorbed or protrude from the skin over a period of several weeks. | Symptoms of Dracunculosis. Dracunculosis is characterized by chronic skin ulcers. Tissue under the skin is infiltrated by developing larvae of the parasitic worm known as Dracunculus medinensis, or Guinea worm. A female worm ready to release larvae produces stinging elevated spots (papules), causing redness and itching of the skin. These symptoms may be an allergic reaction to the parasite. The spots form blisters and later rupture, developing into painful ulcers. Multiple ulcers (usually on the legs) are common. Without treatment, the worms are absorbed or protrude from the skin over a period of several weeks. | 379 | Dracunculosis |
nord_379_2 | Causes of Dracunculosis | The cause of dracunculosis is the consumption of water contaminated by the larvae of the parasitic worm Dracunculus medinensis, which live in an intermediate host in the water. The larvae are released from the intermediate host while in the stomach, where they mate and grow. This stage lasts for as long as a year. The female apparently survives this process and may grow to three feet in length. The symptoms and characteristic ulcers and infections occur when the female moves from the stomach or intestine to tissues under the skin. | Causes of Dracunculosis. The cause of dracunculosis is the consumption of water contaminated by the larvae of the parasitic worm Dracunculus medinensis, which live in an intermediate host in the water. The larvae are released from the intermediate host while in the stomach, where they mate and grow. This stage lasts for as long as a year. The female apparently survives this process and may grow to three feet in length. The symptoms and characteristic ulcers and infections occur when the female moves from the stomach or intestine to tissues under the skin. | 379 | Dracunculosis |
nord_379_3 | Affects of Dracunculosis | In 1986, there were approximately 3.2 million cases of dracunculosis worldwide. However, due to the efforts of several national and international organizations in cooperation with local governments, the incidence of the disease has significantly decreased. According to current estimates, there are now fewer than 100,000 cases of dracunculosis worldwide, with the remaining cases primarily occurring in Sudan and certain countries in West Africa, such as Nigeria and Niger. | Affects of Dracunculosis. In 1986, there were approximately 3.2 million cases of dracunculosis worldwide. However, due to the efforts of several national and international organizations in cooperation with local governments, the incidence of the disease has significantly decreased. According to current estimates, there are now fewer than 100,000 cases of dracunculosis worldwide, with the remaining cases primarily occurring in Sudan and certain countries in West Africa, such as Nigeria and Niger. | 379 | Dracunculosis |
nord_379_4 | Related disorders of Dracunculosis | Related disorders of Dracunculosis. | 379 | Dracunculosis |
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nord_379_5 | Diagnosis of Dracunculosis | In individuals with dracunculosis, the condition is diagnosed based upon characteristic symptoms (e.g., fever, pain, and blistering and ulceration of the affected area) in association with the emergence of the adult worm through the individual's skin. | Diagnosis of Dracunculosis. In individuals with dracunculosis, the condition is diagnosed based upon characteristic symptoms (e.g., fever, pain, and blistering and ulceration of the affected area) in association with the emergence of the adult worm through the individual's skin. | 379 | Dracunculosis |
nord_379_6 | Therapies of Dracunculosis | TreatmentThe administration of certain medications that are destructive to worms (antihelmintic therapy), such as metronidazole or thiabendazole, may help to alleviate associated symptoms. However, the effectiveness of such agents against the guinea worm's activity has not been demonstrated.In most cases, once the worm begins to emerge, it may be gradually extracted by a few centimeters daily through winding of a small stick. Complete removal of the worm usually takes from weeks to months. In some cases, the worm may be surgically removed.Boiling, appropriate chemical treatment, and filtering of contaminated drinking water may help to prevent transmission of dracunculosis. | Therapies of Dracunculosis. TreatmentThe administration of certain medications that are destructive to worms (antihelmintic therapy), such as metronidazole or thiabendazole, may help to alleviate associated symptoms. However, the effectiveness of such agents against the guinea worm's activity has not been demonstrated.In most cases, once the worm begins to emerge, it may be gradually extracted by a few centimeters daily through winding of a small stick. Complete removal of the worm usually takes from weeks to months. In some cases, the worm may be surgically removed.Boiling, appropriate chemical treatment, and filtering of contaminated drinking water may help to prevent transmission of dracunculosis. | 379 | Dracunculosis |
nord_380_0 | Overview of Dravet Syndrome | Dravet syndrome (DS) is a severe form of epilepsy characterized by frequent, prolonged seizures often triggered by high body temperature (hyperthermia), developmental delay, speech impairment, ataxia, hypotonia, sleep disturbances, and other health problems. DS is thought to be at the severe end of a spectrum of disorders associated with changes (mutations) in genes for the sodium ion channel. The sodium ion channel is a gated pore-like structure in the cell membrane that regulates the movement of sodium ions into and out of the cell, helping to propagate electrical signals along neurons. Sodium ion channels are critical components of any tissue requiring electrical signals including the brain and heart. More than 80% of patients with Dravet syndrome have a mutation in the SCN1A gene (Rosander 2015), but not all SCN1A mutations lead to Dravet syndrome. DS is considered an epileptic encephalopathy, or disorder of the brain due to seizures. In addition, it is considered a “channelopathy” because the effects of the mutation on the sodium channel appear to contribute to the disorder independently of the seizures.DS appears during the first year of life in an otherwise healthy infant, usually with a generalized tonic clonic or hemiclonic seizure which is often prolonged (>5 minutes). Status epilepticus, or a seizure lasting longer than 5 minutes and sometimes 30 minutes or more, is common, especially in the early years, and requires emergency medical intervention. Additional seizure types including myoclonic, atypical absence, and complex partial seizures appear before age 5 years (Wirrell 2017).The EEG, imaging, and development are usually normal at first, but abnormal EEGs and developmental delays often appear in the 2nd and 3rd years of life (Wirrell 2017). Delay can range from mild (rare) to moderate/severe (common), and most adult patients are dependent on caregivers (Catarino 2011).Incoordination (ataxia) and low muscle tone (hypotonia) are often apparent in the early years and remain a characteristic of the syndrome throughout life (Villas 2017). Gait may worsen over time leading to decreased mobility in adolescence. Speech delay is frequently seen before age 2 years. Physical, occupational, and speech therapy are recommended (Wirrell 2017). Other common characteristics and health problems include behavioral issues, growth and nutrition issues, and disruptions of the autonomic nervous system, which regulates things such as body temperature and sweating (Lagae 2018).Mortality is elevated in Dravet syndrome above that found in the general population of epilepsy patients. Estimates of mortality range from 15% to 20% by adulthood. Sudden unexpected death in epilepsy (SUDEP) is the most common cause of death and usually occurs during sleep. The second most common cause of death is status epilepticus (SE) and complications from SE (Cooper 2016).Other conditions believed to be on the spectrum of SCN1A-associated disorders include (in order of increasing severity): | Overview of Dravet Syndrome. Dravet syndrome (DS) is a severe form of epilepsy characterized by frequent, prolonged seizures often triggered by high body temperature (hyperthermia), developmental delay, speech impairment, ataxia, hypotonia, sleep disturbances, and other health problems. DS is thought to be at the severe end of a spectrum of disorders associated with changes (mutations) in genes for the sodium ion channel. The sodium ion channel is a gated pore-like structure in the cell membrane that regulates the movement of sodium ions into and out of the cell, helping to propagate electrical signals along neurons. Sodium ion channels are critical components of any tissue requiring electrical signals including the brain and heart. More than 80% of patients with Dravet syndrome have a mutation in the SCN1A gene (Rosander 2015), but not all SCN1A mutations lead to Dravet syndrome. DS is considered an epileptic encephalopathy, or disorder of the brain due to seizures. In addition, it is considered a “channelopathy” because the effects of the mutation on the sodium channel appear to contribute to the disorder independently of the seizures.DS appears during the first year of life in an otherwise healthy infant, usually with a generalized tonic clonic or hemiclonic seizure which is often prolonged (>5 minutes). Status epilepticus, or a seizure lasting longer than 5 minutes and sometimes 30 minutes or more, is common, especially in the early years, and requires emergency medical intervention. Additional seizure types including myoclonic, atypical absence, and complex partial seizures appear before age 5 years (Wirrell 2017).The EEG, imaging, and development are usually normal at first, but abnormal EEGs and developmental delays often appear in the 2nd and 3rd years of life (Wirrell 2017). Delay can range from mild (rare) to moderate/severe (common), and most adult patients are dependent on caregivers (Catarino 2011).Incoordination (ataxia) and low muscle tone (hypotonia) are often apparent in the early years and remain a characteristic of the syndrome throughout life (Villas 2017). Gait may worsen over time leading to decreased mobility in adolescence. Speech delay is frequently seen before age 2 years. Physical, occupational, and speech therapy are recommended (Wirrell 2017). Other common characteristics and health problems include behavioral issues, growth and nutrition issues, and disruptions of the autonomic nervous system, which regulates things such as body temperature and sweating (Lagae 2018).Mortality is elevated in Dravet syndrome above that found in the general population of epilepsy patients. Estimates of mortality range from 15% to 20% by adulthood. Sudden unexpected death in epilepsy (SUDEP) is the most common cause of death and usually occurs during sleep. The second most common cause of death is status epilepticus (SE) and complications from SE (Cooper 2016).Other conditions believed to be on the spectrum of SCN1A-associated disorders include (in order of increasing severity): | 380 | Dravet Syndrome |
nord_380_1 | Symptoms of Dravet Syndrome | The average age at seizure onset is 5.2 months, with a range of 1-18 months, but most often under 12 months (Cetica 2017, Wirrell 2017). The first seizure is often prolonged, either of the generalized tonic clonic or hemiclonic variation, and may or may not be associated with fever. Shorter seizures may also occur. Hyperthermia, or overheating, is a common seizure trigger in DS, and patients display heightened sensitivity to warm baths, fevers, exertion, and other forms of temperature elevation (Wirrell 2017). Myoclonic seizures, when they occur, are typically seen by age 2 years but are not required for diagnosis. Non-convulsive status (obtundation status) focal seizures with impaired awareness and atypical absence seizures generally occur after 2 years. Typical absence seizures and epileptic spasms are unusual. The initial EEG, CT, MRI, and spinal tap are often normal, although background slowing may be evident if performed after a seizure. Subsequent EEGs may show diffuse slowing and/or generalized discharges while other imaging remains normal. MRI may show mild generalized atrophy or hippocampal sclerosis later in life. Development is usually on track during the first year but delay often appears in the 2nd and 3rd years of life and is usually evident by age 18-60 months (Wirrell 2017). In older children and adults, seizures persist, though status epilepticus becomes less frequent with time. Developmental delay, speech impairment, crouched gait, hypotonia, lack of coordination, and impaired dexterity are evident. Any patient with a clinical history suggestive of DS should undergo genetic testing for SCN1A and/or other epilepsy-related genes. The presence of an SCN1A mutation can help confirm diagnosis, but the presence of a mutation alone is not sufficient for diagnosis, nor does the absence of a mutation exclude diagnosis. Most experts believe an infant with two or more prolonged generalized tonic clonic or hemiclonic seizures with or without fever before age 12 months should undergo genetic testing (Wirrell 2017). | Symptoms of Dravet Syndrome. The average age at seizure onset is 5.2 months, with a range of 1-18 months, but most often under 12 months (Cetica 2017, Wirrell 2017). The first seizure is often prolonged, either of the generalized tonic clonic or hemiclonic variation, and may or may not be associated with fever. Shorter seizures may also occur. Hyperthermia, or overheating, is a common seizure trigger in DS, and patients display heightened sensitivity to warm baths, fevers, exertion, and other forms of temperature elevation (Wirrell 2017). Myoclonic seizures, when they occur, are typically seen by age 2 years but are not required for diagnosis. Non-convulsive status (obtundation status) focal seizures with impaired awareness and atypical absence seizures generally occur after 2 years. Typical absence seizures and epileptic spasms are unusual. The initial EEG, CT, MRI, and spinal tap are often normal, although background slowing may be evident if performed after a seizure. Subsequent EEGs may show diffuse slowing and/or generalized discharges while other imaging remains normal. MRI may show mild generalized atrophy or hippocampal sclerosis later in life. Development is usually on track during the first year but delay often appears in the 2nd and 3rd years of life and is usually evident by age 18-60 months (Wirrell 2017). In older children and adults, seizures persist, though status epilepticus becomes less frequent with time. Developmental delay, speech impairment, crouched gait, hypotonia, lack of coordination, and impaired dexterity are evident. Any patient with a clinical history suggestive of DS should undergo genetic testing for SCN1A and/or other epilepsy-related genes. The presence of an SCN1A mutation can help confirm diagnosis, but the presence of a mutation alone is not sufficient for diagnosis, nor does the absence of a mutation exclude diagnosis. Most experts believe an infant with two or more prolonged generalized tonic clonic or hemiclonic seizures with or without fever before age 12 months should undergo genetic testing (Wirrell 2017). | 380 | Dravet Syndrome |
nord_380_2 | Causes of Dravet Syndrome | Dravet syndrome is associated with a mutation in the SCN1A gene in 80-90% of cases (Rosander 2015). Improved genetic testing including duplication, deletion, and mosaicism identification continues to increase this percentage (Djemie 2016). Missense (40%), nonsense (20%), frameshift (20%), duplications/deletions (7%), and splice site mutations (10%) have all been associated with Dravet syndrome. (A description of different types of gene mutations is available here: https://ghr.nlm.nih.gov/primer/mutationsanddisorders/possiblemutations ) Milder presentations (phenotypes) of conditions associated with SCN1A are more often associated with missense mutations, but neither the type of mutation nor the location on the gene corresponds to clinical severity of DS. (gzneurosci.com/scn1adatabase/by_im_phenotype.php) 90% of mutations appear to be de novo, or new to the child and not inherited from a parent. In the documented cases of inherited SCN1A mutations, the parent has a milder form of epilepsy or no neurological symptoms, whereas the child presents with DS. Improved testing has discovered mosaic mutations in parents who previously tested negative for an SCN1A mutation. Mosaicism is a condition in which some cells within a person differ genetically from other cells within that same person. This can happen shortly after fertilization, when a single cell within a cluster of cells undergoes a spontaneous mutation. Only the cells descending from that mutated cell will carry the mutation: The non-mutated cells will give rise to healthy cells, and thus the developed individual may have slightly different makeup of his/her cells. Risk of recurrence is 50% in families with inherited SCN1A mutations. Because of the identification of mosaicism and the possibility of mutations in egg or sperm cells (germ-line mutations), the risk of recurrence for even apparently de novo mutations is elevated above that of the general public, and thus genetic counseling is recommended.Other genes have been associated with DS including SCN2A, SCN8A, GABRA1, GABARG2, PCDH19, STXBP1, and SCN1B, but the clinical presentation in these cases is often somewhat atypical of DS (Wirrell 2017). | Causes of Dravet Syndrome. Dravet syndrome is associated with a mutation in the SCN1A gene in 80-90% of cases (Rosander 2015). Improved genetic testing including duplication, deletion, and mosaicism identification continues to increase this percentage (Djemie 2016). Missense (40%), nonsense (20%), frameshift (20%), duplications/deletions (7%), and splice site mutations (10%) have all been associated with Dravet syndrome. (A description of different types of gene mutations is available here: https://ghr.nlm.nih.gov/primer/mutationsanddisorders/possiblemutations ) Milder presentations (phenotypes) of conditions associated with SCN1A are more often associated with missense mutations, but neither the type of mutation nor the location on the gene corresponds to clinical severity of DS. (gzneurosci.com/scn1adatabase/by_im_phenotype.php) 90% of mutations appear to be de novo, or new to the child and not inherited from a parent. In the documented cases of inherited SCN1A mutations, the parent has a milder form of epilepsy or no neurological symptoms, whereas the child presents with DS. Improved testing has discovered mosaic mutations in parents who previously tested negative for an SCN1A mutation. Mosaicism is a condition in which some cells within a person differ genetically from other cells within that same person. This can happen shortly after fertilization, when a single cell within a cluster of cells undergoes a spontaneous mutation. Only the cells descending from that mutated cell will carry the mutation: The non-mutated cells will give rise to healthy cells, and thus the developed individual may have slightly different makeup of his/her cells. Risk of recurrence is 50% in families with inherited SCN1A mutations. Because of the identification of mosaicism and the possibility of mutations in egg or sperm cells (germ-line mutations), the risk of recurrence for even apparently de novo mutations is elevated above that of the general public, and thus genetic counseling is recommended.Other genes have been associated with DS including SCN2A, SCN8A, GABRA1, GABARG2, PCDH19, STXBP1, and SCN1B, but the clinical presentation in these cases is often somewhat atypical of DS (Wirrell 2017). | 380 | Dravet Syndrome |
nord_380_3 | Affects of Dravet Syndrome | Dravet syndrome affects an estimated 1:15,700 individuals in the U.S., or 0.0064% of the population (Wu 2015). Approximately 80-90% of those, or 1:20,900 individuals, have both an SCN1A mutation and a clinical diagnosis of DS. This represents an estimated 0.17% of all epilepsies. | Affects of Dravet Syndrome. Dravet syndrome affects an estimated 1:15,700 individuals in the U.S., or 0.0064% of the population (Wu 2015). Approximately 80-90% of those, or 1:20,900 individuals, have both an SCN1A mutation and a clinical diagnosis of DS. This represents an estimated 0.17% of all epilepsies. | 380 | Dravet Syndrome |
nord_380_4 | Related disorders of Dravet Syndrome | Patients with Dravet syndrome may be misdiagnosed with myoclonic atonic epilepsy, Lennox-Gastaut syndrome, myoclonic epilepsy of infancy, genetic epilepsy with febrile seizures plus, atypical febrile seizures, and mitochondrial disorders. Additionally, some children may be diagnosed with focal epilepsy. Conversely, patients with myoclonic atonic epilepsy, myoclonic epilepsy of infancy, and PCDH19-associated epilepsy may be misdiagnosed with Dravet syndrome (Wirrell 2017). Close examination of the clinical history and characteristic progression of Dravet syndrome is important to make a differential diagnosis.Several genes including SCN2A, SCN8A, GABRA1, GABARG2, STXBP1, PCDH19, and SCN1B have been reported in DS patients who test negative for SCN1A mutations. However, the clinical presentation in most of these cases is atypical for DS (Wirrell 2017). | Related disorders of Dravet Syndrome. Patients with Dravet syndrome may be misdiagnosed with myoclonic atonic epilepsy, Lennox-Gastaut syndrome, myoclonic epilepsy of infancy, genetic epilepsy with febrile seizures plus, atypical febrile seizures, and mitochondrial disorders. Additionally, some children may be diagnosed with focal epilepsy. Conversely, patients with myoclonic atonic epilepsy, myoclonic epilepsy of infancy, and PCDH19-associated epilepsy may be misdiagnosed with Dravet syndrome (Wirrell 2017). Close examination of the clinical history and characteristic progression of Dravet syndrome is important to make a differential diagnosis.Several genes including SCN2A, SCN8A, GABRA1, GABARG2, STXBP1, PCDH19, and SCN1B have been reported in DS patients who test negative for SCN1A mutations. However, the clinical presentation in most of these cases is atypical for DS (Wirrell 2017). | 380 | Dravet Syndrome |
nord_380_5 | Diagnosis of Dravet Syndrome | Dravet syndrome is a clinical diagnosis. Presentation is uniquely characteristic and, according to the 2017 consensus of North American neurologists with expertise in DS, includes:In older children and adults: | Diagnosis of Dravet Syndrome. Dravet syndrome is a clinical diagnosis. Presentation is uniquely characteristic and, according to the 2017 consensus of North American neurologists with expertise in DS, includes:In older children and adults: | 380 | Dravet Syndrome |
nord_380_6 | Therapies of Dravet Syndrome | Treatment
Although there is no cure for Dravet syndrome, most treatments aim to reduce seizures. First line anti-seizure medications include clobazam (Onfi, Frisium) and valproic acid (Depakote, Depakene). Second line treatments include stiripentol (Diacomit), topiramate (Topamax), and the ketogenic diet. Variations of the ketogenic diet including the Modified Atkins Diet may also be beneficial in DS. Third line treatments include clonazepam (Klonopin), levetiracetam (Keppra), zonisamide (Zonegran), ethosuximide (Zarontin), and vagal nerve stimulator (VNS) (Wirrell 2017). In 2018, Epidiolex (cannabidiol or CBD) was approved by the U.S. Food and Drug Administration (FDA) to treat seizures associated with Dravet syndrome in patients two years of age and older. Epidiolex was the first FDA-approved product to treat Dravet syndrome. Also in 2018, Dicomit (stiripentol) was approved for the treatment of seizures associated with Dravet syndrome in patients two years of age and older who are also taking clobazam. Most recently, in 2020, Fintepla (fenfluramine) was approved for the treatment of seizures associated with Dravet syndrome in patients two years of age and older. Medications that SHOULD NOT be used in DS include sodium channel blockers such as carbamazepine (Tegretol), oxcarbazepine (Trileptal), lamotrigine (Lamictal), vigabatrin (Sabril), rufinamide (Banzel), phenytoin (Dilantin), fosphenytoin (Cerebyx, Prodilantin). Note that phenytoin and fosphenytoin should be avoided as a daily medication but their efficacy in emergency treatment of status epilepticus is unclear. Status epilepticus is frequent in DS and caregivers should be trained to administer at-home medications to stop prolonged seizures. Rectal diazepam and buccal (by mouth) or intranasal (via the nose) midazolam are frequently used. | Therapies of Dravet Syndrome. Treatment
Although there is no cure for Dravet syndrome, most treatments aim to reduce seizures. First line anti-seizure medications include clobazam (Onfi, Frisium) and valproic acid (Depakote, Depakene). Second line treatments include stiripentol (Diacomit), topiramate (Topamax), and the ketogenic diet. Variations of the ketogenic diet including the Modified Atkins Diet may also be beneficial in DS. Third line treatments include clonazepam (Klonopin), levetiracetam (Keppra), zonisamide (Zonegran), ethosuximide (Zarontin), and vagal nerve stimulator (VNS) (Wirrell 2017). In 2018, Epidiolex (cannabidiol or CBD) was approved by the U.S. Food and Drug Administration (FDA) to treat seizures associated with Dravet syndrome in patients two years of age and older. Epidiolex was the first FDA-approved product to treat Dravet syndrome. Also in 2018, Dicomit (stiripentol) was approved for the treatment of seizures associated with Dravet syndrome in patients two years of age and older who are also taking clobazam. Most recently, in 2020, Fintepla (fenfluramine) was approved for the treatment of seizures associated with Dravet syndrome in patients two years of age and older. Medications that SHOULD NOT be used in DS include sodium channel blockers such as carbamazepine (Tegretol), oxcarbazepine (Trileptal), lamotrigine (Lamictal), vigabatrin (Sabril), rufinamide (Banzel), phenytoin (Dilantin), fosphenytoin (Cerebyx, Prodilantin). Note that phenytoin and fosphenytoin should be avoided as a daily medication but their efficacy in emergency treatment of status epilepticus is unclear. Status epilepticus is frequent in DS and caregivers should be trained to administer at-home medications to stop prolonged seizures. Rectal diazepam and buccal (by mouth) or intranasal (via the nose) midazolam are frequently used. | 380 | Dravet Syndrome |
nord_381_0 | Overview of Drug Reaction with Eosinophilia and Systemic Symptoms (DReSS) | Summary
Drug reaction with eosinophilia and systemic symptoms (DReSS) is a rare disorder that can affect the skin, blood and any internal organs, most commonly the liver, kidney, lungs and heart. The cause of DReSS is multifactorial involving drug-exposure, genetic predisposition, viral reactivation and immune system responses. Clinical features of this condition are delayed after drug exposure, and proceed in a stepwise and variable fashion, making this syndrome challenging for both patients and physicians to recognize and diagnose. The prognosis for DReSS is highly dependent on the severity of the reaction and the speed with which diagnosis is made, the drug is discontinued and treatment is initiated. Possible outcomes of DReSS include complete recovery with no complications, illness related to end organ dysfunction, long term autoimmune disease and in rare cases, death. The mainstay treatment of DReSS is immediate withdrawal of the culprit drug, supportive treatment and immunosuppression depending on the severity of disease. Long term follow-up and slow treatment tapers are critical for preventing complications. Assessing viral reactivation is an important component in the management of the disease. Introduction
DReSS is a rare drug reaction that can affect nearly any organ in the human body. Compared to other severe drug reactions like Stevens-Johnson syndrome or toxic epidermal necrolysis (SJS and TEN), DReSS has a more varied clinical presentation making it more challenging to diagnose. The combination of the three features of fever, skin rash and elevated eosinophils (a specific type of white blood cell) has been recognized since the 1930s, but the term DReSS is more recent. As eosinophilia is not always present and other blood count changes may occur (such as low platelets or anemia), many different names have been used to define this syndrome. Originally recognized as anticonvulsant hypersensitivity syndrome, other terms have been proposed over time such as drug-induced pseudolymphoma, drug-induced delayed multiorgan hypersensitivity syndrome (DIDMOHS) and hypersensitivity syndrome. In 1996 the term DRESS (drug rash with eosinophilia and systemic symptoms) was proposed to encompass these similar reactions and differentiate them from other severe drug reactions without eosinophilia. The word “rash” in DReSS was subsequently changed to “reaction” due to its diverse skin findings. The lowercase “e” is often used to denote that eosinophilia is not always present and other blood count changes may be seen. The term DReSS became internationally recognized and gained popularity in multiple countries, although it is not used everywhere. More recently, some have suggested that the “D” in DReSS should be re-examined as vaccines have also been shown to trigger DReSS. Based on the diversity of the clinical features and non-drug causes of DReSS, a further change in nomenclature may be required in the future. | Overview of Drug Reaction with Eosinophilia and Systemic Symptoms (DReSS). Summary
Drug reaction with eosinophilia and systemic symptoms (DReSS) is a rare disorder that can affect the skin, blood and any internal organs, most commonly the liver, kidney, lungs and heart. The cause of DReSS is multifactorial involving drug-exposure, genetic predisposition, viral reactivation and immune system responses. Clinical features of this condition are delayed after drug exposure, and proceed in a stepwise and variable fashion, making this syndrome challenging for both patients and physicians to recognize and diagnose. The prognosis for DReSS is highly dependent on the severity of the reaction and the speed with which diagnosis is made, the drug is discontinued and treatment is initiated. Possible outcomes of DReSS include complete recovery with no complications, illness related to end organ dysfunction, long term autoimmune disease and in rare cases, death. The mainstay treatment of DReSS is immediate withdrawal of the culprit drug, supportive treatment and immunosuppression depending on the severity of disease. Long term follow-up and slow treatment tapers are critical for preventing complications. Assessing viral reactivation is an important component in the management of the disease. Introduction
DReSS is a rare drug reaction that can affect nearly any organ in the human body. Compared to other severe drug reactions like Stevens-Johnson syndrome or toxic epidermal necrolysis (SJS and TEN), DReSS has a more varied clinical presentation making it more challenging to diagnose. The combination of the three features of fever, skin rash and elevated eosinophils (a specific type of white blood cell) has been recognized since the 1930s, but the term DReSS is more recent. As eosinophilia is not always present and other blood count changes may occur (such as low platelets or anemia), many different names have been used to define this syndrome. Originally recognized as anticonvulsant hypersensitivity syndrome, other terms have been proposed over time such as drug-induced pseudolymphoma, drug-induced delayed multiorgan hypersensitivity syndrome (DIDMOHS) and hypersensitivity syndrome. In 1996 the term DRESS (drug rash with eosinophilia and systemic symptoms) was proposed to encompass these similar reactions and differentiate them from other severe drug reactions without eosinophilia. The word “rash” in DReSS was subsequently changed to “reaction” due to its diverse skin findings. The lowercase “e” is often used to denote that eosinophilia is not always present and other blood count changes may be seen. The term DReSS became internationally recognized and gained popularity in multiple countries, although it is not used everywhere. More recently, some have suggested that the “D” in DReSS should be re-examined as vaccines have also been shown to trigger DReSS. Based on the diversity of the clinical features and non-drug causes of DReSS, a further change in nomenclature may be required in the future. | 381 | Drug Reaction with Eosinophilia and Systemic Symptoms (DReSS) |
nord_381_1 | Symptoms of Drug Reaction with Eosinophilia and Systemic Symptoms (DReSS) | DReSS most commonly begins with a flu-like prodrome of malaise, sore throat, fever and swollen lymph nodes. The lag time between drug exposure and symptom onset is typically between 2-8 weeks (although longer and shorter times have been reported). Additionally, with re-exposure to the drug symptoms can develop in just hours or days. Skin findings typically occur a few days after the flu-like illness and are varied in their presentation. Typically, more than 50% of total body surface area is involved with a symmetric distribution starting on the face, upper trunk and upper extremities. The most common rashes reported are numerous small red bumps (maculopapular or “morbilliform”), hive-like (urticated papular) and full body redness with scaling (exfoliative erythroderma). Additionally, there can be target-like lesions, eczema-like lesions, dark purple patches and plaques (purpura), or a combination of all of these. Swelling of the face is often dramatic and can be a distinguishing feature from other drug rashes. Mucosal involvement is less common and may include oral ulcers and lip erosions, crusting and inflammation. The bone marrow and blood cell counts are often affected in DReSS. Hypereosinophilia is the most common finding, followed by an elevated total white blood cell count (leukocytosis), elevated atypical lymphocytes, low lymphocytes, low white cell count and low or high platelets. Depression of all blood cell lines (pancytopenia) is associated with a more severe prognosis.Systemic features of DReSS can occur days to weeks after initial symptom onset. Hence, it is important to closely monitor the signs and symptoms of possible systemic involvement as they may occur days to weeks after the initial presentation of the rash. The liver is the internal organ most commonly impaired in DReSS, occurring in up to 97% of cases. Manifestations range from asymptomatic elevation of liver enzymes to liver failure requiring liver transplant. The next most involved organ is the kidney which can present as mild acute kidney injury or severe kidney inflammation resulting in permanent end-stage renal disease. Elderly patients, allopurinol-associated DReSS, and those with pre-existing kidney disease are at the highest risk of renal impairment. The lung is the third most frequently impaired organ, with interstitial pneumonitis (lung inflammation) being the most common manifestation. Cardiac involvement in DReSS is becoming more frequently recognized, typically presenting as inflammation of the heart muscle or the lining around the heart (myocarditis or pericarditis). Heart involvement is often delayed in DReSS, occurring an average of 70 days after initial symptom onset. The most common signs and symptoms of cardiac DReSS are shortness of breath, chest pain, low blood pressure and elevated heart rate. More infrequently there have been reports of DReSS causing inflammation in the pancreas, brain, meninges, colon, gallbladder and other organs. | Symptoms of Drug Reaction with Eosinophilia and Systemic Symptoms (DReSS). DReSS most commonly begins with a flu-like prodrome of malaise, sore throat, fever and swollen lymph nodes. The lag time between drug exposure and symptom onset is typically between 2-8 weeks (although longer and shorter times have been reported). Additionally, with re-exposure to the drug symptoms can develop in just hours or days. Skin findings typically occur a few days after the flu-like illness and are varied in their presentation. Typically, more than 50% of total body surface area is involved with a symmetric distribution starting on the face, upper trunk and upper extremities. The most common rashes reported are numerous small red bumps (maculopapular or “morbilliform”), hive-like (urticated papular) and full body redness with scaling (exfoliative erythroderma). Additionally, there can be target-like lesions, eczema-like lesions, dark purple patches and plaques (purpura), or a combination of all of these. Swelling of the face is often dramatic and can be a distinguishing feature from other drug rashes. Mucosal involvement is less common and may include oral ulcers and lip erosions, crusting and inflammation. The bone marrow and blood cell counts are often affected in DReSS. Hypereosinophilia is the most common finding, followed by an elevated total white blood cell count (leukocytosis), elevated atypical lymphocytes, low lymphocytes, low white cell count and low or high platelets. Depression of all blood cell lines (pancytopenia) is associated with a more severe prognosis.Systemic features of DReSS can occur days to weeks after initial symptom onset. Hence, it is important to closely monitor the signs and symptoms of possible systemic involvement as they may occur days to weeks after the initial presentation of the rash. The liver is the internal organ most commonly impaired in DReSS, occurring in up to 97% of cases. Manifestations range from asymptomatic elevation of liver enzymes to liver failure requiring liver transplant. The next most involved organ is the kidney which can present as mild acute kidney injury or severe kidney inflammation resulting in permanent end-stage renal disease. Elderly patients, allopurinol-associated DReSS, and those with pre-existing kidney disease are at the highest risk of renal impairment. The lung is the third most frequently impaired organ, with interstitial pneumonitis (lung inflammation) being the most common manifestation. Cardiac involvement in DReSS is becoming more frequently recognized, typically presenting as inflammation of the heart muscle or the lining around the heart (myocarditis or pericarditis). Heart involvement is often delayed in DReSS, occurring an average of 70 days after initial symptom onset. The most common signs and symptoms of cardiac DReSS are shortness of breath, chest pain, low blood pressure and elevated heart rate. More infrequently there have been reports of DReSS causing inflammation in the pancreas, brain, meninges, colon, gallbladder and other organs. | 381 | Drug Reaction with Eosinophilia and Systemic Symptoms (DReSS) |
nord_381_2 | Causes of Drug Reaction with Eosinophilia and Systemic Symptoms (DReSS) | DReSS is a hypersensitivity reaction that results from a complex interaction between drug exposure, genetic predisposition and viral reactivation. Why some develop this condition while others do not, despite the same exposure, is thought to be a result of the cumulative effect of multiple risk factors. Drugs are the clear cause of the development of DReSS syndrome. The most common DReSS-inducing drugs are anti-seizure medications, allopurinol, sulfa-containing medications (e.g., sulfamethoxazole, sulfasalazine, dapsone) and antibiotics such as rifampin, minocycline and vancomycin. Carbamazepine is the most common cause of DReSS both overall and within the anticonvulsant grouping. It is important to note that more recently vaccines and biological drugs have been shown to be capable of triggering DReSS.The relationship between viral reactivation and DReSS has been studied extensively. Despite this, there is still much controversy surrounding this topic. Viral reactivation typically occurs 2-4 weeks after symptom onset and has been associated with longer disease duration, flares and more severe outcomes. Historically, human herpes virus-6 (HHV-6) has been most associated with DReSS, although other human herpes viruses have been reported including HHV-7, cytomegalovirus (CMV), Epstein-Barr virus (EBV) and herpes simplex virus (HSV). Despite the vast amount of research on this topic, it remains unknown whether viral reactivation is a causative factor that drives disease or an unintended consequence. Today, it is advised to assess viral reactivation as part of the management of this condition.There are several well described genetic changes in the human leukocyte antigen (HLA) system that can increase a patient’s risk of DReSS. These HLA proteins are involved in how drugs are presented to the immune system. Importantly, certain high-risk HLA types are present in some ethnicities more than others, making ethnic background an important predisposing factor to DReSS. For example, Han-Chinese patients show a strong association with HLA-B*58:01 and allopurinol-induced DReSS. As a result, there is a strong recommendation to test for the HLA‐B*58:01 allele in selected subpopulations prior to the initiation of allopurinol. Similarly, multiple studies have shown association between HLA-A*31:01 and carbamazepine-induced DReSS among multiple ethnicities (most notably European, Chinese, Korean and Japanese). The Canadian Pharmacogenomics Network for Drug Safety recommends genetic testing for HLA-A*31:01 for all patients before initiation of carbamazepine therapy. There are many other well described associations between HLA alleles and particular drugs in certain ethnicities. Variants (mutations) in genes for several drug detoxification enzymes have also been linked to DReSS, providing another heritable risk factor for the development of DReSS. | Causes of Drug Reaction with Eosinophilia and Systemic Symptoms (DReSS). DReSS is a hypersensitivity reaction that results from a complex interaction between drug exposure, genetic predisposition and viral reactivation. Why some develop this condition while others do not, despite the same exposure, is thought to be a result of the cumulative effect of multiple risk factors. Drugs are the clear cause of the development of DReSS syndrome. The most common DReSS-inducing drugs are anti-seizure medications, allopurinol, sulfa-containing medications (e.g., sulfamethoxazole, sulfasalazine, dapsone) and antibiotics such as rifampin, minocycline and vancomycin. Carbamazepine is the most common cause of DReSS both overall and within the anticonvulsant grouping. It is important to note that more recently vaccines and biological drugs have been shown to be capable of triggering DReSS.The relationship between viral reactivation and DReSS has been studied extensively. Despite this, there is still much controversy surrounding this topic. Viral reactivation typically occurs 2-4 weeks after symptom onset and has been associated with longer disease duration, flares and more severe outcomes. Historically, human herpes virus-6 (HHV-6) has been most associated with DReSS, although other human herpes viruses have been reported including HHV-7, cytomegalovirus (CMV), Epstein-Barr virus (EBV) and herpes simplex virus (HSV). Despite the vast amount of research on this topic, it remains unknown whether viral reactivation is a causative factor that drives disease or an unintended consequence. Today, it is advised to assess viral reactivation as part of the management of this condition.There are several well described genetic changes in the human leukocyte antigen (HLA) system that can increase a patient’s risk of DReSS. These HLA proteins are involved in how drugs are presented to the immune system. Importantly, certain high-risk HLA types are present in some ethnicities more than others, making ethnic background an important predisposing factor to DReSS. For example, Han-Chinese patients show a strong association with HLA-B*58:01 and allopurinol-induced DReSS. As a result, there is a strong recommendation to test for the HLA‐B*58:01 allele in selected subpopulations prior to the initiation of allopurinol. Similarly, multiple studies have shown association between HLA-A*31:01 and carbamazepine-induced DReSS among multiple ethnicities (most notably European, Chinese, Korean and Japanese). The Canadian Pharmacogenomics Network for Drug Safety recommends genetic testing for HLA-A*31:01 for all patients before initiation of carbamazepine therapy. There are many other well described associations between HLA alleles and particular drugs in certain ethnicities. Variants (mutations) in genes for several drug detoxification enzymes have also been linked to DReSS, providing another heritable risk factor for the development of DReSS. | 381 | Drug Reaction with Eosinophilia and Systemic Symptoms (DReSS) |
nord_381_3 | Affects of Drug Reaction with Eosinophilia and Systemic Symptoms (DReSS) | While DReSS does occur in children, it is predominantly seen in adults with a mean age of onset between 40 and 60 years old. Female patients tend to be significantly younger than their male counterparts, and while several studies have found a slight female predominance in DReSS, many more have not replicated this finding. There is significant association between ethnic background and DReSS, with an abundance of research showing HLA alleles being a strong risk factor with exposure to certain drugs. Specific ethnicities at risk include Han-Chinese, Korean, Thai and Europeans with allopurinol exposure, the Chinese with dapsone, and European, Chinese, Korean and Japanese groups with carbamazepine.Incidence rates of DReSS range from 3.89 per 10,000 inpatients in Spain, to 0.9 per 100,000 people in a West Indian population. Prevalence estimates include 2.18 per 100,000 in the US and 9.63 cases per 100,000 inpatients in Thailand. | Affects of Drug Reaction with Eosinophilia and Systemic Symptoms (DReSS). While DReSS does occur in children, it is predominantly seen in adults with a mean age of onset between 40 and 60 years old. Female patients tend to be significantly younger than their male counterparts, and while several studies have found a slight female predominance in DReSS, many more have not replicated this finding. There is significant association between ethnic background and DReSS, with an abundance of research showing HLA alleles being a strong risk factor with exposure to certain drugs. Specific ethnicities at risk include Han-Chinese, Korean, Thai and Europeans with allopurinol exposure, the Chinese with dapsone, and European, Chinese, Korean and Japanese groups with carbamazepine.Incidence rates of DReSS range from 3.89 per 10,000 inpatients in Spain, to 0.9 per 100,000 people in a West Indian population. Prevalence estimates include 2.18 per 100,000 in the US and 9.63 cases per 100,000 inpatients in Thailand. | 381 | Drug Reaction with Eosinophilia and Systemic Symptoms (DReSS) |
nord_381_4 | Related disorders of Drug Reaction with Eosinophilia and Systemic Symptoms (DReSS) | There are many conditions that mimic DReSS, including viral infections (EBV, SARS-CoV-2, CMV, and HIV), sepsis, toxic shock syndrome, Kawasaki’s Disease, Still’s disease, lymphoma, mycosis fungoides, hypereosinophilic syndromes, connective tissue diseases, hemophagocytic syndrome and angioimmunoblastic lymphadenopathy. Simple maculopapular exanthem (MPE) has similar symptoms but is distinguished based on the degree of systemic involvement. MPE is a drug-induced hypersensitivity reaction characterized by an acute and generalized eruption of erythematous macules and papules often without overlying scale. It typically occurs 5-7 days after drug exposure, compared to the lengthy lag time seen in DReSS. Furthermore, there is no fever, flu-like prodrome or internal organ involvement in MPE. Compared to DReSS, the systemic symptoms of Stevens-Johnson syndrome/toxic epidermal necrosis (SJS/TEN), often in the liver or lung, are less frequent and often milder. Furthermore, the skin findings are typically more severe with skin necrosis, extensive sloughing, and severe ulcerative mucosal disease involving the mouth, nose, eyes, genitals and urethra. Blistering in DReSS can occur from excessive fluid in the skin due to inflammation, but the blisters are typically tense compared to the flaccid blisters of SJS/TEN.Acute generalized exanthematous pustulosis (AGEP) is characterized by multiple pinpoint pustules often in the folded areas like the armpits and groin. While DReSS may also show pustules, it lacks predilection for the folds and is often not the dominantfeature. Additionally, AGEP typically occurs within 48 hours after drug exposure and resolves within a few weeks. DReSS typically takes many weeks and even months for lab markers to return completely back to baseline. | Related disorders of Drug Reaction with Eosinophilia and Systemic Symptoms (DReSS). There are many conditions that mimic DReSS, including viral infections (EBV, SARS-CoV-2, CMV, and HIV), sepsis, toxic shock syndrome, Kawasaki’s Disease, Still’s disease, lymphoma, mycosis fungoides, hypereosinophilic syndromes, connective tissue diseases, hemophagocytic syndrome and angioimmunoblastic lymphadenopathy. Simple maculopapular exanthem (MPE) has similar symptoms but is distinguished based on the degree of systemic involvement. MPE is a drug-induced hypersensitivity reaction characterized by an acute and generalized eruption of erythematous macules and papules often without overlying scale. It typically occurs 5-7 days after drug exposure, compared to the lengthy lag time seen in DReSS. Furthermore, there is no fever, flu-like prodrome or internal organ involvement in MPE. Compared to DReSS, the systemic symptoms of Stevens-Johnson syndrome/toxic epidermal necrosis (SJS/TEN), often in the liver or lung, are less frequent and often milder. Furthermore, the skin findings are typically more severe with skin necrosis, extensive sloughing, and severe ulcerative mucosal disease involving the mouth, nose, eyes, genitals and urethra. Blistering in DReSS can occur from excessive fluid in the skin due to inflammation, but the blisters are typically tense compared to the flaccid blisters of SJS/TEN.Acute generalized exanthematous pustulosis (AGEP) is characterized by multiple pinpoint pustules often in the folded areas like the armpits and groin. While DReSS may also show pustules, it lacks predilection for the folds and is often not the dominantfeature. Additionally, AGEP typically occurs within 48 hours after drug exposure and resolves within a few weeks. DReSS typically takes many weeks and even months for lab markers to return completely back to baseline. | 381 | Drug Reaction with Eosinophilia and Systemic Symptoms (DReSS) |
nord_381_5 | Diagnosis of Drug Reaction with Eosinophilia and Systemic Symptoms (DReSS) | The diagnosis of DReSS is clinical. There are two sets of diagnostic criteria that currently exist: The RegiSCAR criteria (Kardaun et al. 2007) and The Japanese Consensus Group criteria (Shiohara et al. 2007). For the RegiSCAR criteria, a score of 5 or higher denotes probable DReSS. For the Japanese Consensus Group criteria all seven criteria are required for a diagnosis of typical DIHS.RegiSCAR criteria:
• Fever
• Enlarged lymph nodes
• Elevated eosinophils
• Atypical lymphocytes
• Skin rash over 50% BSA, clinically and on histologically consistent with DReSS
• Internal organ involvement
• Resolution ≥ 15 days
• Evaluation of other causes negative (ANA, blood culture, serology for hepatitis A/hepatitis B/hepatitis C, chlamydia, Mycoplasma pneumoniae)Japanese Consensus Group criteria:
• Maculopapular rash >3 weeks following administration of drug
• Prolonged clinical symptoms after discontinuation of the causative drug
• Fever
• Liver abnormalities or other organ involvement
• White blood cell abnormalities
• Enlarged lymph nodes
• HHV-6 reactivation | Diagnosis of Drug Reaction with Eosinophilia and Systemic Symptoms (DReSS). The diagnosis of DReSS is clinical. There are two sets of diagnostic criteria that currently exist: The RegiSCAR criteria (Kardaun et al. 2007) and The Japanese Consensus Group criteria (Shiohara et al. 2007). For the RegiSCAR criteria, a score of 5 or higher denotes probable DReSS. For the Japanese Consensus Group criteria all seven criteria are required for a diagnosis of typical DIHS.RegiSCAR criteria:
• Fever
• Enlarged lymph nodes
• Elevated eosinophils
• Atypical lymphocytes
• Skin rash over 50% BSA, clinically and on histologically consistent with DReSS
• Internal organ involvement
• Resolution ≥ 15 days
• Evaluation of other causes negative (ANA, blood culture, serology for hepatitis A/hepatitis B/hepatitis C, chlamydia, Mycoplasma pneumoniae)Japanese Consensus Group criteria:
• Maculopapular rash >3 weeks following administration of drug
• Prolonged clinical symptoms after discontinuation of the causative drug
• Fever
• Liver abnormalities or other organ involvement
• White blood cell abnormalities
• Enlarged lymph nodes
• HHV-6 reactivation | 381 | Drug Reaction with Eosinophilia and Systemic Symptoms (DReSS) |
nord_381_6 | Therapies of Drug Reaction with Eosinophilia and Systemic Symptoms (DReSS) | The mainstay treatment of DReSS remains systemic steroids alongside identification and immediate withdrawal the culprit drug. All patients should be hospitalized, at least in the initial phase, to monitor for delayed systemic involvement and response to treatment. It should be clearly communicated to the patient that the causative drug needs to be avoided indefinitely. In non-serious DReSS with no systemic involvement or only stage I drug-induced liver injury or stage I kidney injury, high potency topical steroids alone may suffice. For DReSS with more severe organ involvement, oral prednisone at a dose ranging from 0.5-1 mg/kg/day is suggested with a gradual taper over 4-6 weeks, or longer. If a relapse occurs during steroid tapering, a more gradual taper is suggested or use of steroid-sparing agents. If control is not obtained with steroids, cyclosporine or alternative immunosuppressants, less evidence-based therapies such as intravenous immunoglobulin (IVIG), plasmapheresis or cyclophosphamide can be used. In cases of viral reactivation, anti-viral treatment is recommended. | Therapies of Drug Reaction with Eosinophilia and Systemic Symptoms (DReSS). The mainstay treatment of DReSS remains systemic steroids alongside identification and immediate withdrawal the culprit drug. All patients should be hospitalized, at least in the initial phase, to monitor for delayed systemic involvement and response to treatment. It should be clearly communicated to the patient that the causative drug needs to be avoided indefinitely. In non-serious DReSS with no systemic involvement or only stage I drug-induced liver injury or stage I kidney injury, high potency topical steroids alone may suffice. For DReSS with more severe organ involvement, oral prednisone at a dose ranging from 0.5-1 mg/kg/day is suggested with a gradual taper over 4-6 weeks, or longer. If a relapse occurs during steroid tapering, a more gradual taper is suggested or use of steroid-sparing agents. If control is not obtained with steroids, cyclosporine or alternative immunosuppressants, less evidence-based therapies such as intravenous immunoglobulin (IVIG), plasmapheresis or cyclophosphamide can be used. In cases of viral reactivation, anti-viral treatment is recommended. | 381 | Drug Reaction with Eosinophilia and Systemic Symptoms (DReSS) |
nord_382_0 | Overview of Duane syndrome | Duane syndrome (DS) is an eye movement disorder present at birth (congenital) characterized by horizontal eye movement limitation: a limited ability to move the eye inward toward the nose (adduction), outward toward the ear (abduction), or in both directions. When the affected eye(s) moves inward toward the nose, the eyeball retracts (pulls in) and the eye opening (palpebral fissure) narrows. In some patients, when the eye attempts to look inward, it moves upward (upshoot) or downward (downshoot).Duane syndrome falls under the larger heading of strabismus (misalignment of the eyes) under the sub-classification of incomitant strabismus (misalignment of the eyes that varies with gaze directions) and subheading of what was previously termed extraocular fibrosis syndromes (conditions associated with fibrosis of the muscles that move the eyes), now termed congenital cranial dysinnervation disorders (CCDDs). The CCDDs are a group of congenital neuromuscular diseases resulting from developmental errors in innervation; the abnormalities involve one or more cranial nerves/nuclei with absence of normal innervation and/or secondary aberrant innervation. The group includes Duane syndrome, congenital fibrosis of the extraocular muscles (CFEOM), congenital ptosis, Marcus Gunn jaw winking, Möbius syndrome, crocodile tears, horizontal gaze palsy and congenital facial palsy, but this is not an exhaustive list. Duane syndrome has been subdivided clinically into three types: type 1, type 2, and type 3. | Overview of Duane syndrome. Duane syndrome (DS) is an eye movement disorder present at birth (congenital) characterized by horizontal eye movement limitation: a limited ability to move the eye inward toward the nose (adduction), outward toward the ear (abduction), or in both directions. When the affected eye(s) moves inward toward the nose, the eyeball retracts (pulls in) and the eye opening (palpebral fissure) narrows. In some patients, when the eye attempts to look inward, it moves upward (upshoot) or downward (downshoot).Duane syndrome falls under the larger heading of strabismus (misalignment of the eyes) under the sub-classification of incomitant strabismus (misalignment of the eyes that varies with gaze directions) and subheading of what was previously termed extraocular fibrosis syndromes (conditions associated with fibrosis of the muscles that move the eyes), now termed congenital cranial dysinnervation disorders (CCDDs). The CCDDs are a group of congenital neuromuscular diseases resulting from developmental errors in innervation; the abnormalities involve one or more cranial nerves/nuclei with absence of normal innervation and/or secondary aberrant innervation. The group includes Duane syndrome, congenital fibrosis of the extraocular muscles (CFEOM), congenital ptosis, Marcus Gunn jaw winking, Möbius syndrome, crocodile tears, horizontal gaze palsy and congenital facial palsy, but this is not an exhaustive list. Duane syndrome has been subdivided clinically into three types: type 1, type 2, and type 3. | 382 | Duane syndrome |
nord_382_1 | Symptoms of Duane syndrome | The three types of Duane syndrome present as follows:Duane syndrome type 1: The ability to move the affected eye(s) outward toward the ear (abduction) is limited, but the ability to move the affected eye(s) inward toward the nose (adduction) is normal or nearly so. The eye opening (palpebral fissure) narrows and the eyeball retracts into the orbit when looking inward toward the nose (adduction). When looking outward toward the ear (abduction), the reverse occurs.Duane syndrome type 2: The ability to move the affected eye(s) inward toward the nose (adduction) is limited, whereas the ability to move the eye outward (abduction) is normal or only slightly limited. The eye opening (palpebral fissure) narrows and the eyeball retracts into the orbit when the affected eye(s) attempts to look inward toward the nose (adduction).Duane syndrome type 3: The ability to move the affected eye(s) both inward toward the nose (adduction) and outward toward the ear (abduction) is limited. The eye opening narrows and the eyeball retracts when the affected eye(s) attempts to look inward toward the nose (adduction).Each of these three types has been further classified into three subgroups designated A, B, and C to describe the eyes when looking straight (in primary gaze). In subgroup A, the affected eye is turned inward toward the nose (esotropia). In subgroup B, the affected eye is turned outward toward the ear (exotropia), and in subgroup C, the eyes are in a straight primary position.Different clinical types may be present within the same family, suggesting that the same genetic defect may produce a range of clinical presentations.The most common clinical presentation is type 1 DS (78% of cases) followed by type 3 (15%) and type 2 (7%). Involvement of both eyes (bilateral) is less common than involvement of one eye only (unilateral). Approximately 80-90% of cases are unilateral. Of the unilateral cases, the left eye is more often affected (72%). Amblyopia (reduced visual acuity in an eye) due to a lack of binocular vision occurs in about 10% of DS cases and is more common in familial autosomal dominant CHN1 gene familial cases.Duane syndrome is usually an isolated finding (approximately 70%), but may be associated with other malformations. Major anomalies associated with DS can be grouped into five categories: skeletal, auricular (having to do with the ears), ocular (having to do with the eyes) and neural (having to do with the nervous system) and renal (having to do with the kidneys and urinary tract).DS can also be associated with other well-defined syndromes. These include Okihiro’s, Wildervanck, Holt-Oram, Goldenhar and Möbius syndromes. | Symptoms of Duane syndrome. The three types of Duane syndrome present as follows:Duane syndrome type 1: The ability to move the affected eye(s) outward toward the ear (abduction) is limited, but the ability to move the affected eye(s) inward toward the nose (adduction) is normal or nearly so. The eye opening (palpebral fissure) narrows and the eyeball retracts into the orbit when looking inward toward the nose (adduction). When looking outward toward the ear (abduction), the reverse occurs.Duane syndrome type 2: The ability to move the affected eye(s) inward toward the nose (adduction) is limited, whereas the ability to move the eye outward (abduction) is normal or only slightly limited. The eye opening (palpebral fissure) narrows and the eyeball retracts into the orbit when the affected eye(s) attempts to look inward toward the nose (adduction).Duane syndrome type 3: The ability to move the affected eye(s) both inward toward the nose (adduction) and outward toward the ear (abduction) is limited. The eye opening narrows and the eyeball retracts when the affected eye(s) attempts to look inward toward the nose (adduction).Each of these three types has been further classified into three subgroups designated A, B, and C to describe the eyes when looking straight (in primary gaze). In subgroup A, the affected eye is turned inward toward the nose (esotropia). In subgroup B, the affected eye is turned outward toward the ear (exotropia), and in subgroup C, the eyes are in a straight primary position.Different clinical types may be present within the same family, suggesting that the same genetic defect may produce a range of clinical presentations.The most common clinical presentation is type 1 DS (78% of cases) followed by type 3 (15%) and type 2 (7%). Involvement of both eyes (bilateral) is less common than involvement of one eye only (unilateral). Approximately 80-90% of cases are unilateral. Of the unilateral cases, the left eye is more often affected (72%). Amblyopia (reduced visual acuity in an eye) due to a lack of binocular vision occurs in about 10% of DS cases and is more common in familial autosomal dominant CHN1 gene familial cases.Duane syndrome is usually an isolated finding (approximately 70%), but may be associated with other malformations. Major anomalies associated with DS can be grouped into five categories: skeletal, auricular (having to do with the ears), ocular (having to do with the eyes) and neural (having to do with the nervous system) and renal (having to do with the kidneys and urinary tract).DS can also be associated with other well-defined syndromes. These include Okihiro’s, Wildervanck, Holt-Oram, Goldenhar and Möbius syndromes. | 382 | Duane syndrome |
nord_382_2 | Causes of Duane syndrome | The majority of Duane syndrome cases are sporadic in origin, with only approximately 10% of patients showing a familial pattern (running in families). Both dominant (most common) and recessive forms of DS have been documented. In some families with dominant DS, it has skipped a generation (shown reduced penetrance) and ranged in severity within the same family (shown variable expressivity). Most familial cases are not associated with other anomalies.Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females. DS is a congenital cranial dysinnervation disorder (CCDD). Genetic, and possibly environmental factors, are known to play a role.Data to support abnormal development of cranial nerve VI (abducens nerve) in DS come from neuropathological, neuroradiological and neurophysiological evidence. Neuropathological evidence comes from autopsies of individuals with DS. These autopsies show abnormal innervation of the lateral rectus muscle (the muscle that moves the eye outward toward the ear) and an absence / failure to develop normally of the abducens nerve (cranial nerve VI) which normally supplies the lateral rectus muscle. In place of the abducens nerve is a nerve branch from the oculomotor nerve (cranial nerve III) which normally supplies other ocular muscles. Recent neuroradiological studies in DS support the postmortem findings and also show, by magnetic resonance imaging (MRI) studies, an absence / failure to develop normally of the abducens nerve (cranial nerve VI).Neurophysiological evidence for neuronal involvement in DS comes from electromyographic (EMG) studies which show that the medial and lateral recti muscles are electrically active in individuals with DS. When individuals with DS attempt to move their eyes inward, both of these muscles contract at the same time, resulting in the eyeball retracting inward (pulling in) and the eye opening narrowing.In familial DS cases both eyes are more likely to be affected. DS type 2 is not seen in those with a positive family history nor in those patients where mutations in genes have been found to cause DS; suggesting a different cause.Genetic linkage studies of two large DS families (with affected members having type 1 and/or type 3 DS inherited autosomal dominantly) without associated abnormalities established the location of a DS gene on chromosome 2. Mutations in the CHN1 gene are the cause, hyperactivating the a2-chimaerin protein. Mutations in the CHN1 gene have also been found in other families.Autosomal dominant DS can also be due to mutations in the MAFB gene on chromosome 20, either as a loss of function or as a dominant negative mutation causing deafness and DS. The combination of focal segmental glomerulosclerosis (FSGS), DS and deafness has been shown to be due to a rare MAFB mutation.A genetic cause for individuals with DRRS (Duane radial ray syndrome; Okihiro syndrome), that is Duane syndrome (unilateral or bilateral) with a skeletal change of radial dysplasia (unilateral or bilateral) ranging from most commonly thumb hypoplasia to most severely a phocomelic limb (similar to that seen in thalidomide cases), has been found. Other features include deafness, renal and ocular manifestations. Inheritance is autosomal dominant. Truncating mutations and SALL4 gene deletions have been identified in DRRS families and there is haploinsufficiency (the level of the protein is not sufficient for normal functioning). No SALL4 gene mutations were found in 25 sporadic cases of isolated DS.DS can also be found as part of a complex autosomal recessive disorder that can include deafness, facial weakness, vascular malformations and learning difficulties due to two mutations in the HOXA1 gene.DS is also associated with mutations in the CDH2 gene which encodes for the N-cadherin protein. These mutations cause a syndromic neurodevelopmental disorder with global developmental delay and/or intellectual disability, axonal pathfinding defects including corpus callosum agenesis or hypoplasia, associated with ocular, cardiac and genital anomalies.Cytogenetic results (a study of chromosomes) of individuals with Duane syndrome and other abnormalities have, in rare cases, shown abnormalities that suggest other locations for genes responsible for causing DS. Deletions of chromosomal material on chromosomes 1, 4, 5 and 8, and the presence of an extra marker chromosome thought to be derived from chromosome 22, have been documented in DS individuals. In addition, DS has been reported with chromosomal duplications.Given the evidence that DS results from an absence / failure to develop normally of the abducens nerve (cranial nerve VI) and aberrant innervation, and that DS is associated with other anomalies in some patients, it is thought that DS results from a disturbance of normal embryonic development by either a genetic or an environmental factor at the time when the cranial nerves and ocular muscles are developing (between the third and sixth week of pregnancy). | Causes of Duane syndrome. The majority of Duane syndrome cases are sporadic in origin, with only approximately 10% of patients showing a familial pattern (running in families). Both dominant (most common) and recessive forms of DS have been documented. In some families with dominant DS, it has skipped a generation (shown reduced penetrance) and ranged in severity within the same family (shown variable expressivity). Most familial cases are not associated with other anomalies.Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females. DS is a congenital cranial dysinnervation disorder (CCDD). Genetic, and possibly environmental factors, are known to play a role.Data to support abnormal development of cranial nerve VI (abducens nerve) in DS come from neuropathological, neuroradiological and neurophysiological evidence. Neuropathological evidence comes from autopsies of individuals with DS. These autopsies show abnormal innervation of the lateral rectus muscle (the muscle that moves the eye outward toward the ear) and an absence / failure to develop normally of the abducens nerve (cranial nerve VI) which normally supplies the lateral rectus muscle. In place of the abducens nerve is a nerve branch from the oculomotor nerve (cranial nerve III) which normally supplies other ocular muscles. Recent neuroradiological studies in DS support the postmortem findings and also show, by magnetic resonance imaging (MRI) studies, an absence / failure to develop normally of the abducens nerve (cranial nerve VI).Neurophysiological evidence for neuronal involvement in DS comes from electromyographic (EMG) studies which show that the medial and lateral recti muscles are electrically active in individuals with DS. When individuals with DS attempt to move their eyes inward, both of these muscles contract at the same time, resulting in the eyeball retracting inward (pulling in) and the eye opening narrowing.In familial DS cases both eyes are more likely to be affected. DS type 2 is not seen in those with a positive family history nor in those patients where mutations in genes have been found to cause DS; suggesting a different cause.Genetic linkage studies of two large DS families (with affected members having type 1 and/or type 3 DS inherited autosomal dominantly) without associated abnormalities established the location of a DS gene on chromosome 2. Mutations in the CHN1 gene are the cause, hyperactivating the a2-chimaerin protein. Mutations in the CHN1 gene have also been found in other families.Autosomal dominant DS can also be due to mutations in the MAFB gene on chromosome 20, either as a loss of function or as a dominant negative mutation causing deafness and DS. The combination of focal segmental glomerulosclerosis (FSGS), DS and deafness has been shown to be due to a rare MAFB mutation.A genetic cause for individuals with DRRS (Duane radial ray syndrome; Okihiro syndrome), that is Duane syndrome (unilateral or bilateral) with a skeletal change of radial dysplasia (unilateral or bilateral) ranging from most commonly thumb hypoplasia to most severely a phocomelic limb (similar to that seen in thalidomide cases), has been found. Other features include deafness, renal and ocular manifestations. Inheritance is autosomal dominant. Truncating mutations and SALL4 gene deletions have been identified in DRRS families and there is haploinsufficiency (the level of the protein is not sufficient for normal functioning). No SALL4 gene mutations were found in 25 sporadic cases of isolated DS.DS can also be found as part of a complex autosomal recessive disorder that can include deafness, facial weakness, vascular malformations and learning difficulties due to two mutations in the HOXA1 gene.DS is also associated with mutations in the CDH2 gene which encodes for the N-cadherin protein. These mutations cause a syndromic neurodevelopmental disorder with global developmental delay and/or intellectual disability, axonal pathfinding defects including corpus callosum agenesis or hypoplasia, associated with ocular, cardiac and genital anomalies.Cytogenetic results (a study of chromosomes) of individuals with Duane syndrome and other abnormalities have, in rare cases, shown abnormalities that suggest other locations for genes responsible for causing DS. Deletions of chromosomal material on chromosomes 1, 4, 5 and 8, and the presence of an extra marker chromosome thought to be derived from chromosome 22, have been documented in DS individuals. In addition, DS has been reported with chromosomal duplications.Given the evidence that DS results from an absence / failure to develop normally of the abducens nerve (cranial nerve VI) and aberrant innervation, and that DS is associated with other anomalies in some patients, it is thought that DS results from a disturbance of normal embryonic development by either a genetic or an environmental factor at the time when the cranial nerves and ocular muscles are developing (between the third and sixth week of pregnancy). | 382 | Duane syndrome |
nord_382_3 | Affects of Duane syndrome | Duane syndrome has been seen in diverse ethnic groups. The frequency of DS in the general population of individuals with eye movement disorders (strabismus) is approximately 1-5%. Most individuals are diagnosed by the age of 10 years. The female to male ratio of individuals with DS is approximately 60:40, showing a slightly higher preponderance of female patients. | Affects of Duane syndrome. Duane syndrome has been seen in diverse ethnic groups. The frequency of DS in the general population of individuals with eye movement disorders (strabismus) is approximately 1-5%. Most individuals are diagnosed by the age of 10 years. The female to male ratio of individuals with DS is approximately 60:40, showing a slightly higher preponderance of female patients. | 382 | Duane syndrome |
nord_382_4 | Related disorders of Duane syndrome | Strabismus is a large category of eye movement disorders in which the eyes are not properly yoked together, and one or both eyes are misaligned and cannot be voluntarily controlled. Strabismus is either concomitant or incomitant. Concomitant strabismus occurs when the misalignment or the angle of deviation between the two eyes remains constant and independent of the direction of gaze. Strabismus is incomitant when the misalignment or the angle of deviation varies with gaze direction. Extraoccular (outside of the eye) fibrosis syndromes are grouped under incomitant strabismus and include Duane syndrome, Brown syndrome, and the congenital fibrosis of the extraocular muscles (CFEOM) syndromes. There are many cases of strabismus and treatments can include surgery and eye patching. Strabismus may be an isolated finding or found in association with other birth defects.Brown syndrome is an incomitant strabismus condition that falls under the heading of extraocular fibrosis syndromes. It presents as an eye movement disorder in which an individual’s affected eye is unable to look inward toward the nose and up. The affected eye may be out of alignment with the unaffected eye and may show a downshoot and/or a widening of the eye opening when looking inward and up. When looking straight, the affected eye may be downward. (For more information on this disorder, choose “Brown” as your search term in the Rare Disease Database.)Congenital fibrosis of the extraocular muscles (CFEOM) refers to a group of congenital, nonprogressive eye movement disorders that fall under the subheading of extraocular fibrosis syndromes and the larger heading of incomitant strabismic disorders. The classic CFEOM presentation includes bilateral ptosis (droopy eyelids) with the eyes in a downward position (CFEOM type 1). Affected eyes have variable ability (from none to normal) to move horizontally and a complete inability to move above the horizontal midline. Individuals compensate by tilting their heads backward with the chin elevated in order to see. In some families, an affected individuals’ presentation can range from very mild to the classic presentation described above. CFEOM can be sporadic, or inherited in either an autosomal dominant or recessive fashion. Family linkage studies have identified regions containing a gene for CFEOM on chromosomes 11, 12, and 16. CFEOM type 1 is inherited autosomal dominantly is most commonly due to mutations in the KIF21A gene on chromosome 12. The rarer CFEOM type 2 is inherited autosomal recessively and is due to mutations in the PHOX2A gene on chromosome 11. CFEOM type 3 has a variable asymmetric presentation where at least one affected family member does not meet CFEOM1 criteria. It is inherited autosomal dominantly and is most commonly due to mutations in the TUBB3 gene on chromosome 16. Autopsy information has shown an absence of the superior division of the oculomotor nerve (cranial nerve III) in one patient with classic CFEOM type 1, suggesting an innervational (nerve) cause rather than a myogenic (muscle) problem. (For more information on these disorders, choose “Congenital Fibrosis of the Extraocular Muscles” as your search term in the Rare Disease Database). | Related disorders of Duane syndrome. Strabismus is a large category of eye movement disorders in which the eyes are not properly yoked together, and one or both eyes are misaligned and cannot be voluntarily controlled. Strabismus is either concomitant or incomitant. Concomitant strabismus occurs when the misalignment or the angle of deviation between the two eyes remains constant and independent of the direction of gaze. Strabismus is incomitant when the misalignment or the angle of deviation varies with gaze direction. Extraoccular (outside of the eye) fibrosis syndromes are grouped under incomitant strabismus and include Duane syndrome, Brown syndrome, and the congenital fibrosis of the extraocular muscles (CFEOM) syndromes. There are many cases of strabismus and treatments can include surgery and eye patching. Strabismus may be an isolated finding or found in association with other birth defects.Brown syndrome is an incomitant strabismus condition that falls under the heading of extraocular fibrosis syndromes. It presents as an eye movement disorder in which an individual’s affected eye is unable to look inward toward the nose and up. The affected eye may be out of alignment with the unaffected eye and may show a downshoot and/or a widening of the eye opening when looking inward and up. When looking straight, the affected eye may be downward. (For more information on this disorder, choose “Brown” as your search term in the Rare Disease Database.)Congenital fibrosis of the extraocular muscles (CFEOM) refers to a group of congenital, nonprogressive eye movement disorders that fall under the subheading of extraocular fibrosis syndromes and the larger heading of incomitant strabismic disorders. The classic CFEOM presentation includes bilateral ptosis (droopy eyelids) with the eyes in a downward position (CFEOM type 1). Affected eyes have variable ability (from none to normal) to move horizontally and a complete inability to move above the horizontal midline. Individuals compensate by tilting their heads backward with the chin elevated in order to see. In some families, an affected individuals’ presentation can range from very mild to the classic presentation described above. CFEOM can be sporadic, or inherited in either an autosomal dominant or recessive fashion. Family linkage studies have identified regions containing a gene for CFEOM on chromosomes 11, 12, and 16. CFEOM type 1 is inherited autosomal dominantly is most commonly due to mutations in the KIF21A gene on chromosome 12. The rarer CFEOM type 2 is inherited autosomal recessively and is due to mutations in the PHOX2A gene on chromosome 11. CFEOM type 3 has a variable asymmetric presentation where at least one affected family member does not meet CFEOM1 criteria. It is inherited autosomal dominantly and is most commonly due to mutations in the TUBB3 gene on chromosome 16. Autopsy information has shown an absence of the superior division of the oculomotor nerve (cranial nerve III) in one patient with classic CFEOM type 1, suggesting an innervational (nerve) cause rather than a myogenic (muscle) problem. (For more information on these disorders, choose “Congenital Fibrosis of the Extraocular Muscles” as your search term in the Rare Disease Database). | 382 | Duane syndrome |
nord_382_5 | Diagnosis of Duane syndrome | When the presence of DS is suspected, a thorough ocular (eye) examination is required, with special attention to the presence of other ocular or systemic malformations. Measurements of the ocular misalignment, ocular range of motion, head turn, globe (eyeball) retraction, palpebral fissure (eye opening) size, upshoots and downshoots and visual acuity are indicated. In addition, an examination of the cervical (neck) and thoracic (chest) spine, palate (roof of mouth), vertebrae, hands, and a hearing test is recommended to rule out disorders associated with DS. | Diagnosis of Duane syndrome. When the presence of DS is suspected, a thorough ocular (eye) examination is required, with special attention to the presence of other ocular or systemic malformations. Measurements of the ocular misalignment, ocular range of motion, head turn, globe (eyeball) retraction, palpebral fissure (eye opening) size, upshoots and downshoots and visual acuity are indicated. In addition, an examination of the cervical (neck) and thoracic (chest) spine, palate (roof of mouth), vertebrae, hands, and a hearing test is recommended to rule out disorders associated with DS. | 382 | Duane syndrome |
nord_382_6 | Therapies of Duane syndrome | Treatment
The standard management of Duane syndrome may involve observation, treatment of amblyopia (such as patching of the better seeing eye) or possibly surgery. The goal of surgery is the elimination or improvement of an unacceptable head turn, the elimination or reduction of significant misalignment of the eyes, the reduction of severe retraction, and the improvement of upshoots and downshoots. Surgery does not eliminate the fundamental abnormality of innervation and no surgical technique has been completely successful in eliminating the abnormal eye movements. Simple horizontal muscle recession procedures, vertical rectus muscle transposition procedures, or combinations of the two may be successful in improving or eliminating head turns and misalignment of the eyes. The choice of procedure must be individualized. | Therapies of Duane syndrome. Treatment
The standard management of Duane syndrome may involve observation, treatment of amblyopia (such as patching of the better seeing eye) or possibly surgery. The goal of surgery is the elimination or improvement of an unacceptable head turn, the elimination or reduction of significant misalignment of the eyes, the reduction of severe retraction, and the improvement of upshoots and downshoots. Surgery does not eliminate the fundamental abnormality of innervation and no surgical technique has been completely successful in eliminating the abnormal eye movements. Simple horizontal muscle recession procedures, vertical rectus muscle transposition procedures, or combinations of the two may be successful in improving or eliminating head turns and misalignment of the eyes. The choice of procedure must be individualized. | 382 | Duane syndrome |
nord_383_0 | Overview of Dubin Johnson Syndrome | Summary Dubin Johnson syndrome (DJS) is a rare, benign genetic liver disorder. It is inherited in an autosomal recessive pattern and is characterized by buildup of bilirubin, which is normally excreted by the liver into the bile. DJS is caused by a defect (gene mutation) in the transporter protein that is responsible for moving the bilirubin, a normal breakdown product of red blood cells, into the bile which then leaves the body through the stool. It is a rare entity that is most often seen in Middle Eastern Jewish and Japanese people. In the Jewish population, about 60% of affected individuals also have an associated blood clotting abnormality, a prolonged prothrombin time (PT), caused by a decrease in factor VII. Most patients are asymptomatic and the other tests that are routinely used to measure liver function are normal. At times there can be jaundice, a yellowish color of the white portion of the eyes, and rarely a slightly enlarged and tender liver. A characteristic aspect of DJS (which is actually unknown to the patient) is that the retained bilirubin pigment gives the liver a unique black color. Onset usually occurs during puberty or adulthood, but it has rarely been described in the newborn period. Use of alcohol, birth control pills, infection, and pregnancy can lead to an increase in jaundice. In almost all cases, the most important aspect of DJS is recognizing that there is not a more serious cause of the jaundice. | Overview of Dubin Johnson Syndrome. Summary Dubin Johnson syndrome (DJS) is a rare, benign genetic liver disorder. It is inherited in an autosomal recessive pattern and is characterized by buildup of bilirubin, which is normally excreted by the liver into the bile. DJS is caused by a defect (gene mutation) in the transporter protein that is responsible for moving the bilirubin, a normal breakdown product of red blood cells, into the bile which then leaves the body through the stool. It is a rare entity that is most often seen in Middle Eastern Jewish and Japanese people. In the Jewish population, about 60% of affected individuals also have an associated blood clotting abnormality, a prolonged prothrombin time (PT), caused by a decrease in factor VII. Most patients are asymptomatic and the other tests that are routinely used to measure liver function are normal. At times there can be jaundice, a yellowish color of the white portion of the eyes, and rarely a slightly enlarged and tender liver. A characteristic aspect of DJS (which is actually unknown to the patient) is that the retained bilirubin pigment gives the liver a unique black color. Onset usually occurs during puberty or adulthood, but it has rarely been described in the newborn period. Use of alcohol, birth control pills, infection, and pregnancy can lead to an increase in jaundice. In almost all cases, the most important aspect of DJS is recognizing that there is not a more serious cause of the jaundice. | 383 | Dubin Johnson Syndrome |
nord_383_1 | Symptoms of Dubin Johnson Syndrome | Approximately 80% to 99% of people with DJS have intermittent jaundice caused by excess bilirubin (bile pigment) that cannot be excreted normally. It builds up in the liver cells and then goes into the blood and is deposited in the eyes and skin. The same pigment can cause an abnormal urine color. The liver functions normally aside from the loss of an important transporter protein needed to move bilirubin out of the liver. Other less common symptoms include fatigue and fever. Rarely, bilirubin levels can become so high that organ damage is possible. | Symptoms of Dubin Johnson Syndrome. Approximately 80% to 99% of people with DJS have intermittent jaundice caused by excess bilirubin (bile pigment) that cannot be excreted normally. It builds up in the liver cells and then goes into the blood and is deposited in the eyes and skin. The same pigment can cause an abnormal urine color. The liver functions normally aside from the loss of an important transporter protein needed to move bilirubin out of the liver. Other less common symptoms include fatigue and fever. Rarely, bilirubin levels can become so high that organ damage is possible. | 383 | Dubin Johnson Syndrome |
nord_383_2 | Causes of Dubin Johnson Syndrome | DJS is caused by changes (mutations) in the ABCC2 gene. This gene codes for a protein called multidrug resistance protein 2 (MRP2). This protein moves substances out of the cell and is found mainly in the liver but is also present in the kidneys, the intestine, and the placenta. The normal functioning protein works to secrete bilirubin into the bile, which is then transported to the gallbladder where it is stored. When the gall bladder is contracted during digestion, the bile is secreted into the intestine and then passes into the feces. Several different mutations have been identified that alter the function of the carrier protein. This process requires energy in the form of ATP and a common site of mutation is the part of the carrier that coordinates this aspect of the process. Pregnancy or use of oral contraceptives may cause the disease to become apparent in women when no symptoms appeared previously. DJS 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% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females. | Causes of Dubin Johnson Syndrome. DJS is caused by changes (mutations) in the ABCC2 gene. This gene codes for a protein called multidrug resistance protein 2 (MRP2). This protein moves substances out of the cell and is found mainly in the liver but is also present in the kidneys, the intestine, and the placenta. The normal functioning protein works to secrete bilirubin into the bile, which is then transported to the gallbladder where it is stored. When the gall bladder is contracted during digestion, the bile is secreted into the intestine and then passes into the feces. Several different mutations have been identified that alter the function of the carrier protein. This process requires energy in the form of ATP and a common site of mutation is the part of the carrier that coordinates this aspect of the process. Pregnancy or use of oral contraceptives may cause the disease to become apparent in women when no symptoms appeared previously. DJS 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% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females. | 383 | Dubin Johnson Syndrome |
nord_383_3 | Affects of Dubin Johnson Syndrome | DJS is a rare disease that affects males and females in equal numbers. Onset occurs slightly earlier in males than females. The disorder can occur in all races. Among Iranian, Iraqi and Moroccan Jews the incidence is as high as one in 1,300. In Japan, an unusually high incidence of DJS was found in an isolated area where there was a high rate of marriage between blood relatives (consanguinity). | Affects of Dubin Johnson Syndrome. DJS is a rare disease that affects males and females in equal numbers. Onset occurs slightly earlier in males than females. The disorder can occur in all races. Among Iranian, Iraqi and Moroccan Jews the incidence is as high as one in 1,300. In Japan, an unusually high incidence of DJS was found in an isolated area where there was a high rate of marriage between blood relatives (consanguinity). | 383 | Dubin Johnson Syndrome |
nord_383_4 | Related disorders of Dubin Johnson Syndrome | Some features of the following disorders can be similar to those of Dubin Johnson syndrome and need to be considered in a patient prior to determining the diagnosis of DNS. Rotor syndrome is very similar to DJS in that the main symptom is also jaundice and both have increases in conjugated or direct bilirubin and otherwise normal liver characteristics (these are all easily measured in the chemistry lab). However, the liver maintains a normal color unlike the liver in patients with DJS, which appears black. Rotor syndrome is much less common than DJS. Two other genetic diseases of bilirubin metabolism, Gilbert and Crigler-Najjar syndrome, also present with jaundice, but both of these have elevated unconjugated or indirect bilirubin. Most diseases of the liver will have jaundice and can be confused with DJS. However, in almost all cases, the other liver tests, specifically the transaminases, will also be abnormal along with the bilirubin. In DJS the bilirubin elevation is usually mild, 2-3 mg/dl (normal is less than 1). Other causes of liver disease include drugs, infections, gallstones, tumors, ischemia or congestion (abnormal blood flow to the liver) other congenital diseases and inflammatory conditions. . Primary biliary cholangitis (PBC), sclerosing cholangitis and autoimmune hepatitis are chronic progressive diseases of the liver and biliary system (the ducts that are within the liver and secrete the bile into the intestines). These three autoimmune disorders are caused by abnormalities in the immune system where the body literally attacks itself. Inflammation, obstruction or injury involving the bile ducts leads to jaundice. Excessive amounts of copper, usually excreted in the bile, also accumulate in the liver. The associated inflammation leads to scarring of the liver and decrease in function. PBC occurs mainly in women during the fourth to the seventh decade of life, and has four progressive stages. (For more information on these disorders, search for them in the Rare Disease Database.) Among the liver infections, viral hepatitis particularly Hepatitis B virus (HBV), are worldwide the most common cause of liver disease. Hepatitis B begins with a prodrome including anorexia (loss of appetite), fever, nausea, lethargy, and vomiting and usually results in jaundice. Hepatitis B is a common cause of chronic hepatitis leading to liver failure, cirrhosis, and / or liver cancer. A mother with HBV has a high likelihood of passing the virus to her baby unless the newborn is immunized and treated immediately after deliver. It can also be easily passed through bodily fluids such as blood, semen and possibly saliva. It is often spread from person to person through intravenous drug use, sexual contact and other injection treatments. | Related disorders of Dubin Johnson Syndrome. Some features of the following disorders can be similar to those of Dubin Johnson syndrome and need to be considered in a patient prior to determining the diagnosis of DNS. Rotor syndrome is very similar to DJS in that the main symptom is also jaundice and both have increases in conjugated or direct bilirubin and otherwise normal liver characteristics (these are all easily measured in the chemistry lab). However, the liver maintains a normal color unlike the liver in patients with DJS, which appears black. Rotor syndrome is much less common than DJS. Two other genetic diseases of bilirubin metabolism, Gilbert and Crigler-Najjar syndrome, also present with jaundice, but both of these have elevated unconjugated or indirect bilirubin. Most diseases of the liver will have jaundice and can be confused with DJS. However, in almost all cases, the other liver tests, specifically the transaminases, will also be abnormal along with the bilirubin. In DJS the bilirubin elevation is usually mild, 2-3 mg/dl (normal is less than 1). Other causes of liver disease include drugs, infections, gallstones, tumors, ischemia or congestion (abnormal blood flow to the liver) other congenital diseases and inflammatory conditions. . Primary biliary cholangitis (PBC), sclerosing cholangitis and autoimmune hepatitis are chronic progressive diseases of the liver and biliary system (the ducts that are within the liver and secrete the bile into the intestines). These three autoimmune disorders are caused by abnormalities in the immune system where the body literally attacks itself. Inflammation, obstruction or injury involving the bile ducts leads to jaundice. Excessive amounts of copper, usually excreted in the bile, also accumulate in the liver. The associated inflammation leads to scarring of the liver and decrease in function. PBC occurs mainly in women during the fourth to the seventh decade of life, and has four progressive stages. (For more information on these disorders, search for them in the Rare Disease Database.) Among the liver infections, viral hepatitis particularly Hepatitis B virus (HBV), are worldwide the most common cause of liver disease. Hepatitis B begins with a prodrome including anorexia (loss of appetite), fever, nausea, lethargy, and vomiting and usually results in jaundice. Hepatitis B is a common cause of chronic hepatitis leading to liver failure, cirrhosis, and / or liver cancer. A mother with HBV has a high likelihood of passing the virus to her baby unless the newborn is immunized and treated immediately after deliver. It can also be easily passed through bodily fluids such as blood, semen and possibly saliva. It is often spread from person to person through intravenous drug use, sexual contact and other injection treatments. | 383 | Dubin Johnson Syndrome |
nord_383_5 | Diagnosis of Dubin Johnson Syndrome | The presenting symptom in DJS is jaundice. The first test performed documents the presence of elevated blood levels of bilirubin and determines if it is direct (conjugated) or indirect, (unconjugated). In conjunction with this examination, the laboratory will look for other evidence of liver disease, by measuring transaminases, proteins found within hepatocytes, liver cells. Elevation implies that there is damage to the liver and rules out DJS. If transaminases are normal and bilirubin is elevated, a diagnosis for DJS is confirmed by examining an unusual feature of bilirubin degradation seen exclusively in DJS. In normal individuals coproprohyrin III is 3-4 times higher than coproporphyrin I in the urine. However, this ratio is reversed in DJS and an elevated ratio of coproporphyrin I to III is seen. The exact mutation responsible for DJS in a given patient, or family, can be determined through genetic testing. A test often employed to investigate other liver diseases, a liver biopsy, is very rarely indicated in a patient with DJS. Another investigation that is not commonly required is a HIDA or DISIDA scan, which is typically performed to investigate biliary system transit. A unique pattern is noted in DJS where the liver immediately shows tracer and then remains prominent for two hours while the gall bladder shows either delayed transit or is not visualized at all. | Diagnosis of Dubin Johnson Syndrome. The presenting symptom in DJS is jaundice. The first test performed documents the presence of elevated blood levels of bilirubin and determines if it is direct (conjugated) or indirect, (unconjugated). In conjunction with this examination, the laboratory will look for other evidence of liver disease, by measuring transaminases, proteins found within hepatocytes, liver cells. Elevation implies that there is damage to the liver and rules out DJS. If transaminases are normal and bilirubin is elevated, a diagnosis for DJS is confirmed by examining an unusual feature of bilirubin degradation seen exclusively in DJS. In normal individuals coproprohyrin III is 3-4 times higher than coproporphyrin I in the urine. However, this ratio is reversed in DJS and an elevated ratio of coproporphyrin I to III is seen. The exact mutation responsible for DJS in a given patient, or family, can be determined through genetic testing. A test often employed to investigate other liver diseases, a liver biopsy, is very rarely indicated in a patient with DJS. Another investigation that is not commonly required is a HIDA or DISIDA scan, which is typically performed to investigate biliary system transit. A unique pattern is noted in DJS where the liver immediately shows tracer and then remains prominent for two hours while the gall bladder shows either delayed transit or is not visualized at all. | 383 | Dubin Johnson Syndrome |
nord_383_6 | Therapies of Dubin Johnson Syndrome | Treatment
Treatment of DJS is symptomatic and supportive. Many patients never require any treatment even though they have recurrent mild jaundice. However, metabolism of certain drugs may be affected in patients with DJS as many pharmaceutical products are metabolized in the liver. Therefore, a physician should carefully supervise medications. Genetic counseling is recommended for patients and their families. | Therapies of Dubin Johnson Syndrome. Treatment
Treatment of DJS is symptomatic and supportive. Many patients never require any treatment even though they have recurrent mild jaundice. However, metabolism of certain drugs may be affected in patients with DJS as many pharmaceutical products are metabolized in the liver. Therefore, a physician should carefully supervise medications. Genetic counseling is recommended for patients and their families. | 383 | Dubin Johnson Syndrome |
nord_384_0 | Overview of Dubowitz Syndrome | Summary Dubowitz syndrome is a rare genetic condition that had been diagnosed in only 150 to 200 people. It can be diagnosed before and after birth based on specific symptoms. These symptoms include small stature (can be seen during pregnancy), slow growth, small head (microcephaly), intellectual disability, eczema, frequent infections, and unusual and specific facial features. These facial features include a narrow or triangle- shaped face, a high or sloping forehead, undeveloped bones around the eyes (hypoplastic supraorbital ridges), droopy eyes (ptosis) that make the eyes look wide and narrow (blepharophimosis), large ears that are placed low on the head, and sparse hair and eyebrows. Other symptoms sometimes seen in this condition include unusual fingers and toes, differences in the skeleton, and poorly formed testicles and penis, or vagina. People can also have problems with their digestive system, heart, nerves, and muscles. Sometimes, people with Dubowitz syndrome develop cancer, especially in the blood (leukemia) or lymph nodes (lymphoma). The exact cancer risk is not known. People with this condition might have behavior problems, such as aggression, difficulty sleeping or eating, and ADHD (attention deficit/ hyperactivity disorder).Some of the structural symptoms of Dubowitz syndrome can be treated through surgery. Specific medications can help treat some of the behavior problems, and the eczema. Growth hormone might help speed up growth. Speech therapy and extra help in school can help treat the intellectual disability. Physical therapy and occupational therapy may also help the child learn self-help skills. The type of cancer treatment depends on which type of cancer the person has.IntroductionDubowitz syndrome was first discovered by Dr. Victor Dubowitz in 1965. Since then, no common genetic cause has been discovered. Researchers have found many different genetic abnormalities that can cause Dubowitz syndrome. For this reason, a few researchers wonder if this is a true genetic condition, or if it is just a group of symptoms that often appear together. However, most researchers still believe that it is a genetic condition that can be passed down through the family. | Overview of Dubowitz Syndrome. Summary Dubowitz syndrome is a rare genetic condition that had been diagnosed in only 150 to 200 people. It can be diagnosed before and after birth based on specific symptoms. These symptoms include small stature (can be seen during pregnancy), slow growth, small head (microcephaly), intellectual disability, eczema, frequent infections, and unusual and specific facial features. These facial features include a narrow or triangle- shaped face, a high or sloping forehead, undeveloped bones around the eyes (hypoplastic supraorbital ridges), droopy eyes (ptosis) that make the eyes look wide and narrow (blepharophimosis), large ears that are placed low on the head, and sparse hair and eyebrows. Other symptoms sometimes seen in this condition include unusual fingers and toes, differences in the skeleton, and poorly formed testicles and penis, or vagina. People can also have problems with their digestive system, heart, nerves, and muscles. Sometimes, people with Dubowitz syndrome develop cancer, especially in the blood (leukemia) or lymph nodes (lymphoma). The exact cancer risk is not known. People with this condition might have behavior problems, such as aggression, difficulty sleeping or eating, and ADHD (attention deficit/ hyperactivity disorder).Some of the structural symptoms of Dubowitz syndrome can be treated through surgery. Specific medications can help treat some of the behavior problems, and the eczema. Growth hormone might help speed up growth. Speech therapy and extra help in school can help treat the intellectual disability. Physical therapy and occupational therapy may also help the child learn self-help skills. The type of cancer treatment depends on which type of cancer the person has.IntroductionDubowitz syndrome was first discovered by Dr. Victor Dubowitz in 1965. Since then, no common genetic cause has been discovered. Researchers have found many different genetic abnormalities that can cause Dubowitz syndrome. For this reason, a few researchers wonder if this is a true genetic condition, or if it is just a group of symptoms that often appear together. However, most researchers still believe that it is a genetic condition that can be passed down through the family. | 384 | Dubowitz Syndrome |
nord_384_1 | Symptoms of Dubowitz Syndrome | While there are some differences in the types and severity of symptoms that a person can have, people with Dubowitz syndrome share a few common symptoms. Almost everyone has short stature and slow growth. This can be seen before birth in an ultrasound. It can also be seen after birth. People usually have a small head (microcephaly), with a small jaw (micrognathia). They also have mild to moderate intellectual disability. People with Dubowitz syndrome have allergies and get infections easily. About half have eczema (rough, red, itchy patches of skin). The best way to diagnose Dubowitz syndrome is through the facial features. People have a narrow or triangle-shaped face with a high or sloping forehead. The bones around their eyes haven’t fully formed (hypoplastic supraorbital ridges) and their eyes are far apart (hypertelorism). They tend to have droopy eyes (ptosis) that make the eyes look wide and narrow (blepharophimosis). Their ears are large, not fully formed, and set low on their head. Affected individuals also tend to have sparse hair and eyebrows. The roof of their mouth tends to be higher than normal (arched palate), and they may have cleft lip/palate. Hearing problems have not been reported, but vision problems such as problems seeing things up close (farsightedness) and cataracts (clouding of the eye lens) have been reported.People with Dubowitz syndrome can have problems with their nerves, which makes their muscles weak and difficult to move properly (hypotonia). There can also be problems with the skeleton, like curved pinky fingers or toes (clinodactyly). Sometimes two toes can be fused together (syndactyly). Other skeletal problems include scoliosis, and poorly formed or missing ribs. Sometimes parts of the spine (vertebra) will be fused together, making it difficult to move. Many people with Dubowitz syndrome have problems with their immune system and have allergies and frequently get infections. The immune system problems are caused by anemia, which is when there are not enough white (and red) blood cells in the blood to fight infections. Some people have poorly formed reproductive organs (genitalia), like the penis, testes, vagina, and clitoris. In men, the testes sometimes do not descend (cryptorchidism), and the urethra may open underneath the penis instead of at the tip (hypospadias). People with this condition may also have poorly formed digestive systems, lungs, and heart. Their voice tends to be high pitched and hoarse.It is not possible to predict the level of intellectual disability; however, it is possible for someone to have normal intelligence. Severe intellectual disability is rare in this condition. Children with Dubowitz syndrome may learn self-help skills later than other children of the same age, such as dressing, eating, and going to the bathroom. They may also have delays in speech development. They may have difficulty learning in school and may have to stay behind a few grades. They may also have behavior problems, like being constantly active and disruptive (hyperactivity). They may have problems focusing and throw temper tantrums. Many children are diagnosed with ADHD. Children may also have problems sleeping and eating. It is important that children with Dubowitz syndrome eat because they are already growing slowly and they need the nutrition to grow.Dubowitz syndrome increases the chances of having specific cancers. The exact cancer risk is not known. Blood cancers like leukemia, and lymph node cancers (lymphomas) are common. People can also get cancers like nerve cell cancer (neuroblastoma), muscle cancer (myosarcoma), and sarcomas (soft tissue/ bone cancers). | Symptoms of Dubowitz Syndrome. While there are some differences in the types and severity of symptoms that a person can have, people with Dubowitz syndrome share a few common symptoms. Almost everyone has short stature and slow growth. This can be seen before birth in an ultrasound. It can also be seen after birth. People usually have a small head (microcephaly), with a small jaw (micrognathia). They also have mild to moderate intellectual disability. People with Dubowitz syndrome have allergies and get infections easily. About half have eczema (rough, red, itchy patches of skin). The best way to diagnose Dubowitz syndrome is through the facial features. People have a narrow or triangle-shaped face with a high or sloping forehead. The bones around their eyes haven’t fully formed (hypoplastic supraorbital ridges) and their eyes are far apart (hypertelorism). They tend to have droopy eyes (ptosis) that make the eyes look wide and narrow (blepharophimosis). Their ears are large, not fully formed, and set low on their head. Affected individuals also tend to have sparse hair and eyebrows. The roof of their mouth tends to be higher than normal (arched palate), and they may have cleft lip/palate. Hearing problems have not been reported, but vision problems such as problems seeing things up close (farsightedness) and cataracts (clouding of the eye lens) have been reported.People with Dubowitz syndrome can have problems with their nerves, which makes their muscles weak and difficult to move properly (hypotonia). There can also be problems with the skeleton, like curved pinky fingers or toes (clinodactyly). Sometimes two toes can be fused together (syndactyly). Other skeletal problems include scoliosis, and poorly formed or missing ribs. Sometimes parts of the spine (vertebra) will be fused together, making it difficult to move. Many people with Dubowitz syndrome have problems with their immune system and have allergies and frequently get infections. The immune system problems are caused by anemia, which is when there are not enough white (and red) blood cells in the blood to fight infections. Some people have poorly formed reproductive organs (genitalia), like the penis, testes, vagina, and clitoris. In men, the testes sometimes do not descend (cryptorchidism), and the urethra may open underneath the penis instead of at the tip (hypospadias). People with this condition may also have poorly formed digestive systems, lungs, and heart. Their voice tends to be high pitched and hoarse.It is not possible to predict the level of intellectual disability; however, it is possible for someone to have normal intelligence. Severe intellectual disability is rare in this condition. Children with Dubowitz syndrome may learn self-help skills later than other children of the same age, such as dressing, eating, and going to the bathroom. They may also have delays in speech development. They may have difficulty learning in school and may have to stay behind a few grades. They may also have behavior problems, like being constantly active and disruptive (hyperactivity). They may have problems focusing and throw temper tantrums. Many children are diagnosed with ADHD. Children may also have problems sleeping and eating. It is important that children with Dubowitz syndrome eat because they are already growing slowly and they need the nutrition to grow.Dubowitz syndrome increases the chances of having specific cancers. The exact cancer risk is not known. Blood cancers like leukemia, and lymph node cancers (lymphomas) are common. People can also get cancers like nerve cell cancer (neuroblastoma), muscle cancer (myosarcoma), and sarcomas (soft tissue/ bone cancers). | 384 | Dubowitz Syndrome |
nord_384_2 | Causes of Dubowitz Syndrome | The cause of Dubowitz syndrome is not known. Some affected individuals have changes (mutations) in the NSUN4 and LIG4 genes, while others have had small additions or deletions of DNA (microduplications/ microdeletions).Research suggests that this condition can be passed through family in an autosomal recessive manner. We each inherit two copies of all our genes, one from our mom and one from our dad. Sometimes genes have mutations that stop them from work properly. If both copies of a specific gene don’t work properly, the person has a specific autosomal recessive genetic condition. If an individual has one normal gene and one non-working gene, the person will be a carrier for the condition, but usually will not show symptoms. The chance of two carrier parents having an affected child is 25% with each pregnancy. The chance of having a child who is also a carrier 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 Dubowitz Syndrome. The cause of Dubowitz syndrome is not known. Some affected individuals have changes (mutations) in the NSUN4 and LIG4 genes, while others have had small additions or deletions of DNA (microduplications/ microdeletions).Research suggests that this condition can be passed through family in an autosomal recessive manner. We each inherit two copies of all our genes, one from our mom and one from our dad. Sometimes genes have mutations that stop them from work properly. If both copies of a specific gene don’t work properly, the person has a specific autosomal recessive genetic condition. If an individual has one normal gene and one non-working gene, the person will be a carrier for the condition, but usually will not show symptoms. The chance of two carrier parents having an affected child is 25% with each pregnancy. The chance of having a child who is also a carrier 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. | 384 | Dubowitz Syndrome |
nord_384_3 | Affects of Dubowitz Syndrome | Males and females have an equal chance of developing Dubowitz syndrome. It can happen in people of all ethnicities and races. There are between 150 and 200 cases recorded in research articles, but researchers believe that there are more people with Dubowitz syndrome who have not been diagnosed. | Affects of Dubowitz Syndrome. Males and females have an equal chance of developing Dubowitz syndrome. It can happen in people of all ethnicities and races. There are between 150 and 200 cases recorded in research articles, but researchers believe that there are more people with Dubowitz syndrome who have not been diagnosed. | 384 | Dubowitz Syndrome |
nord_384_4 | Related disorders of Dubowitz Syndrome | Dubowitz syndrome is often confused with other genetic conditions because of similar symptoms. These other genetic conditions include Bloom syndrome, Fanconi anemia, and fetal alcohol syndrome. People with Bloom syndrome also have short stature, slow growth, frequently get infections, and are more likely to have cancers. The main difference between Bloom syndrome and Dubowitz syndrome is that the facial features of Dubowitz syndrome are not similar to the facial features of Bloom syndrome. Also, people with Bloom syndrome have red and purple patches on their skin caused by blood vessels.Fanconi anemia is a genetic form on aplastic anemia. Aplastic anemia is when the bone marrow does not make enough red and white blood cells. It is a rare symptom of Dubowitz syndrome. The way to tell Fanconi anemia and Dubowitz syndrome apart is by the specific facial features of Dubowitz syndrome. Fanconi anemia does not have those facial features.Fetal alcohol syndrome is caused by mothers drinking too much alcohol while pregnant. Their babies are born with short stature and a small head. They also have difficulty growing and are intellectually delayed. However, fetal alcohol syndrome has its own set of facial features that are different from the facial features of Dubowitz syndrome. Specifically, people with fetal alcohol syndrome have thin upper lips, and no skin folds under their nose (philtrum). | Related disorders of Dubowitz Syndrome. Dubowitz syndrome is often confused with other genetic conditions because of similar symptoms. These other genetic conditions include Bloom syndrome, Fanconi anemia, and fetal alcohol syndrome. People with Bloom syndrome also have short stature, slow growth, frequently get infections, and are more likely to have cancers. The main difference between Bloom syndrome and Dubowitz syndrome is that the facial features of Dubowitz syndrome are not similar to the facial features of Bloom syndrome. Also, people with Bloom syndrome have red and purple patches on their skin caused by blood vessels.Fanconi anemia is a genetic form on aplastic anemia. Aplastic anemia is when the bone marrow does not make enough red and white blood cells. It is a rare symptom of Dubowitz syndrome. The way to tell Fanconi anemia and Dubowitz syndrome apart is by the specific facial features of Dubowitz syndrome. Fanconi anemia does not have those facial features.Fetal alcohol syndrome is caused by mothers drinking too much alcohol while pregnant. Their babies are born with short stature and a small head. They also have difficulty growing and are intellectually delayed. However, fetal alcohol syndrome has its own set of facial features that are different from the facial features of Dubowitz syndrome. Specifically, people with fetal alcohol syndrome have thin upper lips, and no skin folds under their nose (philtrum). | 384 | Dubowitz Syndrome |
nord_384_5 | Diagnosis of Dubowitz Syndrome | There is a debate among researchers about whether Dubowitz syndrome is a true genetic condition because specific gene mutations or genetic differences that cause the condition have not been confirmed. Some researchers believe that Dubowitz syndrome is a group of symptoms that often appear together. This makes diagnosing Dubowitz syndrome somewhat tricky because geneticists can’t order a definitive genetic test. They can only diagnose someone based on the symptoms they show, and affected people show different types of symptoms. The main symptoms that geneticists look for are short stature, slow growth, small head, specific facial features, intellectual disabilities, and eczema. Clinical Testing and Workup
People with Dubowitz syndrome should have frequent medical checkups based on the symptoms they have. Since vision problems are common, they should visit the eye doctor once a year. Children might also visit a hormone specialist (endocrinologist) to check on their growth as they get older. They should also have blood tests often to check for anemia or potential cancer. They might also have to visit a skin specialist (dermatologist) to keep an eye on the eczema and help find a good treatment for it. | Diagnosis of Dubowitz Syndrome. There is a debate among researchers about whether Dubowitz syndrome is a true genetic condition because specific gene mutations or genetic differences that cause the condition have not been confirmed. Some researchers believe that Dubowitz syndrome is a group of symptoms that often appear together. This makes diagnosing Dubowitz syndrome somewhat tricky because geneticists can’t order a definitive genetic test. They can only diagnose someone based on the symptoms they show, and affected people show different types of symptoms. The main symptoms that geneticists look for are short stature, slow growth, small head, specific facial features, intellectual disabilities, and eczema. Clinical Testing and Workup
People with Dubowitz syndrome should have frequent medical checkups based on the symptoms they have. Since vision problems are common, they should visit the eye doctor once a year. Children might also visit a hormone specialist (endocrinologist) to check on their growth as they get older. They should also have blood tests often to check for anemia or potential cancer. They might also have to visit a skin specialist (dermatologist) to keep an eye on the eczema and help find a good treatment for it. | 384 | Dubowitz Syndrome |
nord_384_6 | Therapies of Dubowitz Syndrome | Treatment
Treatment for Dubowitz syndrome depends on the symptoms that people have. The eczema can be difficult to treat because half of people find that corticosteroid cream (which is often used to treat eczema) doesn’t work for them. The dermatologist can help determine what works best to treat the eczema. Glasses or contact lenses help with vision problems. Cataracts (clouding of the lens) in the eye must be removed surgically. Surgery can also correct many skeletal problems, especially with the fingers, hands, and feet. Some facial features can also be corrected with surgery, such as cleft palate and droopy eyes. In some people, taking extra growth hormone helped to speed up growth. If cancer is present, the type of cancer treatment depends on which type of cancer the person has. While there is no treatment for the intellectual disabilities, there are a few things that can help. Children do better when they have frequent sessions of speech therapy and special help or tutoring with school subjects. Occupational therapy or physical therapy may also help teach children self-help skills. Behavioral problems, like ADHD, refusal to eat, or temper tantrums, can be treated with medication or with behavioral therapy. | Therapies of Dubowitz Syndrome. Treatment
Treatment for Dubowitz syndrome depends on the symptoms that people have. The eczema can be difficult to treat because half of people find that corticosteroid cream (which is often used to treat eczema) doesn’t work for them. The dermatologist can help determine what works best to treat the eczema. Glasses or contact lenses help with vision problems. Cataracts (clouding of the lens) in the eye must be removed surgically. Surgery can also correct many skeletal problems, especially with the fingers, hands, and feet. Some facial features can also be corrected with surgery, such as cleft palate and droopy eyes. In some people, taking extra growth hormone helped to speed up growth. If cancer is present, the type of cancer treatment depends on which type of cancer the person has. While there is no treatment for the intellectual disabilities, there are a few things that can help. Children do better when they have frequent sessions of speech therapy and special help or tutoring with school subjects. Occupational therapy or physical therapy may also help teach children self-help skills. Behavioral problems, like ADHD, refusal to eat, or temper tantrums, can be treated with medication or with behavioral therapy. | 384 | Dubowitz Syndrome |
nord_385_0 | Overview of Duchenne Muscular Dystrophy | SummaryDuchenne muscular dystrophy (DMD) is a rare muscle disorder but it is one of the most frequent genetic conditions affecting approximately 1 in 3,500 male births worldwide. It is usually recognized between three and six years of age. DMD is characterized by weakness and wasting (atrophy) of the muscles of the pelvic area followed by the involvement of the shoulder muscles. As the disease progresses, muscle weakness and atrophy spread to affect the trunk and forearms and gradually progress to involve additional muscles of the body. In addition, the calves appear enlarged in most patients. The disease is progressive and most affected individuals require a wheelchair by the teenage years. Serious life-threatening complications may ultimately develop including disease of the heart muscle (cardiomyopathy) and breathing (respiratory) difficulties.DMD is caused by changes (mutations) of the DMD gene on the X chromosome. The gene regulates the production of a protein called dystrophin that is found in association with the inner side of the membrane of skeletal and cardiac muscle cells. Dystrophin is thought to play an important role in maintaining the membrane (sarcolemma) of muscle cells.IntroductionMuscular dystrophies are characterized by specific abnormalities (e.g. variation of muscle fiber size, muscle fiber necrosis, scar tissue formation and inflammation) in muscle biopsy from the patients. Approximately 30 different genetic conditions make up the muscular dystrophies. DMD is classified as a dystrophinopathy. The dystrophinopathies are a spectrum of muscle diseases, each caused by alterations in the dystrophin gene. The most severe end of the spectrum is known as Duchenne muscular dystrophy lacking completely dystrophin protein. Decreased or truncated dystrophin protein is associated with less severe form is Becker muscular dystrophy.The clinical hallmarks of DMD include weakness and wasting of various voluntary muscles of the body. In most advanced stages of the disease, the heart and gut muscles will be affected. | Overview of Duchenne Muscular Dystrophy. SummaryDuchenne muscular dystrophy (DMD) is a rare muscle disorder but it is one of the most frequent genetic conditions affecting approximately 1 in 3,500 male births worldwide. It is usually recognized between three and six years of age. DMD is characterized by weakness and wasting (atrophy) of the muscles of the pelvic area followed by the involvement of the shoulder muscles. As the disease progresses, muscle weakness and atrophy spread to affect the trunk and forearms and gradually progress to involve additional muscles of the body. In addition, the calves appear enlarged in most patients. The disease is progressive and most affected individuals require a wheelchair by the teenage years. Serious life-threatening complications may ultimately develop including disease of the heart muscle (cardiomyopathy) and breathing (respiratory) difficulties.DMD is caused by changes (mutations) of the DMD gene on the X chromosome. The gene regulates the production of a protein called dystrophin that is found in association with the inner side of the membrane of skeletal and cardiac muscle cells. Dystrophin is thought to play an important role in maintaining the membrane (sarcolemma) of muscle cells.IntroductionMuscular dystrophies are characterized by specific abnormalities (e.g. variation of muscle fiber size, muscle fiber necrosis, scar tissue formation and inflammation) in muscle biopsy from the patients. Approximately 30 different genetic conditions make up the muscular dystrophies. DMD is classified as a dystrophinopathy. The dystrophinopathies are a spectrum of muscle diseases, each caused by alterations in the dystrophin gene. The most severe end of the spectrum is known as Duchenne muscular dystrophy lacking completely dystrophin protein. Decreased or truncated dystrophin protein is associated with less severe form is Becker muscular dystrophy.The clinical hallmarks of DMD include weakness and wasting of various voluntary muscles of the body. In most advanced stages of the disease, the heart and gut muscles will be affected. | 385 | Duchenne Muscular Dystrophy |
nord_385_1 | Symptoms of Duchenne Muscular Dystrophy | DMD usually becomes apparent early during childhood. Affected children develop weakness and wasting (atrophy) of the muscles closest to the trunk (proximal muscles) such as those of the upper legs and pelvic area and upper arms and shoulder area. However, a few other muscles appear disproportionally bulky. As the disease progresses, muscle weakness and atrophy spread to affect the lower legs, forearms, neck and trunk. The rate of progression is quite similar from person to person but individual variation may happen.In children with DMD, initial findings may include delays in reaching developmental milestones such as sitting or standing without assistance; toe walking; an unusual, waddling manner of walking (gait); difficulty climbing stairs or rising from a sitting position (Gower’s sign); and repeated falling. Toddlers and young children may seem awkward and clumsy and may exhibit abnormal enlargement of the calves due to scarring of muscles (pseudohypertrophy). Parents may be falsely encouraged by an apparent improvement between the ages of 3 and 5, but this may be due to natural growth and development. As the disease progresses, additional abnormalities may develop such as progressive curvature of the spine (scoliosis or lordosis), wasting of thigh and pectoral muscles, and abnormal fixation of certain joints (contractures). A contracture occurs when thickening and shortening of tissue such as muscle fibers causes deformity and restricts movement of affected areas, especially the joints. Without physical therapy treatment, leg braces may be needed by age 8-9 to assist affected individuals to walk. By approximately ages 10 to 12, most affected individuals require a wheelchair.Children with DMD have reduced bone density and an increased risk of developing fractures of certain bones, such as hips and spine. Many affected individuals will display mild to moderate degrees of non-progressive intellectual impairment and learning disabilities.By the late teens, DMD may also be characterized by additional potentially life-threatening complications including weakness and deterioration of the heart muscle (cardiomyopathy). Cardiomyopathy can result in impairment in the ability of the heart to pump blood, irregular heartbeats (arrhythmias), and heart failure. Another serious complication associated with DMD is weakness and deterioration of muscles in the rib cage. This can result in an increased susceptibility to respiratory infections (e.g., pneumonia), difficulty coughing, and, ultimately, respiratory failure.Involvement of muscles within the gastrointestinal tract may result in dysmotility, a condition in which the passage of food through the digestive tract usually because of slow and uncoordinated movements of the muscles of the digestive tract. Gastrointestinal dysmotility may result in constipation and diarrhea.One third of patients with DMD may have various degree of cognitive impairment including learning disability, attention deficit and autistic spectrum disorder. | Symptoms of Duchenne Muscular Dystrophy. DMD usually becomes apparent early during childhood. Affected children develop weakness and wasting (atrophy) of the muscles closest to the trunk (proximal muscles) such as those of the upper legs and pelvic area and upper arms and shoulder area. However, a few other muscles appear disproportionally bulky. As the disease progresses, muscle weakness and atrophy spread to affect the lower legs, forearms, neck and trunk. The rate of progression is quite similar from person to person but individual variation may happen.In children with DMD, initial findings may include delays in reaching developmental milestones such as sitting or standing without assistance; toe walking; an unusual, waddling manner of walking (gait); difficulty climbing stairs or rising from a sitting position (Gower’s sign); and repeated falling. Toddlers and young children may seem awkward and clumsy and may exhibit abnormal enlargement of the calves due to scarring of muscles (pseudohypertrophy). Parents may be falsely encouraged by an apparent improvement between the ages of 3 and 5, but this may be due to natural growth and development. As the disease progresses, additional abnormalities may develop such as progressive curvature of the spine (scoliosis or lordosis), wasting of thigh and pectoral muscles, and abnormal fixation of certain joints (contractures). A contracture occurs when thickening and shortening of tissue such as muscle fibers causes deformity and restricts movement of affected areas, especially the joints. Without physical therapy treatment, leg braces may be needed by age 8-9 to assist affected individuals to walk. By approximately ages 10 to 12, most affected individuals require a wheelchair.Children with DMD have reduced bone density and an increased risk of developing fractures of certain bones, such as hips and spine. Many affected individuals will display mild to moderate degrees of non-progressive intellectual impairment and learning disabilities.By the late teens, DMD may also be characterized by additional potentially life-threatening complications including weakness and deterioration of the heart muscle (cardiomyopathy). Cardiomyopathy can result in impairment in the ability of the heart to pump blood, irregular heartbeats (arrhythmias), and heart failure. Another serious complication associated with DMD is weakness and deterioration of muscles in the rib cage. This can result in an increased susceptibility to respiratory infections (e.g., pneumonia), difficulty coughing, and, ultimately, respiratory failure.Involvement of muscles within the gastrointestinal tract may result in dysmotility, a condition in which the passage of food through the digestive tract usually because of slow and uncoordinated movements of the muscles of the digestive tract. Gastrointestinal dysmotility may result in constipation and diarrhea.One third of patients with DMD may have various degree of cognitive impairment including learning disability, attention deficit and autistic spectrum disorder. | 385 | Duchenne Muscular Dystrophy |
nord_385_2 | Causes of Duchenne Muscular Dystrophy | DMD is inherited as an X-linked disease. X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and manifest mostly in males. Females that have a defective gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the defective gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a defective gene he will develop the disease.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% chance to have a son affected with the disease and a 25% chance to have an unaffected son.If a male with an X-linked disorder is able to reproduce, he will pass the defective gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.Some females who inherit a single copy of the disease gene for DMD (gene carriers or heterozygotes) may exhibit some of the symptoms associated with the disease such as weakness of certain muscles, especially those of the arms, legs, and back Carrier females who develop symptoms of DMD are also at risk for developing heart abnormalities, which may present as exercise intolerance or shortness of breath. If left untreated, heart abnormalities can cause life-threatening complications in such affected females.DMD is caused by mutations of the DMD gene located on the short arm (p) of the X chromosome (Xp21.2). 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. For example, “chromosome Xp21.2” refers to band 21.2 on the short arm of the X chromosome. The numbered bands specify the location of the thousands of genes that are present on each chromosome.The DMD gene regulates (encodes for) the production of dystrophin, a protein that appears to play an essential role in maintaining the integrity of cell membrane in skeletal (voluntary) and cardiac muscle cells. Dystrophin is found attached to the inner side of the membrane that surrounds muscle fibers. Mutation of the DMD gene will result in absence of the dystrophin protein, leading to degeneration of muscle fibers. The body can replace (regenerate) some muscle fibers, but over time more and more muscle fiber is lost. Such degeneration leads to the symptoms and findings associated with DMD. In Becker muscular dystrophy, a related disorder, dystrophin is present, but it is truncated or only present in insufficient levels to properly perform its functions.Although most boys with DMD inherit the abnormal gene from their mothers, some may develop the diseases as the result of a spontaneous mutation of the dystrophin gene that occurs randomly for unknown reasons (de novo or sporadic cases). | Causes of Duchenne Muscular Dystrophy. DMD is inherited as an X-linked disease. X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and manifest mostly in males. Females that have a defective gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the defective gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a defective gene he will develop the disease.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% chance to have a son affected with the disease and a 25% chance to have an unaffected son.If a male with an X-linked disorder is able to reproduce, he will pass the defective gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.Some females who inherit a single copy of the disease gene for DMD (gene carriers or heterozygotes) may exhibit some of the symptoms associated with the disease such as weakness of certain muscles, especially those of the arms, legs, and back Carrier females who develop symptoms of DMD are also at risk for developing heart abnormalities, which may present as exercise intolerance or shortness of breath. If left untreated, heart abnormalities can cause life-threatening complications in such affected females.DMD is caused by mutations of the DMD gene located on the short arm (p) of the X chromosome (Xp21.2). 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. For example, “chromosome Xp21.2” refers to band 21.2 on the short arm of the X chromosome. The numbered bands specify the location of the thousands of genes that are present on each chromosome.The DMD gene regulates (encodes for) the production of dystrophin, a protein that appears to play an essential role in maintaining the integrity of cell membrane in skeletal (voluntary) and cardiac muscle cells. Dystrophin is found attached to the inner side of the membrane that surrounds muscle fibers. Mutation of the DMD gene will result in absence of the dystrophin protein, leading to degeneration of muscle fibers. The body can replace (regenerate) some muscle fibers, but over time more and more muscle fiber is lost. Such degeneration leads to the symptoms and findings associated with DMD. In Becker muscular dystrophy, a related disorder, dystrophin is present, but it is truncated or only present in insufficient levels to properly perform its functions.Although most boys with DMD inherit the abnormal gene from their mothers, some may develop the diseases as the result of a spontaneous mutation of the dystrophin gene that occurs randomly for unknown reasons (de novo or sporadic cases). | 385 | Duchenne Muscular Dystrophy |
nord_385_3 | Affects of Duchenne Muscular Dystrophy | DMD is the most common childhood onset form of muscular dystrophy and affects males almost exclusively. The birth prevalence is estimated to be 1 in every 3,500 live male births. Age of onset is usually between 3 and 5 years of age. The muscular dystrophies as a whole are estimated to affect 250,000 individuals in the United States. | Affects of Duchenne Muscular Dystrophy. DMD is the most common childhood onset form of muscular dystrophy and affects males almost exclusively. The birth prevalence is estimated to be 1 in every 3,500 live male births. Age of onset is usually between 3 and 5 years of age. The muscular dystrophies as a whole are estimated to affect 250,000 individuals in the United States. | 385 | Duchenne Muscular Dystrophy |
nord_385_4 | Related disorders of Duchenne Muscular Dystrophy | Symptoms of the following disorders can be similar to those of DMD. Comparisons may be useful for a differential diagnosis.Becker muscular dystrophy is in the category of inherited muscle wasting diseases caused by gene abnormalities (mutations) that result in deficient or abnormal production of the dystrophin protein (dystrophinopathies). The abnormal gene is the same as for DMD and is located on the X chromosome. Becker muscular dystrophy also follows X-linked inheritance so it mostly affects males, but some female carriers are affected. Becker muscular dystrophy usually begins in the teens or early twenties, but can begin as late as the sixties and symptoms vary greatly between affected individuals. Muscle weakness and deterioration progress slowly but usually results in the need for a wheelchair. Muscles of the heart deteriorate (cardiomyopathy) in some affected individuals more seriously than the skeletal muscles of the body, and this process can become life threatening potentially causing heart failure. Learning disabilities involving visual abilities may be present but rarely. In Becker muscular dystrophy, dystrophin levels are reduced where in DMD they are absent or nearly absent. Consequently, the symptoms of these two disorders are similar, but most cases of Becker muscular dystrophy are less severe. (For more information on this disorder, choose “Becker” as your search term in the Rare Disease Database.)Emery-Dreifuss muscular dystrophy (EDMD) is a rare, often slowly progressive genetic disorder affecting the muscles of the arms, legs, face, neck, spine and heart. The disorder consists of the clinical triad of weakness and degeneration (atrophy) of certain muscles, joints that are fixed in a flexed or extended position (contractures), and abnormalities affecting the heart (cardiomyopathy) in mainly adults. Major symptoms may include muscle wasting and weakness particularly in arms and lower legs (humeroperoneal regions) and contractures of the elbows, Achilles tendons, and upper back muscles. In some patients, additional abnormalities may be present. In most cases, EDMD is inherited as an X-linked or autosomal dominant trait. In extremely rare cases, autosomal recessive inheritance has been reported. Although EDMD has different modes of inheritance, the symptoms are nearly the same. (For more information on this disorder, choose “Emery Dreifuss” as your search term in the Rare Disease Database.)Limb-girdle muscular dystrophy (LGMD) is a general term for a group of rare progressive genetic disorders that are characterized by wasting (atrophy) and weakness of the voluntary muscles of the hip and shoulder areas (limb-girdle area). Muscle weakness and atrophy are progressive and may spread to affect other muscles of the body. Approximately 15 different subtypes have been identified based upon abnormal changes (mutations) of certain genes. The age of onset, severity, and progression of symptoms of these subtypes varies greatly even among individuals in the same family. Some individuals may have a mild, slowly progressive form of the disease; other may have a rapidly progressive form that may cause severe disability. The various forms of LGMDs can now be distinguished by genetic and/or protein analysis. The various forms of LGMD may be inherited as an autosomal dominant or recessive trait. Autosomal dominant LGMD is known as LGMD1 and has five subtypes (LGMDA-E). Autosomal recessive LGMD is known as LGMD2 and has 10 subtypes (LGMDA-J). (For more information on this disorder, choose “limb-girdle muscular dystrophy” as your search term in the Rare Disease Database.)Spinal muscular atrophy (SMA) that is caused by a deletion of the SMN gene on chromosome 5 is an inherited progressive neuromuscular disorder characterized by degeneration of groups of nerve cells (lower motor neurons) within the lowest region of the brain (lower brainstem) and certain motor neurons in the spinal cord (anterior horn cells). Motor neurons are nerve cells that transmit nerve impulses from the spinal cord or brain (central nervous system) to muscle or glandular tissue. Typical symptoms are a slowly progressive muscle weakness and muscle wasting (atrophy). Affected individuals have poor muscle tone, muscle weakness on both sides of the body without, or with minimal, involvement of the face muscles, twitching tongue and a lack of deep tendon reflexes. SMA is divided into subtypes based on age of onset of symptoms and maximum function achieved. (For more information on this disorder, choose “spinal muscular atrophy” as your search term in the Rare Disease Database.) | Related disorders of Duchenne Muscular Dystrophy. Symptoms of the following disorders can be similar to those of DMD. Comparisons may be useful for a differential diagnosis.Becker muscular dystrophy is in the category of inherited muscle wasting diseases caused by gene abnormalities (mutations) that result in deficient or abnormal production of the dystrophin protein (dystrophinopathies). The abnormal gene is the same as for DMD and is located on the X chromosome. Becker muscular dystrophy also follows X-linked inheritance so it mostly affects males, but some female carriers are affected. Becker muscular dystrophy usually begins in the teens or early twenties, but can begin as late as the sixties and symptoms vary greatly between affected individuals. Muscle weakness and deterioration progress slowly but usually results in the need for a wheelchair. Muscles of the heart deteriorate (cardiomyopathy) in some affected individuals more seriously than the skeletal muscles of the body, and this process can become life threatening potentially causing heart failure. Learning disabilities involving visual abilities may be present but rarely. In Becker muscular dystrophy, dystrophin levels are reduced where in DMD they are absent or nearly absent. Consequently, the symptoms of these two disorders are similar, but most cases of Becker muscular dystrophy are less severe. (For more information on this disorder, choose “Becker” as your search term in the Rare Disease Database.)Emery-Dreifuss muscular dystrophy (EDMD) is a rare, often slowly progressive genetic disorder affecting the muscles of the arms, legs, face, neck, spine and heart. The disorder consists of the clinical triad of weakness and degeneration (atrophy) of certain muscles, joints that are fixed in a flexed or extended position (contractures), and abnormalities affecting the heart (cardiomyopathy) in mainly adults. Major symptoms may include muscle wasting and weakness particularly in arms and lower legs (humeroperoneal regions) and contractures of the elbows, Achilles tendons, and upper back muscles. In some patients, additional abnormalities may be present. In most cases, EDMD is inherited as an X-linked or autosomal dominant trait. In extremely rare cases, autosomal recessive inheritance has been reported. Although EDMD has different modes of inheritance, the symptoms are nearly the same. (For more information on this disorder, choose “Emery Dreifuss” as your search term in the Rare Disease Database.)Limb-girdle muscular dystrophy (LGMD) is a general term for a group of rare progressive genetic disorders that are characterized by wasting (atrophy) and weakness of the voluntary muscles of the hip and shoulder areas (limb-girdle area). Muscle weakness and atrophy are progressive and may spread to affect other muscles of the body. Approximately 15 different subtypes have been identified based upon abnormal changes (mutations) of certain genes. The age of onset, severity, and progression of symptoms of these subtypes varies greatly even among individuals in the same family. Some individuals may have a mild, slowly progressive form of the disease; other may have a rapidly progressive form that may cause severe disability. The various forms of LGMDs can now be distinguished by genetic and/or protein analysis. The various forms of LGMD may be inherited as an autosomal dominant or recessive trait. Autosomal dominant LGMD is known as LGMD1 and has five subtypes (LGMDA-E). Autosomal recessive LGMD is known as LGMD2 and has 10 subtypes (LGMDA-J). (For more information on this disorder, choose “limb-girdle muscular dystrophy” as your search term in the Rare Disease Database.)Spinal muscular atrophy (SMA) that is caused by a deletion of the SMN gene on chromosome 5 is an inherited progressive neuromuscular disorder characterized by degeneration of groups of nerve cells (lower motor neurons) within the lowest region of the brain (lower brainstem) and certain motor neurons in the spinal cord (anterior horn cells). Motor neurons are nerve cells that transmit nerve impulses from the spinal cord or brain (central nervous system) to muscle or glandular tissue. Typical symptoms are a slowly progressive muscle weakness and muscle wasting (atrophy). Affected individuals have poor muscle tone, muscle weakness on both sides of the body without, or with minimal, involvement of the face muscles, twitching tongue and a lack of deep tendon reflexes. SMA is divided into subtypes based on age of onset of symptoms and maximum function achieved. (For more information on this disorder, choose “spinal muscular atrophy” as your search term in the Rare Disease Database.) | 385 | Duchenne Muscular Dystrophy |
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