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Overview of Oculocutaneous Albinism
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Oculocutaneous albinism (OCA) is a group of rare inherited disorders characterized by a reduction or complete lack of melanin pigment in the skin, hair and eyes. These conditions are caused by mutations in specific genes that are necessary for the production of melanin pigment in specialized cells called melanocytes. Absent or insufficient melanin pigment results in abnormal development of the eyes, resulting in vision abnormalities, and light skin that is very susceptible to damage from the sun including skin cancer. Visual changes include nystagmus (involuntary side to side eye movement), strabismus and photophobia (sensitivity to light). Other changes include foveal hypoplasia (which affects visual acuity) and mis-routing of the optic nerves. All individuals with OCA have the above visual changes but the amount of skin, hair and iris pigment can vary depending on the gene (or type of OCA) and mutation involved.There are seven types of OCA (OCA1-7) caused by mutations in seven different genes. Oculocutaneous albinism is inherited as an autosomal recessive genetic condition.
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Overview of Oculocutaneous Albinism. Oculocutaneous albinism (OCA) is a group of rare inherited disorders characterized by a reduction or complete lack of melanin pigment in the skin, hair and eyes. These conditions are caused by mutations in specific genes that are necessary for the production of melanin pigment in specialized cells called melanocytes. Absent or insufficient melanin pigment results in abnormal development of the eyes, resulting in vision abnormalities, and light skin that is very susceptible to damage from the sun including skin cancer. Visual changes include nystagmus (involuntary side to side eye movement), strabismus and photophobia (sensitivity to light). Other changes include foveal hypoplasia (which affects visual acuity) and mis-routing of the optic nerves. All individuals with OCA have the above visual changes but the amount of skin, hair and iris pigment can vary depending on the gene (or type of OCA) and mutation involved.There are seven types of OCA (OCA1-7) caused by mutations in seven different genes. Oculocutaneous albinism is inherited as an autosomal recessive genetic condition.
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Oculocutaneous Albinism
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Symptoms of Oculocutaneous Albinism
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Several vision problems can occur with this condition including an involuntary movement of eyes back and forth (nystagmus), reduced iris pigment (iris transillumination), reduced retinal pigment, lack of development of the macula (macular hypoplasia) resulting in abnormal foveal development (the area of the eye responsible for visual acuity), poor visual acuity, and abnormal connections in the nerves from the retina to the brain that prevents the eyes from tracking together (strabismus) and reduces depth perception. Visual acuity in individuals can range from 20/60 to 20/400, usually depending on the amount of pigment present in the eye. Vision acuity is usually better in those individuals with greater amounts of pigment. Oculocutaneous albinism type 2 (OCA2) is associated with the same vision problems that occur in OCA1. Individuals with OCA2 have a wide range of skin pigmentation that is partially dependent on their genetic background and the mutations present. Hair color is usually not completely white and there can be some pigment present in the skin but skin color is usually lighter than in unaffected relatives. Individuals with extensive sun exposure can develop pigmented nevi and lentigines. This does not occur with other types of OCA. A reduction in skin pigment is apparent in Africans and African-Americans but skin coloration appears close to normal in other populations with normally lighter pigmentation but affected individuals do not tan. Brown OCA is a type of OCA2 where hair and skin coloration is darker. This type of OCA2 has only been reported in individuals with African ancestry. OCA2 is associated with mutations in the OCA2 gene, formerly called the P gene.Oculocutaneous albinism type 3 (OCA3) was initially described in the African population. Affected individuals have red to reddish-brown skin, ginger or reddish hair, and hazel or brown eyes and the condition was initially termed rufous albinism. OCA3 has now been identified in several additional populations especially of Asian descent including Chinese and Japanese, as well as in Asian Indian and Northern European individuals. Affected individuals of Asian heritage can have blond hair with light brown eyebrows with skin lighter than their parents. Both hair and skin pigmentation increases with age. Vision problems are not as severe as OCA1 or OCA2. Nystagmus and photophobia may not be present. OCA3 is associated with mutations in the tyrosinase related protein 1 (TYRP1) gene.Oculocutaneous albinism type 4 (OCA4) is characterized by physical features that are similar to those of OCA2. Hair color of affected individuals can range from yellow to brown. Visual acuity can range from 20/30 to 20/400 depending on the amount of pigment that is present, but acuity is usually in the range of 20/100 to 20/200. Vision is usually stable after childhood. OCA4 was initially identified in an individual of Turkish origin and has been found in Asian populations including Japanese and Korean and German individuals, OCA4 is associated with mutations in the SLC45A2 gene (formerly called MATP), a membrane-associated transport protein.
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Symptoms of Oculocutaneous Albinism. Several vision problems can occur with this condition including an involuntary movement of eyes back and forth (nystagmus), reduced iris pigment (iris transillumination), reduced retinal pigment, lack of development of the macula (macular hypoplasia) resulting in abnormal foveal development (the area of the eye responsible for visual acuity), poor visual acuity, and abnormal connections in the nerves from the retina to the brain that prevents the eyes from tracking together (strabismus) and reduces depth perception. Visual acuity in individuals can range from 20/60 to 20/400, usually depending on the amount of pigment present in the eye. Vision acuity is usually better in those individuals with greater amounts of pigment. Oculocutaneous albinism type 2 (OCA2) is associated with the same vision problems that occur in OCA1. Individuals with OCA2 have a wide range of skin pigmentation that is partially dependent on their genetic background and the mutations present. Hair color is usually not completely white and there can be some pigment present in the skin but skin color is usually lighter than in unaffected relatives. Individuals with extensive sun exposure can develop pigmented nevi and lentigines. This does not occur with other types of OCA. A reduction in skin pigment is apparent in Africans and African-Americans but skin coloration appears close to normal in other populations with normally lighter pigmentation but affected individuals do not tan. Brown OCA is a type of OCA2 where hair and skin coloration is darker. This type of OCA2 has only been reported in individuals with African ancestry. OCA2 is associated with mutations in the OCA2 gene, formerly called the P gene.Oculocutaneous albinism type 3 (OCA3) was initially described in the African population. Affected individuals have red to reddish-brown skin, ginger or reddish hair, and hazel or brown eyes and the condition was initially termed rufous albinism. OCA3 has now been identified in several additional populations especially of Asian descent including Chinese and Japanese, as well as in Asian Indian and Northern European individuals. Affected individuals of Asian heritage can have blond hair with light brown eyebrows with skin lighter than their parents. Both hair and skin pigmentation increases with age. Vision problems are not as severe as OCA1 or OCA2. Nystagmus and photophobia may not be present. OCA3 is associated with mutations in the tyrosinase related protein 1 (TYRP1) gene.Oculocutaneous albinism type 4 (OCA4) is characterized by physical features that are similar to those of OCA2. Hair color of affected individuals can range from yellow to brown. Visual acuity can range from 20/30 to 20/400 depending on the amount of pigment that is present, but acuity is usually in the range of 20/100 to 20/200. Vision is usually stable after childhood. OCA4 was initially identified in an individual of Turkish origin and has been found in Asian populations including Japanese and Korean and German individuals, OCA4 is associated with mutations in the SLC45A2 gene (formerly called MATP), a membrane-associated transport protein.
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Oculocutaneous Albinism
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Causes of Oculocutaneous Albinism
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Melanin pigment is the major pigment responsible for coloration of skin, hair and eyes. There are two types of melanin pigment, brown-black eumelanin and yellow-red pheomelanin. All melanin pigment is a combination of these two types of pigment. Melanin pigment is produced in specialized cells called melanocytes. Mutations in genes responsible for the proteins that are necessary for the melanocyte to make melanin pigment result in a reduction or absence of melanin pigment in the skin, hair and eyes of the affected individual and this condition is termed oculocutaneous albinism (OCA). OCA is inherited as an autosomal recessive genetic condition. 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, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.Seven genes have been identified that are associated with different types of OCA. Each of these genes is important in the production of melanin pigment that takes place in cells called melanocytes that are located in the skin, hair follicle, iris and retina of the eye. In the case of skin and hair pigmentation, the melanocyte transfers the melanin pigment to the keratinocyte, the cell that is responsible for skin and hair. Pigment in the eye is produced in the iris and in the retinal pigment epithelium.Different Types of Oculocutaneous AlbinismOculocutaneous Albinism Type I (OCA1)Oculocutaneous albinism type 1 (OCA1) is associated with reduced production of melanin in the skin, hair and eyes. There are two types of OCA1. Individuals affected with OCA1A have a complete absence of melanin pigment resulting in white hair and white skin at birth and irises that do not become darker over time. Visual acuity in individuals can range from 20/200 to 20/400. Individuals with OCA1B have white or light yellow hair at birth that can darken over time, white skin that darkens over time and irises that may change from light blue to green or brown over time. Vision is usually better in individuals with OCA1B than in those with OCA1A.OCA1 is associated with abnormalities (mutations) in the tyrosinase (TYR) gene. The TYR gene is responsible for the production of the enzyme tyrosinase which is the key enzyme in the formation of melanin pigment. Some TYR mutations result in the production of a completely nonfunctioning tyrosinase enzyme and no melanin pigment is formed. This results in OCA1A. Different TYR mutations result in the production of a tyrosinase enzyme with limited enzymatic activity but it is still able to produce small amounts of melanin pigment. This type of OCA1 is called OCA1B. In the case of OCA1B, melanin pigment will accumulate with time in the skin, hair and eyes.Oculocutaneous Albinism Type II (OCA2)Oculocutaneous albinism type II (OCA2) is associated with the same vision problems that occur in OCA1. Individuals with OCA2 have a wide range of skin pigmentation that is partially dependent on their genetic background of the affected individual and the mutations present. Hair color is usually not completely white and there can be some pigment present in the skin but skin color is usually lighter than in unaffected relatives. Individuals with extensive sun exposure can develop pigmented nevi and lentigines (dark spots on the skin). This does not occur with other types of OCA. A reduction in skin pigment is apparent in Africans and African-Americans but skin coloration appears close to normal in other populations with normally lighter skin pigmentation but affected individuals do not tan. Brown OCA is a type of OCA2 where hair and skin coloration is darker. This type of OCA2 has only been reported in individuals with African ancestry.OCA2 is associated with mutations in the OCA2 gene (also called the P gene). The OCA2 gene is responsible for production of the OCA2 protein. The precise function of the OCA2 protein is unknown, but it is thought to be important in regulating the movement of the substrate tyrosine into the melanosome as well as regulating the internal environment of the melanosome.Oculocutaneous Albinism Type III (OCA3)Oculocutaneous albinism type III (OCA3) was initially described in the African population. Affected individuals have red to reddish-brown skin, ginger or reddish hair, and hazel or brown eyes and the condition was initially termed rufous albinism. OCA3 has now been identified in several additional populations including those of Asian descent (Chinese and Japanese), Asian Indian and Northern European. Affected individuals of Asian heritage can have blond hair with light brown eyebrows with skin lighter than their parents. Both hair and skin pigmentation increases with age. Reduction in visual acuity is not as severe as in OCA1 or OCA2. Nystagmus and photophobia may not be present.OCA3 is associated with mutations in the tyrosinase related protein 1 (TYRP1) gene. This gene is responsible for the production of tyrosinase-related protein-1, an enzyme like tyrosinase, which is involved in the production of melanin. The TYRP1 enzyme is part of a gene family that includes tyrosinase and the tyrosinase related protein-2 (TYRP2), all of which are enzymes involved in melanin biosynthesis. The TYRP1 enzyme is responsible for later steps (after the initial tyrosinase step) in melanin pigment production.Oculocutaneous Albinism Type IV (OCA4)Oculocutaneous albinism type IV (OCA4) is characterized by physical features that are similar to those of OCA2. Hair color of affected individuals can range from yellow to brown. Visual acuity can range from 20/30 to 20/400 depending on the amount of pigment that is present, but acuity is usually in the range of 20/100 to 20/200. OCA4 was initially identified in an individual of Turkish origin and has been also found in Asian populations including Japanese and Korean and German individuals.OCA4 is associated with mutations in the SLC45A2 gene (also called the membrane-associated transporter protein; MATP). The SLC45A2 gene is responsible for the production of a membrane associated transporter protein formed with 12 transmembrane helices. The precise function of this protein is unknown but it is required for the normal production of melanin by the melanocyte.Oculocutaneous Albinism Type V (OCA5)Oculocutaneous albinism type V (OCA5) has been found in only one family in Pakistan. Affected individuals have golden colored hair, white skin and the same visual problems that occur in OCA1. Visual acuity in this family was 6/60.The gene responsible for OCA5 has been located on chromosome 4 (4q24). 14 genes are in this location, but the specific causative gene for OCA5 has not yet been determined.Oculocutaneous Albinism Type VI (OCA6)Oculocutaneous albinism type VI (OCA6) is characterized as having golden to light to dark brown hair, white skin and brownish irides and has been classified as autosomal recessive ocular albinism (AROA), though individuals are hypopigmented when compared to their parents. Only a few individuals have been identified with this type of albinism and all of the clinical features of OCA6 have not been determined but it is assumed that the reduction in visual acuity will not be as severe as seen in OCA1.OCA6 is associated with mutations in the SLC24A5 gene. The SLC24A5 gene is responsible for the production of a membrane associated transporter protein. The precise function of this protein is unknown but it belongs to a family of potassium-dependent sodium/calcium exchangers. It may be involved in the maturation of melanosomes.Oculocutaneous Albinism Type VII (OCA7)Oculocutaneous albinism type 7 (OCA7) is characterized with blond to dark brown hair and skin which is more hypopigmented than parents. Individuals had nystagmus and iris transillumination. Visual acuity ranges from 6/18 to 3/60.OCA7 is associated with mutations in C10orf11. The isoform 1 open reading frame encodes a 226 amino acid protein containing a leucine-rich repeat. The function of the protein is unknown but is thought to play a role in melanocyte differentiation.Mutations and Oculocutaneous AlbinismMost mutations described associated with OCA have been single base substitutions that result in either amino acid substitutions, RNA splicing abnormalities or premature stop codons (nonsense or frameshift mutations). New evidence has shown that larger deletions and chromosome rearrangements are also important mechanisms for mutating genes associated with OCA. Deletions or duplications are thought to account for over 5% of mutations associated with OCA.It is important to note that all individuals carry 4-5 abnormal genes among the 30,000 or so genes that we have. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.Four genes have been identified that are associated with different types of OCA. Each of these genes is important in the production of melanin that takes place in cells called melanocytes that are located in the skin, hair follicle and iris and retina of the eye. In the case of skin and hair pigmentation, the melanocyte transfers the melanin pigment to the keritinocyte and make up skin and hair.OCA1 is associated with abnormalities (mutations) in the tyrosinase (TYR) gene. The TYR gene is responsible for the production of the enzyme tyrosinase which is responsible for the first step in the formation of melanin pigment. Some TYR mutations result in the production of a nonfunctioning tyrosinase enzyme and no melanin pigment is formed. This type of OCA1 is called OCA type 1A (OCA1A). Other TYR mutations result in the production of a tyrosinase enzyme with reduced function so that a reduced amount of melanin pigment is formed. This type of OCA1 is called OCA type 1B (OCA1B). In the case of OCA1B, melanin pigment will accumulate with time.OCA2 is associated with mutations in the OCA2 gene (also called the P gene). The OCA2 gene is responsible for production of the OCA2 protein. The precise function of the OCA2 protein is unknown, but it is thought to be important in regulating the movement of the substrate tyrosine into the melanosome as well as regulating the internal environment of the melanosome.OCA3 is associated with mutations in the tyrosinase related protein 1 (TYRP1) gene. This gene is responsible for the production of tyrosinase-related protein-1, an enzyme, like tyrosinase, that is involved in the production of melanin. The TYRP1 enzyme is part of a gene family that includes tyrosinase and the tyrosinase related protein-2 (TYRP2), all of which are enzymes involved in melanin biosynthesis. The TYRP1 enzyme is responsible for later steps (after the initial tyrosinase step) in melanin pigment production.OCA4 is associated with mutations in the SLC45A2 gene (also called the MATP). The SLC45A2 gene is responsible for the production of this membrane associated transporter protein. The precise function of this protein is unknown but it is required for the normal production of melanin by the melanocyte.It is important to note that all individuals carry 4-5 abnormal genes among the 30,000 or so genes that we have. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
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Causes of Oculocutaneous Albinism. Melanin pigment is the major pigment responsible for coloration of skin, hair and eyes. There are two types of melanin pigment, brown-black eumelanin and yellow-red pheomelanin. All melanin pigment is a combination of these two types of pigment. Melanin pigment is produced in specialized cells called melanocytes. Mutations in genes responsible for the proteins that are necessary for the melanocyte to make melanin pigment result in a reduction or absence of melanin pigment in the skin, hair and eyes of the affected individual and this condition is termed oculocutaneous albinism (OCA). OCA is inherited as an autosomal recessive genetic condition. 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, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.Seven genes have been identified that are associated with different types of OCA. Each of these genes is important in the production of melanin pigment that takes place in cells called melanocytes that are located in the skin, hair follicle, iris and retina of the eye. In the case of skin and hair pigmentation, the melanocyte transfers the melanin pigment to the keratinocyte, the cell that is responsible for skin and hair. Pigment in the eye is produced in the iris and in the retinal pigment epithelium.Different Types of Oculocutaneous AlbinismOculocutaneous Albinism Type I (OCA1)Oculocutaneous albinism type 1 (OCA1) is associated with reduced production of melanin in the skin, hair and eyes. There are two types of OCA1. Individuals affected with OCA1A have a complete absence of melanin pigment resulting in white hair and white skin at birth and irises that do not become darker over time. Visual acuity in individuals can range from 20/200 to 20/400. Individuals with OCA1B have white or light yellow hair at birth that can darken over time, white skin that darkens over time and irises that may change from light blue to green or brown over time. Vision is usually better in individuals with OCA1B than in those with OCA1A.OCA1 is associated with abnormalities (mutations) in the tyrosinase (TYR) gene. The TYR gene is responsible for the production of the enzyme tyrosinase which is the key enzyme in the formation of melanin pigment. Some TYR mutations result in the production of a completely nonfunctioning tyrosinase enzyme and no melanin pigment is formed. This results in OCA1A. Different TYR mutations result in the production of a tyrosinase enzyme with limited enzymatic activity but it is still able to produce small amounts of melanin pigment. This type of OCA1 is called OCA1B. In the case of OCA1B, melanin pigment will accumulate with time in the skin, hair and eyes.Oculocutaneous Albinism Type II (OCA2)Oculocutaneous albinism type II (OCA2) is associated with the same vision problems that occur in OCA1. Individuals with OCA2 have a wide range of skin pigmentation that is partially dependent on their genetic background of the affected individual and the mutations present. Hair color is usually not completely white and there can be some pigment present in the skin but skin color is usually lighter than in unaffected relatives. Individuals with extensive sun exposure can develop pigmented nevi and lentigines (dark spots on the skin). This does not occur with other types of OCA. A reduction in skin pigment is apparent in Africans and African-Americans but skin coloration appears close to normal in other populations with normally lighter skin pigmentation but affected individuals do not tan. Brown OCA is a type of OCA2 where hair and skin coloration is darker. This type of OCA2 has only been reported in individuals with African ancestry.OCA2 is associated with mutations in the OCA2 gene (also called the P gene). The OCA2 gene is responsible for production of the OCA2 protein. The precise function of the OCA2 protein is unknown, but it is thought to be important in regulating the movement of the substrate tyrosine into the melanosome as well as regulating the internal environment of the melanosome.Oculocutaneous Albinism Type III (OCA3)Oculocutaneous albinism type III (OCA3) was initially described in the African population. Affected individuals have red to reddish-brown skin, ginger or reddish hair, and hazel or brown eyes and the condition was initially termed rufous albinism. OCA3 has now been identified in several additional populations including those of Asian descent (Chinese and Japanese), Asian Indian and Northern European. Affected individuals of Asian heritage can have blond hair with light brown eyebrows with skin lighter than their parents. Both hair and skin pigmentation increases with age. Reduction in visual acuity is not as severe as in OCA1 or OCA2. Nystagmus and photophobia may not be present.OCA3 is associated with mutations in the tyrosinase related protein 1 (TYRP1) gene. This gene is responsible for the production of tyrosinase-related protein-1, an enzyme like tyrosinase, which is involved in the production of melanin. The TYRP1 enzyme is part of a gene family that includes tyrosinase and the tyrosinase related protein-2 (TYRP2), all of which are enzymes involved in melanin biosynthesis. The TYRP1 enzyme is responsible for later steps (after the initial tyrosinase step) in melanin pigment production.Oculocutaneous Albinism Type IV (OCA4)Oculocutaneous albinism type IV (OCA4) is characterized by physical features that are similar to those of OCA2. Hair color of affected individuals can range from yellow to brown. Visual acuity can range from 20/30 to 20/400 depending on the amount of pigment that is present, but acuity is usually in the range of 20/100 to 20/200. OCA4 was initially identified in an individual of Turkish origin and has been also found in Asian populations including Japanese and Korean and German individuals.OCA4 is associated with mutations in the SLC45A2 gene (also called the membrane-associated transporter protein; MATP). The SLC45A2 gene is responsible for the production of a membrane associated transporter protein formed with 12 transmembrane helices. The precise function of this protein is unknown but it is required for the normal production of melanin by the melanocyte.Oculocutaneous Albinism Type V (OCA5)Oculocutaneous albinism type V (OCA5) has been found in only one family in Pakistan. Affected individuals have golden colored hair, white skin and the same visual problems that occur in OCA1. Visual acuity in this family was 6/60.The gene responsible for OCA5 has been located on chromosome 4 (4q24). 14 genes are in this location, but the specific causative gene for OCA5 has not yet been determined.Oculocutaneous Albinism Type VI (OCA6)Oculocutaneous albinism type VI (OCA6) is characterized as having golden to light to dark brown hair, white skin and brownish irides and has been classified as autosomal recessive ocular albinism (AROA), though individuals are hypopigmented when compared to their parents. Only a few individuals have been identified with this type of albinism and all of the clinical features of OCA6 have not been determined but it is assumed that the reduction in visual acuity will not be as severe as seen in OCA1.OCA6 is associated with mutations in the SLC24A5 gene. The SLC24A5 gene is responsible for the production of a membrane associated transporter protein. The precise function of this protein is unknown but it belongs to a family of potassium-dependent sodium/calcium exchangers. It may be involved in the maturation of melanosomes.Oculocutaneous Albinism Type VII (OCA7)Oculocutaneous albinism type 7 (OCA7) is characterized with blond to dark brown hair and skin which is more hypopigmented than parents. Individuals had nystagmus and iris transillumination. Visual acuity ranges from 6/18 to 3/60.OCA7 is associated with mutations in C10orf11. The isoform 1 open reading frame encodes a 226 amino acid protein containing a leucine-rich repeat. The function of the protein is unknown but is thought to play a role in melanocyte differentiation.Mutations and Oculocutaneous AlbinismMost mutations described associated with OCA have been single base substitutions that result in either amino acid substitutions, RNA splicing abnormalities or premature stop codons (nonsense or frameshift mutations). New evidence has shown that larger deletions and chromosome rearrangements are also important mechanisms for mutating genes associated with OCA. Deletions or duplications are thought to account for over 5% of mutations associated with OCA.It is important to note that all individuals carry 4-5 abnormal genes among the 30,000 or so genes that we have. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.Four genes have been identified that are associated with different types of OCA. Each of these genes is important in the production of melanin that takes place in cells called melanocytes that are located in the skin, hair follicle and iris and retina of the eye. In the case of skin and hair pigmentation, the melanocyte transfers the melanin pigment to the keritinocyte and make up skin and hair.OCA1 is associated with abnormalities (mutations) in the tyrosinase (TYR) gene. The TYR gene is responsible for the production of the enzyme tyrosinase which is responsible for the first step in the formation of melanin pigment. Some TYR mutations result in the production of a nonfunctioning tyrosinase enzyme and no melanin pigment is formed. This type of OCA1 is called OCA type 1A (OCA1A). Other TYR mutations result in the production of a tyrosinase enzyme with reduced function so that a reduced amount of melanin pigment is formed. This type of OCA1 is called OCA type 1B (OCA1B). In the case of OCA1B, melanin pigment will accumulate with time.OCA2 is associated with mutations in the OCA2 gene (also called the P gene). The OCA2 gene is responsible for production of the OCA2 protein. The precise function of the OCA2 protein is unknown, but it is thought to be important in regulating the movement of the substrate tyrosine into the melanosome as well as regulating the internal environment of the melanosome.OCA3 is associated with mutations in the tyrosinase related protein 1 (TYRP1) gene. This gene is responsible for the production of tyrosinase-related protein-1, an enzyme, like tyrosinase, that is involved in the production of melanin. The TYRP1 enzyme is part of a gene family that includes tyrosinase and the tyrosinase related protein-2 (TYRP2), all of which are enzymes involved in melanin biosynthesis. The TYRP1 enzyme is responsible for later steps (after the initial tyrosinase step) in melanin pigment production.OCA4 is associated with mutations in the SLC45A2 gene (also called the MATP). The SLC45A2 gene is responsible for the production of this membrane associated transporter protein. The precise function of this protein is unknown but it is required for the normal production of melanin by the melanocyte.It is important to note that all individuals carry 4-5 abnormal genes among the 30,000 or so genes that we have. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
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Oculocutaneous Albinism
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Affects of Oculocutaneous Albinism
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The frequency of OCA1 is approximately 1/40,000 in the world population. Most of the individuals identified with OCA1 have OCA type 1A. The frequency of OCA type 1B is unknown.The prevalence of OCA2 in some African populations can be as high as 1/1,500-1/8,000. The prevalence in the African American population has been estimated to be as high as 1/10,000.The frequency of OCA is approximately 1:17,000. This can vary between different populations depending on the type of OCA and the population being studied.The frequency of OCA1 is approximately 1/40,000 in the world population but this can vary in different populations. For example, the population frequency in Northern Ireland is estimated to be 1/10,000. Most of the individuals identified with OCA1 have OCA type 1A. The frequency of OCA type 1B is unknown.The prevalence of OCA2 in some African populations can be as high as 1/1,500-1/8,000. The prevalence in the African American population has been estimated to be as high as 1/10,000. The prevalence of OCA2 in most other populations is approximately 1/38,000-1/40,000.The prevalence of OCA3 is not known. Individuals with OCA3 have so far been identified in several populations including Asian, Turkish and Northern European.The prevalence of OCA4 is approximately 1/100,000 in most world populations. OCA4 is most common in Japan but has also been found in Northern European, Indian and Moroccan populations.The prevalence of OCA5 is unknown. OCA5 has only been reported in one family.The prevalence of OCA6 is unknown. OCA6 has only been reported in two individuals, one in China and a second in India.The prevalence of OCA7 is unknown. OCA7 has been reported in several individuals from the Faroe Islands, Denmark, where all were homozygous for the same mutation, a nonsense mutation (p.Arg194*). An additional individual from Lithuania was homozygous for a different mutation (c.66dupC) in the same gene.It is important to note that common changes in the DNA sequence within these four genes are also associated with normal variation in skin, hair and eye color.
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Affects of Oculocutaneous Albinism. The frequency of OCA1 is approximately 1/40,000 in the world population. Most of the individuals identified with OCA1 have OCA type 1A. The frequency of OCA type 1B is unknown.The prevalence of OCA2 in some African populations can be as high as 1/1,500-1/8,000. The prevalence in the African American population has been estimated to be as high as 1/10,000.The frequency of OCA is approximately 1:17,000. This can vary between different populations depending on the type of OCA and the population being studied.The frequency of OCA1 is approximately 1/40,000 in the world population but this can vary in different populations. For example, the population frequency in Northern Ireland is estimated to be 1/10,000. Most of the individuals identified with OCA1 have OCA type 1A. The frequency of OCA type 1B is unknown.The prevalence of OCA2 in some African populations can be as high as 1/1,500-1/8,000. The prevalence in the African American population has been estimated to be as high as 1/10,000. The prevalence of OCA2 in most other populations is approximately 1/38,000-1/40,000.The prevalence of OCA3 is not known. Individuals with OCA3 have so far been identified in several populations including Asian, Turkish and Northern European.The prevalence of OCA4 is approximately 1/100,000 in most world populations. OCA4 is most common in Japan but has also been found in Northern European, Indian and Moroccan populations.The prevalence of OCA5 is unknown. OCA5 has only been reported in one family.The prevalence of OCA6 is unknown. OCA6 has only been reported in two individuals, one in China and a second in India.The prevalence of OCA7 is unknown. OCA7 has been reported in several individuals from the Faroe Islands, Denmark, where all were homozygous for the same mutation, a nonsense mutation (p.Arg194*). An additional individual from Lithuania was homozygous for a different mutation (c.66dupC) in the same gene.It is important to note that common changes in the DNA sequence within these four genes are also associated with normal variation in skin, hair and eye color.
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Oculocutaneous Albinism
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Related disorders of Oculocutaneous Albinism
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Symptoms of the following disorders can be similar to those of oculocutaneous albinism. Comparisons may be useful for a differential diagnosis:Hermansky-Pudlak syndrome is a rare, hereditary disorder that consists of three characteristics: reduced skin, hair and eye pigmentation (oculocutaneous albinism, with associated vision problems), blood platelet dysfunction leading to prolonged bleeding, and abnormal storage of a fatty-like substance (ceroid lipofuscin) in various tissues of the body. Several different genes have been associated with Hermansky-Pudlak syndrome. (For more information on this disorder, choose “Hermansky” as your search term in the Rare Disease Database.)Ocular albinism is an X-linked recessive disorder that affects the pigment cells of the eyes. Affected individuals (mostly males) have vision problems and hair and skin color may be fairer than that of other family members. (For more information on this disorder, choose “albinism, ocular” as your search term in the Rare Disease Database.)Congenital motor nystagmus is a genetic condition characterized by an involuntary movement of eyes back and forth (nystagmus). Affected individuals will often turn or bob their head to try to improve vision clarity.OCA Genes and Normal Skin and Hair Pigment Variation
It is interesting to note that several of these genes responsible for OCA are also involved in normal variation in hair and skin pigmentation. Variation in the genes associated with OCA1, OCA2, OCA4 and OCA6 have also been associated with differences in skin and hair color. For example, variation in the OCA2 gene has been associated with either brown or blue eyes and variation in the OCA3 gene has been associated with either brown or blond hair. In these cases, the mutation does not eliminate all function of the protein (or the individuals would have OCA), but only slightly alters the protein function resulting in increases or decreases in the amount of melanin pigment produced.
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Related disorders of Oculocutaneous Albinism. Symptoms of the following disorders can be similar to those of oculocutaneous albinism. Comparisons may be useful for a differential diagnosis:Hermansky-Pudlak syndrome is a rare, hereditary disorder that consists of three characteristics: reduced skin, hair and eye pigmentation (oculocutaneous albinism, with associated vision problems), blood platelet dysfunction leading to prolonged bleeding, and abnormal storage of a fatty-like substance (ceroid lipofuscin) in various tissues of the body. Several different genes have been associated with Hermansky-Pudlak syndrome. (For more information on this disorder, choose “Hermansky” as your search term in the Rare Disease Database.)Ocular albinism is an X-linked recessive disorder that affects the pigment cells of the eyes. Affected individuals (mostly males) have vision problems and hair and skin color may be fairer than that of other family members. (For more information on this disorder, choose “albinism, ocular” as your search term in the Rare Disease Database.)Congenital motor nystagmus is a genetic condition characterized by an involuntary movement of eyes back and forth (nystagmus). Affected individuals will often turn or bob their head to try to improve vision clarity.OCA Genes and Normal Skin and Hair Pigment Variation
It is interesting to note that several of these genes responsible for OCA are also involved in normal variation in hair and skin pigmentation. Variation in the genes associated with OCA1, OCA2, OCA4 and OCA6 have also been associated with differences in skin and hair color. For example, variation in the OCA2 gene has been associated with either brown or blue eyes and variation in the OCA3 gene has been associated with either brown or blond hair. In these cases, the mutation does not eliminate all function of the protein (or the individuals would have OCA), but only slightly alters the protein function resulting in increases or decreases in the amount of melanin pigment produced.
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Oculocutaneous Albinism
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Diagnosis of Oculocutaneous Albinism
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Though physical appearance can help in diagnosing the correct type of albinism, DNA sequencing of the seven responsible genes is required to accurately determine which type of OCA is present.In the case of affected individuals with African ancestry, testing for the 2.7 kb exon deletion within the OCA2 gene is necessary.
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Diagnosis of Oculocutaneous Albinism. Though physical appearance can help in diagnosing the correct type of albinism, DNA sequencing of the seven responsible genes is required to accurately determine which type of OCA is present.In the case of affected individuals with African ancestry, testing for the 2.7 kb exon deletion within the OCA2 gene is necessary.
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Oculocutaneous Albinism
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Therapies of Oculocutaneous Albinism
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TreatmentIndividuals diagnosed with OCA should be evaluated by an ophthalmologist at the time of diagnosis to determine the extent of the disease and have ongoing ophthalmologic examinations annually. Glasses or contact lenses can improve vision. Additionally, visual acuity can improve with age, so regular visits to the ophthalmologist are necessary. Dark glasses or a hat with a wide brim can help to reduce sun sensitivity (photophobia). Affected individuals should also be evaluated to determine the amount of pigment in the skin. Skin should be protected from sun exposure with the use of clothing and sun block to reduce the risk of sunburn, skin damage and skin cancer. Specific recommendations for skin care depend on the pigment status.
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Therapies of Oculocutaneous Albinism. TreatmentIndividuals diagnosed with OCA should be evaluated by an ophthalmologist at the time of diagnosis to determine the extent of the disease and have ongoing ophthalmologic examinations annually. Glasses or contact lenses can improve vision. Additionally, visual acuity can improve with age, so regular visits to the ophthalmologist are necessary. Dark glasses or a hat with a wide brim can help to reduce sun sensitivity (photophobia). Affected individuals should also be evaluated to determine the amount of pigment in the skin. Skin should be protected from sun exposure with the use of clothing and sun block to reduce the risk of sunburn, skin damage and skin cancer. Specific recommendations for skin care depend on the pigment status.
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Oculocutaneous Albinism
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Overview of Oculopharyngeal Muscular Dystrophy
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Oculopharyngeal muscular dystrophy (OPMD) is a rare genetic muscle disorder with onset during adulthood most often between 40 and 60 years of age. OPMD is characterized by slowly progressive muscle disease (myopathy) affecting the muscles of the upper eyelids and the throat. Affected individuals may develop drooping of the eyelids (ptosis), trouble moving their eyes (ophthalmoplegia) and/or difficulty swallowing (dysphagia). Double vision (diplopia) is uncommon. Eventually, additional muscles may become involved including those of the upper legs and arms (proximal limb weakness). In some cases, muscle weakness of the legs may eventually cause difficulty walking. OPMD may be inherited as an autosomal dominant or recessive trait.OPMD belongs to a group of rare genetic muscle disorders known as the muscular dystrophies. These disorders are characterized by weakness and atrophy 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. Unlike OPMD, most forms of muscular dystrophy have onset during childhood or adolescence.
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Overview of Oculopharyngeal Muscular Dystrophy. Oculopharyngeal muscular dystrophy (OPMD) is a rare genetic muscle disorder with onset during adulthood most often between 40 and 60 years of age. OPMD is characterized by slowly progressive muscle disease (myopathy) affecting the muscles of the upper eyelids and the throat. Affected individuals may develop drooping of the eyelids (ptosis), trouble moving their eyes (ophthalmoplegia) and/or difficulty swallowing (dysphagia). Double vision (diplopia) is uncommon. Eventually, additional muscles may become involved including those of the upper legs and arms (proximal limb weakness). In some cases, muscle weakness of the legs may eventually cause difficulty walking. OPMD may be inherited as an autosomal dominant or recessive trait.OPMD belongs to a group of rare genetic muscle disorders known as the muscular dystrophies. These disorders are characterized by weakness and atrophy 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. Unlike OPMD, most forms of muscular dystrophy have onset during childhood or adolescence.
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Oculopharyngeal Muscular Dystrophy
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Symptoms of Oculopharyngeal Muscular Dystrophy
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Although the defective gene that causes OPMD is present at birth, the symptoms usually do not appear until adulthood sometime between 40 and 60 years of age. OPMD is characterized by progressive weakness of certain muscles around the eyes, in the throat, and less commonly in the pelvic and shoulder areas including the muscles of the upper legs and arms. The rate of progression and specific symptoms associated with OPMD vary greatly from case to case even among members of the same family. The two most common initial symptoms of OPMD are drooping of the upper eyelid (ptosis) and difficulty swallowing. Ptosis can cause visual impairment if the eyelids droop over the pupils obstructing sight. As a result, some affected individuals may tilt their head back to compensate. Both eyes are usually affected (bilateral). Eventually, additional muscles around the eye may gradually weaken; potentially restricting the movements of the eyes, but this is rarely complete. Some individuals with OPMD may develop double vision (diplopia). Affected individuals who experience difficulty swallowing may feel as if food is getting stuck in their throats. If swallowing difficulties become severe enough, they can lead to the ingestion of food or liquids into the lungs (aspiration), which can cause inflammation or infection of the lungs (aspiration pneumonia). As the disease progresses, some individuals will develop weakness and degeneration (atrophy) of the muscles of the upper legs (proximal muscles). Proximal muscles are the muscles that are closest to the center of the body such as the muscles of the shoulder, pelvis, and upper arms and legs. Muscle weakness may spread from the proximal muscles to affect distal muscles. 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. The distal muscles of the legs may become involved in some cases of OPMD. Weakness of the muscles of legs does not correlate to the severity of muscle weakness of the eyelids or throat and can occur early in the disease or later. It may be mild or severe. In severe cases, weakness of the leg muscles can affect an individual's ability to kneel, climb stairs, squat, or walk. In approximately 10 percent of cases, affected individuals may eventually require a wheelchair. Additional symptoms may eventually occur including weakness and degeneration (atrophy) of the tongue, weakness and atrophy of the proximal muscles of the arms, limitation of upward gaze, difficulty speaking (dysphonia), and weakness of additional facial muscles.
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Symptoms of Oculopharyngeal Muscular Dystrophy. Although the defective gene that causes OPMD is present at birth, the symptoms usually do not appear until adulthood sometime between 40 and 60 years of age. OPMD is characterized by progressive weakness of certain muscles around the eyes, in the throat, and less commonly in the pelvic and shoulder areas including the muscles of the upper legs and arms. The rate of progression and specific symptoms associated with OPMD vary greatly from case to case even among members of the same family. The two most common initial symptoms of OPMD are drooping of the upper eyelid (ptosis) and difficulty swallowing. Ptosis can cause visual impairment if the eyelids droop over the pupils obstructing sight. As a result, some affected individuals may tilt their head back to compensate. Both eyes are usually affected (bilateral). Eventually, additional muscles around the eye may gradually weaken; potentially restricting the movements of the eyes, but this is rarely complete. Some individuals with OPMD may develop double vision (diplopia). Affected individuals who experience difficulty swallowing may feel as if food is getting stuck in their throats. If swallowing difficulties become severe enough, they can lead to the ingestion of food or liquids into the lungs (aspiration), which can cause inflammation or infection of the lungs (aspiration pneumonia). As the disease progresses, some individuals will develop weakness and degeneration (atrophy) of the muscles of the upper legs (proximal muscles). Proximal muscles are the muscles that are closest to the center of the body such as the muscles of the shoulder, pelvis, and upper arms and legs. Muscle weakness may spread from the proximal muscles to affect distal muscles. 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. The distal muscles of the legs may become involved in some cases of OPMD. Weakness of the muscles of legs does not correlate to the severity of muscle weakness of the eyelids or throat and can occur early in the disease or later. It may be mild or severe. In severe cases, weakness of the leg muscles can affect an individual's ability to kneel, climb stairs, squat, or walk. In approximately 10 percent of cases, affected individuals may eventually require a wheelchair. Additional symptoms may eventually occur including weakness and degeneration (atrophy) of the tongue, weakness and atrophy of the proximal muscles of the arms, limitation of upward gaze, difficulty speaking (dysphonia), and weakness of additional facial muscles.
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Oculopharyngeal Muscular Dystrophy
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Causes of Oculopharyngeal Muscular Dystrophy
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OPMD may be inherited as an autosomal dominant or recessive trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. 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.Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. Investigators have determined that OPMD is caused by disruptions or changes (mutations) of the polyadenylate binding protein nuclear 1 (PABPN1) gene located on the long arm (q) of chromosome 14 (14q11.2-q13. 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 11p13” refers to band 13 on the short arm of chromosome 11. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
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Causes of Oculopharyngeal Muscular Dystrophy. OPMD may be inherited as an autosomal dominant or recessive trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. 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.Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. Investigators have determined that OPMD is caused by disruptions or changes (mutations) of the polyadenylate binding protein nuclear 1 (PABPN1) gene located on the long arm (q) of chromosome 14 (14q11.2-q13. 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 11p13” refers to band 13 on the short arm of chromosome 11. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
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Oculopharyngeal Muscular Dystrophy
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Affects of Oculopharyngeal Muscular Dystrophy
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OPMD is a rare disorder that affects males and females in equal numbers. The disorder has been reported in approximately 29 countries. The largest grouping (cluster) of cases was reported in French descendents in Quebec, Canada (1 in 1000). Clusters have also been reported in the Bukhara Jews of Israel and a Hispanic population of New Mexico. One published report estimated the prevalence of OPMD in France at 1 in 100,000 individuals. The autosomal dominant form of OPMD is more common than the autosomal recessive form. OPMD was first reported in the medical literature in 1915. The muscular dystrophies affect approximately 250,000 people in the United States.
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Affects of Oculopharyngeal Muscular Dystrophy. OPMD is a rare disorder that affects males and females in equal numbers. The disorder has been reported in approximately 29 countries. The largest grouping (cluster) of cases was reported in French descendents in Quebec, Canada (1 in 1000). Clusters have also been reported in the Bukhara Jews of Israel and a Hispanic population of New Mexico. One published report estimated the prevalence of OPMD in France at 1 in 100,000 individuals. The autosomal dominant form of OPMD is more common than the autosomal recessive form. OPMD was first reported in the medical literature in 1915. The muscular dystrophies affect approximately 250,000 people in the United States.
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Oculopharyngeal Muscular Dystrophy
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Related disorders of Oculopharyngeal Muscular Dystrophy
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Symptoms of the following disorders can be similar to those of OPMD. Comparisons may be useful for a differential diagnosis.Myasthenia gravis is a neuromuscular disorder primarily characterized by muscle weakness and muscle fatigue. Although the disorder usually becomes apparent during adulthood, symptom onset may occur at any age. The condition may be restricted to certain muscle groups, particularly those of the eyes (ocular myasthenia gravis), or may become more generalized (generalized myasthenia gravis), involving multiple muscle groups. Most individuals with myasthenia gravis develop weakness and drooping of the eyelids (ptosis); weakness of eye muscles, resulting in double vision (diplopia); and excessive muscle fatigue following activity. Additional features commonly include weakness of facial muscles; impaired articulation of speech (dysarthria); difficulties chewing and swallowing (dysphagia); and weakness of the upper arms and legs (proximal limb weakness). In addition, in about 10 percent of cases, affected individuals may develop potentially life-threatening complications due to severe involvement of muscles used during breathing (myasthenic crisis). Myasthenia gravis results from an abnormal immune reaction in which the body's natural immune defenses (i.e., antibodies) inappropriately attack and gradually destroy certain receptors in muscles that receive nerve impulses (antibody-mediated autoimmune response). (For more information on this disorder, choose “myasthenia gravis” as your search term in the Rare Disease Database.)Chronic progressive external ophthalmoplegia (CPEO or Kearns-Sayre syndrome) is a mitochondrial disorder. Mitochondria are the “energy factories” of cells and contain a separate DNA from the “regular” genes. Inheritance of mitochondrial DNA only occurs through the mother and therefore CPEO passes through the mother's side of the family. Patients with CPEO develop progressive drooping of the eyelids and inability to move the eyes. The poor eye movements are generally symmetric, and patients do not develop double vision. Although mitochondria exist in every cell of the body, many patients do not experience other symptoms. Others may experience a slow or abnormal heart rate, systemic muscle weakness, or visual loss. These patients typically do not suffer from difficulty swallowing or speaking. No specific genetic testing is available to diagnose CPEO, however numerous mutations have been identified for mitochondrial disorders in general. In some instances, a muscle biopsy from the quadriceps in the leg may be performed. It may show a characteristic pattern indicating a mitochondrial disorder. (For more information on this disorder, choose “Kearns-Sayre syndrome” as your search term in the Rare Disease Database.) Blepharophimosis, ptosis, epicanthus inversus syndrome (BPES) is a rare disorder that is inherited as an autosomal dominant trait. The main findings of this disorder are eyelids that are abnormally narrow horizontally (blepharophimosis), a vertical fold of skin from the lower eyelid up either side of the nose (epicanthus inversus), and drooping of the upper eyelids (ptosis). There are thought to be two types of the syndrome. Type I BPES may involve female infertility and is inherited as an autosomal dominant genetic trait. Both male and female children of a male with type I BPES have a 50% chance of being affected. If females with type I BPES are able to have children, the odds are 50% that each child (male or female) will have type I BPES. Type II BPES is also transmitted as an autosomal dominant trait meaning that either parent may transmit the disorder and the children have a 50% chance of being affected. Type II is not associated with female infertility. (For more information on this disorder, choose “BPES” as your search term in the Rare Disease Database.)Oculopharyngodistal myopathy is an extremely rare disorder characterized by droopy eyelids (ptosis) and slowly progressive weakening of muscles of the throat resulting in difficulty swallowing (dysphagia). Affected individuals also experience severe facial muscle weakness, including external eye (ocular) muscles often resulting in limitations in eye movement. Individuals with oculopharyngodistal myopathy also develop weakness of the muscles of the lower legs (distal muscles). Over time, the muscles of the upper legs and arms become involved. Affected individuals may eventually require a wheelchair.
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Related disorders of Oculopharyngeal Muscular Dystrophy. Symptoms of the following disorders can be similar to those of OPMD. Comparisons may be useful for a differential diagnosis.Myasthenia gravis is a neuromuscular disorder primarily characterized by muscle weakness and muscle fatigue. Although the disorder usually becomes apparent during adulthood, symptom onset may occur at any age. The condition may be restricted to certain muscle groups, particularly those of the eyes (ocular myasthenia gravis), or may become more generalized (generalized myasthenia gravis), involving multiple muscle groups. Most individuals with myasthenia gravis develop weakness and drooping of the eyelids (ptosis); weakness of eye muscles, resulting in double vision (diplopia); and excessive muscle fatigue following activity. Additional features commonly include weakness of facial muscles; impaired articulation of speech (dysarthria); difficulties chewing and swallowing (dysphagia); and weakness of the upper arms and legs (proximal limb weakness). In addition, in about 10 percent of cases, affected individuals may develop potentially life-threatening complications due to severe involvement of muscles used during breathing (myasthenic crisis). Myasthenia gravis results from an abnormal immune reaction in which the body's natural immune defenses (i.e., antibodies) inappropriately attack and gradually destroy certain receptors in muscles that receive nerve impulses (antibody-mediated autoimmune response). (For more information on this disorder, choose “myasthenia gravis” as your search term in the Rare Disease Database.)Chronic progressive external ophthalmoplegia (CPEO or Kearns-Sayre syndrome) is a mitochondrial disorder. Mitochondria are the “energy factories” of cells and contain a separate DNA from the “regular” genes. Inheritance of mitochondrial DNA only occurs through the mother and therefore CPEO passes through the mother's side of the family. Patients with CPEO develop progressive drooping of the eyelids and inability to move the eyes. The poor eye movements are generally symmetric, and patients do not develop double vision. Although mitochondria exist in every cell of the body, many patients do not experience other symptoms. Others may experience a slow or abnormal heart rate, systemic muscle weakness, or visual loss. These patients typically do not suffer from difficulty swallowing or speaking. No specific genetic testing is available to diagnose CPEO, however numerous mutations have been identified for mitochondrial disorders in general. In some instances, a muscle biopsy from the quadriceps in the leg may be performed. It may show a characteristic pattern indicating a mitochondrial disorder. (For more information on this disorder, choose “Kearns-Sayre syndrome” as your search term in the Rare Disease Database.) Blepharophimosis, ptosis, epicanthus inversus syndrome (BPES) is a rare disorder that is inherited as an autosomal dominant trait. The main findings of this disorder are eyelids that are abnormally narrow horizontally (blepharophimosis), a vertical fold of skin from the lower eyelid up either side of the nose (epicanthus inversus), and drooping of the upper eyelids (ptosis). There are thought to be two types of the syndrome. Type I BPES may involve female infertility and is inherited as an autosomal dominant genetic trait. Both male and female children of a male with type I BPES have a 50% chance of being affected. If females with type I BPES are able to have children, the odds are 50% that each child (male or female) will have type I BPES. Type II BPES is also transmitted as an autosomal dominant trait meaning that either parent may transmit the disorder and the children have a 50% chance of being affected. Type II is not associated with female infertility. (For more information on this disorder, choose “BPES” as your search term in the Rare Disease Database.)Oculopharyngodistal myopathy is an extremely rare disorder characterized by droopy eyelids (ptosis) and slowly progressive weakening of muscles of the throat resulting in difficulty swallowing (dysphagia). Affected individuals also experience severe facial muscle weakness, including external eye (ocular) muscles often resulting in limitations in eye movement. Individuals with oculopharyngodistal myopathy also develop weakness of the muscles of the lower legs (distal muscles). Over time, the muscles of the upper legs and arms become involved. Affected individuals may eventually require a wheelchair.
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Oculopharyngeal Muscular Dystrophy
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Diagnosis of Oculopharyngeal Muscular Dystrophy
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A diagnosis of OPMD is suspected based upon a thorough clinical evaluation, a detailed patient history, and identification of characteristic findings. A diagnosis is confirmed through commercially available blood tests that can detect the specific genetic abnormality associated with OPMD (i.e., mutation of the PABPN1 gene).
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Diagnosis of Oculopharyngeal Muscular Dystrophy. A diagnosis of OPMD is suspected based upon a thorough clinical evaluation, a detailed patient history, and identification of characteristic findings. A diagnosis is confirmed through commercially available blood tests that can detect the specific genetic abnormality associated with OPMD (i.e., mutation of the PABPN1 gene).
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Therapies of Oculopharyngeal Muscular Dystrophy
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Treatment
The treatment of OPMD is directed toward the specific symptoms that are apparent in each individual. Ptosis may be treated cautiously with plastic surgery on the eyelids (blepharoptosis repair). The goal of surgery is to raise the eyelids above the visual axis so the patient may see. However, because the muscles that close the eyelids are weak, the patient may not be able to completely close their eyelids after surgery. In cases where difficulty swallowing (dysphagia) is severe, a surgical procedure known as cricopharyngeal myotomy may be used. In this procedure, the cricopharyngeal muscle of the throat is cut so that when swallowing occurs the muscle remains relaxed allowing the passage of food or liquid. In other cases, a feeding tube can be placed directly into the small intestine to bypass swallowing altogether.Orthopedic devices such as canes, leg braces, or walkers can assist individuals who have difficulty walking. Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
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Therapies of Oculopharyngeal Muscular Dystrophy. Treatment
The treatment of OPMD is directed toward the specific symptoms that are apparent in each individual. Ptosis may be treated cautiously with plastic surgery on the eyelids (blepharoptosis repair). The goal of surgery is to raise the eyelids above the visual axis so the patient may see. However, because the muscles that close the eyelids are weak, the patient may not be able to completely close their eyelids after surgery. In cases where difficulty swallowing (dysphagia) is severe, a surgical procedure known as cricopharyngeal myotomy may be used. In this procedure, the cricopharyngeal muscle of the throat is cut so that when swallowing occurs the muscle remains relaxed allowing the passage of food or liquid. In other cases, a feeding tube can be placed directly into the small intestine to bypass swallowing altogether.Orthopedic devices such as canes, leg braces, or walkers can assist individuals who have difficulty walking. Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
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Oculopharyngeal Muscular Dystrophy
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Overview of Ogilvie syndrome
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Ogilvie syndrome is a rare, acquired disorder characterized by abnormalities affecting the involuntary, rhythmic muscular contractions (peristalsis) within the colon. Peristalsis propels food and other material through the digestive system through the coordination of muscles, nerves and hormones. The colon is often significantly widened (dilated). Symptoms are similar to other forms of intestinal pseudo-obstruction and can include nausea, vomiting, abdominal bloating or swelling and constipation. The symptoms of Ogilvie syndrome mimic those of mechanical obstruction of the colon, but no such physical obstruction is present. Mechanical obstruction refers to something (e.g., tumor, scar tissue, etc.) physically blocking the passage of food and other material through the GI tract. Ogilvie syndrome is usually associated with an underlying disorder, trauma or surgery. Ogilvie syndrome can be managed with conservative treatment, but if unrecognized and untreated can lead to serious, potentially life-threatening complications.Ogilvie syndrome was first described in the medical literature in 1948 by a British surgeon named Sir William Ogilvie. The disorder is also known as acute colonic pseudo-obstruction (ACPO). It is not the same as chronic intestinal pseudo-obstruction, a similar, but distinct disorder.
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Overview of Ogilvie syndrome. Ogilvie syndrome is a rare, acquired disorder characterized by abnormalities affecting the involuntary, rhythmic muscular contractions (peristalsis) within the colon. Peristalsis propels food and other material through the digestive system through the coordination of muscles, nerves and hormones. The colon is often significantly widened (dilated). Symptoms are similar to other forms of intestinal pseudo-obstruction and can include nausea, vomiting, abdominal bloating or swelling and constipation. The symptoms of Ogilvie syndrome mimic those of mechanical obstruction of the colon, but no such physical obstruction is present. Mechanical obstruction refers to something (e.g., tumor, scar tissue, etc.) physically blocking the passage of food and other material through the GI tract. Ogilvie syndrome is usually associated with an underlying disorder, trauma or surgery. Ogilvie syndrome can be managed with conservative treatment, but if unrecognized and untreated can lead to serious, potentially life-threatening complications.Ogilvie syndrome was first described in the medical literature in 1948 by a British surgeon named Sir William Ogilvie. The disorder is also known as acute colonic pseudo-obstruction (ACPO). It is not the same as chronic intestinal pseudo-obstruction, a similar, but distinct disorder.
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Symptoms of Ogilvie syndrome
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The symptoms and severity of Ogilvie syndrome can vary greatly from one person to another. Ogilvie syndrome can potentially cause serious, life-threatening complications. The disorder most often occurs in hospitalized or institutionalized patients who have an underlying illness or have recently undergone surgery. Common symptoms of Ogilvie syndrome include abdominal swelling (distention) and bloating, abdominal pain, nausea and vomiting. Some individuals have a history of chronic, sometimes severe constipation. Abdominal distention usually develops over several days, but can potentially develop rapidly within a 24-hour period. Colonic distention can be massive. Additional symptoms that can occur including fever, marked abdominal tenderness and an abnormal increase in the number of white blood cells (leukocytosis) often due to infection. Fever, marked abdominal tenderness, and leukocytosis are more common individuals with perforation or ischemia, but can occur in the absence of these conditions. Distention of the colon in Ogilvie syndrome can potentially lead to serious, life-threatening complications including the formation of a hole in the wall of the colon (perforation) or lack of blood flow (ischemia) to the colon. Perforation may allow the contents of the colon to spill out into the abdominal cavity. A perforated bowel can cause intense abdominal pain, fever, and sepsis, a severe blood infection. The cecum, the large pouch that marks the beginning of the large intestines, is the area most often where the greatest dilation occurs and consequently is most at risk of perforation. Perforation in Ogilvie syndrome is rare developing in only 1-3 percent of affected individuals.Ischemic bowel results in tissue damage or death in the affected portion of the bowel. Individuals with a perforated or ischemic bowel have a greater incidence of fever and may have signs of inflammation of the peritoneum (peritonitis). The peritoneum is the thin tissue that lines the inside of the abdominal wall and covers most of the abdominal organs.
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Symptoms of Ogilvie syndrome. The symptoms and severity of Ogilvie syndrome can vary greatly from one person to another. Ogilvie syndrome can potentially cause serious, life-threatening complications. The disorder most often occurs in hospitalized or institutionalized patients who have an underlying illness or have recently undergone surgery. Common symptoms of Ogilvie syndrome include abdominal swelling (distention) and bloating, abdominal pain, nausea and vomiting. Some individuals have a history of chronic, sometimes severe constipation. Abdominal distention usually develops over several days, but can potentially develop rapidly within a 24-hour period. Colonic distention can be massive. Additional symptoms that can occur including fever, marked abdominal tenderness and an abnormal increase in the number of white blood cells (leukocytosis) often due to infection. Fever, marked abdominal tenderness, and leukocytosis are more common individuals with perforation or ischemia, but can occur in the absence of these conditions. Distention of the colon in Ogilvie syndrome can potentially lead to serious, life-threatening complications including the formation of a hole in the wall of the colon (perforation) or lack of blood flow (ischemia) to the colon. Perforation may allow the contents of the colon to spill out into the abdominal cavity. A perforated bowel can cause intense abdominal pain, fever, and sepsis, a severe blood infection. The cecum, the large pouch that marks the beginning of the large intestines, is the area most often where the greatest dilation occurs and consequently is most at risk of perforation. Perforation in Ogilvie syndrome is rare developing in only 1-3 percent of affected individuals.Ischemic bowel results in tissue damage or death in the affected portion of the bowel. Individuals with a perforated or ischemic bowel have a greater incidence of fever and may have signs of inflammation of the peritoneum (peritonitis). The peritoneum is the thin tissue that lines the inside of the abdominal wall and covers most of the abdominal organs.
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Causes of Ogilvie syndrome
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The exact cause and underlying mechanisms of Ogilvie syndrome are not fully understood and controversial. The disorder most often occurs in individuals with a recent, serious medical condition or surgical procedure. The list of conditions that have been associated with Ogilvie syndrome is extensive. The three most common conditions associated with Ogilvie syndrome are non-operative trauma, infection and heart disease, especially a heart attack (myocardial infarction) or congestive heart failure. The most common infections associated with Ogilvie syndrome are pneumonia and sepsis. Surgeries that have been associated with Ogilvie syndrome include abdominal, orthopedic (especially total hip replacement), neurologic, urologic and cardiac surgery. Severe pulmonary disease, malignancy, kidney (renal) disease, respiratory failure, metabolic disorders and severe electrolyte imbalances have also been associated with Ogilvie syndrome. The use of certain medications has also been associated with the development of Ogilvie syndrome including neuroleptic medications, anticholinergics, amphetamines, steroids and narcotics. Ogilvie syndrome most likely results from abnormalities affecting the autonomic nervous system's control of colonic motor function. The autonomic nervous system is the portion of the nervous system that controls or regulates certain involuntary body functions including heart rate, blood pressure, temperature regulation, breathing and more. The autonomic nervous system also controls or regulates the bowels and bladder.
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Causes of Ogilvie syndrome. The exact cause and underlying mechanisms of Ogilvie syndrome are not fully understood and controversial. The disorder most often occurs in individuals with a recent, serious medical condition or surgical procedure. The list of conditions that have been associated with Ogilvie syndrome is extensive. The three most common conditions associated with Ogilvie syndrome are non-operative trauma, infection and heart disease, especially a heart attack (myocardial infarction) or congestive heart failure. The most common infections associated with Ogilvie syndrome are pneumonia and sepsis. Surgeries that have been associated with Ogilvie syndrome include abdominal, orthopedic (especially total hip replacement), neurologic, urologic and cardiac surgery. Severe pulmonary disease, malignancy, kidney (renal) disease, respiratory failure, metabolic disorders and severe electrolyte imbalances have also been associated with Ogilvie syndrome. The use of certain medications has also been associated with the development of Ogilvie syndrome including neuroleptic medications, anticholinergics, amphetamines, steroids and narcotics. Ogilvie syndrome most likely results from abnormalities affecting the autonomic nervous system's control of colonic motor function. The autonomic nervous system is the portion of the nervous system that controls or regulates certain involuntary body functions including heart rate, blood pressure, temperature regulation, breathing and more. The autonomic nervous system also controls or regulates the bowels and bladder.
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Affects of Ogilvie syndrome
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Ogilvie syndrome is believed to affect males and females in equal numbers, although one large study suggested that males may be affected more often than females. Ogilvie syndrome can potentially affect individuals of any age, but most often occurs in late middle age (mean age in the 60s). The exact incidence and prevalence of the disorder is unknown. Because cases can go unrecognized and resolve spontaneously, determining the true frequency of the disorder is the general population is difficult. Ogilvie syndrome generally develops in hospitalized or institutionalized individuals following an acute illness or surgery.
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Affects of Ogilvie syndrome. Ogilvie syndrome is believed to affect males and females in equal numbers, although one large study suggested that males may be affected more often than females. Ogilvie syndrome can potentially affect individuals of any age, but most often occurs in late middle age (mean age in the 60s). The exact incidence and prevalence of the disorder is unknown. Because cases can go unrecognized and resolve spontaneously, determining the true frequency of the disorder is the general population is difficult. Ogilvie syndrome generally develops in hospitalized or institutionalized individuals following an acute illness or surgery.
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Related disorders of Ogilvie syndrome
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Symptoms of the following disorders can be similar to those of Ogilvie syndrome. Comparisons may be useful for a differential diagnosis.Chronic intestinal pseudo-obstruction (CIP) is a rare, potentially disabling gastrointestinal disorder characterized by abnormalities affecting the involuntary, rhythmic muscular contractions (a process called peristalsis) within the gastrointestinal (GI) tract. Peristalsis propels food and other material through the digestive system through the coordination of muscles, nerves and hormones. CIP usually results from abnormalities affecting the muscles or nerves that are involved in peristalsis. Consequently, peristalsis becomes altered and inefficient. The symptoms of CIP resemble those caused by mechanical obstruction of the GI tract. Mechanical obstruction refers to something (such as a tumor, scar tissue, etc.) physically blocking the passage of food and other material through the GI tract. In individuals with CIP no such physical obstruction is present, hence the term pseudo-obstruction. Common symptoms include nausea, abdominal pain, abdominal swelling (distention) and constipation. Ultimately, normal nutritional requirements cannot be met leading to unintended weight loss and malnourishment. CIP can potentially cause severe, even life-threatening complications. Some individuals with CIP may experience a sudden, rapid onset of the disorder that can be mistaken for Ogilvie syndrome. (For more information on this disorder, choose “chronic intestinal pseudo-obstruction” as your search term in the Rare Disease Database.)The signs and symptoms of mechanical obstruction of the GI tract are almost indistinguishable from those associated with Ogilvie syndrome. Such symptoms include abdominal pain and bloating, nausea and vomiting and constipation. Mechanical obstruction can be caused by a variety of conditions including adhesions and scar tissue, foreign (ingested) material, gallstones, tumors, hernia, abnormal tissue growth, twisting of a loop of the intestines back around itself (volvulus), and intussusception, a condition in which one portion of the intestines slides into another much like a collapsing telescope. It is extremely important to distinguish Ogilvie syndrome from mechanical obstruction of the GI tract as the underlying process and potential treatments are different. A variety of gastrointestinal disorders can have signs and symptoms that are similar to those seen in Ogilvie syndrome. Such disorders include irritable bowel syndrome (IBS), gastroparesis, functional dyspepsia, Crohn's disease, and cyclic vomiting syndrome. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Related disorders of Ogilvie syndrome. Symptoms of the following disorders can be similar to those of Ogilvie syndrome. Comparisons may be useful for a differential diagnosis.Chronic intestinal pseudo-obstruction (CIP) is a rare, potentially disabling gastrointestinal disorder characterized by abnormalities affecting the involuntary, rhythmic muscular contractions (a process called peristalsis) within the gastrointestinal (GI) tract. Peristalsis propels food and other material through the digestive system through the coordination of muscles, nerves and hormones. CIP usually results from abnormalities affecting the muscles or nerves that are involved in peristalsis. Consequently, peristalsis becomes altered and inefficient. The symptoms of CIP resemble those caused by mechanical obstruction of the GI tract. Mechanical obstruction refers to something (such as a tumor, scar tissue, etc.) physically blocking the passage of food and other material through the GI tract. In individuals with CIP no such physical obstruction is present, hence the term pseudo-obstruction. Common symptoms include nausea, abdominal pain, abdominal swelling (distention) and constipation. Ultimately, normal nutritional requirements cannot be met leading to unintended weight loss and malnourishment. CIP can potentially cause severe, even life-threatening complications. Some individuals with CIP may experience a sudden, rapid onset of the disorder that can be mistaken for Ogilvie syndrome. (For more information on this disorder, choose “chronic intestinal pseudo-obstruction” as your search term in the Rare Disease Database.)The signs and symptoms of mechanical obstruction of the GI tract are almost indistinguishable from those associated with Ogilvie syndrome. Such symptoms include abdominal pain and bloating, nausea and vomiting and constipation. Mechanical obstruction can be caused by a variety of conditions including adhesions and scar tissue, foreign (ingested) material, gallstones, tumors, hernia, abnormal tissue growth, twisting of a loop of the intestines back around itself (volvulus), and intussusception, a condition in which one portion of the intestines slides into another much like a collapsing telescope. It is extremely important to distinguish Ogilvie syndrome from mechanical obstruction of the GI tract as the underlying process and potential treatments are different. A variety of gastrointestinal disorders can have signs and symptoms that are similar to those seen in Ogilvie syndrome. Such disorders include irritable bowel syndrome (IBS), gastroparesis, functional dyspepsia, Crohn's disease, and cyclic vomiting syndrome. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Diagnosis of Ogilvie syndrome
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A diagnosis of Ogilvie syndrome is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests to rule out other conditions or identify underlying causes.Clinical Testing and Work-UpOgilvie syndrome is virtually indistinguishable from mechanical obstruction based solely on signs and symptoms. X-ray examination of the colon will be performed to rule out mechanical obstruction. Plain abdominal films (radiographs) can reveal an abnormally expanded (dilated) colon. Plain abdominal radiographs can also reveal dilation and abnormal air-fluid levels in the small bowel, both of which are indicative of intestinal obstruction.A water-soluble enema or computed tomography should be performed to rule out mechanical obstruction in cases where gas and distention does not occur throughout the entire colon. A water-soluble enema is a procedure that allows a physician to evaluate the large bowel. During the exam, a soft, thin tube is inserted into the anal passage. Dye is injected into the tube and x-rays will be taken. The dye will show the outline of the large bowel on the x-ray, revealing mechanical obstruction if present. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures such as the colon.
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Diagnosis of Ogilvie syndrome. A diagnosis of Ogilvie syndrome is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests to rule out other conditions or identify underlying causes.Clinical Testing and Work-UpOgilvie syndrome is virtually indistinguishable from mechanical obstruction based solely on signs and symptoms. X-ray examination of the colon will be performed to rule out mechanical obstruction. Plain abdominal films (radiographs) can reveal an abnormally expanded (dilated) colon. Plain abdominal radiographs can also reveal dilation and abnormal air-fluid levels in the small bowel, both of which are indicative of intestinal obstruction.A water-soluble enema or computed tomography should be performed to rule out mechanical obstruction in cases where gas and distention does not occur throughout the entire colon. A water-soluble enema is a procedure that allows a physician to evaluate the large bowel. During the exam, a soft, thin tube is inserted into the anal passage. Dye is injected into the tube and x-rays will be taken. The dye will show the outline of the large bowel on the x-ray, revealing mechanical obstruction if present. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures such as the colon.
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Therapies of Ogilvie syndrome
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TreatmentThere is no specific therapy for Ogilvie syndrome. Therapeutic options include support therapy, medications, decompression and surgery. Most therapeutic options have not undergone extensive controlled clinical study.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease progression; the presence or absence of certain symptoms; the status of the bowel; an individual's age and general health; and/or other elements. Decisions concerning the use of particular therapeutic options should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.When planning treating, physicians must weigh conservative treatment and observation versus proceeding with a surgical decompression of the dilated colon. Most individuals respond to conservative management.The initial management of Ogilvie syndrome requires an examination to detect signs of bowel perforation or ischemia. Signs of these complications require immediate medical intervention.In cases where an identifiable cause for Ogilvie syndrome (e.g., respiratory failure, congestive heart failure, infection) has been established, treatment of the underlying condition is mandatory. If Ogilvie syndrome is linked to the use of certain medications, affected individuals must stop taking the medications.Supportive therapy may include withholding oral food and fluid intake, administering intravenous fluids to correct fluid and electrolyte imbalances, employing nasogastric suction to limit the amount of air that is swallowed to avoid air from further expanding the colon, and inserting a long, thin tube into the rectum to allow the release of gas and stool, a procedure known as rectal tube to gravity drainage. Stopping the use of medications that can affect colon motility such as opiates and anticholinergics is also recommended. The success of supportive therapy varies among affected individuals.One of the few treatment options for Ogilvie syndrome that has undergone clinical study is a medication known as neostigmine. Studies have shown that intravenous administration of neostigmine has led to rapid decompression of the colon in individuals with Ogilvie syndrome who did not respond to conservative management. Neostigmine is believed to interfere with the breakdown of the neurotransmitter acetylcholine, increasing the duration and activity of acetylcholine. Acetylcholine helps the communication between nerve and muscle cells, such as those in the GI tract. Neostigmine improves GI motility and increases the transit of food and other material through the GI tract. Although infrequent, colonic distention can recur following successful treatment with neostigmine.Some individuals with Ogilvie syndrome may be treated with colonic decompression, a procedure that reduces pressure within the colon. Usually, this treatment is reserved for individuals with persistent, marked colonic distention who have not responded to other treatment options. A specific procedure known as colonoscopic decompression, in which a thin, flexible tube is inserted into the anal passage and threaded up to the colon, may be used. Although colonoscopic decompression has not undergone clinical study, numerous reports in the medical literature cite it as an effective method for removing air from the colon and, potentially, reducing the risk of perforation. In addition, some individuals may require the insertion of a decompression tube within the colon in to order to achieve decompression or reduce the risk of recurrence. Decompression techniques carry risks including perforation. There is also a risk of disease recurrence.In rare cases, individuals with Ogilvie syndrome may require surgical intervention. Surgery is used when affected individuals have signs of perforation or ischemia or have failed to respond to other treatment options. Surgery can be associated with significant morbidity and mortality due in part to the severity of the underlying condition. The specific type of surgery used may vary depending upon the status of the bowel. If perforation or ischemia is not present, a cecostomy is usually performed. A cecostomy is a procedure in which an artificial opening is created in the cecum, allowing physicians to "vent" excess air or contents from the colon. This procedure has a high success rate in individuals with Ogilvie syndrome.If perforation or ischemia is present, surgery to remove a portion of the colon (subtotal colectomy) may be necessary. The specific surgical procedure used can vary based upon several factors such as the status of the cecum.
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Therapies of Ogilvie syndrome. TreatmentThere is no specific therapy for Ogilvie syndrome. Therapeutic options include support therapy, medications, decompression and surgery. Most therapeutic options have not undergone extensive controlled clinical study.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease progression; the presence or absence of certain symptoms; the status of the bowel; an individual's age and general health; and/or other elements. Decisions concerning the use of particular therapeutic options should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.When planning treating, physicians must weigh conservative treatment and observation versus proceeding with a surgical decompression of the dilated colon. Most individuals respond to conservative management.The initial management of Ogilvie syndrome requires an examination to detect signs of bowel perforation or ischemia. Signs of these complications require immediate medical intervention.In cases where an identifiable cause for Ogilvie syndrome (e.g., respiratory failure, congestive heart failure, infection) has been established, treatment of the underlying condition is mandatory. If Ogilvie syndrome is linked to the use of certain medications, affected individuals must stop taking the medications.Supportive therapy may include withholding oral food and fluid intake, administering intravenous fluids to correct fluid and electrolyte imbalances, employing nasogastric suction to limit the amount of air that is swallowed to avoid air from further expanding the colon, and inserting a long, thin tube into the rectum to allow the release of gas and stool, a procedure known as rectal tube to gravity drainage. Stopping the use of medications that can affect colon motility such as opiates and anticholinergics is also recommended. The success of supportive therapy varies among affected individuals.One of the few treatment options for Ogilvie syndrome that has undergone clinical study is a medication known as neostigmine. Studies have shown that intravenous administration of neostigmine has led to rapid decompression of the colon in individuals with Ogilvie syndrome who did not respond to conservative management. Neostigmine is believed to interfere with the breakdown of the neurotransmitter acetylcholine, increasing the duration and activity of acetylcholine. Acetylcholine helps the communication between nerve and muscle cells, such as those in the GI tract. Neostigmine improves GI motility and increases the transit of food and other material through the GI tract. Although infrequent, colonic distention can recur following successful treatment with neostigmine.Some individuals with Ogilvie syndrome may be treated with colonic decompression, a procedure that reduces pressure within the colon. Usually, this treatment is reserved for individuals with persistent, marked colonic distention who have not responded to other treatment options. A specific procedure known as colonoscopic decompression, in which a thin, flexible tube is inserted into the anal passage and threaded up to the colon, may be used. Although colonoscopic decompression has not undergone clinical study, numerous reports in the medical literature cite it as an effective method for removing air from the colon and, potentially, reducing the risk of perforation. In addition, some individuals may require the insertion of a decompression tube within the colon in to order to achieve decompression or reduce the risk of recurrence. Decompression techniques carry risks including perforation. There is also a risk of disease recurrence.In rare cases, individuals with Ogilvie syndrome may require surgical intervention. Surgery is used when affected individuals have signs of perforation or ischemia or have failed to respond to other treatment options. Surgery can be associated with significant morbidity and mortality due in part to the severity of the underlying condition. The specific type of surgery used may vary depending upon the status of the bowel. If perforation or ischemia is not present, a cecostomy is usually performed. A cecostomy is a procedure in which an artificial opening is created in the cecum, allowing physicians to "vent" excess air or contents from the colon. This procedure has a high success rate in individuals with Ogilvie syndrome.If perforation or ischemia is present, surgery to remove a portion of the colon (subtotal colectomy) may be necessary. The specific surgical procedure used can vary based upon several factors such as the status of the cecum.
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Overview of Okur-Chung Neurodevelopmental Syndrome
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Summary
Okur-Chung neurodevelopmental syndrome (OCNDS) is an ultra-rare genetic neurodevelopmental syndrome caused by changes (variants or mutations) in the CSNK2A1 gene. These gene variants cause symptoms that affect individuals differently. Common symptoms include speech and motor delays, intellectual disabilities, behavioral challenges, sleep issues and other neurological problems. There are no known treatments or cures for OCNDS, so treatment is focused on symptom management. Most often, this gene change happens spontaneously and is not inherited, however, patients have been reported who have inherited a CSNK2A1 gene variant from a parent. OCNDS follows an autosomal dominant inheritance pattern, meaning that an individual with OCNDS has a 50% risk of passing the CSNK2A1 variant to each child.
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Overview of Okur-Chung Neurodevelopmental Syndrome. Summary
Okur-Chung neurodevelopmental syndrome (OCNDS) is an ultra-rare genetic neurodevelopmental syndrome caused by changes (variants or mutations) in the CSNK2A1 gene. These gene variants cause symptoms that affect individuals differently. Common symptoms include speech and motor delays, intellectual disabilities, behavioral challenges, sleep issues and other neurological problems. There are no known treatments or cures for OCNDS, so treatment is focused on symptom management. Most often, this gene change happens spontaneously and is not inherited, however, patients have been reported who have inherited a CSNK2A1 gene variant from a parent. OCNDS follows an autosomal dominant inheritance pattern, meaning that an individual with OCNDS has a 50% risk of passing the CSNK2A1 variant to each child.
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Symptoms of Okur-Chung Neurodevelopmental Syndrome
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Generally, individuals with OCNDS have developmental delays that vary in severity. OCNDS should be considered in individuals with the following clinical findings:• Mild-to-moderate developmental delay (DD) or intellectual disability (ID)
• Generalized hypotonia in infancy and/or childhood
• Speech delayAND• Any of the following features presenting in infancy or childhood:
o Infant feeding difficulties
o Seizures, ranging from a single seizure event to intractable epilepsy
o Behavioral findings including repetitive (stereotypic) movements, autism spectrum disorder, aggressiveness and tantrums and attention-deficit/hyperactivity disorder
o Slow growth, failure to thrive or difficulty gaining weight
o Nonspecific facial differences (e.g., round face, short broad nasal tip)The frequency, age of onset and age of resolution of symptoms is not well established, but the most observed symptoms of OCNDS are:• Speech delay/inability to speak
• Motor delay (i.e., walking)
• Intellectual disabilities, learning disabilities, features of autism spectrum disorder
• Behavioral challenges such as tantrums, hand flapping other stereotypic movements
• Sleep problems due to a disrupted sleep-wake cycle (circadian rhythm)
• Neurologic characteristics (e.g., low muscle tone (hypotonia), clumsy movements, small head (microcephaly), epilepsy (seizures) gait abnormalities)
• Nonspecific structural abnormalities in the brain
• Short stature; often without growth hormone deficiency
• Feeding difficulties starting from birth, reflux (heartburn), constipation
• Minor infections of the ears and lungs
• Crooked (misaligned) teeth and cavities
• Hypermobility, hernias, hip dysplasia
• Vision issues such as strabismus, near/far sightedness, astigmatism
• Minor skeletal deformations in vertebraeInformation about disease progression and life expectancy are not known at this time.
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Symptoms of Okur-Chung Neurodevelopmental Syndrome. Generally, individuals with OCNDS have developmental delays that vary in severity. OCNDS should be considered in individuals with the following clinical findings:• Mild-to-moderate developmental delay (DD) or intellectual disability (ID)
• Generalized hypotonia in infancy and/or childhood
• Speech delayAND• Any of the following features presenting in infancy or childhood:
o Infant feeding difficulties
o Seizures, ranging from a single seizure event to intractable epilepsy
o Behavioral findings including repetitive (stereotypic) movements, autism spectrum disorder, aggressiveness and tantrums and attention-deficit/hyperactivity disorder
o Slow growth, failure to thrive or difficulty gaining weight
o Nonspecific facial differences (e.g., round face, short broad nasal tip)The frequency, age of onset and age of resolution of symptoms is not well established, but the most observed symptoms of OCNDS are:• Speech delay/inability to speak
• Motor delay (i.e., walking)
• Intellectual disabilities, learning disabilities, features of autism spectrum disorder
• Behavioral challenges such as tantrums, hand flapping other stereotypic movements
• Sleep problems due to a disrupted sleep-wake cycle (circadian rhythm)
• Neurologic characteristics (e.g., low muscle tone (hypotonia), clumsy movements, small head (microcephaly), epilepsy (seizures) gait abnormalities)
• Nonspecific structural abnormalities in the brain
• Short stature; often without growth hormone deficiency
• Feeding difficulties starting from birth, reflux (heartburn), constipation
• Minor infections of the ears and lungs
• Crooked (misaligned) teeth and cavities
• Hypermobility, hernias, hip dysplasia
• Vision issues such as strabismus, near/far sightedness, astigmatism
• Minor skeletal deformations in vertebraeInformation about disease progression and life expectancy are not known at this time.
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Causes of Okur-Chung Neurodevelopmental Syndrome
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OCNDS is caused by changes (variants or mutations) in the CSNK2A1 gene. OCNDS follows autosomal dominant inheritance. This means that an individual only needs a single pathogenic variant (referred to as heterozygous) in the CSNK2A1 gene to cause medical problems. The gene variant can be inherited from either parent or can be the result of a changed gene in the affected individual (known as de novo). The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females. Heterozygous mutations are like having two different versions of a gene in the body's instructions. Genes can be considered as small pieces of code that tell the body how to grow, develop and work properly. Usually, we inherit one set of genes from our mother and another set from our father. When a variant happens, it means there's a small change in one of those gene sets. Heterozygous means the genetic code is different in each of the two genes (i.e., one gene with the regular code, and the other gene has a slightly altered code). Sometimes variants lead to unique traits or health conditions, such as OCNDS.The CSNK2A1 gene provides instructions to produce (encode) the alpha subunit of a protein called casein kinase 2 (CK2). CK2 is an important kinase (enzyme) that is abundant in the brain and is important for the development of neurons and synaptic transmission. Synaptic transmission is how neurons communicate with each other – they send messages across small gaps called synapses. This process helps our brain process information and is important for learning and memory. Research is still ongoing to determine how variants in CSNK2A1 affect normal functioning.
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Causes of Okur-Chung Neurodevelopmental Syndrome. OCNDS is caused by changes (variants or mutations) in the CSNK2A1 gene. OCNDS follows autosomal dominant inheritance. This means that an individual only needs a single pathogenic variant (referred to as heterozygous) in the CSNK2A1 gene to cause medical problems. The gene variant can be inherited from either parent or can be the result of a changed gene in the affected individual (known as de novo). The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females. Heterozygous mutations are like having two different versions of a gene in the body's instructions. Genes can be considered as small pieces of code that tell the body how to grow, develop and work properly. Usually, we inherit one set of genes from our mother and another set from our father. When a variant happens, it means there's a small change in one of those gene sets. Heterozygous means the genetic code is different in each of the two genes (i.e., one gene with the regular code, and the other gene has a slightly altered code). Sometimes variants lead to unique traits or health conditions, such as OCNDS.The CSNK2A1 gene provides instructions to produce (encode) the alpha subunit of a protein called casein kinase 2 (CK2). CK2 is an important kinase (enzyme) that is abundant in the brain and is important for the development of neurons and synaptic transmission. Synaptic transmission is how neurons communicate with each other – they send messages across small gaps called synapses. This process helps our brain process information and is important for learning and memory. Research is still ongoing to determine how variants in CSNK2A1 affect normal functioning.
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Affects of Okur-Chung Neurodevelopmental Syndrome
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OCNDS has been reported in an equal number of males and females. As of July 2023, over 180 individuals are registered with the CSNK2A1 Foundation, a non-profit patient advocacy group dedicated to finding a cure for Okur-Chung neurodevelopmental syndrome and ensuring affected individuals have the opportunities and supports necessary for happy and full lives. A map of global cases is available here.
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Affects of Okur-Chung Neurodevelopmental Syndrome. OCNDS has been reported in an equal number of males and females. As of July 2023, over 180 individuals are registered with the CSNK2A1 Foundation, a non-profit patient advocacy group dedicated to finding a cure for Okur-Chung neurodevelopmental syndrome and ensuring affected individuals have the opportunities and supports necessary for happy and full lives. A map of global cases is available here.
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Related disorders of Okur-Chung Neurodevelopmental Syndrome
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Poirier-Bienvenu neurodevelopmental syndrome (POBINDS) is a neurological disorder caused by variants in the CSNK2B gene. The severity of symptoms is variable however, and POBINDS differs from OCNDS in that most individuals with POBINDS experience early-onset seizures that may be refractory (unresponsive) to medications. Like OCNDS, POBINDS causes intellectual disability, developmental delay and growth abnormalities.
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Related disorders of Okur-Chung Neurodevelopmental Syndrome. Poirier-Bienvenu neurodevelopmental syndrome (POBINDS) is a neurological disorder caused by variants in the CSNK2B gene. The severity of symptoms is variable however, and POBINDS differs from OCNDS in that most individuals with POBINDS experience early-onset seizures that may be refractory (unresponsive) to medications. Like OCNDS, POBINDS causes intellectual disability, developmental delay and growth abnormalities.
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Okur-Chung Neurodevelopmental Syndrome
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nord_903_5
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Diagnosis of Okur-Chung Neurodevelopmental Syndrome
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OCNDS can only be diagnosed through genetic testing (e.g., whole exome or whole genome sequencing). There are likely many individuals with OCNDS who do not have a formal diagnosis due to lack of access to testing. OCNDS shares symptoms with many other neurodevelopmental disorders, and there is not a specific symptom that prompts a clinician to order genetic testing, which can lead to delayed diagnosis or misdiagnosis. Diagnostic challenges for families are lack of access to testing and genetic counselors.
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Diagnosis of Okur-Chung Neurodevelopmental Syndrome. OCNDS can only be diagnosed through genetic testing (e.g., whole exome or whole genome sequencing). There are likely many individuals with OCNDS who do not have a formal diagnosis due to lack of access to testing. OCNDS shares symptoms with many other neurodevelopmental disorders, and there is not a specific symptom that prompts a clinician to order genetic testing, which can lead to delayed diagnosis or misdiagnosis. Diagnostic challenges for families are lack of access to testing and genetic counselors.
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Okur-Chung Neurodevelopmental Syndrome
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nord_903_6
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Therapies of Okur-Chung Neurodevelopmental Syndrome
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As of July 2023, no clinical practice or consensus guidelines have been published. Recommended evaluations include the following:• Neurologic (EEG, MRI, gait/coordination)
• Development (motor, cognitive, speech/language)
• Neuropsychiatric (behavioral concerns, sleep issues, anxiety, ADHD, ASD-like behaviors)
• Gastrointestinal (nutritional status, oromotor function)
• Ophthalmologic
• Cardiovascular
• Genitourinary
• Respiratory/sleep
• Genetic counseling A detailed list of recommendations is available in this GeneReview.Therapies that may be used include:• Feeding therapy (including gastrostomy tube)
• Growth hormone therapy (to treat short stature in individuals with evidence of growth hormone deficiency)
• Standardized anti-seizure medications (ASM) for individuals with epilepsy. No single ASM has been shown to be effective specifically for OCNDS.
• Orthopedics, physical therapy, occupational therapy (for motor coordination issues)
• Early intervention programs for developmental delay/intellectual disability
• Applied behavioral analysis (ABA) therapy for autism spectrum disorder
• Other therapies may be appropriate. Consultations with developmental pediatricians and/or pediatric psychiatrists may be helpful depending on the individual.
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Therapies of Okur-Chung Neurodevelopmental Syndrome. As of July 2023, no clinical practice or consensus guidelines have been published. Recommended evaluations include the following:• Neurologic (EEG, MRI, gait/coordination)
• Development (motor, cognitive, speech/language)
• Neuropsychiatric (behavioral concerns, sleep issues, anxiety, ADHD, ASD-like behaviors)
• Gastrointestinal (nutritional status, oromotor function)
• Ophthalmologic
• Cardiovascular
• Genitourinary
• Respiratory/sleep
• Genetic counseling A detailed list of recommendations is available in this GeneReview.Therapies that may be used include:• Feeding therapy (including gastrostomy tube)
• Growth hormone therapy (to treat short stature in individuals with evidence of growth hormone deficiency)
• Standardized anti-seizure medications (ASM) for individuals with epilepsy. No single ASM has been shown to be effective specifically for OCNDS.
• Orthopedics, physical therapy, occupational therapy (for motor coordination issues)
• Early intervention programs for developmental delay/intellectual disability
• Applied behavioral analysis (ABA) therapy for autism spectrum disorder
• Other therapies may be appropriate. Consultations with developmental pediatricians and/or pediatric psychiatrists may be helpful depending on the individual.
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Okur-Chung Neurodevelopmental Syndrome
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nord_904_0
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Overview of Olivopontocerebellar Atrophy
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The term olivopontocerebellar atrophy (OPCA) has historically been used to describe a group of disorders that affect the central nervous system and are termed neurodegenerative diseases because they result in a progressive deterioration of nerve cells in certain parts of the brain. These conditions are characterized by progressive balance problems (disequilibrium), progressive impairment of the ability to coordinate voluntary movements (cerebellar ataxia), and difficulty speaking or slurred speech (dysarthria).OPCA has been classified based on clinical, genetic, and neuropathological findings and there is significant controversy and confusion in the medical literature because of its association with two distinct groups of disorders, specifically multiple system atrophy (MSA) and spinocerebellar ataxia (SCA). Hereditary OPCA usually refers to the group of disorders that overlap with SCA. These conditions are discussed in detail in the NORD report on autosomal dominant hereditary ataxias. Sporadic OPCA refers to the group of disorders for which there is not yet evidence of a hereditary component. Some individuals with sporadic OPCA will develop MSA and this disorder is discussed in detail in the NORD report on MSA. In addition, there are rare types of OPCA that follow autosomal recessive inheritance including Fickler-Winkler type OPCA and the pontocerebellar hypoplasia conditions. One type of SCA follows X-linked inheritance. Currently, neurologists usually use the term OPCA as a preliminary diagnosis until a more specific diagnosis can be made with genetic testing or by ruling out other conditions.
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Overview of Olivopontocerebellar Atrophy. The term olivopontocerebellar atrophy (OPCA) has historically been used to describe a group of disorders that affect the central nervous system and are termed neurodegenerative diseases because they result in a progressive deterioration of nerve cells in certain parts of the brain. These conditions are characterized by progressive balance problems (disequilibrium), progressive impairment of the ability to coordinate voluntary movements (cerebellar ataxia), and difficulty speaking or slurred speech (dysarthria).OPCA has been classified based on clinical, genetic, and neuropathological findings and there is significant controversy and confusion in the medical literature because of its association with two distinct groups of disorders, specifically multiple system atrophy (MSA) and spinocerebellar ataxia (SCA). Hereditary OPCA usually refers to the group of disorders that overlap with SCA. These conditions are discussed in detail in the NORD report on autosomal dominant hereditary ataxias. Sporadic OPCA refers to the group of disorders for which there is not yet evidence of a hereditary component. Some individuals with sporadic OPCA will develop MSA and this disorder is discussed in detail in the NORD report on MSA. In addition, there are rare types of OPCA that follow autosomal recessive inheritance including Fickler-Winkler type OPCA and the pontocerebellar hypoplasia conditions. One type of SCA follows X-linked inheritance. Currently, neurologists usually use the term OPCA as a preliminary diagnosis until a more specific diagnosis can be made with genetic testing or by ruling out other conditions.
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Olivopontocerebellar Atrophy
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nord_904_1
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Symptoms of Olivopontocerebellar Atrophy
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Among the different classifications, there is wide variation in severity and age of onset. The symptoms of OPCA differ from person to person. Most patients experience difficulty with balance and coordination of the legs and arms (ataxia) and slurred speech (dysarthria). Other symptoms may include muscle spasms or weakness and stiffness of the muscles; numbness or tingling of the hands or feet; shaking (tremor) of the hand or arm; reduction or slowness of movements; loss of thinking and/or memory skills; difficulty controlling the bladder or bowels; and feeling faint when standing up. Some patients also have fatigue and/or trouble with sleep. Generally, symptoms of OPCA begin in mid-adult life and progress slowly over the course of many years.OPCA is characterized by progressive degeneration of certain structures of the brain, especially the cerebellum, pons, and inferior olivae. The cerebellum is the part of the brain that plays a role in maintaining balance and posture as well as coordinating voluntary movement. The pons is part of the brainstem and contains important neuronal pathways between the cerebrum, spinal cord, and cerebellum. The pons serves as a relay point for messages between these structures. The inferior olivae are two round structures that contain nuclei that are involved with balance, coordination and motor activity.
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Symptoms of Olivopontocerebellar Atrophy. Among the different classifications, there is wide variation in severity and age of onset. The symptoms of OPCA differ from person to person. Most patients experience difficulty with balance and coordination of the legs and arms (ataxia) and slurred speech (dysarthria). Other symptoms may include muscle spasms or weakness and stiffness of the muscles; numbness or tingling of the hands or feet; shaking (tremor) of the hand or arm; reduction or slowness of movements; loss of thinking and/or memory skills; difficulty controlling the bladder or bowels; and feeling faint when standing up. Some patients also have fatigue and/or trouble with sleep. Generally, symptoms of OPCA begin in mid-adult life and progress slowly over the course of many years.OPCA is characterized by progressive degeneration of certain structures of the brain, especially the cerebellum, pons, and inferior olivae. The cerebellum is the part of the brain that plays a role in maintaining balance and posture as well as coordinating voluntary movement. The pons is part of the brainstem and contains important neuronal pathways between the cerebrum, spinal cord, and cerebellum. The pons serves as a relay point for messages between these structures. The inferior olivae are two round structures that contain nuclei that are involved with balance, coordination and motor activity.
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Olivopontocerebellar Atrophy
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nord_904_2
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Causes of Olivopontocerebellar Atrophy
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Most types of inherited OPCA are spinocerebellar ataxias that follow autosomal dominant inheritance. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.Fickler-Winkler type OPCA and the pontocerebellar hypoplasia conditions follow autosomal recessive inheritance. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. OPCA-X (SCA-X1) follows X-linked inheritance. X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome and occur mostly in males. Females that have a disease 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 one is inactivated so that the genes on that chromosome are nonfunctioning. It is usually the X chromosome with the abnormal gene that is inactivated. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a disease gene he will usually 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. Males with X-linked disorders pass the disease gene to all of their 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. The cause of sporadic OPCA is not yet defined but it is associated with abnormalities in the alpha-synuclein protein found in the deteriorating nerve cells.
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Causes of Olivopontocerebellar Atrophy. Most types of inherited OPCA are spinocerebellar ataxias that follow autosomal dominant inheritance. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.Fickler-Winkler type OPCA and the pontocerebellar hypoplasia conditions follow autosomal recessive inheritance. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. OPCA-X (SCA-X1) follows X-linked inheritance. X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome and occur mostly in males. Females that have a disease 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 one is inactivated so that the genes on that chromosome are nonfunctioning. It is usually the X chromosome with the abnormal gene that is inactivated. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a disease gene he will usually 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. Males with X-linked disorders pass the disease gene to all of their 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. The cause of sporadic OPCA is not yet defined but it is associated with abnormalities in the alpha-synuclein protein found in the deteriorating nerve cells.
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Olivopontocerebellar Atrophy
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nord_904_3
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Affects of Olivopontocerebellar Atrophy
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OPCA is a group of rare disorders that affects males and females in equal numbers. Because of confusion regarding the naming and classification of these disorders, determining their frequency in the general population is difficult. The frequency of all forms of OPCA has been estimated to be 3-5/100,000 in the United States.
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Affects of Olivopontocerebellar Atrophy. OPCA is a group of rare disorders that affects males and females in equal numbers. Because of confusion regarding the naming and classification of these disorders, determining their frequency in the general population is difficult. The frequency of all forms of OPCA has been estimated to be 3-5/100,000 in the United States.
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Olivopontocerebellar Atrophy
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nord_904_4
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Related disorders of Olivopontocerebellar Atrophy
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The following disorders overlap with OPCA. Comparisons may be useful for a differential diagnosis:Spinocerebellar ataxia (SCA) is a group of neurodegenerative disorders affecting the brainstem and spinal cord. Most follow autosomal dominant inheritance and are usually identified as SCA1 through SCA25. The symptoms of SCA vary between types and among individuals affected with the same type. (For more information on these disorders, choose “ataxia, hereditary, autosomal dominant” as your search term in the Rare Disease Database.)Multiple system atrophy (MSA) is a rare progressive neurological disorder characterized by a varying combination of symptoms. Affected individuals may experience symptoms similar to those found in Parkinson's disease (parkinsonism); cerebellar signs such as progressive impairment of the ability to coordinate voluntary movements (cerebellar ataxia); and impaired functioning of the portion of the nervous system (autonomic nervous system) that regulates certain involuntary body functions (autonomic failure) such as heart rate, blood pressure, sweating, and bowel and bladder control. The exact cause of multiple system atrophy is unknown. (For more information on this disorder, choose “multiple system atrophy” as your search term in the Rare Disease Database.)
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Related disorders of Olivopontocerebellar Atrophy. The following disorders overlap with OPCA. Comparisons may be useful for a differential diagnosis:Spinocerebellar ataxia (SCA) is a group of neurodegenerative disorders affecting the brainstem and spinal cord. Most follow autosomal dominant inheritance and are usually identified as SCA1 through SCA25. The symptoms of SCA vary between types and among individuals affected with the same type. (For more information on these disorders, choose “ataxia, hereditary, autosomal dominant” as your search term in the Rare Disease Database.)Multiple system atrophy (MSA) is a rare progressive neurological disorder characterized by a varying combination of symptoms. Affected individuals may experience symptoms similar to those found in Parkinson's disease (parkinsonism); cerebellar signs such as progressive impairment of the ability to coordinate voluntary movements (cerebellar ataxia); and impaired functioning of the portion of the nervous system (autonomic nervous system) that regulates certain involuntary body functions (autonomic failure) such as heart rate, blood pressure, sweating, and bowel and bladder control. The exact cause of multiple system atrophy is unknown. (For more information on this disorder, choose “multiple system atrophy” as your search term in the Rare Disease Database.)
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Olivopontocerebellar Atrophy
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nord_904_5
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Diagnosis of Olivopontocerebellar Atrophy
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A diagnosis of OPCA is a preliminary diagnosis that is made by a thorough clinical examination and identification of characteristic symptoms. Hereditary OPCA can be diagnosed based on a family history of the same condition or by molecular genetic testing for gene mutations known to be associated with the condition. Molecular genetic testing is available for several of the SCAs. A diagnosis of sporadic OPCA is made if hereditary OPCAs and other conditions associated with symptoms of OPCA are ruled out. Testing may include blood work to rule out other conditions, MRI scans of the brain to look for degenerative changes in the brainstem, EMG testing to look at the electrical testing of muscles and nerves and sometimes examination of spinal fluid.
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Diagnosis of Olivopontocerebellar Atrophy. A diagnosis of OPCA is a preliminary diagnosis that is made by a thorough clinical examination and identification of characteristic symptoms. Hereditary OPCA can be diagnosed based on a family history of the same condition or by molecular genetic testing for gene mutations known to be associated with the condition. Molecular genetic testing is available for several of the SCAs. A diagnosis of sporadic OPCA is made if hereditary OPCAs and other conditions associated with symptoms of OPCA are ruled out. Testing may include blood work to rule out other conditions, MRI scans of the brain to look for degenerative changes in the brainstem, EMG testing to look at the electrical testing of muscles and nerves and sometimes examination of spinal fluid.
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Olivopontocerebellar Atrophy
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nord_904_6
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Therapies of Olivopontocerebellar Atrophy
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TreatmentNo specific treatment exists for individuals with OPCA. Treatment is symptomatic and supportive. Continuous medical supervision may be necessary to avoid potential complications involving the heart, lungs, spine, bone and muscle. Prevention of infection is a challenge in the care of individuals with advanced stages of OPCA.Dopaminergic medications, which are used to treat individuals with Parkinson's disease, are sometimes used for individuals with OPCA, however often with limited benefit. The drug propranolol has been used to treat tremor associated with OPCA, also with limited benefit. Baclofen may be prescribed for spasticity.Individuals with OCPA often receive physical, occupational and speech therapy. Devices to assist walking (e.g., canes) may be necessary in some cases.Genetic counseling is recommended for individuals with hereditary OPCA and their family members.
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Therapies of Olivopontocerebellar Atrophy. TreatmentNo specific treatment exists for individuals with OPCA. Treatment is symptomatic and supportive. Continuous medical supervision may be necessary to avoid potential complications involving the heart, lungs, spine, bone and muscle. Prevention of infection is a challenge in the care of individuals with advanced stages of OPCA.Dopaminergic medications, which are used to treat individuals with Parkinson's disease, are sometimes used for individuals with OPCA, however often with limited benefit. The drug propranolol has been used to treat tremor associated with OPCA, also with limited benefit. Baclofen may be prescribed for spasticity.Individuals with OCPA often receive physical, occupational and speech therapy. Devices to assist walking (e.g., canes) may be necessary in some cases.Genetic counseling is recommended for individuals with hereditary OPCA and their family members.
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Olivopontocerebellar Atrophy
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nord_905_0
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Overview of Ollier Disease
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SummaryOllier disease is a rare skeletal disorder characterized by abnormal bone development (skeletal dysplasia). While this disorder may be present at birth (congenital), it may not become apparent until early childhood when symptoms such as deformities or improper limb growth are more obvious. Ollier disease primarily affects the long bones and cartilage of the joints of the arms and legs, specifically the area where the shaft and head of a long bone meet (metaphyses). The pelvis is often involved; and more rarely, the ribs, breast bone (sternum), and/or skull may also be affected.Ollier disease manifests as greater than normal growth of the cartilage in the long bones of the legs and arms so that growth is abnormal and the outer layer (cortical bone) of the bone becomes thin and more fragile. These masses of cartilage are benign (non-cancerous) tumors known as enchondromas. Enchondromas may occur at any time. In about 30% of patients, the enchondromas may undergo malignant changes to a cancer such as chondrosarcomas. Malignant transformation is more likely to occur in the long tubular and flat bones. IntroductionThere are seven major subtypes of enchondromas: the most common are Ollier disease (subtype I) and Maffucci syndrome (subtype II). When the enchondromas are accompanied by substantial, most often benign, proliferation of blood vessels (vascular anomalies), the array of symptoms is known as Maffucci syndrome. The others are metachondromatosis, genochondromatosis, spondyloenchondrodysplasia, dysspondyloenchondromatosis and cheirospondyloenchondromatosis. The classification of subtypes is based on how the disease affects the patient, whether or not the spine is involved, and the pattern of inheritance.
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Overview of Ollier Disease. SummaryOllier disease is a rare skeletal disorder characterized by abnormal bone development (skeletal dysplasia). While this disorder may be present at birth (congenital), it may not become apparent until early childhood when symptoms such as deformities or improper limb growth are more obvious. Ollier disease primarily affects the long bones and cartilage of the joints of the arms and legs, specifically the area where the shaft and head of a long bone meet (metaphyses). The pelvis is often involved; and more rarely, the ribs, breast bone (sternum), and/or skull may also be affected.Ollier disease manifests as greater than normal growth of the cartilage in the long bones of the legs and arms so that growth is abnormal and the outer layer (cortical bone) of the bone becomes thin and more fragile. These masses of cartilage are benign (non-cancerous) tumors known as enchondromas. Enchondromas may occur at any time. In about 30% of patients, the enchondromas may undergo malignant changes to a cancer such as chondrosarcomas. Malignant transformation is more likely to occur in the long tubular and flat bones. IntroductionThere are seven major subtypes of enchondromas: the most common are Ollier disease (subtype I) and Maffucci syndrome (subtype II). When the enchondromas are accompanied by substantial, most often benign, proliferation of blood vessels (vascular anomalies), the array of symptoms is known as Maffucci syndrome. The others are metachondromatosis, genochondromatosis, spondyloenchondrodysplasia, dysspondyloenchondromatosis and cheirospondyloenchondromatosis. The classification of subtypes is based on how the disease affects the patient, whether or not the spine is involved, and the pattern of inheritance.
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Ollier Disease
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nord_905_1
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Symptoms of Ollier Disease
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Ollier disease is not always apparent at birth, but symptoms will usually become evident by early childhood. Between the ages of one and four years, abnormal and/or slow growth of arms and legs is often observed. Usually one leg and/or arm is affected, but both legs and/or arms may be involved. If both legs are involved, short stature may result; if only one leg is involved, then an affected individual may limp.The pelvis is sometimes involved and rarely, the ribs, breast bone (sternum), and/or skull may be affected. Deformities may also develop in the wrists and ankles. Limb shortening and bowing of the long bones may occur in some affected individuals. Ollier disease also hampers proper development of bone (ossification). Fractures are a common occurrence in people affected by this disorder and usually heal well. In some patients, the development of some forms of malignant bone growths has been associated with Ollier disease.Other rare complications can arise, such as gliomas and juvenile granulosa cell tumors. Gliomas are a type of brain tumor; they are referred to as intra-axial brain tumors, which refer to the growth of the brain tumors within the brain tissue itself. Juvenile granulosa cell tumor (JGCT) is a rare ovarian cancer; it has a favorable prognosis if diagnosed early.
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Symptoms of Ollier Disease. Ollier disease is not always apparent at birth, but symptoms will usually become evident by early childhood. Between the ages of one and four years, abnormal and/or slow growth of arms and legs is often observed. Usually one leg and/or arm is affected, but both legs and/or arms may be involved. If both legs are involved, short stature may result; if only one leg is involved, then an affected individual may limp.The pelvis is sometimes involved and rarely, the ribs, breast bone (sternum), and/or skull may be affected. Deformities may also develop in the wrists and ankles. Limb shortening and bowing of the long bones may occur in some affected individuals. Ollier disease also hampers proper development of bone (ossification). Fractures are a common occurrence in people affected by this disorder and usually heal well. In some patients, the development of some forms of malignant bone growths has been associated with Ollier disease.Other rare complications can arise, such as gliomas and juvenile granulosa cell tumors. Gliomas are a type of brain tumor; they are referred to as intra-axial brain tumors, which refer to the growth of the brain tumors within the brain tissue itself. Juvenile granulosa cell tumor (JGCT) is a rare ovarian cancer; it has a favorable prognosis if diagnosed early.
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Ollier Disease
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nord_905_2
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Causes of Ollier Disease
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The underlying cause of Ollier disease is not known. Changes (mutations) in IDH1, IDH2 and PTHR1 genes have been linked to Ollier disease and Maffucci syndrome. The mutations are due to somatic mosaicism, which means that the mutation is present only in a percentage of the cells, not all the cells in the body. In Ollier disease, the mutation is present only in the enchondromas.So far, all the cases of Ollier disease have been sporadic in their families and not inherited. But, in theory, if a gene mutation is present in the egg or sperm (germline), the condition could be passed on in an autosomal dominant pattern. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a de novo 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.
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Causes of Ollier Disease. The underlying cause of Ollier disease is not known. Changes (mutations) in IDH1, IDH2 and PTHR1 genes have been linked to Ollier disease and Maffucci syndrome. The mutations are due to somatic mosaicism, which means that the mutation is present only in a percentage of the cells, not all the cells in the body. In Ollier disease, the mutation is present only in the enchondromas.So far, all the cases of Ollier disease have been sporadic in their families and not inherited. But, in theory, if a gene mutation is present in the egg or sperm (germline), the condition could be passed on in an autosomal dominant pattern. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a de novo 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.
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Ollier Disease
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nord_905_3
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Affects of Ollier Disease
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The estimated prevalence of the disease is 1/100,000. Ollier disease is a very rare disorder that affects males and females in equal numbers. Symptoms are most often observed in children but can occur in adolescents and adults. This disorder can affect all races.
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Affects of Ollier Disease. The estimated prevalence of the disease is 1/100,000. Ollier disease is a very rare disorder that affects males and females in equal numbers. Symptoms are most often observed in children but can occur in adolescents and adults. This disorder can affect all races.
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Ollier Disease
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nord_905_4
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Related disorders of Ollier Disease
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Symptoms of the following disorders can be similar to those of Ollier disease. Comparisons may be useful for a differential diagnosis:Metachondromatosis presents with enchondromas and osteochondroma (exostoses). The enchondromas most commonly involve the long bones of the legs and the hip. The osteochondroma lesions usually appear on the hands and feet. Most of the time, these lesions do not cause bone deformities. There are less than 30 reported cases currently. Genochondromatosis is an extremely rare autosomal dominant disorder. Patients have normal stature and enchondromas are distributed symmetrically with characteristic localization in the metaphyses of the upper part of the arms (proximal humerus) and lower part of the thigh bone (distal femur). Two subtypes are distinguished: genochondromatosis type I includes the presence of a enchondromas on the inner side (medial side) of the clavicle, while in type II the short tubular bones of the hand, wrist and feet are affected while the clavicle is normal.Spondyloenchondrodysplasia (SPENCD, enchondromatosis Spranger type IV) is an autosomal recessive inherited disorder caused by mutations in the ACP5 gene. It is characterized by vertebral dysplasia combined with enchondroma like lesions in the pelvis or long tubular bones. Dysspondyloenchondromatosis is a nonhereditary skeletal dysplasia characterized by abnormally varying sizes of verterbral bodies (anisospondyly), which comprise the bones of the spine, and multiple enchondromas in vertebrae and the metaphyseal and diaphyseal parts of long tubular bones, leading to kyphoscoliosis and lower limb asymmetry.Cheirospondyloenchondromatosis (generalized enchondromatosis with platyspondyly, enchondromatosis Spranger type VI) combines symmetrically distributed multiple enchondromas with marked involvement of metacarpals and phalanges resulting in short hands and feet with mild flattening of the vertebral bodies of the spine (platyspondyly). It occurs at a very early age. There is mild to moderate dwarfism and joints, especially of the fingers, become enlarged. In addition, intellectual disability is frequently associated with this disease. Maffucci syndrome is a rare genetic disorder characterized by enchondromas, skeletal deformities, and dark red irregularly shaped patches of skin, resulting from benign growths on the skin (cutaneous) consisting of masses of blood vessels (vascular anomalies). Enchondromas are most often found in certain bones (phalanges) of the hands and feet. Skeletal malformations may include legs that are disproportionate in length and/or abnormal side-to-side curvature of the spine (scoliosis). In many patients, bones may tend to fracture easily. In most patients, hemangiomas appear at birth or during early childhood and may be progressive. Maffucci syndrome is also a sporadic disease and no inherited cases have been reported so far. (For more information on this disorder, choose “Maffucci” as your search term in the Rare Disease Database).Hereditary multiple osteochondromas (HMO) is a rare genetic disorder characterized by multiple benign (noncancerous) bone tumors that are covered by cartilage (osteochondromas), often on the growing end (metaphysis) of the long bones of the legs, arms, and digits. These osteochondromas usually continue to grow until shortly after puberty and may lead to bone deformities, skeletal abnormalities, short stature, nerve compression and reduced range of motion. Hereditary multiple osteochondromas is inherited as an autosomal dominant genetic condition and is associated with mutations in the EXT1 or EXT2 genes. (For more information on this disorder, choose “hereditary multiple osteochondromas” as your search term in the Rare Disease Database).
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Related disorders of Ollier Disease. Symptoms of the following disorders can be similar to those of Ollier disease. Comparisons may be useful for a differential diagnosis:Metachondromatosis presents with enchondromas and osteochondroma (exostoses). The enchondromas most commonly involve the long bones of the legs and the hip. The osteochondroma lesions usually appear on the hands and feet. Most of the time, these lesions do not cause bone deformities. There are less than 30 reported cases currently. Genochondromatosis is an extremely rare autosomal dominant disorder. Patients have normal stature and enchondromas are distributed symmetrically with characteristic localization in the metaphyses of the upper part of the arms (proximal humerus) and lower part of the thigh bone (distal femur). Two subtypes are distinguished: genochondromatosis type I includes the presence of a enchondromas on the inner side (medial side) of the clavicle, while in type II the short tubular bones of the hand, wrist and feet are affected while the clavicle is normal.Spondyloenchondrodysplasia (SPENCD, enchondromatosis Spranger type IV) is an autosomal recessive inherited disorder caused by mutations in the ACP5 gene. It is characterized by vertebral dysplasia combined with enchondroma like lesions in the pelvis or long tubular bones. Dysspondyloenchondromatosis is a nonhereditary skeletal dysplasia characterized by abnormally varying sizes of verterbral bodies (anisospondyly), which comprise the bones of the spine, and multiple enchondromas in vertebrae and the metaphyseal and diaphyseal parts of long tubular bones, leading to kyphoscoliosis and lower limb asymmetry.Cheirospondyloenchondromatosis (generalized enchondromatosis with platyspondyly, enchondromatosis Spranger type VI) combines symmetrically distributed multiple enchondromas with marked involvement of metacarpals and phalanges resulting in short hands and feet with mild flattening of the vertebral bodies of the spine (platyspondyly). It occurs at a very early age. There is mild to moderate dwarfism and joints, especially of the fingers, become enlarged. In addition, intellectual disability is frequently associated with this disease. Maffucci syndrome is a rare genetic disorder characterized by enchondromas, skeletal deformities, and dark red irregularly shaped patches of skin, resulting from benign growths on the skin (cutaneous) consisting of masses of blood vessels (vascular anomalies). Enchondromas are most often found in certain bones (phalanges) of the hands and feet. Skeletal malformations may include legs that are disproportionate in length and/or abnormal side-to-side curvature of the spine (scoliosis). In many patients, bones may tend to fracture easily. In most patients, hemangiomas appear at birth or during early childhood and may be progressive. Maffucci syndrome is also a sporadic disease and no inherited cases have been reported so far. (For more information on this disorder, choose “Maffucci” as your search term in the Rare Disease Database).Hereditary multiple osteochondromas (HMO) is a rare genetic disorder characterized by multiple benign (noncancerous) bone tumors that are covered by cartilage (osteochondromas), often on the growing end (metaphysis) of the long bones of the legs, arms, and digits. These osteochondromas usually continue to grow until shortly after puberty and may lead to bone deformities, skeletal abnormalities, short stature, nerve compression and reduced range of motion. Hereditary multiple osteochondromas is inherited as an autosomal dominant genetic condition and is associated with mutations in the EXT1 or EXT2 genes. (For more information on this disorder, choose “hereditary multiple osteochondromas” as your search term in the Rare Disease Database).
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Ollier Disease
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Diagnosis of Ollier Disease
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Methods of diagnosing Ollier disease include bone biopsy, x-rays, magnetic resonance imaging (MRI), and recording of internal body images (tomography). Affected individuals should be checked routinely by a physician for malignant changes in the bones and joints (e.g., chondrosarcoma).
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Diagnosis of Ollier Disease. Methods of diagnosing Ollier disease include bone biopsy, x-rays, magnetic resonance imaging (MRI), and recording of internal body images (tomography). Affected individuals should be checked routinely by a physician for malignant changes in the bones and joints (e.g., chondrosarcoma).
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Ollier Disease
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Therapies of Ollier Disease
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Treatment
Surgical correction of deformities of the affected limb(s) has been helpful. In severe cases, artificial (prosthetic) joint replacement may become necessary. Fractures routinely heal without complications. A supportive team approach for children with Ollier disease may be of benefit. Such a team approach may include physical therapy and other medical, social, or vocational services. Other treatment is symptomatic and supportive.
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Therapies of Ollier Disease. Treatment
Surgical correction of deformities of the affected limb(s) has been helpful. In severe cases, artificial (prosthetic) joint replacement may become necessary. Fractures routinely heal without complications. A supportive team approach for children with Ollier disease may be of benefit. Such a team approach may include physical therapy and other medical, social, or vocational services. Other treatment is symptomatic and supportive.
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Ollier Disease
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nord_906_0
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Overview of Opsoclonus-Myoclonus Syndrome
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Opsoclonus-myoclonus syndrome (OMS) is an inflammatory neurological disorder, often with paraneoplastic etiology. It is characterized by associated ocular, motor, behavioral, sleep, and language disturbances. The onset is usually abrupt, often severe, and it can become chronic.
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Overview of Opsoclonus-Myoclonus Syndrome. Opsoclonus-myoclonus syndrome (OMS) is an inflammatory neurological disorder, often with paraneoplastic etiology. It is characterized by associated ocular, motor, behavioral, sleep, and language disturbances. The onset is usually abrupt, often severe, and it can become chronic.
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Opsoclonus-Myoclonus Syndrome
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Symptoms of Opsoclonus-Myoclonus Syndrome
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The component features of OMS include repeated, random and rapid eye movements in both horizontal, vertical and diagonal directions (opsoclonus); unsteady gait or loss of ability to stand and walk (ataxia); brief, repeated, shock-like spasms of several muscles within the arms, legs (myoclonus), or tremor interfering with hand use. Behavioral and sleep disturbances, including extreme irritability, inconsolable crying, reduced and fragmented sleep (insomnia) and rage attacks are common. Difficulty articulating speech (dysarthria), sometimes with complete loss of speech and language may occur. Additional symptoms such as decreased muscle tone (hypotonia) and vomiting are common.
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Symptoms of Opsoclonus-Myoclonus Syndrome. The component features of OMS include repeated, random and rapid eye movements in both horizontal, vertical and diagonal directions (opsoclonus); unsteady gait or loss of ability to stand and walk (ataxia); brief, repeated, shock-like spasms of several muscles within the arms, legs (myoclonus), or tremor interfering with hand use. Behavioral and sleep disturbances, including extreme irritability, inconsolable crying, reduced and fragmented sleep (insomnia) and rage attacks are common. Difficulty articulating speech (dysarthria), sometimes with complete loss of speech and language may occur. Additional symptoms such as decreased muscle tone (hypotonia) and vomiting are common.
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Opsoclonus-Myoclonus Syndrome
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Causes of Opsoclonus-Myoclonus Syndrome
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The most common cause of OMS in young children is paraneoplastic. A small, often hidden tumor presumably provokes the immune system into attacking the nervous system, which may also control the tumor or even cause it to regress. Tumors are NOT in the brain, but are in other areas of the body, usually in chest or abdomen. In 50-80 percent of affected young children, a tumor of embryonic nerve cells (neuroblastoma or ganglioneuroblastoma) is responsible for the symptoms associated with OMS. In other affected individuals, the disorder has been designated ‘idiopathic’ or attributed to various mostly viral infections. However, the high rate of spontaneous tumor regression means that the tumor may be gone before it is looked for. In older children or teens, viral infections are the most frequent apparent cause of OMS. In adults, paraneoplastic etiology is more common, most due to lung or breast cancers. In contrast to paraneoplastic OMS in infants and young children, whose tumors are biologically inactive and often benign, the tumors in adults are commonly malignant, often disseminated.
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Causes of Opsoclonus-Myoclonus Syndrome. The most common cause of OMS in young children is paraneoplastic. A small, often hidden tumor presumably provokes the immune system into attacking the nervous system, which may also control the tumor or even cause it to regress. Tumors are NOT in the brain, but are in other areas of the body, usually in chest or abdomen. In 50-80 percent of affected young children, a tumor of embryonic nerve cells (neuroblastoma or ganglioneuroblastoma) is responsible for the symptoms associated with OMS. In other affected individuals, the disorder has been designated ‘idiopathic’ or attributed to various mostly viral infections. However, the high rate of spontaneous tumor regression means that the tumor may be gone before it is looked for. In older children or teens, viral infections are the most frequent apparent cause of OMS. In adults, paraneoplastic etiology is more common, most due to lung or breast cancers. In contrast to paraneoplastic OMS in infants and young children, whose tumors are biologically inactive and often benign, the tumors in adults are commonly malignant, often disseminated.
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Opsoclonus-Myoclonus Syndrome
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Affects of Opsoclonus-Myoclonus Syndrome
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OMS is a rare disorder: 1 per million individuals worldwide. It usually affects infants and young children, although it is also known to affect adults. The peak age in children is about 18 months, with very few diagnosed before 1 year, and a long tail out to about 5 – 6 years. Occurrence of opsoclonus in infants under 6 months old is quite uncommon, and opsoclonus in that age group, when isolated, is usually from another cause. OMS occurs in only slightly more girls than boys. It occurs in about 3% of all children with neuroblastomas.
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Affects of Opsoclonus-Myoclonus Syndrome. OMS is a rare disorder: 1 per million individuals worldwide. It usually affects infants and young children, although it is also known to affect adults. The peak age in children is about 18 months, with very few diagnosed before 1 year, and a long tail out to about 5 – 6 years. Occurrence of opsoclonus in infants under 6 months old is quite uncommon, and opsoclonus in that age group, when isolated, is usually from another cause. OMS occurs in only slightly more girls than boys. It occurs in about 3% of all children with neuroblastomas.
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Opsoclonus-Myoclonus Syndrome
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Related disorders of Opsoclonus-Myoclonus Syndrome
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Symptoms of the following disorders can be similar to those of OMS. Comparisons may be useful for a differential diagnosis:About 95% of children with OMS are initially diagnosed as having acute cerebellar ataxia, a much more common disorder. In children with OMS, the ataxia may appear before the eye findings. This diagnosis may cause delay in recognition and treatment of OMS. Once opsoclonus is present, however, the diagnosis cannot be acute cerebellar ataxia. Also, children with only occasional or subtle opsoclonus or myoclonus are harder to recognize and may carry the wrong diagnosis for years.Myoclonus and tremor can occur in other conditions without opsoclonus and with or without ataxia. It may be epileptic or non-epileptic, rhythmical or arrhythmic, generalized or localized. Myoclonus may accompany a number of neurologic diseases, including seizure disorders, brain injuries, hereditary brain disorders, viral infections, and metabolic or toxic disorders. (For more information on this disorder, choose “general myoclonus” as your search term in the Rare Disease Database.)
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Related disorders of Opsoclonus-Myoclonus Syndrome. Symptoms of the following disorders can be similar to those of OMS. Comparisons may be useful for a differential diagnosis:About 95% of children with OMS are initially diagnosed as having acute cerebellar ataxia, a much more common disorder. In children with OMS, the ataxia may appear before the eye findings. This diagnosis may cause delay in recognition and treatment of OMS. Once opsoclonus is present, however, the diagnosis cannot be acute cerebellar ataxia. Also, children with only occasional or subtle opsoclonus or myoclonus are harder to recognize and may carry the wrong diagnosis for years.Myoclonus and tremor can occur in other conditions without opsoclonus and with or without ataxia. It may be epileptic or non-epileptic, rhythmical or arrhythmic, generalized or localized. Myoclonus may accompany a number of neurologic diseases, including seizure disorders, brain injuries, hereditary brain disorders, viral infections, and metabolic or toxic disorders. (For more information on this disorder, choose “general myoclonus” as your search term in the Rare Disease Database.)
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Opsoclonus-Myoclonus Syndrome
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Diagnosis of Opsoclonus-Myoclonus Syndrome
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The diagnosis is clinical; there is no diagnostic test yet, as the antigen remains unidentified. The presence of the ‘dancing eyes’, the shock-like muscle spasms, and the impairment of gait, especially if accompanied by irritability, are highly reliable indicators of this syndrome. To detect a tumor in children, either a CT scan with oral and IV contrast or MRI with gadolinium of the neck, chest, abdomen, and pelvis need to be done. PET scanning is often done in adults with OMS looking for other occult tumors. In addition, a spinal tap to detect neuroinflammation is necessary. Besides routine tests for infection, recommended CSF studies include so-called “MS panel”, to include oligoclonal bands (with paired serum sample), looking for antibodies secreted by B cells in the CSF. Also, lymphocyte subset analysis (flow cytometry) using immunophenotyping reveals an increased frequency of CSF CD 19+ B cells, which is an invaluable biomarker of OMS disease activity. Autoantibodies in some children with OMS have been at detected in research laboratories, but commercial autoantibody testing is not cost-effective and best reserved for atypical cases.
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Diagnosis of Opsoclonus-Myoclonus Syndrome. The diagnosis is clinical; there is no diagnostic test yet, as the antigen remains unidentified. The presence of the ‘dancing eyes’, the shock-like muscle spasms, and the impairment of gait, especially if accompanied by irritability, are highly reliable indicators of this syndrome. To detect a tumor in children, either a CT scan with oral and IV contrast or MRI with gadolinium of the neck, chest, abdomen, and pelvis need to be done. PET scanning is often done in adults with OMS looking for other occult tumors. In addition, a spinal tap to detect neuroinflammation is necessary. Besides routine tests for infection, recommended CSF studies include so-called “MS panel”, to include oligoclonal bands (with paired serum sample), looking for antibodies secreted by B cells in the CSF. Also, lymphocyte subset analysis (flow cytometry) using immunophenotyping reveals an increased frequency of CSF CD 19+ B cells, which is an invaluable biomarker of OMS disease activity. Autoantibodies in some children with OMS have been at detected in research laboratories, but commercial autoantibody testing is not cost-effective and best reserved for atypical cases.
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Opsoclonus-Myoclonus Syndrome
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Therapies of Opsoclonus-Myoclonus Syndrome
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Treatment
The goal of treatment of OMS is early and aggressive immunotherapy with the goal of gaining a durable complete neurological remission. If a tumor is present, surgical resection is standard. The tumors in young children are usually low stage neuroblastomas or ganglioneuroblastomas (stage I or II), and tumor chemotherapy or radiation therapy are not generally indicated. Tumor resection does not usually provide sufficient clinical benefit for OMS, however.OMS treatment, which is usually continued over at least 1-2 years, should involve combined immunotherapies as soon as possible after diagnosis. A three-agent protocol involving initial use of high-dose ACTH (corticotropin), IVIg, and rituximab has the best-documented outcomes for moderately severe and severe cases. Rituximab is a monoclonal antibody against B cells (anti-CD20). Almost all patients (80-90%) show improvement with this treatment, but maintaining sustained improvement may require additional treatment and very gradual weaning. Over time, treatment with ACTH may have substantial cortisol-related adverse effects that must be monitored carefully, particularly weight gain, hypertension, and reductions in bone density. Monthly pulse dose dexamethasone instead of ACTH is an option in mild and more moderate cases. The use of prednisone-type oral steroids is not recommended, because they are the least effective of the steroids for pediatric OMS. For OMS relapse, low-dose IV cyclophosphamide (3-6 cycles) or repeated courses of rituximab (1-2 cycles) are given. Oral weekly methotrexate may be a useful steroid sparer in chronic relapse.OutcomeAlmost all children with neuroblastoma and OMS survive their tumor, which usually does not behave aggressively, though some tumors may be large and pose difficulties for resection. In contrast, the tumors that are associated with OMS in adults are often aggressive and are sometimes fatal. The OMS relapse rate in children treated with only conventional agents is 50-75%. Increased immunosuppression has improved neurodevelopmental outcomes in OMS. With more aggressive initial therapies in children, the relapse rate appears to be much lower. OMS onset in the first two years of life is particularly damaging to expressive speech and language development, and may result in a higher incidence of residual cognitive impairment. The best responders appear to be those who received early combination therapy and were only of mild to moderate severity. Failure to achieve complete neurological remission and multiple relapses may result in chronic-progressive OMS, with permanent deficits, such as attention deficient disorder (ADD) attention-deficit/hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), and irreversible cognitive impairment (low IQ). Children in the chronic sick role can become oppositional, depressed, and aggressive, and attention to these issues often helps to improve quality of life. Parents with a severely ill infant or child may develop “fragile child syndrome” and have difficulty ever seeing their child as a normal, thriving individual, with “ordinary” behavioral issues of childhood. These parents may benefit from counselling to gradually adjust their management of their child’s ongoing behavioral and developmental issues.
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Therapies of Opsoclonus-Myoclonus Syndrome. Treatment
The goal of treatment of OMS is early and aggressive immunotherapy with the goal of gaining a durable complete neurological remission. If a tumor is present, surgical resection is standard. The tumors in young children are usually low stage neuroblastomas or ganglioneuroblastomas (stage I or II), and tumor chemotherapy or radiation therapy are not generally indicated. Tumor resection does not usually provide sufficient clinical benefit for OMS, however.OMS treatment, which is usually continued over at least 1-2 years, should involve combined immunotherapies as soon as possible after diagnosis. A three-agent protocol involving initial use of high-dose ACTH (corticotropin), IVIg, and rituximab has the best-documented outcomes for moderately severe and severe cases. Rituximab is a monoclonal antibody against B cells (anti-CD20). Almost all patients (80-90%) show improvement with this treatment, but maintaining sustained improvement may require additional treatment and very gradual weaning. Over time, treatment with ACTH may have substantial cortisol-related adverse effects that must be monitored carefully, particularly weight gain, hypertension, and reductions in bone density. Monthly pulse dose dexamethasone instead of ACTH is an option in mild and more moderate cases. The use of prednisone-type oral steroids is not recommended, because they are the least effective of the steroids for pediatric OMS. For OMS relapse, low-dose IV cyclophosphamide (3-6 cycles) or repeated courses of rituximab (1-2 cycles) are given. Oral weekly methotrexate may be a useful steroid sparer in chronic relapse.OutcomeAlmost all children with neuroblastoma and OMS survive their tumor, which usually does not behave aggressively, though some tumors may be large and pose difficulties for resection. In contrast, the tumors that are associated with OMS in adults are often aggressive and are sometimes fatal. The OMS relapse rate in children treated with only conventional agents is 50-75%. Increased immunosuppression has improved neurodevelopmental outcomes in OMS. With more aggressive initial therapies in children, the relapse rate appears to be much lower. OMS onset in the first two years of life is particularly damaging to expressive speech and language development, and may result in a higher incidence of residual cognitive impairment. The best responders appear to be those who received early combination therapy and were only of mild to moderate severity. Failure to achieve complete neurological remission and multiple relapses may result in chronic-progressive OMS, with permanent deficits, such as attention deficient disorder (ADD) attention-deficit/hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), and irreversible cognitive impairment (low IQ). Children in the chronic sick role can become oppositional, depressed, and aggressive, and attention to these issues often helps to improve quality of life. Parents with a severely ill infant or child may develop “fragile child syndrome” and have difficulty ever seeing their child as a normal, thriving individual, with “ordinary” behavioral issues of childhood. These parents may benefit from counselling to gradually adjust their management of their child’s ongoing behavioral and developmental issues.
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Opsoclonus-Myoclonus Syndrome
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nord_907_0
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Overview of Optic Nerve Hypoplasia
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Summary Optic nerve hypoplasia (ONH) is a congenital disorder characterized by underdevelopment (hypoplasia) of the optic nerves. The optic nerves transmit impulses from the nerve-rich membranes lining the retina of the eye to the brain. Most people with ONH have abnormal eye movements (nystagmus) and vision can range from no light perception to good functional vision, or even full vision in one eye.Children with ONH may have brain malformations and pituitary problems. Abnormalities of structures of the brain may include hypoplasia of the corpus callosum (nerve fibers that connect the two hemispheres of the brain), underdeveloped nerve fibers (white matter) in any other location, and abnormal migration of neurons to the surface of the brain (cortical heterotopia). The common association of absence of the septum pellucidum has no known functional consequence, and may occur with or without other brain malformations. The hypothalamus at the base of the brain is frequently abnormal. This is not usually visible on MRI scan. However, in the majority of patients, this results in abnormal function of the pituitary gland because of its control over the pituitary.Only a minority of affected individuals have visible neuroradiographic abnormalities of the pituitary gland. The pituitary gland is a hormone-producing gland at the base of the brain that controls hormones in the body that are necessary for growth, energy, and sexual development.Some affected children have normal intelligence and others have learning disabilities and developmental delays. Deficiencies of certain hormones may result in growth retardation, poor development, and may be life-threatening without treatment. Hormone deficiencies can be controlled with daily hormone replacement therapy and close monitoring by an endocrinologist (hormone doctor). Approximately 10% of children diagnosed with ONH prior to age 2 years have no pituitary problems and normal MRI scans of the brain. Those children are still at risk for developmental delays.The cause of ONH is not understood.IntroductionOptic nerve hypoplasia is the unifying feature of a spectrum condition, commonly known as septo-optic dysplasia (SOD) or DeMorsier syndrome, which includes hypopituitarism and absence of the septum pellucidum on MRI scan. The terms SOD and DeMorsier syndrome have fallen into disfavor because of recognition that absence of the septum pellucidum, which occurs in 1/3 of patients, has no clinically predictive value. In addition, DeMorsier was not describing this syndrome when he coined the term, septo-optic dysplasia.
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Overview of Optic Nerve Hypoplasia. Summary Optic nerve hypoplasia (ONH) is a congenital disorder characterized by underdevelopment (hypoplasia) of the optic nerves. The optic nerves transmit impulses from the nerve-rich membranes lining the retina of the eye to the brain. Most people with ONH have abnormal eye movements (nystagmus) and vision can range from no light perception to good functional vision, or even full vision in one eye.Children with ONH may have brain malformations and pituitary problems. Abnormalities of structures of the brain may include hypoplasia of the corpus callosum (nerve fibers that connect the two hemispheres of the brain), underdeveloped nerve fibers (white matter) in any other location, and abnormal migration of neurons to the surface of the brain (cortical heterotopia). The common association of absence of the septum pellucidum has no known functional consequence, and may occur with or without other brain malformations. The hypothalamus at the base of the brain is frequently abnormal. This is not usually visible on MRI scan. However, in the majority of patients, this results in abnormal function of the pituitary gland because of its control over the pituitary.Only a minority of affected individuals have visible neuroradiographic abnormalities of the pituitary gland. The pituitary gland is a hormone-producing gland at the base of the brain that controls hormones in the body that are necessary for growth, energy, and sexual development.Some affected children have normal intelligence and others have learning disabilities and developmental delays. Deficiencies of certain hormones may result in growth retardation, poor development, and may be life-threatening without treatment. Hormone deficiencies can be controlled with daily hormone replacement therapy and close monitoring by an endocrinologist (hormone doctor). Approximately 10% of children diagnosed with ONH prior to age 2 years have no pituitary problems and normal MRI scans of the brain. Those children are still at risk for developmental delays.The cause of ONH is not understood.IntroductionOptic nerve hypoplasia is the unifying feature of a spectrum condition, commonly known as septo-optic dysplasia (SOD) or DeMorsier syndrome, which includes hypopituitarism and absence of the septum pellucidum on MRI scan. The terms SOD and DeMorsier syndrome have fallen into disfavor because of recognition that absence of the septum pellucidum, which occurs in 1/3 of patients, has no clinically predictive value. In addition, DeMorsier was not describing this syndrome when he coined the term, septo-optic dysplasia.
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Optic Nerve Hypoplasia
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Symptoms of Optic Nerve Hypoplasia
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ONH is present at birth, but many symptoms may not be apparent until childhood, or even adolescence. Most infants with ONH have involuntary, rapid eye movements (nystagmus) and/or mild to severe visual impairment of one or both eyes. Vision often improves modestly in early childhood even though there is no growth of the optic nerves after birth. Due to underdevelopment of the optic nerves, the optic disk is smaller than normal size in one or both eyes when viewed by a doctor using an ophthalmoscope. Also referred to as the “blind spot,” the optic disk is the structure in which nerve fibers from the retina combine to form the optic nerve before leaving the back of the eye. The optic nerves meet to form the optic chiasm and optic tracts at the base of the hypothalamus.Affected individuals may also exhibit symptoms due to underdevelopment of the hypothalamus at the base of the brain. The hypothalamus is divided into several different regions that have different functions. The hypothalamus is responsible for regulating basic body functions such as thirst, hunger, sleep, and body temperature. As a result, children with ONH frequently have problems with these functions. Although the hypothalamus is commonly abnormal in individuals with ONH, the abnormalities are rarely visible on MRI scans.The hypothalamus also coordinates the function of the pituitary gland by controlling the gland’s release of certain hormones. The pituitary gland, a small structure beneath the hypothalamus produces several hormones and releases them directly into the bloodstream. It is located directly below the optic nerves and is connected to the hypothalamus by a short stalk of nerve fibers and blood vessels. In most individuals with ONH, the hypothalamus does not communicate with the pituitary gland properly, resulting in a failure of the pituitary gland to produce or release the normal levels of certain hormones into the bloodstream.The specific hormones that are affected and the severity of such hormone deficiencies may vary greatly from person to person. The majority of affected individuals lack sufficient levels of growth hormone (GH), which stimulates normal growth and development. Growth hormone deficiency is usually apparent before 6 years of age, when there is a decline in the normal growth rate that may ultimately result in short stature and other maturation delays.Some individuals with ONH also have abnormally low levels of several other hormones such as adrenocorticotropic hormone (ACTH), which stimulates the adrenal gland to release corticosteroids to maintain blood sugar and blood pressure during times of physical or emotional stress. Follicle-stimulating hormone (FSH) and luteinizing hormone (LH), from the pituitary play a role in coordinating the function of the male and female sexual organs and are essential for normal sexual development. Thyroid stimulating hormone (TSH) stimulates the thyroid gland to release thyroid hormones, which is responsible for energy metabolism. Absence of this hormone during infancy results in intellectual disability. The pituitary also releases antidiuretic hormone (ADH), which controls salt levels in the body by controlling urine output. Deficiencies in these hormone deficiencies may result in: intellectual disability; obesity; delayed sexual maturation; low levels of glucose in the blood (hypoglycemia); seizures; diabetes insipidus, a disorder characterized by excessive excretion of urine and excessive thirst. (For more information on hypothyroidism, hypoglycemia and diabetes insipidus, please see the Related Disorders section of this report.)Other structures within the brain may also develop improperly. As a result, such brain structures may be absent, incompletely developed (hypoplastic), and/or malformed (dysplastic). For example, individuals with ONH frequently do not have the membrane (septum pellucidum) that normally separates the fluid-filled cavities (lateral ventricles) in both sides of the brain. Absence of the septum pellucidum does not cause any known problems and most commonly occurs in otherwise normal individuals. In many people with ONH, the thick band of nerve fibers that connects the left and right hemispheres of the brain (corpus callosum) is underdeveloped or absent. Such individuals are at increased risk for cognitive or developmental delay.Many people with ONH may exhibit additional abnormalities. Delays in the acquisition of skills that require the coordination of mental and muscular activity (psychomotor retardation) are common in infants. Some affected children have normal intelligence and others have learning disabilities and intellectual disability. Autism is frequently diagnosed in children with ONH.
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Symptoms of Optic Nerve Hypoplasia. ONH is present at birth, but many symptoms may not be apparent until childhood, or even adolescence. Most infants with ONH have involuntary, rapid eye movements (nystagmus) and/or mild to severe visual impairment of one or both eyes. Vision often improves modestly in early childhood even though there is no growth of the optic nerves after birth. Due to underdevelopment of the optic nerves, the optic disk is smaller than normal size in one or both eyes when viewed by a doctor using an ophthalmoscope. Also referred to as the “blind spot,” the optic disk is the structure in which nerve fibers from the retina combine to form the optic nerve before leaving the back of the eye. The optic nerves meet to form the optic chiasm and optic tracts at the base of the hypothalamus.Affected individuals may also exhibit symptoms due to underdevelopment of the hypothalamus at the base of the brain. The hypothalamus is divided into several different regions that have different functions. The hypothalamus is responsible for regulating basic body functions such as thirst, hunger, sleep, and body temperature. As a result, children with ONH frequently have problems with these functions. Although the hypothalamus is commonly abnormal in individuals with ONH, the abnormalities are rarely visible on MRI scans.The hypothalamus also coordinates the function of the pituitary gland by controlling the gland’s release of certain hormones. The pituitary gland, a small structure beneath the hypothalamus produces several hormones and releases them directly into the bloodstream. It is located directly below the optic nerves and is connected to the hypothalamus by a short stalk of nerve fibers and blood vessels. In most individuals with ONH, the hypothalamus does not communicate with the pituitary gland properly, resulting in a failure of the pituitary gland to produce or release the normal levels of certain hormones into the bloodstream.The specific hormones that are affected and the severity of such hormone deficiencies may vary greatly from person to person. The majority of affected individuals lack sufficient levels of growth hormone (GH), which stimulates normal growth and development. Growth hormone deficiency is usually apparent before 6 years of age, when there is a decline in the normal growth rate that may ultimately result in short stature and other maturation delays.Some individuals with ONH also have abnormally low levels of several other hormones such as adrenocorticotropic hormone (ACTH), which stimulates the adrenal gland to release corticosteroids to maintain blood sugar and blood pressure during times of physical or emotional stress. Follicle-stimulating hormone (FSH) and luteinizing hormone (LH), from the pituitary play a role in coordinating the function of the male and female sexual organs and are essential for normal sexual development. Thyroid stimulating hormone (TSH) stimulates the thyroid gland to release thyroid hormones, which is responsible for energy metabolism. Absence of this hormone during infancy results in intellectual disability. The pituitary also releases antidiuretic hormone (ADH), which controls salt levels in the body by controlling urine output. Deficiencies in these hormone deficiencies may result in: intellectual disability; obesity; delayed sexual maturation; low levels of glucose in the blood (hypoglycemia); seizures; diabetes insipidus, a disorder characterized by excessive excretion of urine and excessive thirst. (For more information on hypothyroidism, hypoglycemia and diabetes insipidus, please see the Related Disorders section of this report.)Other structures within the brain may also develop improperly. As a result, such brain structures may be absent, incompletely developed (hypoplastic), and/or malformed (dysplastic). For example, individuals with ONH frequently do not have the membrane (septum pellucidum) that normally separates the fluid-filled cavities (lateral ventricles) in both sides of the brain. Absence of the septum pellucidum does not cause any known problems and most commonly occurs in otherwise normal individuals. In many people with ONH, the thick band of nerve fibers that connects the left and right hemispheres of the brain (corpus callosum) is underdeveloped or absent. Such individuals are at increased risk for cognitive or developmental delay.Many people with ONH may exhibit additional abnormalities. Delays in the acquisition of skills that require the coordination of mental and muscular activity (psychomotor retardation) are common in infants. Some affected children have normal intelligence and others have learning disabilities and intellectual disability. Autism is frequently diagnosed in children with ONH.
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Causes of Optic Nerve Hypoplasia
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The cause of ONH is not known. In most cases, the disorder appears to occur randomly for unknown reasons (sporadic). Rare families have been reported with more than one affected child, suggesting the possibility of autosomal recessive inheritance. A few cases of “SOD” have been reported to result from a mutation HESX1, SOX2, SOX3, OTX2 or PROKR2 genes. The diagnosis of SOD has been loosely defined in these cases, with the majority having normal optic nerves or ocular malformations other than ONH. The vast majority of individuals with ONH do not have mutations in any of these genes, suggesting that other genes and/or environmental factors are involved in the development of this condition.Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.
Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
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Causes of Optic Nerve Hypoplasia. The cause of ONH is not known. In most cases, the disorder appears to occur randomly for unknown reasons (sporadic). Rare families have been reported with more than one affected child, suggesting the possibility of autosomal recessive inheritance. A few cases of “SOD” have been reported to result from a mutation HESX1, SOX2, SOX3, OTX2 or PROKR2 genes. The diagnosis of SOD has been loosely defined in these cases, with the majority having normal optic nerves or ocular malformations other than ONH. The vast majority of individuals with ONH do not have mutations in any of these genes, suggesting that other genes and/or environmental factors are involved in the development of this condition.Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.
Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
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Affects of Optic Nerve Hypoplasia
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ONH is thought to affect males and females in equal numbers. The prevalence is estimated to be 1 in 10,000 children.
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Affects of Optic Nerve Hypoplasia. ONH is thought to affect males and females in equal numbers. The prevalence is estimated to be 1 in 10,000 children.
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Related disorders of Optic Nerve Hypoplasia
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Symptoms of the following disorders can be similar to those of ONH. Comparisons may be useful for a differential diagnosis:Holoprosencephaly (HPE) is the failure of the prosencephalon (a region of the brain in the fetus that develops into parts of the adult brain), or forebrain, to develop normally. Instead of the normal completely distinct left and right halves of the forebrain, there is an abnormal continuity between the two sides. Intellectual disability is associated and seizures are often present. Children with holoprosencephaly may also have defects in the development of the middle of the face such as closely set eyes (hypotelorism), tooth abnormalities (single central incisor), cleft lip/palate, and an abnormally small head (microcephaly). (For more information on this condition, choose “holoprosencephaly” as your search term in the Rare Disease Database.)The following conditions may be associated with ONH as secondary characteristics. They are not necessary for a differential diagnosis:Diabetes insipidus, a rare metabolic disorder, is characterized by a deficiency of antidiuretic hormone (ADH), a hormone that is stored in the back (posterior) lobe of the pituitary gland. Major symptoms include excessive excretion of urine (polyuria) and excessive thirst (polydipsia). Diabetes insipidus may have a number of different causes. It may be an inherited condition, occur in association with other underlying disorders, and/or occur as a result of lesions, either congenital or acquired, that damage the posterior lobe of the pituitary gland. (For more information on this disorder, choose “diabetes insipidus” as your search term in the Rare Disease Database.)Hypothyroidism is a condition characterized by abnormally decreased activity of the thyroid gland and underproduction of thyroid hormones. Symptoms may vary greatly from person to person. Affected individuals may demonstrate mental and physical sluggishness (lethargy); muscle weakness; a slowed heart rate; dry, flaky skin; abnormal hair loss; unusual deepening of the voice; and/or weight gain in association with abnormal thickening of the skin and other body tissues (myxedema). Some people with hypothyroidism may exhibit abnormal enlargement of the thyroid gland (goiter). If hypothyroidism occurs during childhood, the condition may cause or contribute to cognitive impairment, growth retardation, delays in sexual maturation, and/or other abnormalities without appropriate treatment. Hypothyroidism may have a number of different causes. It may be an inherited condition, occur due to or in association with other underlying disorders (such as certain autoimmune diseases and/or disorders affecting the hypothalamus and/or pituitary gland), result from surgery, and/or be due to the use of certain medications. Hypoglycemia is a condition characterized by abnormally low levels of sugar (glucose) in the blood. Affected individuals may experience faintness, weakness, sweating, excessive hunger, and nervousness. Additional symptoms may include headaches, confusion, visual disturbances, muscle weakness, impaired coordination of voluntary movement (ataxia), marked personality changes, and seizures. Hypoglycemia may have a number of causes such as excessive secretion or administration of insulin, prolonged abuse of alcohol without appropriate food intake, and/or deficiencies of certain hormones such as glucocorticoids or growth hormone. In rare cases, hypoglycemia may occur temporarily in some children for unknown reasons.
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Related disorders of Optic Nerve Hypoplasia. Symptoms of the following disorders can be similar to those of ONH. Comparisons may be useful for a differential diagnosis:Holoprosencephaly (HPE) is the failure of the prosencephalon (a region of the brain in the fetus that develops into parts of the adult brain), or forebrain, to develop normally. Instead of the normal completely distinct left and right halves of the forebrain, there is an abnormal continuity between the two sides. Intellectual disability is associated and seizures are often present. Children with holoprosencephaly may also have defects in the development of the middle of the face such as closely set eyes (hypotelorism), tooth abnormalities (single central incisor), cleft lip/palate, and an abnormally small head (microcephaly). (For more information on this condition, choose “holoprosencephaly” as your search term in the Rare Disease Database.)The following conditions may be associated with ONH as secondary characteristics. They are not necessary for a differential diagnosis:Diabetes insipidus, a rare metabolic disorder, is characterized by a deficiency of antidiuretic hormone (ADH), a hormone that is stored in the back (posterior) lobe of the pituitary gland. Major symptoms include excessive excretion of urine (polyuria) and excessive thirst (polydipsia). Diabetes insipidus may have a number of different causes. It may be an inherited condition, occur in association with other underlying disorders, and/or occur as a result of lesions, either congenital or acquired, that damage the posterior lobe of the pituitary gland. (For more information on this disorder, choose “diabetes insipidus” as your search term in the Rare Disease Database.)Hypothyroidism is a condition characterized by abnormally decreased activity of the thyroid gland and underproduction of thyroid hormones. Symptoms may vary greatly from person to person. Affected individuals may demonstrate mental and physical sluggishness (lethargy); muscle weakness; a slowed heart rate; dry, flaky skin; abnormal hair loss; unusual deepening of the voice; and/or weight gain in association with abnormal thickening of the skin and other body tissues (myxedema). Some people with hypothyroidism may exhibit abnormal enlargement of the thyroid gland (goiter). If hypothyroidism occurs during childhood, the condition may cause or contribute to cognitive impairment, growth retardation, delays in sexual maturation, and/or other abnormalities without appropriate treatment. Hypothyroidism may have a number of different causes. It may be an inherited condition, occur due to or in association with other underlying disorders (such as certain autoimmune diseases and/or disorders affecting the hypothalamus and/or pituitary gland), result from surgery, and/or be due to the use of certain medications. Hypoglycemia is a condition characterized by abnormally low levels of sugar (glucose) in the blood. Affected individuals may experience faintness, weakness, sweating, excessive hunger, and nervousness. Additional symptoms may include headaches, confusion, visual disturbances, muscle weakness, impaired coordination of voluntary movement (ataxia), marked personality changes, and seizures. Hypoglycemia may have a number of causes such as excessive secretion or administration of insulin, prolonged abuse of alcohol without appropriate food intake, and/or deficiencies of certain hormones such as glucocorticoids or growth hormone. In rare cases, hypoglycemia may occur temporarily in some children for unknown reasons.
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Diagnosis of Optic Nerve Hypoplasia
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ONH is diagnosed by a complete ophthalmologic examination. Imaging studies such as magnetic resonance imaging (MRI) and computerized tomography (CT) are used to examine the corpus callosum and optic nerves. ONH may be suspected, but not diagnosed, based on MRI findings, as other abnormalities can mimic the MRI findings of ONH. Abnormal levels of serum cortisol and growth hormone help to confirm the diagnosis.
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Diagnosis of Optic Nerve Hypoplasia. ONH is diagnosed by a complete ophthalmologic examination. Imaging studies such as magnetic resonance imaging (MRI) and computerized tomography (CT) are used to examine the corpus callosum and optic nerves. ONH may be suspected, but not diagnosed, based on MRI findings, as other abnormalities can mimic the MRI findings of ONH. Abnormal levels of serum cortisol and growth hormone help to confirm the diagnosis.
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Therapies of Optic Nerve Hypoplasia
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Treatment
The treatment of ONH is directed toward the specific symptoms in each individual. Treatment may require the coordinated efforts of a team of specialists including pediatricians, ophthalmologists, neurologists, endocrinologists and/or other health care professionals.Specific therapies for ONH are symptomatic and supportive. Hormone deficiencies are treated with hormone replacement therapy. The vision abnormalities are usually not treatable.Developmental testing should be performed to determine if deficiencies are present in gross or fine motor skills or in intelligence. Early intervention is important to ensure that children with ONH reach their potential. Special services that may be beneficial to affected children may include vision therapy, physical therapy, and occupational therapy.Genetic counseling may be beneficial for affected children and their families.
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Therapies of Optic Nerve Hypoplasia. Treatment
The treatment of ONH is directed toward the specific symptoms in each individual. Treatment may require the coordinated efforts of a team of specialists including pediatricians, ophthalmologists, neurologists, endocrinologists and/or other health care professionals.Specific therapies for ONH are symptomatic and supportive. Hormone deficiencies are treated with hormone replacement therapy. The vision abnormalities are usually not treatable.Developmental testing should be performed to determine if deficiencies are present in gross or fine motor skills or in intelligence. Early intervention is important to ensure that children with ONH reach their potential. Special services that may be beneficial to affected children may include vision therapy, physical therapy, and occupational therapy.Genetic counseling may be beneficial for affected children and their families.
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Overview of Oral-Facial-Digital Syndrome
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Oral-facial-digital syndrome (OFDS) is a group of conditions that affect the development of their oral cavity (mouth, tongue, teeth, and jaw), face (head, eyes and nose) and finger and toes (digits).Common signs and symptoms include a split (cleft) in the lip and a tongue with an unusual lobed shape. There may also be growth of noncancerous tumors or nodules on the tongue. Affected people may have extra, missing, or differently shaped teeth. Another common feature is an opening in the roof of the mouth (cleft palate). Some people with OFDS have bands of extra tissue (gingival frenula) that attach the lip to the gums. Distinct facial features include a wide nose with a broad, flat nasal bridge and widely spaced eyes (hypertelorism). Fusion of certain digits (syndactyly), short digits (brachydactyly), curved digits (clinodactyly) or extra fingers/toes (polydactyly) are commonly seen in OFDS. People with OFDS also have issues with the development and structure of the brain. Mild to severe intellectual disability is seen in affected people.There are 14 different types of OFDS, some of which are not well-defined. The signs and symptoms vary widely, making diagnosis difficult. OFDS type I is the most common, but all the OFDS types are very rare. Depending on the type of OFDS there can be other features related with the condition. For example, polycystic kidney disease, seizures, heart defects and distinct skeletal features.Treatment is mainly supportive and depends on the signs and symptoms seen in each person.IntroductionOFDS type I was first reported by Papillon-Leage and Psaume in 1954 and further defined by Gorlin and Psaume in 1962. The first person with this condition was reported in 1941. Since then a number of different OFDS types with overlapping signs and symptoms have been described. The gene responsible for causing OFDS type I was identified in 2001 and for a while remained the only OFD gene known. In the last few years, a number of genes responsible for other types of OFDS have been identified.
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Overview of Oral-Facial-Digital Syndrome. Oral-facial-digital syndrome (OFDS) is a group of conditions that affect the development of their oral cavity (mouth, tongue, teeth, and jaw), face (head, eyes and nose) and finger and toes (digits).Common signs and symptoms include a split (cleft) in the lip and a tongue with an unusual lobed shape. There may also be growth of noncancerous tumors or nodules on the tongue. Affected people may have extra, missing, or differently shaped teeth. Another common feature is an opening in the roof of the mouth (cleft palate). Some people with OFDS have bands of extra tissue (gingival frenula) that attach the lip to the gums. Distinct facial features include a wide nose with a broad, flat nasal bridge and widely spaced eyes (hypertelorism). Fusion of certain digits (syndactyly), short digits (brachydactyly), curved digits (clinodactyly) or extra fingers/toes (polydactyly) are commonly seen in OFDS. People with OFDS also have issues with the development and structure of the brain. Mild to severe intellectual disability is seen in affected people.There are 14 different types of OFDS, some of which are not well-defined. The signs and symptoms vary widely, making diagnosis difficult. OFDS type I is the most common, but all the OFDS types are very rare. Depending on the type of OFDS there can be other features related with the condition. For example, polycystic kidney disease, seizures, heart defects and distinct skeletal features.Treatment is mainly supportive and depends on the signs and symptoms seen in each person.IntroductionOFDS type I was first reported by Papillon-Leage and Psaume in 1954 and further defined by Gorlin and Psaume in 1962. The first person with this condition was reported in 1941. Since then a number of different OFDS types with overlapping signs and symptoms have been described. The gene responsible for causing OFDS type I was identified in 2001 and for a while remained the only OFD gene known. In the last few years, a number of genes responsible for other types of OFDS have been identified.
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Symptoms of Oral-Facial-Digital Syndrome
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The various types of OFDS present with some combination of signs and symptoms from the list below. Face and skin: Eyes set widely apart (hypertelorism), small eyes; eyes looking in different directions (strabismus), a small jaw, a loss of hair (alopecia), abnormalities in the structure of the nostrils; broad nose at the base and/or tip; one nostril smaller than the other; angled ears Oral cavity: split in the lip (cleft lip); opening in the roof of the mouth (cleft palate); lobed or split tongue; tumors of the tongue; extra or missing teeth; smaller than usual jaw; over, under, or lateral bite; bands of extra tissue (gingival frenula) that attach the lip to the gums. Fingers and Toes features: Extra fingers and/or toes (polydactyly); fused fingers (syndactyly), unusually short fingers (brachydactyly); webbed toes and/or fingers; clubfoot; rigid, bent fingers (clinodactyly) Intellectual and central nervous system (CNS) problems: Intellectual disability of varying degrees; brain abnormalities; seizures; spastic movement and/or tics; delayed development of speech and motor control Other: Reduction in growth; heart and kidney problems; sunken chest; vulnerability to respiratory infection Characteristics associated with specific types of oral-facial-digital syndrome are described below. OFDS type I disease (Papillon-Leage-Psaume syndrome) OFDS type I is marked by coarse thin hair, grainy skin lesions (milia) on the face, and extra fingers on one hand (polysyndactyly). Polycystic kidney disease (PKD) is seen in around 50% of patients. PKD may not be seen until the affected person is a teenager. Oral issues include: clefting of the hard or soft palate, cleft lip, tumors or nodules of the tongue, missing or extra teeth, multiple bands of extra tissue that abnormally attach the lip to the gums (gingival frenulae) and other dental issues. Facial features include widely spaced eyes, broad nasal bridge, small jaw and differently shaped nostrils. Issues with digits affecting the hands more often than the feet. These include short fingers (brachydactyly), fused fingers (syndactyly), bent fingers (clinodactyly) especially the fifth finger and extra fingers or toes (polydactyly). Adult-onset polycystic kidney disease (PKD) leading to kidney failure is a distinct feature of OFDS type 1. It can be the presenting feature in females with mild signs and symptoms. PKD can lead to end-stage renal disease (ESRD). Central nervous system involvement includes brain malformations. People with OFDS type I have varying degrees of intellectual disability. The condition is mostly lethal in males due to its mode of inheritance. However, a few male patients have been reported. The males had chronic kidney diseases leading to ESRD, but with varying degrees of other oral-facial and digital defects and central nervous system involvement. Signs and symptoms of OFDS type I can vary within and between families. OFDS type II disease (Mohr syndrome) Has the same set of symptoms as those of Type I. It may also include the presence of extra toes on both feet (polydactyly) and the nose being split into two parts (bifid nose). Affected people do not have milia or polycystic kidney disease. They have thick hair and rarely have heart problems; cysts or cavities in the brain (porencephaly) or build-up of fluid in the brain (hydrocephaly). OFDS type III (Sugarman syndrome) Is characterized by seesaw winking in which the eye blinks (winks) as the jaw moves. Other features seen are extra fingers or toes (polydactyly), epilepsy-like myoclonic jerks, and profound intellectual disability. Some affected people have extra teeth, low-set ears, and broad tip of the nose. End stage kidney failure can occur in the teens and 20s. OFDS type IV (Baraister-Burn syndrome) Can be told apart from other types of OFDS by short tibias (bone in the leg, connecting the knee to the ankle) which leads to short limbs. An affected person’s chest may be sunken in. Kidney (renal) cysts, low-set ears and small jaw have been seen in people with OFDS type IV. OFDS type V (Thurston syndrome) Is marked by a midline cleft lip and extra fingers and toes (polydactyly) only. Bands of extra tissue that attach the lip to the gums (gingival frenulae) have been reported rarely. This type of OFDS has been seen mostly in people of Indian ancestry. OFDS type VI (Varadi syndrome) Is marked by extra toes and fingers. The extra digits are usually located between the second and third digits (central polydactyly). The kidney may be smaller than normal or even absent (renal agenesis/ renal dysplasia). Abnormal brain MRI results showing a molar tooth sign have been noted for people with OFDS type VI. Affected people may have varying degrees of intellectual disability. OFDS type VII (Whelan syndrome) Is the same as type I. OFDS type VII has been shown to be due to changes (mutations) in OFD1 gene and is no longer considered a separate type. OFDS type VIII (Edwards syndrome) Is characterized by extra fingers and toes (polydactyly) and shortening of some long bones of the arm (radius) and leg (tibia). It is also characterized by issues in the structure of the epiglottis (flap in the throat that prevents food from entering the windpipe and the lungs while swallowing). Other features include a midline cleft lip, large nose and the thumb being split into two (bifid thumb). OFDS type IX (Gurrieri syndrome) Clinical features include abnormal development of the retina, and cleft lip (usually lateral/located on the sides of the mouth). Affected people may have one eyeball smaller than the other, short stature, nodules on the tongue, and cleft palate. Heart problems like a hole in the heart (septal defects) have been reported. OFDS type X (Figuera syndrome) Common features include cleft palate, flat nasal bridge and gingival frenulae. The lower jaw is set behind the upper jaw (retrognathia) for some affected people. It is marked by the shortening of some long bones of the arm (radius) and the absence of the smaller bone of the lower leg (agenesis of the fibula). Other features seen are the presence of fewer than five fingers or toes on a hand or foot (oligodactyly). OFDS XI (Gabrielli syndrome/Toriello syndrome) Is characterized by incomplete or underdevelopment of the odontoid (tooth-like bony structure in the upper spine) and other defects in the spine. Other features seen are enlargement of the ventricles of the brain (ventriculomegaly), small holes near the ears (auricular pits) and underdeveloped eyelids causing them to not open as far as usual (blepharophimosis). Deafness, severe intellectual disability, and behavioural problems have also been seen. OFDS XII (Moran-Barroso syndrome) Has been described in only one person who had several malformations of the brain and shortening of the long bone of the leg (tibia). They were also noted to have extra teeth, tongue with a groove, or split (bifid tongue) and a large head (macrocephaly). Along with club feet and extra toes and fingers (polydactyly). OFDS XIII (Degner syndrome) Has also been reported in one person. Features include psychiatric issues and epilepsy. Abnormal MRI results showing changes in the appearance of the white matter of the brain (leukokaraiosis) have been seen. The affected person also had tumors of the tongue, cleft lip, and short, bent, and fused fingers (syndactyly). OFDS type XIV Includes small size of the head (microcephaly) and intellectual disability. Affected people have abnormal brain MRI results showing a molar tooth sign. Small size of the penis (micropenis) and other common oral features of OFDS have also been seen.
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Symptoms of Oral-Facial-Digital Syndrome. The various types of OFDS present with some combination of signs and symptoms from the list below. Face and skin: Eyes set widely apart (hypertelorism), small eyes; eyes looking in different directions (strabismus), a small jaw, a loss of hair (alopecia), abnormalities in the structure of the nostrils; broad nose at the base and/or tip; one nostril smaller than the other; angled ears Oral cavity: split in the lip (cleft lip); opening in the roof of the mouth (cleft palate); lobed or split tongue; tumors of the tongue; extra or missing teeth; smaller than usual jaw; over, under, or lateral bite; bands of extra tissue (gingival frenula) that attach the lip to the gums. Fingers and Toes features: Extra fingers and/or toes (polydactyly); fused fingers (syndactyly), unusually short fingers (brachydactyly); webbed toes and/or fingers; clubfoot; rigid, bent fingers (clinodactyly) Intellectual and central nervous system (CNS) problems: Intellectual disability of varying degrees; brain abnormalities; seizures; spastic movement and/or tics; delayed development of speech and motor control Other: Reduction in growth; heart and kidney problems; sunken chest; vulnerability to respiratory infection Characteristics associated with specific types of oral-facial-digital syndrome are described below. OFDS type I disease (Papillon-Leage-Psaume syndrome) OFDS type I is marked by coarse thin hair, grainy skin lesions (milia) on the face, and extra fingers on one hand (polysyndactyly). Polycystic kidney disease (PKD) is seen in around 50% of patients. PKD may not be seen until the affected person is a teenager. Oral issues include: clefting of the hard or soft palate, cleft lip, tumors or nodules of the tongue, missing or extra teeth, multiple bands of extra tissue that abnormally attach the lip to the gums (gingival frenulae) and other dental issues. Facial features include widely spaced eyes, broad nasal bridge, small jaw and differently shaped nostrils. Issues with digits affecting the hands more often than the feet. These include short fingers (brachydactyly), fused fingers (syndactyly), bent fingers (clinodactyly) especially the fifth finger and extra fingers or toes (polydactyly). Adult-onset polycystic kidney disease (PKD) leading to kidney failure is a distinct feature of OFDS type 1. It can be the presenting feature in females with mild signs and symptoms. PKD can lead to end-stage renal disease (ESRD). Central nervous system involvement includes brain malformations. People with OFDS type I have varying degrees of intellectual disability. The condition is mostly lethal in males due to its mode of inheritance. However, a few male patients have been reported. The males had chronic kidney diseases leading to ESRD, but with varying degrees of other oral-facial and digital defects and central nervous system involvement. Signs and symptoms of OFDS type I can vary within and between families. OFDS type II disease (Mohr syndrome) Has the same set of symptoms as those of Type I. It may also include the presence of extra toes on both feet (polydactyly) and the nose being split into two parts (bifid nose). Affected people do not have milia or polycystic kidney disease. They have thick hair and rarely have heart problems; cysts or cavities in the brain (porencephaly) or build-up of fluid in the brain (hydrocephaly). OFDS type III (Sugarman syndrome) Is characterized by seesaw winking in which the eye blinks (winks) as the jaw moves. Other features seen are extra fingers or toes (polydactyly), epilepsy-like myoclonic jerks, and profound intellectual disability. Some affected people have extra teeth, low-set ears, and broad tip of the nose. End stage kidney failure can occur in the teens and 20s. OFDS type IV (Baraister-Burn syndrome) Can be told apart from other types of OFDS by short tibias (bone in the leg, connecting the knee to the ankle) which leads to short limbs. An affected person’s chest may be sunken in. Kidney (renal) cysts, low-set ears and small jaw have been seen in people with OFDS type IV. OFDS type V (Thurston syndrome) Is marked by a midline cleft lip and extra fingers and toes (polydactyly) only. Bands of extra tissue that attach the lip to the gums (gingival frenulae) have been reported rarely. This type of OFDS has been seen mostly in people of Indian ancestry. OFDS type VI (Varadi syndrome) Is marked by extra toes and fingers. The extra digits are usually located between the second and third digits (central polydactyly). The kidney may be smaller than normal or even absent (renal agenesis/ renal dysplasia). Abnormal brain MRI results showing a molar tooth sign have been noted for people with OFDS type VI. Affected people may have varying degrees of intellectual disability. OFDS type VII (Whelan syndrome) Is the same as type I. OFDS type VII has been shown to be due to changes (mutations) in OFD1 gene and is no longer considered a separate type. OFDS type VIII (Edwards syndrome) Is characterized by extra fingers and toes (polydactyly) and shortening of some long bones of the arm (radius) and leg (tibia). It is also characterized by issues in the structure of the epiglottis (flap in the throat that prevents food from entering the windpipe and the lungs while swallowing). Other features include a midline cleft lip, large nose and the thumb being split into two (bifid thumb). OFDS type IX (Gurrieri syndrome) Clinical features include abnormal development of the retina, and cleft lip (usually lateral/located on the sides of the mouth). Affected people may have one eyeball smaller than the other, short stature, nodules on the tongue, and cleft palate. Heart problems like a hole in the heart (septal defects) have been reported. OFDS type X (Figuera syndrome) Common features include cleft palate, flat nasal bridge and gingival frenulae. The lower jaw is set behind the upper jaw (retrognathia) for some affected people. It is marked by the shortening of some long bones of the arm (radius) and the absence of the smaller bone of the lower leg (agenesis of the fibula). Other features seen are the presence of fewer than five fingers or toes on a hand or foot (oligodactyly). OFDS XI (Gabrielli syndrome/Toriello syndrome) Is characterized by incomplete or underdevelopment of the odontoid (tooth-like bony structure in the upper spine) and other defects in the spine. Other features seen are enlargement of the ventricles of the brain (ventriculomegaly), small holes near the ears (auricular pits) and underdeveloped eyelids causing them to not open as far as usual (blepharophimosis). Deafness, severe intellectual disability, and behavioural problems have also been seen. OFDS XII (Moran-Barroso syndrome) Has been described in only one person who had several malformations of the brain and shortening of the long bone of the leg (tibia). They were also noted to have extra teeth, tongue with a groove, or split (bifid tongue) and a large head (macrocephaly). Along with club feet and extra toes and fingers (polydactyly). OFDS XIII (Degner syndrome) Has also been reported in one person. Features include psychiatric issues and epilepsy. Abnormal MRI results showing changes in the appearance of the white matter of the brain (leukokaraiosis) have been seen. The affected person also had tumors of the tongue, cleft lip, and short, bent, and fused fingers (syndactyly). OFDS type XIV Includes small size of the head (microcephaly) and intellectual disability. Affected people have abnormal brain MRI results showing a molar tooth sign. Small size of the penis (micropenis) and other common oral features of OFDS have also been seen.
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Oral-Facial-Digital Syndrome
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nord_908_2
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Causes of Oral-Facial-Digital Syndrome
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Chromosomes, which are present in the nucleus of human cells, carry the genetic information (DNA) for each individual. The genetic information is carried in genes. Harmful gene changes (mutations) can cause the gene to not properly. This can lead to genetic conditions. Specific gene changes have been found for type I, II, III, IV, V, VI, IX and XIV. Genetic causes of the other types of OFDS have not been identified, and some of the genes have only been identified recently. Type X, XI, XII, XIII have been reported in very few people/families and do not have an identified genetic cause. Hence, are thought to occur by chance and are not known to follow a mode of inheritance. Mode of inheritance of OFDS types: X-Linked Dominant: OFDS type I/VII X-Linked Recessive: OFDS type VIII Autosomal Recessive: OFDS type II, III, IV, V, VI, IX, IV X-linked Recessive and Dominant InheritanceX-linked genetic disorders are conditions caused by a non-working gene on the X chromosome and manifest mostly in males. Females that have a non-working 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 non-working gene. Males have only one X chromosome that is inherited from their mother as well as a Y from the father. If a male inherits an X chromosome that contains a non-working 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 non-working 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 (not the X) to male children. X-linked dominant disorders are caused by a non-working gene on the X chromosome and occur mostly in females. Females with these rare conditions are affected when they have just one X chromosome with the non-working gene for a particular disease. Males with a non-working gene for an X-linked dominant disorder are more severely affected than females and often do not survive. The following types of OFSD have shown to follow an X-linked inheritance pattern: OFDS type I is associated with changes (mutations) in the OFD1 gene (previously called CXORF5). The gene is located on the X chromosome and follows an X-linked dominant pattern of inheritance. Approximately 75% of females with OFDS type 1 have no family history of OFDS. OFDS Type VIII is inherited in an X-linked recessive form, but a gene has not been associated with this type. Autosomal Recessive Inheritance Recessive genetic conditions 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. Parents who are close relatives (consanguineous) have a high chance to carry the same change (mutation). Hence, increasing the risk to have children with recessive genetic conditions, compared to unrelated parents. The following types are known to follow autosomal recessive inheritance: OFDS Type II has been linked with mutations in the NEK1 gene. OFDS type III has been linked with mutations in the TMEM231 gene. OFDS type IV has been linked with mutations in the TCTN3 and WDPCP genes. OFDS type V has been linked with mutations in the DDX59 gene. OFDS type VI has been linked with mutations in the OFD1, TMEM216, C4orf42, TMEME138, TMEM107 and KIAAO753 genes. Different changes (mutations) in these genes are also known to cause other conditions like Joubert Syndrome and Meckel-gruber Syndrome. OFDS type IX has been linked with mutations in the SCLT1 and TBC1D32/C6orf170 genes. OFDS type XIV has been linked with mutations in the C2CD3 gene.
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Causes of Oral-Facial-Digital Syndrome. Chromosomes, which are present in the nucleus of human cells, carry the genetic information (DNA) for each individual. The genetic information is carried in genes. Harmful gene changes (mutations) can cause the gene to not properly. This can lead to genetic conditions. Specific gene changes have been found for type I, II, III, IV, V, VI, IX and XIV. Genetic causes of the other types of OFDS have not been identified, and some of the genes have only been identified recently. Type X, XI, XII, XIII have been reported in very few people/families and do not have an identified genetic cause. Hence, are thought to occur by chance and are not known to follow a mode of inheritance. Mode of inheritance of OFDS types: X-Linked Dominant: OFDS type I/VII X-Linked Recessive: OFDS type VIII Autosomal Recessive: OFDS type II, III, IV, V, VI, IX, IV X-linked Recessive and Dominant InheritanceX-linked genetic disorders are conditions caused by a non-working gene on the X chromosome and manifest mostly in males. Females that have a non-working 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 non-working gene. Males have only one X chromosome that is inherited from their mother as well as a Y from the father. If a male inherits an X chromosome that contains a non-working 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 non-working 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 (not the X) to male children. X-linked dominant disorders are caused by a non-working gene on the X chromosome and occur mostly in females. Females with these rare conditions are affected when they have just one X chromosome with the non-working gene for a particular disease. Males with a non-working gene for an X-linked dominant disorder are more severely affected than females and often do not survive. The following types of OFSD have shown to follow an X-linked inheritance pattern: OFDS type I is associated with changes (mutations) in the OFD1 gene (previously called CXORF5). The gene is located on the X chromosome and follows an X-linked dominant pattern of inheritance. Approximately 75% of females with OFDS type 1 have no family history of OFDS. OFDS Type VIII is inherited in an X-linked recessive form, but a gene has not been associated with this type. Autosomal Recessive Inheritance Recessive genetic conditions 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. Parents who are close relatives (consanguineous) have a high chance to carry the same change (mutation). Hence, increasing the risk to have children with recessive genetic conditions, compared to unrelated parents. The following types are known to follow autosomal recessive inheritance: OFDS Type II has been linked with mutations in the NEK1 gene. OFDS type III has been linked with mutations in the TMEM231 gene. OFDS type IV has been linked with mutations in the TCTN3 and WDPCP genes. OFDS type V has been linked with mutations in the DDX59 gene. OFDS type VI has been linked with mutations in the OFD1, TMEM216, C4orf42, TMEME138, TMEM107 and KIAAO753 genes. Different changes (mutations) in these genes are also known to cause other conditions like Joubert Syndrome and Meckel-gruber Syndrome. OFDS type IX has been linked with mutations in the SCLT1 and TBC1D32/C6orf170 genes. OFDS type XIV has been linked with mutations in the C2CD3 gene.
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Oral-Facial-Digital Syndrome
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nord_908_3
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Affects of Oral-Facial-Digital Syndrome
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All types of oral-facial-digital syndrome are rare, with type I being the least rare. The incidence of OFDS type I is thought to be between 1 per 50,000 births and 1 per 250,000 births, and type II is thought to occur 1 in 300,000 births. Some types of OFDS have only been reported in a few people/families.
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Affects of Oral-Facial-Digital Syndrome. All types of oral-facial-digital syndrome are rare, with type I being the least rare. The incidence of OFDS type I is thought to be between 1 per 50,000 births and 1 per 250,000 births, and type II is thought to occur 1 in 300,000 births. Some types of OFDS have only been reported in a few people/families.
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Oral-Facial-Digital Syndrome
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nord_908_4
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Related disorders of Oral-Facial-Digital Syndrome
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Symptoms of the following conditions can be similar to those of OFSD syndrome. Comparisons may be useful to help make a diagnosis: Juberg-Hayward syndrome (orocraniodigital syndrome) is a rare disorder characterized by cleft lip and palate, a smaller than the normal sized head, abnormal number and development of the thumbs and toes, and growth hormone deficiency resulting in short stature. Nager acrofacial dysostosis/AFD/ Nager type/Mandibulofacial dysostosis is a rare disorder that affects the limbs and face. This results in cleft lip and palate, abnormal development of bones of the jaw and arms, and smaller than normal thumbs. The condition is caused by mutations in the SF3B4 gene. While most cases occur in families with no prior history of the disorder, autosomal dominant and autosomal recessive inheritance have been reported. Some people who were given the diagnosis of Autosomal dominant polycystic kidney disease (ADPKD) diagnosis who were later found to have mutations in the OFD1 gene. The origin and size of the cysts in the kidneys differs between OFDS type I and ADPKD. Other differentiating features are the mode of inheritance and the absence of oral, facial, digital, or brain defects in ADPKD. The two genes in which changes (mutations) are known to cause ADPKD are PKD1 and PKD2. Multiple genes associated with OFDS are also known to cause ciliopathies (a category of diseases thought to be caused by dysfunction of cilia and flagella) like Joubert Syndrome and Meckel-Gruber Syndrome. Changes (mutations) in TMEM216, TMEM138, TMEM231, TMEM107, OFD1 and C5orf42/CPLANE1 are known to cause OFDS type VI and Joubert Syndrome. Changes (mutations) in TMEM231, TCTN3, TMEM107 and C5orf42/CPLANE1 are also known to cause Meckel-Gruber Syndrome. Joubert syndrome is a hereditary neurological disorder marked by malformation of the area of the brain which controls balance and coordination. Issues with muscles and eye movement similar to those of oral-facial-digital syndrome occur. The molar tooth sign is seen on brain MRI. Weak muscle tone (hypotonia), abnormal breathing patterns and eye movement are seen, along with intellectual disability. There are multiple genes known to cause Joubert Syndrome, many of which overlap with OFDS. Inheritance is usually autosomal recessive, but rarely it may be X-linked recessive Meckel-Gruber syndrome is characterized by nervous system malformations, multiple cysts in the kidneys, extra digits (polydactyly), and leads to an early death. Other findings include cleft lip and palate, problems with development of external genital organs, small head (microcephaly), and one or both eyeballs being small (microphthalmia). Affected people also have multiple other defects of the eye, especially the retina. It is also inherited in an autosomal recessive manner.
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Related disorders of Oral-Facial-Digital Syndrome. Symptoms of the following conditions can be similar to those of OFSD syndrome. Comparisons may be useful to help make a diagnosis: Juberg-Hayward syndrome (orocraniodigital syndrome) is a rare disorder characterized by cleft lip and palate, a smaller than the normal sized head, abnormal number and development of the thumbs and toes, and growth hormone deficiency resulting in short stature. Nager acrofacial dysostosis/AFD/ Nager type/Mandibulofacial dysostosis is a rare disorder that affects the limbs and face. This results in cleft lip and palate, abnormal development of bones of the jaw and arms, and smaller than normal thumbs. The condition is caused by mutations in the SF3B4 gene. While most cases occur in families with no prior history of the disorder, autosomal dominant and autosomal recessive inheritance have been reported. Some people who were given the diagnosis of Autosomal dominant polycystic kidney disease (ADPKD) diagnosis who were later found to have mutations in the OFD1 gene. The origin and size of the cysts in the kidneys differs between OFDS type I and ADPKD. Other differentiating features are the mode of inheritance and the absence of oral, facial, digital, or brain defects in ADPKD. The two genes in which changes (mutations) are known to cause ADPKD are PKD1 and PKD2. Multiple genes associated with OFDS are also known to cause ciliopathies (a category of diseases thought to be caused by dysfunction of cilia and flagella) like Joubert Syndrome and Meckel-Gruber Syndrome. Changes (mutations) in TMEM216, TMEM138, TMEM231, TMEM107, OFD1 and C5orf42/CPLANE1 are known to cause OFDS type VI and Joubert Syndrome. Changes (mutations) in TMEM231, TCTN3, TMEM107 and C5orf42/CPLANE1 are also known to cause Meckel-Gruber Syndrome. Joubert syndrome is a hereditary neurological disorder marked by malformation of the area of the brain which controls balance and coordination. Issues with muscles and eye movement similar to those of oral-facial-digital syndrome occur. The molar tooth sign is seen on brain MRI. Weak muscle tone (hypotonia), abnormal breathing patterns and eye movement are seen, along with intellectual disability. There are multiple genes known to cause Joubert Syndrome, many of which overlap with OFDS. Inheritance is usually autosomal recessive, but rarely it may be X-linked recessive Meckel-Gruber syndrome is characterized by nervous system malformations, multiple cysts in the kidneys, extra digits (polydactyly), and leads to an early death. Other findings include cleft lip and palate, problems with development of external genital organs, small head (microcephaly), and one or both eyeballs being small (microphthalmia). Affected people also have multiple other defects of the eye, especially the retina. It is also inherited in an autosomal recessive manner.
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Oral-Facial-Digital Syndrome
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nord_908_5
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Diagnosis of Oral-Facial-Digital Syndrome
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Diagnosis of OFD syndromes with a known genetic cause (OFDS type I, III, IV, V, VI, IX, XIV) can be confirmed by genetic testing. However, diagnosis is generally made based on the clinical symptoms presented. Clinical Testing and Work Up The initial workup for people with OFDS includes: Surveillance for people with OFDS type I includes the following: Surveillance for OFDS types having brain malformations features can include receiving regular brain MRIs.
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Diagnosis of Oral-Facial-Digital Syndrome. Diagnosis of OFD syndromes with a known genetic cause (OFDS type I, III, IV, V, VI, IX, XIV) can be confirmed by genetic testing. However, diagnosis is generally made based on the clinical symptoms presented. Clinical Testing and Work Up The initial workup for people with OFDS includes: Surveillance for people with OFDS type I includes the following: Surveillance for OFDS types having brain malformations features can include receiving regular brain MRIs.
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Oral-Facial-Digital Syndrome
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nord_908_6
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Therapies of Oral-Facial-Digital Syndrome
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Treatment Treatment of oral-facial-digital syndrome may involve reconstructive surgery for facial clefts, removal of extra teeth, surgery to repair fused fingers or digit anomalies. It can also include management of renal disease including hemodialysis/peritoneal dialysis or a kidney transplant. Management of seizures if present and evaluations for learning disabilities may be required based on the type. Speech therapy and special education may be recommended as well. Other treatment is supportive and based on symptoms. Genetic counseling is recommended for patients and their families
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Therapies of Oral-Facial-Digital Syndrome. Treatment Treatment of oral-facial-digital syndrome may involve reconstructive surgery for facial clefts, removal of extra teeth, surgery to repair fused fingers or digit anomalies. It can also include management of renal disease including hemodialysis/peritoneal dialysis or a kidney transplant. Management of seizures if present and evaluations for learning disabilities may be required based on the type. Speech therapy and special education may be recommended as well. Other treatment is supportive and based on symptoms. Genetic counseling is recommended for patients and their families
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Oral-Facial-Digital Syndrome
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nord_909_0
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Overview of Organizing Pneumonia
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Organizing pneumonia (OP) is a rare inflammatory lung disorder characterized by clinical symptoms such as flu-like illness as well as cough and shortness of breath with exertional activities. Wheezing and hemoptysis (blood when coughing) may occur rarely. OP refers to organized swirls of inflammatory tissue filling the small spherical units of the lungs called alveoli as well as the alveolar ducts. Individuals with OP experience inflammation of the bronchioles and alveolar lung spherical units simultaneously, which distinguishes it from other similar inflammatory lung disorders. Though the term pneumonia is used, OP is not an infection. It is a different disease from obliterative bronchiolitis which refers to scarring and narrowing of the small airways. Several different known causes of OP have been identified, but most cases occur for no known reason (idiopathic). Idiopathic organizing pneumonia may also be called cryptogenic organizing pneumonia (COP). Some people affected with this condition do not need treatment. When treatment is needed, corticosteroids, such as prednisone, are the most used medication. If the symptoms do not improve other treatment may be needed.Since the first description in 1980 as bronchiolitis obliterans organizing pneumonia (BOOP), OP has been known by different names.
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Overview of Organizing Pneumonia. Organizing pneumonia (OP) is a rare inflammatory lung disorder characterized by clinical symptoms such as flu-like illness as well as cough and shortness of breath with exertional activities. Wheezing and hemoptysis (blood when coughing) may occur rarely. OP refers to organized swirls of inflammatory tissue filling the small spherical units of the lungs called alveoli as well as the alveolar ducts. Individuals with OP experience inflammation of the bronchioles and alveolar lung spherical units simultaneously, which distinguishes it from other similar inflammatory lung disorders. Though the term pneumonia is used, OP is not an infection. It is a different disease from obliterative bronchiolitis which refers to scarring and narrowing of the small airways. Several different known causes of OP have been identified, but most cases occur for no known reason (idiopathic). Idiopathic organizing pneumonia may also be called cryptogenic organizing pneumonia (COP). Some people affected with this condition do not need treatment. When treatment is needed, corticosteroids, such as prednisone, are the most used medication. If the symptoms do not improve other treatment may be needed.Since the first description in 1980 as bronchiolitis obliterans organizing pneumonia (BOOP), OP has been known by different names.
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Organizing Pneumonia
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nord_909_1
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Symptoms of Organizing Pneumonia
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Symptoms of organizing pneumonia vary from person to person depending upon the specific type. For example, people with idiopathic OP have a flu-like illness, while people with OP associated with an underlying connective-tissue disorder have cough or shortness of breath. Some individuals with OP such as focal OP may have no apparent symptoms, while others may have severe respiratory distress as in acute, rapidly progressive OP.Symptoms usually develop slowly over a few weeks or months. The most common symptom is a persistent, nonproductive cough. Some affected individuals develop a flu-like illness characterized by a sore throat, a general feeling of ill health (malaise), weight loss and fatigue. Eventually, shortness of breath, especially from exertional activities may develop. The shortness of breath and cough may become progressively worse.Individuals with OP may develop small crackling or rattling sounds in the lung (crackles or rales) that are apparent upon physical examination. In rare cases affected individuals may experience chest pain, joint pain (arthralgia), night sweats or coughing up blood (hemoptysis).A rapidly progressive form of OP exists that can progress from symptom onset to acute respiratory failure in only a few days. This form of OP may be associated with an underlying fibrotic process.
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Symptoms of Organizing Pneumonia. Symptoms of organizing pneumonia vary from person to person depending upon the specific type. For example, people with idiopathic OP have a flu-like illness, while people with OP associated with an underlying connective-tissue disorder have cough or shortness of breath. Some individuals with OP such as focal OP may have no apparent symptoms, while others may have severe respiratory distress as in acute, rapidly progressive OP.Symptoms usually develop slowly over a few weeks or months. The most common symptom is a persistent, nonproductive cough. Some affected individuals develop a flu-like illness characterized by a sore throat, a general feeling of ill health (malaise), weight loss and fatigue. Eventually, shortness of breath, especially from exertional activities may develop. The shortness of breath and cough may become progressively worse.Individuals with OP may develop small crackling or rattling sounds in the lung (crackles or rales) that are apparent upon physical examination. In rare cases affected individuals may experience chest pain, joint pain (arthralgia), night sweats or coughing up blood (hemoptysis).A rapidly progressive form of OP exists that can progress from symptom onset to acute respiratory failure in only a few days. This form of OP may be associated with an underlying fibrotic process.
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Organizing Pneumonia
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nord_909_2
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Causes of Organizing Pneumonia
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In most cases, the cause of OP is unknown and is referred to as idiopathic OP. Causes of OP include radiation therapy; exposure to certain fumes or chemicals, exposure to birds, post respiratory infections, after organ transplantation; and from more than 35 medications. Systemic disorders associated with OP include connective-tissue diseases, immunological disorders and inflammatory bowel disease. Organizing pneumonia has also been seen in association with lung abscess, lung cancer and lymphoma. Importantly, the OP lesion is seen as a co-existent pathologic finding in individuals with idiopathic pulmonary fibrosis (IPF) and in these situations, the primary pathologic disorder is the IPF, and the secondary process is OP.
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Causes of Organizing Pneumonia. In most cases, the cause of OP is unknown and is referred to as idiopathic OP. Causes of OP include radiation therapy; exposure to certain fumes or chemicals, exposure to birds, post respiratory infections, after organ transplantation; and from more than 35 medications. Systemic disorders associated with OP include connective-tissue diseases, immunological disorders and inflammatory bowel disease. Organizing pneumonia has also been seen in association with lung abscess, lung cancer and lymphoma. Importantly, the OP lesion is seen as a co-existent pathologic finding in individuals with idiopathic pulmonary fibrosis (IPF) and in these situations, the primary pathologic disorder is the IPF, and the secondary process is OP.
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Organizing Pneumonia
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nord_909_3
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Affects of Organizing Pneumonia
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Organizing pneumonia affects males and females in equal numbers. It develops in individuals between 40-60 years old, but the disorder may affect individuals of any age. Organizing pneumonia is estimated to account for 5 to 10% of the chronic infiltrative lung disease in the United States. Organizing pneumonia has been reported throughout the world.
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Affects of Organizing Pneumonia. Organizing pneumonia affects males and females in equal numbers. It develops in individuals between 40-60 years old, but the disorder may affect individuals of any age. Organizing pneumonia is estimated to account for 5 to 10% of the chronic infiltrative lung disease in the United States. Organizing pneumonia has been reported throughout the world.
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Organizing Pneumonia
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nord_909_4
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Related disorders of Organizing Pneumonia
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Symptoms of the following disorders can be similar to those of OP. Comparisons may be useful for a differential diagnosis.Idiopathic pulmonary fibrosis (IPF) is a fibrosing (scar-producing) and inflammatory lung disorder of unknown origin (idiopathic) characterized by abnormal formation of scar and fibrosis between the spherical, alveolar structures in the lung, which is referred to as the interstitium. Shortness of breath, mild at first and then severe is the major symptom. Cough sometimes occurs. When severe, the skin may appear slightly bluish (cyanotic) due to lack of circulating oxygen. Complications such as infection or heart problems may develop. The OP process is sometimes seen in IPF as the inflammation component. In this situation, the OP is secondary to the underlying IPF disorder, and treatment with prednisone may eliminate the OP, yet the underlying IPF continues. (For more information on this disorder, choose “idiopathic pulmonary fibrosis” as your search term in the Rare Disease Database.)Acute interstitial pneumonia (AIP) is an inflammatory lung disorder that progresses rapidly and is distinguished by the nature or pattern of cells found on biopsy of the lung. This pattern is almost identical to that found with acute respiratory distress syndrome (ARDS) and may be confused with it. The name and its abbreviation, AIP, are limited to those cases of unknown cause. (For more information on this disorder, choose “acute interstitial pneumonia” as your search term in the Rare Disease Database.)
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Related disorders of Organizing Pneumonia. Symptoms of the following disorders can be similar to those of OP. Comparisons may be useful for a differential diagnosis.Idiopathic pulmonary fibrosis (IPF) is a fibrosing (scar-producing) and inflammatory lung disorder of unknown origin (idiopathic) characterized by abnormal formation of scar and fibrosis between the spherical, alveolar structures in the lung, which is referred to as the interstitium. Shortness of breath, mild at first and then severe is the major symptom. Cough sometimes occurs. When severe, the skin may appear slightly bluish (cyanotic) due to lack of circulating oxygen. Complications such as infection or heart problems may develop. The OP process is sometimes seen in IPF as the inflammation component. In this situation, the OP is secondary to the underlying IPF disorder, and treatment with prednisone may eliminate the OP, yet the underlying IPF continues. (For more information on this disorder, choose “idiopathic pulmonary fibrosis” as your search term in the Rare Disease Database.)Acute interstitial pneumonia (AIP) is an inflammatory lung disorder that progresses rapidly and is distinguished by the nature or pattern of cells found on biopsy of the lung. This pattern is almost identical to that found with acute respiratory distress syndrome (ARDS) and may be confused with it. The name and its abbreviation, AIP, are limited to those cases of unknown cause. (For more information on this disorder, choose “acute interstitial pneumonia” as your search term in the Rare Disease Database.)
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Organizing Pneumonia
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nord_909_5
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Diagnosis of Organizing Pneumonia
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A diagnosis of OP may be made based upon a clinical evaluation, a detailed patient history, identification of characteristic findings and specialized tests such as x-ray studies, especially a high-resolution chest computed tomography (HRCT), pulmonary function studies that includes a diffusing capacity test and often a lung biopsy for microscopic tissue analysis. Lung biopsy may infrequently be made via conventional transbronchial biopsy, transbronchial cryobiopsy which is newer and recovers a larger bit of tissue, or in selected cases, open lung biopsy. The HRCT scan often shows “ground glass” densities that are often triangular with the base of the triangle along the chest wall and the airways can often be seen in the ground-glass opacities. There are other less common findings such as inflammation along the air tubes or bronchi as well as single spots or nodules which are sometimes confused with malignancy, or the so-called ‘atoll’ spots which are areas of inflammation with central darker areas on HRCT.
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Diagnosis of Organizing Pneumonia. A diagnosis of OP may be made based upon a clinical evaluation, a detailed patient history, identification of characteristic findings and specialized tests such as x-ray studies, especially a high-resolution chest computed tomography (HRCT), pulmonary function studies that includes a diffusing capacity test and often a lung biopsy for microscopic tissue analysis. Lung biopsy may infrequently be made via conventional transbronchial biopsy, transbronchial cryobiopsy which is newer and recovers a larger bit of tissue, or in selected cases, open lung biopsy. The HRCT scan often shows “ground glass” densities that are often triangular with the base of the triangle along the chest wall and the airways can often be seen in the ground-glass opacities. There are other less common findings such as inflammation along the air tubes or bronchi as well as single spots or nodules which are sometimes confused with malignancy, or the so-called ‘atoll’ spots which are areas of inflammation with central darker areas on HRCT.
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Therapies of Organizing Pneumonia
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Treatment
In some patients, the symptoms of OP may resolve without treatment, especially the post breast radiation-type. In some mild cases such as individuals without symptoms or who have non-progressive disease, the process can be monitored and treated later if necessary. Many individuals with OP require treatment with the anti-inflammatory, corticosteroid medication, usually in the form of prednisone. This therapy often results in dramatic improvement with resolution of symptoms within days or weeks. In some people, the OP may recur as the dose is decreased, but the OP will respond to an additional course of treatment. There is a role for the use of clarithromycin, an antibiotic, in patients with mild disease. Clarithromycin has an anti-inflammatory effect and is not being used to treat an infection. A recent study of clarithromycin in addition to prednisone for 12 weeks to treat organizing pneumonia caused by radiation, showed no advantage over prednisone alone for 24 weeks. The rapidly progressive form of OP is treated with intravenous corticosteroid medication and sometimes with cyclophosphamide (Cytoxan). Individuals with secondary OP may improve after treating the underlying condition. Additional treatment is symptomatic and supportive.
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Therapies of Organizing Pneumonia. Treatment
In some patients, the symptoms of OP may resolve without treatment, especially the post breast radiation-type. In some mild cases such as individuals without symptoms or who have non-progressive disease, the process can be monitored and treated later if necessary. Many individuals with OP require treatment with the anti-inflammatory, corticosteroid medication, usually in the form of prednisone. This therapy often results in dramatic improvement with resolution of symptoms within days or weeks. In some people, the OP may recur as the dose is decreased, but the OP will respond to an additional course of treatment. There is a role for the use of clarithromycin, an antibiotic, in patients with mild disease. Clarithromycin has an anti-inflammatory effect and is not being used to treat an infection. A recent study of clarithromycin in addition to prednisone for 12 weeks to treat organizing pneumonia caused by radiation, showed no advantage over prednisone alone for 24 weeks. The rapidly progressive form of OP is treated with intravenous corticosteroid medication and sometimes with cyclophosphamide (Cytoxan). Individuals with secondary OP may improve after treating the underlying condition. Additional treatment is symptomatic and supportive.
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Overview of Ornithine Transcarbamylase Deficiency
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Ornithine transcarbamylase (OTC) deficiency is a rare X-linked genetic disorder characterized by complete or partial lack of the enzyme ornithine transcarbamylase (OTC). OTC is one of six enzymes that play a role in the break down and removal of nitrogen the body, a process known as the urea cycle. The lack of the OTC enzyme results in excessive accumulation of nitrogen, in the form of ammonia (hyperammonemia), in the blood. Excess ammonia, which is a neurotoxin, travels to the central nervous system through the blood, resulting in the symptoms and physical findings associated with OTC deficiency. Symptoms include vomiting, refusal to eat, progressive lethargy, and coma.
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Overview of Ornithine Transcarbamylase Deficiency. Ornithine transcarbamylase (OTC) deficiency is a rare X-linked genetic disorder characterized by complete or partial lack of the enzyme ornithine transcarbamylase (OTC). OTC is one of six enzymes that play a role in the break down and removal of nitrogen the body, a process known as the urea cycle. The lack of the OTC enzyme results in excessive accumulation of nitrogen, in the form of ammonia (hyperammonemia), in the blood. Excess ammonia, which is a neurotoxin, travels to the central nervous system through the blood, resulting in the symptoms and physical findings associated with OTC deficiency. Symptoms include vomiting, refusal to eat, progressive lethargy, and coma.
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Ornithine Transcarbamylase Deficiency
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Symptoms of Ornithine Transcarbamylase Deficiency
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The severity and age of onset of OTC deficiency vary from person to person, even within the same family. A severe form of the disorder affects some infants, typically males, shortly after birth (neonatal period). A milder form of the disorder affects some children later in infancy. Both males and females may develop symptoms of OTC deficiency during childhood. Most carrier females are healthy, but may be prone to severe headaches following protein intake.Children and adults with mild forms of the disorder may only have a partial OTC enzyme deficiency and therefore a greater tolerance to protein in the diet. Male infants with the severe form of the disorder often have a complete lack of the OTC enzyme.The severe form of OTC deficiency occurs in some affected males anywhere between 24 hours to a few days after birth, usually following a protein feeding. Initial symptoms may include refusal to eat, poor suck, vomiting, progressive lethargy, and irritability. The disorder may rapidly progress to include seizures, diminished muscle tone (hypotonia), an enlarged liver (hepatomegaly) and respiratory abnormalities. Affected infants and children may also exhibit the accumulation of fluid (edema) within the brain.If left untreated, infants with the severe form of OTC deficiency may fall into coma and may potentially develop neurological abnormalities such as intellectual disability, developmental delays, and cerebral palsy. The longer an infant remains in hyperammonemic coma the greater the chance neurological abnormalities may develop. In most cases, the longer an infant is in hyperammonemic coma the more severe these neurological abnormalities become. If left untreated, hyperammonemic coma may result in life-threatening complications.Some infants and children may have a milder form of OTC deficiency. These infants and children may not exhibit symptoms of OTC deficiency until later during life. Children who develop OTC deficiency later during life often express the disorder during an episode of illness, and present with hyperammonemia at that time. These episodes can recur, alternating between periods of wellness.During a hyperammonemic episode, affected children may experience vomiting, lethargy, and irritability. Additional symptoms may include confusion or delirium, hyperactivity, self-mutilation such as biting oneself, and an impaired ability to coordinate voluntary movements (ataxia). If left untreated a hyperammonemic episode may progress to coma and life-threatening complications.OTC deficiency may not become apparent until adulthood. Adults who have OTC deficiency may exhibit migraines; nausea; difficulty forming words (dysarthria); an impaired ability to coordinate voluntary movements (ataxia); confusion; hallucinations; and blurred vision.
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Symptoms of Ornithine Transcarbamylase Deficiency. The severity and age of onset of OTC deficiency vary from person to person, even within the same family. A severe form of the disorder affects some infants, typically males, shortly after birth (neonatal period). A milder form of the disorder affects some children later in infancy. Both males and females may develop symptoms of OTC deficiency during childhood. Most carrier females are healthy, but may be prone to severe headaches following protein intake.Children and adults with mild forms of the disorder may only have a partial OTC enzyme deficiency and therefore a greater tolerance to protein in the diet. Male infants with the severe form of the disorder often have a complete lack of the OTC enzyme.The severe form of OTC deficiency occurs in some affected males anywhere between 24 hours to a few days after birth, usually following a protein feeding. Initial symptoms may include refusal to eat, poor suck, vomiting, progressive lethargy, and irritability. The disorder may rapidly progress to include seizures, diminished muscle tone (hypotonia), an enlarged liver (hepatomegaly) and respiratory abnormalities. Affected infants and children may also exhibit the accumulation of fluid (edema) within the brain.If left untreated, infants with the severe form of OTC deficiency may fall into coma and may potentially develop neurological abnormalities such as intellectual disability, developmental delays, and cerebral palsy. The longer an infant remains in hyperammonemic coma the greater the chance neurological abnormalities may develop. In most cases, the longer an infant is in hyperammonemic coma the more severe these neurological abnormalities become. If left untreated, hyperammonemic coma may result in life-threatening complications.Some infants and children may have a milder form of OTC deficiency. These infants and children may not exhibit symptoms of OTC deficiency until later during life. Children who develop OTC deficiency later during life often express the disorder during an episode of illness, and present with hyperammonemia at that time. These episodes can recur, alternating between periods of wellness.During a hyperammonemic episode, affected children may experience vomiting, lethargy, and irritability. Additional symptoms may include confusion or delirium, hyperactivity, self-mutilation such as biting oneself, and an impaired ability to coordinate voluntary movements (ataxia). If left untreated a hyperammonemic episode may progress to coma and life-threatening complications.OTC deficiency may not become apparent until adulthood. Adults who have OTC deficiency may exhibit migraines; nausea; difficulty forming words (dysarthria); an impaired ability to coordinate voluntary movements (ataxia); confusion; hallucinations; and blurred vision.
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Causes of Ornithine Transcarbamylase Deficiency
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OTC deficiency is inherited as an X-linked genetic condition. 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. However, approximately 20% of female carriers of the OTC gene are symptomatic. 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. Many males with OTC deficiency have an abnormal OTC gene as the result of a new mutation as opposed to a mutation inherited from the mother.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 X-linked disorders 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.
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Causes of Ornithine Transcarbamylase Deficiency. OTC deficiency is inherited as an X-linked genetic condition. 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. However, approximately 20% of female carriers of the OTC gene are symptomatic. 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. Many males with OTC deficiency have an abnormal OTC gene as the result of a new mutation as opposed to a mutation inherited from the mother.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 X-linked disorders 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.
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Affects of Ornithine Transcarbamylase Deficiency
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OTC deficiency affects males more often than females and is fully expressed in males only. In males, symptoms typically begin during the first few days of life. Late-onset OTC deficiency can present later in childhood, but may also occur with onset at 40-50 years of age. Approximately 20% of carrier females have mild symptoms of the disorder and rarely may be severely affected in childhood. Some women who are carriers may not experience abnormally high levels of ammonia (hyperammonemia) until pregnancy or delivery.The estimated frequency of OTC deficiency is 1/50,000 – 80,000. The estimated frequency of urea cycle disorders collectively is 1/35,000. However, because urea cycle disorders like OTC deficiency often go unrecognized, these disorders are under-diagnosed, making it difficult to determine the true frequency of urea cycle disorders in the general population.
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Affects of Ornithine Transcarbamylase Deficiency. OTC deficiency affects males more often than females and is fully expressed in males only. In males, symptoms typically begin during the first few days of life. Late-onset OTC deficiency can present later in childhood, but may also occur with onset at 40-50 years of age. Approximately 20% of carrier females have mild symptoms of the disorder and rarely may be severely affected in childhood. Some women who are carriers may not experience abnormally high levels of ammonia (hyperammonemia) until pregnancy or delivery.The estimated frequency of OTC deficiency is 1/50,000 – 80,000. The estimated frequency of urea cycle disorders collectively is 1/35,000. However, because urea cycle disorders like OTC deficiency often go unrecognized, these disorders are under-diagnosed, making it difficult to determine the true frequency of urea cycle disorders in the general population.
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Ornithine Transcarbamylase Deficiency
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Related disorders of Ornithine Transcarbamylase Deficiency
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Symptoms of the following disorders can be similar to those of ornithine transcarbamylase deficiency. Comparisons may be useful for a differential diagnosis:The urea cycle disorders are a group of rare disorders affecting the urea cycle, a series of biochemical processes in which nitrogen is converted into urea and removed from the body through the urine. Nitrogen is a waste product of protein metabolism. The symptoms of all urea cycle disorders vary in severity and result from the excessive accumulation of ammonia in the blood and body tissues (hyperammonemia). Common symptoms include lack of appetite, vomiting, drowsiness, seizures, and/or coma. The liver may be abnormally enlarged (hepatomegaly). In some individuals, life-threatening complications may result. In addition to OTC deficiency, the other urea cycle disorders are: carbamyl phosphate synthetase (CPS) deficiency; argininosuccinate synthetase deficiency (citrullinemia); argininosuccinate lyase (ASL) deficiency; arginase deficiency (argininemia); and N-acetylglutamate synthetase (NAGS) deficiency. (For more information on these disorders, choose the specific disorder name as your search terms in the Rare Disease Database.)Reye syndrome is a rare childhood disease characterized by liver failure, abnormal brain function (encephalopathy), abnormally low levels of glucose (hypoglycemia), and high levels of ammonia in the blood. This disorder usually follows a viral infection. It may be triggered by the use of aspirin in children recovering from chicken pox or influenza. Deficiencies of the urea cycle enzymes are thought to play a role in the development of Reye syndrome. Symptoms include vomiting, diarrhea, rapid breathing, irritability, fatigue, and behavioral changes. Neurological symptoms may be life-threatening and include seizures, stupor, and coma. (For more information on this disorder, choose “Reye” as your search term in the Rare Disease Database.)Organic acidemias are a group of rare inherited metabolic disorders characterized by the excessive accumulation of various acids in the blood. Symptoms may include constipation, muscle weakness and low levels of platelets in the blood (thrombocytopenia). People with these disorders also have hyperammonemia and experience symptoms that are similar to those of urea cycle enzyme disorders. (For more information, choose “organic acidemia” as your search term in the Rare Disease Database.)
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Related disorders of Ornithine Transcarbamylase Deficiency. Symptoms of the following disorders can be similar to those of ornithine transcarbamylase deficiency. Comparisons may be useful for a differential diagnosis:The urea cycle disorders are a group of rare disorders affecting the urea cycle, a series of biochemical processes in which nitrogen is converted into urea and removed from the body through the urine. Nitrogen is a waste product of protein metabolism. The symptoms of all urea cycle disorders vary in severity and result from the excessive accumulation of ammonia in the blood and body tissues (hyperammonemia). Common symptoms include lack of appetite, vomiting, drowsiness, seizures, and/or coma. The liver may be abnormally enlarged (hepatomegaly). In some individuals, life-threatening complications may result. In addition to OTC deficiency, the other urea cycle disorders are: carbamyl phosphate synthetase (CPS) deficiency; argininosuccinate synthetase deficiency (citrullinemia); argininosuccinate lyase (ASL) deficiency; arginase deficiency (argininemia); and N-acetylglutamate synthetase (NAGS) deficiency. (For more information on these disorders, choose the specific disorder name as your search terms in the Rare Disease Database.)Reye syndrome is a rare childhood disease characterized by liver failure, abnormal brain function (encephalopathy), abnormally low levels of glucose (hypoglycemia), and high levels of ammonia in the blood. This disorder usually follows a viral infection. It may be triggered by the use of aspirin in children recovering from chicken pox or influenza. Deficiencies of the urea cycle enzymes are thought to play a role in the development of Reye syndrome. Symptoms include vomiting, diarrhea, rapid breathing, irritability, fatigue, and behavioral changes. Neurological symptoms may be life-threatening and include seizures, stupor, and coma. (For more information on this disorder, choose “Reye” as your search term in the Rare Disease Database.)Organic acidemias are a group of rare inherited metabolic disorders characterized by the excessive accumulation of various acids in the blood. Symptoms may include constipation, muscle weakness and low levels of platelets in the blood (thrombocytopenia). People with these disorders also have hyperammonemia and experience symptoms that are similar to those of urea cycle enzyme disorders. (For more information, choose “organic acidemia” as your search term in the Rare Disease Database.)
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Diagnosis of Ornithine Transcarbamylase Deficiency
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A diagnosis of OTC deficiency should be considered in any newborn that has an undiagnosed illness characterized by vomiting, progressive lethargy, and irritability.Blood tests may reveal excessive amounts of ammonia in the blood, the characteristic finding of urea cycles disorders. However, high levels of ammonia in the blood may characterize other disorders such as the organic acidemias, congenital lactic acidosis, and fatty acid oxidation disorders. Urea cycle disorders can be differentiated from these disorders through the examination of urine for elevated levels of organic acids and examination for alterations in plasma amino acids and plasma acylcarnitines. The study of blood plasma and urine is used to differentiate OTC deficiency from other urea cycle disorders. Individuals with OTC deficiency usually have both low levels of citrulline and high glutamine in the blood and high levels of orotic acid in the urine.In rare cases, OTC deficiency may be detected by surgical removal (biopsy) and microscopic examination of tissue samples from the liver, duodenum, and rectum where deficient enzyme activity may be seen.DNA genetic testing is available to confirm the diagnosis. Mutations in the OTC gene have been identified in approximately 80% of individuals with a documented enzyme deficiency.Carrier testing and prenatal diagnosis of OTC deficiency is possible if the disease-causing mutation has been identified in an affected family member.Newborn screening for OTC deficiency is not currently routinely available.
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Diagnosis of Ornithine Transcarbamylase Deficiency. A diagnosis of OTC deficiency should be considered in any newborn that has an undiagnosed illness characterized by vomiting, progressive lethargy, and irritability.Blood tests may reveal excessive amounts of ammonia in the blood, the characteristic finding of urea cycles disorders. However, high levels of ammonia in the blood may characterize other disorders such as the organic acidemias, congenital lactic acidosis, and fatty acid oxidation disorders. Urea cycle disorders can be differentiated from these disorders through the examination of urine for elevated levels of organic acids and examination for alterations in plasma amino acids and plasma acylcarnitines. The study of blood plasma and urine is used to differentiate OTC deficiency from other urea cycle disorders. Individuals with OTC deficiency usually have both low levels of citrulline and high glutamine in the blood and high levels of orotic acid in the urine.In rare cases, OTC deficiency may be detected by surgical removal (biopsy) and microscopic examination of tissue samples from the liver, duodenum, and rectum where deficient enzyme activity may be seen.DNA genetic testing is available to confirm the diagnosis. Mutations in the OTC gene have been identified in approximately 80% of individuals with a documented enzyme deficiency.Carrier testing and prenatal diagnosis of OTC deficiency is possible if the disease-causing mutation has been identified in an affected family member.Newborn screening for OTC deficiency is not currently routinely available.
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Ornithine Transcarbamylase Deficiency
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Therapies of Ornithine Transcarbamylase Deficiency
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TreatmentTreatment of an individual with OTC deficiency may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, geneticist, dieticians, and physicians who are familiar with metabolic disorders may need to work together to ensure a comprehensive approach to treatment. Occupational, speech language, and physical therapists may be needed to treat children with developmental disabilities.The treatment of OTC deficiency is aimed at preventing excessive ammonia from being formed or from removing excessive ammonia during a hyperammonemic episode. Long-term therapy for OTC deficiency combines dietary restrictions and the stimulation of alternative methods of converting and excreting nitrogen from the body (alternative pathways therapy).Dietary restrictions in individuals with OTC deficiency are aimed at limiting the amount of protein intake to avoid the development of excess ammonia. However, enough protein must be taken in by an affected infant to ensure proper growth. Infants with OTC deficiency are placed on a low protein, high calorie diet supplemented by essential amino acids. A combination of a high biological value natural protein such as breast milk or cow’s milk formulate, an essential amino acid formula (e.g., UCD Anamix Junior, Nutricia; Cyclinex, Abbott; WN1, Mead Johnson; or UCD Trio, Vitaflo), and a calorie supplement without protein is often used (e.g., Pro-Phree, Abbott, PFD, Mead Johnson,). Essential amino acids supplements may also be used (EAA mix, Nutricia; EAA supplement Vitaflo).In addition to dietary restrictions, individuals with OTC deficiency are treated by medications that stimulate the removal of nitrogen from the body. These medications provide an alternative method to the urea cycle in converting and removing nitrogen waste. These medications are unpalatable to many patients and are often administered via a tube that is placed in the stomach through the abdominal wall (gastrostomy tube) or a narrow tube that reaches the stomach via the nose (nasogastric tube).The orphan drug sodium phenylbutyrate (Buphenyl), manufactured by Hyperion Therapeutics, has been approved by the Food and Drug Administration (FDA) for the treatment of chronic hyperammonemia in OTC deficiency. In 2013, a new medication, glycerol phenylgutyrate (Ravicti), also manufactured by Hyperion Therapeutics, was approved by the FDA for treatment of chronic hyperammonemia in patients with urea cycle disorders. Ammonul (sodium phenylacetate and sodium benzoate), manufactured by Valeant Pharmaceuticals, is the only FDA-approved adjunctive therapy for the treatment of acute hyperammonemia in patients with urea cycle disorders.Individuals with OTC deficiency benefit from treatment with arginine, or its precursor citrulline, which are needed in order to maintain a normal rate of protein synthesis. Multiple vitamins and calcium supplements may also be used in the treatment of OTC deficiency.Prompt treatment is necessary when individuals have extremely high ammonia levels (severe hyperammonemic episode). Prompt treatment can avoid hyperammonemic coma and associated neurological symptoms. However, in some individuals, especially those with complete enzyme deficiency, prompt treatment will not prevent recurrent episodes of hyperammonemia and the potential development of serious complications.Aggressive treatment is needed in hyperammonemic episodes that have progressed to vomiting and increased lethargy. Affected individuals may be hospitalized and protein may be completely eliminated from the diet for 24 hours. Affected individuals may also receive treatment with intravenous administration of arginine and a combination of sodium benzoate and sodium phenylacetate. Non-protein calories may be also provided as glucose or lipids (fat).In cases where there is no improvement or in cases where hyperammonemic coma develops, the removal of wastes by filtering an affected individual’s blood through a machine (hemodialysis) may be necessary. Hemodialysis is also used to treat infants, children, and adults who are first diagnosed with OTC deficiency during hyperammonemic coma.Preventive Care
After diagnosis of OTC deficiency, steps can be taken to anticipate the onset of a hyperammonemic episode. Affected individuals should receive periodic blood tests to determine the levels of ammonia in the blood. In addition, elevated levels of an amino acid (glutamine) in the blood often precede the development of hyperammonemia by days or weeks. Affected individuals should receive periodic tests to measure the amount of amino acids such as glutamine in the blood. Detection of elevated levels of ammonia or glutamine may allow treatment before clinical symptoms appear. Blood tests should also be performed to monitor phenylbutyrate levels in order to assure a proper dose is used and to avoid a potential overdose.Genetic counseling is recommended for individuals with OTC deficiency and their families.In some cases, liver transplantation, either cadaveric or from a living donor, may be an appropriate treatment option. Liver transplantation can cure the hyperammonemia in OTC deficiency. However, this operation is risky and may result in post-operative complications. Also, after liver transplantation, patients will need to take medications life-long for immunosuppression.
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Therapies of Ornithine Transcarbamylase Deficiency. TreatmentTreatment of an individual with OTC deficiency may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, geneticist, dieticians, and physicians who are familiar with metabolic disorders may need to work together to ensure a comprehensive approach to treatment. Occupational, speech language, and physical therapists may be needed to treat children with developmental disabilities.The treatment of OTC deficiency is aimed at preventing excessive ammonia from being formed or from removing excessive ammonia during a hyperammonemic episode. Long-term therapy for OTC deficiency combines dietary restrictions and the stimulation of alternative methods of converting and excreting nitrogen from the body (alternative pathways therapy).Dietary restrictions in individuals with OTC deficiency are aimed at limiting the amount of protein intake to avoid the development of excess ammonia. However, enough protein must be taken in by an affected infant to ensure proper growth. Infants with OTC deficiency are placed on a low protein, high calorie diet supplemented by essential amino acids. A combination of a high biological value natural protein such as breast milk or cow’s milk formulate, an essential amino acid formula (e.g., UCD Anamix Junior, Nutricia; Cyclinex, Abbott; WN1, Mead Johnson; or UCD Trio, Vitaflo), and a calorie supplement without protein is often used (e.g., Pro-Phree, Abbott, PFD, Mead Johnson,). Essential amino acids supplements may also be used (EAA mix, Nutricia; EAA supplement Vitaflo).In addition to dietary restrictions, individuals with OTC deficiency are treated by medications that stimulate the removal of nitrogen from the body. These medications provide an alternative method to the urea cycle in converting and removing nitrogen waste. These medications are unpalatable to many patients and are often administered via a tube that is placed in the stomach through the abdominal wall (gastrostomy tube) or a narrow tube that reaches the stomach via the nose (nasogastric tube).The orphan drug sodium phenylbutyrate (Buphenyl), manufactured by Hyperion Therapeutics, has been approved by the Food and Drug Administration (FDA) for the treatment of chronic hyperammonemia in OTC deficiency. In 2013, a new medication, glycerol phenylgutyrate (Ravicti), also manufactured by Hyperion Therapeutics, was approved by the FDA for treatment of chronic hyperammonemia in patients with urea cycle disorders. Ammonul (sodium phenylacetate and sodium benzoate), manufactured by Valeant Pharmaceuticals, is the only FDA-approved adjunctive therapy for the treatment of acute hyperammonemia in patients with urea cycle disorders.Individuals with OTC deficiency benefit from treatment with arginine, or its precursor citrulline, which are needed in order to maintain a normal rate of protein synthesis. Multiple vitamins and calcium supplements may also be used in the treatment of OTC deficiency.Prompt treatment is necessary when individuals have extremely high ammonia levels (severe hyperammonemic episode). Prompt treatment can avoid hyperammonemic coma and associated neurological symptoms. However, in some individuals, especially those with complete enzyme deficiency, prompt treatment will not prevent recurrent episodes of hyperammonemia and the potential development of serious complications.Aggressive treatment is needed in hyperammonemic episodes that have progressed to vomiting and increased lethargy. Affected individuals may be hospitalized and protein may be completely eliminated from the diet for 24 hours. Affected individuals may also receive treatment with intravenous administration of arginine and a combination of sodium benzoate and sodium phenylacetate. Non-protein calories may be also provided as glucose or lipids (fat).In cases where there is no improvement or in cases where hyperammonemic coma develops, the removal of wastes by filtering an affected individual’s blood through a machine (hemodialysis) may be necessary. Hemodialysis is also used to treat infants, children, and adults who are first diagnosed with OTC deficiency during hyperammonemic coma.Preventive Care
After diagnosis of OTC deficiency, steps can be taken to anticipate the onset of a hyperammonemic episode. Affected individuals should receive periodic blood tests to determine the levels of ammonia in the blood. In addition, elevated levels of an amino acid (glutamine) in the blood often precede the development of hyperammonemia by days or weeks. Affected individuals should receive periodic tests to measure the amount of amino acids such as glutamine in the blood. Detection of elevated levels of ammonia or glutamine may allow treatment before clinical symptoms appear. Blood tests should also be performed to monitor phenylbutyrate levels in order to assure a proper dose is used and to avoid a potential overdose.Genetic counseling is recommended for individuals with OTC deficiency and their families.In some cases, liver transplantation, either cadaveric or from a living donor, may be an appropriate treatment option. Liver transplantation can cure the hyperammonemia in OTC deficiency. However, this operation is risky and may result in post-operative complications. Also, after liver transplantation, patients will need to take medications life-long for immunosuppression.
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Overview of Orocraniodigital Syndrome
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Orocraniodigital syndrome is an extremely rare inherited disorder characterized by multiple malformations of the head and face (craniofacial area) and the fingers and toes (digits). Major characteristics may include a vertical groove in the upper lip (cleft lip) and/or the inside, upper portion of the mouth (cleft palate), an abnormally small head (microcephaly), widely spaced eyes (ocular hypertelorism), improper development (hypoplasia) of the thumbs and/or toes, and/or webbing (syndactyly) of the toes. In some cases, malformations of certain skeletal bones may also be present. Mental retardation has occurred in the majority of cases. Orocraniodigital syndrome may be inherited as an autosomal recessive genetic trait.
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Overview of Orocraniodigital Syndrome. Orocraniodigital syndrome is an extremely rare inherited disorder characterized by multiple malformations of the head and face (craniofacial area) and the fingers and toes (digits). Major characteristics may include a vertical groove in the upper lip (cleft lip) and/or the inside, upper portion of the mouth (cleft palate), an abnormally small head (microcephaly), widely spaced eyes (ocular hypertelorism), improper development (hypoplasia) of the thumbs and/or toes, and/or webbing (syndactyly) of the toes. In some cases, malformations of certain skeletal bones may also be present. Mental retardation has occurred in the majority of cases. Orocraniodigital syndrome may be inherited as an autosomal recessive genetic trait.
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Symptoms of Orocraniodigital Syndrome
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In many cases, orocraniodigital syndrome is characterized by cleft lip and/or palate, malformations of the mouth and/or lips that are noticeable at birth (congenital). A cleft is an incomplete closure or groove on the inside, upper portion of the mouth (palate) or lips, or both. Clefts may be barely noticeable (occult), or they may cause severe deformities leading to difficulties in speaking. There are several varieties of cleft lip and palate malformations. The most severe types of clefts involve the lips, gums, and certain tissues on the roof of the mouth (hard and soft palates). Less severe clefts may involve only one of these structures. Clefts may occur on one (unilateral) or both sides (bilateral) of the lips and/or palate. Other primary symptoms of orocraniodigital syndrome may include an abnormally small head (microcephaly), widely spaced eyes (ocular hypertelorism), eyebrows that are slanted upward, and/or abnormalities affecting the thumbs and/or toes. These abnormalities may include improper development (hypoplasia) or absence (agenesis) of the thumbs; webbing (syndactyly) of the toes; stiff thumbs; and/or thumbs that are located lower or higher than normal. In some cases, affected infants may also have low birthweight and/or kidneys that are joined at the base (horseshoe kidneys). The bone on the thumb side of the upper arm (radius) may be abnormally short or displaced (dislocated). In addition, affected individuals may also have abnormally formed elbows that may limit mobility (arm extension) and/or minor malformations of the spine, ribs, and/or certain bones in the hands (carpal bones). In the majority of cases, mental retardation may also occur.
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Symptoms of Orocraniodigital Syndrome. In many cases, orocraniodigital syndrome is characterized by cleft lip and/or palate, malformations of the mouth and/or lips that are noticeable at birth (congenital). A cleft is an incomplete closure or groove on the inside, upper portion of the mouth (palate) or lips, or both. Clefts may be barely noticeable (occult), or they may cause severe deformities leading to difficulties in speaking. There are several varieties of cleft lip and palate malformations. The most severe types of clefts involve the lips, gums, and certain tissues on the roof of the mouth (hard and soft palates). Less severe clefts may involve only one of these structures. Clefts may occur on one (unilateral) or both sides (bilateral) of the lips and/or palate. Other primary symptoms of orocraniodigital syndrome may include an abnormally small head (microcephaly), widely spaced eyes (ocular hypertelorism), eyebrows that are slanted upward, and/or abnormalities affecting the thumbs and/or toes. These abnormalities may include improper development (hypoplasia) or absence (agenesis) of the thumbs; webbing (syndactyly) of the toes; stiff thumbs; and/or thumbs that are located lower or higher than normal. In some cases, affected infants may also have low birthweight and/or kidneys that are joined at the base (horseshoe kidneys). The bone on the thumb side of the upper arm (radius) may be abnormally short or displaced (dislocated). In addition, affected individuals may also have abnormally formed elbows that may limit mobility (arm extension) and/or minor malformations of the spine, ribs, and/or certain bones in the hands (carpal bones). In the majority of cases, mental retardation may also occur.
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Causes of Orocraniodigital Syndrome
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Orocraniodigital syndrome is thought to be inherited as an autosomal recessive genetic trait. However, autosomal dominant inheritance has yet to be ruled out. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother. In recessive disorders, the condition does not appear unless a person inherits the same defective gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease, but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy.
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Causes of Orocraniodigital Syndrome. Orocraniodigital syndrome is thought to be inherited as an autosomal recessive genetic trait. However, autosomal dominant inheritance has yet to be ruled out. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother. In recessive disorders, the condition does not appear unless a person inherits the same defective gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease, but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy.
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Affects of Orocraniodigital Syndrome
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Approximately 10 cases of orocraniodigital syndrome have been reported in the medical literature. The symptoms are usually obvious at birth.
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Affects of Orocraniodigital Syndrome. Approximately 10 cases of orocraniodigital syndrome have been reported in the medical literature. The symptoms are usually obvious at birth.
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Related disorders of Orocraniodigital Syndrome
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Craniofrontonasal dysplasia is a rare inherited disorder characterized by widely spaced eyes (ocular hypertelorism), a missing or grooved tip of the nose, a broad nasal bridge, and/or malformation of the long flat vertical bone in the center of the chest (sternum). Other abnormalities associated with this disorder may include an unusually wide mouth, webbed fingers and/or toes (syndactyly), split nails, a broad index finger, malformed (dysplastic) ears, and/or a broad high forehead. Craniofrontonasal dysplasia is thought to be inherited as an autosomal dominant genetic trait. (For more information on this disorder, choose “Craniofrontonasal Dysplasia” as your search term in the Rare Disease Database.)Oral-facial-digital syndrome is a very rare inherited disorder that has four subdivisions. Symptoms common to all subdivisions include splits in the jaw; a split tongue; a broad nose; a vertical groove in the upper lip (cleft lip); extra fingers and/or toes (polydactyly); unusually short fingers and/or toes; and/or an extra fold of skin on either side of the nose that may cover the eyes' inner corners (epicanthal folds). The exact cause of oral-facial-digital syndrome is unknown. Type I is believed to be inherited as an autosomal dominant genetic trait; Types II, III, and IV may be inherited as autosomal recessive genetic traits. (For more information on this disorder, choose “Oral-Facial-Digital” as your search term in the Rare Disease Database.) Frontofacionasal dysplasia is a very rare disorder characterized by cleft lip and/or palate, an unusually wide space between the eyes (ocular hypertelorism), an abnormally large distance between the upper and lower eyelids (telecanthus), a short broad head (brachycephaly), and/or underdevelopment of the middle portion of the face (e.g., forehead, nose, and/or chin). Additional abnormalities may include an abnormal opening in the skull (cranium bifidum occultum) through which membranes that cover the brain may protrude (encephalocele) and/or a fatty tumor (lipomata) on the frontal lobe of the brain. Frontofacionasal dysplasia is inherited as an autosomal recessive genetic trait. (For more information on this disorder, choose “Frontofacionasal Dysplasia” as your search term in the Rare Disease Database.) Frontonasal dysplasia, also known as median cleft face syndrome, is a very rare inherited disorder characterized by widely spaced eyes, a broad nose, a vertical groove down the tip of the nose or a nose that may be split in two, and/or an abnormal, covered gap in the skull (cranium bifidum occultum). Other symptoms may include a short head (brachycephaly); cleft lip and/or palate; abnormally small eyeballs (microphthalmia); and/or mild mental retardation. The cause of frontonasal dysplasia is not known; most cases tend to occur randomly with no apparent cause (sporadic). (For more information on this disorder, choose “Frontonasal” as your search term in the Rare Disease Database.)
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Related disorders of Orocraniodigital Syndrome. Craniofrontonasal dysplasia is a rare inherited disorder characterized by widely spaced eyes (ocular hypertelorism), a missing or grooved tip of the nose, a broad nasal bridge, and/or malformation of the long flat vertical bone in the center of the chest (sternum). Other abnormalities associated with this disorder may include an unusually wide mouth, webbed fingers and/or toes (syndactyly), split nails, a broad index finger, malformed (dysplastic) ears, and/or a broad high forehead. Craniofrontonasal dysplasia is thought to be inherited as an autosomal dominant genetic trait. (For more information on this disorder, choose “Craniofrontonasal Dysplasia” as your search term in the Rare Disease Database.)Oral-facial-digital syndrome is a very rare inherited disorder that has four subdivisions. Symptoms common to all subdivisions include splits in the jaw; a split tongue; a broad nose; a vertical groove in the upper lip (cleft lip); extra fingers and/or toes (polydactyly); unusually short fingers and/or toes; and/or an extra fold of skin on either side of the nose that may cover the eyes' inner corners (epicanthal folds). The exact cause of oral-facial-digital syndrome is unknown. Type I is believed to be inherited as an autosomal dominant genetic trait; Types II, III, and IV may be inherited as autosomal recessive genetic traits. (For more information on this disorder, choose “Oral-Facial-Digital” as your search term in the Rare Disease Database.) Frontofacionasal dysplasia is a very rare disorder characterized by cleft lip and/or palate, an unusually wide space between the eyes (ocular hypertelorism), an abnormally large distance between the upper and lower eyelids (telecanthus), a short broad head (brachycephaly), and/or underdevelopment of the middle portion of the face (e.g., forehead, nose, and/or chin). Additional abnormalities may include an abnormal opening in the skull (cranium bifidum occultum) through which membranes that cover the brain may protrude (encephalocele) and/or a fatty tumor (lipomata) on the frontal lobe of the brain. Frontofacionasal dysplasia is inherited as an autosomal recessive genetic trait. (For more information on this disorder, choose “Frontofacionasal Dysplasia” as your search term in the Rare Disease Database.) Frontonasal dysplasia, also known as median cleft face syndrome, is a very rare inherited disorder characterized by widely spaced eyes, a broad nose, a vertical groove down the tip of the nose or a nose that may be split in two, and/or an abnormal, covered gap in the skull (cranium bifidum occultum). Other symptoms may include a short head (brachycephaly); cleft lip and/or palate; abnormally small eyeballs (microphthalmia); and/or mild mental retardation. The cause of frontonasal dysplasia is not known; most cases tend to occur randomly with no apparent cause (sporadic). (For more information on this disorder, choose “Frontonasal” as your search term in the Rare Disease Database.)
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Diagnosis of Orocraniodigital Syndrome
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Diagnosis of Orocraniodigital Syndrome.
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Therapies of Orocraniodigital Syndrome
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Orocraniodigital Syndrome is usually diagnosed shortly after birth (neonatal period) based upon a thorough clinical evaluation. Treatment of this disorder depends upon the specifics and severity of each individual case. Surgery may correct some of the craniofacial deformities associated with this disorder. For example, infants with cleft lip may require surgery; in some cases, additional surgery may be necessary when the child grows older. Cleft palate may also be surgically repaired. In some cases, hand and/or feet malformations associated with Orocraniodigital Syndrome may also be surgically corrected.Genetic counseling will be of benefit for affected individuals and their families. A team approach for infants and children with this disorder may be of benefit and may include special social, educational, and medical services. Other treatment is symptomatic and supportive.
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Therapies of Orocraniodigital Syndrome. Orocraniodigital Syndrome is usually diagnosed shortly after birth (neonatal period) based upon a thorough clinical evaluation. Treatment of this disorder depends upon the specifics and severity of each individual case. Surgery may correct some of the craniofacial deformities associated with this disorder. For example, infants with cleft lip may require surgery; in some cases, additional surgery may be necessary when the child grows older. Cleft palate may also be surgically repaired. In some cases, hand and/or feet malformations associated with Orocraniodigital Syndrome may also be surgically corrected.Genetic counseling will be of benefit for affected individuals and their families. A team approach for infants and children with this disorder may be of benefit and may include special social, educational, and medical services. Other treatment is symptomatic and supportive.
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Overview of Orthostatic Hypotension
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Orthostatic hypotension (OH) is a common condition characterized as a drop in blood pressure that occurs when a person stands up. OH can cause lightheadedness, dizziness or even causing a person to faint. Symptoms can also be subtle or absent. By definition, the drop in blood pressure must be greater than 20mm Hg of mercury in systolic BP and/or more than 10 mm of mercury in diastolic BP within 3 minutes upon standing from sitting or from a lying down face-up (supine) position. There are numerous, varied causes of OH. Neurogenic orthostatic hypotension (NOH) is a rare subtype caused by underlying neurologic disorders that affect a specific part of the autonomic nervous system. The autonomic nervous system is the part of the nervous system that regulates certain involuntary body functions such as heart rate, blood pressure, sweating, and bowel and bladder control. The treatment of OH depends upon several factors including the specific underlying cause.
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Overview of Orthostatic Hypotension. Orthostatic hypotension (OH) is a common condition characterized as a drop in blood pressure that occurs when a person stands up. OH can cause lightheadedness, dizziness or even causing a person to faint. Symptoms can also be subtle or absent. By definition, the drop in blood pressure must be greater than 20mm Hg of mercury in systolic BP and/or more than 10 mm of mercury in diastolic BP within 3 minutes upon standing from sitting or from a lying down face-up (supine) position. There are numerous, varied causes of OH. Neurogenic orthostatic hypotension (NOH) is a rare subtype caused by underlying neurologic disorders that affect a specific part of the autonomic nervous system. The autonomic nervous system is the part of the nervous system that regulates certain involuntary body functions such as heart rate, blood pressure, sweating, and bowel and bladder control. The treatment of OH depends upon several factors including the specific underlying cause.
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Symptoms of Orthostatic Hypotension
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In some people, there may not be any noticeable symptoms despite a sudden and extreme drop in blood pressure upon rising from a reclining position. When symptoms occur they can vary greatly in expression from one individual to another. Common symptoms can include dizziness, lightheadedness, generalized weakness, leg buckling, nausea, blurry vision, fatigue, and headaches. Additional symptoms can include chest pain (angina), head and neck pain (often affecting neck and shoulders with a coat hanger distribution), and a decline in cognitive functioning such as difficulty concentrating.Affected individuals may experience a temporary loss of consciousness or “blackout,” a condition known as syncope. There may be a gradual build up to an episode of syncope or it can occur suddenly.A serious complication of OH is the risk of falling, which can lead to physical damage such as a broken hip or other broken bones. The constant dropping and raising of blood pressure associated with OH has also been identified as a risk factor in the development of stroke and other cardiovascular diseases.Symptoms of OH on standing have been aggravated by raised ambient heat, such as hot weather, hot shower, hot tub, or when an affected individual has a fever. OH is often more common and more severe in the morning. Some individuals with NOH develop postprandial hypotension, which is defined as the development or worsening of hypotension approximately 30 minutes to 2 hours after eating a meal, particularly large meals high in carbohydrates.Some individuals with NOH may also have high blood pressure when lying down (supine hypertension). Supine hypertension complicates treatment options for affected individuals.
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Symptoms of Orthostatic Hypotension. In some people, there may not be any noticeable symptoms despite a sudden and extreme drop in blood pressure upon rising from a reclining position. When symptoms occur they can vary greatly in expression from one individual to another. Common symptoms can include dizziness, lightheadedness, generalized weakness, leg buckling, nausea, blurry vision, fatigue, and headaches. Additional symptoms can include chest pain (angina), head and neck pain (often affecting neck and shoulders with a coat hanger distribution), and a decline in cognitive functioning such as difficulty concentrating.Affected individuals may experience a temporary loss of consciousness or “blackout,” a condition known as syncope. There may be a gradual build up to an episode of syncope or it can occur suddenly.A serious complication of OH is the risk of falling, which can lead to physical damage such as a broken hip or other broken bones. The constant dropping and raising of blood pressure associated with OH has also been identified as a risk factor in the development of stroke and other cardiovascular diseases.Symptoms of OH on standing have been aggravated by raised ambient heat, such as hot weather, hot shower, hot tub, or when an affected individual has a fever. OH is often more common and more severe in the morning. Some individuals with NOH develop postprandial hypotension, which is defined as the development or worsening of hypotension approximately 30 minutes to 2 hours after eating a meal, particularly large meals high in carbohydrates.Some individuals with NOH may also have high blood pressure when lying down (supine hypertension). Supine hypertension complicates treatment options for affected individuals.
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Causes of Orthostatic Hypotension
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Orthostatic hypotension may be a temporary condition or one that occurs consistently over time (chronic). Some sources break down the causes of OH into drugs, non-neurogenic, primary neurogenic and secondary neurogenic causes. In many cases, the underlying cause of OH remains unknown or unproven (idiopathic). Most idiopathic cases are believed to have an underlying neurogenic cause.OH can be caused by certain chemotherapy drugs which can cause an autonomic neuropathy. A common cause of OH is the decrease in volume of circulating blood (hypovolemia) resulting from excessive use of medications that increase urination and sodium loss (diuretics), or from drug therapy that widens blood vessels (vasodilators) for the treatment of high blood pressure, heart failure or chest pains (i.e., calcium blockers and nitrates). Commonly used vasodilator drugs include levodopa for Parkinson’s disease, nitroglycerine and drugs taken to treat erectile dysfunction (sildenafil, tadalafil). A variety of drugs that interfere with the autonomic nervous system’s reflexes can also cause OH, such as certain antipsychotic (i.e., phenothiazine) and antidepressant drugs. Alcohol can also cause OH.Non-neurogenic causes can include hypovolemia, cardiac pump failure, and venous pooling. Hypovolemia can be caused by several conditions including dehydration, chronic bleeding, adrenal insufficiency, diabetes insipidus, diarrhea, and chronic vomiting.Cardiac pump failure refers to when the heart cannot pump blood sufficiently enough to maintain blood flow to meet the demands of the body and can be associated with heart block, disorders of heart rhythm (tachyarrhythmias), narrowing (stenosis) of the main artery of the body (aorta), or a heart attack (myocardial infarction).Venous pooling is a normal occurrence in which gravity causes blood to pool downward within the abdomen and legs upon standing. This results in reduced venous return to the heart. There are certain conditions cause excessive venous pooling. Such conditions include rising quickly after prolonged sitting or lying down (recumbency), prolonged motionless standing, fever, heat exposure, or carbohydrate heavy meals.Primary neurogenic causes refers to individuals with an underlying primary disorder that is involved with malfunction of the autonomic nervous system such as multiple system atrophy, Parkinson’s disease, pure autonomic failure, dopamine beta-hydroxylase deficiency, Lewy body disease, familial dysautonomia, and non-diabetic autonomic neuropathy.Secondary neurogenic causes can include spinal cord problems such as transverse myelitis or tumors of the spinal cord and various peripheral neuropathies such as amyloidosis, Guillain-Barre syndrome, diabetes mellitus, and the hereditary sensory and autonomic neuropathies. Individuals with OH due to primary or secondary neurogenic causes are referred to as having neurogenic orthostatic hypotension (NOH).The symptoms of OH result from the failure of the body to compensate for the normal drop in blood pressure that occurs upon standing or sitting up. Upon standing, gravity causes the blood in the body to pool downward into the legs and trunk. Consequently, less blood is returned to the heart and cardiac filling pressure is reduced, resulting in diminished cardiac output. In a matter of seconds, the body goes through a normal series of involuntary responses that compensate for this drop in blood pressure. These responses are controlled by the autonomic nervous system and include signaling blood vessels to narrow so that more blood is pushed upward and signaling the heart to beat faster (increased heart rate) to pump more blood and ensure proper blood flow and pressure.Any interruption in these involuntary processes can result in OH. For example, the baroreflex is essential in maintaining proper blood pressure and does not function properly in individuals with NOH. The baroreflex refers to specialized cells called baroreceptors that trigger the autonomic nervous system to increase levels of certain hormones called catecholamines, specifically norepinephrine. Norepinephrine is a chemical messenger that is necessary for nerves to communicate in order to trigger blood vessels to narrow to increase blood pressure upon standing (vasoconstriction). This response is known as the baroreflex. When the baroreflex is impaired the body fails to produce sufficient amounts of norepinephrine and cannot offset the drop in blood pressure that occurs upon standing, resulting in the symptoms of OH.Not all cases of OH result from dysfunction of the autonomic nervous system. Conditions that cause hypovolemia such as dehydration cause OH because the loss of blood volume prevents the body from compensating for the decreased blood pressure that occurs upon standing. Conditions that affect the heart such as cardiac pump failure prevent the heart from pumping efficiently or rapidly enough to compensate for the drop in blood pressure that occurs upon standing.
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Causes of Orthostatic Hypotension. Orthostatic hypotension may be a temporary condition or one that occurs consistently over time (chronic). Some sources break down the causes of OH into drugs, non-neurogenic, primary neurogenic and secondary neurogenic causes. In many cases, the underlying cause of OH remains unknown or unproven (idiopathic). Most idiopathic cases are believed to have an underlying neurogenic cause.OH can be caused by certain chemotherapy drugs which can cause an autonomic neuropathy. A common cause of OH is the decrease in volume of circulating blood (hypovolemia) resulting from excessive use of medications that increase urination and sodium loss (diuretics), or from drug therapy that widens blood vessels (vasodilators) for the treatment of high blood pressure, heart failure or chest pains (i.e., calcium blockers and nitrates). Commonly used vasodilator drugs include levodopa for Parkinson’s disease, nitroglycerine and drugs taken to treat erectile dysfunction (sildenafil, tadalafil). A variety of drugs that interfere with the autonomic nervous system’s reflexes can also cause OH, such as certain antipsychotic (i.e., phenothiazine) and antidepressant drugs. Alcohol can also cause OH.Non-neurogenic causes can include hypovolemia, cardiac pump failure, and venous pooling. Hypovolemia can be caused by several conditions including dehydration, chronic bleeding, adrenal insufficiency, diabetes insipidus, diarrhea, and chronic vomiting.Cardiac pump failure refers to when the heart cannot pump blood sufficiently enough to maintain blood flow to meet the demands of the body and can be associated with heart block, disorders of heart rhythm (tachyarrhythmias), narrowing (stenosis) of the main artery of the body (aorta), or a heart attack (myocardial infarction).Venous pooling is a normal occurrence in which gravity causes blood to pool downward within the abdomen and legs upon standing. This results in reduced venous return to the heart. There are certain conditions cause excessive venous pooling. Such conditions include rising quickly after prolonged sitting or lying down (recumbency), prolonged motionless standing, fever, heat exposure, or carbohydrate heavy meals.Primary neurogenic causes refers to individuals with an underlying primary disorder that is involved with malfunction of the autonomic nervous system such as multiple system atrophy, Parkinson’s disease, pure autonomic failure, dopamine beta-hydroxylase deficiency, Lewy body disease, familial dysautonomia, and non-diabetic autonomic neuropathy.Secondary neurogenic causes can include spinal cord problems such as transverse myelitis or tumors of the spinal cord and various peripheral neuropathies such as amyloidosis, Guillain-Barre syndrome, diabetes mellitus, and the hereditary sensory and autonomic neuropathies. Individuals with OH due to primary or secondary neurogenic causes are referred to as having neurogenic orthostatic hypotension (NOH).The symptoms of OH result from the failure of the body to compensate for the normal drop in blood pressure that occurs upon standing or sitting up. Upon standing, gravity causes the blood in the body to pool downward into the legs and trunk. Consequently, less blood is returned to the heart and cardiac filling pressure is reduced, resulting in diminished cardiac output. In a matter of seconds, the body goes through a normal series of involuntary responses that compensate for this drop in blood pressure. These responses are controlled by the autonomic nervous system and include signaling blood vessels to narrow so that more blood is pushed upward and signaling the heart to beat faster (increased heart rate) to pump more blood and ensure proper blood flow and pressure.Any interruption in these involuntary processes can result in OH. For example, the baroreflex is essential in maintaining proper blood pressure and does not function properly in individuals with NOH. The baroreflex refers to specialized cells called baroreceptors that trigger the autonomic nervous system to increase levels of certain hormones called catecholamines, specifically norepinephrine. Norepinephrine is a chemical messenger that is necessary for nerves to communicate in order to trigger blood vessels to narrow to increase blood pressure upon standing (vasoconstriction). This response is known as the baroreflex. When the baroreflex is impaired the body fails to produce sufficient amounts of norepinephrine and cannot offset the drop in blood pressure that occurs upon standing, resulting in the symptoms of OH.Not all cases of OH result from dysfunction of the autonomic nervous system. Conditions that cause hypovolemia such as dehydration cause OH because the loss of blood volume prevents the body from compensating for the decreased blood pressure that occurs upon standing. Conditions that affect the heart such as cardiac pump failure prevent the heart from pumping efficiently or rapidly enough to compensate for the drop in blood pressure that occurs upon standing.
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Affects of Orthostatic Hypotension
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OH is most common in the elderly, postpartum mothers, those who have been on bed rest, and teenagers, because of their large amounts of growth over a small time period. The prevalence increases with age. Institutionalized elderly have higher rates of OH than individuals who remain living in the community.
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Affects of Orthostatic Hypotension. OH is most common in the elderly, postpartum mothers, those who have been on bed rest, and teenagers, because of their large amounts of growth over a small time period. The prevalence increases with age. Institutionalized elderly have higher rates of OH than individuals who remain living in the community.
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Related disorders of Orthostatic Hypotension
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Symptoms of the following disorders can be similar to those of orthostatic hypotension. Comparisons may be useful for a differential diagnosis:Neurally mediated syncope is a general term for a group of conditions in which sudden change in the activity of the autonomic nervous system results in a fall in blood pressure. Neurally mediated syncope can lead to a temporary loss of consciousness (syncope). Individuals often experience nonspecific symptoms just before the onset of an episode (prodome). Such symptoms include pallor, yawning, sighing, nausea, and abdominal discomfort. This is usually followed by additional symptoms such as difficulty concentrating, cognitive impairment, and disturbances in hearing and or sight. This group of disorders includes vasovagal syncope, which there is a temporary impairment of blood circulation in the brain. It may occur during emotional stress, pain or mild shock. It may also result from prolonged bed rest, anemia, fever, fasting or mild heart disease.Postural tachycardia syndrome (POTS) is a rare condition characterized by a continued heart rate of greater than 30 beats per minute that occurs upon 10 minutes of standing. In many cases, the heart rate is closer to 120 beats per minute. Additional symptoms include lightheadedness, blurry vision, tremulousness, and weakness, particularly of the legs. Excessive fatigue, shortness of breath and exercise intolerance may also occur. Some affected individuals may experience nausea, difficulty concentrating, anxiety, headaches, and pain or coldness. The exact cause of POTS is unknown. Most researchers believe that disorder results from multiple factors (e.g. environmental, genetic, immunologic).
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Related disorders of Orthostatic Hypotension. Symptoms of the following disorders can be similar to those of orthostatic hypotension. Comparisons may be useful for a differential diagnosis:Neurally mediated syncope is a general term for a group of conditions in which sudden change in the activity of the autonomic nervous system results in a fall in blood pressure. Neurally mediated syncope can lead to a temporary loss of consciousness (syncope). Individuals often experience nonspecific symptoms just before the onset of an episode (prodome). Such symptoms include pallor, yawning, sighing, nausea, and abdominal discomfort. This is usually followed by additional symptoms such as difficulty concentrating, cognitive impairment, and disturbances in hearing and or sight. This group of disorders includes vasovagal syncope, which there is a temporary impairment of blood circulation in the brain. It may occur during emotional stress, pain or mild shock. It may also result from prolonged bed rest, anemia, fever, fasting or mild heart disease.Postural tachycardia syndrome (POTS) is a rare condition characterized by a continued heart rate of greater than 30 beats per minute that occurs upon 10 minutes of standing. In many cases, the heart rate is closer to 120 beats per minute. Additional symptoms include lightheadedness, blurry vision, tremulousness, and weakness, particularly of the legs. Excessive fatigue, shortness of breath and exercise intolerance may also occur. Some affected individuals may experience nausea, difficulty concentrating, anxiety, headaches, and pain or coldness. The exact cause of POTS is unknown. Most researchers believe that disorder results from multiple factors (e.g. environmental, genetic, immunologic).
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Diagnosis of Orthostatic Hypotension
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Although the symptoms are sometimes vague, OH can be diagnosed by a simple test of an individual’s blood pressure when sitting down and then immediately upon standing up. A significant fall in blood pressure during this test will indicate OH. Heart rate is also monitored in both the sitting and standing position and can aid in diagnosis. A tilt table test may also be conducted in order to assess blood pressure. In this test, a patient will lie flat on a special table or bed while connected to an electrocardiogram (ECG) and blood pressure monitors. The table then tilts to create a change in posture from lying to standing. Autonomic reflex testing provides an evaluation of autonomic reflexes including baroreflexes and determines whether the OH is neurogenic or not.A detailed examination and assessment of the central nervous system may be performed to evaluate affected individuals for signs or symptoms of conditions associated with NOH such as Parkinson’s disease or multiple system atrophy. A thorough evaluation might involve an autonomic reflex screen (to evaluate adrenergic, sudomotor and cardiovagal function), thermoregulatory sweat test (to evaluate the distribution of anhidrosis), tests for an autonomic neuropathy (such as diabetes, amyloid, autoimmunity) and measurement of plasma norepinephrine supine and standing.
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Diagnosis of Orthostatic Hypotension. Although the symptoms are sometimes vague, OH can be diagnosed by a simple test of an individual’s blood pressure when sitting down and then immediately upon standing up. A significant fall in blood pressure during this test will indicate OH. Heart rate is also monitored in both the sitting and standing position and can aid in diagnosis. A tilt table test may also be conducted in order to assess blood pressure. In this test, a patient will lie flat on a special table or bed while connected to an electrocardiogram (ECG) and blood pressure monitors. The table then tilts to create a change in posture from lying to standing. Autonomic reflex testing provides an evaluation of autonomic reflexes including baroreflexes and determines whether the OH is neurogenic or not.A detailed examination and assessment of the central nervous system may be performed to evaluate affected individuals for signs or symptoms of conditions associated with NOH such as Parkinson’s disease or multiple system atrophy. A thorough evaluation might involve an autonomic reflex screen (to evaluate adrenergic, sudomotor and cardiovagal function), thermoregulatory sweat test (to evaluate the distribution of anhidrosis), tests for an autonomic neuropathy (such as diabetes, amyloid, autoimmunity) and measurement of plasma norepinephrine supine and standing.
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Therapies of Orthostatic Hypotension
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Treatment
The treatment of OH can be challenging as the ultimate goal is to improve blood pressure upon standing, but this must be accomplished without excessively increasing blood pressure when lying down (supine hypertension). Supine hypertension is of particular concern in individuals with NOH.Specific therapies depend upon the underlying cause. When OH is caused by a decrease in volume of circulating blood (hypovolemia) due to the use of certain medication(s), it is treated by adjusting the dosage or discontinuing the medication, under a doctor’s supervision. Hypovolemia also responds to an increase in salt intake. Low blood pressure resulting from extended bed rest can be corrected by allowing the affected individual to sit up each day at certain times with increasing frequency.Some relief particularly in mild cases may be achieved by taking some simple precautions such as avoiding hot baths that lower blood pressure, avoiding long walks in hot weather, and taking medications that help raise blood pressure, strengthen bladder tone, or prevent constipation. Taking one’s time when changing positions including rising from a chair or getting up from bed can help. Elevating the head of the bed may be of benefit in some cases. Limiting alcohol intake and avoiding large carbohydrate-laden meals can help in specific cases. Exercise programs geared toward improving conditioning and strengthening the legs can be of benefit. These programs may also teach specific physical maneuvers designed to avoid OH such as toe raises, thigh contractions, leg crossing, and bending over at the waist.Maintaining an elevated salt-intake may be prescribed, either through sodium supplements or drinks containing electrolytes. Drinking a large quantity of fluids also can aid in preventing OH episodes by preventing dehydration. Increasing fluid and salt intake are essential to help to expand blood volume. Water boluses, which involve drinking glasses of water in rapid succession, can help to expand blood volume. The specific amount reported in the medical literature varies, but is approximately two 8 ounce glasses of water.In some cases, the legs may be fitted for elastic stocking that can help maintain blood pressure upon standing. A medical compression garment known as an abdominal binder used alone or in combination with elastic, compression stockings may provide relief of OH.In 1996, the drug midodrine hydrochloride (ProAmatine®) was approved by the U.S. Food and Drug Administration (FDA) to treat OH by reducing the radius of blood vessels and thus, increasing blood pressure. In 2011, the FDA requested additional clinical trials to assess the efficacy of midodrine in individuals with OH.In February of 2014, the FDA approved droxidopa (Northera®) for the treatment of adults with NOH caused by Parkinson’s disease, multiple system atrophy, pure autonomic failure, dopamine beta-hydroxylase deficiency and non-diabetic autonomic neuropathy. Northera was approved under the FDA’s accelerated approval program and has demonstrated short-term relief from the symptoms of NOH. The continued safety and effectiveness of this drug is continually being assessed.Other medications have been used off label to treat individuals with OH including pyridostigmine. This drug acts on the sympathetic baroreflex pathway, which is active during standing. The drug can improve OH without worsening or aggravating supine hypertension. However, the effects of pyridostigmine are mild and the drug is generally used for individuals with mild cases of OH. In more severe cases, fludrocortisone (Florinef®) may be used. This drug increases blood volume and enhances the response of blood vessels to catecholamines such as norepinephrine.Additional medications have shown some benefit in treating OH including non-steroidal anti-inflammatories (NSAIDs), caffeine, and erythropoietin. These drugs may be given alone on in combination.
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Therapies of Orthostatic Hypotension. Treatment
The treatment of OH can be challenging as the ultimate goal is to improve blood pressure upon standing, but this must be accomplished without excessively increasing blood pressure when lying down (supine hypertension). Supine hypertension is of particular concern in individuals with NOH.Specific therapies depend upon the underlying cause. When OH is caused by a decrease in volume of circulating blood (hypovolemia) due to the use of certain medication(s), it is treated by adjusting the dosage or discontinuing the medication, under a doctor’s supervision. Hypovolemia also responds to an increase in salt intake. Low blood pressure resulting from extended bed rest can be corrected by allowing the affected individual to sit up each day at certain times with increasing frequency.Some relief particularly in mild cases may be achieved by taking some simple precautions such as avoiding hot baths that lower blood pressure, avoiding long walks in hot weather, and taking medications that help raise blood pressure, strengthen bladder tone, or prevent constipation. Taking one’s time when changing positions including rising from a chair or getting up from bed can help. Elevating the head of the bed may be of benefit in some cases. Limiting alcohol intake and avoiding large carbohydrate-laden meals can help in specific cases. Exercise programs geared toward improving conditioning and strengthening the legs can be of benefit. These programs may also teach specific physical maneuvers designed to avoid OH such as toe raises, thigh contractions, leg crossing, and bending over at the waist.Maintaining an elevated salt-intake may be prescribed, either through sodium supplements or drinks containing electrolytes. Drinking a large quantity of fluids also can aid in preventing OH episodes by preventing dehydration. Increasing fluid and salt intake are essential to help to expand blood volume. Water boluses, which involve drinking glasses of water in rapid succession, can help to expand blood volume. The specific amount reported in the medical literature varies, but is approximately two 8 ounce glasses of water.In some cases, the legs may be fitted for elastic stocking that can help maintain blood pressure upon standing. A medical compression garment known as an abdominal binder used alone or in combination with elastic, compression stockings may provide relief of OH.In 1996, the drug midodrine hydrochloride (ProAmatine®) was approved by the U.S. Food and Drug Administration (FDA) to treat OH by reducing the radius of blood vessels and thus, increasing blood pressure. In 2011, the FDA requested additional clinical trials to assess the efficacy of midodrine in individuals with OH.In February of 2014, the FDA approved droxidopa (Northera®) for the treatment of adults with NOH caused by Parkinson’s disease, multiple system atrophy, pure autonomic failure, dopamine beta-hydroxylase deficiency and non-diabetic autonomic neuropathy. Northera was approved under the FDA’s accelerated approval program and has demonstrated short-term relief from the symptoms of NOH. The continued safety and effectiveness of this drug is continually being assessed.Other medications have been used off label to treat individuals with OH including pyridostigmine. This drug acts on the sympathetic baroreflex pathway, which is active during standing. The drug can improve OH without worsening or aggravating supine hypertension. However, the effects of pyridostigmine are mild and the drug is generally used for individuals with mild cases of OH. In more severe cases, fludrocortisone (Florinef®) may be used. This drug increases blood volume and enhances the response of blood vessels to catecholamines such as norepinephrine.Additional medications have shown some benefit in treating OH including non-steroidal anti-inflammatories (NSAIDs), caffeine, and erythropoietin. These drugs may be given alone on in combination.
| 912 |
Orthostatic Hypotension
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nord_913_0
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Overview of OSMED, Heterozygous
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Heterozygous OSMED (oto-spondyl-megaepiphyseal dysplasia) is a rare genetic disorder characterized by skeletal malformations resulting in shortening of the upper limbs and thighs and short stature (rhizomelic dwarfism). Additional symptoms include distinctive facial features and delays in psychomotor development. After the initial period of growth deficiency, affected individuals experience gradual improvement in bone growth that leads to normal physical development by early childhood. Mental and motor development is also normal by early childhood. In some cases, affected individuals develop hearing loss. Heterozygous OSMED occurs because of disruptions or changes (mutations) to the COL11A2 gene.A group of collagen disorders (i.e., OSMED, Weissenbacher-Zweymuller syndrome and non-ocular Stickler syndrome or Stickler syndrome type III) are all caused by mutations to the COL11A2 gene (allelic disorders). Some researchers consider these three disorders separate entities; others believe that they are the same disorder or different expresses of one disorder. Recently, some researchers have suggested that the name OSMED be used as a general heading to consist of “heterozygous OSMED,” which encompasses Weissenbacher-Zweymuller syndrome and Stickler syndrome type III and is inherited as an autosomal dominant trait and “homozygous OSMED,” which encompasses autosomal recessive cases of oto-spondylo-megaepiphyseal dysplasia.
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Overview of OSMED, Heterozygous. Heterozygous OSMED (oto-spondyl-megaepiphyseal dysplasia) is a rare genetic disorder characterized by skeletal malformations resulting in shortening of the upper limbs and thighs and short stature (rhizomelic dwarfism). Additional symptoms include distinctive facial features and delays in psychomotor development. After the initial period of growth deficiency, affected individuals experience gradual improvement in bone growth that leads to normal physical development by early childhood. Mental and motor development is also normal by early childhood. In some cases, affected individuals develop hearing loss. Heterozygous OSMED occurs because of disruptions or changes (mutations) to the COL11A2 gene.A group of collagen disorders (i.e., OSMED, Weissenbacher-Zweymuller syndrome and non-ocular Stickler syndrome or Stickler syndrome type III) are all caused by mutations to the COL11A2 gene (allelic disorders). Some researchers consider these three disorders separate entities; others believe that they are the same disorder or different expresses of one disorder. Recently, some researchers have suggested that the name OSMED be used as a general heading to consist of “heterozygous OSMED,” which encompasses Weissenbacher-Zweymuller syndrome and Stickler syndrome type III and is inherited as an autosomal dominant trait and “homozygous OSMED,” which encompasses autosomal recessive cases of oto-spondylo-megaepiphyseal dysplasia.
| 913 |
OSMED, Heterozygous
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nord_913_1
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Symptoms of OSMED, Heterozygous
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Heterozygous OSMED is characterized by skeletal malformations, distinct facial features and delayed psychomotor development. The specific symptoms affecting each child vary from case to case. Affected children have abnormally short bones of the upper arms and thighs (rhizomelia) resulting in short stature during infancy and early childhood (rhizomelic dwarfism). The long bones of the upper arm (humeri) and thigh (femora) are short with broad heads (dumbbell-shaped). Affected individuals may also have clefts that resemble fractures in certain bones of the vertebrae (vertebral coronal clefts). Affected infants may also exhibit a delay in the acquisition of skills requiring coordination of muscular and mental activity (psychomotor delays). As affected individuals age, they experience an increase in growth rate eventually reaching normal height by 5 or 6 years of age. Mental and motor development also becomes normal by this age. Distinctive facial features associated with heterozygous OSMED include an abnormally small jaw (micrognathia), widely spaced eyes (hypertelorism), depressed nasal bridge, a small upturned nose, and underdevelopment of the bones of the middle portion of the face (midface hypoplasia) giving the face a flat appearance. Affected individuals may also have Pierre-Robin sequence, an assortment of abnormalities that may occur as a distinct syndrome or as part of another underlying disorder. Pierre-Robin sequence is characterized by an unusually small jaw (micrognathia), downward displacement or retraction of the tongue (glossoptosis), and incomplete closure of the roof of the mouth (cleft palate). Cleft palate may also occur as an isolated finding. Some individuals develop hearing loss because of an impaired ability of the auditory nerves to transmit sensory input to the brain (sensorineural hearing loss). Such hearing loss may become progressively more pronounced.
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Symptoms of OSMED, Heterozygous. Heterozygous OSMED is characterized by skeletal malformations, distinct facial features and delayed psychomotor development. The specific symptoms affecting each child vary from case to case. Affected children have abnormally short bones of the upper arms and thighs (rhizomelia) resulting in short stature during infancy and early childhood (rhizomelic dwarfism). The long bones of the upper arm (humeri) and thigh (femora) are short with broad heads (dumbbell-shaped). Affected individuals may also have clefts that resemble fractures in certain bones of the vertebrae (vertebral coronal clefts). Affected infants may also exhibit a delay in the acquisition of skills requiring coordination of muscular and mental activity (psychomotor delays). As affected individuals age, they experience an increase in growth rate eventually reaching normal height by 5 or 6 years of age. Mental and motor development also becomes normal by this age. Distinctive facial features associated with heterozygous OSMED include an abnormally small jaw (micrognathia), widely spaced eyes (hypertelorism), depressed nasal bridge, a small upturned nose, and underdevelopment of the bones of the middle portion of the face (midface hypoplasia) giving the face a flat appearance. Affected individuals may also have Pierre-Robin sequence, an assortment of abnormalities that may occur as a distinct syndrome or as part of another underlying disorder. Pierre-Robin sequence is characterized by an unusually small jaw (micrognathia), downward displacement or retraction of the tongue (glossoptosis), and incomplete closure of the roof of the mouth (cleft palate). Cleft palate may also occur as an isolated finding. Some individuals develop hearing loss because of an impaired ability of the auditory nerves to transmit sensory input to the brain (sensorineural hearing loss). Such hearing loss may become progressively more pronounced.
| 913 |
OSMED, Heterozygous
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nord_913_2
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Causes of OSMED, Heterozygous
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Heterozygous OSMED is inherited as an autosomal dominant trait. Some cases occur randomly as the result of a spontaneous genetic change (i.e., new mutation). 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.Investigators have determined that some cases of heterozygous OSMED occur due to changes or disruptions (mutations) of the collagen XI, apha-2 polypeptide (COL11A2) gene located on the short arm (p) of chromosome 6 (6p21.3). 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 6p21.3” refers to band 21.3 on the short arm of chromosome 6. The numbered bands specify the location of the thousands of genes that are present on each chromosome.The COL11A2 gene is involved in the formation (synthesis) of collagen, specifically type XI collagen. Collagen is the body's major structural protein forming an essential part of connective tissues and is the main component of ligaments, tendons and cartilage. Collagen is also found in bone. Type XI collagen is usually found in cartilage, the specialized tissue that serves as a buffer or cushion for bones at joints. The COL11A2 gene encodes for proteins that are essential to the development and function of type XI collagen. Mutations to this gene result in abnormalities in the production of collagen XI, which in turn affects the proper formation and development cartilage and bone.
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Causes of OSMED, Heterozygous. Heterozygous OSMED is inherited as an autosomal dominant trait. Some cases occur randomly as the result of a spontaneous genetic change (i.e., new mutation). 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.Investigators have determined that some cases of heterozygous OSMED occur due to changes or disruptions (mutations) of the collagen XI, apha-2 polypeptide (COL11A2) gene located on the short arm (p) of chromosome 6 (6p21.3). 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 6p21.3” refers to band 21.3 on the short arm of chromosome 6. The numbered bands specify the location of the thousands of genes that are present on each chromosome.The COL11A2 gene is involved in the formation (synthesis) of collagen, specifically type XI collagen. Collagen is the body's major structural protein forming an essential part of connective tissues and is the main component of ligaments, tendons and cartilage. Collagen is also found in bone. Type XI collagen is usually found in cartilage, the specialized tissue that serves as a buffer or cushion for bones at joints. The COL11A2 gene encodes for proteins that are essential to the development and function of type XI collagen. Mutations to this gene result in abnormalities in the production of collagen XI, which in turn affects the proper formation and development cartilage and bone.
| 913 |
OSMED, Heterozygous
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nord_913_3
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Affects of OSMED, Heterozygous
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Heterozygous OSMED affects males and females in equal numbers. Both heterozygous and homozygous OSMED are extremely rare; approximately 30 cases have been reported in the medical literature. The exact incidence of this disorder is unknown. These disorders may be underdiagnosed making it difficult to determine their true frequency in the general population. Heterozygous OSMED may be referred to as a type XI collagen disorder (collagenopathy). Type XI collagenopathies are disorders that involve abnormalities affecting type XI collagen and include homozygous OSMED and Stickler syndrome type II.
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Affects of OSMED, Heterozygous. Heterozygous OSMED affects males and females in equal numbers. Both heterozygous and homozygous OSMED are extremely rare; approximately 30 cases have been reported in the medical literature. The exact incidence of this disorder is unknown. These disorders may be underdiagnosed making it difficult to determine their true frequency in the general population. Heterozygous OSMED may be referred to as a type XI collagen disorder (collagenopathy). Type XI collagenopathies are disorders that involve abnormalities affecting type XI collagen and include homozygous OSMED and Stickler syndrome type II.
| 913 |
OSMED, Heterozygous
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nord_913_4
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Related disorders of OSMED, Heterozygous
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Symptoms of the following disorders can be similar to those of heterozygous OSMED. Comparisons may be useful for a differential diagnosis.Homozygous OSMED is an extremely rare genetic disorder characterized by malformation (dysplasia) of certain bones, hearing loss and distinct facial features. Skeletal malformations affect the bones of the arms, legs and spines eventually resulting in disproportionate short stature. Hearing loss is often progressive and severe. Intelligence is normal. Homozygous OSMED occurs because of disruptions or changes (mutations) to the COL11A2 gene and is inherited as an autosomal recessive trait. (For more information on this disorder, choose “OSMED, homozygous” as your search term in the Rare Disease Database.)Stickler syndrome refers to a group of disorders of the connective tissue that involves several of the body's organ systems such as the eye, skeleton, inner ear, and/or the head and face. Connective tissue is made up of a protein known as collagen that develops into the several varieties found in the body. It is the tissue that physically supports many organs in the body and may act like glue or an elastic band that allows muscles to stretch and contract. Stickler syndrome often affects the connective tissue of the eye, especially in the interior of the eyeball (vitreous humor), and the ends of the bones that make up the joints of the body (epiphysis). Most authorities agree that there are four types of Stickler syndrome, of which three are reasonably well differentiated and a fourth remains not well understood. Stickler syndrome type I (STL1) is responsible for about 75% of reported cases and presents with a full array of symptoms (eye, ear, jaw and cleft, joints); Stickler syndrome type II; (STL2) also presents with a full array of symptoms; Stickler syndrome type III (STL3) presents with a “Stickler-like” syndrome that affects the joints and hearing without involving the eyes. Some researchers believe that this form is the same disorder as heterozygous oto-spondylo-megaepiphyseal dysplasia (OSMED). (For more information on this disorder, choose “Stickler syndrome” as your search term in the Rare Disease Database.)Kniest dysplasia is one of several forms of dwarfism that is caused by a change (mutation) in a gene known as COL2A1. This gene is involved in the production of a particular protein that forms type II collagen, which is essential for the normal development of bones and other connective tissue. Changes in the composition of type 2 collagen lead to abnormal skeletal growth and, thus, to a variety of dwarfing conditions known as skeletal dysplasias. Some of the signs and symptoms of Kniest dysplasia, such as short stature, enlarged knees, and cleft palate, are usually present at birth. Other characteristics may not appear for two or three years. (For more information on this disorder, choose “Kniest dysplasia” as your search term in the Rare Disease Database.)Marshall syndrome is a rare genetic disorder. Major symptoms may include a distinctive face with a flattened nasal bridge and nostrils that are tilted upward, widely spaced eyes (hyperterlorism), nearsightedness, cataracts and moderate to severe hearing loss. Affected individuals experience degeneration of the thick fluid that fills the center of the eye and the membrane (retina) that lines the back of the eye (vitreoretinal degeneration). Malformation of certain bones of the arms (e.g., bowing of the arm bones) may also occur. Affected individuals may also have Pierre-Robin sequence. Pierre-Robin sequence consists of an unusually small jaw (micrognathia), downward displacement or retraction of the tongue (glossoptosis), and, in some cases, incomplete closure of the roof of the mouth (cleft palate). Cleft palate may also occur as an isolated finding. Marshall syndrome is inherited as an autosomal dominant trait. The relationship between Marshall syndrome and Stickler syndrome is not well understood. The site of the gene for Marshall syndrome is the same as the site of the gene for Stickler syndrome type II. (For more information choose “Marshall syndrome” as your search term in the Rare Disease Database.)Congenital spondyloepiphyseal dysplasia is a rare genetic disorder characterized by growth deficiency before birth (prenatally), spinal malformations, and/or abnormalities affecting the eyes. As affected individuals age, growth deficiency eventually results in short stature (dwarfism) due, in part, to a disproportionately short neck and trunk, and a hip deformity in which the thighbone is angled toward the center of the body (coxa vara). In most cases, affected individuals may have diminished muscle tone (hypotonia), abnormal front-to-back and side-to-side curvature of the spine (kyphoscoliosis), abnormal inward curvature of the spine (lumbar lordosis), and/or unusual protrusion of the breast bone (sternum), a condition known as pectus carinatum. Affected individuals also have abnormalities affecting the eyes including nearsightedness (myopia) and, in approximately 50 percent of cases, detachment of the nerve-rich membrane lining the eye (retina). Congenital spondyloepiphyseal dysplasia is inherited as an autosomal dominant trait. (For more information on this disorder, choose “spondyloepiphyseal dysplasia” as your search term in the Rare Disease Database.)
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Related disorders of OSMED, Heterozygous. Symptoms of the following disorders can be similar to those of heterozygous OSMED. Comparisons may be useful for a differential diagnosis.Homozygous OSMED is an extremely rare genetic disorder characterized by malformation (dysplasia) of certain bones, hearing loss and distinct facial features. Skeletal malformations affect the bones of the arms, legs and spines eventually resulting in disproportionate short stature. Hearing loss is often progressive and severe. Intelligence is normal. Homozygous OSMED occurs because of disruptions or changes (mutations) to the COL11A2 gene and is inherited as an autosomal recessive trait. (For more information on this disorder, choose “OSMED, homozygous” as your search term in the Rare Disease Database.)Stickler syndrome refers to a group of disorders of the connective tissue that involves several of the body's organ systems such as the eye, skeleton, inner ear, and/or the head and face. Connective tissue is made up of a protein known as collagen that develops into the several varieties found in the body. It is the tissue that physically supports many organs in the body and may act like glue or an elastic band that allows muscles to stretch and contract. Stickler syndrome often affects the connective tissue of the eye, especially in the interior of the eyeball (vitreous humor), and the ends of the bones that make up the joints of the body (epiphysis). Most authorities agree that there are four types of Stickler syndrome, of which three are reasonably well differentiated and a fourth remains not well understood. Stickler syndrome type I (STL1) is responsible for about 75% of reported cases and presents with a full array of symptoms (eye, ear, jaw and cleft, joints); Stickler syndrome type II; (STL2) also presents with a full array of symptoms; Stickler syndrome type III (STL3) presents with a “Stickler-like” syndrome that affects the joints and hearing without involving the eyes. Some researchers believe that this form is the same disorder as heterozygous oto-spondylo-megaepiphyseal dysplasia (OSMED). (For more information on this disorder, choose “Stickler syndrome” as your search term in the Rare Disease Database.)Kniest dysplasia is one of several forms of dwarfism that is caused by a change (mutation) in a gene known as COL2A1. This gene is involved in the production of a particular protein that forms type II collagen, which is essential for the normal development of bones and other connective tissue. Changes in the composition of type 2 collagen lead to abnormal skeletal growth and, thus, to a variety of dwarfing conditions known as skeletal dysplasias. Some of the signs and symptoms of Kniest dysplasia, such as short stature, enlarged knees, and cleft palate, are usually present at birth. Other characteristics may not appear for two or three years. (For more information on this disorder, choose “Kniest dysplasia” as your search term in the Rare Disease Database.)Marshall syndrome is a rare genetic disorder. Major symptoms may include a distinctive face with a flattened nasal bridge and nostrils that are tilted upward, widely spaced eyes (hyperterlorism), nearsightedness, cataracts and moderate to severe hearing loss. Affected individuals experience degeneration of the thick fluid that fills the center of the eye and the membrane (retina) that lines the back of the eye (vitreoretinal degeneration). Malformation of certain bones of the arms (e.g., bowing of the arm bones) may also occur. Affected individuals may also have Pierre-Robin sequence. Pierre-Robin sequence consists of an unusually small jaw (micrognathia), downward displacement or retraction of the tongue (glossoptosis), and, in some cases, incomplete closure of the roof of the mouth (cleft palate). Cleft palate may also occur as an isolated finding. Marshall syndrome is inherited as an autosomal dominant trait. The relationship between Marshall syndrome and Stickler syndrome is not well understood. The site of the gene for Marshall syndrome is the same as the site of the gene for Stickler syndrome type II. (For more information choose “Marshall syndrome” as your search term in the Rare Disease Database.)Congenital spondyloepiphyseal dysplasia is a rare genetic disorder characterized by growth deficiency before birth (prenatally), spinal malformations, and/or abnormalities affecting the eyes. As affected individuals age, growth deficiency eventually results in short stature (dwarfism) due, in part, to a disproportionately short neck and trunk, and a hip deformity in which the thighbone is angled toward the center of the body (coxa vara). In most cases, affected individuals may have diminished muscle tone (hypotonia), abnormal front-to-back and side-to-side curvature of the spine (kyphoscoliosis), abnormal inward curvature of the spine (lumbar lordosis), and/or unusual protrusion of the breast bone (sternum), a condition known as pectus carinatum. Affected individuals also have abnormalities affecting the eyes including nearsightedness (myopia) and, in approximately 50 percent of cases, detachment of the nerve-rich membrane lining the eye (retina). Congenital spondyloepiphyseal dysplasia is inherited as an autosomal dominant trait. (For more information on this disorder, choose “spondyloepiphyseal dysplasia” as your search term in the Rare Disease Database.)
| 913 |
OSMED, Heterozygous
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nord_913_5
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Diagnosis of OSMED, Heterozygous
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A diagnosis of heterozygous OSMED is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic symptoms, and a variety of specialized tests including x-rays. X-ray studies reveal characteristic skeletal malformations associated with heterozygous OSMED.
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Diagnosis of OSMED, Heterozygous. A diagnosis of heterozygous OSMED is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic symptoms, and a variety of specialized tests including x-rays. X-ray studies reveal characteristic skeletal malformations associated with heterozygous OSMED.
| 913 |
OSMED, Heterozygous
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nord_913_6
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Therapies of OSMED, Heterozygous
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TreatmentThe treatment of heterozygous OSMED is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, physicians who diagnose and treat abnormalities of the skeleton, joints, muscles, and related tissues (orthopedists), orthopedic surgeons, specialists who asses and treat hearing problems (audiologists), and other healthcare professionals may need to systematically and comprehensively plan an affect child's treatment.Hearing aids may be used to treat hearing loss. Surgery may be necessary to correct certain skeletal malformations and abnormalities such as cleft palate. Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
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Therapies of OSMED, Heterozygous. TreatmentThe treatment of heterozygous OSMED is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, physicians who diagnose and treat abnormalities of the skeleton, joints, muscles, and related tissues (orthopedists), orthopedic surgeons, specialists who asses and treat hearing problems (audiologists), and other healthcare professionals may need to systematically and comprehensively plan an affect child's treatment.Hearing aids may be used to treat hearing loss. Surgery may be necessary to correct certain skeletal malformations and abnormalities such as cleft palate. Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
| 913 |
OSMED, Heterozygous
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nord_914_0
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Overview of OSMED, Homozygous
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Homozygous OSMED (oto-spondylo-megaepiphyseal dysplasia) is an extremely rare genetic disorder characterized by malformation (dysplasia) of certain bones, hearing loss and distinct facial features. Skeletal malformations affect the bones of the arms, legs and spines eventually resulting in disproportionate short stature. Hearing loss is often severe. Intelligence is normal. Homozygous OSMED occurs because of disruptions or changes (mutations) to the COL11A2 gene and is inherited as an autosomal recessive trait.Two additional disorders, Weissenbacher-Zweymuller syndrome and Stickler syndrome III, more commonly known as non-ocular Stickler syndrome, are also caused by mutations to this gene (allelic disorders). Some clinical researchers believe that each of these three disorders is a separate and distinct entity. Others believe that the three represent a range of severity of one syndrome. Regardless, these disorders involve alterations (mutations) of the collagen gene, COL11A2. Some researchers have suggested that the name OSMED be used as a general heading to consist of “heterozygous OSMED,” which encompasses Weissenbacher-Zweymuller syndrome and Stickler syndrome type III and is inherited as an autosomal dominant trait, and “homozygous OSMED,” which encompasses autosomal recessive cases of oto-spondylo-megaepiphyseal dysplasia.
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Overview of OSMED, Homozygous. Homozygous OSMED (oto-spondylo-megaepiphyseal dysplasia) is an extremely rare genetic disorder characterized by malformation (dysplasia) of certain bones, hearing loss and distinct facial features. Skeletal malformations affect the bones of the arms, legs and spines eventually resulting in disproportionate short stature. Hearing loss is often severe. Intelligence is normal. Homozygous OSMED occurs because of disruptions or changes (mutations) to the COL11A2 gene and is inherited as an autosomal recessive trait.Two additional disorders, Weissenbacher-Zweymuller syndrome and Stickler syndrome III, more commonly known as non-ocular Stickler syndrome, are also caused by mutations to this gene (allelic disorders). Some clinical researchers believe that each of these three disorders is a separate and distinct entity. Others believe that the three represent a range of severity of one syndrome. Regardless, these disorders involve alterations (mutations) of the collagen gene, COL11A2. Some researchers have suggested that the name OSMED be used as a general heading to consist of “heterozygous OSMED,” which encompasses Weissenbacher-Zweymuller syndrome and Stickler syndrome type III and is inherited as an autosomal dominant trait, and “homozygous OSMED,” which encompasses autosomal recessive cases of oto-spondylo-megaepiphyseal dysplasia.
| 914 |
OSMED, Homozygous
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nord_914_1
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Symptoms of OSMED, Homozygous
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Symptoms associated with homozygous OSMED vary from case to case. Affected individuals have progressive, severe hearing loss, skeletal malformations and distinctive facial features. Hearing loss in individuals with homozygous OSMED may be progressive and severe and occurs because of an impaired ability of the auditory nerves to transmit sensory input to the brain (sensorineural hearing loss). During infancy, affected individuals may also experience feeding difficulties, recurrent pulmonary infections, and inflammation of the main air passages (bronchioles) to the lung (bronchitis), and pneumonia.Skeletal abnormalities associated with homozygous OSMED include malformation (dysplasia) of the long bones of the arms (humeri) and legs (femora). The “growing portion” or head of the long bones (epiphyses) is abnormally large and broad and the end portion of the shaft of the long bones is abnormally widened (metaphyseal flaring) resulting in a dumbbell shape. Affected individuals may also have joint contractures, abnormally large bones of the ankle (tarsal bones), and short hands with stubby fingers. In some cases, the upper portion (capital) of the thighbone where it meets the hip (capital femoral epiphyses) is abnormally small or absent. As affected individuals age, they may develop progressive front-to-back curvature of the spine (lordosis) and large, painful joints with reduced mobility. Skeletal abnormalities associated with homozygous OSMED eventually result in short stature with disproportionately short limbs. Affected individuals may also develop osteoarthritis, a condition characterized by the breakdown of cartilage and pain, degeneration, and stiffness of affected joints. Individuals with homozygous OSMED also have flattening of the central regions of bones in the spinal column (platyspondyly) and progressive fusion of the eight small bones of the wrists (carpal bones). Distinctive facial features associated with homozygous OSMED include an underdeveloped jaw bone (mandibular hypoplasia), a rounded (bulbous) upturned nose with nostrils that are flared forward (anteverted nares), and underdevelopment of the bones of the middle of the face (midface hypoplasia) resulting in a flat facial appearance. Affected individuals may also have Pierre-Robin sequence, an assortment of abnormalities that may occur as a distinct syndrome or as part of another underlying disorder. Pierre-Robin sequence is characterized by an unusually small jaw (micrognathia), downward displacement or retraction of the tongue (glossoptosis), and incomplete closure of the roof of the mouth (cleft palate). Cleft palate may also occur as an isolated finding
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Symptoms of OSMED, Homozygous. Symptoms associated with homozygous OSMED vary from case to case. Affected individuals have progressive, severe hearing loss, skeletal malformations and distinctive facial features. Hearing loss in individuals with homozygous OSMED may be progressive and severe and occurs because of an impaired ability of the auditory nerves to transmit sensory input to the brain (sensorineural hearing loss). During infancy, affected individuals may also experience feeding difficulties, recurrent pulmonary infections, and inflammation of the main air passages (bronchioles) to the lung (bronchitis), and pneumonia.Skeletal abnormalities associated with homozygous OSMED include malformation (dysplasia) of the long bones of the arms (humeri) and legs (femora). The “growing portion” or head of the long bones (epiphyses) is abnormally large and broad and the end portion of the shaft of the long bones is abnormally widened (metaphyseal flaring) resulting in a dumbbell shape. Affected individuals may also have joint contractures, abnormally large bones of the ankle (tarsal bones), and short hands with stubby fingers. In some cases, the upper portion (capital) of the thighbone where it meets the hip (capital femoral epiphyses) is abnormally small or absent. As affected individuals age, they may develop progressive front-to-back curvature of the spine (lordosis) and large, painful joints with reduced mobility. Skeletal abnormalities associated with homozygous OSMED eventually result in short stature with disproportionately short limbs. Affected individuals may also develop osteoarthritis, a condition characterized by the breakdown of cartilage and pain, degeneration, and stiffness of affected joints. Individuals with homozygous OSMED also have flattening of the central regions of bones in the spinal column (platyspondyly) and progressive fusion of the eight small bones of the wrists (carpal bones). Distinctive facial features associated with homozygous OSMED include an underdeveloped jaw bone (mandibular hypoplasia), a rounded (bulbous) upturned nose with nostrils that are flared forward (anteverted nares), and underdevelopment of the bones of the middle of the face (midface hypoplasia) resulting in a flat facial appearance. Affected individuals may also have Pierre-Robin sequence, an assortment of abnormalities that may occur as a distinct syndrome or as part of another underlying disorder. Pierre-Robin sequence is characterized by an unusually small jaw (micrognathia), downward displacement or retraction of the tongue (glossoptosis), and incomplete closure of the roof of the mouth (cleft palate). Cleft palate may also occur as an isolated finding
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OSMED, Homozygous
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